A brief overview of the structural organization of the lungs, essential for understanding pathological changes
Clinical ─ N/A for normal histology, but serves as a baseline for all diagnostic work
Macro ─
─ Spongy, pink, cone-shaped organs located in the pleural cavities
─ Right lung ─ Typically 3 lobes (superior, middle, inferior) separated by 2 fissures (oblique, horizontal)
─ Left lung ─ Typically 2 lobes (superior, inferior) separated by 1 fissure (oblique); features a lingula (homologue of the middle lobe) and a cardiac notch
─ Hilum ─ Central point on the medial aspect of each lung for entry/exit of main bronchi, pulmonary arteries, pulmonary veins, bronchial arteries/veins, lymphatic vessels, and nerves
Micro ─
─ Conducting Airways
─ Trachea and Bronchi ─ Lined by pseudostratified ciliated columnar epithelium containing goblet cells and basal cells; submucosa contains seromucinous glands and is supported by C-shaped cartilage rings (trachea) or irregular cartilage plates (bronchi)
─ Bronchioles ─ Intralobular airways, lack cartilage and submucosal glands; lined by ciliated columnar to cuboidal epithelium with club cells (formerly Clara cells) and fewer goblet cells proximally, transitioning to predominantly club cells distally; possess a layer of smooth muscle
─ Terminal bronchioles ─ Smallest purely conducting bronchioles; lead to respiratory bronchioles
─ Transitional and Respiratory Zone (Acinus components)
─ Respiratory bronchioles ─ Lined by simple cuboidal epithelium (ciliated and club cells); walls are interrupted by alveoli, participating in gas exchange
─ Alveolar ducts ─ Lined by attenuated squamous epithelium (type I pneumocytes) and smooth muscle "knobs" at alveolar entrances
─ Alveolar sacs ─ Clusters of alveoli, representing the terminal end of the airway
─ Alveoli ─ Primary sites of gas exchange; thin-walled, sac-like structures
─ Alveolar epithelium ─ Composed of:
─ Type I pneumocytes ─ Large, flat squamous cells covering ~95% of the alveolar surface; form the thin air-blood barrier
─ Type II pneumocytes ─ Cuboidal cells, often in corners of alveoli; produce and secrete surfactant, act as progenitor cells for both Type I and Type II pneumocytes after injury
─ Alveolar macrophages (dust cells) ─ Phagocytic cells residing in alveolar spaces and interstitium
─ Alveolar capillaries ─ Dense network within interalveolar septa, lined by endothelial cells
─ Interstitium (Interalveolar septum) ─ Connective tissue framework containing capillaries, elastic fibers, collagen, and sparse mesenchymal cells
─ Pleura
─ Visceral pleura ─ Mesothelial lining (simple squamous epithelium) covering the lung surface, including interlobar fissures
─ Parietal pleura ─ Mesothelial lining covering the inner surface of the chest wall, diaphragm, and mediastinum
Ancillary studies ─
─ IHC (Immunohistochemistry) is generally not required for identifying normal structures but can highlight specific cell types:
─ IHC (+) Epithelial cells: TTF-1 (thyroid transcription factor-1) and Napsin A (type II pneumocytes, some respiratory epithelium); p63 and CK5/6 (basal cells of bronchial epithelium); CK7 (most lung epithelia); Surfactant proteins (e.g., SP-A, SP-B via IHC - type II pneumocytes)
─ IHC (+) Endothelial cells: CD31, CD34, ERG
─ IHC (+) Mesothelial cells: Calretinin, WT1 (nuclear), D2-40 (podoplanin), CK5/6
─ IHC (+) Club cells: Secretoglobin family 1A member 1 (SCGB1A1 / CC10 / CCSP)
─ IHC (-) N/A for normal structures
─ Molecular ─ N/A for normal structures
DDx ─
─ N/A (This section is primarily for pathological entities)
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Congenital Anomalies

Congenital Pulmonary Airway Malformation (CPAM)

A developmental anomaly of the lower respiratory tract characterized by cystic and/or adenomatoid proliferation of bronchiolar structures, with variable degrees of airway malformation and a lack of normal alveolar development
Clinical ─
─ Presentation ─ Often diagnosed prenatally by ultrasound or postnatally with respiratory distress in newborns/infants; can be asymptomatic and found incidentally in older children/adults
─ Complications ─ Pneumothorax, infection, rarely malignant transformation (e.g., pleuropulmonary blastoma in Type 4, mucinous adenocarcinoma in Type 1)
─ Formerly known as Congenital Cystic Adenomatoid Malformation (CCAM)
Macro ─
─ Usually unilateral, involving a single lobe; can be multicystic, solid, or mixed
─ Cut surface shows variably sized cysts or a spongy, glandular appearance
─ Connection to the tracheobronchial tree is typically present (unlike sequestration)
Micro ─
─ Classification into 5 types (Stocker classification):
─ Type 0 (Acinar Dysplasia/Agenesis) ─ Rare, incompatible with life; small, firm lungs with diffuse bronchiolar-like structures and thickened septa
─ Type 1 (Bronchial/Bronchiolar Type) ─ ~70% of cases; large, single or multiple cysts (>2 cm, often up to 10 cm); cyst walls lined by ciliated pseudostratified columnar epithelium, may have mucus cells and cartilage plates (in ~10%); underlying fibromuscular tissue
─ Type 2 (Bronchiolar Type) ─ ~15-20% of cases; multiple, smaller, more uniform cysts (<2 cm); cysts resemble dilated bronchioles lined by ciliated columnar to cuboidal epithelium; often associated with other congenital anomalies
─ Type 3 (Bronchiolar/Alveolar Duct Type) ─ ~5% of cases; large, firm, bulky lesion with microcysts (<0.5 cm) giving a solid appearance; irregular bronchiolar-like structures lined by cuboidal epithelium separated by thickened septa; poor prognosis in neonates if large
─ Type 4 (Peripheral/Alveolar Type) ─ ~5-10% of cases; large peripheral cysts lined by flattened to cuboidal epithelium (Type I and II pneumocyte-like cells); thin walls, bland stroma; associated with risk of pneumothorax and pleuropulmonary blastoma
─ Common features across types ─ Adenomatoid proliferation of terminal bronchiolar structures, abnormal airway branching, absence of normal cartilage distribution (except sometimes in Type 1), variable inflammation or meconium aspiration
Ancillary studies ─
─ Generally not required for diagnosis if classic histologic features are present
─ IHC (+) TTF-1, Napsin A in epithelial lining cells confirms pulmonary origin
─ IHC (+) Mucus stains (e.g., Alcian blue, PAS) can highlight mucinous cells, especially in Type 1
─ Molecular ─ DICER1 mutations are associated with Type 4 CPAM and pleuropulmonary blastoma
DDx ─
─ Pulmonary sequestration (especially intralobar, lacks communication with tracheobronchial tree, has systemic arterial supply)
─ Bronchogenic cyst (typically unilocular, mediastinal or intrapulmonary, wall contains cartilage and seromucinous glands)
─ Congenital lobar overinflation (hyperinflation of normal lung tissue, no intrinsic cystic or adenomatoid change)
─ Pleuropulmonary blastoma (Type I - cystic variant, must be distinguished from Type 4 CPAM)
─ Other cystic lung diseases (e.g., lymphangiectasia, cystic bronchiectasis)
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Pulmonary Sequestration

A congenital malformation characterized by a segment of non-functional lung tissue that lacks normal communication with the tracheobronchial tree and receives its arterial blood supply from a systemic artery
Clinical ─
─ Intralobar Sequestration (ILS) ─ ~75-85% of cases; shares visceral pleura with adjacent normal lung; presents later in childhood/adulthood with recurrent pneumonia, cough, or incidentally; rarely associated with other anomalies
─ Extralobar Sequestration (ELS) ─ ~15-25% of cases; has its own separate visceral pleural investment; often diagnosed in infancy due to respiratory distress or associated congenital anomalies (e.g., diaphragmatic hernia, cardiac defects); more common on the left side, often subdiaphragmatic
─ Venous drainage ─ ILS typically to pulmonary veins; ELS often to systemic veins (e.g., azygous system)
Macro ─
─ ILS ─ Firm, consolidated, often cystic or fibrotic area within a lobe (commonly posterior basal segment of a lower lobe); aberrant systemic artery usually from thoracic or abdominal aorta
─ ELS ─ Rubbery, pyramidal, or rounded mass separate from normal lung; systemic arterial supply clearly identifiable
Micro ─
─ Non-functional lung tissue with variable features:
─ Dilated, irregularly branched bronchiolar structures
─ Cystic changes are common, cysts may be lined by respiratory, squamous, or denuded epithelium
─ Alveolar spaces may be poorly developed, emphysematous, or fibrotic
─ Thick-walled, often elastic systemic arteries within the sequestered tissue; veins may also be prominent
─ Chronic inflammation, fibrosis, and hemosiderin deposition are frequent, especially in ILS due to recurrent infections
─ Lymphoid aggregates common
─ Normal cartilage may or may not be present in airway walls
Ancillary studies ─
─ Imaging (CT angiography, MRA) is key to demonstrate systemic arterial supply preoperatively
─ Histology is usually diagnostic post-resection
─ Elastic stains (e.g., VVG) can highlight the muscular, elastic systemic arteries
DDx ─
─ Congenital Pulmonary Airway Malformation (CPAM) (especially if cystic; CPAM has normal pulmonary arterial supply and communicates with airways)
─ Bronchogenic cyst (typically unilocular, different arterial supply)
─ Chronic pneumonia or organizing pneumonia with fibrosis (acquired lesion)
─ Scimitar syndrome (partial anomalous pulmonary venous return with hypoplastic lung and systemic arterial supply to normal lung)
─ Hybrid lesions (features of both sequestration and CPAM can occur)
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Bronchial Atresia / Stenosis

Congenital focal obliteration (atresia) or narrowing (stenosis) of a lobar, segmental, or subsegmental bronchus, leading to distal mucus impaction and hyperinflation of the affected lung segment
Clinical ─
─ Often asymptomatic and detected incidentally on imaging in adolescents or young adults
─ Symptoms may include recurrent pneumonia, cough, dyspnea, or chest pain
─ Most commonly affects the apicoposterior segment of the left upper lobe, followed by right upper or middle lobes
Macro ─
─ Affected bronchus ends blindly or is markedly narrowed proximally
─ Distal to the atresia/stenosis, the bronchus is dilated and filled with impacted mucus (bronchocele or mucocele)
─ Lung parenchyma distal to the obstruction is typically hyperinflated due to collateral air drift (pores of Kohn, canals of Lambert)
Micro ─
─ Atretic/stenotic segment ─ Fibrous obliteration or severe narrowing of the bronchial lumen; cartilage may be present but deformed or absent at the point of atresia
─ Bronchocele/Mucocele ─ Markedly dilated bronchus distal to obstruction, filled with inspissated mucus, cellular debris, and sometimes Curschmann spirals or Charcot-Leyden crystals if allergic component present
─ Epithelial lining of mucocele may be flattened, ulcerated, or show squamous metaplasia; goblet cell hyperplasia is common
─ Surrounding parenchyma ─ Alveolar spaces are overdistended (hyperinflation); alveolar walls may be thinned or ruptured; mild chronic inflammation or organizing pneumonia can be present
─ No intrinsic malformation of the distal lung parenchyma (unlike CPAM)
Ancillary studies ─
─ Diagnosis is often made by characteristic imaging findings (hyperlucent lung segment with central tubular/branching opacity representing the mucocele) combined with pathological confirmation
─ Special stains for mucin (e.g., Alcian blue, PAS) highlight impacted mucus
DDx ─
─ Allergic bronchopulmonary aspergillosis (ABPA) (can cause mucoid impaction and bronchiectasis, but usually more diffuse and with eosinophilia)
─ Acquired bronchial obstruction (e.g., foreign body, tumor, extrinsic compression)
─ Cystic fibrosis (diffuse bronchiectasis and mucoid impaction)
─ Bronchiectasis of other causes
─ Congenital lobar overinflation (no focal bronchial atresia or mucocele, though hyperinflation is shared)
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Congenital Lobar Overinflation (Congenital Lobar Emphysema)

A condition characterized by postnatal overdistension of one or more pulmonary lobes, usually due to partial bronchial obstruction (intrinsic or extrinsic), or rarely, an alveolar abnormality, leading to air trapping and respiratory distress
Clinical ─
─ Typically presents in neonates or early infancy (first 6 months) with progressive respiratory distress, wheezing, cyanosis, or tachypnea
─ Most commonly affects: Left upper lobe (~40-50%), right middle lobe (~20-30%), right upper lobe (~20%)
─ May be associated with cardiac anomalies in ~15% of cases
Macro ─
─ Affected lobe is markedly enlarged, pale, and hyperlucent; it does not deflate upon opening the chest and may herniate across the midline
─ Adjacent lobes and contralateral lung may be compressed (atelectasis)
─ Cut surface shows overly distended airspaces; no obvious cystic or adenomatoid changes
Micro ─
─ Alveolar spaces are markedly overdistended and septa are thinned; the number of alveoli may be normal or, in some cases, increased (polyalveolar lobe variant)
─ Bronchial abnormalities may be identified in some cases as the cause of obstruction:
─ Intrinsic: Cartilage defects/hypoplasia (bronchomalacia), redundant mucosal folds, bronchial webs, stenosis, atresia (if very focal and leading to overinflation rather than mucocele)
─ Extrinsic: Compression by anomalous vessels, masses, or cysts
─ If no mechanical obstruction is found, it may be termed "idiopathic" or potentially related to abnormalities in alveolar development/surfactant or a polyalveolar lobe (increased number of structurally normal alveoli)
─ No intrinsic cystic or adenomatoid change of CPAM type
Ancillary studies ─
─ Diagnosis is primarily based on clinical and radiological findings, confirmed by pathology
─ Histology helps exclude other causes of neonatal respiratory distress (e.g., CPAM, sequestration)
DDx ─
─ Congenital Pulmonary Airway Malformation (CPAM) (especially Type 3 or 4 if microcystic or large cysts, but CPAM has intrinsic adenomatoid/cystic architecture)
─ Pneumothorax (requires imaging to differentiate)
─ Compensatory hyperinflation secondary to atelectasis of other lobes
─ Bronchial atresia (will typically have a bronchocele/mucocele)
─ Pulmonary interstitial emphysema (air in interstitium, not just overdistended alveoli)
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Bronchogenic Cyst (Parenchymal/Intrapulmonary)

A congenital cyst derived from abnormal budding or branching of the ventral foregut or tracheobronchial tree, typically lined by respiratory-type epithelium and possessing elements of bronchial wall structure (cartilage, smooth muscle, glands) within its wall
Clinical ─
─ Often asymptomatic and discovered incidentally on imaging at any age
─ If symptomatic, can cause cough, dyspnea, chest pain, or recurrent infections due to compression of adjacent structures or secondary infection of the cyst itself
─ Parenchymal (intrapulmonary) cysts are less common than mediastinal bronchogenic cysts
─ Typically solitary and unilocular
Macro ─
─ Usually a well-circumscribed, spherical or oval, unilocular cyst
─ Size varies from small to several centimeters
─ Filled with clear, white, mucoid, or brownish fluid/material; rarely air-filled if communication with airway develops
─ Cyst wall is typically smooth, with variable thickness
Micro ─
─ Cyst lining: Characteristically ciliated pseudostratified columnar (respiratory) epithelium; may show areas of squamous metaplasia, cuboidal or flattened epithelium, or be denuded, especially if inflamed
─ Cyst wall: Contains elements found in a normal bronchial wall, which are key for diagnosis:
─ Hyaline cartilage plates or islands (most specific feature, but may not be present in all sections or all cysts)
─ Smooth muscle bundles or layers
─ Seromucinous glands (bronchial-type glands)
─ Fibrous connective tissue
─ Lymphoid aggregates may be present in the wall
─ Acute or chronic inflammation, hemorrhage, or cholesterol clefts may be seen if the cyst is complicated by infection or rupture
Ancillary studies ─
─ Generally not required for diagnosis; morphology is usually sufficient
─ Mucin stains (e.g., PAS, Alcian blue) can highlight mucin within the cyst or goblet cells in the lining
DDx ─
─ Congenital Pulmonary Airway Malformation (CPAM Type 1) (CPAM has adenomatoid proliferation and branching bronchiolar structures, less organized wall elements than a classic bronchogenic cyst)
─ Pulmonary sequestration (especially if cystic, but sequestration has systemic arterial supply and lacks typical bronchial wall elements)
─ Abscess (contains purulent material, necrotic debris, and granulation tissue, lacks organized bronchial wall structures)
─ Bulla or bleb (thin-walled air spaces, lined by attenuated epithelium or none, lack bronchial wall elements)
─ Infected pre-existing cyst of other origin (e.g., hydatid cyst, healed infectious cavity)
─ Enteric duplication cyst (if intrapulmonary, rare; typically has gastrointestinal-type mucosa and two muscle layers)
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Infections of the Lung

Bacterial Pneumonias

An overview of lung inflammation caused by bacterial infection, characterized by various histological patterns and a wide range of etiological agents
Clinical ─
─ Presentation ─ Acute onset fever, chills, cough (productive or non-productive), dyspnea, chest pain; symptoms vary with pathogen, host immune status, and extent of disease
─ Classification can be based on:
─ Setting of acquisition: Community-acquired (CAP), Hospital-acquired (HAP), Ventilator-associated (VAP), Aspiration pneumonia
─ Typical vs. Atypical: "Typical" often refers to abrupt onset with productive cough (e.g., Streptococcus pneumoniae); "Atypical" for more insidious onset, non-productive cough (e.g., Mycoplasma, Chlamydia, Legionella)
─ Risk factors ─ Extremes of age, immunosuppression, chronic lung disease (COPD, cystic fibrosis), smoking, alcoholism, impaired consciousness (aspiration risk)
Macro ─
─ Lobar pneumonia ─ Consolidation of an entire lobe or large portion thereof; classically described stages (congestion, red hepatization, gray hepatization, resolution)
─ Bronchopneumonia (Lobular pneumonia) ─ Patchy consolidation centered on airways, often bilateral and basal
─ Interstitial pneumonia ─ Inflammation primarily affecting the interstitium; less common for typical bacteria but can be seen with some atypical pathogens
─ Abscess formation ─ Localized area of necrosis and pus formation
Micro ─
─ Lobar pneumonia ─ Diffuse intra-alveolar exudate, initially with edema and bacteria, followed by neutrophils and red blood cells (red hepatization), then dense neutrophils and fibrin with macrophage infiltration (gray hepatization), and finally enzymatic digestion and resolution
─ Common etiology: Streptococcus pneumoniae ─ Bronchopneumonia ─ Acute inflammation of bronchioles (suppurative bronchiolitis) with extension into adjacent peribronchiolar alveoli; patchy intra-alveolar neutrophilic exudate
─ Common etiologies: Staphylococcus aureus, Haemophilus influenzae, Pseudomonas aeruginosa, Klebsiella pneumoniae, various Gram-negative rods
─ Interstitial pneumonia pattern (less classic for bacteria) ─ Interstitial lymphoplasmacytic infiltrates with minimal alveolar exudate; may be seen with Mycoplasma pneumoniae, Chlamydophila pneumoniae ─ Aspiration pneumonia ─ Often mixed bacterial flora (aerobes and anaerobes); chemical pneumonitis component initially, followed by bacterial infection; may show foreign material, granulomatous reaction to food particles, and necrotizing inflammation; typically in dependent lung segments
─ Specific bacterial features:
─ Klebsiella pneumoniae ─ "Currant jelly" sputum clinically; abundant capsular polysaccharide, may lead to bulging fissure sign, often necrotizing
─ Pseudomonas aeruginosa ─ Common in HAP/VAP, cystic fibrosis; often necrotizing with vasculitis and hemorrhage (ecthyma gangrenosum-like changes in severe cases)
─ Legionella pneumophila ─ Requires special culture media/tests; may show intra-alveolar neutrophils and macrophages, fibrin; diagnosis often by IHC, DFA, or PCR on tissue/fluids
Ancillary studies ─
─ Gram stain on sputum or tissue sections to identify bacteria and guide initial therapy
─ Culture of sputum, blood, pleural fluid, or lung tissue for definitive identification and susceptibility testing
─ Histochemical stains ─ Gram stain (e.g., Brown-Hopps, Brown-Brenn) can be attempted on tissue but sensitivity is variable
─ IHC or molecular tests (e.g., PCR) for specific organisms if suspected and difficult to culture (e.g., Legionella, atypical bacteria)
DDx ─
─ Viral pneumonia (often interstitial, lymphocytic infiltrate)
─ Fungal pneumonia (requires special stains for organisms)
─ Non-infectious inflammatory conditions (e.g., DAD, organizing pneumonia, hypersensitivity pneumonitis)
─ Aspiration of gastric contents (chemical pneumonitis without prominent infection initially)
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Viral Pneumonias

An overview of lung inflammation caused by viral infections, typically characterized by interstitial inflammation and variable degrees of alveolar damage
Clinical ─
─ Presentation ─ Often flu-like symptoms: fever, cough (usually non-productive initially), malaise, myalgias, headache; dyspnea may develop with more severe disease
─ Common viruses ─ Influenza A and B, Respiratory Syncytial Virus (RSV), Parainfluenza virus, Adenovirus, Human Metapneumovirus, Coronaviruses (e.g., SARS-CoV-2), Cytomegalovirus (CMV), Herpes Simplex Virus (HSV), Varicella-Zoster Virus (VZV)
─ Risk factors for severe disease ─ Immunocompromised status (e.g., transplant recipients, HIV/AIDS, chemotherapy), extremes of age, chronic underlying diseases
Macro ─
─ Lungs may appear congested, edematous, and heavy
─ Patchy or diffuse consolidation can occur, often less well-defined than bacterial lobar pneumonia
─ Pleural effusions are less common than in bacterial pneumonia
Micro ─
─ Interstitial inflammation ─ Predominantly lymphocytic and macrophagic infiltrates within the alveolar septa and peribronchiolar connective tissue
─ Alveolar damage ─ Variable, ranging from reactive type II pneumocyte hyperplasia to diffuse alveolar damage (DAD) with hyaline membrane formation in severe cases
─ Epithelial changes ─ Necrosis of bronchial, bronchiolar, or alveolar epithelial cells; viral cytopathic effects (CPE) may be present and can be diagnostic or suggestive for certain viruses:
─ CMV ─ Enlarged cells with large, basophilic intranuclear inclusions ("owl's eye") and smaller cytoplasmic inclusions; typically in endothelial cells, macrophages, epithelial cells
─ HSV/VZV ─ Multinucleated giant cells with molded, ground-glass intranuclear inclusions (Cowdry A or B type)
─ Adenovirus ─ Necrotizing bronchiolitis/pneumonia; characteristic "smudge cells" or basophilic intranuclear inclusions completely filling the nucleus or surrounded by a halo
─ Measles virus ─ Multinucleated giant cells (Warthin-Finkeldey cells) in airways or interstitium, with eosinophilic intranuclear and intracytoplasmic inclusions
─ RSV ─ Bronchiolitis with syncytial cell formation, intracytoplasmic eosinophilic inclusions (less prominent)
─ Other features ─ Squamous metaplasia, organizing pneumonia, airway inflammation (bronchitis/bronchiolitis)
─ SARS-CoV-2 (COVID-19) ─ Can show a range of patterns, including DAD, organizing pneumonia, capillaritis, microthrombi
Ancillary studies ─
─ Viral cultures (less commonly performed on tissue now)
─ PCR or other molecular assays on respiratory secretions, bronchoalveolar lavage (BAL) fluid, or tissue for viral detection and identification (most sensitive and specific method)
─ IHC stains for specific viral antigens (e.g., CMV, HSV, influenza, SARS-CoV-2) can be performed on tissue sections
─ Serology (for documenting recent infection, less useful for acute diagnosis in tissue)
DDx ─
─ Other infectious pneumonias (bacterial, fungal - especially those with interstitial patterns like Mycoplasma or Pneumocystis)
─ Acute interstitial pneumonia (AIP) / DAD of non-infectious cause
─ Hypersensitivity pneumonitis (interstitial inflammation, often with poorly formed granulomas)
─ Drug reactions
─ Connective tissue disease-associated ILD
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Fungal Pneumonias

An overview of lung inflammation caused by fungal infections, encompassing a variety of organisms and host responses, often opportunistic in immunocompromised individuals but can occur in immunocompetent hosts (endemic fungi)
Clinical ─
─ Presentation ─ Highly variable; can be asymptomatic, acute, subacute, or chronic; symptoms include fever, cough, dyspnea, chest pain, hemoptysis
─ Risk factors ─ Immunosuppression (HIV/AIDS, transplant, chemotherapy, corticosteroids), neutropenia, underlying lung disease (e.g., cavities, bronchiectasis), diabetes mellitus, exposure in endemic areas
─ Key Fungal Groups/Species:
─ Aspergillus spp. (e.g., A. fumigatus, A. flavus)
─ Pneumocystis jirovecii (formerly P. carinii)
─ Endemic fungi: Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides immitis/posadasii ─ Cryptococcus neoformans/gattii ─ Mucormycetes (e.g., Rhizopus, Mucor, Lichtheimia)
─ Candida spp. (rarely a primary lung pathogen, more often colonization or disseminated disease)
Macro ─
─ Variable: Nodules (solitary or multiple), consolidation, cavitation, miliary pattern, fungus balls (aspergilloma) within pre-existing cavities, infarcts (due to angioinvasion)
Micro ─
─ Host reaction patterns:
─ Suppurative inflammation (neutrophils): Often seen with Aspergillus, Candida ─ Granulomatous inflammation (macrophages, giant cells, lymphocytes): Characteristic for endemic fungi (Histoplasma, Blastomyces, Coccidioides), Cryptococcus, and chronic forms of aspergillosis
─ Mixed suppurative and granulomatous
─ Eosinophilic infiltrates: Can be seen in allergic bronchopulmonary aspergillosis (ABPA)
─ Necrosis: Caseating (common with Histoplasma, Cryptococcus) or non-caseating granulomas; coagulative necrosis with angioinvasive fungi
─ Angioinvasion: Characteristic of Aspergillus and Mucormycetes, leading to thrombosis and infarction
─ Fungal morphology (visualized with H&E but confirmed with special stains):
─ Aspergillus spp.: Septate hyphae (4-6 µm wide) with acute angle (45°) branching
─ Pneumocystis jirovecii: Characteristic foamy or "honeycomb" eosinophilic intra-alveolar exudate; cysts seen as ~5-8 µm cup-shaped or collapsed crescentic structures on GMS or other silver stains; trophozoites are tiny dots within exudate
─ Histoplasma capsulatum: Small (2-5 µm) oval yeast forms, often intracellular within macrophages; narrow-based budding
─ Blastomyces dermatitidis: Large (8-15 µm) yeasts with thick, refractile cell walls and broad-based budding
─ Coccidioides spp.: Spherules (20-60 µm, up to 200 µm) containing endospores; empty or ruptured spherules may be seen; hyphae present in culture or rarely in cavitary lesions
─ Cryptococcus neoformans/gattii: Pleomorphic yeasts (5-15 µm) with prominent polysaccharide capsule (visualized with mucin stains like mucicarmine or Alcian blue); narrow-based budding
─ Mucormycetes: Broad (5-20 µm), pauciseptate or non-septate hyphae with irregular, wide-angle (often 90°) branching; ribbon-like appearance
Ancillary studies ─
─ Histochemical stains are essential for visualization and morphological identification:
─ Grocott Methenamine Silver (GMS) and Periodic Acid-Schiff (PAS) are broad-spectrum fungal stains
─ Mucicarmine or Alcian blue for Cryptococcus capsule
─ Fontana-Masson for melanin in dematiaceous fungi or Cryptococcus cell wall (less common in lung diagnosis)
─ IHC for specific fungal antigens (e.g., Aspergillus, Pneumocystis) can be helpful, especially if organisms are sparse or morphology is atypical
─ Culture of respiratory specimens or tissue for definitive identification and susceptibility testing
─ Molecular assays (e.g., PCR) on tissue or BAL for fungal DNA
─ Serology or antigen testing (e.g., galactomannan for Aspergillus, beta-D-glucan, cryptococcal antigen) in blood or BAL fluid
DDx ─
─ Other infections (bacterial, mycobacterial, viral)
─ Non-infectious granulomatous diseases (e.g., sarcoidosis, GPA)
─ Neoplasms (e.g., carcinoma, lymphoma) that can mimic nodules or infiltrates
─ Pulmonary alveolar proteinosis (can mimic Pneumocystis pneumonia due to PAS+ material, but GMS negative for organisms)
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Mycobacterial Infections

An overview of lung diseases caused by mycobacteria, primarily Mycobacterium tuberculosis (causing tuberculosis - TB) and nontuberculous mycobacteria (NTM)
Clinical ─
─ Tuberculosis (TB):
─ Presentation: Highly variable; can be asymptomatic, insidious onset (cough, weight loss, fever, night sweats, hemoptysis), or acute; depends on immune status and stage (primary, postprimary/secondary, miliary)
─ Transmission: Inhalation of aerosolized droplets containing M. tuberculosis ─ Risk factors for active disease: Immunosuppression (HIV, TNF-alpha inhibitors), malnutrition, silicosis, diabetes, close contact with active TB cases
─ Nontuberculous Mycobacteria (NTM):
─ Presentation: Often chronic cough, fatigue, weight loss; can cause progressive lung disease, especially in individuals with pre-existing lung conditions (e.g., COPD, bronchiectasis) or immunosuppression
─ Organisms: Common examples include Mycobacterium avium complex (MAC), M. kansasii, M. abscessus ─ Transmission: Environmental sources (water, soil); generally not person-to-person
Macro ─
─ Tuberculosis:
─ Primary TB: Ghon focus (subpleural granuloma, often mid-lung zone) and Ghon complex (Ghon focus + hilar lymph node involvement); usually heals with calcification
─ Postprimary (Secondary/Reactivation) TB: Typically apical/posterior segments of upper lobes; caseous necrosis, cavitation, fibrosis, pleural thickening/effusions are common
─ Miliary TB: Diffuse, small (1-2 mm) yellow-white granulomas scattered throughout lung parenchyma (and other organs) due to hematogenous dissemination
─ NTM: Variable; may include nodules, infiltrates, bronchiectasis, cavities (often thin-walled compared to TB), tree-in-bud opacities on imaging
Micro ─
─ Tuberculosis (M. tuberculosis):
─ Characteristic feature: Caseating granulomas ─ aggregates of epithelioid histiocytes, Langhans giant cells, and lymphocytes, with central acellular, eosinophilic, granular necrosis (caseation)
─ Acid-fast bacilli (AFB) may be demonstrable within granulomas (especially in caseous material) or macrophages using Ziehl-Neelsen or Kinyoun stains (appear as red rods)
─ Fibrosis and calcification are common in healed or chronic lesions
─ Nontuberculous Mycobacteria (NTM):
─ Histologic patterns can be variable and may overlap with TB, but often:
─ Granulomas may be less well-formed, non-caseating, or have minimal necrosis
─ Chronic inflammation, bronchiectasis, bronchiolitis, and fibrosis are common
─ "Hot tub lung" (hypersensitivity-like reaction to MAC in immunocompetent individuals) shows well-formed non-necrotizing granulomas in a bronchiolocentric distribution
─ AFB are often less numerous than in TB and may be harder to find
Ancillary studies ─
─ Acid-fast bacilli (AFB) stains (Ziehl-Neelsen, Kinyoun, or fluorescent auramine-rhodamine) on sputum, BAL, or tissue sections
─ Culture of mycobacteria from sputum, BAL, or tissue is the gold standard for diagnosis and speciation (allows for susceptibility testing)
─ Nucleic acid amplification tests (NAATs), such as PCR for M. tuberculosis complex, on respiratory specimens or tissue for rapid detection
─ Interferon-Gamma Release Assays (IGRAs) or Tuberculin Skin Test (TST) for latent TB infection (not diagnostic of active disease)
DDx ─
─ Fungal infections (e.g., Histoplasma, Cryptococcus can cause caseating granulomas; special stains for fungi are crucial)
─ Sarcoidosis (typically well-formed, non-caseating granulomas; AFB and fungal stains negative)
─ Other granulomatous diseases (e.g., GPA, foreign body reaction)
─ Neoplasms (e.g., squamous cell carcinoma with cavitation, lymphoma)
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Parasitic Pneumonias

An overview of lung infections caused by various parasitic organisms, which can occur through different routes of transmission and elicit diverse host responses
Clinical ─
─ Presentation: Highly variable depending on the parasite, host immune status, and burden of infection; can range from asymptomatic eosinophilia to severe respiratory distress, cough, fever, hemoptysis, chest pain
─ Selected examples:
─ Strongyloides stercoralis: Larvae can migrate through lungs (part of autoinfection cycle), causing cough, wheezing, transient infiltrates, or severe hemorrhagic pneumonia (hyperinfection syndrome) in immunocompromised hosts; peripheral eosinophilia common
─ Echinococcus granulosus (Hydatid disease): Larval cysts (hydatid cysts) develop in the lung; can be asymptomatic or cause symptoms due to mass effect, rupture (anaphylaxis, secondary cysts), or infection
─ Paragonimus spp. (Lung flukes): Ingestion of raw/undercooked freshwater crabs/crayfish; chronic cough, chest pain, rusty sputum (hemoptysis), fever; lung lesions can be cystic, nodular, or fibrotic
─ Toxoplasma gondii: Usually in severely immunocompromised (e.g., AIDS, transplant); diffuse interstitial pneumonitis; tachyzoites and cysts in tissue
─ Dirofilaria immitis (Dog heartworm): Humans are accidental hosts; typically presents as an incidental solitary peripheral pulmonary nodule ("coin lesion") formed around a degenerating worm
─ Schistosoma spp.: Ova embolize to pulmonary arterioles, eliciting granulomatous inflammation, leading to pulmonary hypertension in chronic heavy infections
Macro ─
─ Variable: Nodules (Dirofilaria, some Paragonimus), cysts (Echinococcus), infiltrates (Strongyloides, Toxoplasma), fibrotic lesions (Paragonimus, chronic schistosomiasis)
Micro ─
─ Strongyloides stercoralis: Filariform larvae may be seen in alveolar spaces, interstitium, or vessel walls; associated with hemorrhage, edema, eosinophilic and neutrophilic infiltrates, DAD in hyperinfection
─ Echinococcus granulosus: Hydatid cyst wall has three layers: outer pericyst (host fibrous reaction), middle acellular laminated membrane, and inner germinal layer (produces scolices and daughter cysts); hooklets may be seen
─ Paragonimus spp.: Encapsulated adult flukes or eggs within granulomatous and fibrotic lesions; eggs are golden-brown, operculated, and often elicit an eosinophilic and granulomatous response; Charcot-Leyden crystals may be present
─ Toxoplasma gondii: Interstitial pneumonitis with lymphoplasmacytic infiltrates, type II pneumocyte hyperplasia; tachyzoites (small, crescentic) or cysts (containing bradyzoites) may be seen in alveolar lining cells or macrophages
─ Dirofilaria immitis: Central degenerating worm (often necrotic and calcified) within a coagulative infarct-like nodule, surrounded by granulomatous inflammation, fibrosis, and often prominent eosinophils
─ Schistosoma spp.: Ova in small pulmonary arteries or arterioles, with surrounding granulomatous inflammation (epithelioid cells, giant cells, eosinophils, lymphocytes); arterial obstruction, arteritis, and vascular remodeling can lead to pulmonary arterial hypertension
Ancillary studies ─
─ Microscopic identification of parasites, larvae, eggs, or cysts in sputum, BAL, pleural fluid, or tissue sections (H&E is often sufficient, but Giemsa or other stains may help)
─ Serological tests for specific parasitic infections (e.g., Echinococcus, Strongyloides, Toxoplasma, Paragonimus, Schistosoma)
─ Stool examination for ova and parasites (e.g., Strongyloides larvae, Paragonimus eggs if swallowed)
─ Imaging studies are crucial for diagnosis of lesions like hydatid cysts or Dirofilaria nodules
DDx ─
─ Other infections (fungal, mycobacterial, bacterial, viral) causing granulomas, eosinophilia, or nodules
─ Neoplasms (primary or metastatic lung tumors)
─ Non-infectious eosinophilic lung diseases
─ Vasculitis or infarcts from other causes
─ Allergic reactions
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Other Infections (e.g., Mycoplasma, Chlamydia)

An overview of lung infections caused by less common bacterial pathogens or those with "atypical" clinical presentations, often characterized by interstitial inflammation
Clinical ─
─ Mycoplasma pneumoniae: Common cause of "atypical pneumonia" or "walking pneumonia," especially in children and young adults; gradual onset of headache, malaise, fever, persistent non-productive cough, sore throat
─ Chlamydophila pneumoniae (formerly Chlamydia pneumoniae): Causes bronchitis, sinusitis, and atypical pneumonia; similar presentation to Mycoplasma, often mild but can be prolonged; common in all age groups
─ Chlamydophila psittaci (Psittacosis): Acquired from infected birds (parrots, pigeons, turkeys); abrupt onset of fever, headache, myalgia, dry cough; can be severe with systemic involvement
─ Coxiella burnetii (Q fever): Acquired from infected animals (cattle, sheep, goats) or their products; acute presentation with fever, headache, myalgia, dry cough; chronic form can cause endocarditis or granulomatous hepatitis
Macro ─
─ Lungs may show patchy or diffuse congestion and consolidation, often less dramatic than typical bacterial pneumonias
Micro ─
─ Mycoplasma pneumoniae and Chlamydophila pneumoniae:
─ Predominantly interstitial pneumonia: Lymphoplasmacytic and macrophagic infiltrates in alveolar septa and peribronchiolar connective tissue
─ Airway inflammation: Bronchitis and bronchiolitis with lymphocytic infiltrates in the airway walls; luminal exudate may be scant
─ Reactive type II pneumocyte hyperplasia may be present
─ Organizing pneumonia or DAD can occur in more severe cases
─ Organisms are not visible by routine light microscopy or Gram stain
─ Chlamydophila psittaci: Similar to above, but can be more severe with intra-alveolar fibrin, hyaline membranes, and prominent macrophage infiltrates; characteristic cytoplasmic inclusions (elementary or reticulate bodies) are rarely seen in routine sections without special methods
─ Coxiella burnetii: May show nonspecific interstitial pneumonitis; characteristic "doughnut granulomas" (fibrin-ring granulomas) can be seen in the lung (more commonly in liver/bone marrow) but are not specific
Ancillary studies ─
─ Diagnosis is often challenging on histology alone as features are nonspecific
─ Serology (antibody detection - IgM, IgG) is a primary diagnostic method for Mycoplasma, Chlamydia species, and Coxiella burnetii ─ PCR or other molecular assays on respiratory specimens (sputum, BAL), blood, or tissue for direct detection of pathogen DNA/RNA (increasingly used and more sensitive/specific than culture for these organisms)
─ Culture for Mycoplasma and Chlamydia is difficult, requires special media, and is not routinely performed in clinical labs for tissue diagnosis
─ IHC can be used for Chlamydia or Coxiella in tissue but is not widely available
DDx ─
─ Viral pneumonias (similar interstitial pattern)
─ Hypersensitivity pneumonitis (interstitial inflammation, often with poorly formed granulomas or eosinophils)
─ Other causes of atypical pneumonia
─ Drug reactions or other non-infectious interstitial lung diseases
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Acute Lung Injury

Diffuse Alveolar Damage (DAD)

A morphologic pattern of acute lung injury characterized by widespread injury to alveolar capillary endothelium and epithelium, leading to increased vascular permeability, alveolar edema, hyaline membrane formation, and type II pneumocyte hyperplasia; the histological hallmark of Acute Respiratory Distress Syndrome (ARDS)
Clinical ─
─ ARDS is a clinical syndrome of acute, severe hypoxemic respiratory failure not fully explained by cardiac failure or fluid overload
─ Causes are numerous:
─ ─ Direct lung injury: Pneumonia (viral, bacterial, fungal), aspiration of gastric contents, pulmonary contusion, fat embolism, near-drowning, inhalational injury (toxins, smoke)
─ ─ Indirect lung injury (systemic processes): Sepsis (most common cause), severe trauma, pancreatitis, shock, multiple transfusions (TRALI), drug reactions, acute liver failure
─ Abrupt onset of dyspnea and hypoxemia, typically developing within hours to days of the inciting event
─ Bilateral pulmonary infiltrates on chest imaging
─ High mortality rate, though varies with underlying cause and severity
Macro ─
─ Lungs are heavy, dark red, congested, and relatively airless (firm, rubbery consistency)
─ Cut surface shows edema and consolidation; may show areas of hemorrhage
Micro ─
─ Histologic features evolve through stages:
─ Exudative Phase (first ~1-7 days):
─ ─ Interstitial and intra-alveolar edema, fibrin deposition
─ ─ Necrosis and sloughing of alveolar epithelial cells (type I pneumocytes predominantly) and endothelial cells
─ ─ Formation of pink, glassy hyaline membranes lining alveolar ducts and alveoli (composed of fibrin, cellular debris, and plasma proteins)
─ ─ Capillary congestion and microthrombi may be present
─ ─ Minimal to moderate interstitial inflammation (neutrophils initially, later lymphocytes)
─ Proliferative/Organizing Phase (typically after ~7 days, can overlap):
─ ─ Proliferation of type II pneumocytes lining alveolar walls (attempt at repair)
─ ─ Organization of intra-alveolar fibrin by granulation tissue (fibroblast proliferation, loose connective tissue - Masson body-like changes within alveoli)
─ ─ Interstitial inflammation becomes more prominent (lymphocytes, plasma cells, macrophages)
─ ─ Myofibroblast proliferation in the interstitium
─ ─ Hyaline membranes may persist or be incorporated into organizing tissue
─ Fibrotic Phase (if not resolved, weeks to months):
─ ─ Progressive interstitial fibrosis, often with architectural remodeling (honeycombing in some cases if chronic)
─ ─ Collagen deposition, thickening of alveolar walls
─ ─ Obliteration of alveolar spaces and capillaries
Ancillary studies ─
─ Diagnosis is primarily morphologic on H&E, in the appropriate clinical context
─ Special stains (e.g., GMS, Gram, AFB) and cultures are important to rule out or identify underlying/superimposed infection
─ Trichrome stain can highlight fibrosis in later stages
DDx ─
─ Acute infectious pneumonia (viral, bacterial, fungal - DAD can be caused by infection, so this is often a search for etiology)
─ Acute Fibrinous and Organizing Pneumonia (AFOP) (predominance of intra-alveolar fibrin "balls" with less prominent hyaline membranes, though overlap exists)
─ Acute Eosinophilic Pneumonia (prominent eosinophilic infiltrates)
─ Pulmonary hemorrhage syndromes (extensive intra-alveolar hemorrhage, capillaritis)
─ Exacerbation of underlying interstitial lung disease (e.g., acute exacerbation of IPF can show DAD pattern)
─ Drug reactions causing lung injury
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Acute Fibrinous and Organizing Pneumonia (AFOP)

A histological pattern of acute lung injury characterized by prominent intra-alveolar fibrin deposition in the form of "fibrin balls" and associated organizing pneumonia, with relatively less prominent or absent hyaline membranes compared to classic DAD
Clinical ─
─ Can present similarly to DAD/ARDS with acute respiratory distress, or as a subacute illness with fever, cough, and dyspnea
─ May be idiopathic or associated with various underlying conditions:
─ ─ Infections (bacterial, viral, fungal)
─ ─ Connective tissue diseases (e.g., lupus, rheumatoid arthritis, dermatomyositis)
─ ─ Drug reactions
─ ─ Hypersensitivity pneumonitis
─ ─ Hematologic malignancies or post-transplant settings
─ Radiologically can show bilateral patchy opacities or consolidation
Macro ─
─ Lungs may show areas of consolidation, often patchy
Micro ─
─ Dominant feature: Abundant intra-alveolar fibrin, often forming large aggregates or "fibrin balls" (amorphous, eosinophilic material)
─ Organizing pneumonia pattern: Fibroblastic plugs (Masson body-like) within alveolar ducts, alveoli, and sometimes small airways, admixed with or replacing fibrin
─ Interstitial inflammation: Mild to moderate, typically lymphoplasmacytic
─ Type II pneumocyte hyperplasia is common
─ Hyaline membranes: Typically absent or sparse and focal; their extensive presence would favor a diagnosis of DAD (though AFOP is considered by some within the spectrum of DAD or acute lung injury patterns)
─ Absence of diffuse eosinophilic infiltrates, granulomas, or vasculitis (unless related to an underlying specific etiology)
Ancillary studies ─
─ Special stains for microorganisms (GMS, AFB, Gram) are important to exclude infection as a cause
─ Trichrome stain can highlight organizing fibrosis
DDx ─
─ Diffuse Alveolar Damage (DAD) (more extensive hyaline membranes, edema, and epithelial necrosis are typical of classic DAD)
─ Cryptogenic Organizing Pneumonia (COP) / Bronchiolitis Obliterans Organizing Pneumonia (BOOP) (organizing pneumonia is the primary feature, but typically lacks the prominent intra-alveolar fibrin balls characteristic of AFOP; clinical context often less acute)
─ Acute Eosinophilic Pneumonia (predominant eosinophilic infiltrate)
─ Infections causing organizing pneumonia with fibrin (careful search for organisms needed)
─ Pulmonary hemorrhage (intra-alveolar hemorrhage and hemosiderin, not fibrin balls)
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Acute Eosinophilic Pneumonia (AEP)

An acute febrile illness characterized by diffuse pulmonary infiltrates and marked eosinophilia in bronchoalveolar lavage fluid and/or lung tissue, often with rapid response to corticosteroids
Clinical ─
─ Acute onset (typically <1 month, often <7 days) of fever, dyspnea, cough, and sometimes chest pain
─ Can lead to severe hypoxemic respiratory failure requiring mechanical ventilation
─ Often affects previously healthy individuals, can be associated with new-onset smoking, dust/allergen exposure, or certain medications
─ Peripheral blood eosinophilia may be present but is not required for diagnosis and can be delayed
─ Bronchoalveolar lavage (BAL) fluid typically shows >25% eosinophils
─ Dramatic and rapid response to corticosteroid therapy is characteristic
Macro ─
─ Lungs may appear edematous and congested; areas of consolidation may be present
Micro ─
─ Diffuse eosinophilic infiltration of the alveolar spaces and interstitium is the hallmark feature
─ Eosinophils are typically numerous and prominent, often admixed with macrophages and fewer lymphocytes or neutrophils
─ Interstitial edema and fibrin deposition may be present
─ Diffuse alveolar damage (DAD) pattern can be seen in severe cases, with hyaline membranes and type II pneumocyte hyperplasia, but with a superimposed prominent eosinophilic infiltrate
─ Organizing pneumonia (fibroblastic plugs) can occur, often with eosinophils within the plugs
─ No evidence of infection (especially parasitic or fungal, which can also cause eosinophilia)
─ No vasculitis, granulomas, or significant necrosis (unless secondary to severe inflammation)
Ancillary studies ─
─ Special stains for microorganisms (GMS, AFB, Gram, and specific stains for parasites if suspected) are crucial to rule out infection
─ Careful review of medication and exposure history is important
DDx ─
─ Infectious causes of pulmonary eosinophilia (e.g., parasitic infections like Strongyloides, Ascaris, Paragonimus; fungal infections like ABPA or coccidioidomycosis)
─ Chronic Eosinophilic Pneumonia (CEP) (more insidious onset, often peripheral infiltrates on imaging, peripheral eosinophilia more common, relapsing course)
─ Eosinophilic Granulomatosis with Polyangiitis (EGPA/Churg-Strauss syndrome) (history of asthma, sinusitis, vasculitis, extravascular granulomas, peripheral eosinophilia)
─ Drug-induced eosinophilic pneumonia (requires correlation with medication history)
─ Allergic Bronchopulmonary Aspergillosis (ABPA) (history of asthma, bronchiectasis, elevated IgE, Aspergillus sensitization)
─ Idiopathic Hypereosinophilic Syndrome (persistent peripheral eosinophilia with multi-organ involvement)
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Vaping-Associated Acute Lung Injury (EVALI)

An acute lung injury syndrome linked to the use of e-cigarette or vaping products, characterized by a spectrum of histopathologic patterns, often including lipoid pneumonia and acute lung injury
Clinical ─
─ Acute to subacute onset of respiratory symptoms (cough, dyspnea, chest pain), often accompanied by gastrointestinal symptoms (nausea, vomiting, diarrhea) and constitutional symptoms (fever, chills, weight loss)
─ Strong association with vaping THC-containing products, particularly those obtained from informal sources and containing vitamin E acetate (used as a cutting agent/thickener)
─ Diagnosis based on history of vaping within 90 days of symptom onset, pulmonary infiltrates on imaging, and exclusion of other plausible causes (e.g., infection)
Macro ─
─ Nonspecific findings of acute lung injury, such as congested, edematous, and heavy lungs; areas of consolidation may be present
Micro ─
─ Spectrum of histologic patterns has been described, often overlapping:
─ Exogenous Lipoid Pneumonia-like pattern: Prominent feature in many reported cases; characterized by numerous finely vacuolated (lipid-laden) macrophages within alveolar spaces and interstitium; lipid may also be seen extracellularly
─ Acute Lung Injury / Diffuse Alveolar Damage (DAD) pattern: Hyaline membranes, alveolar edema, fibrin deposition, type II pneumocyte hyperplasia
─ Organizing Pneumonia pattern: Fibroblastic plugs (Masson-like bodies) in distal airspaces
─ Fibrinous Pneumonitis (similar to AFOP): Abundant intra-alveolar fibrin
─ Acute Eosinophilic Pneumonia-like pattern: Less common, but eosinophilic infiltrates can be seen
─ Bronchiolitis: Acute or chronic inflammation of bronchioles, sometimes with neutrophils, lymphocytes, or fibrin
─ Foamy macrophages may also be seen in airway lumens
Ancillary studies ─
─ Oil Red O stain (on frozen sections of lung tissue or cytological preparations of BAL fluid) can confirm the presence of neutral lipids within macrophages and extracellularly (suggestive of exogenous lipoid pneumonia component)
─ Special stains for microorganisms (GMS, Gram, AFB) and viral IHC/PCR are crucial to rule out infection
─ Analysis of BAL fluid for vitamin E acetate (by CDC or specialized labs) was a key diagnostic marker during the 2019-2020 outbreak
DDx ─
─ Infectious pneumonia (viral, bacterial, fungal – must be excluded)
─ Other causes of DAD (e.g., sepsis, shock)
─ Idiopathic lipoid pneumonia (endogenous or other exogenous sources)
─ Acute Eosinophilic Pneumonia (if eosinophils are prominent)
─ Organizing Pneumonia from other causes
─ Hypersensitivity pneumonitis
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Idiopathic Interstitial Pneumonias

Usual Interstitial Pneumonia (UIP) / Idiopathic Pulmonary Fibrosis (IPF)

UIP is a distinctive histopathological pattern of chronic, progressive, fibrosing interstitial pneumonia; IPF is a specific clinical diagnosis for patients with progressive fibrosing pneumonia of unknown cause that occurs primarily in older adults, is limited to the lungs, and is associated with a UIP pattern on HRCT or surgical lung biopsy
Clinical ─
─ IPF typically affects adults >50 years of age, more common in males and ever-smokers
─ Insidious onset of progressive dyspnea on exertion and non-productive cough over months to years
─ Bibasilar inspiratory crackles ("Velcro rales") on auscultation; digital clubbing common in advanced disease
─ Median survival is poor (typically 3-5 years from diagnosis) without treatment (antifibrotic therapies may slow progression)
─ UIP pattern can also be seen in other conditions (secondary UIP), e.g., connective tissue diseases (especially rheumatoid arthritis), chronic hypersensitivity pneumonitis, asbestosis, drug toxicity, Hermansky-Pudlak syndrome
Macro ─
─ Lungs are often shrunken, firm, and fibrotic, especially in the lower lobes and subpleural regions
─ Pleural surface often has a "cobblestone" appearance due to retraction of scars along interlobular septa
─ Cut surface shows dense fibrosis, most prominent subpleurally and peripherally, with characteristic honeycomb change (cystic, dilated, fibrotic airspaces typically <1 cm)
Micro ─
─ Key diagnostic features of UIP pattern (all four are required for definite UIP):
─ Patchwork pattern of lung involvement (spatial heterogeneity): Areas of established fibrosis and architectural distortion (scarring) alternating abruptly with areas of less affected or relatively normal lung parenchyma, often at low magnification
─ Temporal heterogeneity: Evidence of ongoing and past injury, with areas of active fibrosis (fibroblastic foci) alongside dense, established acellular collagen fibrosis and honeycomb change
─ Fibroblastic foci: Discrete collections of actively proliferating fibroblasts and myofibroblasts embedded in a pale, myxoid-appearing stroma, typically located at the interface between dense scar and more normal alveolar walls; a hallmark of active fibrogenesis in UIP
─ Architectural distortion: Including scarring and honeycomb change (cystic fibrotic airspaces often lined by bronchiolar-type epithelium and filled with mucin or inflammatory cells)
─ Interstitial inflammation: Usually mild and patchy, composed of lymphocytes and plasma cells; may be more prominent away from areas of dense fibrosis
─ Smooth muscle hyperplasia is common within areas of fibrosis and around honeycomb cysts
─ Absence of features suggesting an alternative diagnosis: e.g., prominent granulomas, diffuse DAD, predominant organizing pneumonia, extensive eosinophilic infiltrates, significant interstitial inflammation away from honeycombing that would suggest NSIP
Ancillary studies ─
─ Trichrome stain (e.g., Masson's trichrome) highlights collagen fibrosis and can help identify fibroblastic foci
─ Elastic stains (e.g., Verhoeff-Van Gieson) can demonstrate destruction of elastic framework and remodeling
─ Mucin stains (e.g., Alcian blue) may highlight mucin within honeycomb cysts
DDx ─
─ (For the UIP pattern):
─ ─ Fibrotic Nonspecific Interstitial Pneumonia (NSIP) (more uniform interstitial fibrosis, lacks significant fibroblastic foci and the marked spatial/temporal heterogeneity of UIP)
─ ─ Chronic Hypersensitivity Pneumonitis (may show UIP-like pattern but often has poorly formed granulomas, airway-centered fibrosis, or prominent lymphoid hyperplasia)
─ ─ Asbestosis (history of asbestos exposure, presence of asbestos bodies, predominantly basilar and subpleural fibrosis)
─ ─ Connective Tissue Disease-Associated ILD (CTD-ILD) (clinical features of CTD; UIP is a common pattern, especially in RA-ILD)
─ ─ End-stage of other fibrosing lung diseases
─ (For IPF diagnosis): Exclusion of known causes of UIP pattern (as listed above)
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Nonspecific Interstitial Pneumonia (NSIP)

An idiopathic interstitial pneumonia characterized by a relatively uniform and temporally homogeneous pattern of interstitial inflammation and/or fibrosis, lacking the specific diagnostic features of UIP, DAD, or organizing pneumonia as the dominant process
Clinical ─
─ Subacute onset of dyspnea and cough, typically over months
─ Can occur at any age, slightly more common in females, often non-smokers
─ Frequently associated with connective tissue diseases (CTDs) (e.g., scleroderma, polymyositis/dermatomyositis, Sjögren syndrome), drug reactions, or HIV infection; can also be idiopathic
─ Generally has a better prognosis than IPF/UIP, especially the cellular variant; response to corticosteroids or immunosuppressive therapy is common
─ Radiologically, typically shows bilateral, symmetric ground-glass opacities, often with reticulation and traction bronchiectasis; subpleural sparing can occur
Macro ─
─ Lungs may appear diffusely or patchily firm, with a more uniform involvement compared to UIP
─ Honeycombing is typically absent or minimal, especially in cellular NSIP
Micro ─
─ Key feature: Relatively uniform and temporally homogeneous interstitial involvement (i.e., appears to be at the same stage of evolution throughout the biopsy)
─ Two main histologic patterns are recognized:
─ Cellular NSIP:
─ ─ Diffuse or patchy interstitial infiltration by a mild to moderate infiltrate of lymphocytes and plasma cells, with minimal associated fibrosis
─ ─ Alveolar septa are thickened by the inflammatory infiltrate, but the underlying lung architecture is generally preserved
─ ─ Type II pneumocyte hyperplasia may be present
─ Fibrotic NSIP:
─ ─ Diffuse or patchy interstitial fibrosis, characterized by relatively uniform thickening of alveolar walls by dense or loose connective tissue
─ ─ The fibrosis appears temporally uniform (no fibroblastic foci or minimal/rare)
─ ─ A variable, usually mild, chronic inflammatory infiltrate (lymphocytes, plasma cells) is often present within the fibrotic areas
─ ─ Architectural distortion may occur, including traction bronchiectasis, but extensive honeycombing characteristic of UIP is absent
─ Absence of features characteristic of UIP (e.g., significant spatial and temporal heterogeneity, prominent fibroblastic foci, extensive honeycombing)
─ Absence of features of other specific IIPs or ILDs (e.g., granulomas, DAD, eosinophilic infiltrates, prominent organizing pneumonia as the primary pattern)
Ancillary studies ─
─ Trichrome stain (e.g., Masson's trichrome) can help assess the extent and pattern of fibrosis
─ Special stains for microorganisms should be performed to exclude infection
DDx ─
─ Usual Interstitial Pneumonia (UIP) (especially fibrotic NSIP vs. early or cellular UIP; UIP has temporal/spatial heterogeneity and fibroblastic foci)
─ Organizing Pneumonia (COP/BOOP) (predominantly intraluminal organizing plugs, though OP can be a component of NSIP)
─ Diffuse Alveolar Damage (DAD), resolving phase (may show some interstitial fibrosis and type II cell hyperplasia, but DAD typically has hyaline membranes in acute phase)
─ Hypersensitivity Pneumonitis (cellular NSIP-like patterns can be seen; look for poorly formed granulomas, airway-centered accentuation, exposure history)
─ Drug-induced interstitial lung disease (can mimic NSIP patterns)
─ Lymphocytic Interstitial Pneumonia (LIP) (more dense and diffuse lymphocytic infiltrates, often with lymphoid follicles and germinal centers)
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Cryptogenic Organizing Pneumonia (COP)

An idiopathic interstitial pneumonia characterized by the histologic pattern of organizing pneumonia (OP), where granulation tissue plugs (Masson bodies) fill alveolar ducts and alveoli, and no determinable cause or specific clinical context is identified
Clinical ─
─ Typically subacute onset (weeks to a few months) of flu-like illness, including non-productive cough, dyspnea, fever, malaise, and weight loss
─ Affects adults, usually between 40-60 years; no sex predilection
─ Pulmonary function tests often show a restrictive pattern and impaired gas exchange
─ Radiologically, characteristic features include bilateral, patchy, often peripheral or peribronchial areas of consolidation (airspace opacities); migratory infiltrates can occur
─ Generally has a good prognosis with corticosteroid treatment, often with complete recovery, though relapses can occur
─ Term "BOOP" (Bronchiolitis Obliterans Organizing Pneumonia) was formerly used but "organizing pneumonia" is preferred for the histologic pattern, and COP for the idiopathic clinical syndrome
Macro ─
─ Patchy areas of gray-white, firm consolidation within the lung parenchyma
─ Lesions may appear somewhat nodular or ill-defined
Micro ─
─ Hallmark: Polypoid plugs of granulation tissue (Masson bodies) within alveolar ducts, alveolar spaces, and to a lesser extent, respiratory bronchioles
─ ─ These plugs consist of fibroblasts and myofibroblasts embedded in a loose, myxoid-appearing connective tissue matrix, often with associated capillaries
─ ─ The granulation tissue is typically all of the same age (temporally uniform)
─ Preservation of underlying lung architecture: Alveolar framework is generally intact despite being filled by OP plugs
─ Mild to moderate chronic interstitial inflammation: Lymphocytes and plasma cells in adjacent alveolar septa
─ Foamy macrophages (lipid-laden) are often present in alveolar spaces surrounding areas of OP
─ Absence of features that would suggest another diagnosis: e.g., no extensive interstitial fibrosis typical of UIP or fibrotic NSIP, no hyaline membranes (or only very focal and not DAD), no granulomas, no significant eosinophilia, no vasculitis, no necrosis
Ancillary studies ─
─ Trichrome stain (e.g., Masson's trichrome) highlights the fibroblastic plugs and can help differentiate them from other intra-alveolar material
─ Special stains for microorganisms (GMS, AFB, Gram) are essential to rule out an infectious cause of organizing pneumonia
DDx ─
─ Secondary Organizing Pneumonia: OP pattern can be secondary to many causes, which must be excluded for a diagnosis of COP:
─ ─ Infections (bacterial, viral, fungal, parasitic)
─ ─ Drug reactions
─ ─ Connective tissue diseases (e.g., rheumatoid arthritis, polymyositis)
─ ─ Aspiration pneumonia
─ ─ Resolving phase of Diffuse Alveolar Damage (DAD)
─ ─ Adjacent to neoplasms or abscesses (obstructive pneumonia)
─ ─ Hypersensitivity pneumonitis
─ Acute Fibrinous and Organizing Pneumonia (AFOP) (characterized by prominent intra-alveolar fibrin balls in addition to OP; considered a distinct pattern or part of the DAD spectrum by some)
─ Chronic Eosinophilic Pneumonia (predominant eosinophilic infiltrate, though some OP can be present)
─ Other IIPs (e.g., NSIP can have foci of OP, but OP is not the dominant pattern)
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Respiratory Bronchiolitis-Associated Interstitial Lung Disease (RB-ILD) & Desquamative Interstitial Pneumonia (DIP)

Two distinct but related smoking-associated idiopathic interstitial pneumonias, both characterized by the accumulation of pigmented macrophages ("smoker's macrophages") within the distal airspaces; RB-ILD is bronchiolocentric, while DIP shows more diffuse alveolar filling
Clinical ─
─ Almost exclusively occur in current or former cigarette smokers (heavy smoking history typical)
─ RB-ILD: Often presents with mild symptoms (cough, dyspnea) or may be an incidental finding in asymptomatic smokers; generally good prognosis with smoking cessation
─ DIP: Typically presents with insidious onset of dyspnea and cough, often more symptomatic than RB-ILD; digital clubbing can occur; generally improves with smoking cessation and/or corticosteroids, but a minority may have progressive disease
─ Both entities are considered part of a spectrum of smoking-related lung injury
Macro ─
─ RB-ILD: Lungs may appear grossly normal or show subtle centrilobular nodules or ground-glass opacities on imaging; biopsy may show mild tan-brown discoloration or thickening of bronchiolar walls
─ DIP: Lungs may appear diffusely gray or pale tan; subtle consolidation or a "ground-glass" appearance on cut section; generally no gross fibrosis or honeycombing unless advanced or overlapping with other conditions
Micro ─
─ Common Feature for Both: Accumulation of pigmented macrophages ("smoker's macrophages")
─ ─ These macrophages are large, with abundant cytoplasm containing finely granular, golden-brown pigment (lipofuscin, particulate matter from smoke); pigment is PAS-positive and typically iron-negative (or only weakly positive)
─ Respiratory Bronchiolitis-Interstitial Lung Disease (RB-ILD):
─ ─ Pigmented macrophages are characteristically clustered within the lumens of respiratory bronchioles and adjacent (peribronchiolar) alveolar spaces and ducts
─ ─ Mild thickening of respiratory bronchiolar walls and surrounding alveolar septa due to a sparse inflammatory infiltrate (lymphocytes, histiocytes) and often mild submucosal/peribronchiolar fibrosis
─ ─ Alveolar septa away from the bronchioles are relatively normal or show only minimal changes
─ Desquamative Interstitial Pneumonia (DIP):
─ ─ Diffuse and prominent accumulation of pigmented macrophages filling numerous alveolar spaces, often forming solid sheets of cells within alveoli throughout the biopsy
─ ─ Alveolar septa are typically mildly thickened by a sparse inflammatory infiltrate (lymphocytes, plasma cells, occasional eosinophils) and minimal to mild interstitial fibrosis; significant fibrosis is uncommon but can occur
─ ─ Alveolar architecture is generally well-preserved despite the macrophage accumulation
─ ─ Type II pneumocyte hyperplasia is often prominent and can be striking
Ancillary studies ─
─ Iron stain (e.g., Prussian blue) can help confirm that the pigment in macrophages is not predominantly hemosiderin (distinguishing from hemorrhage-related macrophage accumulation)
─ PAS stain highlights the granules in smoker's macrophages
DDx ─
─ For RB-ILD:
─ ─ Respiratory Bronchiolitis (RB) (histologic finding of pigmented macrophages in airways of asymptomatic smokers; RB-ILD implies clinical disease with symptoms and/or PFT/imaging abnormalities)
─ ─ Hypersensitivity pneumonitis (cellular bronchiolitis, but typically with poorly formed granulomas or giant cells, different exposure history)
─ ─ Follicular bronchiolitis (prominent lymphoid follicles around airways)
─ For DIP:
─ ─ Pulmonary Alveolar Proteinosis (PAP) (alveoli filled with granular, eosinophilic, PAS-positive material that is acellular or contains few cells; GMS negative for fungi)
─ ─ Acute Eosinophilic Pneumonia (if eosinophils are prominent in DIP-like pattern, though usually AEP is more acute and diffuse eosinophils)
─ ─ Infections causing alveolar filling (e.g., Pneumocystis jirovecii pneumonia – foamy intra-alveolar exudate, GMS positive)
─ ─ Other conditions with macrophage accumulation (e.g., resolving DAD, amiodarone lung)
─ Distinguishing RB-ILD from DIP: RB-ILD shows a clear bronchiolocentric distribution of pigmented macrophages; DIP shows a more diffuse and extensive pan-acinar filling of alveoli. Some cases may show overlapping features.
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Lymphocytic Interstitial Pneumonia (LIP) - Idiopathic

A rare idiopathic interstitial pneumonia characterized by diffuse and extensive interstitial infiltration by lymphocytes, plasma cells, and other lymphoreticular cells, often forming lymphoid follicles
Clinical ─
─ Insidious onset of progressive dyspnea and cough over months to years; systemic symptoms like fever and weight loss may occur
─ Can occur in adults (median age ~50s) and children
─ While this entry focuses on idiopathic LIP, it is more commonly associated with:
─ ─ Autoimmune diseases (especially Sjögren syndrome, also SLE, rheumatoid arthritis, myasthenia gravis)
─ ─ Immunodeficiency states (particularly common in children with HIV infection; less so in adults with HIV)
─ ─ Other conditions (e.g., Castleman disease, viral infections like EBV)
─ Idiopathic LIP is a diagnosis of exclusion after ruling out associated conditions and lymphoma
─ Pulmonary function tests typically show a restrictive pattern
─ Prognosis is variable; some respond to corticosteroids or immunosuppression, others may progress to fibrosis
Macro ─
─ Lungs may show diffuse, rubbery consolidation, a reticulonodular pattern, or cystic changes in advanced cases
Micro ─
─ Dense, diffuse (or sometimes patchy) interstitial infiltrates composed predominantly of small lymphocytes (mostly mature T-cells, but B-cells are also present)
─ Significant numbers of plasma cells are typically admixed with the lymphocytes
─ Other lymphoreticular cells may be present, including macrophages, histiocytes, and occasional immunoblasts
─ Lymphoid follicles, sometimes with reactive germinal centers, are frequently seen along airways (bronchovascular bundles) and within the interlobular septa or alveolar interstitium
─ The interstitial infiltrates cause thickening of alveolar septa
─ Type II pneumocyte hyperplasia is common
─ Interstitial fibrosis can develop in later stages, sometimes leading to architectural distortion and honeycombing, but is usually not the dominant feature in early LIP
─ Relative sparing of vascular structures from direct infiltration by the lymphoid cells (unlike lymphomatoid granulomatosis)
─ Absence of features definitively diagnostic of lymphoma: e.g., sheets of atypical lymphoid cells, destructive infiltrates, significant cytologic atypia, clear monoclonality by IHC (though reactive processes can sometimes show focal light chain restriction or skewed kappa/lambda ratios that require careful interpretation)
Ancillary studies ─
─ IHC stains:
─ ─ CD3 to highlight T-lymphocytes
─ ─ CD20 to highlight B-lymphocytes and lymphoid follicles
─ ─ Kappa and Lambda light chain stains to assess for polyclonality of the plasma cell population (monoclonality would raise concern for lymphoma/plasmacytoma)
─ ─ CD138 for plasma cells
─ Flow cytometry on BAL fluid or fresh tissue can assess lymphocyte populations and clonality if lymphoma is a concern
─ Molecular studies: T-cell receptor (TCR) or immunoglobulin (Ig) gene rearrangement studies if lymphoma is strongly suspected (LIP is typically polyclonal)
DDx ─
─ Hypersensitivity Pneumonitis (HP) (also has lymphocytic interstitial infiltrates, but HP often shows poorly formed granulomas, giant cells, and/or airway-centered accentuation; exposure history important)
─ Nonspecific Interstitial Pneumonia (NSIP), cellular variant (lymphocytic infiltrate, but LIP typically has denser, more polymorphous infiltrate with prominent plasma cells and often well-formed lymphoid follicles)
─ Low-grade B-cell Lymphoma of MALT type (MALT Lymphoma) (can be very difficult to distinguish, especially on small biopsies; MALT lymphoma is monoclonal, often shows lymphoepithelial lesions, and may have more atypical lymphocytes or destructive growth)
─ Follicular Bronchiolitis/Bronchitis (lymphoid follicles primarily restricted to peribronchial/peribronchiolar tissue without significant interstitial extension characteristic of LIP)
─ Viral pneumonia (acute inflammation, may have specific viral cytopathic effects)
─ Other lymphoproliferative disorders involving the lung
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Acute Interstitial Pneumonia (AIP)

A rare and rapidly progressive idiopathic interstitial pneumonia characterized histologically by diffuse alveolar damage (DAD) of unknown etiology; it represents an idiopathic form of Acute Respiratory Distress Syndrome (ARDS)
Clinical ─
─ Abrupt onset (typically days to <3 weeks) of severe dyspnea and hypoxemic respiratory failure, often in previously healthy individuals
─ Symptoms mimic ARDS: fever, cough, rapidly worsening shortness of breath
─ No identifiable cause or predisposing condition for DAD (e.g., sepsis, trauma, aspiration, known infection, drug reaction) despite extensive clinical investigation
─ High mortality rate (often >50%), similar to severe ARDS from known causes
─ Historically referred to as Hamman-Rich syndrome (though this term originally described a more heterogeneous group)
Macro ─
─ Lungs are typically heavy, edematous, congested, and firm, reflecting diffuse alveolar damage and consolidation
─ Similar to gross findings in DAD from known causes
Micro ─
─ The histologic pattern is identical to Diffuse Alveolar Damage (DAD), evolving through stages:
─ Exudative Phase:
─ ─ Widespread alveolar edema, intra-alveolar fibrin deposition
─ ─ Formation of prominent eosinophilic hyaline membranes lining alveolar ducts and alveoli
─ ─ Necrosis and sloughing of type I pneumocytes and alveolar capillary endothelial cells
─ ─ Interstitial inflammation, initially often with neutrophils, later with lymphocytes
─ Organizing/Proliferative Phase:
─ ─ Proliferation of type II pneumocytes covering denuded alveolar surfaces
─ ─ Organization of intra-alveolar fibrin by proliferating fibroblasts and myofibroblasts (forming intra-alveolar fibroblastic plugs, Masson-like bodies)
─ ─ Interstitial fibroblast proliferation and deposition of loose connective tissue
─ ─ Chronic interstitial inflammation (lymphocytes, plasma cells)
─ The diagnosis of AIP requires that the DAD pattern is idiopathic, meaning known causes of DAD have been excluded
Ancillary studies ─
─ Crucial to exclude infectious etiologies:
─ ─ Special stains for microorganisms (GMS, PAS for fungi; AFB for mycobacteria; Gram stain for bacteria) on lung tissue
─ ─ Viral IHC or molecular tests (e.g., PCR for influenza, CMV, SARS-CoV-2)
─ ─ Cultures of lung tissue or BAL fluid if obtained
─ No specific ancillary tests confirm AIP itself; it's a diagnosis based on idiopathic DAD morphology and clinical exclusion
DDx ─
─ Diffuse Alveolar Damage (DAD) secondary to a known cause (most important distinction):
─ ─ Infections (severe viral, bacterial, fungal pneumonia)
─ ─ Sepsis, shock, severe trauma
─ ─ Aspiration of gastric contents
─ ─ Drug reactions or toxin exposure
─ ─ Transfusion-related acute lung injury (TRALI)
─ Acute exacerbation of Idiopathic Pulmonary Fibrosis (IPF) (underlying UIP pattern should be identifiable)
─ Other rapidly progressive interstitial lung diseases (e.g., severe acute eosinophilic pneumonia, rapidly progressive CTD-ILD, acute hypersensitivity pneumonitis – these usually have other specific histologic clues)
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Idiopathic Pleuroparenchymal Fibroelastosis (PPFE)

A rare idiopathic interstitial pneumonia characterized by fibrosis predominantly involving the visceral pleura and subpleural lung parenchyma, with prominent elastosis of the fibrotic areas, typically most severe in the upper lobes
Clinical ─
─ Insidious onset, often with progressive dyspnea, chronic dry cough, weight loss, and recurrent respiratory infections
─ Pneumothorax is a common and often recurrent complication (in up to 25-50% of patients)
─ Can occur at any age, but often diagnosed in middle-aged to older adults
─ May be idiopathic or associated with factors such as prior chemotherapy, radiotherapy, bone marrow or lung transplantation, chronic infections, or autoimmune features (though "idiopathic" implies no clear secondary cause)
─ Pulmonary function tests show a restrictive pattern
─ Radiologically characterized by bilateral, predominantly upper lobe pleural thickening and subpleural consolidation/reticulation; "apical cap" like appearance but more extensive; upward hilar retraction
─ Prognosis is variable, often progressive despite treatment
Macro ─
─ Marked, dense, pearly white thickening of the visceral pleura, typically most prominent over the upper lobes
─ Underlying lung parenchyma shows subpleural consolidation and fibrosis, extending inwards
─ The affected lobes may be shrunken
Micro ─
─ Dense, mature, often paucicellular collagenous fibrosis involving the visceral pleura and extending into the subpleural lung parenchyma along interlobular septa and around bronchovascular bundles
─ Striking and characteristic feature: Prominent elastosis within the fibrotic areas – abundant, thickened, curled, and fragmented elastic fibers, often arranged in dense aggregates or parallel arrays within the collagenous scar tissue
─ Alveolar septa within the fibrotic areas are thickened and incorporated into the fibrotic process; alveoli may be collapsed or show mild cystic change (but not typical UIP-like honeycombing)
─ Relatively abrupt transition from the densely fibrotic subpleural areas to more normal or less affected underlying lung parenchyma
─ Minimal to mild chronic inflammation (lymphocytes, plasma cells) is usually present within the fibrotic areas
─ Absence of features of other specific IIPs (e.g., fibroblastic foci of UIP, granulomas, DAD, extensive OP)
Ancillary studies ─
─ Elastic stains (e.g., Verhoeff-Van Gieson - VVG, orcein, Weigert's resorcin-fuchsin) are essential to demonstrate the prominent and abnormal elastic fiber deposition
─ Trichrome stain highlights the collagenous fibrosis
─ Special stains for microorganisms to exclude chronic infection
DDx ─
─ Apical cap (localized fibroelastotic scar at lung apices, usually an incidental finding, less extensive and typically not associated with progressive symptoms or pneumothorax of PPFE)
─ Usual Interstitial Pneumonia (UIP) (different distribution – usually basilar predominant; UIP has fibroblastic foci, temporal heterogeneity, and typical honeycombing; elastosis is not the defining feature)
─ Fibrotic Nonspecific Interstitial Pneumonia (NSIP) (more diffuse interstitial involvement, lacks the striking pleural and subpleural upper lobe predominance and marked elastosis of PPFE)
─ Sequelae of chronic infections (e.g., tuberculosis, fungal infections can cause apical fibrosis, but PPFE has a characteristic elastosis and pleural involvement pattern)
─ Radiation fibrosis (history of radiation, different histologic features of fibrosis)
─ Ankylosing spondylitis-associated apical fibrosis (similar location but different clinical context)
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Interstitial Lung Diseases (ILDs) of Known Cause

Connective Tissue Disease-Associated Interstitial Lung Disease (CTD-ILD) - General patterns

Interstitial lung disease that occurs in patients with established systemic autoimmune connective tissue diseases, characterized by a variety of histologic patterns and variable clinical courses
Clinical ─
─ ILD is a common and significant complication of many CTDs, contributing to morbidity and mortality
─ Respiratory symptoms (dyspnea on exertion, cough) may be present, or ILD can be subclinical and detected on imaging or PFTs
─ ILD can be the presenting manifestation of a CTD or develop years after the CTD diagnosis
─ Specific CTDs commonly associated with ILD:
─ ─ Systemic Sclerosis (SSc) / Scleroderma (NSIP is most common pattern)
─ ─ Rheumatoid Arthritis (RA) (UIP is a common pattern, but NSIP, OP, follicular bronchiolitis also occur)
─ ─ Polymyositis/Dermatomyositis (PM/DM), especially anti-synthetase syndrome (NSIP and OP are common)
─ ─ Sjögren Syndrome (LIP, NSIP, follicular bronchiolitis are common)
─ ─ Systemic Lupus Erythematosus (SLE) (pleuritis, acute lupus pneumonitis/DAD, shrinking lung syndrome, chronic ILD - NSIP, LIP, OP patterns)
─ ─ Mixed Connective Tissue Disease (MCTD) (can show various patterns, often NSIP)
Macro ─
─ Variable, depending on the underlying histologic pattern and severity; may show areas of fibrosis, consolidation, ground-glass appearance, or honeycombing in UIP-pattern cases
Micro ─
─ Several histologic patterns of ILD can be seen in CTD patients; one patient may exhibit more than one pattern, or patterns can evolve
─ Common patterns include:
─ ─ Nonspecific Interstitial Pneumonia (NSIP): The most frequent pattern overall in CTD-ILD. Can be cellular or fibrotic NSIP. Histologically similar to idiopathic NSIP but may have more prominent lymphoid aggregates or plasma cell infiltrates.
─ ─ Usual Interstitial Pneumonia (UIP): Common in RA-ILD, but can occur in other CTDs. Histologically similar to idiopathic UIP (patchwork fibrosis, fibroblastic foci, honeycombing) but often has features suggesting a "secondary UIP" such as more prominent inflammation, lymphoid follicles with germinal centers, or areas overlapping with NSIP or OP.
─ ─ Organizing Pneumonia (OP): Can occur as the predominant pattern or as a component of other patterns in many CTDs.
─ ─ Diffuse Alveolar Damage (DAD): Can present as an acute, severe manifestation (e.g., acute lupus pneumonitis, scleroderma renal crisis associated lung injury).
─ ─ Lymphocytic Interstitial Pneumonia (LIP): Particularly associated with Sjögren syndrome and SLE. Characterized by dense interstitial lymphocytic and plasmacytic infiltrates, often with lymphoid follicles.
─ Other frequently observed features in CTD-ILD (may be more pronounced than in idiopathic counterparts):
─ ─ Prominent lymphoid aggregates, often with reactive germinal centers
─ ─ Dense interstitial plasma cell infiltrates
─ ─ Follicular bronchiolitis/bronchitis (lymphoid follicles around airways)
─ ─ Pleuritis (fibrous thickening, inflammation)
─ ─ Pulmonary vascular disease / pulmonary arterial hypertension (PAH) changes (intimal fibrosis, medial hypertrophy of pulmonary arteries/arterioles)
Ancillary studies ─
─ Histologic pattern dictates which stains may be useful (e.g., Trichrome for fibrosis in NSIP/UIP, special stains to exclude infection)
─ Clinical correlation with specific autoantibody profiles (e.g., anti-Scl-70 in SSc, anti-Jo-1 in anti-synthetase syndrome, RF/anti-CCP in RA) and systemic features of CTD is paramount for diagnosis
DDx ─
─ Idiopathic Interstitial Pneumonias (IPF, idiopathic NSIP, COP, idiopathic LIP – clinical information is key to distinguish CTD-ILD from its idiopathic counterpart)
─ Drug-induced interstitial lung disease (many CTD patients are on medications known to cause ILD, e.g., methotrexate, cyclophosphamide, TNF-alpha inhibitors)
─ Infections (CTD patients are often immunosuppressed due to their disease or treatment, increasing susceptibility to opportunistic infections that can mimic ILD)
─ Overlap syndromes where features of more than one CTD are present
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Drug-Induced Lung Diseases - Common patterns

A heterogeneous group of pulmonary disorders resulting from adverse reactions to medications, capable of mimicking a wide range of infectious and non-infectious lung diseases
Clinical ─
─ Onset can be acute, subacute, or chronic, depending on the drug, dose, duration of therapy, and host factors
─ Symptoms are variable and depend on the pattern of lung injury; may include cough, dyspnea, fever, chest pain, eosinophilia
─ A detailed medication history is crucial for diagnosis (prescription, over-the-counter, herbal supplements, illicit drugs, and timeline of use relative to symptom onset)
─ Diagnosis often relies on temporal association, exclusion of other causes, and sometimes improvement upon drug withdrawal (dechallenge); rechallenge is rarely performed intentionally
Macro ─
─ Nonspecific and varies with the histologic pattern; may include diffuse consolidation, patchy infiltrates, nodules, or fibrosis
Micro ─
─ Drugs can cause a wide variety of histologic patterns of lung injury; a single drug may cause different patterns, and different drugs can cause the same pattern:
─ Diffuse Alveolar Damage (DAD): Common pattern for many cytotoxic drugs (e.g., bleomycin, cyclophosphamide, busulfan), amiodarone, nitrofurantoin (acute reaction)
─ Nonspecific Interstitial Pneumonia (NSIP) - Cellular or Fibrotic: Can be caused by amiodarone, methotrexate, statins, biologic agents (e.g., TNF-alpha inhibitors), interferons
─ Organizing Pneumonia (OP): Associated with amiodarone, bleomycin, methotrexate, cyclophosphamide, interferons, sirolimus, gold salts
─ Hypersensitivity Pneumonitis-like reaction: Lymphocytic interstitial inflammation, cellular bronchiolitis, often poorly formed non-necrotizing granulomas; e.g., methotrexate, sirolimus, nitrofurantoin, sulfonamides
─ Eosinophilic Pneumonia (Acute or Chronic): Characterized by prominent eosinophilic infiltrates in alveoli and interstitium; e.g., nitrofurantoin, sulfonamides, NSAIDs, daptomycin, minocycline
─ Pulmonary Hemorrhage / Capillaritis: Diffuse alveolar hemorrhage with or without capillaritis; e.g., anticoagulants, penicillamine, hydralazine, propylthiouracil, all-trans retinoic acid, infliximab
─ Exogenous Lipoid Pneumonia: Due to aspiration or inhalation of oil-based medications (e.g., mineral oil laxatives, oil-based nasal drops); characterized by lipid-laden macrophages
─ Granulomatous Reactions: Non-necrotizing granulomas; e.g., BCG therapy, immune checkpoint inhibitors, methotrexate, TNF-alpha inhibitors
─ Pulmonary Hypertension: Associated with certain appetite suppressants (e.g., fenfluramine derivatives), dasatinib
─ Chronic Fibrosis (UIP-like or unclassifiable): Can be the end-stage of various drug-induced injuries; e.g., chronic amiodarone or nitrofurantoin toxicity, bleomycin
─ Specific findings for some drugs: Foamy (lipid-laden) macrophages are characteristic of amiodarone toxicity (phospholipidosis), but not entirely specific
Ancillary studies ─
─ Primarily aimed at excluding other conditions, especially infection (GMS, AFB, Gram stains)
─ Bronchoalveolar lavage (BAL) may show eosinophilia (in drug-induced eosinophilic pneumonia), lymphocytosis (in HP-like reactions), or lipid-laden macrophages (in amiodarone lung or lipoid pneumonia)
─ No specific IHC or molecular tests for drug-induced lung disease itself; diagnosis is clinicopathologic
DDx ─
─ Highly dependent on the histologic pattern observed:
─ ─ Idiopathic Interstitial Pneumonias (e.g., IPF, idiopathic NSIP, COP, AIP)
─ ─ Infections (viral, bacterial, fungal, parasitic)
─ ─ Connective Tissue Disease-Associated ILD (CTD-ILD)
─ ─ Hypersensitivity Pneumonitis (non-drug induced)
─ ─ Other specific lung diseases relevant to the pattern
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Hypersensitivity Pneumonitis - Acute and Chronic

An immune-mediated interstitial lung disease resulting from sensitization and recurrent inhalation of an inciting antigen, typically organic dusts (e.g., thermophilic actinomycetes in moldy hay - Farmer's lung), avian proteins (Bird Fancier's lung), or certain chemicals
Clinical ─
─ Presentation depends on the intensity/frequency of exposure and host immune response:
─ Acute HP: Develops 4-12 hours after heavy exposure; flu-like symptoms (fever, chills, malaise, myalgia, headache), cough, dyspnea, chest tightness; often resolves within 24-48 hours with antigen avoidance
─ Subacute (Intermittent) HP: More gradual onset of cough, dyspnea, fatigue, anorexia over weeks to months with recurrent, less intense exposures
─ Chronic HP: Develops with prolonged low-level exposure or repeated subacute episodes; insidious onset of progressive dyspnea, cough, fatigue, weight loss; can lead to irreversible fibrosis and may mimic IPF
─ Detailed environmental and occupational exposure history is critical for diagnosis
─ Serum precipitating antibodies (IgG) against specific antigens may be present (supportive, but not diagnostic alone; absence does not exclude HP)
─ BAL often shows marked lymphocytosis (typically CD8+ T-cell predominant in acute/subacute phases)
Macro ─
─ Acute/Subacute: Lungs may appear normal or show ill-defined patchy ground-glass opacities or fine nodularity, often more prominent in upper/mid zones
─ Chronic: Shows variable fibrosis, which can be diffuse or patchy; may involve upper, mid, or lower lung zones; honeycombing can occur in advanced fibrotic cases
Micro ─
─ Classic histologic triad (more often seen in acute/subacute forms; may not all be present, especially in chronic HP or small biopsies):
─ 1. Cellular bronchiolitis: Lymphoplasmacytic inflammation centered on terminal and respiratory bronchioles, sometimes with extension into adjacent interstitium
─ 2. Interstitial inflammation: Diffuse or patchy, non-uniform lymphoplasmacytic infiltrates in alveolar septa, often with scattered foamy macrophages in airspaces
─ 3. Poorly formed, non-necrotizing interstitial granulomas: Small, loose clusters of epithelioid histiocytes, often without prominent giant cells or a dense lymphocytic cuff; may be subtle and easily missed; typically located in the interstitium or peribronchiolar regions
─ Other common features:
─ ─ Organizing pneumonia (OP) pattern can be present, sometimes prominent
─ ─ Foamy macrophages (lipid-laden) in alveolar spaces or interstitium
─ ─ Peribronchiolar metaplasia (cuboidal metaplasia of bronchiolar epithelium)
─ Chronic HP:
─ ─ Shows more established interstitial fibrosis, which can exhibit various patterns:
─ ─ ─ NSIP-like pattern (cellular or fibrotic)
─ ─ ─ UIP-like pattern (patchwork fibrosis, fibroblastic foci, honeycombing); clues suggesting HP over IPF in a UIP pattern include airway-centered fibrosis ("bridging fibrosis" between airways or centrilobular fibrosis), peribronchiolar metaplasia, persistent poorly formed granulomas (if found), or areas of cellular NSIP/OP elsewhere
─ ─ ─ Mixed patterns or unclassifiable fibrosis
─ ─ Dense peribronchiolar collagen deposition can be a feature
─ ─ Lymphoid follicles with germinal centers may be seen
Ancillary studies ─
─ Special stains for microorganisms (GMS, AFB) are essential to exclude infection, especially if granulomas are present
─ Trichrome stain can highlight fibrosis in chronic forms
DDx ─
─ Acute HP: Viral or atypical pneumonia, acute asthma exacerbation, organic dust toxic syndrome
─ Subacute/Chronic HP:
─ ─ Idiopathic Interstitial Pneumonias (IPF/UIP, NSIP, COP – careful search for subtle HP features and strong clinical/exposure correlation needed)
─ ─ Sarcoidosis (granulomas are typically well-formed, non-necrotizing, with a different distribution - lymphangitic; different clinical picture)
─ ─ Connective tissue disease-associated ILD
─ ─ Drug-induced lung disease (some drugs cause HP-like reactions)
─ ─ Asthma with fungal sensitization (e.g., ABPA, but ABPA has prominent eosinophilia and mucoid impaction)
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Sarcoidosis

A multisystem granulomatous disorder of unknown etiology, characterized pathologically by the presence of well-formed, non-necrotizing epithelioid granulomas in affected organs; the lungs and intrathoracic lymph nodes are the most commonly involved sites
Clinical ─
─ Highly variable presentation: Many patients are asymptomatic (diagnosis on incidental chest imaging); others present with insidious onset of dry cough, dyspnea, chest pain, fatigue, fever, night sweats, weight loss
─ Pulmonary involvement occurs in >90% of cases; hilar/mediastinal lymphadenopathy is very common
─ Extrapulmonary involvement is frequent: Skin (erythema nodosum, lupus pernio, plaques), eyes (uveitis), liver, spleen, peripheral lymph nodes, nervous system (neuro-sarcoidosis), heart (cardiac sarcoidosis), musculoskeletal system
─ Elevated serum angiotensin-converting enzyme (ACE) levels in ~60% of patients (not specific or sensitive enough for diagnosis alone)
─ Hypercalcemia/hypercalciuria can occur due to unregulated vitamin D metabolism by macrophages in granulomas
─ Diagnosis requires compatible clinical/radiological picture, histologic evidence of non-necrotizing granulomas, and exclusion of other known causes of granulomatous disease
Macro ─
─ Lungs may show diffuse, small, pale tan miliary nodules (1-5 mm), larger confluent nodules, or extensive fibrosis and honeycombing in advanced (Stage IV) disease
─ Hilar and mediastinal lymph nodes are often symmetrically enlarged and may appear fleshy or firm
─ Pleural involvement is uncommon but can occur (pleural effusion, pleural granulomas/plaques)
Micro ─
─ Hallmark: Well-formed, discrete, non-necrotizing epithelioid granulomas:
─ ─ Composed of tightly clustered epithelioid histiocytes (activated macrophages with abundant eosinophilic cytoplasm and indistinct cell borders), often surrounded by a rim of lymphocytes (predominantly CD4+ T-helper cells) and occasional plasma cells
─ ─ Multinucleated giant cells (Langhans type or foreign-body type) are frequently present within or at the periphery of granulomas
─ ─ Necrosis is typically absent or minimal and punctate (minor central fibrinoid necrosis); extensive caseous necrosis should raise strong suspicion for infection (e.g., tuberculosis)
─ Distribution: Granulomas characteristically follow a lymphangitic pathway: along bronchovascular bundles, interlobular septa, and in the visceral pleura (subpleural granulomas)
─ Inclusions within giant cells (not specific to sarcoidosis, can be seen in other granulomatous diseases):
─ ─ Schaumann bodies: Laminated, calcified concretions (basophilic)
─ ─ Asteroid bodies: Eosinophilic, stellate (star-shaped) intracytoplasmic structures
─ Progression and Fibrosis (Chronic/Fibrotic Sarcoidosis):
─ ─ Granulomas may resolve completely or undergo hyalinization (replacement by dense, acellular collagen)
─ ─ Progressive interstitial fibrosis can occur, leading to architectural distortion, traction bronchiectasis, and eventually honeycomb lung in advanced stages (Stage IV pulmonary sarcoidosis)
─ Other features: Granulomatous vasculitis (involvement of vessel walls by granulomas) can be seen; airway involvement with endobronchial granulomas can occur
Ancillary studies ─
─ Special stains for microorganisms (AFB for mycobacteria, GMS for fungi) are MANDATORY on all biopsies showing granulomas to exclude an infectious etiology – this is the most critical step
─ Polarized light microscopy to look for birefringent foreign material if foreign body granuloma is a consideration
─ Serum ACE levels, calcium levels, PFTs, BAL (lymphocytosis with increased CD4/CD8 ratio is supportive) contribute to the overall clinical picture but are not solely diagnostic from a pathology standpoint
DDx ─
─ Infectious granulomatous diseases:
─ ─ Tuberculosis (key differential; granulomas are often caseating, AFB stain positive)
─ ─ Fungal infections (e.g., histoplasmosis, coccidioidomycosis, blastomycosis, cryptococcosis; granulomas may be caseating or non-caseating, GMS/PAS positive for organisms)
─ Hypersensitivity Pneumonitis (granulomas are usually poorly formed, interstitial, and airway-centered; different clinical/exposure context)
─ Berylliosis (history of beryllium exposure; granulomas identical to sarcoid; requires specialized testing like beryllium lymphocyte proliferation test)
─ Granulomatosis with Polyangiitis (GPA) (granulomas are often necrotizing and associated with vasculitis; ANCA positivity)
─ Crohn's disease with pulmonary involvement (rare; history of Crohn's, may have non-necrotizing granulomas)
─ Foreign body granulomas (foreign material identifiable, often polarizable)
─ Lymphoma with granulomatous reaction (rare)
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Pneumoconioses - Core Group (Silicosis, Coal Worker's Pneumoconiosis, Asbestosis, Berylliosis)

A group of non-neoplastic lung diseases resulting from the inhalation and deposition of specific inorganic mineral or metallic dusts and the tissue's reaction to them, primarily in an occupational setting
Clinical ─
─ A detailed occupational and exposure history is paramount for diagnosis
─ Symptoms (e.g., dyspnea, cough) often develop insidiously after years of exposure, may progress even after exposure ceases
─ Asymptomatic individuals may show radiological changes
Macro ─
─ Variable depending on the specific dust and severity:
─ ─ Silicosis/CWP: Multiple small nodules, larger confluent masses (Progressive Massive Fibrosis - PMF), hilar lymphadenopathy; PMF masses are often black, rubbery
─ ─ Asbestosis: Diffuse interstitial fibrosis, particularly in lower lobes; pleural plaques (fibrous, often calcified thickenings on parietal pleura) are markers of exposure but not part of asbestosis (which is parenchymal fibrosis)
─ ─ Berylliosis: May show diffuse miliary nodularity or fibrosis, similar to sarcoidosis
Micro ─
─ Silicosis:
─ ─ Hallmark: Silicotic nodule – well-circumscribed, rounded nodule composed of concentrically arranged (whorled) hyalinized collagen fibers; often a relatively acellular center
─ ─ Periphery of nodules may show dust-laden macrophages and lymphocytes
─ ─ Silica particles (crystalline silicon dioxide) are weakly birefringent under polarized light, best seen in macrophages or less hyalinized areas; may be sparse in dense nodules
─ ─ Progressive Massive Fibrosis (PMF): Large, conglomerate, hyalinized masses, often with central ischemic necrosis or cavitation; entrapped dust and anthracotic pigment are common
─ Coal Worker's Pneumoconiosis (CWP):
─ ─ Coal macule: Accumulations of carbon-laden macrophages (coal dust macules) around respiratory bronchioles, associated with focal emphysema (centrilobular) and minimal stromal reaction/fibrosis
─ ─ Coal nodule (complicated CWP): Larger lesions where coal macules are admixed with a network of delicate collagenous fibrosis; may be palpable
─ ─ PMF: Similar to silicosis PMF, but masses are typically deeply pigmented black due to abundant coal dust; can also necrose and cavitate
─ ─ Caplan Syndrome: Rheumatoid nodules superimposed on CWP or silicosis in patients with rheumatoid arthritis
─ Asbestosis:
─ ─ Diffuse interstitial fibrosis, typically beginning in the peribronchiolar regions of the lower lobes and extending subpleurally; pattern can resemble Usual Interstitial Pneumonia (UIP) with temporal and spatial heterogeneity, fibroblastic foci, and eventual honeycombing in advanced cases
─ ─ Asbestos bodies: Characteristic finding; consist of a translucent core (asbestos fiber, usually amphibole) coated with iron and protein, appearing as golden-brown, beaded or fusiform, segmented structures; typically 20-50 µm long. (Ferruginous body is a more general term for any dust coated with iron/protein)
─ ─ Increased risk of lung carcinoma (especially in smokers) and malignant mesothelioma
─ Berylliosis (Chronic):
─ ─ Histologically indistinguishable from sarcoidosis or chronic hypersensitivity pneumonitis
─ ─ Characterized by well-formed, non-necrotizing epithelioid granulomas, often with associated lymphocytic infiltrates
─ ─ Granulomas may be found in interstitium, along lymphatics, or within lymph nodes
─ ─ Diagnosis requires history of beryllium exposure AND evidence of beryllium sensitization (e.g., positive beryllium lymphocyte proliferation test - BeLPT on blood or BAL fluid)
─ ─ Acute berylliosis (rare now) presents as a chemical pneumonitis/DAD
Ancillary studies ─
─ Polarized light microscopy: Essential to identify birefringent particles (e.g., silica - weakly birefringent; talc, some silicates - strongly birefringent). Asbestos fibers themselves are usually too small to see with light microscopy unless part of an asbestos body.
─ Iron stain (e.g., Prussian blue): Highlights the iron coating of asbestos bodies, making them more conspicuous
─ Special stains for microorganisms (GMS, AFB): Important, especially if PMF lesions cavitate (risk of superimposed infection like TB)
─ Analytical electron microscopy with energy-dispersive X-ray analysis (EDXA): Can identify the specific elemental composition of dust particles (primarily for research or medicolegal purposes, not routine diagnosis)
─ Beryllium Lymphocyte Proliferation Test (BeLPT): For diagnosing beryllium sensitization in suspected berylliosis
DDx ─
─ Silicosis/CWP: Other causes of nodular lung disease, infections (TB, fungi in PMF cavities), sarcoidosis (if granulomas present with CWP/silicosis), metastatic carcinoma
─ Asbestosis: Idiopathic Pulmonary Fibrosis (IPF)/UIP (asbestosis often has a UIP pattern; asbestos bodies and exposure history are key), other fibrosing ILDs
─ Berylliosis: Sarcoidosis (key differential, histologically identical), hypersensitivity pneumonitis, infectious granulomatous diseases (TB, fungi – must be excluded by stains/cultures)
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Pulmonary Amyloidosis

A disorder characterized by the extracellular deposition of abnormal, insoluble fibrillar protein (amyloid) in the lung parenchyma, airways, or blood vessels, which can be localized or part of a systemic amyloidosis
Clinical ─
─ Presentation is highly variable, depending on the pattern and extent of deposition:
─ ─ Asymptomatic (incidental finding on imaging or autopsy)
─ ─ Symptoms: Dyspnea, cough, hemoptysis, wheezing (if airway involvement), chest pain
─ Can be primary (AL amyloidosis - due to monoclonal plasma cell proliferation) or secondary (AA amyloidosis - due to chronic inflammation/infection), or related to hereditary forms (e.g., ATTR - transthyretin)
─ Patterns of pulmonary involvement:
─ ─ Nodular parenchymal amyloidosis: Most common localized form; solitary or multiple nodules/masses
─ ─ Diffuse alveolar septal amyloidosis: Widespread infiltration of alveolar walls; often associated with systemic amyloidosis (AL or ATTR) and carries a poorer prognosis
─ ─ Tracheobronchial amyloidosis: Deposits in the walls of the trachea and bronchi, leading to plaques, stenosis, or submucosal masses; can cause obstruction
Macro ─
─ Nodular form: Firm, waxy, gray-tan nodules or masses, may show calcification or ossification
─ Diffuse form: Lungs may be diffusely firm and rubbery, with a waxy appearance on cut section
─ Tracheobronchial form: Mucosal plaques, thickening, or stenosis of airways
Micro ─
─ Deposition of amorphous, eosinophilic, hyaline, acellular material (amyloid) in various locations:
─ ─ Nodular pattern: Large, confluent deposits of amyloid forming nodules, often surrounded by a lymphoplasmacytic infiltrate and foreign body giant cell reaction; calcification, ossification, and even bone marrow elements can occur within chronic nodules
─ ─ Diffuse alveolar septal pattern: Amyloid deposited within alveolar walls and around capillaries, causing thickening of the septa and narrowing of capillary lumens
─ ─ Tracheobronchial pattern: Amyloid deposits in the submucosa and surrounding cartilage of the trachea and bronchi; may extend into peribronchial tissue
─ ─ Vascular involvement is common in all patterns, with amyloid deposited in the walls of small arteries, arterioles, and veins
─ Amyloid characteristically shows apple-green birefringence under polarized light after staining with Congo red (most specific diagnostic feature)
─ May exhibit faint pink coloration with PAS stain
─ Associated inflammatory infiltrate (lymphocytes, plasma cells, macrophages, giant cells) can be variable, often more prominent in nodular AL type
Ancillary studies ─
─ Congo red stain: Essential for diagnosis; examined under polarized light for apple-green birefringence
─ IHC or mass spectrometry-based proteomics (on formalin-fixed paraffin-embedded tissue): Crucial for typing the amyloid protein (e.g., Lambda or Kappa light chains for AL, Serum Amyloid A for AA, Transthyretin for ATTR, Beta-2 microglobulin for dialysis-related). Typing has significant prognostic and therapeutic implications.
─ Thioflavin T or S staining (fluorescent stains for amyloid) can also be used but Congo red is standard
DDx ─
─ Hyaline sclerosis/fibrosis or other hyaline-like deposits (e.g., colloid, fibrin) – these are Congo red negative
─ Light Chain Deposition Disease (LCDD) (deposition of monoclonal light chains, but typically granular and non-fibrillar, Congo red negative or only weakly and atypically positive; often involves basement membranes)
─ Necrotic debris or inspissated secretions (can appear eosinophilic and amorphous)
─ Pulmonary Alveolar Proteinosis (intra-alveolar PAS-positive material, but different morphology and Congo red negative)
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Graft-versus-Host Disease (GVHD) of the Lung (Overview)

A significant complication following allogeneic hematopoietic stem cell transplantation (HSCT), where donor T-lymphocytes recognize host tissues (including lung) as foreign, leading to immune-mediated injury; can also occur less commonly after solid organ transplantation (e.g., lung transplant)
Clinical ─
─ Pulmonary complications are common after HSCT, and GVHD is a major non-infectious cause
─ Presentation varies with acute vs. chronic GVHD:
─ ─ Acute GVHD: Less commonly involves the lungs as a primary target early post-HSCT, but pulmonary symptoms can occur with systemic acute GVHD affecting other organs (skin, liver, gut); may manifest as an idiopathic pneumonia syndrome (IPS) like picture
─ ─ Chronic GVHD: More frequent and well-defined pulmonary manifestations, typically occurring >100 days post-HSCT or as a progression from acute GVHD
─ ─ ─ Bronchiolitis Obliterans Syndrome (BOS) is the most characteristic pulmonary manifestation of chronic GVHD, leading to progressive airflow obstruction
─ Symptoms: Dyspnea, non-productive cough, wheezing, decline in pulmonary function tests (typically obstructive pattern in BOS; restrictive or mixed patterns in other manifestations)
Macro ─
─ Often nonspecific; lungs may appear grossly normal, or show changes of airway thickening, fibrosis, or patchy consolidation depending on the specific manifestation and severity
Micro ─
─ Histologic manifestations of pulmonary GVHD can be varied and may overlap with other transplant-related complications:
─ Bronchiolitis Obliterans (BO) / Constrictive Bronchiolitis: The hallmark of chronic pulmonary GVHD (leading to BOS).
─ ─ Characterized by lymphocytic inflammation in and around small airways (membranous and respiratory bronchioles), often with epithelial injury/necrosis, followed by concentric submucosal and peribronchiolar fibrosis leading to luminal narrowing or complete obliteration of small airways
─ ─ May see "lymphocytic bronchiolitis" as an earlier or associated finding
─ Other patterns that can be associated with GVHD (though often multifactorial in the HSCT setting):
─ ─ Lymphocytic Infiltrates: Perivascular, peribronchial, or interstitial infiltrates of lymphocytes (predominantly T-cells)
─ ─ Organizing Pneumonia (OP) pattern
─ ─ Diffuse Alveolar Damage (DAD) (can be part of an Idiopathic Pneumonia Syndrome - IPS, where GVHD may be one contributing factor)
─ ─ Interstitial Pneumonia patterns (e.g., NSIP-like)
─ Diagnosis of pulmonary GVHD on biopsy is often challenging due to:
─ ─ Patchy nature of lesions (sampling error, especially with transbronchial biopsies)
─ ─ Concurrent opportunistic infections, drug toxicity (e.g., from conditioning regimens or immunosuppressants), or other transplant-related complications (e.g., engraftment syndrome, IPS) which can have similar histologic features
Ancillary studies ─
─ Lung biopsy findings must be interpreted in the context of the patient's HSCT history, clinical presentation, PFTs, and imaging
─ Special stains for microorganisms (GMS, AFB, Gram) and viral IHC/PCR are CRITICAL on all biopsies from HSCT recipients to rule out infection, which is a common and serious complication
─ IHC may help characterize lymphocytic infiltrates (e.g., CD3, CD4, CD8, CD20) but is usually not specific for GVHD diagnosis
DDx ─
─ Infections (viral – especially CMV, adenovirus; fungal – Aspergillus, Pneumocystis; bacterial) – MOST IMPORTANT
─ Drug toxicity (e.g., from conditioning regimens like busulfan, cyclophosphamide; immunosuppressants like cyclosporine, tacrolimus, sirolimus; antibiotics)
─ Idiopathic Pneumonia Syndrome (IPS) (a broader term for diffuse lung injury post-HSCT, often multifactorial, can include DAD, OP, where GVHD is one potential mechanism)
─ Aspiration pneumonia
─ Pulmonary edema / fluid overload
─ Diffuse alveolar hemorrhage
─ Engraftment syndrome
─ Recurrence of underlying hematologic malignancy in the lung (rare)
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IgG4-Related Disease involving the Lung

A fibroinflammatory condition that can affect multiple organs, including the lungs, characterized by a dense lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells, storiform fibrosis, obliterative phlebitis, and often elevated serum IgG4 levels
Clinical ─
─ Pulmonary involvement can manifest as solitary or multiple nodules/masses, diffuse infiltrates, ground-glass opacities, thickening of bronchovascular bundles or interlobular septa, or pleural lesions
─ Symptoms may include cough, dyspnea, chest pain, or may be asymptomatic and detected incidentally
─ Often affects middle-aged to older males; may have a history of other organ involvement by IgG4-RD (e.g., autoimmune pancreatitis, sialadenitis, retroperitoneal fibrosis)
─ Generally responsive to corticosteroid therapy, though relapse can occur
Macro ─
─ Well-circumscribed yellowish-white nodules or masses (can mimic malignancy)
─ Diffuse thickening or consolidation of lung parenchyma
─ Pleural thickening or effusion may be present
Micro ─
─ Key histologic features (not all may be present in every biopsy):
─ Dense lymphoplasmacytic infiltrate: Composed of lymphocytes, numerous plasma cells, and often eosinophils
─ Increased IgG4-positive plasma cells:
─ ─ An absolute increase in the number of IgG4+ plasma cells per high-power field (e.g., often >50/hpf, though thresholds vary by organ and consensus)
─ ─ An increased ratio of IgG4+ to IgG+ plasma cells (typically >40%)
─ Storiform fibrosis: Characteristic "cartwheel" or irregularly whorled pattern of fibrosis, with spindle cells (fibroblasts/myofibroblasts) arranged in a storiform or "patternless" pattern within a collagenous stroma
─ Obliterative phlebitis/venulitis: Inflammation and obliteration of the lumens of small to medium-sized veins by the lymphoplasmacytic infiltrate; arteries may also be involved (obliterative arteritis) but less commonly
─ Mild to moderate tissue eosinophilia is common
─ Other features: Germinal centers may be present within the lymphoid infiltrate; alveolar pneumocytes may show reactive hyperplasia
─ Lesions can be centered on airways, vessels, or form tumefactive masses
Ancillary studies ─
─ IHC for IgG and IgG4: Essential to identify plasma cells and calculate the number of IgG4+ plasma cells per high-power field and the IgG4+/IgG+ plasma cell ratio
─ Serum IgG4 levels: Often elevated, but normal levels do not exclude the diagnosis, and elevated levels are not entirely specific
─ Special stains for microorganisms (GMS, AFB, Gram) to rule out infection
─ Congo red stain to rule out amyloidosis if extensive hyalinization is present
DDx ─
─ Inflammatory Myofibroblastic Tumor (IMT) (can have prominent plasma cells and fibrosis; IMT is often ALK-positive, IgG4 staining usually not as prominent or diffuse as in IgG4-RD)
─ Lymphoma, especially MALT lymphoma or lymphoplasmacytic lymphoma (lymphoma is monoclonal; IgG4-RD shows polyclonal plasma cells, though reactive plasmacytosis can be florid)
─ Plasma cell granuloma (older term, many cases likely represented IgG4-RD or IMT)
─ Vasculitis (e.g., Granulomatosis with Polyangiitis - GPA, Eosinophilic Granulomatosis with Polyangiitis - EGPA) (GPA has necrotizing granulomas and capillaritis; EGPA has prominent eosinophils and asthma/allergic history, often ANCA positive)
─ Sarcoidosis (well-formed non-necrotizing granulomas are the hallmark, not storiform fibrosis or obliterative phlebitis)
─ Granulomatous infections (e.g., TB, fungal – special stains positive)
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Radiation Pneumonitis and Fibrosis

Lung damage resulting from exposure to ionizing radiation, typically as a complication of radiotherapy for thoracic (lung, esophagus, mediastinum), breast, or head and neck malignancies, evolving from an acute inflammatory phase (pneumonitis) to a chronic fibrotic phase
Clinical ─
─ Acute Radiation Pneumonitis:
─ ─ Onset usually 1-6 months following completion of radiotherapy (can be earlier with higher doses or concurrent chemotherapy)
─ ─ Symptoms: Dry cough, dyspnea, low-grade fever, chest pain or discomfort, fatigue; severity depends on dose, volume of lung irradiated, and individual factors
─ ─ Symptoms often correlate with the irradiated lung volume (radiation port)
─ Chronic Radiation Fibrosis:
─ ─ Develops gradually months to years after radiation, may be preceded by acute pneumonitis or arise insidiously
─ ─ Symptoms: Progressive dyspnea, chronic cough; fibrosis is generally irreversible and can lead to chronic respiratory insufficiency
Macro ─
─ Acute Pneumonitis: Affected lung areas (corresponding to radiation field) may be congested, edematous, and consolidated
─ Chronic Fibrosis: Lung tissue in the irradiated field becomes firm, contracted, and fibrotic, often with sharp demarcation from adjacent non-irradiated lung; pleural thickening and adhesions are common; volume loss in the affected region
Micro ─
─ Acute Radiation Pneumonitis (Exudative/Organizing DAD-like Phase - typically weeks to months post-RT):
─ ─ Diffuse Alveolar Damage (DAD) pattern is common: Alveolar edema, fibrin deposition, formation of hyaline membranes lining alveoli
─ ─ Atypical reactive type II pneumocytes: Enlarged cells with large, hyperchromatic, pleomorphic, or smudgy nuclei and prominent nucleoli (radiation atypia); may be multinucleated
─ ─ Endothelial cell injury and swelling, capillary congestion, and sometimes microthrombi
─ ─ Foamy (lipid-laden) macrophages in alveolar spaces
─ ─ Interstitial inflammation (lymphocytes, plasma cells, macrophages)
─ ─ Organizing pneumonia (OP) pattern (intra-alveolar fibroblastic plugs) can also be a prominent feature or occur during resolution
─ Chronic Radiation Fibrosis (Late/Fibrotic Phase - typically >6 months post-RT, can be progressive):
─ ─ Dense interstitial fibrosis with broad bands of compact collagen deposition, often sharply demarcated if corresponding to a radiation port
─ ─ Architectural distortion, including traction bronchiectasis and bronchiolectasis, and obliteration of alveolar spaces
─ ─ Persistent atypical fibroblasts and reactive pneumocytes with radiation atypia may be seen within fibrotic areas
─ ─ Vascular changes: Intimal fibrosis, medial hypertrophy, and hyalinization of vessel walls (endarteritis obliterans)
─ ─ Pleural fibrosis and thickening are common
Ancillary studies ─
─ Clinical history of radiation therapy (dose, field, timing) is paramount for diagnosis
─ Special stains for microorganisms (GMS, AFB, Gram) are essential to rule out infection, especially in immunocompromised cancer patients
─ Trichrome stain highlights fibrosis
DDx ─
─ Infection (bacterial, viral, fungal, Pneumocystis – especially in patients who are also immunocompromised from cancer or chemotherapy)
─ Diffuse Alveolar Damage (DAD) from other causes (e.g., sepsis, shock, drug toxicity – if clinical context is unclear)
─ Drug-induced lung injury (many cancer patients receive concurrent or sequential chemotherapy known to cause lung toxicity, e.g., bleomycin, methotrexate, taxanes)
─ Recurrent or metastatic tumor infiltration in the lung (tumor cells would be present)
─ Other interstitial lung diseases (e.g., IPF, NSIP – if onset is delayed and not clearly port-related, though radiation can also trigger or exacerbate underlying ILD)
─ Lymphangitic carcinomatosis (tumor in lymphatics, different pattern)
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Smoking-Related Lung Diseases

Emphysema

A condition of the lung characterized by abnormal, permanent enlargement of airspaces distal to the terminal bronchiole (i.e., within the acinus), accompanied by destruction of their walls and without obvious or significant fibrosis (though some inflammation and remodeling fibrosis of small airways may be present)
Clinical ─
─ Primarily associated with cigarette smoking; genetic predisposition (e.g., alpha-1 antitrypsin deficiency) is a less common cause
─ Progressive dyspnea, initially on exertion, is the hallmark symptom; cough (often attributed to chronic bronchitis), wheezing, and pursed-lip breathing may occur
─ Barrel-shaped chest can develop due to hyperinflation
─ Pulmonary function tests show airflow limitation (reduced FEV1/FVC ratio) that is not fully reversible
Macro ─
─ Lungs are typically voluminous, pale, and feel light and hyperinflated; they may not collapse readily when the chest is opened
─ Bullae (airspaces >1 cm in diameter in distended state) and blebs (smaller air collections within the layers of the visceral pleura) may be present, especially in paraseptal and advanced emphysema
─ Cut surface shows enlarged airspaces; specific patterns (centriacinar, panacinar) may be discernible depending on the type and severity
Micro ─
─ Essential feature: Destruction of alveolar walls leading to permanent enlargement of airspaces distal to the terminal bronchiole
─ Loss of alveolar attachments to small airways, contributing to expiratory airway collapse and airflow limitation
─ Minimal to mild chronic inflammation (lymphocytes, macrophages, occasional neutrophils) in remaining alveolar septa and around small airways (respiratory bronchiolitis is often a precursor or coexistent finding in smokers)
─ Vascular abnormalities: Reduction in the alveolar capillary bed, intimal thickening and muscular hypertrophy of pulmonary arterioles (can contribute to pulmonary hypertension in advanced disease)
─ Types of emphysema based on the part of the acinus predominantly affected:
─ Centriacinar (Centrilobular) Emphysema:
─ ─ Most common type, strongly associated with cigarette smoking
─ ─ Dilatation and destruction begin in the respiratory bronchioles (center of the acinus), with relative sparing of distal alveoli initially; eventually, the entire acinus may become involved in severe cases
─ ─ More severe and frequent in the upper lobes and apical segments
─ ─ Anthracotic pigment is often prominent around the involved airways
─ Panacinar (Panlobular) Emphysema:
─ ─ The entire acinus, from respiratory bronchiole to the terminal alveoli, is more or less uniformly dilated and destroyed
─ ─ More common and severe in the lower lobes and anterior margins of the lungs
─ ─ Classically associated with alpha-1 antitrypsin deficiency, but can also be seen in elderly individuals and smokers (often mixed with centriacinar)
─ Paraseptal (Distal Acinar) Emphysema:
─ ─ Preferential involvement of the distal part of the acinus (alveolar ducts and sacs) adjacent to the pleura and along interlobular septa
─ ─ Often associated with the formation of subpleural bullae or blebs, which can lead to spontaneous pneumothorax, especially in young adults
─ ─ May occur alone or in conjunction with centriacinar emphysema
─ Irregular (Paracicatricial) Emphysema:
─ ─ Irregular airspace enlargement and destruction adjacent to areas of scarring from previous inflammation or injury (e.g., old granulomas, infarcts, fibrosis)
─ ─ Usually localized and clinically less significant unless extensive
Ancillary studies ─
─ Histologic examination confirms airspace enlargement and wall destruction; morphometry can quantify these changes but is not used in routine diagnosis
─ Elastic stains can highlight loss and fragmentation of elastic fibers in alveolar walls
─ Imaging (especially high-resolution CT - HRCT) is more sensitive for the in vivo diagnosis, typing, and quantification of emphysema than plain radiography or histology on limited samples
DDx ─
─ Cystic lung diseases (e.g., Lymphangioleiomyomatosis - LAM, Pulmonary Langerhans Cell Histiocytosis - PLCH, Birt-Hogg-Dubé syndrome – these have distinct cysts with characteristic wall features and cellular infiltrates, not just simple airspace enlargement with wall destruction)
─ Bronchiectasis (permanent dilation of bronchi and bronchioles, not primarily alveolar destruction, though can coexist)
─ Congenital lobar overinflation (hyperinflation of a lobe without significant alveolar wall destruction, usually in infants)
─ Interstitial emphysema (air dissecting into the interstitium, often acute)
─ Simple airspace enlargement of aging (senile lung) (some airspace dilation, but generally without significant alveolar wall destruction characteristic of emphysema)
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Chronic Bronchitis and Small Airways Disease

Chronic bronchitis is a clinical diagnosis of persistent cough with sputum production for at least 3 months in at least 2 consecutive years, pathologically associated with mucous gland hyperplasia in large airways; Small Airways Disease (Chronic Bronchiolitis) involves inflammation, fibrosis, and remodeling of bronchioles (<2mm), contributing significantly to airflow obstruction in COPD
Clinical ─
─ Often coexist and are major components of Chronic Obstructive Pulmonary Disease (COPD), primarily caused by cigarette smoking
─ Symptoms: Chronic productive cough (hallmark of chronic bronchitis), dyspnea (especially with small airways disease and emphysema), wheezing, frequent respiratory infections
─ Airflow limitation on pulmonary function tests (reduced FEV1/FVC ratio) is characteristic of COPD
Macro ─
─ Large airways (trachea, bronchi) in chronic bronchitis may show mucosal hyperemia, edema, and an excess of mucus on the surface; bronchial walls may appear thickened
─ Lungs may be hyperinflated if emphysema is also present (common in COPD)
─ Small airway changes are generally not grossly apparent but contribute to air trapping
Micro ─
─ Chronic Bronchitis (Large Airways - Bronchi):
─ ─ Hyperplasia and hypertrophy of submucosal mucous glands: The most characteristic feature. Quantified by the Reid Index (ratio of mucous gland layer thickness to the thickness of the bronchial wall between the epithelial basement membrane and the cartilage perichondrium); a Reid Index >0.4 is considered abnormal (normal is <0.4)
─ ─ Goblet cell hyperplasia and metaplasia in the surface epithelium of bronchi
─ ─ Squamous metaplasia of the respiratory epithelium may occur with chronic irritation
─ ─ Chronic inflammation of the bronchial wall (lymphocytes, plasma cells, macrophages, sometimes neutrophils during exacerbations)
─ ─ Smooth muscle hypertrophy and hyperplasia in bronchial walls
─ ─ Thickening of the epithelial basement membrane may be seen
─ Small Airways Disease (Bronchioles <2 mm diameter):
─ ─ Goblet cell metaplasia (normally few or absent in distal/terminal bronchioles) leading to increased mucus production
─ ─ Mucous plugging of bronchiolar lumens
─ ─ Chronic inflammation of the bronchiolar wall (lymphocytes, macrophages, neutrophils)
─ ─ Peribronchiolar fibrosis (fibrous tissue deposition around the airway)
─ ─ Smooth muscle hypertrophy and hyperplasia in bronchiolar walls
─ ─ Luminal narrowing, distortion, and potential obliteration (constrictive bronchiolitis in severe cases)
─ ─ Respiratory bronchiolitis (accumulation of pigmented macrophages in respiratory bronchioles and adjacent alveoli) is often present in smokers and can be a precursor or component
Ancillary studies ─
─ Pathologic diagnosis is largely based on H&E morphology in the appropriate clinical context; ancillary studies are generally not required for these specific diagnoses
─ PAS (Periodic Acid-Schiff) and Alcian blue stains can highlight mucus and goblet cells
DDx ─
─ Asthma (distinguished by prominent eosinophilic inflammation, more pronounced basement membrane thickening, smooth muscle hypertrophy as a primary feature, and largely reversible airflow obstruction)
─ Bronchiectasis (permanent abnormal dilation and destruction of bronchial walls, often with chronic infection)
─ Cystic fibrosis (genetic disorder leading to thick mucus, chronic infection, bronchiectasis, and pancreatic insufficiency)
─ Other causes of chronic bronchiolitis (e.g., post-infectious, connective tissue disease-associated, inhalational injury from other toxins)
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Pulmonary Langerhans Cell Histiocytosis (PLCH)

A rare, smoking-related interstitial lung disease characterized by the clonal proliferation and accumulation of Langerhans cells within the lungs, forming characteristic nodular and cystic lesions, primarily affecting young adult cigarette smokers
Clinical ─
─ Almost exclusively occurs in current or former cigarette smokers (90-100% of adult cases), typically young adults (20-40 years)
─ Symptoms can be variable: Non-productive cough, dyspnea, chest pain, fatigue, weight loss, fever; up to 25% may be asymptomatic
─ Spontaneous pneumothorax is a common presentation or complication (in ~10-25% of patients)
─ Extrapulmonary involvement (e.g., bone lesions, diabetes insipidus from pituitary involvement, skin rash) is rare in adult PLCH but defines disseminated Langerhans Cell Histiocytosis
─ Pulmonary hypertension can develop in advanced disease
─ Smoking cessation is crucial and may lead to regression or stabilization in some cases
Macro ─
─ Early lesions appear as ill-defined, small (1-5 mm) grayish-white nodules, often with a stellate configuration
─ Later lesions evolve into irregular, bizarrely shaped cystic airspaces, which may be thin or thick-walled
─ Lesions are typically bilateral and more prominent in the upper and mid lung zones, with relative sparing of the lung bases and costophrenic angles
─ Fibrosis may be present around chronic lesions and cysts
Micro ─
─ Cellular (early) lesions: Characterized by poorly defined nodules or interstitial infiltrates composed of Langerhans cells admixed with a variable number of eosinophils (often prominent), lymphocytes, plasma cells, macrophages, and neutrophils
─ ─ Langerhans cells: The diagnostic cells; relatively large with abundant, often eosinophilic cytoplasm, indistinct cell borders, and vesicular nuclei that are characteristically grooved, indented, folded, or twisted ("coffee-bean" or convoluted appearance)
─ Fibrotic (late/chronic) lesions: Stellate (star-shaped) scars representing regressed cellular lesions; Langerhans cells may be sparse or absent in these fibrotic areas, but eosinophils can persist
─ Cyst formation: A key feature; the cellular lesions often undergo central cavitation, leading to the formation of irregular, often bizarrely shaped cysts lined by reactive pneumocytes or bronchiolar epithelium. Adjacent cysts may coalesce.
─ Bronchiolocentric distribution: Lesions are typically centered on small airways (terminal and respiratory bronchioles), with destructive changes in the bronchiolar walls
─ Vascular involvement by the cellular infiltrate can occur, sometimes leading to luminal narrowing
─ Interstitial fibrosis can become prominent around chronic lesions and cysts
Ancillary studies ─
─ IHC is essential for confirming the presence of Langerhans cells:
─ ─ CD1a: Strong membranous and cytoplasmic staining (highly sensitive and specific)
─ ─ S100 protein: Nuclear and cytoplasmic staining (sensitive but less specific than CD1a or Langerin)
─ ─ Langerin (CD207): Membranous and cytoplasmic staining (highly specific, corresponds to Birbeck granules)
─ Electron Microscopy (EM): Demonstration of Birbeck granules (intracytoplasmic, pentalaminar, "tennis-racket" shaped organelles) in the Langerhans cells is pathognomonic but rarely necessary for diagnosis given the specificity of IHC markers like CD1a and Langerin
─ Molecular: BRAF V600E mutations are found in approximately 40-50% of PLCH cases, suggesting a neoplastic component to the proliferation
DDx ─
─ Eosinophilic Pneumonia (diffuse eosinophilic infiltrates without the characteristic Langerhans cells or nodular/cystic evolution of PLCH)
─ Hypersensitivity Pneumonitis (lymphocytic interstitial infiltrates, cellular bronchiolitis, often poorly formed granulomas; lacks Langerhans cells)
─ Other cystic lung diseases:
─ ─ Lymphangioleiomyomatosis (LAM) (smooth muscle proliferation around cysts, HMB-45 positive, almost exclusively in women)
─ ─ Birt-Hogg-Dubé syndrome (cysts often basilar, associated with skin fibrofolliculomas and renal tumors)
─ ─ Emphysema (simple airspace enlargement with wall destruction, lacks cellular infiltrates or specific cyst wall features of PLCH)
─ Vasculitis (if vascular involvement is prominent in PLCH, but lacks systemic features or ANCA usually)
─ Infections causing cavitary nodules (e.g., fungal, mycobacterial – special stains negative in PLCH)
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Granulomatous Diseases (Non-infectious, Non-Sarcoid/HP)

Granulomatosis with Polyangiitis (GPA)

A systemic necrotizing vasculitis of unknown etiology characterized by the classic triad of: 1) necrotizing granulomatous inflammation of the upper respiratory tract (nose, sinuses, ears) and/or lower respiratory tract (lungs); 2) necrotizing vasculitis affecting small to medium-sized vessels (capillaries, venules, arterioles, arteries); and 3) glomerulonephritis (typically pauci-immune necrotizing and crescentic)
Clinical ─
─ Highly variable presentation, can affect any organ system; formerly known as Wegener's Granulomatosis
─ Upper airway symptoms: Sinusitis, nasal crusting/ulceration, epistaxis, otitis media, hearing loss, saddle-nose deformity
─ Lower airway (pulmonary) symptoms: Cough, dyspnea, hemoptysis (can be life-threatening from diffuse alveolar hemorrhage), chest pain, pleurisy
─ Renal involvement: Hematuria, proteinuria, rapidly progressive glomerulonephritis leading to renal failure if untreated
─ Constitutional symptoms: Fever, malaise, weight loss, arthralgias are common
─ Skin (purpura, ulcers), eyes (scleritis, uveitis), nervous system (mononeuritis multiplex) involvement can occur
─ Strongly associated with anti-neutrophil cytoplasmic antibodies (ANCA), specifically PR3-ANCA (proteinase 3-ANCA, also known as c-ANCA or cytoplasmic ANCA pattern) in ~80-95% of patients with active systemic disease
Macro ─
─ Lungs may show solitary or multiple nodules (often bilateral), which frequently cavitate; lesions can range from small (<1 cm) to large masses (>10 cm)
─ Diffuse pulmonary infiltrates or areas of consolidation due to hemorrhage or pneumonia can occur
─ Tracheal or bronchial stenosis from granulomatous inflammation may be seen
Micro ─
─ Key histologic features (not all may be present in every biopsy, especially small transbronchial biopsies):
─ Necrotizing granulomatous inflammation:
─ ─ Granulomas are often characterized by central "geographic" or "serpiginous" areas of basophilic necrosis (often containing neutrophils and eosinophils, referred to as "dirty necrosis" or "microabscesses")
─ ─ Surrounding the necrosis are palisading histiocytes, lymphocytes, plasma cells, multinucleated giant cells (Langhans or foreign body type), and often eosinophils
─ ─ Granulomas may not always be well-formed or classically epithelioid; can be more diffuse and inflammatory
─ Vasculitis: Necrotizing vasculitis affecting small to medium-sized arteries, arterioles, venules, and capillaries (capillaritis).
─ ─ Characterized by fibrinoid necrosis of vessel walls with a transmural inflammatory infiltrate (neutrophils, lymphocytes, histiocytes, eosinophils)
─ ─ Granulomatous inflammation may directly involve and destroy vessel walls
─ ─ Elastic stains can help highlight vessel destruction
─ Diffuse Alveolar Hemorrhage (DAH) with Capillaritis: Manifests as intra-alveolar hemorrhage, numerous hemosiderin-laden macrophages, neutrophilic infiltration of alveolar septa (capillaritis), and sometimes fibrin thrombi in capillaries
─ Other patterns: Organizing pneumonia, interstitial fibrosis (in chronic/treated cases), prominent eosinophilic infiltrates (can sometimes overlap with EGPA features if eosinophils are very numerous, but typically lacks asthma history and has PR3-ANCA)
Ancillary studies ─
─ Special stains for microorganisms (GMS, AFB, Gram) are MANDATORY on all biopsies with necrotizing granulomas to exclude infection, which can closely mimic GPA histologically
─ Elastic stains (e.g., Verhoeff-Van Gieson - VVG) can aid in identifying vasculitis by highlighting destruction of vessel walls
─ Serological testing for ANCA (PR3-ANCA/c-ANCA) is highly supportive of the diagnosis in the appropriate clinicopathologic context, but ANCA negativity does not exclude GPA, especially in limited forms
DDx ─
─ Infections causing necrotizing granulomas:
─ ─ Tuberculosis (caseous necrosis, AFB positive)
─ ─ Fungal infections (e.g., aspergillosis, mucormycosis, endemic mycoses – GMS/PAS positive)
─ ─ Nocardiosis or other bacterial infections causing abscesses/granulomas
─ Other ANCA-associated vasculitides:
─ ─ Microscopic Polyangiitis (MPA) (necrotizing vasculitis, often capillaritis and glomerulonephritis; granulomatous inflammation is typically absent or minimal; usually MPO-ANCA/p-ANCA positive)
─ ─ Eosinophilic Granulomatosis with Polyangiitis (EGPA/Churg-Strauss) (history of asthma/allergy, prominent peripheral and tissue eosinophilia, necrotizing vasculitis, granulomas often eosinophil-rich; usually MPO-ANCA positive)
─ Lymphomatoid Granulomatosis (EBV-driven B-cell lymphoproliferative disorder with angiocentric and angiodestructive infiltrates of atypical lymphoid cells)
─ Necrotizing pneumonia due to other causes (e.g., aspiration, bacterial)
─ Squamous cell carcinoma or other neoplasms with central necrosis/cavitation
─ Sarcoidosis (granulomas are typically non-necrotizing and well-formed)
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Eosinophilic Granulomatosis with Polyangiitis (EGPA)

A systemic small to medium-sized vessel necrotizing vasculitis characterized by a triad of asthma, prominent peripheral blood and tissue eosinophilia, and extravascular necrotizing eosinophilic granulomas; formerly known as Churg-Strauss Syndrome
Clinical ─
─ Typically evolves through three phases, which may overlap:
─ ─ 1. Prodromal/Allergic Phase: Late-onset asthma, allergic rhinitis, sinusitis, nasal polyposis
─ ─ 2. Eosinophilic Phase: Marked peripheral blood eosinophilia (>10% or >1500/µL) and eosinophilic infiltration of organs (e.g., lungs – Löffler-like eosinophilic pneumonia, eosinophilic gastroenteritis, myocarditis)
─ ─ 3. Vasculitic Phase: Systemic necrotizing vasculitis affecting various organs, most commonly skin (purpura, nodules), peripheral nerves (mononeuritis multiplex), heart (myocarditis, pericarditis, coronary arteritis), gastrointestinal tract, and less frequently kidneys (glomerulonephritis is usually milder than in GPA or MPA)
─ MPO-ANCA (myeloperoxidase-ANCA, p-ANCA pattern) is positive in approximately 40-60% of patients, often associated more with vasculitic manifestations; ANCA-negative patients may have more prominent eosinophilic/cardiac involvement
Macro ─
─ Lungs may show nodules (which can cavitate), areas of consolidation (consistent with eosinophilic pneumonia), or evidence of pulmonary hemorrhage
─ Pleural effusions (often eosinophilic) can occur
Micro ─
─ Key histologic features:
─ Eosinophil-rich inflammation: Dense infiltration of tissues by eosinophils is a hallmark. This includes involvement of vessel walls, perivascular areas, interstitium, and granulomas
─ Necrotizing vasculitis: Affects small to medium-sized arteries and veins; characterized by fibrinoid necrosis of the vessel wall and a transmural inflammatory infiltrate rich in eosinophils
─ Extravascular granulomas: Often prominent, typically necrotizing, and characteristically contain abundant eosinophils and eosinophilic debris (sometimes forming "flame figures" – central eosinophilic material surrounded by palisading histiocytes and giant cells)
─ Eosinophilic pneumonia pattern: Alveolar spaces filled with eosinophils, macrophages, and fibrin; interstitial eosinophilic infiltrates
─ Other findings may include organizing pneumonia or diffuse alveolar damage in some cases
Ancillary studies ─
─ Peripheral blood eosinophilia is a key laboratory finding
─ MPO-ANCA/p-ANCA serology (positive in a subset)
─ Special stains for microorganisms (GMS, AFB, Gram) are important to exclude infectious causes of eosinophilia and granulomas (especially parasitic or fungal infections)
─ Elastic stains can help highlight vessel wall destruction in vasculitis
DDx ─
─ Granulomatosis with Polyangiitis (GPA) (less prominent eosinophilia, typically PR3-ANCA positive, different character of granulomas and necrosis)
─ Microscopic Polyangiitis (MPA) (necrotizing vasculitis without granulomas, asthma, or significant eosinophilia; usually MPO-ANCA positive)
─ Idiopathic Hypereosinophilic Syndrome (HES) (persistent peripheral eosinophilia and end-organ damage due to eosinophils, but typically lacks vasculitis or well-formed granulomas of EGPA)
─ Allergic Bronchopulmonary Aspergillosis (ABPA) (asthma, eosinophilia, mucoid impaction, Aspergillus sensitization, but vasculitis and systemic features of EGPA are absent)
─ Parasitic infections causing pulmonary eosinophilia and granulomas (e.g., strongyloidiasis, ascariasis, paragonimiasis – requires travel/exposure history and specific tests)
─ Drug reactions with eosinophilia and systemic symptoms (DRESS syndrome) or other drug-induced eosinophilic pneumonias (medication history is key)
─ Chronic Eosinophilic Pneumonia (CEP) (typically lacks vasculitis and systemic features of EGPA)
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Foreign Body Granulomas / Aspiration Pneumonia (Granulomatous aspects)

Foreign body granulomas are localized tissue reactions to poorly digestible exogenous or endogenous particulate matter, leading to granuloma formation; Aspiration pneumonia results from inhalation of oropharyngeal or gastric contents, potentially causing chemical pneumonitis, bacterial infection, and/or a chronic granulomatous response to aspirated particulates
Clinical ─
─ Foreign Body Granulomas (non-aspirated):
─ ─ May be asymptomatic or cause symptoms depending on location, size, and nature of the foreign material (e.g., cough if airway, nodule on imaging)
─ ─ History of exposure is key: e.g., talc (IV drug use, pleurodesis), suture material (post-surgical), silicone (cosmetic procedures), various industrial dusts if not causing classical pneumoconiosis
─ Aspiration Pneumonia (with granulomatous reaction):
─ ─ Acute aspiration can cause immediate chemical pneumonitis or later bacterial pneumonia
─ ─ Chronic or recurrent aspiration (often in patients with impaired swallowing, neurologic disorders, GERD, alcoholism, or altered consciousness) can lead to chronic inflammation, fibrosis, and foreign body granulomas around aspirated material
─ ─ Symptoms: Recurrent pneumonia, chronic cough, low-grade fever, weight loss, dyspnea
Macro ─
─ Foreign Body Granulomas: May form nodules or ill-defined areas of induration; visible foreign material may be present
─ Aspiration Pneumonia: Affected areas (often dependent lung segments like posterior segments of upper lobes or basal segments of lower lobes) may show consolidation, fibrosis, bronchiectasis, or abscess formation; aspirated material sometimes grossly visible
Micro ─
─ Foreign Body Granulomas:
─ ─ Presence of foreign material: This is the defining feature. Material can be:
─ ─ ─ Exogenous: Talc crystals (plate-like, brightly birefringent under polarized light, often seen in IV drug users' lungs - "talcosis"), silica (weakly birefringent, can be from drug fillers), suture material, cellulose fibers (from pill fillers), metallic fragments, etc.
─ ─ ─ Endogenous: Cholesterol clefts (from necrotic debris), keratin, calcific debris
─ ─ Granulomatous inflammation: Composed of macrophages, epithelioid histiocytes, and characteristically foreign body-type multinucleated giant cells (nuclei haphazardly arranged or clustered centrally) that are often seen engulfing or surrounding the foreign material
─ ─ Associated lymphocytes, plasma cells, and variable fibrosis
─ Granulomatous Reaction in Aspiration Pneumonia:
─ ─ Identification of aspirated material within airways or alveolar spaces:
─ ─ ─ Food particles: Vegetable matter (plant cells with cellulose walls, sometimes showing retained cellular structure), meat fibers (amorphous eosinophilic material)
─ ─ ─ Pill fragments (may contain birefringent fillers like talc or microcrystalline cellulose)
─ ─ ─ Gastric contents (mucus, partially digested food)
─ ─ Chronic inflammatory infiltrate: Lymphocytes, plasma cells, foamy macrophages
─ ─ Foreign body-type giant cells and granulomas forming around the aspirated material
─ ─ Organizing pneumonia, interstitial fibrosis, bronchiolitis obliterans, or abscess formation can also be present as part of the spectrum of aspiration-related injury
Ancillary studies ─
─ Polarized light microscopy: Essential for identifying birefringent foreign materials (e.g., talc, silica, cellulose, suture material)
─ Special stains for microorganisms (GMS, AFB, Gram): Important if secondary infection is suspected, especially in aspiration pneumonia
─ Stains for mucin or specific food components are generally not used but morphology is key
DDx ─
─ Other granulomatous diseases:
─ ─ Sarcoidosis (granulomas are typically non-necrotizing, epithelioid, well-formed, and lack identifiable foreign material; different clinical context)
─ ─ Infectious granulomas (e.g., tuberculosis, fungal infections – special stains positive for organisms; necrosis may be present)
─ ─ Hypersensitivity pneumonitis (granulomas usually poorly formed, interstitial, airway-centered; lacks obvious foreign particles of aspiration type)
─ Pneumoconioses (e.g., silicosis, CWP – specific dusts and nodular patterns, occupational history)
─ Neoplasms (can sometimes elicit a foreign body giant cell reaction to necrotic tumor or keratin)
─ For aspiration pneumonia: Differentiate from primary bacterial pneumonia (if no aspirated material seen) or pure chemical pneumonitis (if acute without prominent granulomas)
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Pulmonary Hypertension and Major Vascular Diseases

Pulmonary Arterial Hypertension (PAH) - Key concepts and causes

A clinical and hemodynamic condition defined by elevated mean pulmonary arterial pressure (mPAP ≥20 mmHg at rest), normal pulmonary capillary wedge pressure (PCWP ≤15 mmHg), and increased pulmonary vascular resistance (PVR ≥3 Wood units), leading to right ventricular strain and failure; this entry focuses on the general concepts and common pathologic changes in pulmonary vasculature
Clinical ─
─ Symptoms: Progressive dyspnea on exertion, fatigue, lethargy, exertional chest pain, syncope or near-syncope, edema (signs of right heart failure in advanced stages)
─ WHO Classification of Pulmonary Hypertension (PH) – Group 1 (PAH):
─ ─ Idiopathic PAH (IPAH)
─ ─ Heritable PAH (e.g., BMPR2, ALK1, ENG, SMAD9, CAV1 mutations)
─ ─ Drug- and toxin-induced PAH (e.g., appetite suppressants like fenfluramine, amphetamines, dasatinib)
─ ─ PAH associated with:
─ ─ ─ Connective tissue diseases (CTDs) (especially scleroderma, SLE, mixed CTD)
─ ─ ─ HIV infection
─ ─ ─ Portal hypertension
─ ─ ─ Congenital heart disease (with systemic-to-pulmonary shunts, e.g., Eisenmenger syndrome)
─ ─ ─ Schistosomiasis (common worldwide cause)
─ ─ PAH with overt features of venous/capillary involvement (PVOD/PCH) - now part of Group 1
─ ─ Persistent PH of the newborn
─ Diagnosis relies on right heart catheterization for hemodynamic measurements
Macro ─
─ Right ventricular hypertrophy and dilatation
─ Main pulmonary artery may be dilated and show atherosclerotic plaques (due to high pressure)
─ Lungs themselves may appear congested or grossly unremarkable, especially in early stages; peripheral pruning of vessels on angiography
Micro ─
─ Spectrum of vascular remodeling changes primarily affecting small pulmonary arteries (<500 µm) and arterioles:
─ Medial hypertrophy: Increased thickness of the smooth muscle layer in the media of muscular arteries and muscularization of arterioles (normally non-muscular)
─ Intimal proliferation and fibrosis: Cellular (endothelial, smooth muscle, myofibroblast proliferation) or fibrotic (collagen deposition) thickening of the intima, leading to luminal narrowing
─ Adventitial proliferation/fibrosis: Thickening of the adventitial layer with fibroblast proliferation and collagen deposition
─ Plexiform lesions: Considered a hallmark of severe, advanced PAH, especially IPAH and heritable forms. Complex glomeruloid or web-like tufts of proliferating endothelial cells, smooth muscle cells, and myofibroblasts forming multiple small vascular channels within a dilated, thin-walled parent artery; often located at or near arterial branch points.
─ Dilatation lesions: Thin-walled, dilated small arteries or arterioles, sometimes forming angiomatoid structures (may represent collateral formation or remodeling)
─ Thrombotic lesions: In situ thrombosis can occur in remodeled and narrowed vessels, further contributing to obstruction (not to be confused with Chronic Thromboembolic PH - CTEPH, which is Group 4 PH)
─ Fibrinoid necrosis and necrotizing arteritis: Rare, seen in severe, accelerated, or "malignant" PAH; involves fibrin deposition and inflammatory cell infiltration in vessel walls
─ Lung parenchyma away from vessels may show changes related to hypoperfusion or congestion, but is not the primary site of pathology in pure PAH
Ancillary studies ─
─ Elastic stains (e.g., Verhoeff-Van Gieson - VVG, orcein) are crucial for assessing vascular remodeling: they highlight medial hypertrophy, intimal thickening, and disruption or reduplication of internal and external elastic laminae (especially useful for plexiform lesions)
─ Trichrome stain can highlight intimal and adventitial fibrosis
─ Lung biopsy for PAH diagnosis is high-risk and rarely performed; pathologic findings are typically from explanted lungs (transplantation) or autopsy material
DDx ─
─ Pulmonary hypertension secondary to other causes (WHO Groups 2-5):
─ ─ Group 2: PH due to left heart disease (e.g., heart failure, valvular disease) – shows post-capillary PH with pulmonary venous congestion, interstitial edema, hemosiderosis, arterial remodeling can occur but plexiform lesions rare
─ ─ Group 3: PH due to lung diseases and/or hypoxia (e.g., COPD, ILD) – vascular remodeling due to chronic hypoxia and parenchymal destruction; plexiform lesions rare
─ ─ Group 4: Chronic Thromboembolic Pulmonary Hypertension (CTEPH) – organized thrombi, fibrous webs/bands in larger elastic pulmonary arteries
─ ─ Group 5: PH with unclear multifactorial mechanisms
─ Pulmonary Veno-Occlusive Disease (PVOD) and Pulmonary Capillary Hemangiomatosis (PCH): Now classified within Group 1 PAH but have distinct histologic features primarily involving veins/venules (PVOD - intimal fibrosis, occlusion) and capillaries (PCH - capillary proliferation). Overlap can exist.
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Eosinophilic Granulomatosis with Polyangiitis (EGPA)

Foreign Body Granulomas / Aspiration Pneumonia (Granulomatous aspects)

Pulmonary Arterial Hypertension (PAH) - Key concepts and causes

Pulmonary Vasculitis

ANCA-Associated Vasculitides (GPA, EGPA, Microscopic Polyangiitis)

A group of systemic autoimmune diseases characterized by necrotizing inflammation of small to medium-sized blood vessels and a frequent association with Anti-Neutrophil Cytoplasmic Antibodies (ANCA); comprises Granulomatosis with Polyangiitis (GPA), Eosinophilic Granulomatosis with Polyangiitis (EGPA), and Microscopic Polyangiitis (MPA)
Clinical ─
─ General features: Often constitutional symptoms (fever, malaise, weight loss); organ involvement varies by type
─ Granulomatosis with Polyangiitis (GPA):
─ ─ Classic triad: Upper/lower respiratory tract necrotizing granulomatous inflammation, systemic necrotizing vasculitis, and glomerulonephritis
─ ─ Primarily associated with PR3-ANCA (c-ANCA)
─ Eosinophilic Granulomatosis with Polyangiitis (EGPA):
─ ─ Characterized by asthma, peripheral blood and tissue eosinophilia, and necrotizing vasculitis often with extravascular eosinophilic granulomas
─ ─ Approximately 40-60% are MPO-ANCA (p-ANCA) positive
─ Microscopic Polyangiitis (MPA):
─ ─ Necrotizing vasculitis with few or no immune deposits (pauci-immune) predominantly affecting small vessels (capillaries, venules, or arterioles)
─ ─ Necrotizing glomerulonephritis is very common (>90%) and often rapidly progressive
─ ─ Pulmonary capillaritis leading to diffuse alveolar hemorrhage (DAH) is a common and severe lung manifestation
─ ─ Granulomatous inflammation is characteristically absent (distinguishes from GPA and EGPA)
─ ─ Primarily associated with MPO-ANCA (p-ANCA)
Macro ─
─ GPA/EGPA: Lungs may show nodules (often cavitating in GPA), consolidations, or hemorrhage (see previous entries)
─ MPA: Lungs often appear diffusely hemorrhagic and congested if DAH is present; specific nodules are not typical
Micro ─
─ GPA: Necrotizing granulomas, vasculitis
─ EGPA: Eosinophil-rich inflammation, necrotizing vasculitis, eosinophilic granulomas

─ Microscopic Polyangiitis (MPA) - Lung involvement:
─ ─ Pulmonary capillaritis: The most common pulmonary lesion. Characterized by neutrophilic infiltration of alveolar septa and capillaries, endothelial injury, fibrin deposition within capillary lumens (microthrombi), and extravasation of red blood cells into alveolar spaces. Leads to DAH.
─ ─ Hemosiderin-laden macrophages become prominent in alveolar spaces after hemorrhage
─ ─ Frank necrotizing vasculitis of arterioles or venules may also be seen, but capillaritis is often the dominant vascular lesion in lung biopsies
─ ─ Absence of significant granulomatous inflammation is a key negative feature for MPA diagnosis in contrast to GPA/EGPA
─ ─ Interstitial fibrosis and type II pneumocyte hyperplasia can occur in chronic or resolving DAH
Ancillary studies ─
─ ANCA serology: PR3-ANCA (c-ANCA) for GPA; MPO-ANCA (p-ANCA) for MPA and a subset of EGPA. Titers can correlate with disease activity.
─ Special stains for microorganisms (GMS, AFB, Gram) are essential on lung biopsies to exclude infection, especially when necrosis or granulomas are present (GPA/EGPA) or in cases of DAH
─ Renal biopsy is often performed for diagnosis and classification if glomerulonephritis is present (shows pauci-immune necrotizing crescentic GN in all three AAVs)
─ Immunofluorescence on biopsy tissue is typically negative or shows only scant immune deposits ("pauci-immune" vasculitis)
DDx ─
─ For pulmonary capillaritis / DAH in MPA:
─ ─ Goodpasture syndrome (anti-GBM disease; linear IgG deposition along alveolar basement membranes on IF)
─ ─ Systemic Lupus Erythematosus (SLE) (can cause capillaritis; often immune complex deposition on IF, other systemic features of SLE)
─ ─ Other causes of DAH (e.g., infections, drug reactions, coagulopathies, idiopathic pulmonary hemosiderosis)
─ Distinguishing among GPA, EGPA, and MPA: Relies on the constellation of clinical features (e.g., presence/absence of asthma, eosinophilia, granulomatous disease in upper/lower airways, type of ANCA) and histopathologic findings (especially presence/type of granulomas)
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Other selected vasculitides (brief overview)

An overview of vasculitides affecting the pulmonary vasculature beyond the ANCA-associated vasculitis group, which are generally less common as primary causes of lung disease
Clinical ─
─ Presentation is highly variable depending on the specific type of vasculitis, the size of vessels involved, and the extent of pulmonary and systemic involvement
Macro ─
─ Findings depend on the specific entity; may include arterial aneurysms, stenoses, thrombosis, or signs of pulmonary hemorrhage or infarction
Micro ─
─ Features vary based on the specific vasculitis type:
─ Large Vessel Vasculitis (rarely primary in lung but can involve pulmonary arteries as part of systemic disease):
─ ─ Giant Cell Arteritis (Temporal Arteritis): Can affect the aorta and its major branches, including pulmonary arteries. Characterized by granulomatous inflammation of the arterial wall, often with multinucleated giant cells, lymphocytes, and plasma cells, typically centered on a disrupted internal elastic lamina.
─ ─ Takayasu Arteritis: Affects aorta and its main branches, including pulmonary arteries (in up to 50% of cases). Shows panarteritis with mononuclear cell infiltrates, giant cells, destruction of the media, intimal proliferation/fibrosis, and adventitial fibrosis, leading to stenosis, occlusion, or aneurysm formation.
─ Immune Complex Small Vessel Vasculitis (pulmonary involvement is uncommon but can occur):
─ ─ IgA Vasculitis (Henoch-Schönlein Purpura): Characterized by leukocytoclastic vasculitis (neutrophilic infiltrate in and around small vessel walls with fibrinoid necrosis, karyorrhexis, and RBC extravasation) with IgA-dominant immune deposits in vessel walls. Pulmonary involvement is rare but can manifest as DAH/capillaritis.
─ ─ Cryoglobulinemic Vasculitis: Deposition of cryoglobulins in small vessels, often associated with Hepatitis C infection or lymphoproliferative disorders. Can cause leukocytoclastic vasculitis with intraluminal cryoprecipitates (hyaline thrombi); pulmonary involvement may include capillaritis and DAH.
─ Behçet Disease: A variable vessel vasculitis (can affect arteries and veins of all sizes). Pulmonary involvement can include pulmonary artery aneurysms (PAA), in situ thrombosis, DAH, and infarcts. Histology may show neutrophilic vascular and perivascular inflammation, or features similar to leukocytoclastic vasculitis or organized thrombi.
─ Isolated Pulmonary Vasculitis: Vasculitis confined to the lung vasculature without evidence of systemic involvement or features allowing specific classification; diagnosis of exclusion and very rare.
Ancillary studies ─
─ Dependent on the suspected type of vasculitis:
─ ─ Elastic stains (e.g., VVG) are useful for assessing large and medium-sized arteries, highlighting elastic lamina destruction or remodeling
─ ─ Immunofluorescence microscopy on fresh/frozen tissue (if available) can detect immune deposits (e.g., IgA in IgA vasculitis, IgG/C3 in cryoglobulinemic vasculitis or lupus-related vasculitis)
─ ─ Serological tests (e.g., ANA for lupus, cryoglobulins, hepatitis C serology) may be relevant depending on clinical suspicion
─ ─ Special stains for microorganisms to exclude infectious arteritis
DDx ─
─ ANCA-associated vasculitides (GPA, EGPA, MPA) – typically pauci-immune
─ Infections causing vascular inflammation or pseudoaneurysms (e.g., septic emboli, mycotic aneurysms from TB or fungi)
─ Embolic phenomena (e.g., thromboemboli, tumor emboli)
─ Connective tissue diseases with secondary vasculitis (e.g., SLE, rheumatoid arthritis can have associated vasculitis)
─ Primary pulmonary hypertension with severe vascular changes (plexiform lesions in PAH are distinct from true vasculitis)
─ Fibrosing mediastinitis (can encase pulmonary vessels leading to stenosis/occlusion)
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Pulmonary Hemorrhage Syndromes

Diffuse Alveolar Hemorrhage (DAH) - Overview

A clinical syndrome characterized by bleeding originating from the pulmonary microvasculature (capillaries, arterioles, venules) into the alveolar spaces, representing a manifestation of various underlying disorders rather than a single disease entity; can be life-threatening
Clinical ─
─ Classic triad: Hemoptysis, anemia (often iron deficiency with chronic DAH), and diffuse pulmonary infiltrates on imaging; however, hemoptysis may be absent in up to one-third of patients, especially in early or less severe episodes
─ Acute onset of dyspnea, cough, fever, and hypoxemia can occur
─ Broadly categorized based on underlying mechanism:
─ ─ Pulmonary Capillaritis: Inflammation and destruction of alveolar capillaries (e.g., ANCA-associated vasculitides, Goodpasture syndrome, SLE)
─ ─ Bland Pulmonary Hemorrhage: Bleeding without significant inflammation of capillaries (e.g., coagulopathies, mitral stenosis, toxic exposures, some drug reactions, idiopathic pulmonary hemosiderosis)
─ ─ Diffuse Alveolar Damage (DAD) with hemorrhage: Hemorrhage as a component of widespread alveolar injury
Macro ─
─ Lungs are often heavy, diffusely congested, and appear hemorrhagic (dark red to maroon)
─ Cut surface may exude bloody fluid
Micro ─
─ Key finding: Presence of extravasated red blood cells (RBCs) within numerous alveolar spaces, often diffusely
─ Acute hemorrhage: Abundant fresh RBCs in alveoli
─ Chronic or recurrent hemorrhage: Numerous hemosiderin-laden macrophages (siderophages) within alveolar spaces and interstitium; hemosiderin pigment appears golden-brown and refractile
─ Fibrin deposition in alveolar spaces may be present
─ Type II pneumocyte hyperplasia is a common reactive change
─ If due to Pulmonary Capillaritis:
─ ─ Neutrophilic infiltration of alveolar septa and capillary walls
─ ─ Endothelial cell injury, swelling, or necrosis
─ ─ Fibrinoid necrosis of capillary walls may be seen (often subtle and focal)
─ ─ Karyorrhectic debris (neutrophil fragmentation) within septa
─ ─ Interstitial edema and inflammation
─ Underlying disease features: Specific findings related to the cause may be present (e.g., granulomas in GPA, hyaline membranes in DAD, linear basement membrane deposits in Goodpasture if IF performed)
Ancillary studies ─
─ Iron stain (e.g., Prussian blue): Highlights hemosiderin pigment within macrophages, confirming past or ongoing hemorrhage
─ Bronchoalveolar lavage (BAL): Classically shows progressively more hemorrhagic return in sequential aliquots during acute bleeding; numerous hemosiderin-laden macrophages (>20% suggests DAH) seen on cytology days to weeks after an episode
─ Investigation for underlying cause is crucial:
─ ─ Serologies: ANCA, anti-GBM antibodies, ANA, dsDNA
─ ─ Coagulation studies
─ ─ Immunofluorescence on lung biopsy (if performed) for immune deposits (e.g., linear IgG in Goodpasture, granular deposits in SLE)
─ ─ Special stains for microorganisms to exclude infection mimicking or causing hemorrhage
DDx ─
─ DAH is a descriptive pattern; the differential diagnosis focuses on its underlying cause (see categories above)
─ Localized pulmonary hemorrhage (e.g., from a tumor, bronchiectasis, cavitary infection, vascular malformation – usually not diffuse)
─ Traumatic lung contusion (history of trauma)
─ Severe pulmonary edema (can be frothy and pink, but primarily edema fluid, not frank hemorrhage)
─ Artefactual hemorrhage due to biopsy procedure (usually focal, less hemosiderin)
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Goodpasture Syndrome / Anti-GBM Disease

An autoimmune disease characterized by circulating autoantibodies targeting the non-collagenous (NC1) domain of the alpha-3 chain of type IV collagen, present in the basement membranes of renal glomeruli (GBM) and pulmonary alveoli (ABM), leading to rapidly progressive glomerulonephritis and diffuse alveolar hemorrhage
Clinical ─
─ "Goodpasture Syndrome": Clinical combination of glomerulonephritis, pulmonary hemorrhage, and detectable anti-GBM antibodies
─ "Anti-GBM Disease": Term used when either kidneys or lungs (or both) are involved, with the presence of anti-GBM antibodies
─ Bimodal age distribution: Peaks in young adult males (20s-30s) and older individuals (60s-70s)
─ Pulmonary symptoms: Hemoptysis (ranging from mild to massive), dyspnea, cough, anemia; pulmonary hemorrhage is more common in smokers
─ Renal symptoms: Hematuria, proteinuria, oliguria, rapidly progressive renal failure due to crescentic glomerulonephritis
─ Systemic symptoms like fever or arthralgia may occur
Macro ─
─ Lungs: Diffusely hemorrhagic, heavy, and congested, similar to DAH from other causes
─ Kidneys: Often enlarged, pale, with petechial hemorrhages on the cortical surface
Micro ─
─ Lung:
─ ─ Diffuse alveolar hemorrhage: Abundant fresh red blood cells in alveolar spaces, hemosiderin-laden macrophages (indicating prior or ongoing bleeding)
─ ─ Pulmonary capillaritis may be present (neutrophilic infiltrates in alveolar septa, endothelial injury) but is often less florid or prominent compared to ANCA-associated DAH; some cases show bland hemorrhage
─ ─ Necrosis of alveolar walls and hyaline membrane formation can occur in severe cases
─ ─ Generally no granulomas or significant vasculitis of larger vessels
─ Kidney:
─ ─ Diffuse necrotizing and crescentic glomerulonephritis is characteristic; crescents (cellular, fibrocellular, or fibrous) in a majority of glomeruli
─ ─ Fibrinoid necrosis of glomerular capillary loops
─ ─ Interstitial inflammation and tubular atrophy in advanced stages
Ancillary studies ─
─ Serology: Detection of circulating anti-GBM antibodies in serum (by ELISA or indirect immunofluorescence) is a key diagnostic criterion
─ Immunofluorescence (IF) microscopy on lung or kidney biopsy: Pathognomonic finding is the diffuse, linear deposition of IgG (and often C3) along the glomerular basement membranes (GBM) and/or alveolar basement membranes (ABM)
─ Iron stain (Prussian blue) on lung tissue highlights hemosiderin
─ ANCA serology: Approximately 10-30% of patients with anti-GBM disease also have ANCA (usually MPO-ANCA), representing a "double-positive" condition with potentially worse prognosis
DDx ─
─ Other causes of DAH with glomerulonephritis (pulmonary-renal syndromes):
─ ─ ANCA-associated vasculitides (GPA, MPA, EGPA): Typically show "pauci-immune" glomerulonephritis on IF (no or minimal immune deposits), ANCA positive, anti-GBM negative
─ ─ Systemic Lupus Erythematosus (SLE): Can cause DAH and lupus nephritis; IF shows "full-house" granular immune deposits (IgG, IgA, IgM, C3, C1q), ANA/dsDNA positive
─ Idiopathic Pulmonary Hemosiderosis (recurrent DAH without renal disease or detectable anti-GBM/ANCA antibodies, linear IF negative)
─ Other causes of DAH without significant renal disease (see DAH overview)
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Idiopathic Pulmonary Hemosiderosis (IPH)

A rare disorder of unknown etiology characterized by recurrent episodes of diffuse alveolar hemorrhage, leading to progressive accumulation of iron (as hemosiderin) in the lungs and development of iron-deficiency anemia, in the absence of any identifiable underlying cause (e.g., systemic autoimmune disease, vasculitis, coagulopathy, or cardiac disease)
Clinical ─
─ Primarily affects children (often before age 10), but can occur in adolescents and young adults
─ Clinical triad: Recurrent episodes of cough and hemoptysis (may be mild or severe), iron-deficiency anemia, and transient or persistent diffuse pulmonary infiltrates on imaging
─ Dyspnea, fatigue, pallor, and failure to thrive (in children) may also occur
─ Course is variable; some have mild disease, others have frequent exacerbations leading to chronic respiratory insufficiency and pulmonary fibrosis
─ By definition, there is no evidence of renal disease, anti-GBM antibodies, ANCA, or other systemic disorders known to cause DAH
Macro ─
─ Lungs may appear brown and indurated ("brown induration") due to chronic hemosiderin deposition, especially in long-standing cases
─ Acute hemorrhage may be visible as dark red areas
Micro ─
─ Key feature: Evidence of diffuse, recurrent, and often chronic alveolar hemorrhage:
─ ─ Abundant hemosiderin-laden macrophages (siderophages) filling alveolar spaces and present within the interstitium; these are the hallmark of chronic bleeding
─ ─ Fresh hemorrhage (intra-alveolar red blood cells) may be seen during acute episodes
─ Alveolar septa may be thickened by interstitial fibrosis and deposition of hemosiderin pigment in chronic cases
─ Reactive type II pneumocyte hyperplasia is common
─ Absence of specific features pointing to other causes of DAH:
─ ─ No significant capillaritis (i.e., no prominent neutrophilic infiltration or necrosis of alveolar capillaries)
─ ─ No vasculitis of larger vessels
─ ─ No granulomas
─ ─ No evidence of immune complex deposition (immunofluorescence, if performed, is negative)
Ancillary studies ─
─ Iron stain (e.g., Prussian blue): Strongly positive, highlighting abundant hemosiderin within macrophages in alveolar spaces and interstitium; confirms the presence of iron overload in the lungs
─ Exclusion of other causes of DAH is critical for the diagnosis of IPH:
─ ─ Negative serologies for anti-GBM antibodies, ANCA, ANA, and other relevant autoantibodies
─ ─ Normal coagulation studies
─ ─ Normal cardiac evaluation (to exclude mitral stenosis or left ventricular failure)
─ ─ Immunofluorescence studies on lung biopsy (if performed) should be negative for immune deposits
─ Bronchoalveolar lavage (BAL) fluid shows numerous hemosiderin-laden macrophages
DDx ─
─ All other known causes of diffuse alveolar hemorrhage must be rigorously excluded:
─ ─ Goodpasture syndrome / Anti-GBM disease (anti-GBM antibodies positive, linear IgG on IF)
─ ─ ANCA-associated vasculitides (GPA, MPA, EGPA) (ANCA positive, often capillaritis or other vasculitic features)
─ ─ Systemic Lupus Erythematosus (SLE)-associated DAH (ANA positive, often other systemic features, granular immune deposits on IF)
─ ─ Coagulation disorders
─ ─ Pulmonary hemorrhage secondary to cardiac disease (e.g., mitral stenosis, left ventricular failure – shows features of pulmonary venous hypertension)
─ ─ DAH associated with infections or toxins
─ Diagnosis of IPH is one of exclusion
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Diseases of Large and Small Airways (Non-neoplastic)

Bronchiectasis

A chronic condition characterized by permanent and irreversible dilatation of bronchi and bronchioles caused by destruction of the muscular and elastic components of their walls, usually resulting from or associated with chronic necrotizing infections, airway obstruction, or congenital abnormalities
Clinical ─
─ Persistent cough, often productive of copious, purulent, and sometimes foul-smelling sputum
─ Recurrent lower respiratory tract infections, hemoptysis (can be significant), dyspnea, wheezing, and pleuritic chest pain
─ Digital clubbing may be present in long-standing, severe cases
─ Causes/Associations:
─ ─ Post-infectious: Severe necrotizing pneumonia (e.g., Staphylococcus aureus, Klebsiella, tuberculosis, measles, pertussis)
─ ─ Bronchial obstruction: Tumors, foreign bodies, mucous impaction (e.g., allergic bronchopulmonary aspergillosis - ABPA)
─ ─ Congenital/Hereditary conditions: Cystic fibrosis (most common cause in developed countries), primary ciliary dyskinesia (e.g., Kartagener syndrome), immunodeficiency syndromes (e.g., agammaglobulinemia), alpha-1 antitrypsin deficiency (less common)
─ ─ Connective tissue diseases (e.g., rheumatoid arthritis, Sjögren syndrome)
─ ─ Idiopathic (a significant portion of cases)
Macro ─
─ Affected bronchi and bronchioles are abnormally dilated, often extending peripherally towards the pleural surface
─ Forms of dilatation: Cylindrical (uniform, tube-like), varicose (irregularly beaded), or saccular/cystic (balloon-like)
─ Bronchial walls may be thickened due to chronic inflammation and fibrosis, or thinned and destructed in cystic forms
─ Lumen frequently contains mucopurulent material or inspissated secretions; fungal balls (e.g., aspergilloma) can colonize ectatic airways
Micro ─
─ Abnormal and permanent dilatation of bronchial and bronchiolar lumens
─ Intense acute and chronic inflammation within the bronchial/bronchiolar walls: Infiltrates of neutrophils, lymphocytes, plasma cells, and macrophages; lymphoid follicles with germinal centers can be prominent
─ Destruction and loss of mural elastic tissue and smooth muscle, replaced by fibrous tissue
─ Mucosal changes:
─ ─ Epithelial ulceration and shedding
─ ─ Squamous metaplasia of the respiratory epithelium
─ ─ Goblet cell hyperplasia and hypertrophy of submucosal mucous glands (if present proximally)
─ Luminal contents: Mucus, pus (neutrophils, necrotic debris), bacterial colonies, sometimes fungal elements
─ Associated parenchymal changes: Peribronchial pneumonia, organizing pneumonia, interstitial fibrosis, abscess formation, or emphysematous changes in surrounding lung
Ancillary studies ─
─ Special stains for microorganisms (Gram, GMS, AFB) if active infection is suspected from histology
─ Elastic stains (e.g., Verhoeff-Van Gieson - VVG) can highlight the destruction and fragmentation of elastic fibers in the airway walls
─ PAS or Alcian blue for mucus
DDx ─
─ Asthma (airway inflammation and remodeling, but bronchoconstriction is largely reversible, and destructive changes of bronchiectasis are absent)
─ Chronic bronchitis (mucous gland hyperplasia and chronic inflammation of larger airways, but without significant permanent dilatation and destruction of walls)
─ Cystic lung diseases (e.g., CPAM, severe emphysema with bullae – distinct cystic structures not necessarily following airway distribution or showing the same wall features)
─ Congenital bronchial abnormalities (e.g., Williams-Campbell syndrome – congenital cartilage deficiency leading to bronchiectasis)
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Asthma - Pathologic features

A chronic inflammatory disorder of the airways characterized by reversible bronchoconstriction, airway inflammation (classically eosinophilic), and structural changes known as airway remodeling, leading to recurrent episodes of wheezing, dyspnea, chest tightness, and cough
Clinical ─
─ Episodic and variable symptoms, often worse at night or in the early morning, frequently triggered by allergens (in atopic/extrinsic asthma), irritants, exercise, cold air, or respiratory infections
─ Reversible airflow obstruction demonstrated by pulmonary function tests (improvement with bronchodilators)
─ Atopic (extrinsic) asthma: Most common form, often begins in childhood, associated with IgE sensitization to common allergens (e.g., dust mites, pollen, animal dander)
─ Non-atopic (intrinsic) asthma: No evidence of allergen sensitization; triggers may include viral infections, irritants, stress; often adult-onset
─ Severe or fatal asthma (status asthmaticus) is a medical emergency
Macro ─
─ In fatal asthma (status asthmaticus), lungs are typically hyperinflated due to air trapping
─ Airways (bronchi and bronchioles) may show thickened walls and marked occlusion of lumens by tenacious, stringy mucous plugs
Micro ─
─ Key features of airway remodeling and inflammation:
─ Thickening of the epithelial basement membrane (subepithelial fibrosis): Due to deposition of collagen types I, III, and V, and other matrix proteins beneath the true basement membrane; appears as a thickened, hyalinized band
─ Hypertrophy and hyperplasia of bronchial smooth muscle: Increased mass of smooth muscle in airway walls, contributing to exaggerated bronchoconstriction
─ Mucous gland hyperplasia and hypersecretion in larger airways, and goblet cell hyperplasia/metaplasia in smaller airways (including bronchioles where they are normally sparse)
─ Airway inflammation:
─ ─ Prominent infiltration by eosinophils is characteristic, especially in atopic asthma, found in airway walls, submucosa, and within mucous plugs
─ ─ Mast cell degranulation and increased numbers in smooth muscle and mucosa
─ ─ Lymphocytic infiltrates (predominantly CD4+ Th2 cells in atopic asthma, but other T-cell subsets and neutrophils can be involved, especially in severe or non-atopic asthma)
─ Mucous plugs in airway lumens: Composed of inspissated mucus, numerous eosinophils, sloughed epithelial cells (often in clusters called Creola bodies), and Charcot-Leyden crystals (crystalloids formed from eosinophil granule proteins, appearing as elongated, bipyramidal, eosinophilic structures)
─ Epithelial shedding, damage, or fragility
─ Increased vascularity (angiogenesis) in the bronchial wall
Ancillary studies ─
─ Stains for eosinophils (e.g., Giemsa, or careful examination of H&E) can highlight eosinophilic infiltrates
─ Mucus stains (e.g., PAS, Alcian blue) demonstrate mucous gland hyperplasia and mucous plugs
─ Immunohistochemistry for specific inflammatory cell markers or cytokines is generally for research purposes
DDx ─
─ Chronic Bronchitis / COPD (neutrophilic inflammation more typical, less prominent eosinophilia, different clinical context of largely irreversible airflow obstruction, mucous gland hyperplasia without the striking BM thickening or smooth muscle hypertrophy of asthma)
─ Bronchiectasis (permanent airway dilation and destruction, purulent sputum)
─ Eosinophilic Pneumonias (parenchymal eosinophilic infiltrates are dominant, not primarily airway-centered inflammation)
─ Allergic Bronchopulmonary Aspergillosis (ABPA) (mucoid impaction often containing fungal hyphae, central bronchiectasis, Aspergillus sensitization, very high IgE levels; can coexist with asthma)
─ Vocal cord dysfunction (mimics asthma symptoms but due to paradoxical vocal cord adduction)
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Bronchiolitis - Major patterns (e.g., Constrictive, Follicular)

Inflammation of the bronchioles (small conducting airways, generally <2 mm in diameter), which can be acute or chronic and occurs in a wide variety of clinical settings and as part of numerous specific lung diseases; this entry provides an overview of major histologic patterns
Clinical ─
─ Symptoms are variable and depend on the underlying cause and severity; may include cough (often dry), dyspnea, wheezing, and constitutional symptoms like fever or malaise
─ Associated with:
─ ─ Infections (viral – RSV, influenza, adenovirus; bacterial – Mycoplasma; fungal)
─ ─ Inhalational injuries (e.g., toxic fumes, gases like NO2 in silo-filler's disease, mineral dusts)
─ ─ Connective tissue diseases (e.g., rheumatoid arthritis, Sjögren syndrome)
─ ─ Aspiration
─ ─ Post-transplantation settings (e.g., constrictive bronchiolitis in chronic lung allograft dysfunction or graft-versus-host disease)
─ ─ Drug reactions
─ ─ Idiopathic forms
Macro ─
─ Often no specific gross findings, especially in diffuse forms
─ Imaging (HRCT) may show centrilobular nodules, tree-in-bud opacities (indicative of luminal plugging/inflammation), mosaic attenuation (due to air trapping), or ground-glass opacities depending on the type and activity
Micro ─
─ Major histologic patterns:
─ Acute Bronchiolitis:
─ ─ Characterized by acute inflammation of bronchiolar walls and lumens, typically with neutrophilic infiltrates (in bacterial or some viral infections) or lymphocytic infiltrates (in many viral infections)
─ ─ Epithelial necrosis, sloughing, and intraluminal exudate (mucus, inflammatory cells, debris) may be present
─ Cellular (Inflammatory) Bronchiolitis:
─ ─ Predominantly chronic inflammatory cell infiltrates (lymphocytes, plasma cells, histiocytes) within the bronchiolar walls (mural and submucosal) and peribronchiolar tissue
─ ─ Follicular Bronchiolitis: A subtype of cellular bronchiolitis characterized by the presence of prominent lymphoid follicles with reactive germinal centers in the walls of bronchioles and along bronchovascular bundles; often associated with CTDs (especially RA, Sjögren's), immunodeficiency states, infections, or can be idiopathic.
─ ─ Eosinophilic Bronchiolitis: Prominent eosinophilic infiltration of bronchiolar walls; can occur in asthma, eosinophilic lung diseases, or parasitic infections.
─ Constrictive (Obliterative) Bronchiolitis / Bronchiolitis Obliterans:
─ ─ Characterized by concentric submucosal and peribronchiolar fibrosis leading to luminal narrowing or complete obliteration of membranous and respiratory bronchioles; the inflammatory infiltrate may be scant in established, fibrotic lesions
─ ─ This is the key lesion in chronic lung allograft rejection (Bronchiolitis Obliterans Syndrome - BOS), chronic GVHD, and can occur post-infectious (e.g., severe viral pneumonia, Mycoplasma), after inhalational injury, with certain drug reactions, or in association with CTDs
─ Respiratory Bronchiolitis (RB): (Covered also under smoking-related diseases)
─ ─ Accumulation of pigmented (smoker's) macrophages within the lumens of respiratory bronchioles and adjacent alveoli, with mild chronic inflammation and fibrosis of bronchiolar walls; almost exclusively seen in smokers and can lead to RB-ILD if symptomatic and extensive.
─ Diffuse Panbronchiolitis (DPB):
─ ─ Chronic inflammation primarily involving respiratory bronchioles, characterized by transmural lymphocytic and plasma cell infiltrates, accumulation of foamy macrophages in lumens and peribronchiolar interstitium, and often lymphoid follicles; more common in East Asian populations.
─ Mineral Dust Airway Disease (MDAD):
─ ─ Deposition of inorganic dust particles (e.g., silica, silicates, coal dust) in and around small airways, with associated chronic inflammation, fibrosis, and sometimes pigment-laden macrophages.
Ancillary studies ─
─ Special stains for microorganisms (Gram, GMS, AFB, viral IHC/PCR) if an infectious etiology is suspected
─ Elastic stains (e.g., Verhoeff-Van Gieson - VVG) can be very helpful in constrictive bronchiolitis to highlight the narrowed or obliterated lumens and peribronchiolar fibrosis
─ IHC for lymphocyte markers (CD20, CD3) can characterize infiltrates in follicular bronchiolitis if needed, though usually not required for diagnosis
─ Polarized light microscopy for birefringent material in MDAD or foreign body-related bronchiolitis
DDx ─
─ Asthma (broader airway involvement, specific remodeling features like prominent eosinophils, basement membrane thickening, smooth muscle hypertrophy)
─ Organizing Pneumonia (COP/BOOP) (intraluminal fibroblastic plugs predominantly in alveolar ducts and alveoli, though some bronchiolar involvement can occur; constrictive bronchiolitis focuses on airway wall fibrosis and luminal obliteration)
─ Usual Interstitial Pneumonia (UIP) or Nonspecific Interstitial Pneumonia (NSIP) (primarily interstitial patterns of fibrosis/inflammation, though airway involvement can be a component)
─ Distinction between different bronchiolitis patterns is based on the dominant inflammatory cell type, the presence and nature of fibrosis, and specific features like lymphoid follicles or pigmented macrophages
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Cystic and Bullous Lung Diseases

Lymphangioleiomyomatosis (LAM)

A rare, progressive systemic disease predominantly affecting women, especially of childbearing age, characterized by the abnormal proliferation of smooth muscle-like cells (LAM cells) leading to cystic lung destruction, lymphatic abnormalities (e.g., chylous effusions), and benign tumors (angiomyolipomas, often renal); associated with mutations in TSC1 or TSC2 genes (tuberous sclerosis complex)
Clinical ─
─ Can be sporadic LAM (sLAM, no other features of TSC) or associated with Tuberous Sclerosis Complex (TSC-LAM)
─ Progressive dyspnea on exertion, recurrent spontaneous pneumothorax (common, ~70%), chylous pleural effusions or ascites (due to lymphatic obstruction by LAM cells)
─ Hemoptysis, chronic cough may occur
─ Renal angiomyolipomas (benign tumors of blood vessels, smooth muscle, fat) are common in both sLAM and TSC-LAM
─ Lymphatic involvement can lead to lymphangioleiomyomas (LAM cell collections in lymphatics/nodes) or chylous ascites/effusions
─ Pulmonary function tests typically show airflow obstruction, hyperinflation, and impaired gas exchange
Macro ─
─ Lungs are diffusely involved with numerous, variably sized, thin-walled cysts distributed throughout all lung fields, without zonal predilection
─ Cysts range from a few millimeters to several centimeters
─ Parenchyma between cysts may appear relatively normal or compressed
─ Chylous fluid may be present in pleural spaces
Micro ─
─ Cysts: Variably sized, generally round to oval, thin-walled, lined by flattened type I pneumocytes or hyperplastic type II pneumocytes
─ LAM cells: The diagnostic feature; proliferation of abnormal-appearing smooth muscle-like cells in nodular aggregates, bundles, or sheets within the lung interstitium, characteristically:
─ ─ Around cysts, blood vessels (especially veins), lymphatics, and bronchioles
─ ─ Composed of two main cell types: spindle-shaped cells (more myoid) and epithelioid cells (plumper, more eosinophilic cytoplasm)
─ ─ LAM cells have pale eosinophilic cytoplasm, ovoid to spindle nuclei, and generally bland cytologic features (mitoses are rare)
─ Lymphatic involvement: Dilated lymphatic channels, often containing LAM cells within their lumens or walls; this can lead to chyle leakage
─ Hemosiderosis (hemosiderin-laden macrophages) can be present due to previous hemorrhage
─ Minimal associated inflammation unless complicated by infection
Ancillary studies ─
─ IHC is crucial for diagnosis: LAM cells characteristically co-express smooth muscle markers and melanocytic markers:
─ ─ IHC (+) Smooth muscle markers: Smooth Muscle Actin (SMA), desmin (often more focal)
─ ─ IHC (+) Melanocytic markers: HMB-45 (human melanoma black 45 - often patchy but highly specific in this context), Melan-A/MART-1
─ ─ IHC (+) Estrogen Receptor (ER) and Progesterone Receptor (PR) are often positive in LAM cells
─ ─ IHC (+) VEGF-D (Vascular Endothelial Growth Factor D) levels may be elevated in serum and can be a useful diagnostic biomarker, especially for sLAM
DDx ─
─ Emphysema (especially bullous or advanced panacinar emphysema; lacks LAM cell proliferation and HMB-45 positivity, shows airspace enlargement with wall destruction)
─ Pulmonary Langerhans Cell Histiocytosis (PLCH) (irregular, often bizarrely shaped cysts, predominantly upper lobe, associated with smoking, Langerhans cells are CD1a+/S100+/Langerin+, HMB-45 negative)
─ Birt-Hogg-Dubé Syndrome (cysts often basilar and subpleural, associated with skin fibrofolliculomas and renal tumors; no LAM cell proliferation)
─ Other cystic lung diseases (e.g., LIP with cystic change, Honeycomb lung in UIP – these have other specific histologic features and lack LAM cells)
─ Benign metastasizing leiomyoma (rare, in women with uterine leiomyomas; nodules of bland smooth muscle, HMB-45 negative)
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Birt-Hogg-Dubé Syndrome (BHD)

An autosomal dominant inherited disorder caused by germline mutations in the FLCN gene (encoding folliculin), characterized by a classic triad of cutaneous fibrofolliculomas/trichodiscomas, multiple bilateral pulmonary cysts with an increased risk of spontaneous pneumothorax, and various types of renal tumors (especially chromophobe RCC, hybrid oncocytic/chromophobe tumors, and oncocytoma)
Clinical ─
─ Skin lesions: Multiple, small, dome-shaped, whitish papules (fibrofolliculomas, trichodiscomas, acrochordons) typically develop in adulthood, commonly on the face, neck, and upper trunk
─ Pulmonary cysts: Often asymptomatic and detected incidentally; however, patients are at high risk (~25-30%) for spontaneous pneumothorax, which can be recurrent
─ Renal tumors: Occur in ~15-30% of affected individuals, often bilateral and multifocal; mean age of onset is around 50 years. Surveillance for renal tumors is important.
─ Other less common associations: Colonic polyps/cancer (controversial), parotid oncocytoma, thyroid nodules
Macro ─
─ Lungs show multiple, thin-walled cysts, which can be variable in size and shape (often oval, lentiform, or irregular)
─ Cysts are frequently located in the basilar and subpleural regions of the lungs, and may be particularly prominent adjacent to interlobular septa and major vessels
─ Parenchyma between cysts is generally normal
Micro ─
─ Pulmonary Cysts:
─ ─ Thin-walled, lined by flattened alveolar epithelium (type I or type II pneumocytes) or may appear denuded in areas
─ ─ Cysts are often irregular in shape, may be multiloculated, or appear to coalesce
─ ─ The walls are typically composed of delicate fibrous tissue with minimal to no inflammation, unless there has been a prior pneumothorax or infection
─ Surrounding lung parenchyma is usually histologically normal; there is no specific interstitial inflammation, fibrosis, or characteristic cellular proliferation (like LAM cells or Langerhans cells) directly related to BHD syndrome itself
─ Diagnosis is primarily based on clinical criteria (skin lesions, renal tumors, family history, pneumothorax history with cysts) and confirmed by genetic testing for FLCN mutations. Lung biopsy, if performed (e.g., for recurrent pneumothorax), shows nonspecific cystic changes; its main role is to exclude other specific cystic lung diseases if the diagnosis is unclear.
Ancillary studies ─
─ Genetic testing for FLCN gene mutations is the gold standard for confirming the diagnosis
─ Pathologic examination of skin lesions (fibrofolliculoma histology) or renal tumors can support the diagnosis
─ For lung cysts, no specific IHC or special stains are diagnostic of BHD; histology is nonspecific
DDx ─
─ Other cystic lung diseases:
─ ─ Lymphangioleiomyomatosis (LAM) (diffuse cysts, LAM cell proliferation HMB-45 positive, almost exclusively in women)
─ ─ Pulmonary Langerhans Cell Histiocytosis (PLCH) (cysts often irregular and upper lobe predominant, associated with smoking, Langerhans cells are CD1a+/S100+/Langerin+)
─ ─ Emphysema (especially paraseptal or bullous; shows airspace enlargement with destruction of alveolar walls, associated with smoking)
─ ─ Other inherited cystic lung diseases (e.g., Marfan syndrome if associated with apical bullae, Ehlers-Danlos)
─ ─ Nonspecific subpleural blebs or bullae (can cause pneumothorax but usually not as numerous or diffuse as BHD cysts, and without syndromic features)
─ ─ Cystic changes in other ILDs (e.g., LIP, desquamative interstitial pneumonia with cystic change)
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Emphysematous Cysts/Bullae (overlap with smoking-related)

Localized, large (>1 cm), thin-walled, air-filled spaces within the lung parenchyma (bullae) or pleura (blebs) resulting from severe emphysematous destruction of alveolar walls; these represent macroscopic cystic manifestations of underlying emphysema, primarily associated with smoking
Clinical ─
─ Often occur in patients with established emphysema, typically centriacinar or paraseptal types
─ Can be asymptomatic and detected incidentally on imaging, or cause significant dyspnea due to compression of adjacent, more functional lung parenchyma (if very large - "giant bulla")
─ Risk of spontaneous pneumothorax if a bulla or bleb ruptures, especially apical bullae in paraseptal emphysema
─ May become secondarily infected (infected bulla)
Macro ─
─ Bullae: Large, air-filled cystic structures (>1 cm diameter, can be many centimeters) located within the lung parenchyma, often at the lung apices or along interlobular septa or pleural margins. Walls are thin and may show trabeculations (remnants of blood vessels or septa).
─ Blebs: Smaller air collections (<1 cm, though some use the term interchangeably with small bullae) located within the layers of the visceral pleura, or just deep to it, appearing as thin-walled blisters on the lung surface.
─ Surrounding lung typically shows evidence of emphysema
Micro ─
─ Wall of a bulla or bleb:
─ ─ Composed of attenuated, fibrotic visceral pleura and markedly compressed, emphysematous lung parenchyma
─ ─ May show remnants of destroyed alveolar septa traversing the space or within the wall
─ Lining: Typically lined by flattened alveolar epithelium (type I pneumocytes) or may be denuded (lacking an epithelial lining) in areas, especially if there has been rupture or inflammation
─ Surrounding lung parenchyma characteristically shows features of emphysema (e.g., enlarged airspaces with destruction of alveolar walls, loss of elastic recoil, carbon pigment if centriacinar)
─ Minimal inflammation is usually present unless there is secondary infection (then neutrophils, exudate) or rupture (then organization, granulation tissue)
─ Absence of specific cellular proliferations (e.g., LAM cells, Langerhans cells) or complex wall structures seen in other primary cystic diseases
Ancillary studies ─
─ Generally not required for the pathologic diagnosis of the bulla/bleb itself if the context of emphysema is clear
─ Histologic examination confirms the nature of the cyst wall and the presence of underlying emphysema
─ Elastic stains can demonstrate the loss and fragmentation of elastic fibers in the surrounding emphysematous lung and cyst wall
DDx ─
─ Other cystic lung diseases:
─ ─ Lymphangioleiomyomatosis (LAM), Pulmonary Langerhans Cell Histiocytosis (PLCH), Birt-Hogg-Dubé Syndrome (these have distinct histologic features in their walls or specific cellular components, and different clinical contexts/distributions)
─ ─ Bronchogenic cyst (congenital, typically solitary, wall contains cartilage and glands)
─ ─ Congenital Pulmonary Airway Malformation (CPAM) (congenital, adenomatoid/cystic bronchiolar structures)
─ Pneumatocele (a thin-walled, air-filled cyst that usually develops acutely following pneumonia, particularly Staphylococcus aureus, or trauma; often transient but can persist)
─ Distinction from other primary cystic lung diseases relies on identifying the underlying emphysematous changes and the lack of specific features characteristic of those other conditions
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Other Non-Neoplastic Lung Diseases

Pulmonary Alveolar Proteinosis (PAP)

A rare syndrome characterized by the abnormal accumulation of excessive surfactant-derived lipoproteinaceous material within alveolar spaces, primarily due to impaired clearance by dysfunctional alveolar macrophages
Clinical ─
─ Presentation is variable: Insidious onset of progressive dyspnea on exertion, non-productive cough, fatigue, weight loss, low-grade fever, hypoxemia
─ Can be asymptomatic and detected incidentally on imaging
─ Characteristic "crazy-paving" pattern on high-resolution CT (HRCT) chest (geographic areas of ground-glass opacity superimposed with interlobular septal thickening)
─ Types:
─ ─ Autoimmune PAP (Primary/Idiopathic PAP): Most common form (~90% of cases); caused by neutralizing autoantibodies against Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF), which is essential for alveolar macrophage maturation and surfactant clearance function
─ ─ Secondary PAP: Associated with underlying conditions that impair macrophage function or increase surfactant production, e.g., hematologic malignancies (myelodysplasia, leukemia), immunosuppression (drugs, HIV), inhalation of dusts (e.g., silica, titanium dioxide), or certain infections
─ ─ Congenital/Hereditary PAP: Rare, due to genetic mutations affecting surfactant protein production (e.g., SFTPB, SFTPC, ABCA3) or GM-CSF receptor function (e.g., CSF2RA, CSF2RB)
─ Whole lung lavage is the standard therapy for autoimmune PAP
Macro ─
─ Lungs are typically heavy, firm, and may appear yellowish-white or pale gray
─ Cut surface exudes a milky, turbid, or granular proteinaceous fluid from the airspaces
Micro ─
─ Alveolar spaces are diffusely filled with abundant, dense, granular, eosinophilic, acellular or paucicellular material
─ This material is strongly PAS (Periodic Acid-Schiff)-positive and diastase-resistant (due to its glycoprotein and lipid content)
─ Within the proteinaceous material, characteristic acicular cholesterol clefts (empty spaces after lipid dissolution) and scattered, rounded, lamellar bodies (ultrastructural remnants of surfactant) may be seen
─ Alveolar septa are usually relatively preserved and may show minimal thickening or mild type II pneumocyte hyperplasia; significant interstitial inflammation or fibrosis is typically absent unless there is superimposed infection or long-standing disease
─ Alveolar macrophages may be present but appear unable to effectively clear the material
Ancillary studies ─
─ PAS stain (with diastase digestion): Strongly positive staining of the intra-alveolar material is a key diagnostic feature
─ GMS (Grocott Methenamine Silver) and AFB stains: Should be negative; crucial to exclude Pneumocystis jirovecii pneumonia (which has foamy intra-alveolar exudates but is GMS positive for organisms) and other infections
─ Electron Microscopy (EM) (on BAL fluid sediment or lung tissue): Can demonstrate the characteristic lamellar bodies (myelin-like figures) of surfactant within the alveolar material
─ Testing for anti-GM-CSF antibodies in serum or BAL fluid is diagnostic for autoimmune PAP
DDx ─
─ Pneumocystis jirovecii Pneumonia (PJP) (foamy intra-alveolar exudate which can be PAS positive, but PJP organisms are highlighted by GMS stain)
─ Cardiogenic pulmonary edema (intra-alveolar fluid is typically pink, homogeneous, and less granular; PAS staining is usually weaker; clinical context of heart failure)
─ Diffuse Alveolar Damage (DAD) (presence of hyaline membranes, epithelial necrosis, and more prominent inflammation/organization)
─ Lipoid pneumonia (alveoli filled with lipid-laden macrophages and free lipid vacuoles; Oil Red O positive on frozen tissue for neutral lipids)
─ Lysinuric protein intolerance (rare genetic disorder, can have PAP-like histology)
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Lipoid Pneumonia

A form of lung disease characterized by the accumulation of lipid (either exogenous or endogenous) within alveolar spaces and interstitium, leading to a chronic inflammatory and often fibrotic reaction
Clinical ─
─ Exogenous Lipoid Pneumonia:
─ ─ Caused by aspiration or inhalation of mineral oils (most common, e.g., liquid paraffin used as laxative, oil-based nasal drops/sprays), animal fats, or vegetable oils
─ ─ Often occurs in individuals with impaired swallowing, gag reflex, or esophageal motility (e.g., elderly, neurologically impaired, GERD) or specific occupational/cultural practices
─ ─ Presentation is often insidious and chronic: cough, dyspnea, low-grade fever, chest pain; may be asymptomatic and found incidentally as lung nodules/masses ("paraffinoma") or consolidations on imaging
─ Endogenous Lipoid Pneumonia (Obstructive Lipoid Pneumonia, Cholesterol Pneumonia):
─ ─ Occurs distal to a chronic airway obstruction (e.g., tumor, bronchiectasis, foreign body, bronchial stenosis)
─ ─ Results from the accumulation of lipid derived from the breakdown of cell membranes of inflammatory cells and sloughed epithelial cells within obstructed airspaces
Macro ─
─ Affected areas of the lung may appear firm, consolidated, and yellowish or golden-brown due to lipid accumulation
─ Exogenous form can produce localized, well-circumscribed tumor-like masses ("paraffinoma" or "oil granuloma") or diffuse infiltrates
─ Endogenous form often associated with features of the underlying obstructive lesion
Micro ─
─ Exogenous Lipoid Pneumonia:
─ ─ Alveolar spaces are filled with numerous lipid-laden macrophages (foamy macrophages or lipophages) containing variably sized, clear, sharply defined, round vacuoles of exogenous lipid (dissolved out during routine paraffin processing, leaving empty spaces)
─ ─ Extracellular lipid vacuoles of varying sizes may also be present in alveoli and interstitium
─ ─ Chronic interstitial inflammation (lymphocytes, plasma cells) and variable degrees of fibrosis are common, often leading to thickening of alveolar septa
─ ─ Foreign body giant cell reaction to the lipid droplets is frequently seen
─ ─ Cholesterol clefts may be present but are usually less prominent than in endogenous lipoid pneumonia
─ Endogenous Lipoid Pneumonia:
─ ─ Sheets of foamy macrophages (lipophages) filling alveolar spaces distal to an obstruction; the lipid within these macrophages is primarily cholesterol and cholesterol esters from cellular breakdown
─ ─ Cholesterol clefts (empty, needle-shaped spaces within the inflammatory infiltrate and giant cells) are often numerous and prominent
─ ─ Chronic inflammation, organizing pneumonia, and fibrosis are typically present
─ ─ The underlying cause of airway obstruction (e.g., tumor cells) may be evident in the biopsy
Ancillary studies ─
─ Oil Red O or Sudan Black B stain (performed on frozen sections of lung tissue or cytological preparations of BAL fluid): Stains neutral lipids (triglycerides, mineral oil) bright red or black respectively. This is diagnostic for exogenous lipoid pneumonia if fresh/frozen tissue or appropriate cytology specimen is available, as these lipids are dissolved during routine paraffin processing.
─ PAS stain: Macrophages may contain PAS-positive granules (ceroid/lipofuscin), but the lipid vacuoles themselves are PAS-negative
DDx ─
─ Pulmonary Alveolar Proteinosis (PAP) (alveoli filled with granular, PAS-positive material, not lipid vacuoles; Oil Red O negative)
─ Pneumocystis jirovecii Pneumonia (PJP) (foamy intra-alveolar exudate, but GMS positive for organisms; lipid stains negative)
─ Drug-induced phospholipidosis (e.g., amiodarone lung – foamy macrophages, but lipid is phospholipid, lamellated inclusions on EM; different clinical context)
─ Malakoplakia (rare, granulomatous inflammation with Michaelis-Gutmann bodies – calcified spherules within macrophages)
─ Xanthogranulomatous inflammation or tumors (sheets of foamy histiocytes, but often with Touton giant cells and other inflammatory cells, usually more destructive or mass-forming)
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Lung Transplantation Pathology

Major Types of Rejection (Acute Cellular, Antibody-Mediated, Chronic - BOS/CLAD) - Lung Transplantation Pathology Overview

An overview of the principal immunologic rejection processes affecting lung allografts, which are major causes of graft dysfunction, morbidity, and mortality following lung transplantation
Clinical ─
─ Symptoms of rejection are variable and depend on the type and severity; may include dyspnea, cough, low-grade fever, decline in pulmonary function tests (especially FEV1 for Bronchiolitis Obliterans Syndrome - BOS), and hypoxemia
─ Surveillance transbronchial biopsies (TBBx) and bronchoalveolar lavage (BAL) are often performed at scheduled intervals and for cause to monitor for rejection and infection
Micro ─
─ Acute Cellular Rejection (ACR): (ISHLT Grading System A0-A4)
─ ─ T-lymphocyte mediated injury targeting primarily airways and/or vessels
─ ─ Grade A (Airway inflammation): Characterized by perivascular and peribronchiolar/bronchial lymphocytic infiltrates. Severity graded based on intensity and extent of infiltrate:
─ ─ ─ A1 (Minimal): Scattered, loose lymphocytic infiltrates
─ ─ ─ A2 (Mild): More organized circumferential infiltrates around vessels/airways
─ ─ ─ A3 (Moderate): Dense infiltrates expanding submucosa/adventitia, may extend into epithelium/media
─ ─ ─ A4 (Severe): Dense infiltrates with associated epithelial damage, necrosis, or ulceration; may form lymphoid follicles
─ ─ Lymphocytic bronchiolitis and/or endothelialitis (lymphocytes attached to or infiltrating vascular endothelium) are key features
─ Antibody-Mediated Rejection (AMR):
─ ─ Mediated by donor-specific antibodies (DSA) against HLA or non-HLA antigens expressed on donor lung endothelium and epithelium
─ ─ Can be acute (early post-transplant) or chronic
─ ─ Histologic features can be subtle, nonspecific, or overlap with ACR, infection, or injury; consensus criteria for pathologic AMR diagnosis are still evolving but often include:
─ ─ ─ Capillary inflammation/endothelialitis: Neutrophils and/or mononuclear cells within alveolar capillaries, endothelial swelling/damage
─ ─ ─ Intravascular accumulation of macrophages in capillaries
─ ─ ─ Interstitial edema, fibrin deposition, or features of Diffuse Alveolar Damage (DAD) in severe cases
─ ─ ─ Positive C4d staining (by IHC or immunofluorescence) in alveolar capillaries (a marker of classical complement activation, highly suggestive but not always present or specific)
─ ─ Diagnosis requires correlation of histologic findings with serologic detection of DSA and clinical graft dysfunction
─ Chronic Lung Allograft Dysfunction (CLAD): The major long-term complication, leading to irreversible airflow obstruction or restriction
─ ─ Bronchiolitis Obliterans Syndrome (BOS): Most common form of CLAD, clinically defined by a persistent decline in FEV1. Pathologic correlate is Bronchiolitis Obliterans (BO) / Constrictive Bronchiolitis:
─ ─ ─ Characterized by fibrotic and inflammatory obliteration of small airways (membranous and respiratory bronchioles). Concentric submucosal and peribronchiolar fibrosis leads to luminal narrowing or complete occlusion. The inflammatory component (lymphocytes, plasma cells) may be active or scant in late stages.
─ ─ Restrictive Allograft Syndrome (RAS) / Azithromycin-Responsive Allograft Dysfunction (ARAD): Another form of CLAD, characterized by a restrictive PFT pattern and often associated with peripheral parenchymal fibrosis (e.g., UIP-like or NSIP-like patterns) on imaging/histology.
Ancillary studies ─
─ For ACR: IHC for T-lymphocyte markers (e.g., CD3, CD4, CD8) can highlight the lymphocytic infiltrates but is generally not required for routine grading
─ For AMR:
─ ─ C4d immunohistochemistry or immunofluorescence on lung tissue (TBBx or explant)
─ ─ Serum testing for Donor-Specific Antibodies (DSA) is crucial
─ Special stains for microorganisms (GMS, AFB, Gram) and viral studies (e.g., CMV IHC/PCR) are MANDATORY on all transplant biopsies to rule out opportunistic infections, which can mimic or coexist with rejection
─ Elastic stains (VVG) can highlight airway obliteration in Bronchiolitis Obliterans
DDx ─
─ Infection (especially viral like CMV, or fungal/bacterial pneumonia – can cause inflammation, DAD, or bronchiolitis that mimics rejection; a major and critical differential)
─ Drug toxicity (from immunosuppressants or other medications)
─ Aspiration pneumonia
─ Recurrence of the primary underlying lung disease (e.g., sarcoidosis, IPF in rare cases)
─ Post-Transplant Lymphoproliferative Disorder (PTLD) (see next entry)
─ Diffuse Alveolar Damage (DAD) from non-rejection causes (e.g., infection, drugs, ischemia-reperfusion injury early post-transplant)
─ Organizing pneumonia (can be a feature of rejection, infection, or idiopathic)
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Common Infections Post-Transplant (Lung Transplant context)

An overview of frequent infectious agents encountered in lung transplant recipients, who are at high risk due to profound immunosuppression, direct exposure of the allograft to the environment, and potential donor-derived infections
Clinical ─
─ Presentation is highly variable: Fever, cough, dyspnea, new or worsening pulmonary infiltrates on imaging, decline in pulmonary function tests (PFTs), malaise; can mimic or coexist with acute or chronic rejection
─ Timing of infection post-transplant can provide clues to likely pathogens:
─ ─ Early (first month): Often nosocomial bacterial pneumonias, aspiration, donor-derived infections, Candida spp.
─ ─ Intermediate (1-6 months): Peak time for opportunistic infections like Cytomegalovirus (CMV), Pneumocystis jirovecii Pneumonia (PJP) (if prophylaxis fails/not given), Aspergillus spp.
─ ─ Late (>6 months): Community-acquired respiratory viruses (influenza, RSV, parainfluenza), recurrent bacterial pneumonias, chronic fungal infections, Nontuberculous Mycobacteria (NTM)
Macro ─
─ Nonspecific; may include areas of consolidation, nodules, cavitation (e.g., fungal, mycobacterial), or diffuse ground-glass opacities depending on the pathogen and host response
Micro ─
─ Bacterial Pneumonia:
─ ─ Common pathogens: Pseudomonas aeruginosa, Staphylococcus aureus (including MRSA), Klebsiella pneumoniae, Haemophilus influenzae, other Gram-negative rods
─ ─ Histologic patterns: Bronchopneumonia, lobar pneumonia, diffuse alveolar damage (DAD), abscess formation; neutrophilic infiltrates are typical but may be blunted in severely immunosuppressed patients
─ Viral Pneumonia:
─ ─ Cytomegalovirus (CMV): Very common and significant. Can cause interstitial pneumonitis, DAD, or nodules. Characteristic viral cytopathic effect: enlarged cells (pneumocytes, endothelial cells, macrophages) with large, basophilic intranuclear inclusions ("owl's eye") and smaller basophilic cytoplasmic inclusions.
─ ─ Respiratory Syncytial Virus (RSV), Parainfluenza virus, Influenza virus, Human Metapneumovirus, Adenovirus: Can cause bronchiolitis (often necrotizing with adenovirus), interstitial pneumonia, or DAD. Specific viral inclusions may be seen (e.g., "smudge cells" for adenovirus).
─ ─ Herpes Simplex Virus (HSV) / Varicella-Zoster Virus (VZV): Less common in lung parenchyma but can cause necrotizing tracheobronchitis or pneumonia with characteristic multinucleated giant cells and Cowdry A/B inclusions.
─ Fungal Pneumonia:
─ ─ Aspergillus spp. (e.g., A. fumigatus): Common and potentially life-threatening. Patterns include:
─ ─ ─ Invasive aspergillosis: Angioinvasion by septate hyphae (acute angle branching) leading to thrombosis, hemorrhage, and infarction with surrounding inflammation.
─ ─ ─ Aspergillus bronchitis/tracheobronchitis: Invasion of airway walls.
─ ─ ─ Aspergilloma: Fungus ball in a pre-existing cavity (less common as primary issue post-transplant).
─ ─ Candida spp.: Often represents colonization of airways, but can cause invasive pneumonia (yeasts and pseudohyphae invading tissue) or tracheobronchitis, especially in severely ill patients.
─ ─ Pneumocystis jirovecii Pneumonia (PJP): Diffuse interstitial pneumonitis with characteristic foamy, eosinophilic, intra-alveolar exudate containing PJP cysts (cup-shaped or crescentic on GMS stain). Prophylaxis is highly effective.
─ ─ Endemic fungi (Histoplasma, Coccidioides, Blastomyces) or Cryptococcus can occur, especially in endemic areas or from donor transmission.
─ Mycobacterial Infections:
─ ─ Mycobacterium tuberculosis (TB) or Nontuberculous Mycobacteria (NTM) (e.g., MAC, M. abscessus)
─ ─ Granulomatous inflammation (may be poorly formed or absent in severely immunosuppressed patients), caseous necrosis (more typical for TB), or chronic fibrocavitary disease. Acid-fast bacilli (AFB) seen on special stains.
Ancillary studies ─
─ Special stains are CRITICAL:
─ ─ GMS (Grocott Methenamine Silver) and PAS for fungi
─ ─ Gram stain (e.g., Brown-Hopps) for bacteria
─ ─ AFB (Ziehl-Neelsen, Kinyoun) for mycobacteria
─ IHC or in situ hybridization (ISH) for viral antigens/nucleic acids (e.g., CMV, HSV, Adenovirus, SARS-CoV-2)
─ Cultures (bacterial, fungal, viral, mycobacterial) from bronchoalveolar lavage (BAL) fluid, protected brushings, or lung tissue are essential for definitive identification and susceptibility testing
─ PCR and other molecular assays on BAL or tissue for rapid detection of pathogens
DDx ─
─ Acute or Chronic Rejection (ACR, AMR, CLAD/BOS) – can have overlapping clinical and radiological features; biopsy interpretation requires careful correlation and exclusion of infection
─ Drug toxicity (from immunosuppressants or other medications)
─ Post-Transplant Lymphoproliferative Disorder (PTLD)
─ Diffuse Alveolar Damage (DAD) from non-infectious causes (e.g., ischemia-reperfusion injury early post-transplant, drug reaction)
─ Aspiration pneumonia
─ Organizing pneumonia (can be post-infectious or related to rejection/drugs)
─ It is common for multiple processes (e.g., infection and rejection) to occur simultaneously
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Post-Transplant Lymphoproliferative Disorders (PTLD) - Overview (Lung Transplant context)

A spectrum of lymphoid proliferations or overt lymphomas that occur in the setting of immunosuppression following solid organ transplantation (SOT) or hematopoietic stem cell transplantation (HSCT); often, but not always, driven by Epstein-Barr Virus (EBV) infection or reactivation in B-lymphocytes
Clinical ─
─ A serious complication of transplantation, with variable clinical presentation
─ May be asymptomatic or cause fever, lymphadenopathy (graft, nodal, or extranodal), weight loss, graft dysfunction (e.g., new pulmonary infiltrates or nodules in lung transplant recipients), or symptoms related to mass lesions in other organs
─ Risk factors: Degree and duration of immunosuppression, EBV serostatus mismatch (recipient EBV-negative / donor EBV-positive at time of transplant confers highest risk), type of organ transplanted (higher incidence after thoracic organ transplants compared to kidney)
─ Can occur at any time post-transplant, but often within the first year or with increased immunosuppression
Macro ─
─ Can manifest as localized nodules or masses within the lung allograft, hilar/mediastinal lymph nodes, or other sites
─ May also present as diffuse infiltrates within the lung parenchyma or pleural effusions
Micro ─
─ WHO Classification categorizes PTLD into a spectrum:
─ Early Lesions (Non-destructive PTLD): Usually polyclonal, often EBV-positive.
─ ─ Plasmacytic Hyperplasia: Diffuse infiltrates of mature-appearing polyclonal plasma cells, often with scattered immunoblasts.
─ ─ Infectious Mononucleosis-like PTLD: Polymorphous infiltrate of activated lymphocytes, immunoblasts, and plasma cells, resembling infectious mononucleosis.
─ Polymorphic PTLD (P-PTLD): Destructive lesions with architectural effacement.
─ ─ Characterized by a mixed infiltrate of small, intermediate, and large atypical lymphocytes, plasma cells, and immunoblasts; Reed-Sternberg-like cells may be seen.
─ ─ Cells show a range of atypia but do not meet criteria for a specific lymphoma subtype. Necrosis is common.
─ ─ Often EBV-positive; may be polyclonal, oligoclonal, or monoclonal by molecular studies.
─ Monomorphic PTLD (M-PTLD): Meets criteria for a specific B-cell or T-cell lymphoma subtype according to WHO classification of lymphoid neoplasms.
─ ─ B-cell PTLDs are most common ( >80-90%):
─ ─ ─ Diffuse Large B-cell Lymphoma (DLBCL)-like PTLD: Most frequent type of M-PTLD; sheets of large, atypical lymphoid cells.
─ ─ ─ Burkitt lymphoma-like PTLD.
─ ─ ─ Other less common B-cell types (e.g., MALT lymphoma-like, plasma cell myeloma-like).
─ ─ T-cell and NK-cell PTLDs are rare, often EBV-negative, and carry a poorer prognosis.
─ Classical Hodgkin Lymphoma-like PTLD (rare).
─ Epstein-Barr Virus (EBV) association:
─ ─ Many PTLDs, especially early lesions and B-cell M-PTLDs, are EBV-driven. EBV infects B-lymphocytes, leading to their proliferation in the setting of suppressed T-cell immunity.
Ancillary studies ─
─ IHC is crucial:
─ ─ CD20 (B-cell marker), CD3 (T-cell marker) to characterize the infiltrate.
─ ─ CD30, CD15 for Hodgkin-like cells.
─ ─ Kappa and Lambda light chain immunohistochemistry to assess B-cell clonality (monoclonality suggests lymphoma, but P-PTLD can be monoclonal).
─ ─ Ki-67 proliferation index (often high in M-PTLD).
─ ─ Markers for specific lymphoma subtypes if M-PTLD is suspected (e.g., BCL2, BCL6, MYC for DLBCL subtyping).
─ In situ hybridization for EBV-encoded RNA (EBER): Positive in the nuclei of neoplastic cells in most EBV-driven PTLDs; highly sensitive and specific for detecting EBV.
─ Flow cytometry on fresh tissue or fluid: Can assess lymphocyte populations and demonstrate B-cell or T-cell clonality.
─ Molecular studies: Immunoglobulin (Ig) heavy and light chain gene rearrangements (for B-cell clonality) and T-cell receptor (TCR) gene rearrangements (for T-cell clonality) can be performed on tissue.
DDx ─
─ Acute Cellular Rejection (ACR) (especially high-grade ACR with dense lymphocytic infiltrates; ACR typically lacks destructive lesions and sheets of atypical cells seen in PTLD, EBER negative, polyclonal T-cells usually).
─ Infections (e.g., severe viral pneumonia like CMV can have atypical lymphocytic infiltrates; some infections can cause reactive lymphoid hyperplasia).
─ Primary lymphoma unrelated to transplant (rare in this setting).
─ Drug reactions causing lymphoid infiltrates.
─ Benign reactive lymphoid hyperplasia (non-destructive, polyclonal, EBER usually negative or only in scattered cells).
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Immunohistochemistry in Lung Tumor Diagnosis - Key Markers

An overview of commonly used immunohistochemical (IHC) stains that are essential tools in the diagnosis, classification, subtyping, and sometimes prognostication or prediction of therapy response for primary and metastatic lung tumors
Clinical ─
─ IHC is crucial when H&E morphology is ambiguous, especially on small biopsies or cytology specimens, for:
─ ─ Distinguishing primary lung carcinomas from metastatic tumors to the lung.
─ ─ Classifying poorly differentiated non-small cell lung carcinomas (NSCLC) into adenocarcinoma, squamous cell carcinoma, or other types (important for guiding molecular testing and therapy).
─ ─ Identifying neuroendocrine differentiation in tumors.
─ ─ Diagnosing mesothelioma and distinguishing it from adenocarcinoma.
─ ─ Identifying specific targetable protein expression (e.g., PD-L1, ALK, ROS1 though molecular methods are gold standard for ALK/ROS1 alterations).
Macro ─ N/A (IHC is a microscopic technique)
Micro ─
─ Key Markers for Lung Carcinoma Subtyping:
─ Adenocarcinoma Markers:
─ ─ TTF-1 (Thyroid Transcription Factor-1): Nuclear stain. Positive in ~75-85% of lung adenocarcinomas. Also positive in thyroid carcinomas, small cell lung carcinoma (SCLC), and some other neuroendocrine tumors.
─ ─ Napsin A: Cytoplasmic granular stain. Positive in ~80-90% of lung adenocarcinomas. Also positive in type II pneumocytes and renal cell carcinoma (papillary and clear cell types).
─ ─ CK7 (Cytokeratin 7): Cytoplasmic stain. Positive in most lung adenocarcinomas and many other adenocarcinomas (e.g., breast, ovary, biliary) and transitional cell carcinoma.
─ Squamous Cell Carcinoma (SCC) Markers:
─ ─ p63: Nuclear stain. Positive in most SCCs. Also stains basal cells in various epithelia, urothelial carcinoma, some salivary gland tumors.
─ ─ p40 (ΔNp63): Nuclear stain. More specific for squamous differentiation than p63 as it primarily stains squamous/basal cells, largely negative in adenocarcinomas.
─ ─ CK5/6 (Cytokeratin 5/6): Cytoplasmic stain. Positive in most SCCs. Also positive in mesothelioma, basal cells, some breast carcinomas.
─ ─ Desmoglein-3, Claudin-1: Less commonly used but can support squamous differentiation.
─ Neuroendocrine Tumor Markers (for Carcinoid tumors, SCLC, Large Cell Neuroendocrine Carcinoma - LCNEC):
─ ─ Chromogranin A: Cytoplasmic granular stain (often focal in SCLC/LCNEC, more diffuse in carcinoids).
─ ─ Synaptophysin: Cytoplasmic diffuse or granular stain (often more sensitive than chromogranin).
─ ─ CD56 (NCAM - Neural Cell Adhesion Molecule): Membranous stain (sensitive but not highly specific).
─ ─ TTF-1: Often positive in SCLC (~80-90%) and some pulmonary carcinoids.
─ ─ Ki-67 Proliferation Index: Nuclear stain. Crucial for grading neuroendocrine tumors: Low (<2%) in typical carcinoid, intermediate (2-20%) in atypical carcinoid, very high (>50-70%) in SCLC and LCNEC.
─ Markers to Differentiate Primary Lung Adenocarcinoma from Metastases:
─ ─ A panel approach is essential, combining lung-specific markers with markers suggestive of other primary sites:
─ ─ ─ TTF-1 (+), Napsin A (+) strongly favor lung primary (adenocarcinoma).
─ ─ ─ CK7 (+), CK20 (-) pattern is common in lung adenocarcinoma (but also seen in breast, thyroid, gynecologic tumors).
─ ─ ─ CK7 (-), CK20 (+) often suggests colorectal primary (CDX2+).
─ ─ ─ CDX2 (colorectal, upper GI, pancreaticobiliary), GATA3 (breast, urothelial), PAX8 (renal, thyroid, Müllerian), PSA/PSAP (prostate), SOX10/Melan-A (melanoma), S100 (melanoma, some sarcomas, nerve sheath), CD45 (lymphoma).
─ Mesothelioma Markers:
─ ─ Positive "mesothelial" markers: Calretinin (nuclear and cytoplasmic), WT1 (nuclear, especially in epithelioid mesothelioma), CK5/6, D2-40 (podoplanin).
─ ─ Negative "carcinoma" markers (to exclude adenocarcinoma): TTF-1, Napsin A, CEA (monoclonal), MOC31, Ber-EP4, Claudin-4 (adenocarcinomas are usually positive for at least some of these).
─ ─ BAP1 (BRCA1 associated protein-1): Loss of nuclear expression by IHC is common in malignant mesothelioma and supports diagnosis over reactive mesothelial hyperplasia.
─ Other Important Markers in Lung Cancer:
─ ─ PD-L1 (Programmed Death-Ligand 1): Membranous +/- cytoplasmic staining on tumor cells and/or immune cells; predicts response to immune checkpoint inhibitors. Scoring methods (TPS, CPS) vary.
─ ─ ALK (Anaplastic Lymphoma Kinase) and ROS1: IHC can screen for protein overexpression due to gene rearrangements in adenocarcinoma (D5F3 clone for ALK, D4D6 for ROS1); positive cases typically confirmed by FISH or molecular methods.
Ancillary studies ─
─ Interpretation of IHC must always be in the context of H&E morphology, clinical information, and radiological findings.
─ Use of appropriate positive and negative controls for each antibody is critical for quality assurance.
─ Panels of antibodies are generally more useful than single stains.
DDx ─
─ The differential diagnosis depends on the specific tumor morphology; IHC helps to narrow down possibilities among different primary lung cancers, metastatic tumors, mesothelioma, or non-neoplastic mimics.
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LUNG: NEOPLASTIC DISEASES

Molecular Pathology of Lung Cancer (EGFR, ALK, ROS1, BRAF, MET, RET, KRAS, HER2/ERBB2, NTRK, PIK3CA, TP53, KEAP1, STK11/LKB1 etc.)

The study of genomic, transcriptomic, and proteomic alterations in lung cancer cells that drive tumorigenesis, define tumor subtypes, predict response or resistance to targeted therapies and immunotherapy, and inform prognosis
Clinical ─
─ Essential for personalized medicine in Non-Small Cell Lung Cancer (NSCLC), particularly adenocarcinoma, to identify patients eligible for specific targeted therapies or immunotherapies
─ Molecular testing is standard of care for advanced/metastatic NSCLC (especially non-squamous) at diagnosis; also increasingly used in early-stage disease for prognostication or adjuvant therapy decisions
─ Performed on tumor tissue (surgical resection, biopsy) or cytology specimens (e.g., FNA, cell blocks, pleural fluid); liquid biopsies (ctDNA) are an alternative if tissue is insufficient/unobtainable
─ Common targetable alterations and their significance (primarily in NSCLC adenocarcinoma unless specified):
─ ─ EGFR (Epidermal Growth Factor Receptor): Activating mutations (e.g., exon 19 deletions, L858R in exon 21) predict response to EGFR Tyrosine Kinase Inhibitors (TKIs) (e.g., osimertinib, gefitinib, erlotinib). EGFR exon 20 insertion mutations are a distinct group, generally less sensitive to older EGFR TKIs but with newer targeted agents available. Acquired resistance mutations (e.g., T790M) can develop, for which specific TKIs exist (e.g., osimertinib targets T790M).
─ ─ ALK (Anaplastic Lymphoma Kinase): Gene rearrangements (fusions, most commonly with EML4) occur in a subset of adenocarcinomas (often younger, never/light smokers). Predict response to ALK TKIs (e.g., alectinib, brigatinib, lorlatinib).
─ ─ ROS1: Gene rearrangements (fusions) in adenocarcinoma. Predict response to ROS1 TKIs (e.g., crizotinib, entrectinib, repotrectinib); often share inhibitors with ALK.
─ ─ BRAF: Activating mutations, most commonly V600E, in adenocarcinoma. Predict response to BRAF inhibitors (e.g., dabrafenib) often combined with MEK inhibitors (e.g., trametinib).
─ ─ MET: MET exon 14 skipping mutations or MET gene amplification in NSCLC (adenocarcinoma, squamous, sarcomatoid). Predict response to MET inhibitors (e.g., capmatinib, tepotinib).
─ ─ RET: Gene rearrangements (fusions) in adenocarcinoma. Predict response to selective RET TKIs (e.g., selpercatinib, pralsetinib).
─ ─ KRAS: Common mutations (e.g., G12C, G12D, G12V) in adenocarcinoma (especially smoking-related) and some SCC. Historically considered "undruggable," but specific KRAS G12C inhibitors (e.g., sotorasib, adagrasib) are now available. Other KRAS mutations are targets of ongoing research. KRAS mutations often confer resistance to EGFR TKIs.
─ ─ HER2 (ERBB2): Activating mutations (especially exon 20 insertions) or gene amplification in adenocarcinoma. Targeted therapies (e.g., antibody-drug conjugates like trastuzumab deruxtecan) are emerging.
─ ─ NTRK (Neurotrophic Tyrosine Receptor Kinase) 1, 2, or 3: Gene fusions occur rarely in various cancers including lung. Predict response to pan-TRK inhibitors (e.g., larotrectinib, entrectinib) – a tumor-agnostic approval.
─ ─ PIK3CA: Activating mutations can occur in NSCLC; role in PI3K/AKT/mTOR pathway. Targeted therapies are under investigation in lung cancer.
─ ─ TP53: Tumor suppressor gene, frequently mutated in most lung cancer types (SCLC, SCC, adenocarcinoma). Generally associated with poorer prognosis and may influence response to therapies but not directly "targetable" with specific inhibitors currently.
─ ─ KEAP1/NRF2 pathway: Alterations (mutations in KEAP1 or NFE2L2) are common in NSCLC, associated with oxidative stress response and often linked to resistance to chemotherapy and immunotherapy.
─ ─ STK11/LKB1: Tumor suppressor gene, mutations are common, especially in KRAS-mutant lung adenocarcinoma (often in smokers). Associated with poor response to immunotherapy (PD-1/PD-L1 inhibitors).
─ Other Molecular Concepts:
─ ─ Tumor Mutational Burden (TMB): Measure of the total number of somatic mutations per megabase of DNA; high TMB may predict response to immunotherapy in some cancers, including NSCLC (though utility is still debated and context-dependent).
Macro ─ N/A
Micro ─ N/A (Molecular alterations are not directly visible by H&E; specific IHC can reflect some protein-level changes, e.g., ALK/ROS1 overexpression)
Ancillary studies ─
─ Methods of detection:
─ ─ Immunohistochemistry (IHC): Can be used as a screening tool for protein overexpression resulting from some rearrangements (e.g., ALK, ROS1) or for specific mutant proteins (e.g., BRAF V600E, EGFR L858R/del19 - less common).
─ ─ Fluorescence In Situ Hybridization (FISH): Detects gene rearrangements (e.g., ALK, ROS1, RET) using break-apart or fusion probes; also for gene amplification (MET, HER2).
─ ─ PCR-based methods: Sanger sequencing (older, for specific known hotspots), real-time PCR (qPCR), digital PCR (dPCR) – for detecting specific point mutations, insertions, deletions (e.g., EGFR, BRAF, KRAS).
─ ─ Next-Generation Sequencing (NGS): Increasingly the standard of care. Allows simultaneous analysis of multiple genes for various types of alterations (point mutations, indels, copy number variations, rearrangements/fusions). Can be DNA-based (targeted panels, whole exome, whole genome) or RNA-based (especially good for fusion detection).
─ ─ RNA sequencing (RNA-seq): Particularly useful for detecting gene fusions and splice variants (e.g., MET exon 14 skipping).
DDx ─ N/A
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Liquid Biopsies in Lung Cancer

A minimally invasive diagnostic approach involving the analysis of circulating tumor-derived material from body fluids, primarily blood (plasma), to detect genomic alterations, monitor disease progression, and assess treatment response in lung cancer patients
Clinical ─
─ Applications in lung cancer management:
─ ─ Initial diagnosis of targetable driver mutations (e.g., EGFR, ALK, ROS1, BRAF, MET, RET) when tissue biopsy is insufficient, unobtainable, difficult, or too risky, or when rapid results are needed.
─ ─ Monitoring response to targeted therapy: Tracking changes in ctDNA levels can indicate treatment efficacy.
─ ─ Detecting mechanisms of acquired resistance to targeted therapies: e.g., emergence of EGFR T790M mutation in patients on first/second-generation EGFR TKIs, or other resistance mutations for ALK/ROS1 inhibitors.
─ ─ Assessing tumor heterogeneity: ctDNA may capture a broader representation of tumor genomic landscape than a single-site tissue biopsy.
─ ─ Potentially for minimal residual disease (MRD) detection after curative-intent therapy or for early cancer detection/screening (largely investigational for these uses).
─ Advantages: Minimally invasive (simple blood draw), allows for serial sampling, can overcome issues of tissue heterogeneity and accessibility.
─ Limitations: Sensitivity depends on tumor burden, stage, location, and rate of shedding of tumor material into circulation. False negatives can occur if ctDNA levels are below the detection limit of the assay. Potential for detecting clonal hematopoiesis of indeterminate potential (CHIP) mutations (somatic mutations in blood cells, not tumor-derived), which can confound interpretation if not carefully considered and filtered.
Macro ─ N/A (procedure is typically a peripheral blood draw)
Micro ─
─ Analytes (circulating tumor-derived material):
─ ─ Cell-free DNA (cfDNA): Small fragments of DNA released into the bloodstream from both normal and tumor cells (through apoptosis, necrosis, or active secretion).
─ ─ ─ Circulating tumor DNA (ctDNA) is the fraction of cfDNA derived specifically from tumor cells; it carries tumor-specific genomic alterations.
─ ─ Circulating Tumor Cells (CTCs): Intact tumor cells that have detached from the primary tumor or metastases and entered the bloodstream. Can be isolated and analyzed for genomic, transcriptomic, or proteomic features. Less commonly used for routine clinical mutation testing in lung cancer compared to ctDNA due to rarity and technical challenges in isolation/analysis.
─ ─ Other analytes (largely investigational for routine diagnostics): Exosomes and other extracellular vesicles (contain tumor-derived nucleic acids and proteins), circulating RNA (e.g., mRNA, microRNA), tumor-educated platelets.
─ Detection Methods for ctDNA:
─ ─ Highly sensitive techniques are required due to the often low fraction of ctDNA in total cfDNA.
─ ─ PCR-based methods: Droplet digital PCR (ddPCR), BEAMing (Beads, Emulsion, Amplification, and Magnetics) – good for detecting known hotspot mutations with high sensitivity.
─ ─ Next-Generation Sequencing (NGS): Targeted gene panels specifically designed for cfDNA analysis (hybrid capture or amplicon-based) are commonly used to detect a broader range of mutations, fusions, and copy number alterations. Requires bioinformatics pipelines optimized for low-input, fragmented DNA.
Ancillary studies ─
─ The liquid biopsy itself is an ancillary diagnostic/monitoring tool.
─ Results should be interpreted in conjunction with clinical information, imaging, and ideally, paired tissue biopsy results when available (tissue remains the gold standard for initial diagnosis and comprehensive molecular profiling if adequate).
─ Orthogonal validation of liquid biopsy findings with tissue testing may be considered, especially for unexpected results or critical treatment decisions.
DDx ─ N/A
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PD-L1 Testing

Immunohistochemical (IHC) assessment of Programmed Death-Ligand 1 (PD-L1) protein expression on tumor cells and/or immune cells, used as a predictive biomarker to guide patient selection for immune checkpoint inhibitor (ICI) therapy (e.g., anti-PD-1 or anti-PD-L1 antibodies) in lung cancer and other malignancies
Clinical ─
─ Guides treatment decisions for patients with advanced or metastatic Non-Small Cell Lung Cancer (NSCLC) and Small Cell Lung Cancer (SCLC), among other cancer types
─ PD-L1 expression levels can help predict the likelihood of response to ICIs, either as monotherapy or in combination with chemotherapy
─ Multiple FDA-approved PD-L1 IHC assays (clones) exist, often paired with specific ICI drugs:
─ ─ 22C3 pharmDx (for pembrolizumab)
─ ─ 28-8 pharmDx (for nivolumab)
─ ─ SP142 (for atezolizumab in some contexts, e.g., breast cancer; historically used in some lung trials)
─ ─ SP263 (for durvalumab, pembrolizumab in some contexts)
─ Scoring systems and interpretation cutoffs (e.g., for positivity) vary depending on the assay, cancer type, and specific therapeutic indication (e.g., first-line vs. subsequent lines of therapy)
Macro ─ N/A (IHC is a microscopic technique)
Micro ─
─ Scoring of PD-L1 expression:
─ Tumor Proportion Score (TPS): The percentage of viable tumor cells showing partial or complete membrane staining for PD-L1 at any intensity. This is the most common scoring method for NSCLC with assays like 22C3 and 28-8/SP263.
─ ─ Cutoffs typically used: e.g., TPS <1%, TPS ≥1%, TPS ≥50% to categorize patients for different treatment regimens.
─ Combined Positive Score (CPS): (Less commonly the primary score for NSCLC, but used in some other cancers and contexts). Calculated as the number of PD-L1 staining cells (tumor cells, lymphocytes, macrophages) divided by the total number of viable tumor cells, multiplied by 100.
─ Immune Cell (IC) Score: Percentage of tumor area occupied by PD-L1 staining tumor-associated immune cells of any intensity (used by some assays like SP142 for certain indications).
─ Staining characteristics: PD-L1 staining is typically membranous, but cytoplasmic staining can also be seen (usually not scored unless specified by assay guidelines).
─ Heterogeneity: PD-L1 expression can be heterogeneous within a tumor and between primary tumor and metastases.
─ Adequacy of specimen: Requires an adequate number of viable tumor cells for accurate assessment (e.g., typically ≥100 tumor cells). Necrosis and crush artifact can interfere with interpretation.
Ancillary studies ─
─ The PD-L1 IHC test itself is the ancillary study.
─ Pathologist interpretation and scoring must strictly follow the validated guidelines for the specific antibody clone, staining platform, and cancer type/indication.
─ Participation in external quality assurance programs is important for consistency.
DDx ─ N/A (This is an assay interpretation for a predictive biomarker, not a disease entity)
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Staging of Lung Cancer (AJCC TNM Classification)

A standardized system for classifying the anatomical extent of malignant lung tumors based on the characteristics of the primary Tumor (T), involvement of regional lymph Nodes (N), and presence or absence of distant Metastasis (M); the American Joint Committee on Cancer (AJCC) TNM system (currently 8th edition, with 9th edition anticipated/being implemented) is the globally accepted standard
Clinical ─
─ Essential for:
─ ─ Determining prognosis for patients
─ ─ Guiding treatment decisions (e.g., surgical resectability, neoadjuvant/adjuvant therapy, radiotherapy, systemic therapy choices)
─ ─ Standardizing communication and comparison of data for clinical trials and cancer registries
─ Staging can be:
─ ─ Clinical Staging (cTNM): Based on all available information obtained before definitive treatment (e.g., physical exam, imaging studies like CT, PET, MRI, bronchoscopy, mediastinoscopy, biopsies of primary or metastatic sites).
─ ─ Pathological Staging (pTNM): Based on information obtained from surgical resection of the primary tumor and lymph nodes, including histologic examination. Generally considered more accurate.
─ ─ Post-therapy Staging (ycTNM or ypTNM): Assesses extent of disease after neoadjuvant therapy.
Macro ─
─ Pathologic staging requires meticulous gross examination of resected specimens (e.g., lobectomy, pneumonectomy, segmentectomy) and lymph nodes:
─ ─ Measuring tumor size accurately (often in 3 dimensions)
─ ─ Assessing local invasion (e.g., visceral pleura, chest wall, diaphragm, mediastinal structures)
─ ─ Identifying separate tumor nodules
─ ─ Dissecting and submitting all relevant lymph node stations for microscopic examination
Micro ─
─ Overview of TNM Components (details are extensive and found in AJCC staging manuals):
─ T (Primary Tumor): Based on factors including:
─ ─ Size of the invasive tumor (largest dimension)
─ ─ Invasion into adjacent structures (e.g., visceral pleura, parietal pleura, chest wall, diaphragm, phrenic nerve, mediastinal pleura, pericardium, great vessels, heart, trachea, esophagus, vertebral body)
─ ─ Endobronchial location and distance from carina
─ ─ Presence of separate tumor nodule(s) in the same lobe, different ipsilateral lobe, or contralateral lobe
─ ─ Categories range from Tis (carcinoma in situ) and T1 (subdivided by size, e.g., T1a, T1b, T1c) to T4 (based on size or extensive invasion).
─ N (Regional Lymph Nodes): Based on the anatomic location of involved lymph nodes:
─ ─ N0: No regional lymph node metastasis.
─ ─ N1: Metastasis to ipsilateral peribronchial and/or ipsilateral hilar lymph nodes, and intrapulmonary nodes (including direct extension).
─ ─ N2: Metastasis to ipsilateral mediastinal and/or subcarinal lymph nodes.
─ ─ N3: Metastasis to contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph nodes.
─ M (Distant Metastasis): Based on the presence and location of distant spread:
─ ─ M0: No distant metastasis.
─ ─ M1a: Separate tumor nodule(s) in a contralateral lobe; tumor with pleural or pericardial nodules; or malignant pleural/pericardial effusion.
─ ─ M1b: Single extrathoracic metastasis in a single organ (and involving a single metastatic lesion).
─ ─ M1c: Multiple extrathoracic metastases in one or more organs.
─ Stage Grouping: The T, N, and M categories are combined to determine overall anatomic stage groups (e.g., Stage 0, IA1, IA2, IA3, IB, IIA, IIB, IIIA, IIIB, IIIC, IVA, IVB), which have prognostic significance.
Ancillary studies ─
─ Histologic confirmation of tumor presence and type is fundamental.
─ Microscopic assessment of margins of resection.
─ Examination of lymph nodes for metastases (number of nodes involved, presence of extracapsular extension).
─ Special stains or IHC may be needed to confirm small foci of metastasis (e.g., cytokeratin for micrometastases).
─ Molecular markers are not part of the anatomical TNM staging itself but provide additional prognostic and predictive information.
DDx ─ N/A (This is a classification system for malignant tumors, not a disease entity itself)
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Precursor Glandular and Squamous Lesions

Atypical Adenomatous Hyperplasia (AAH)

A localized, small (typically ≤0.5 cm) proliferation of mildly to moderately atypical pneumocytes (usually resembling type II pneumocytes or club cells) lining alveolar walls and sometimes respiratory bronchioles, with preservation of the underlying alveolar architecture; considered a preinvasive precursor lesion to adenocarcinoma, particularly lepidic-predominant adenocarcinoma and adenocarcinoma in situ
Clinical ─
─ Usually an incidental finding, detected as a small (<5 mm or ≤5 mm) ground-glass nodule (GGN) on high-resolution CT (HRCT) chest scans, or found microscopically in lung tissue resected for other reasons (e.g., primary lung cancer elsewhere in the lung)
─ Generally asymptomatic
─ More common in older individuals, current or former smokers, and often found in lungs that also harbor adenocarcinoma, suggesting a field effect
─ Risk of progression to adenocarcinoma in situ (AIS) and then invasive adenocarcinoma is low but definite over time for individual lesions
Macro ─
─ Typically not visible grossly due to small size and subtle nature
─ If discernible, may appear as a tiny, ill-defined, grayish or whitish, soft, subcentimeter focus or nodule
Micro ─
─ Well-circumscribed, focal lesion, by definition ≤5 mm in greatest dimension
─ Characterized by the replacement of normal flat type I pneumocytes by a proliferation of atypical cuboidal to low columnar cells lining intact alveolar septa (lepidic-like growth pattern)
─ Alveolar architecture is preserved; no significant destruction of alveolar walls, fibrosis, or stromal invasion
─ Atypical cells:
─ ─ Mildly to moderately atypical: Nuclei are slightly enlarged, round to oval, with increased nuclear-to-cytoplasmic ratio compared to normal pneumocytes
─ ─ Nuclear chromatin may be finely granular or hyperchromatic; nuclear contours can be irregular but are not usually markedly pleomorphic
─ ─ Small, inconspicuous nucleoli may be present
─ ─ Cytoplasm is often scant to moderate, eosinophilic, or clear/vacuolated
─ ─ Cells are generally monotonous, without significant pleomorphism or high-grade atypia
─ Cell density: The lining cells are more crowded than normal reactive pneumocytes but less crowded and less atypical than in adenocarcinoma in situ (AIS)
─ Mitotic figures are rare or absent
─ No significant stromal reaction or desmoplasia within the lesion
─ Often sharply demarcated from the surrounding normal alveolar parenchyma
Ancillary studies ─
─ IHC:
─ ─ The atypical cells are typically positive for pneumocyte markers: TTF-1 (nuclear) and Napsin A (cytoplasmic), consistent with type II pneumocyte or club cell differentiation.
─ ─ Ki-67 proliferation index is characteristically very low (<1-2%, often approaching 0%).
─ Molecular: Some AAH lesions harbor EGFR or KRAS mutations, similar to those found in lung adenocarcinomas, supporting their role as precursor lesions.
DDx ─
─ Reactive type II pneumocyte hyperplasia: Occurs in response to lung injury (e.g., DAD, inflammation, infection); cells are reactive with enlarged nuclei and prominent nucleoli but generally lack the degree of nuclear atypia or the discrete nodular proliferation of AAH; often more diffuse or patchy and associated with underlying injury pattern.
─ Adenocarcinoma in situ (AIS): AIS is also typically ≤3 cm (AAH is ≤0.5 cm) with pure lepidic growth of neoplastic cells lining alveolar walls. AIS cells are generally more crowded, have greater nuclear atypia (more hyperchromasia, pleomorphism, prominent nucleoli), and often more abundant cytoplasm than AAH cells. The distinction can be subtle, especially between large AAH and small AIS; size is a key criterion. AIS is considered noninvasive carcinoma, while AAH is preinvasive.
─ Metastatic adenocarcinoma with a lepidic pattern (rare, but possible): Clinical history of a primary adenocarcinoma elsewhere is crucial. IHC panel for site-specific markers (e.g., CDX2, GATA3, PAX8) may be helpful if atypia is marked or morphology is unusual for lung primary.
─ Other benign epithelial proliferations (e.g., minute meningothelioid-like nodules – these are interstitial, not alveolar lining).
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Adenocarcinoma in Situ (AIS) - Non-mucinous and Mucinous types

A localized small adenocarcinoma (defined as ≤3 cm in greatest dimension) characterized by a nearly pure lepidic growth pattern (tumor cells proliferating along pre-existing alveolar structures) without evidence of stromal, vascular, lymphatic, or pleural invasion, and lacking papillary or micropapillary patterns or intra-alveolar tumor cells; it is a preinvasive lesion considered a direct precursor to invasive adenocarcinoma
Clinical ─
─ Usually asymptomatic and detected incidentally as a solitary or sometimes multiple ground-glass nodule (GGN) or part-solid GGN on high-resolution CT (HRCT) chest scans
─ Excellent prognosis following complete surgical resection, with near 100% disease-specific survival
─ Represents a non-invasive stage in the stepwise progression of lung adenocarcinoma (AAH → AIS → MIA → Invasive Adenocarcinoma)
─ Formerly encompassed within the term "bronchioloalveolar carcinoma (BAC)," which is now obsolete
─ Two main subtypes: Non-mucinous AIS (more common) and Mucinous AIS
Macro ─
─ Often appears as an ill-defined, grayish or whitish, subsolid or ground-glass nodule, typically ≤3 cm (most are smaller, often <1-2 cm)
─ May not be grossly visible or palpable if very small or purely ground-glass
Micro ─
─ Diagnostic criteria:
─ ─ Size ≤3 cm in greatest dimension
─ ─ Predominantly (>95-100%) lepidic growth pattern: Neoplastic cells line alveolar walls, using the pre-existing alveolar septa as a scaffold, without destroying the underlying architecture
─ ─ No evidence of stromal invasion (i.e., no tumor cells infiltrating into the alveolar septal stroma or forming glandular structures within a desmoplastic stroma)
─ ─ No vascular or lymphatic invasion
─ ─ No pleural invasion (involvement of visceral pleura)
─ ─ No papillary or micropapillary growth patterns
─ ─ No significant numbers of intra-alveolar tumor cells (e.g., detached clusters or sheets of tumor cells filling alveolar spaces)
─ Non-mucinous AIS:
─ ─ More common subtype
─ ─ Neoplastic cells are typically cuboidal to low columnar, resembling type II pneumocytes or club cells
─ ─ Nuclei show mild to moderate atypia: enlarged, often round to oval, with variably hyperchromatic chromatin, irregular nuclear contours, and nucleoli that may be inconspicuous or visible. Cellular crowding is more pronounced than in AAH.
─ ─ Cytoplasm is usually scant to moderate, eosinophilic or clear
─ Mucinous AIS:
─ ─ Less common subtype
─ ─ Neoplastic cells are tall columnar cells with abundant intracytoplasmic mucin, often displacing the nuclei to the base (goblet cell-like or tall columnar mucinous cells)
─ ─ Nuclear atypia is often mild, but can be more pronounced in some cases
─ ─ May be multifocal or present as part of a spectrum with invasive mucinous adenocarcinoma if invasive components are found elsewhere
─ ─ Preservation of alveolar architecture with neoplastic mucinous cells lining septa
Ancillary studies ─
─ Non-mucinous AIS:
─ ─ IHC (+) TTF-1 (nuclear), Napsin A (cytoplasmic) are characteristic
─ ─ IHC (+) CK7
─ ─ IHC (-) Ki-67 proliferation index is typically very low (<5%, often <1%)
─ Mucinous AIS:
─ ─ IHC (+) Often TTF-1 negative or only focally positive/weak
─ ─ IHC (+) CK7 is usually positive; CK20 expression is variable
─ ─ IHC (+) Mucin stains (e.g., PAS with diastase, Alcian blue at pH 2.5, MUC5AC) are positive for intracytoplasmic mucin
─ ─ IHC (-) Napsin A is typically negative
─ Molecular:
─ ─ Non-mucinous AIS: EGFR mutations are common (especially in Asian populations, never-smokers). KRAS mutations can also occur.
─ ─ Mucinous AIS: KRAS mutations are common. EGFR mutations are rare.
DDx ─
─ Atypical Adenomatous Hyperplasia (AAH): Smaller lesion (≤0.5 cm), less cellular crowding, and milder nuclear atypia compared to AIS. AAH is preinvasive, AIS is noninvasive carcinoma.
─ Minimally Invasive Adenocarcinoma (MIA): Similar lepidic growth pattern but contains a small focus (≤0.5 cm in greatest dimension) of stromal invasion. This is the key distinguishing feature.
─ Lepidic-predominant Invasive Adenocarcinoma: Shows a predominant lepidic pattern but has an invasive component >0.5 cm, or presence of other invasive patterns (acinar, papillary, micropapillary, solid), or stromal/vascular/pleural invasion.
─ Reactive type II pneumocyte hyperplasia: Occurs in response to lung injury; cells are reactive with prominent nucleoli but generally lack the monotonous proliferation, consistent atypia, or discrete nodular formation of AIS; often associated with an underlying injury pattern (e.g., DAD, inflammation).
─ Metastatic adenocarcinoma with a lepidic pattern (e.g., from pancreas, ovary, breast – rare): Clinical history of a primary adenocarcinoma elsewhere is crucial. IHC panel for site-specific markers may be helpful.
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Squamous Dysplasia (Low-grade and High-grade) and Carcinoma in Situ (CIS)

A spectrum of preinvasive lesions of the bronchial or bronchiolar epithelium characterized by atypical squamous differentiation, representing precursors to invasive squamous cell carcinoma of the lung; graded based on the degree of cytological atypia and architectural disorganization
Clinical ─
─ Strongly associated with cigarette smoking and other carcinogen exposure
─ Often found in individuals with a history of or concurrent squamous cell carcinoma elsewhere in the respiratory tract
─ Typically detected by surveillance bronchoscopy with biopsies (may appear as mucosal thickening, erythema, granularity, or leukoplakia) or found incidentally in lung resection specimens
─ Risk of progression to invasive SCC increases with the grade of dysplasia/CIS
Macro ─
─ Mucosal lesions, often subtle or invisible to the naked eye on gross examination of resection specimens
─ Bronchoscopy may reveal areas of mucosal abnormality as described above
Micro ─
─ General features: Replacement of the normal pseudostratified ciliated columnar (respiratory) epithelium by a stratified squamous epithelium showing varying degrees of:
─ ─ Cellular atypia: Nuclear enlargement, hyperchromasia, irregular nuclear contours, increased nuclear-to-cytoplasmic (N:C) ratio, pleomorphism
─ ─ Abnormal maturation: Disordered stratification, loss of normal polarity of basal cells, delayed or abnormal keratinization (dyskeratosis)
─ ─ Increased mitotic activity: Mitoses may be present above the basal layer and can be atypical in higher grades
─ Grading (Simplified two-tiered system: Low-grade vs. High-grade, or three-tiered: Mild, Moderate, Severe Dysplasia/CIS):
─ Squamous Dysplasia, Low-grade (encompasses mild and often moderate dysplasia):
─ ─ Atypical squamous cells are confined to the lower one-third to one-half of the epithelial thickness
─ ─ Nuclear atypia is generally mild to moderate
─ ─ Orderly maturation towards the surface may still be somewhat preserved
─ ─ Mitotic figures are usually basal and not atypical
─ Squamous Dysplasia, High-grade (encompasses severe dysplasia and often CIS, as distinction can be subjective):
─ ─ Atypical squamous cells extend into the upper one-half to two-thirds or nearly the full thickness of the epithelium
─ ─ Marked nuclear atypia, significant pleomorphism, high N:C ratio, loss of cellular polarity, and disordered maturation are prominent
─ ─ Mitotic figures may be numerous, extend into suprabasal layers, and can be atypical
─ Squamous Cell Carcinoma in Situ (CIS):
─ ─ Full-thickness replacement of the epithelium by markedly atypical squamous cells, demonstrating severe cytologic atypia and complete loss of surface maturation and polarity
─ ─ Basement membrane remains intact, with no evidence of stromal invasion (this is the defining feature of "in situ")
─ ─ Often considered the most severe end of the high-grade dysplasia spectrum
─ Angiogenic Squamous Dysplasia:
─ ─ A specific variant of squamous dysplasia (can be low or high grade) characterized by the presence of ill-developed capillaries growing upwards from the submucosa into the dysplastic epithelial layer itself
─ ─ Thought to be associated with a higher and more rapid risk of progression to invasive squamous cell carcinoma
Ancillary studies ─
─ IHC:
─ ─ p53: Overexpression (strong, diffuse nuclear staining) or complete absence (null pattern due to truncating mutation) can be seen, more commonly in high-grade dysplasia and CIS, reflecting TP53 gene alterations
─ ─ Ki-67: Proliferation index is increased compared to normal or metaplastic epithelium; the proportion and extent of Ki-67 positive cells towards the surface increase with the grade of dysplasia
─ ─ Cytokeratins (e.g., CK5/6) and p63/p40: Confirm squamous lineage of the dysplastic cells but do not help in grading the dysplasia itself
DDx ─
─ Reactive squamous metaplasia: Replacement of respiratory epithelium by mature squamous epithelium without significant atypia; occurs in response to chronic irritation (e.g., smoking, infection); cells show orderly maturation and lack significant nuclear atypia or mitotic activity beyond basal layer
─ Reparative atypia / Regenerative atypia: Can occur in areas of epithelial injury and repair; may show some nuclear atypia (enlarged nuclei, prominent nucleoli) but usually lacks the degree of pleomorphism, hyperchromasia, disordered maturation, or extensive suprabasal mitoses seen in true dysplasia; often associated with underlying inflammation or ulceration
─ Invasive squamous cell carcinoma: Distinguished by the presence of neoplastic squamous cells infiltrating beyond the basement membrane into the underlying stroma
─ Viral cytopathic changes (e.g., HPV-related changes if koilocytes are present, though primary HPV-driven squamous dysplasia is rare in the lower respiratory tract compared to upper aerodigestive tract)
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Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia (DIPNECH)

A rare preinvasive lesion characterized by a generalized proliferation of pulmonary neuroendocrine cells (PNECs) within the epithelium of bronchioles and sometimes bronchi, often associated with constrictive bronchiolitis, airway fibrosis, and the subsequent development of multiple carcinoid tumorlets and/or carcinoid tumors; "idiopathic" implies it is not secondary to other known chronic lung diseases
Clinical ─
─ Predominantly affects middle-aged to older women (often 50s-60s), frequently never-smokers
─ Symptoms can be chronic and slowly progressive, often mimicking asthma or chronic obstructive airway disease: persistent dry cough, dyspnea, wheezing
─ Pulmonary function tests may show airflow obstruction that is often irreversible or only partially reversible
─ High-resolution CT (HRCT) chest findings can be suggestive: mosaic attenuation pattern (due to air trapping from bronchiolar obstruction), diffuse bronchial/bronchiolar wall thickening, and often multiple small pulmonary nodules (representing tumorlets or small carcinoid tumors)
─ Considered a preneoplastic condition with potential for progression to carcinoid tumors
Macro ─
─ Lungs may appear grossly normal or show subtle findings such as ill-defined nodularity, patchy fibrosis, or areas of airway thickening
─ Discrete tumorlets or small carcinoid tumors may be visible as small, firm, whitish nodules if present
Micro ─
─ Widespread proliferation of neuroendocrine cells within the epithelium of bronchioles (most commonly terminal and respiratory bronchioles) and sometimes larger bronchi:
─ ─ Proliferating cells can appear as single scattered cells, small clusters (neuroepithelial bodies - NEBs), or more extensive linear arrangements along the basement membrane, sometimes forming small intramucosal protrusions
─ ─ The neuroendocrine cells are typically small to medium-sized, with round to oval nuclei, finely granular "salt-and-pepper" chromatin, inconspicuous nucleoli, and scant to moderate eosinophilic cytoplasm
─ Extension beyond the basement membrane: Proliferating neuroendocrine cells may extend as small buds or nodules (<0.5 mm, sometimes up to 5 mm if termed tumorlet) into the peribronchiolar stroma; these are considered tumorlets if they meet size criteria and are invasive. DIPNECH is often associated with multiple tumorlets.
─ Airway remodeling and fibrosis: Frequently associated with constrictive/obliterative bronchiolitis, characterized by fibrous thickening and narrowing of the lumens of small airways, likely secondary to growth factors or other mediators secreted by the hyperplastic neuroendocrine cells
─ Chronic inflammation in and around affected airways may be present
─ No significant cytologic atypia or mitotic activity within the hyperplastic neuroendocrine cells (Ki-67 index is very low, <2%)
Ancillary studies ─
─ IHC is essential to highlight the neuroendocrine cell proliferation:
─ ─ Positive for general neuroendocrine markers: Chromogranin A, Synaptophysin, CD56 (NCAM)
─ ─ Ki-67 proliferation index is characteristically very low
─ ─ TTF-1 may be positive in some neuroendocrine cells
DDx ─
─ Reactive neuroendocrine cell hyperplasia: Secondary proliferation of PNECs in response to chronic lung injury, inflammation, fibrosis (e.g., in chronic bronchitis, bronchiectasis, interstitial lung diseases, hypoxia). Reactive NEH is usually less extensive, less diffuse, and not typically associated with the progressive airway disease or predisposition to multiple tumorlet/carcinoid formation to the same degree as DIPNECH. The "idiopathic" nature and diffuse extent are key for DIPNECH.
─ Carcinoid tumorlets: These are often found in association with DIPNECH. DIPNECH refers to the diffuse epithelial hyperplasia, while tumorlets are discrete nodules <0.5 cm that have breached the basement membrane.
─ Typical or Atypical Carcinoid tumors: Larger (≥0.5 cm), more organized, overtly invasive neuroendocrine neoplasms with distinct tumor architecture. DIPNECH can be a precursor.
─ Metastatic neuroendocrine tumors (e.g., from GI tract or pancreas): Clinical history of a primary elsewhere is crucial; IHC for site-specific markers (e.g., CDX2, ISL1 for pancreatic NETs) may be helpful.
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Pulmonary Neuroendocrine Cell Hyperplasia (NEH) / Tumorlets (Incidental)

Pulmonary Neuroendocrine Cell Hyperplasia (NEH) is a focal or multifocal proliferation of neuroendocrine cells confined within bronchial/bronchiolar epithelium; Tumorlets are small, discrete aggregates or nodules of neuroendocrine cells, <0.5 cm in diameter, that have breached the epithelial basement membrane and extend into peribronchial/peribronchiolar stroma, often found incidentally
Clinical ─
─ Reactive NEH:
─ ─ Usually an asymptomatic, incidental microscopic finding in lungs affected by various chronic inflammatory conditions, fibrosis, bronchiectasis, chronic hypoxia (e.g., high altitude, chronic heart failure), or adjacent to other lesions like tumors or infarcts
─ ─ Not considered a preneoplastic lesion in itself, but rather a reactive proliferation
─ Tumorlets:
─ ─ Almost always asymptomatic and discovered incidentally during microscopic examination of lung tissue resected for other reasons, or as tiny nodules on high-resolution CT imaging
─ ─ No known metastatic potential and are considered benign; however, their presence, especially if multiple, can sometimes be associated with underlying conditions like chronic lung disease or DIPNECH
Macro ─
─ NEH is a microscopic finding and not grossly visible
─ Tumorlets are usually not grossly apparent due to their small size (<0.5 cm). If seen, they may appear as tiny, firm, whitish or grayish nodules.
Micro ─
─ Pulmonary Neuroendocrine Cell Hyperplasia (NEH):
─ ─ Characterized by a focal or multifocal increase in the number of neuroendocrine cells within the bronchial or bronchiolar epithelium (lining the airways)
─ ─ Proliferating cells can be single, in small clusters (neuroepithelial bodies), or form short linear arrangements along the basement membrane, without extending beyond it
─ ─ Cells have typical neuroendocrine morphology: round to oval nuclei with "salt-and-pepper" chromatin, scant cytoplasm
─ ─ This is distinguished from DIPNECH by being focal/multifocal and often clearly secondary to another process, rather than diffuse and idiopathic with associated airway disease
─ Tumorlet:
─ ─ A well-demarcated, unencapsulated nodule or aggregate of neuroendocrine cells, measuring <0.5 cm in greatest dimension
─ ─ Cells are uniform, with round to oval nuclei, finely granular "salt-and-pepper" chromatin, and scant to moderate eosinophilic cytoplasm
─ ─ Growth patterns are typically organoid: nests, trabeculae, ribbons, or solid arrangements of cells, often embedded in a delicate fibrovascular stroma
─ ─ Crucially, tumorlets show evidence of breaching the epithelial basement membrane and infiltrating into the surrounding peribronchial or peribronchiolar connective tissue
─ ─ Mitotic figures are rare or absent (typically <2 per 2 mm² or 10 HPF); necrosis is absent
─ ─ Often found in association with areas of scarring, chronic inflammation, bronchiectasis, or interstitial fibrosis
Ancillary studies ─
─ IHC is essential for confirmation:
─ ─ Both NEH and tumorlets stain positively for general neuroendocrine markers: Chromogranin A, Synaptophysin, CD56 (NCAM)
─ ─ Ki-67 proliferation index is characteristically very low (<2%) in both NEH and tumorlets
─ ─ TTF-1 may be positive in some cells
DDx ─
─ For NEH:
─ ─ Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia (DIPNECH): DIPNECH is a distinct clinicopathologic entity characterized by diffuse, widespread idiopathic NEH often associated with constrictive bronchiolitis and a predisposition to multiple tumorlets/carcinoids; reactive NEH is more localized and secondary to other lung pathology.
─ For Tumorlet:
─ ─ Typical Carcinoid Tumor: Distinction is primarily based on size; lesions ≥0.5 cm are classified as typical carcinoid tumors. Tumorlets and typical carcinoids share similar cytomorphology and IHC profile, but tumorlets by definition are <0.5 cm and have no metastatic potential.
─ ─ Metastatic small cell carcinoma or carcinoid tumor (from another site): Very rarely would present as such a small, well-defined, incidental nodule without a known primary; clinical history and comparison with primary tumor histology (if available) are key. Metastases often show higher grade features if from SCLC.
─ ─ Glomus tumor (rare in lung parenchyma, different spindle/epithelioid cell morphology, positive for SMA, negative for neuroendocrine markers)
─ ─ Atypical Adenomatous Hyperplasia (AAH) or Adenocarcinoma in situ (AIS) (composed of atypical pneumocytes, not neuroendocrine cells; positive for TTF-1/Napsin A, negative for neuroendocrine markers)
─ ─ Paraganglioma (rarely intrapulmonary, nested "zellballen" pattern, S100+ sustentacular cells, different IHC profile)
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Bronchiolar Columnar Cell Dysplasia (BCCD)

A putative preinvasive or atypical lesion characterized by a proliferation of atypical columnar cells, often with hobnail morphology and tufting, lining respiratory bronchioles and sometimes extending to alveolar ducts; its exact significance and risk of progression to adenocarcinoma are still under investigation, but it is often found in lungs with chronic injury or adjacent to lung cancers
Clinical ─
─ Usually an incidental microscopic finding, not typically associated with specific symptoms or distinct radiological features itself
─ Often identified in lung tissue resected for other reasons, such as primary lung cancer, or in lungs with chronic interstitial diseases (e.g., UIP, fibrotic NSIP), chronic inflammation, or significant smoking-related damage
─ Considered by some to be a form of bronchiolar atypia or dysplasia that may represent a precursor to adenocarcinoma, particularly peripheral adenocarcinomas with bronchioloalveolar features
Macro ─
─ Not grossly visible; a microscopic lesion
Micro ─
─ Focal proliferation of atypical columnar epithelial cells lining the surfaces of respiratory bronchioles, and may extend into adjacent alveolar ducts
─ Cells are typically cuboidal to tall columnar, and frequently exhibit "hobnail" morphology (apical nuclei that bulge into the lumen, creating a "cobblestone" or "hobnail" appearance)
─ Cytoplasmic tufting or small, non-complex, micropapillary-like projections into the lumen may be present, but these lack true fibrovascular cores
─ Nuclear atypia is mild to moderate: nuclei are often enlarged, hyperchromatic, with irregular nuclear contours; nucleoli may be prominent
─ The underlying bronchiolar architecture is generally preserved, and there is no evidence of stromal invasion
─ Often associated with peribronchiolar chronic inflammation and fibrosis (scarring)
─ Mitotic activity is usually low
Ancillary studies ─
─ IHC:
─ ─ The atypical cells may be positive for TTF-1 and CK7
─ ─ Napsin A expression can be variable, sometimes less consistently positive compared to AAH or adenocarcinoma
─ ─ Ki-67 proliferation index is generally low
DDx ─
─ Reactive bronchiolar epithelial atypia: Occurs in response to acute or chronic injury, inflammation, or repair. Reactive cells can show nuclear enlargement and prominent nucleoli but typically lack the consistent hobnail morphology, tufting, or degree of atypia seen in BCCD; often associated with more active inflammation or granulation tissue.
─ Atypical Adenomatous Hyperplasia (AAH) / Adenocarcinoma in Situ (AIS): These lesions typically involve alveolar spaces more diffusely with a lepidic growth pattern along alveolar walls, rather than being centered on bronchioles. Cytology also differs (AAH/AIS cells often more cuboidal, less hobnail).
─ Invasive adenocarcinoma with lepidic or micropapillary features: Distinguished by the presence of stromal invasion or true complex micropapillary structures with fibrovascular cores.
─ Papillary adenoma or other benign papillary lesions (rare, but would have true fibrovascular cores).
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Adenocarcinoma Spectrum

Atypical Goblet Cell Hyperplasia (AGCH)

A proliferation of atypical goblet cells within the bronchial or bronchiolar epithelium, which is considered by some authors as a potential, though less well-established, preinvasive lesion or marker of increased risk for mucinous types of adenocarcinoma or adenocarcinoma in situ (mucinous AIS), particularly in the context of chronic airway inflammation or irritation
Clinical ─
─ Typically an incidental microscopic finding, not associated with specific symptoms or distinct radiological features itself
─ Often found in the lungs of smokers or in association with chronic bronchitis, bronchiectasis, or other chronic inflammatory airway conditions that predispose to goblet cell metaplasia
─ Its direct precursor role and risk of progression are less clearly defined compared to AAH or squamous dysplasia
Macro ─
─ Not grossly visible; a microscopic lesion
Micro ─
─ Focal or multifocal proliferation of goblet cells within the respiratory epithelium of bronchi or bronchioles, demonstrating cytologic atypia
─ Atypical features include:
─ ─ Nuclear enlargement, hyperchromasia, irregular nuclear membranes, and variably prominent nucleoli within the goblet cells
─ ─ Increased nuclear-to-cytoplasmic (N:C) ratio, although the cytoplasm is often distended by abundant mucin, pushing the atypical nucleus basally or laterally
─ ─ Stratification or tufting of these atypical goblet cells may be present
─ ─ Some atypical cells might show mucin depletion, making their cytoplasm appear more eosinophilic and the nuclear atypia more overt
─ No evidence of stromal invasion by the atypical goblet cells
─ Typically occurs in areas of pre-existing goblet cell metaplasia or hyperplasia
Ancillary studies ─
─ IHC:
─ ─ Mucin stains (e.g., PAS with diastase, Alcian blue at pH 2.5) confirm the presence of intracytoplasmic mucin in the atypical cells
─ ─ CK7 is often positive
─ ─ TTF-1 is usually negative or only rarely focally positive (consistent with mucinous lineage which often lacks TTF-1)
─ ─ Ki-67 proliferation index may be slightly elevated compared to normal or metaplastic goblet cells but is generally low
DDx ─
─ Goblet cell metaplasia or hyperplasia without atypia: Common reactive change where goblet cells are increased in number but lack significant nuclear atypia or architectural disarray.
─ Mucinous Adenocarcinoma in Situ (AIS): Characterized by a more extensive and established neoplastic proliferation of atypical mucinous cells (goblet cells or tall columnar mucinous cells) growing in a lepidic pattern along alveolar walls; AIS generally shows more pronounced and consistent atypia and represents a noninvasive carcinoma.
─ Invasive Mucinous Adenocarcinoma: Shows invasion of the stroma by neoplastic mucinous cells.
─ Reactive atypia in goblet cells due to acute or chronic inflammation: Can be difficult to distinguish; reactive atypia may be less uniform and associated with more active inflammation and repair, resolving with treatment of the underlying condition.
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Minimally Invasive Adenocarcinoma (MIA) - Non-mucinous and Mucinous types

A small, solitary adenocarcinoma (defined as ≤3 cm in greatest dimension) characterized by a predominantly lepidic growth pattern and a small focus of stromal invasion measuring ≤0.5 cm (5 mm) in greatest dimension (measured in any one focus if multiple foci of invasion exist); MIA excludes tumors with any other invasive patterns (acinar, papillary, micropapillary, solid) if those patterns constitute the entirety of the invasive component unless that component is still ≤0.5 cm and the overall tumor is predominantly lepidic. There should be no lymphovascular invasion, pleural invasion, or tumor necrosis.
Clinical ─
─ Usually asymptomatic and detected incidentally as a small, solitary, subsolid (often part-solid with a dominant ground-glass component and a small solid portion) nodule on high-resolution CT (HRCT) chest scans
─ Represents an early stage of invasive adenocarcinoma, bridging the gap between adenocarcinoma in situ (AIS) and overtly invasive adenocarcinoma
─ Excellent prognosis following complete surgical resection, with near 100% disease-specific survival and very low risk of recurrence
─ Two main subtypes: Non-mucinous MIA (more common) and Mucinous MIA (rare)
Macro ─
─ Appears as a small, often ill-defined or somewhat circumscribed, grayish or whitish, subsolid or partly solid nodule, by definition ≤3 cm in greatest dimension
─ The invasive component (≤0.5 cm) is usually not grossly discernible from the lepidic component
Micro ─
─ Diagnostic criteria:
─ ─ Overall tumor size ≤3 cm
─ ─ Predominantly lepidic growth pattern (neoplastic cells lining alveolar walls, preserving alveolar architecture) as the main component of the tumor
─ ─ Presence of a small focus of stromal invasion, defined as:
─ ─ ─ Neoplastic cells infiltrating into the alveolar septal stroma (often associated with a fibroblastic or desmoplastic stromal reaction, or destruction of the normal alveolar framework), OR
─ ─ ─ Presence of non-lepidic invasive histologic patterns (i.e., acinar, papillary, micropapillary, or solid growth) if the total extent of this non-lepidic invasive component measures ≤0.5 cm in its greatest dimension. If multiple small foci of invasion exist, the largest one must be ≤0.5 cm.
─ ─ No lymphovascular invasion (LVI)
─ ─ No visceral pleural invasion (VPI)
─ ─ No tumor necrosis
─ Non-mucinous MIA:
─ ─ More common subtype; lepidic component cells resemble type II pneumocytes or club cells with mild to moderate atypia.
─ ─ Invasive component (≤0.5 cm) often consists of small acinar structures, individual cells, or clusters of cells infiltrating a desmoplastic stroma, or a small focus of papillary/micropapillary/solid growth.
─ Mucinous MIA:
─ ─ Rare; lepidic component consists of tall columnar mucinous cells (goblet cells or tall columnar cells with abundant apical mucin).
─ ─ Invasive component (≤0.5 cm) consists of mucinous adenocarcinoma cells infiltrating stroma, often as glands or clusters within a desmoplastic stroma.
Ancillary studies ─
─ Elastic stains (e.g., Verhoeff-Van Gieson - VVG): Can be very helpful to highlight stromal invasion by demonstrating destruction or interruption of the normal alveolar elastic framework or encasement of elastic fibers by invasive tumor cells, and to define the extent of the invasive focus.
─ Non-mucinous MIA:
─ ─ IHC (+) TTF-1 (nuclear), Napsin A (cytoplasmic) are characteristic in the lepidic and invasive components.
─ ─ IHC (+) CK7.
─ ─ IHC (-) Ki-67 proliferation index is generally low but may be slightly higher in the invasive focus compared to the lepidic component.
─ Mucinous MIA:
─ ─ IHC (+) Often TTF-1 negative or only focally positive/weak.
─ ─ IHC (+) CK7 is usually positive; CK20 expression is variable.
─ ─ IHC (+) Mucin stains (e.g., PAS with diastase, Alcian blue) are positive.
─ ─ IHC (-) Napsin A is typically negative.
─ Molecular:
─ ─ Non-mucinous MIA: EGFR mutations are common. KRAS mutations can also occur.
─ ─ Mucinous MIA: KRAS mutations are common. EGFR mutations are rare.
DDx ─
─ Adenocarcinoma in situ (AIS): Lacks any evidence of stromal invasion (key distinguishing feature). AIS is purely lepidic.
─ Lepidic-predominant Invasive Adenocarcinoma: If the invasive component (stromal invasion or presence of non-lepidic patterns) is >0.5 cm in greatest dimension, or if there is LVI, VPI, or tumor necrosis, then it is classified as lepidic-predominant invasive adenocarcinoma, not MIA.
─ Atypical Adenomatous Hyperplasia (AAH): Smaller lesion (≤0.5 cm overall), with milder cellular atypia and less cellular crowding than the lepidic component of MIA, and by definition, no invasion.
─ Reactive lesions with fibrosis or scarring (e.g., organizing pneumonia, interstitial fibrosis with reactive pneumocyte atypia): Fibrosis may mimic stromal invasion, but the epithelial cells are reactive and lack the consistent atypia and clonal proliferation of neoplastic cells. Elastic stains can help distinguish reactive fibrosis from desmoplastic stroma associated with invasion.
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Invasive Adenocarcinoma, Non-mucinous

An invasive malignant epithelial tumor demonstrating glandular differentiation (e.g., acini, papillae) or mucin production by tumor cells, with evidence of stromal invasion greater than that allowed for Minimally Invasive Adenocarcinoma (MIA), or the presence of specific invasive architectural patterns. This entry focuses on the non-mucinous subtypes, which constitute the majority of lung adenocarcinomas.
Clinical ─
─ Most common histologic type of lung cancer, particularly in never-smokers, women, and younger patients, although it is also frequently seen in smokers
─ Symptoms are variable: cough, dyspnea, chest pain, hemoptysis, weight loss; may be asymptomatic and detected as a peripheral nodule or mass on imaging
─ Presentation and prognosis can vary depending on the predominant histologic pattern, grade, stage, and molecular alterations
Macro ─
─ Typically peripheral tumors, but can occur centrally
─ May present as solitary nodules or masses, sometimes ill-defined and infiltrative, or as multifocal disease
─ Cut surface is often gray-white or tan, firm, and may show central scarring, fibrosis, hemorrhage, or anthracotic pigmentation
─ Pleural puckering or retraction is common due to stromal desoplasia
Micro ─
─ Definitive evidence of invasion is required, which can manifest as:
─ ─ Stromal invasion: Infiltration of tumor cells into the lung stroma (e.g., alveolar septa, desmoplastic stroma), often with destruction of the underlying alveolar architecture. If the tumor is predominantly lepidic, the invasive component must be >0.5 cm.
─ ─ Presence of specific invasive architectural patterns (acinar, papillary, micropapillary, solid) regardless of the size of this component (if the tumor is >0.5 cm overall or if AIS/MIA criteria are not met).
─ ─ Lymphovascular invasion or pleural invasion also signifies invasive disease.
─ Architectural Patterns (tumors are often heterogeneous and are classified by the predominant pattern; percentages of each pattern should be reported, typically in 5% increments):
─ Lepidic pattern: Neoplastic cells proliferate along the surfaces of intact (pre-existing) alveolar walls, without significant stromal invasion or destruction of alveolar architecture. This pattern itself is non-invasive; if it's the sole pattern in a tumor ≤3cm, it's AIS or MIA (if ≤0.5cm invasion). In invasive adenocarcinoma, it often forms the peripheral component.
─ Acinar pattern: Forms well-defined glandular structures (acini or tubules) with distinct lumens, often arranged back-to-back or infiltrating a desmoplastic stroma. Glands can be round, oval, or irregular.
─ Papillary pattern: Tumor cells grow on fibrovascular cores, forming finger-like or branching papillary projections into airspaces or glandular lumens. True papillae have central fibrovascular cores.
─ Micropapillary pattern: Tumor cells grow in small, cohesive, ill-defined tufts or clusters that lack true fibrovascular cores. These tufts often appear to be floating within alveolar spaces or retracted from the surrounding stroma. This pattern is associated with more aggressive behavior, increased risk of lymph node metastasis, and poorer prognosis.
─ Solid pattern: Tumor cells proliferate in sheets or solid nests with little to no discernible gland formation or lepidic growth. Intracellular mucin (≥2 cells per cluster in ≥1 high-power field, demonstrable by mucin stains if not obvious on H&E) is required to classify a solid tumor as adenocarcinoma; otherwise, if TTF-1/Napsin A are positive, it's adenocarcinoma, if negative, it may be poorly differentiated NSCLC-NOS or other entity.
─ Cribriform pattern: Fused glandular structures with back-to-back glands creating slit-like or rounded spaces, resembling a sieve. Often considered a high-grade pattern.
─ Cytologic features: Variable, ranging from well-differentiated (cells with relatively bland nuclei, similar to those in AIS/MIA but invasive) to poorly differentiated (cells with marked nuclear pleomorphism, hyperchromasia, high N:C ratio, prominent nucleoli, and frequent or atypical mitoses).
─ Mucin assessment: While these are "non-mucinous" adenocarcinomas, small amounts of intracellular mucin may be present. If extracellular mucin is abundant or cells are predominantly goblet cell or columnar mucinous type, then a diagnosis of Invasive Mucinous Adenocarcinoma should be considered. For solid pattern adenocarcinomas, mucin stains (e.g., PAS with diastase, Alcian blue) are recommended if glandular differentiation is not apparent on H&E.
─ Grading of Invasive Non-Mucinous Adenocarcinoma (IASLC Proposed Grading System, 2020):
─ ─ Based on predominant histologic pattern and presence of high-grade patterns (solid, micropapillary, cribriform; some also include complex glandular patterns).
─ ─ Grade 1: Lepidic-predominant tumors with no or <20% high-grade patterns.
─ ─ Grade 2: Acinar or papillary-predominant tumors with no or <20% high-grade patterns.
─ ─ Grade 3: Any tumor with ≥20% high-grade patterns (solid, micropapillary, cribriform), OR any tumor that is predominantly solid, micropapillary, or cribriform.
─ ─ (Simplified schema: Grade 1=Lepidic predominant; Grade 2=Acinar/Papillary predominant; Grade 3=Micropapillary/Solid/Cribriform predominant, OR presence of ≥20% of any of these if not predominant). This grading system has prognostic significance.
─ Tumor stroma: Often desmoplastic, especially in association with acinar or solid patterns.
─ Lymphovascular invasion (LVI) and visceral pleural invasion (VPI) are important prognostic factors and should be carefully assessed and reported.
Ancillary studies ─
─ IHC:
─ ─ TTF-1 (nuclear stain): Positive in the majority (~75-85%) of non-mucinous lung adenocarcinomas.
─ ─ Napsin A (cytoplasmic granular stain): Positive in the majority (~80-90%) of non-mucinous lung adenocarcinomas. Co-expression of TTF-1 and Napsin A is highly specific for lung adenocarcinoma origin.
─ ─ CK7 (Cytokeratin 7): Usually positive.
─ ─ Mucin stains (PAS with diastase, Alcian blue): To detect intracellular mucin, especially helpful in confirming adenocarcinoma differentiation in solid patterns.
─ ─ Elastic stains (e.g., Verhoeff-Van Gieson - VVG): Can help assess for visceral pleural invasion (invasion beyond the elastic layer of the pleura) and vascular invasion.
─ Molecular testing: Standard of care for advanced/metastatic non-mucinous adenocarcinomas to identify targetable driver mutations/rearrangements (e.g., EGFR, ALK, ROS1, BRAF, MET, RET, KRAS, HER2, NTRK) and to assess PD-L1 expression for immunotherapy.
DDx ─
─ Squamous Cell Carcinoma (SCC): Positive for squamous markers (p63, p40, CK5/6), negative for TTF-1/Napsin A. May show keratinization, intercellular bridges.
─ Large Cell Carcinoma: A diagnosis of exclusion for poorly differentiated NSCLC lacking clear adeno or squamous differentiation by H&E and IHC (i.e., negative for TTF-1, Napsin A, p40, CK5/6, and neuroendocrine markers).
─ Metastatic Adenocarcinoma to the lung (e.g., from colon, breast, pancreas, ovary, kidney): Clinical history of a primary elsewhere is critical. IHC panel for site-specific markers is essential (e.g., CDX2, SATB2 for colorectal; GATA3, mammaglobin for breast; PAX8 for renal/Müllerian; etc.). TTF-1 and Napsin A are key for lung primary.
─ Malignant Mesothelioma (if pleural-based and epithelioid): Positive for mesothelial markers (calretinin, WT1, CK5/6, D2-40), negative for adenocarcinoma markers (TTF-1, Napsin A, CEA, MOC31, BerEP4).
─ Minimally Invasive Adenocarcinoma (MIA): If invasive component is ≤0.5 cm and predominantly lepidic without LVI, VPI, or necrosis.
─ Adenocarcinoma in Situ (AIS): Purely lepidic growth, ≤3 cm, no invasion.
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Invasive Mucinous Adenocarcinoma

An invasive adenocarcinoma characterized by tumor cells with abundant intracytoplasmic mucin, often exhibiting goblet cell or tall columnar cell morphology, and growing in various invasive patterns (lepidic, acinar, papillary, micropapillary, or solid with extracellular mucin); it represents a distinct subtype from non-mucinous adenocarcinomas based on morphology, IHC, and molecular features. This category includes tumors formerly part of "mucinous bronchioloalveolar carcinoma (BAC)."
Clinical ─
─ May present as a solitary peripheral nodule or mass, as multifocal or multilobar disease, or as diffuse pneumonic-type consolidation (formerly "pneumonic BAC")
─ Symptoms can include cough, dyspnea, and sometimes voluminous watery sputum (bronchorrhea) in cases with extensive mucin production
─ Often shows less association with smoking compared to non-mucinous adenocarcinoma, though can occur in smokers
─ Prognosis can be variable, with pneumonic forms often associated with a worse outcome
Macro ─
─ Appearance is variable: Solitary or multiple nodules, or extensive consolidation resembling pneumonia
─ Cut surface is often grayish-white, gelatinous, or mucoid due to abundant mucin production
Micro ─
─ Predominantly composed of mucin-producing neoplastic epithelial cells:
─ ─ Cells are typically tall columnar or goblet cell-like, with abundant pale, vacuolated, or granular eosinophilic cytoplasm due to intracytoplasmic mucin
─ ─ Nuclei are often basally located, may appear small and relatively bland despite the invasive nature, but can show varying degrees of atypia (hyperchromasia, pleomorphism, prominent nucleoli) in higher-grade areas
─ Invasive architectural patterns: Any combination of lepidic (tumor cells lining alveolar walls), acinar (gland formation), papillary, micropapillary, or solid growth (sheets of cells, often with extracellular mucin pools) may be present. The tumor is classified by the predominant pattern.
─ Alveolar spaces are frequently filled with abundant extracellular mucin, which may contain detached tumor cells or inflammatory cells
─ Stromal invasion by neoplastic cells is a defining feature
─ Signet ring cells (intracytoplasmic mucin displacing the nucleus to the periphery) can be a component; if signet ring cells constitute >50% of the tumor, it should be classified as Primary Signet Ring Cell Carcinoma of the lung (see separate entry).
─ Colloid features (large pools of extracellular mucin dissecting and replacing stroma) can be present; if this pattern is dominant (>90%), consider Colloid Adenocarcinoma (see separate entry).
Ancillary studies ─
─ IHC:
─ ─ TTF-1: Characteristically negative or only focally/weakly positive in the majority of invasive mucinous adenocarcinomas (a key distinction from most non-mucinous lung adenocarcinomas)
─ ─ Napsin A: Usually negative
─ ─ CK7 (Cytokeratin 7): Typically positive
─ ─ CK20 (Cytokeratin 20): Expression is variable but can be positive more often than in non-mucinous adenocarcinomas, sometimes diffusely (can create diagnostic confusion with metastatic colorectal adenocarcinoma if TTF-1 is negative)
─ ─ CDX2: Generally negative (helps distinguish from colorectal metastases, though rare pulmonary mucinous adenocarcinomas can express CDX2)
─ ─ Mucin core proteins: MUC5AC is often expressed; MUC2 expression can also be seen
─ Histochemical mucin stains: PAS (Periodic Acid-Schiff) with diastase and Alcian blue (pH 2.5) are strongly positive, highlighting both intracellular and extracellular mucin
─ Molecular:
─ ─ KRAS mutations are common (one of the most frequent alterations in this subtype)
─ ─ EGFR mutations are rare
─ ─ ALK rearrangements can occur but are less frequent than in non-mucinous adenocarcinomas; some fusions like NTRK or RET have also been reported
─ ─ GNAS mutations have been reported in some cases, similar to colloid adenocarcinoma
DDx ─
─ Metastatic mucinous adenocarcinoma to the lung: Most important differential, especially from pancreas (PAX8 variable, IMP3+), colorectum (CDX2+, CK20+, CK7-, SATB2+), ovary (PAX8+, WT1 variable), breast (GATA3+, ER/PR+). A comprehensive IHC panel and clinical history are crucial.
─ Non-mucinous adenocarcinoma with focal mucin production: If mucinous differentiation is not the predominant feature.
─ Colloid Adenocarcinoma: If colloid pattern comprises >90% of the tumor.
─ Mucinous Adenocarcinoma in Situ (AIS) or Minimally Invasive Adenocarcinoma (MIA), mucinous type: Distinguished by the absence of significant stromal invasion (AIS) or very limited stromal invasion ≤0.5 cm (MIA).
─ Infections causing mucinous exudate (e.g., some bacterial pneumonias – but lack neoplastic cells).
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Colloid Adenocarcinoma

A rare variant of invasive adenocarcinoma of the lung characterized by abundant extracellular mucin (typically constituting >90% of the tumor volume) forming large pools that dissect through the stroma and replace normal lung parenchyma, containing sparse clusters, strips, or glands of neoplastic mucinous epithelial cells
Clinical ─
─ Similar presentation to other peripheral lung adenocarcinomas: often asymptomatic and found as a solitary nodule or mass on imaging, or may cause cough, dyspnea
─ May have a slightly better prognosis than conventional mucinous or non-mucinous adenocarcinomas of similar stage, though data is limited due to rarity
Macro ─
─ Typically appears as a well-circumscribed, lobulated, gelatinous or mucoid mass
─ Cut surface is glistening, gray-white to tan, and often exudes abundant mucin
Micro ─
─ Dominant feature: Extensive pools of acellular or paucicellular extracellular mucin, often pale basophilic or amphophilic on H&E, that fill and expand alveolar spaces and dissect through the stroma, leading to destruction of underlying lung architecture
─ Tumor cells:
─ ─ Relatively sparse neoplastic epithelial cells are present, typically arranged as small clusters, strips, individual cells (including signet ring cells), or lining the edges of the mucin pools or residual alveolar septa
─ ─ Cells are usually mucinous, with goblet cell or tall columnar morphology, containing intracytoplasmic mucin and often bland or mildly atypical nuclei; however, areas with higher-grade atypia can occur
─ Stroma: Usually scant, compressed between the large mucin pools; may show a mild desmoplastic reaction or chronic inflammation
─ Invasion is evident by the dissecting nature of the mucin pools through tissue planes and the presence of tumor cells infiltrating stroma or floating within mucin that has replaced parenchyma
Ancillary studies ─
─ IHC:
─ ─ Tumor cells often show a similar profile to invasive mucinous adenocarcinoma: TTF-1 is frequently negative or only focally positive.
─ ─ CK7 is usually positive; CK20 expression is variable (can be positive).
─ ─ CDX2 is generally negative.
─ ─ Mucin core proteins like MUC2 and MUC5AC may be expressed.
─ Histochemical mucin stains: PAS with diastase and Alcian blue (pH 2.5) strongly stain the abundant extracellular mucin and any intracellular mucin.
─ Molecular: KRAS mutations are common. GNAS mutations have also been frequently reported in colloid adenocarcinomas of the lung (similar to some appendiceal and pancreatic mucinous neoplasms).
DDx ─
─ Invasive Mucinous Adenocarcinoma with prominent extracellular mucin: Colloid adenocarcinoma is considered when the colloid pattern (large pools of extracellular mucin) constitutes the vast majority (>90%) of the tumor. If less, it's invasive mucinous adenocarcinoma with colloid features.
─ Mucocele or Mucinous Cystadenoma (benign): These are typically well-circumscribed cystic lesions lined by benign mucinous epithelium and filled with mucin, but they lack evidence of stromal invasion or the destructive, dissecting growth pattern of colloid adenocarcinoma. Atypia is minimal or absent.
─ Metastatic Colloid Adenocarcinoma: From other sites known to produce colloid carcinomas, such as colorectum, pancreas, breast, or ovary. Clinical history and a panel of IHC stains (e.g., CDX2, SATB2, CK20, PAX8, GATA3, ER/PR) are essential to exclude metastasis.
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Fetal Adenocarcinoma (Low-grade and High-grade types)

A rare variant of pulmonary adenocarcinoma that morphologically resembles fetal lung tissue at different stages of embryonic development; it is divided into Low-grade Fetal Adenocarcinoma (L-FLAC) and High-grade Fetal Adenocarcinoma (H-FLAC), the latter often being a component of biphasic pulmonary blastoma
Clinical ─
─ Low-grade Fetal Adenocarcinoma (L-FLAC):
─ ─ Very rare, typically occurs in younger adults (median age 30s-40s, but can range from children to older adults), with a slight male predominance.
─ ─ Often presents as an asymptomatic solitary peripheral lung mass found incidentally on imaging.
─ ─ Generally has a relatively good prognosis after complete surgical resection.
─ ─ Formerly known as "well-differentiated fetal adenocarcinoma" or "pulmonary endodermal tumor resembling fetal lung."
─ High-grade Fetal Adenocarcinoma (H-FLAC):
─ ─ Also very rare, can occur as a pure epithelial tumor or, more commonly, as the epithelial component of a biphasic pulmonary blastoma (which also contains a primitive mesenchymal/sarcomatous stroma).
─ ─ Occurs across a wide age range, including children and adults.
─ ─ Generally more aggressive behavior and poorer prognosis than L-FLAC.
Macro ─
─ Typically presents as a well-circumscribed, solitary peripheral or sometimes central lung mass
─ Size can vary widely
─ Cut surface may be solid, fleshy, grayish-white or tan, sometimes with cystic areas, hemorrhage, or necrosis (especially in H-FLAC or blastoma)
Micro ─
─ Low-grade Fetal Adenocarcinoma (L-FLAC):
─ ─ Histologically resembles fetal lung in the pseudoglandular stage of development (approximately 10-16 weeks gestation).
─ ─ Composed of complex tubules and glandular structures lined by non-ciliated columnar epithelial cells that are rich in glycogen.
─ ─ Tumor cells typically have clear or eosinophilic cytoplasm due to abundant glycogen content, with round to oval nuclei, smooth nuclear contours, and inconspicuous nucleoli; cytologic atypia is minimal.
─ ─ Characteristic subnuclear or supranuclear glycogen vacuoles (which indent the nucleus) are a key feature (best seen with PAS stain, diastase-sensitive).
─ ─ Morules: Solid, well-demarcated nests or whorls of cells with bland, ovoid to spindle nuclei and eosinophilic or clear cytoplasm, often showing biotin-rich, optically clear nuclei; these are frequently present and are a highly characteristic diagnostic feature of L-FLAC. Morules may show nuclear beta-catenin accumulation.
─ ─ Stroma is often cellular and spindle-shaped but is not overtly malignant or sarcomatous.
─ High-grade Fetal Adenocarcinoma (H-FLAC):
─ ─ Resembles less differentiated fetal lung tissue or has features similar to embryonal carcinoma.
─ ─ Composed of glands, tubules, sheets, or papillary structures lined by more primitive-appearing epithelial cells.
─ ─ Cells show higher-grade nuclear atypia (pleomorphism, hyperchromasia, prominent nucleoli), increased mitotic activity (including atypical mitoses), and often necrosis.
─ ─ Glycogen content in tumor cells may be less prominent or absent compared to L-FLAC. Morules are less common or absent.
─ ─ If occurring as part of a biphasic pulmonary blastoma, it is intimately admixed with a malignant mesenchymal (sarcomatous) component. If no sarcomatous component is present, it is considered pure H-FLAC.
Ancillary studies ─
─ L-FLAC:
─ ─ PAS stain (with diastase digestion): Highlights the abundant glycogen in the cytoplasm of tumor cells (PAS-positive, diastase-sensitive).
─ ─ IHC: Tumor cells are often positive for TTF-1, CK7, and EMA. Nuclear accumulation of beta-catenin (due to Wnt pathway activation, often via CTNNB1 mutations) is common, especially in morules. Alpha-fetoprotein (AFP) and SALL4 may be focally positive. Glypican-3 can also be expressed. Ki-67 index is low.
─ H-FLAC:
─ ─ IHC: Similar to L-FLAC but may show higher Ki-67 proliferation index. SALL4, AFP, and Glypican-3 are often more consistently and diffusely positive. Nuclear beta-catenin is also common.
DDx ─
─ For L-FLAC:
─ ─ Clear Cell Adenocarcinoma of the lung (cells have abundant clear cytoplasm due to glycogen, but typically lacks morules and the complex glandular/tubular architecture of L-FLAC; nuclear features may be more pleomorphic).
─ ─ Metastatic Renal Cell Carcinoma, clear cell type (PAX8 positive, TTF-1 negative; lacks morules).
─ ─ Carcinoid tumor (neuroendocrine markers positive, different morphology).
─ ─ Sclerosing Pneumocytoma (has papillary, solid, sclerotic, and hemorrhagic patterns with two cell types – surface cuboidal cells and stromal round/oval cells; different IHC profile).
─ For H-FLAC:
─ ─ Poorly differentiated Non-Small Cell Lung Carcinoma (NSCLC), NOS (lacks specific features of H-FLAC like primitive glands or consistent AFP/SALL4/Glypican-3 expression).
─ ─ Metastatic Embryonal Carcinoma or Yolk Sac Tumor (usually in younger patients with testicular or mediastinal primary; SALL4 and AFP can be positive in both, but morphology and clinical context differ).
─ ─ Biphasic Pulmonary Blastoma (distinguished from pure H-FLAC by the presence of a malignant mesenchymal/sarcomatous component).
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Enteric-type Adenocarcinoma (Pulmonary adenocarcinoma with enteric differentiation)

A rare variant of primary pulmonary adenocarcinoma characterized by morphologic features that closely resemble adenocarcinoma of the gastrointestinal tract, particularly colorectal adenocarcinoma; diagnosis requires exclusion of metastasis from an actual gastrointestinal primary
Clinical ─
─ Symptoms are similar to other types of lung adenocarcinoma (e.g., cough, dyspnea, chest pain) or may be an incidental finding
─ May be associated with elevated serum Carcinoembryonic Antigen (CEA) levels
─ Diagnosis of primary pulmonary enteric adenocarcinoma is one of exclusion, requiring thorough clinical and endoscopic investigation to rule out a GI primary tumor
Macro ─
─ Typically presents as a peripheral solitary nodule or mass, but can be central
─ Cut surface may be gray-white, firm, sometimes with areas of necrosis or mucin
Micro ─
─ Resembles adenocarcinoma of gastrointestinal origin, particularly colorectal type:
─ ─ Glandular, cribriform, or complex papillary architectural patterns are common
─ ─ Tumor cells are often tall columnar with elongated, hyperchromatic, pseudostratified nuclei (nuclear palisading) and eosinophilic cytoplasm
─ ─ "Dirty necrosis" (abundant granular necrotic debris within glandular lumens) is a characteristic, though not invariably present, feature strongly suggestive of enteric differentiation
─ ─ Goblet cells may be present but are not usually the predominant cell type (unlike mucinous adenocarcinoma)
─ ─ Villous architecture can also be seen
Ancillary studies ─
─ IHC panel is crucial for diagnosis and to help distinguish from metastatic GI adenocarcinoma:
─ ─ IHC (+) Often positive for CK7 (Cytokeratin 7), which is typically negative or only focally positive in most colorectal adenocarcinomas, thus CK7 positivity favors a lung primary in this context
─ ─ IHC (+) TTF-1 (Thyroid Transcription Factor-1) is positive in a significant subset of primary pulmonary enteric adenocarcinomas (reportedly ~50%), which strongly supports lung origin as GI adenocarcinomas are almost always TTF-1 negative (rare neuroendocrine GI tumors can be an exception)
─ ─ IHC (+) CDX2 (Caudal type homeobox 2) can be positive in a variable proportion of pulmonary enteric adenocarcinomas (e.g., ~30-70%), creating a diagnostic challenge as it is also a sensitive marker for colorectal primary. However, co-expression of TTF-1 and CDX2 would strongly favor lung primary.
─ ─ IHC (+) CK20 (Cytokeratin 20) is often positive, similar to GI adenocarcinomas
─ ─ IHC (+) Villin may be positive (marker of brush border, common in enteric differentiation)
─ ─ IHC (-) SATB2 (Special AT-rich sequence-binding protein 2) is usually negative; SATB2 positivity is a highly specific marker for colorectal primary and its absence supports lung origin in an enteric-patterned tumor
─ ─ IHC (-) Napsin A is usually negative or only weakly/focally positive (unlike typical non-mucinous lung adenocarcinoma)
─ Molecular: KRAS mutations are common. EGFR mutations are less frequent compared to conventional non-mucinous lung adenocarcinoma. Alterations in APC or beta-catenin have been reported, further mimicking GI pathway alterations.
DDx ─
─ Metastatic adenocarcinoma from the gastrointestinal tract (especially colorectal, pancreaticobiliary, or upper GI): This is the most critical differential. Requires thorough clinical investigation (endoscopy, imaging) to rule out a GI primary. An IHC panel including TTF-1, CK7, CK20, CDX2, and SATB2 is essential. (e.g., Colorectal metastasis: typically TTF-1 neg, CK7 neg, CK20 pos, CDX2 pos, SATB2 pos).
─ Invasive Mucinous Adenocarcinoma of the lung: While both are mucin-producing, invasive mucinous adenocarcinoma typically has more prominent goblet cells or tall columnar cells with voluminous apical mucin, often with lepidic or aerogenous spread, and usually lacks the "dirty necrosis" or complex glandular/cribriform patterns with nuclear palisading characteristic of enteric type. IHC profile also differs (mucinous adeno usually TTF-1 neg, CK20 variable, CDX2 variable but often neg).
─ Other primary lung adenocarcinoma subtypes with glandular patterns: May show some overlapping features, but lack the full constellation of enteric morphology and specific IHC profile.
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Signet Ring Cell Carcinoma (Primary pulmonary, >50% signet ring cells)

A rare and aggressive variant of adenocarcinoma (which can be mucinous or non-mucinous in its non-signet ring component) defined by the presence of >50% signet ring cells within the tumor; primary pulmonary origin must be established by thorough exclusion of metastasis from other common sites of signet ring cell carcinoma
Clinical ─
─ Often associated with aggressive clinical behavior, advanced stage at presentation, poor prognosis, and frequent lymphangitic spread or pleural effusions
─ Symptoms may include dyspnea, cough, chest pain, weight loss
─ Can occur in smokers and non-smokers, and across a wide age range
─ Diagnosis of primary pulmonary signet ring cell carcinoma is one of exclusion
Macro ─
─ Often presents as an ill-defined, infiltrative mass or diffuse consolidation rather than a discrete nodule
─ May show a gelatinous appearance if mucin production is prominent
─ Pleural involvement and thickening are common
Micro ─
─ Predominant component (>50% of tumor cells) consists of signet ring cells:
─ ─ These cells are characterized by large intracytoplasmic vacuoles (typically containing mucin, but can sometimes be empty or contain other material) that compress and displace the nucleus to the periphery, creating a crescentic or "signet ring" shape
─ Tumor cells can infiltrate the stroma individually, in small clusters, cords, sheets, or form poorly defined glandular structures
─ Background stroma is often desmoplastic and abundant (linitis plastica-like pattern can occur)
─ The non-signet ring component, if present (<50%), can show features of conventional adenocarcinoma (lepidic, acinar, papillary, etc.) or mucinous adenocarcinoma
─ Lymphovascular invasion is common
Ancillary studies ─
─ IHC:
─ ─ Mucin stains (e.g., PAS with diastase, Alcian blue, mucicarmine) confirm the presence of intracytoplasmic mucin within the signet ring cells in most cases
─ ─ Tumor cells are usually positive for cytokeratins (e.g., CK7)
─ ─ TTF-1 and Napsin A expression is variable: They may be positive (especially if the underlying adenocarcinoma component is non-mucinous and TTF-1 positive before signet ring differentiation) or negative (particularly if the tumor has a strong mucinous phenotype, where TTF-1 is often negative). Their positivity supports lung primary.
─ ─ Markers to exclude metastasis are crucial: e.g., CDX2/SATB2 (for GI, especially stomach/colon), GATA3/GCDFP-15 (for breast), PAX8 (for ovary/stomach), E-cadherin (loss can be seen in some signet ring cell carcinomas, e.g., lobular breast Ca, diffuse gastric Ca).
─ Molecular: ALK gene rearrangements and ROS1 gene rearrangements have been reported with a higher frequency in primary pulmonary adenocarcinomas with signet ring cell features, particularly in younger, non-smoking patients. KRAS mutations can also occur.
DDx ─
─ Metastatic Signet Ring Cell Carcinoma: This is the MOST IMPORTANT differential diagnosis and must be rigorously excluded. Common primary sites include stomach (most frequent), colon, breast (invasive lobular carcinoma often has signet ring cells), pancreas, ovary, bladder. Requires thorough clinical investigation (e.g., endoscopy, imaging of abdomen/pelvis) and an extensive IHC panel.
─ Other primary lung adenocarcinoma subtypes with focal signet ring cells: If signet ring cells constitute <50% of the tumor, it is classified as adenocarcinoma with signet ring features, rather than pure signet ring cell carcinoma.
─ Malignant Mesothelioma with signet ring-like features: Rare, but epithelioid mesothelioma can have cells with cytoplasmic vacuoles mimicking signet rings; mesothelial markers (calretinin, WT1, CK5/6, D2-40) would be positive, and adenocarcinoma markers negative.
─ Lymphoma with signet ring cell features: Extremely rare; lymphoid markers (e.g., CD45, CD20, CD3) would be positive.
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Clear Cell Adenocarcinoma

A rare variant of primary pulmonary adenocarcinoma characterized by a predominant component (generally defined as >50% or >90% of the tumor, though criteria vary) of tumor cells with abundant clear cytoplasm, typically due to glycogen accumulation, or less commonly, lipid
Clinical ─
─ Presentation is similar to other types of lung adenocarcinoma; may be an asymptomatic peripheral nodule or cause cough, dyspnea, chest pain
─ No specific distinct clinical features are strongly associated with this variant compared to conventional adenocarcinoma
Macro ─
─ Usually presents as a solitary, peripheral, solid nodule or mass
─ Cut surface may appear grayish-white, tan, or somewhat yellowish if lipid content is high
Micro ─
─ Predominant population of tumor cells with abundant clear or pale eosinophilic, finely granular cytoplasm; cell borders are often distinct ("plant cell-like" appearance can occur)
─ Nuclei are usually centrally or eccentrically located and may show variable degrees of atypia, ranging from relatively bland with small nucleoli (low grade) to markedly pleomorphic with prominent nucleoli (high grade)
─ Growth patterns can be solid (sheets of clear cells), acinar (gland formation with clear cell lining), papillary, or trabecular
─ Stroma is often delicate and vascular, sometimes hyalinized
─ Mitotic activity is variable
─ The clear appearance of the cytoplasm is most commonly due to glycogen accumulation; less frequently, it can be due to lipid
Ancillary studies ─
─ Histochemical stains:
─ ─ PAS (Periodic Acid-Schiff) stain: Typically positive (magenta granules) in the clear cytoplasm if due to glycogen.
─ ─ PAS with diastase (PAS-D): Glycogen is removed by diastase, so PAS staining will be lost or significantly reduced, confirming glycogen.
─ ─ Oil Red O or Sudan black B stains (performed on frozen sections of fresh tissue, as lipids are dissolved during routine paraffin processing): Positive if the clear cytoplasm is due to lipid accumulation (less common).
─ IHC:
─ ─ Usually positive for adenocarcinoma markers supporting lung primary: TTF-1 (nuclear), Napsin A (cytoplasmic), and CK7 (cytoplasmic). This pattern is key for distinguishing from metastases.
─ ─ Negative for markers of Renal Cell Carcinoma (RCC), clear cell type: PAX8 (though some lung adenocarcinomas can be PAX8+ focally, diffuse strong PAX8 is more typical of RCC), RCCma (Renal Cell Carcinoma marker antibody), CD10, CAIX (Carbonic Anhydrase IX – often strong membranous in clear cell RCC).
─ ─ Negative for markers of other clear cell tumors from other sites: e.g., HMB-45/Melan-A (for clear cell sarcoma of soft tissue or malignant melanoma), S100 (can be positive in some clear cell sarcomas or melanomas but also in some lung adeno).
DDx ─
─ Metastatic Clear Cell Renal Cell Carcinoma (ccRCC): This is the most important differential. ccRCC is typically TTF-1 negative, CK7 negative or focal, and positive for PAX8, CD10, and CAIX. Clinical history of a renal mass is crucial.
─ Clear cell tumors from other primary sites: e.g., gynecologic tract (ovary, uterus), thyroid, adrenal gland, salivary glands, skin (clear cell melanoma). Requires appropriate IHC panel based on morphology and clinical context.
─ PEComa (Perivascular Epithelioid Cell Tumor) of the lung: Can have clear cell features; positive for melanocytic markers (HMB-45, Melan-A) and smooth muscle markers (SMA, desmin).
─ Sugar Tumor (Benign Clear Cell Tumor of the Lung): Benign neoplasm with sheets of clear cells rich in glycogen; positive for HMB-45 and SMA (considered part of the PEComa family); lacks significant atypia or invasion.
─ Squamous Cell Carcinoma with clear cell features: Will be positive for squamous markers (p63, p40, CK5/6).
─ Large Cell Carcinoma with clear cells: A diagnosis of exclusion if no clear adeno or squamous differentiation by H&E or IHC.
─ Non-neoplastic conditions with clear cells: e.g., alveolar macrophages filled with surfactant or debris (usually not forming solid sheets or showing atypia).
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Oncocytic Adenocarcinoma

A rare variant of primary pulmonary adenocarcinoma characterized by a predominant component (typically defined as >50% of the tumor) of neoplastic cells with oncocytic features, meaning they possess abundant, granular, deeply eosinophilic cytoplasm due to a massive accumulation of mitochondria
Clinical ─
─ Presentation is similar to other types of lung adenocarcinoma; may be an asymptomatic peripheral nodule discovered incidentally or present with symptoms like cough, dyspnea, or chest pain
─ No specific distinct clinical or epidemiological features are strongly associated with this variant compared to conventional adenocarcinoma, though it is generally rare
Macro ─
─ Usually presents as a solitary, peripheral, solid nodule or mass
─ Cut surface may appear tan-brown or mahogany due to the eosinophilic nature of the cells and high mitochondrial content, distinguishing it from the more common grayish-white appearance of typical adenocarcinoma
Micro ─
─ Predominant population (>50%) of oncocytic tumor cells:
─ ─ Cells are typically large, polygonal, with abundant, deeply eosinophilic, granular cytoplasm
─ ─ Cell borders are usually well-defined
─ Nuclei are often centrally or eccentrically located, typically round to oval, and may have prominent, centrally located nucleoli; nuclear atypia can vary from low to high grade
─ Growth patterns can be acinar (glandular), papillary, solid, or less commonly, lepidic. The underlying adenocarcinoma architecture should be evident.
─ Tumor cells are arranged in nests, glands, sheets, or lining papillae
─ The granular appearance of the cytoplasm is due to the extensive accumulation of mitochondria
Ancillary studies ─
─ IHC:
─ ─ Positive for adenocarcinoma markers supporting lung primary and glandular differentiation: TTF-1 (nuclear) and Napsin A (cytoplasmic) are usually positive, CK7 (cytoplasmic) is also typically positive.
─ ─ The cytoplasm of oncocytic cells shows strong positivity with immunohistochemical stains for mitochondrial antigens (e.g., anti-mitochondrial antibody [AMA, clone 113-1]) or histochemical stains like phosphotungstic acid hematoxylin (PTAH), which highlights mitochondria (though PTAH is less specific).
─ Electron Microscopy (EM): Although rarely performed for routine diagnosis now, EM provides definitive confirmation of oncocytic differentiation by demonstrating cytoplasm packed with numerous, often pleomorphic, mitochondria.
DDx ─
─ Other tumors with oncocytic features:
─ ─ Oncocytic Carcinoid Tumor (Pulmonary Neuroendocrine Tumor with Oncocytic Features): Will be positive for neuroendocrine markers (chromogranin, synaptophysin, CD56) and typically negative or only focally positive for Napsin A. TTF-1 can be positive in both.
─ ─ Metastatic Oncocytic Tumors: From other primary sites such as kidney (oncocytoma or oncocytic renal cell carcinoma – PAX8+, CD10 variable, TTF-1 negative), thyroid (Hürthle cell/oncocytic carcinoma – thyroglobulin+, PAX8+, TTF-1 often positive but different context), or salivary gland (oncocytoma, oncocytic carcinoma – specific salivary markers like DOG1, S100, SOX10 may be useful). Clinical history and a panel of site-specific IHC markers are crucial.
─ Granular Cell Tumor: Rare in lung; cells have abundant eosinophilic granular cytoplasm (PAS-positive, diastase-resistant granules which are lysosomes, not mitochondria). Strongly S100 positive, SOX10 positive. Negative for TTF-1, Napsin A.
─ Reactive oncocytic metaplasia or hyperplasia: Can occur in chronically inflamed airways or around scars; cells are bland, usually not forming a distinct invasive mass, and lack significant atypia.
─ Adenocarcinoma with eosinophilic cytoplasm (not truly oncocytic): If eosinophilia is due to other reasons (e.g., abundant smooth endoplasmic reticulum) rather than massive mitochondrial accumulation. Mitochondrial stains/EM would clarify.
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Squamous Cell Carcinoma

Invasive Squamous Cell Carcinoma (SCC)

An invasive malignant epithelial tumor originating from bronchial or bronchiolar epithelium that demonstrates squamous differentiation, defined by the presence of keratinization (intercellular bridges and/or keratin pearl formation) and/or other morphological or immunohistochemical features indicative of squamous cells
Clinical ─
─ Strongly associated with cigarette smoking (vast majority of cases); other risk factors include exposure to radon, arsenic, and other environmental carcinogens
─ Historically more common in males, but incidence in females has risen with smoking patterns
─ Typically presents in older individuals (peak incidence 60s-70s)
─ Central/hilar tumors (arising from major or lobar bronchi) are common, often leading to symptoms like persistent cough, hemoptysis, dyspnea due to airway obstruction, post-obstructive pneumonia, or chest pain. Peripheral SCCs are also increasingly recognized.
─ May cause Pancoast syndrome if apical, or superior vena cava syndrome if mediastinal invasion.
─ Paraneoplastic syndromes can occur, notably hypercalcemia due to tumor production of parathyroid hormone-related protein (PTHrP).
Macro ─
─ Central tumors: Often firm, gray-white, endobronchial, exophytic, fungating masses that may infiltrate the bronchial wall and surrounding lung parenchyma, leading to bronchial obstruction.
─ Peripheral tumors: Typically solid, firm, gray-white or tan masses, frequently exhibiting central necrosis and cavitation (due to rapid growth outstripping blood supply or keratin breakdown).
─ Invasion into adjacent structures (e.g., chest wall, mediastinum, blood vessels) can occur.
Micro ─
─ Definitive evidence of squamous differentiation is required for diagnosis:
─ ─ Keratinization: Manifests as either:
─ ─ ─ Keratin pearls: Concentric, lamellated whorls of squamous cells with progressive keratinization towards the center, appearing as dense, eosinophilic, anucleated material.
─ ─ ─ Individual cell keratinization (dyskeratosis): Single or small groups of cells showing dense, glassy, deeply eosinophilic cytoplasm and often pyknotic (small, dark, condensed) nuclei.
─ ─ Intercellular bridges (desmosomes): Visible as fine, linear, spine-like strands connecting adjacent tumor cells; best appreciated on high power in areas where cells are slightly separated.
─ Tumor cells are typically polygonal with abundant, often dense or glassy, eosinophilic cytoplasm and distinct cell borders.
─ Nuclei are usually large, irregular in shape and contour, hyperchromatic, with coarse chromatin and often prominent nucleoli. Marked nuclear pleomorphism is common.
─ Mitotic activity is usually brisk and atypical mitoses can be frequent.
─ Invasive growth pattern: Tumor cells infiltrate the stroma as nests, sheets, cords, or irregular trabeculae. Stromal desmoplasia is variable.
─ Lymphovascular invasion and perineural invasion may be present and are poor prognostic indicators.
─ Subtypes (WHO classification based on degree of keratinization and predominant cell type):
─ Keratinizing Squamous Cell Carcinoma:
─ ─ Characterized by obvious and widespread keratinization (abundant keratin pearls and/or individual cell keratinization) throughout much of the tumor. Intercellular bridges are usually prominent.
─ ─ Can be further graded as well, moderately, or poorly differentiated based on the extent of keratinization, degree of nuclear atypia, and resemblance to normal squamous epithelium.
─ Non-keratinizing Squamous Cell Carcinoma:
─ ─ Shows other features of squamous differentiation (e.g., intercellular bridges, sheet-like growth of polygonal cells with eosinophilic cytoplasm, expression of squamous IHC markers) but lacks obvious or widespread keratinization, or has only focal/minimal keratinization.
─ ─ Often poorly differentiated, and distinction from poorly differentiated adenocarcinoma or large cell carcinoma may require immunohistochemistry.
─ Basaloid Squamous Cell Carcinoma:
─ ─ A rare, aggressive variant composed predominantly of small to medium-sized cells with scant cytoplasm, hyperchromatic nuclei, high N:C ratio, and often peripheral palisading of nuclei within tumor nests, resembling basal cell carcinoma of the skin.
─ ─ Foci of conventional squamous cell carcinoma differentiation (keratinization or intercellular bridges) are usually present and required for diagnosis.
─ ─ High mitotic rate and tumor necrosis are common.
Ancillary studies ─
─ IHC is key for diagnosis, especially in poorly differentiated tumors or small biopsies where classic morphologic features are limited:
─ ─ Positive for squamous differentiation markers (at least one is usually required):
─ ─ ─ p40 (ΔNp63 isoform): Nuclear stain, considered the most specific marker for squamous differentiation.
─ ─ ─ p63: Nuclear stain, highly sensitive but less specific than p40 (also stains basal cells in other epithelia, some adenocarcinomas, urothelial carcinoma).
─ ─ ─ CK5/6 (Cytokeratin 5/6): Cytoplasmic stain.
─ ─ ─ Desmoglein-3, Claudin-1: Less commonly used but can support squamous lineage.
─ ─ Typically negative for adenocarcinoma markers (TTF-1, Napsin A) and neuroendocrine markers (Chromogranin, Synaptophysin, CD56).
─ ─ Basaloid SCC: Positive for squamous markers (p40, p63, CK5/6); may sometimes show focal or weak expression of some neuroendocrine markers but should not be the dominant pattern. Ki-67 proliferation index is high.
─ Special stains for mucin (e.g., PAS-D, Alcian blue) are typically negative (or only very focal intracellular mucin in rare cases, not true glandular differentiation).
DDx ─
─ Metastatic Squamous Cell Carcinoma: From other sites such as head and neck (oral cavity, pharynx, larynx), esophagus, cervix, skin, anus. Clinical history of a primary SCC elsewhere and comparison with that primary's histology are essential. p16 IHC can be helpful if an HPV-related head and neck primary is suspected (diffuse block-positive p16 is characteristic of HPV-driven oropharyngeal SCC), but p16 can also be positive (often patchy) in some primary lung SCCs unrelated to HPV.
─ Adenocarcinoma with squamous metaplasia: The primary component is adenocarcinoma (TTF-1/Napsin A positive), with areas of benign-appearing squamous metaplasia.
─ Adenosquamous Carcinoma: Contains distinct, unequivocal components of both adenocarcinoma and squamous cell carcinoma, with each component constituting at least 10% of the tumor.
─ Poorly Differentiated Non-Small Cell Carcinoma, Not Otherwise Specified (NSCLC-NOS): If the tumor is so poorly differentiated that definitive squamous or glandular features cannot be identified by H&E or IHC.
─ Large Cell Neuroendocrine Carcinoma (LCNEC): Can have large cells and sheet-like growth but will be positive for neuroendocrine markers.
─ Malignant Mesothelioma, sarcomatoid or desmoplastic type (if peripheral and invading chest wall; mesothelial markers positive).
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Papillary Squamous Cell Carcinoma

A variant of invasive squamous cell carcinoma characterized by a predominantly exophytic papillary growth pattern, where finger-like projections with central fibrovascular cores are lined by atypical squamous epithelium showing features of malignancy; it can occur as an endobronchial mass or as a peripheral invasive tumor
Clinical ─
─ Endobronchial papillary SCCs often present earlier with symptoms of airway obstruction, such as cough, dyspnea, wheezing, or post-obstructive pneumonia; hemoptysis is also common
─ Peripheral papillary SCCs may be asymptomatic or present similarly to conventional peripheral SCCs
─ Strong association with smoking, similar to conventional SCC
─ Prognosis is generally considered similar to or slightly better than conventional SCC of the same stage, particularly for exophytic endobronchial lesions if completely resected without deep invasion
Macro ─
─ Endobronchial lesions: Typically appear as exophytic, polypoid, warty, or cauliflower-like masses protruding into the bronchial lumen
─ Peripheral lesions: May present as relatively well-circumscribed nodules or masses, which can show central necrosis or cavitation; papillary architecture may not be grossly obvious
Micro ─
─ Predominant architectural pattern consists of true papillae: Finger-like or branching projections with central fibrovascular cores, which contain blood vessels and connective tissue
─ Papillae are lined by malignant squamous epithelium, which shows features of squamous differentiation:
─ ─ Intercellular bridges, stratification, and often keratinization (keratin pearls or individual cell dyskeratosis)
─ ─ Cells exhibit nuclear atypia (enlargement, hyperchromasia, irregular contours, pleomorphism), increased N:C ratio, and mitotic activity (which can be atypical)
─ Invasion: For invasive papillary SCC, there is evidence of invasion by the malignant squamous cells into the underlying stroma of the bronchial wall (if endobronchial) or surrounding lung parenchyma (if peripheral)
─ An in situ component (squamous cell carcinoma in situ with papillary architecture) may be present, especially in endobronchial lesions, but invasive papillary SCC by definition shows stromal invasion
─ The degree of squamous differentiation and atypia can vary (well, moderately, or poorly differentiated)
Ancillary studies ─
─ IHC:
─ ─ Positive for squamous differentiation markers: p40 (most specific), p63, CK5/6.
─ ─ Typically negative for adenocarcinoma markers (TTF-1, Napsin A) and neuroendocrine markers.
DDx ─
─ Squamous Papilloma (of the bronchus): A benign lesion with papillary architecture lined by bland squamous epithelium without significant atypia or invasion; distinction from well-differentiated papillary SCC in situ can be challenging on small biopsies if atypia is borderline.
─ Squamous Cell Carcinoma in Situ with papillary growth: Malignant squamous cells confined to the epithelium (no stromal invasion), but with a papillary surface architecture.
─ Adenocarcinoma with papillary features: Tumor cells will show glandular differentiation and be positive for adenocarcinoma markers (TTF-1, Napsin A), negative for squamous markers.
─ Adenosquamous Carcinoma with a prominent papillary squamous component: Requires a distinct adenocarcinoma component (each >10% of tumor).
─ Verrucous Carcinoma: A rare, very well-differentiated variant of SCC with a warty, pushing border of invasion, typically lacks significant cytologic atypia of conventional papillary SCC.
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Spindle Cell Squamous Cell Carcinoma (part of Sarcomatoid Carcinoma)

A poorly differentiated variant of squamous cell carcinoma composed predominantly or exclusively of atypical spindle-shaped tumor cells that demonstrate squamous differentiation by immunohistochemistry or ultrastructure, or by an identifiable origin from or association with conventional squamous cell carcinoma or squamous carcinoma in situ; it is classified as a subtype of Sarcomatoid Carcinoma of the lung
Clinical ─
─ Rare and aggressive tumors, generally associated with a poor prognosis compared to conventional SCC
─ Strong association with cigarette smoking, similar to other SCCs
─ Typically affects older individuals, with a male predominance
─ Often presents as large peripheral tumors, but can be central; may cause symptoms like cough, dyspnea, chest pain, hemoptysis
Macro ─
─ Usually large, fleshy, firm or friable masses, often with areas of necrosis and hemorrhage
─ May show infiltrative borders
Micro ─
─ Predominantly or exclusively composed of atypical spindle cells arranged in fascicles, storiform patterns, or haphazardly
─ Spindle cells are elongated, with fusiform or pleomorphic nuclei, often hyperchromatic, with variable amounts of eosinophilic cytoplasm; mitotic figures are usually frequent and can be atypical
─ Evidence of squamous differentiation is required for diagnosis:
─ ─ May be overt if there are foci of conventional squamous cell carcinoma (keratinizing or non-keratinizing) or squamous carcinoma in situ from which the spindle cell component appears to arise or merge
─ ─ If no morphologic squamous component is seen, IHC demonstration of squamous markers (see below) in the spindle cells is necessary
─ Stroma is variable, can be desmoplastic or myxoid
─ Necrosis and hemorrhage are common
Ancillary studies ─
─ IHC is crucial, especially in cases lacking overt squamous differentiation on H&E:
─ ─ Positive for broad-spectrum cytokeratins (e.g., AE1/AE3, CAM5.2, MNF116) and high-molecular-weight cytokeratins (e.g., CK5/6)
─ ─ Positive for squamous differentiation markers: p40 and/or p63 (nuclear staining in spindle cells) at least focally.
─ ─ Tumor cells may co-express vimentin (a mesenchymal marker), which is common in sarcomatoid carcinomas reflecting epithelial-mesenchymal transition or divergence.
─ ─ Typically negative for adenocarcinoma markers (TTF-1, Napsin A) and neuroendocrine markers.
─ Electron microscopy (rarely used now): Can show ultrastructural features of squamous differentiation (e.g., tonofilaments, desmosomes) in spindle cells.
DDx ─
─ Other Sarcomatoid Carcinomas of the lung:
─ ─ Pleomorphic Carcinoma (contains malignant spindle cells and/or giant cells, OR conventional NSCLC component (adeno, SCC, large cell) making up <10% of tumor; spindle cell SCC is a subtype where the NSCLC component is squamous or IHC confirms squamous lineage of spindle cells).
─ ─ Carcinosarcoma (contains both a malignant epithelial component (carcinoma) and a malignant mesenchymal component (sarcoma) with heterologous elements like rhabdomyosarcoma, chondrosarcoma, osteosarcoma).
─ ─ Giant Cell Carcinoma (predominantly bizarre multinucleated giant cells).
─ ─ Pulmonary Blastoma (biphasic, with primitive epithelial (fetal adenocarcinoma-like) and primitive mesenchymal components).
─ Primary Pulmonary Sarcoma (e.g., fibrosarcoma, leiomyosarcoma, synovial sarcoma): These are purely mesenchymal tumors and will be negative for cytokeratins and specific squamous markers; they will express specific mesenchymal markers (e.g., SMA/desmin for leiomyosarcoma, specific translocations for synovial sarcoma).
─ Metastatic Sarcoma or Sarcomatoid Carcinoma from another site: Clinical history is essential.
─ Malignant Melanoma, spindle cell type: S100 protein and SOX10 positive.
─ Inflammatory Myofibroblastic Tumor (IMT): Bland spindle cells, prominent inflammatory infiltrate (plasma cells, lymphocytes), ALK rearrangement common; lacks marked atypia and squamous markers of spindle cell SCC.
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Acantholytic/Pseudoglandular Squamous Cell Carcinoma

A variant of invasive squamous cell carcinoma characterized by significant loss of cohesion (acantholysis) between tumor cells, leading to the formation of pseudoglandular or pseudoluminal spaces lined by atypical squamous cells; these spaces may contain detached, rounded, acantholytic tumor cells. It is also known as pseudoadenoid or adenoid-squamous SCC.
Clinical ─
─ Similar clinical presentation, risk factors (smoking), and prognosis to conventional squamous cell carcinoma of the lung of similar stage and grade
─ No specific distinct clinical features are strongly associated with this variant
Macro ─
─ Gross appearance is similar to conventional squamous cell carcinoma; may be a central or peripheral mass, often with necrosis or cavitation
Micro ─
─ Underlying features of squamous cell carcinoma are present: Infiltrating nests or sheets of polygonal cells with eosinophilic cytoplasm, nuclear atypia, and evidence of squamous differentiation (intercellular bridges and/or keratinization), at least focally
─ Hallmark feature: Prominent acantholysis, which is the loss of intercellular cohesion between neoplastic squamous cells. This results in:
─ ─ Formation of clefts, slits, or larger pseudoglandular or pseudoluminal spaces within tumor nests
─ ─ These spaces are lined by atypical squamous cells and may contain detached, rounded, acantholytic tumor cells, often with eosinophilic cytoplasm and pyknotic nuclei (dyskeratotic cells)
─ The pseudoglandular spaces are "false" glands because they lack true glandular differentiation (e.g., mucin production by lining cells, true basement membrane-lined lumens formed by polarized glandular cells)
─ Central comedo-like necrosis can be seen within tumor nests, and the acantholytic cells may float within this necrotic debris or proteinaceous fluid
─ Keratinization (pearls or individual cell) and intercellular bridges should be identifiable, at least focally, to confirm squamous lineage
Ancillary studies ─
─ IHC:
─ ─ Positive for squamous differentiation markers: p40, p63, CK5/6.
─ ─ Negative for adenocarcinoma markers: TTF-1, Napsin A.
─ ─ Mucin stains (e.g., PAS with diastase, Alcian blue): Negative within the pseudoglandular spaces and tumor cells (helps distinguish from adenosquamous carcinoma or adenocarcinoma with glandular spaces).
DDx ─
─ Adenosquamous Carcinoma: Contains a true glandular component (adenocarcinoma) with mucin production, in addition to a squamous cell carcinoma component. The glandular lumens in adenosquamous carcinoma are true lumens lined by glandular cells, not pseudolumens formed by acantholysis of squamous cells. IHC will show positivity for both adeno and squamous markers in respective components.
─ Adenocarcinoma with acantholytic features or clear cell features: If the tumor cells forming glandular structures are positive for adenocarcinoma markers (TTF-1, Napsin A) and negative for squamous markers, it is an adenocarcinoma, even if some cells appear detached or have clear cytoplasm.
─ Angiosarcoma: A malignant vascular tumor that can form anastomosing channels and pseudolumens lined by atypical endothelial cells; these cells will be positive for vascular markers (CD31, CD34, ERG) and negative for squamous markers.
─ Other poorly differentiated carcinomas with discohesive cells or cystic degeneration: Careful search for definitive squamous features (keratinization, intercellular bridges) and appropriate IHC panel are key.
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Lymphoepithelioma-like Carcinoma (LELC)

A rare type of undifferentiated carcinoma of the lung characterized by malignant epithelial cells with a syncytial growth pattern (indistinct cell borders) and a prominent, non-neoplastic lymphoplasmacytic infiltrate intimately admixed with the tumor cells; in the lung, it is often strongly associated with Epstein-Barr Virus (EBV) infection, particularly in patients from East Asian populations
Clinical ─
─ Occurs over a wide age range, can affect younger individuals compared to other lung cancers
─ No consistent strong association with smoking, especially for EBV-positive cases
─ May present as a solitary peripheral nodule or mass, or less commonly as a central lesion; symptoms are similar to other lung cancers (cough, dyspnea, chest pain) or may be asymptomatic
─ Prognosis is generally considered to be better than other conventional non-small cell lung carcinomas (NSCLC) of similar stage, particularly for EBV-positive LELC
─ Though listed under SCC variants in the provided Table of Contents, LELC is often classified as a distinct type of NSCLC, specifically within the category of "other and unclassified carcinomas" or as a subtype of large cell carcinoma in some older classifications, due to its undifferentiated nature. Its prominent lymphoid stroma is a defining feature.
Macro ─
─ Typically a solitary or occasionally multiple well-circumscribed or infiltrative nodule(s) or mass(es)
─ Cut surface is often fleshy, firm, and grayish-white or tan
Micro ─
─ Tumor cells:
─ ─ Large, undifferentiated epithelial cells with vesicular (open or pale) nuclei, prominent central eosinophilic nucleoli, and indistinct cell borders, giving a syncytial appearance (cells appear to merge)
─ ─ Cells are typically arranged in cohesive sheets, nests, anastomosing trabeculae, or irregular clusters
─ ─ Cytoplasm is usually moderate in amount, eosinophilic or amphophilic
─ ─ Mitotic figures can be variable but are often present
─ Stroma:
─ ─ Characterized by a dense and prominent non-neoplastic lymphoplasmacytic infiltrate, composed of mature lymphocytes (mostly T-cells), plasma cells, histiocytes, and sometimes eosinophils and neutrophils, intimately admixed with and surrounding the tumor cell clusters
─ ─ The lymphoid stroma is reactive, not part of the neoplastic component
─ Squamous differentiation (keratinization, intercellular bridges) and glandular differentiation are typically absent or minimal; if overt squamous or glandular features are present, other diagnoses should be considered.
Ancillary studies ─
─ IHC:
─ ─ Tumor cells are positive for broad-spectrum cytokeratins (e.g., AE1/AE3, CAM5.2, EMA)
─ ─ CK5/6 may be positive in tumor cells; p40 and p63 can also be positive in a subset of cases, especially EBV-negative LELC, which can lead to its occasional misclassification with poorly differentiated SCC if the lymphoid stroma is not appreciated or EBV status unknown.
─ ─ Tumor cells are negative for TTF-1 and Napsin A (helping to distinguish from adenocarcinoma)
─ ─ Negative for specific neuroendocrine markers (distinguishing from neuroendocrine carcinomas with lymphoid stroma)
─ ─ Lymphoid infiltrate is polyclonal, composed of CD3+ T-cells and CD20+ B-cells
─ ─ PD-L1 expression is often high on tumor cells and/or immune cells
─ In situ hybridization for EBV-encoded RNA (EBER):
─ ─ This is a key diagnostic test. EBER is positive in the nuclei of the malignant epithelial cells in most cases of LELC, particularly those occurring in endemic regions (East Asia).
─ ─ EBV-negative LELC also exists (more common in Western populations), which may have a different molecular profile and possibly different clinical behavior.
DDx ─
─ Poorly Differentiated Squamous Cell Carcinoma with prominent inflammation or lymphoepithelioma-like features: Conventional SCC usually has more overt squamous morphology (keratinization, intercellular bridges) and the lymphoid stroma is typically more reactive and less integral than in LELC. EBER status helps.
─ Lymphoepithelioma of the nasopharynx (or other head/neck sites) metastatic to the lung: Clinically exclude a nasopharyngeal primary (or other primary LELC site) as LELC morphology is similar regardless of origin; EBV association is also strong in nasopharyngeal LELC.
─ Lymphoma, especially Hodgkin lymphoma (classic or lymphocyte-rich types) or some T-cell lymphomas: Tumor cells in LELC are CD45 negative and cytokeratin positive, distinguishing them from lymphoid cells. Reed-Sternberg cells in Hodgkin lymphoma have characteristic morphology and IHC profile (CD30+, CD15+).
─ Thymic Carcinoma with lymphoid stroma metastatic to lung: Typically a mediastinal primary; different IHC profile (e.g., CD5, CD117 may be positive in some thymic carcinomas).
─ Germ cell tumors (e.g., seminoma) with prominent lymphoid stroma metastatic to lung: Seminoma cells are positive for PLAP, OCT3/4, SALL4.
─ Undifferentiated carcinoma with lymphoid stroma not otherwise specified.
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Neuroendocrine Tumors of the Lung

Typical Carcinoid Tumor

A low-grade malignant neuroendocrine neoplasm of the lung, composed of cells with characteristic neuroendocrine morphology (organoid patterns, "salt-and-pepper" chromatin), defined by <2 mitoses per 2 mm² (approximately 10 high-power fields, field size dependent) and the absence of necrosis; it is part of the spectrum of pulmonary neuroendocrine tumors (PNETs)
Clinical ─
─ Occurs over a wide age range, including adolescents and young adults, with a peak incidence around 40-60 years; no strong association with smoking for typical carcinoids, unlike other major lung cancer types
─ Often presents as an asymptomatic peripheral nodule found incidentally on imaging, or as a central/endobronchial lesion causing symptoms related to airway obstruction (cough, wheezing, recurrent pneumonia, hemoptysis)
─ Carcinoid syndrome (flushing, diarrhea, bronchospasm due to systemic release of serotonin or other vasoactive substances) is rare with pulmonary carcinoids (<5%), as these substances are usually inactivated by the liver; it is more common if there are liver metastases
─ Generally has an excellent prognosis with high long-term survival rates ( >85-95% at 10 years) following complete surgical resection, especially for peripheral tumors
─ Regional lymph node metastases can occur in ~5-15% of cases but do not necessarily confer a significantly worse prognosis if completely resected
Macro ─
─ Central tumors: Typically arise in main, lobar, or segmental bronchi; often appear as well-circumscribed, polypoid, exophytic, endobronchial masses covered by intact respiratory mucosa; cut surface is often reddish-tan, yellowish, or gray-white, and firm.
─ Peripheral tumors: Usually solitary, well-circumscribed, solid nodules or masses located within the lung parenchyma, not visibly connected to a major bronchus; cut surface similar to central tumors.
Micro ─
─ Characteristic neuroendocrine architecture: Tumor cells are arranged in distinct organoid patterns:
─ ─ Nests: Solid, well-defined clusters of cells.
─ ─ Trabeculae: Cords or ribbons of cells, often one to several cells thick.
─ ─ Rosettes (pseudorosettes): Gland-like structures with cells arranged around a central lumen or fibrillary core.
─ ─ Festoons or gyriform patterns: Undulating ribbons of cells.
─ ─ Solid sheets (less common as a pure pattern).
─ ─ These structures are typically separated by a delicate, well-vascularized fibrovascular stroma.
─ Tumor cells: Generally uniform, small to medium-sized, polygonal, round, oval, or sometimes spindle-shaped, with moderate amounts of eosinophilic, finely granular cytoplasm.
─ Nuclei: Round to oval, with finely granular, stippled ("salt-and-pepper") chromatin; nucleoli are usually inconspicuous or small.
─ Mitotic activity: Low, defined as <2 mitoses per 2 mm² (this area is equivalent to approximately ten 40x high-power fields, but exact HPF count depends on microscope field diameter – use of a 2 mm² area or standardized counting method is recommended). Atypical mitoses are absent.
─ Necrosis: Absent by definition. Any amount of true tumor necrosis (not crush artifact or ischemic change) would classify the tumor as at least an atypical carcinoid.
─ Cytologic atypia is minimal.
─ Variants: Spindle cell, oncocytic, or clear cell features can be seen focally or predominantly.
Ancillary studies ─
─ IHC: Essential for confirming neuroendocrine differentiation:
─ ─ Positive for general neuroendocrine markers:
─ ─ ─ Chromogranin A (cytoplasmic granular staining)
─ ─ ─ Synaptophysin (cytoplasmic diffuse or granular staining – often more sensitive than chromogranin)
─ ─ ─ CD56 (NCAM - Neural Cell Adhesion Molecule; membranous staining – sensitive but less specific)
─ ─ TTF-1 (Thyroid Transcription Factor-1): Can be positive in a subset of pulmonary carcinoids (both central and peripheral types, ~30-50%), supporting lung origin.
─ ─ Ki-67 proliferation index: Characteristically very low, typically <2-5% (often <2%).
DDx ─
─ Atypical Carcinoid Tumor: Distinguished by the presence of 2-10 mitoses per 2 mm² AND/OR the presence of necrosis (usually punctate or focal). Cytologic atypia may be more pronounced.
─ Small Cell Lung Carcinoma (SCLC) or Large Cell Neuroendocrine Carcinoma (LCNEC): High-grade neuroendocrine carcinomas with much higher mitotic rates (>10/2mm²), extensive necrosis, significant nuclear atypia, and different architectural patterns (sheets, diffuse infiltrates in SCLC; large cells, organoid patterns with high grade features in LCNEC).
─ Tumorlets: Small (<0.5 cm) aggregates of neuroendocrine cells, often incidental and associated with scars or chronic inflammation; cytologically similar to typical carcinoid but distinguished by size. No metastatic potential.
─ Metastatic Neuroendocrine Tumor (e.g., from gastrointestinal tract, pancreas): Clinical history of a primary elsewhere is key. IHC for site-specific markers (e.g., CDX2 for GI midgut/hindgut, ISL1 for pancreatic, PAX8 for pancreatic) can be helpful. TTF-1 positivity strongly favors a pulmonary primary.
─ Paraganglioma (rare in lung): Nested ("zellballen") pattern with S100-positive sustentacular cells at the periphery of nests; different IHC profile (e.g., GATA3 often positive).
─ Glomus Tumor (rare in lung): Different perivascular epithelioid/spindle cell morphology, positive for smooth muscle actin (SMA).
─ Sclerosing Pneumocytoma: Can have areas resembling carcinoid, but shows two cell types (surface cuboidal, stromal round cells), papillary and sclerotic patterns, and different IHC (surface cells TTF-1+, stromal cells EMA focal/neg).
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Atypical Carcinoid Tumor

A malignant neuroendocrine neoplasm of the lung that is intermediate in grade between typical carcinoid and high-grade neuroendocrine carcinomas (Small Cell Lung Carcinoma and Large Cell Neuroendocrine Carcinoma); it is defined by features similar to typical carcinoid but with either the presence of necrosis (usually punctate/focal) OR a mitotic count of 2 to 10 mitoses per 2 mm² (approximately 10 high-power fields, field size dependent)
Clinical ─
─ Occurs over a wide age range, similar to typical carcinoids, but may have a slightly older mean age and a stronger association with cigarette smoking compared to typical carcinoids
─ Can present as a peripheral nodule/mass or a central/endobronchial lesion; symptoms may include cough, hemoptysis, chest pain, dyspnea, or post-obstructive pneumonia. May also be an asymptomatic incidental finding.
─ Compared to typical carcinoids, atypical carcinoids have a higher likelihood of lymph node metastasis (~30-50%) and distant metastasis, and thus a less favorable prognosis, although still significantly better than high-grade neuroendocrine carcinomas.
─ Carcinoid syndrome is rare.
Macro ─
─ Often larger than typical carcinoids (frequently >3 cm), but can be any size.
─ May appear well-circumscribed or show more infiltrative borders compared to typical carcinoids.
─ Cut surface is typically gray-white, tan, or yellowish, fleshy, and may show focal areas of hemorrhage or necrosis (if present, these are important for classification).
Micro ─
─ Overall architectural patterns are similar to typical carcinoid: organoid arrangements such as nests, trabeculae, ribbons, festoons, rosettes, or solid sheets, supported by a fibrovascular stroma.
─ Tumor cells exhibit neuroendocrine morphology: generally uniform, polygonal to spindle-shaped cells with moderate amounts of eosinophilic, finely granular cytoplasm. Nuclei are round to oval with "salt-and-pepper" (stippled) chromatin.
─ Key diagnostic criteria (presence of EITHER is sufficient for diagnosis of Atypical Carcinoid):
─ ─ Mitotic count: 2 to 10 mitoses per 2 mm² (equivalent to approximately ten 40x high-power fields; careful counting in the most mitotically active areas is crucial). Atypical mitoses can sometimes be present.
─ ─ Necrosis: Present, usually punctate (small foci of single or clustered necrotic cells and debris) or limited comedo-type necrosis (central necrosis within tumor nests). Extensive, sheet-like necrosis is more characteristic of high-grade neuroendocrine carcinomas.
─ Cytologic atypia: May be more pronounced than in typical carcinoid, including nuclear pleomorphism, hyperchromasia, and more prominent nucleoli, but these features alone without meeting mitotic or necrosis criteria are not sufficient for a diagnosis of atypical carcinoid.
─ Spindle cell, oncocytic, or clear cell variants can occur.
Ancillary studies ─
─ IHC:
─ ─ Positive for general neuroendocrine markers: Chromogranin A, Synaptophysin, CD56 (NCAM). Expression may sometimes be more focal or less intense than in typical carcinoids.
─ ─ TTF-1 (Thyroid Transcription Factor-1): Can be positive in a subset of cases, similar to typical carcinoids.
─ ─ Ki-67 proliferation index: Typically higher than in typical carcinoid, often in the range of 5-20% (but the mitotic count and presence/absence of necrosis are the defining criteria, not Ki-67 alone).
DDx ─
─ Typical Carcinoid Tumor: Lacks necrosis AND has a mitotic count of <2 mitoses per 2 mm². This is the most critical distinction.
─ Large Cell Neuroendocrine Carcinoma (LCNEC): A high-grade neuroendocrine carcinoma with >10 mitoses per 2 mm², extensive necrosis, often larger cells with more prominent nucleoli, and more disorganized architecture, though some organoid features can persist. Ki-67 is usually very high (>20-30%).
─ Small Cell Lung Carcinoma (SCLC): Another high-grade neuroendocrine carcinoma characterized by small cells, scant cytoplasm, nuclear molding, finely granular chromatin, absent/inconspicuous nucleoli, very high mitotic rate, and extensive necrosis.
─ Metastatic Neuroendocrine Tumor (e.g., from GI tract, pancreas): Clinical history and comparison with primary (if known) are essential. IHC for site-specific markers (CDX2, ISL1, PAX8, etc.) and TTF-1 (positivity favors lung primary) can be helpful.
─ Non-neuroendocrine carcinomas with neuroendocrine differentiation or features mimicking neuroendocrine morphology (e.g., solid adenocarcinoma, basaloid SCC): Require careful IHC panel to exclude.
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Small Cell Carcinoma (SCLC)

A highly aggressive, high-grade neuroendocrine carcinoma composed of small malignant cells with scant cytoplasm, ill-defined cell borders, finely granular ("salt-and-pepper") nuclear chromatin, absent or inconspicuous nucleoli, frequent mitoses, extensive necrosis, and often prominent nuclear molding; it is very strongly associated with cigarette smoking
Clinical ─
─ One of the most aggressive types of lung cancer, characterized by rapid growth, early development of widespread metastases, and poor prognosis if untreated (though often initially sensitive to chemotherapy and radiotherapy)
─ Overwhelmingly occurs in heavy smokers (>95% of cases)
─ Typically presents in older individuals (60s-70s)
─ Often arises centrally as a hilar or perihilar mass with extensive mediastinal lymphadenopathy, frequently encasing major bronchi and blood vessels
─ Symptoms: Cough, dyspnea, chest pain, hemoptysis, weight loss, fatigue. Due to central location and rapid growth, can cause superior vena cava syndrome, hoarseness (recurrent laryngeal nerve palsy), or dysphagia.
─ Paraneoplastic syndromes are common: Syndrome of Inappropriate Antidiuretic Hormone (SIADH) secretion, Cushing's syndrome (ectopic ACTH production), Lambert-Eaton myasthenic syndrome, cerebellar degeneration, limbic encephalitis.
─ Usually metastatic at diagnosis (Extensive-Stage Disease - ES-SCLC); less commonly confined to one hemithorax (Limited-Stage Disease - LS-SCLC).
Macro ─
─ Often large, infiltrative, centrally located masses, appearing soft, friable, and grayish-white or tan
─ Extensive necrosis and hemorrhage are common on cut section
─ Frequently involves mediastinal lymph nodes, which can be bulky
Micro ─
─ Tumor cells are characteristically small (typically less than 3 times the diameter of a resting lymphocyte, though some variation exists) and may be round, oval, or spindle-shaped.
─ Scant cytoplasm and ill-defined cell borders, often giving a syncytial appearance where cells seem to merge.
─ Nuclei: Round to fusiform, with finely granular, stippled ("salt-and-pepper") or sometimes hyperchromatic chromatin. Nucleoli are characteristically absent or inconspicuous.
─ Nuclear molding: Nuclei are closely apposed and appear to indent or deform each other due to cellular crowding and scant cytoplasm.
─ High mitotic rate: Numerous mitoses are typically easily found (usually >10 mitoses per 2 mm², often much higher, e.g., >60-80 per 2 mm²). Atypical mitoses are common.
─ Extensive necrosis: Often geographic, sheet-like, or single-cell necrosis.
─ Azzopardi effect: Basophilic staining of blood vessel walls due to encrustation by DNA released from necrotic tumor cells.
─ Crush artifact: Common in small biopsy specimens (e.g., transbronchial biopsy, core needle biopsy) due to the fragile nature of the tumor cells; cells appear as streaks of dark blue nuclear material.
─ Growth patterns: Diffuse sheets, ribbons, clusters, nests, or perivascular streaming of tumor cells. Rosette formation is rare.
─ Combined Small Cell Carcinoma (c-SCLC): Defined as SCLC that contains a component of any other Non-Small Cell Lung Cancer (NSCLC) type, such as squamous cell carcinoma, adenocarcinoma, or large cell carcinoma. The NSCLC component must be clearly identifiable morphologically and/or immunohistochemically. This occurs in a subset of SCLC cases and may have therapeutic implications.
Ancillary studies ─
─ IHC:
─ ─ Positive for neuroendocrine markers: Synaptophysin (often strong and diffuse), Chromogranin A (can be focal or weak, sometimes negative), CD56 (NCAM - usually strong and diffuse). At least one neuroendocrine marker should be positive.
─ ─ TTF-1 (Thyroid Transcription Factor-1): Positive in the majority of cases (~80-90%), showing nuclear staining.
─ ─ Ki-67 proliferation index: Characteristically very high (typically >70-80%, often approaching 100%).
─ ─ In Combined SCLC (c-SCLC): The SCLC component will show the above IHC profile, while the NSCLC component will express its respective markers (e.g., p40/p63 for squamous component; Napsin A for adenocarcinoma component).
DDx ─
─ Other small round blue cell tumors:
─ ─ Lymphoma (especially diffuse large B-cell lymphoma or lymphoblastic lymphoma): Positive for CD45 (LCA) and specific lymphoid markers (e.g., CD20 for B-cells, CD3 for T-cells, TdT for lymphoblastic). Negative for cytokeratins and neuroendocrine markers.
─ ─ Ewing sarcoma / Peripheral Neuroectodermal Tumor (PNET): Rare in lung; positive for CD99 (membranous), FLI1 (nuclear); characteristic EWSR1 gene rearrangements.
─ ─ Embryonal Rhabdomyosarcoma: Positive for muscle markers (myogenin, MyoD1, desmin).
─ ─ Metastatic small cell carcinoma from other sites (e.g., Merkel cell carcinoma of skin – often CK20 dot-like positive; small cell prostate cancer – PSA positive; neuroendocrine carcinoma from GI/pancreas – may have different IHC profile like CDX2 or ISL1 positivity). Clinical history is crucial. TTF-1 positivity strongly favors lung primary for SCLC.
─ Basaloid Squamous Cell Carcinoma: Can have small cells with high N:C ratio, but usually shows peripheral palisading, connection to surface squamous dysplasia/CIS if bronchial, and is positive for squamous markers (p40, p63, CK5/6) while being negative or only very focally positive for neuroendocrine markers.
─ Large Cell Neuroendocrine Carcinoma (LCNEC): Composed of larger cells with more abundant cytoplasm, vesicular nuclei with prominent nucleoli, and often more organoid architecture (though still high grade with high mitoses and necrosis). The distinction can sometimes be challenging on small biopsies, especially if crush artifact is extensive in SCLC.
─ Crushed typical or atypical carcinoid tumor or even crushed benign lymphocytes: Can mimic SCLC in small, crushed biopsies. IHC for neuroendocrine markers, Ki-67, and lymphoid markers is essential to resolve. Carcinoids have low Ki-67.
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Large Cell Neuroendocrine Carcinoma (LCNEC)

A high-grade malignant neuroendocrine neoplasm of the lung composed of large cells with neuroendocrine morphology (organoid nesting, trabecular growth, rosettes, peripheral palisading), prominent nucleoli, a high mitotic rate (typically >10 mitoses per 2 mm²), and frequent extensive necrosis; it lacks the characteristic cytologic features of small cell carcinoma
Clinical ─
─ An aggressive tumor with a poor prognosis, similar to or slightly better than Small Cell Lung Carcinoma (SCLC) but worse than atypical carcinoid
─ Strongly associated with cigarette smoking
─ Typically affects older individuals, with a male predominance
─ Often presents as a large peripheral or sometimes central mass; metastatic disease at presentation is common
─ Paraneoplastic syndromes can occur but are less frequent than with SCLC
Macro ─
─ Usually large, often bulky tumors, typically >3 cm
─ Cut surface is gray-white or tan, fleshy, frequently with extensive areas of necrosis and hemorrhage
─ May show infiltrative borders into surrounding lung parenchyma
Micro ─
─ Neuroendocrine morphology:
─ ─ Tumor cells are typically arranged in organoid nests, trabeculae, ribbons, rosettes, or show peripheral palisading of nuclei within tumor nests
─ ─ Solid, sheet-like growth can also be seen
─ Cellular features:
─ ─ Cells are large (typically ≥3 times the diameter of a resting lymphocyte), polygonal, with moderate to abundant cytoplasm (more cytoplasm than SCLC)
─ ─ Nuclei are generally vesicular or coarsely granular (unlike the finely stippled "salt-and-pepper" chromatin of SCLC), often with prominent, easily identifiable eosinophilic nucleoli
─ ─ Nuclear pleomorphism can be moderate to marked
─ High mitotic rate: Defined as >10 mitoses per 2 mm² (approximately 10 high-power fields; careful counting in most active areas is essential). Atypical mitoses are common.
─ Extensive necrosis: Usually geographic or comedo-type necrosis is characteristic and often widespread
─ Nuclear molding and crush artifact are typically less prominent or absent compared to SCLC
─ Combined Large Cell Neuroendocrine Carcinoma (c-LCNEC): Defined as LCNEC that contains a component of any other Non-Small Cell Lung Cancer (NSCLC) type (e.g., adenocarcinoma, squamous cell carcinoma, large cell carcinoma) or, rarely, SCLC. The non-LCNEC component must be clearly identifiable morphologically and/or immunohistochemically.
Ancillary studies ─
─ IHC is essential for diagnosis and classification:
─ ─ Positive for at least one general neuroendocrine marker: Chromogranin A (often focal), Synaptophysin (often more diffuse), CD56 (NCAM - usually strong).
─ ─ TTF-1 (Thyroid Transcription Factor-1): Can be positive in a subset of cases (~30-50%).
─ ─ Ki-67 proliferation index: Characteristically high (typically >40-50%, often significantly higher).
─ ─ In Combined LCNEC (c-LCNEC): The LCNEC component will show the above IHC profile, while the NSCLC component will express its respective markers (e.g., Napsin A for adenocarcinoma component; p40/p63 for squamous component).
─ ─ Cytokeratins (e.g., AE1/AE3, CAM5.2) are usually positive.
DDx ─
─ Small Cell Lung Carcinoma (SCLC): SCLC cells are smaller, have scant cytoplasm, finely granular chromatin, absent/inconspicuous nucleoli, and more prominent nuclear molding and crush artifact. Distinction can be difficult on small, crushed biopsies; IHC (especially for nucleoli visibility and chromatin pattern) and Ki-67 can help, but some overlap exists.
─ Atypical Carcinoid Tumor: Has lower mitotic rate (2-10/2mm²), less extensive necrosis (punctate or focal), generally less cytologic atypia, and lower Ki-67 index.
─ Poorly Differentiated Non-Small Cell Carcinoma (NSCLC) with focal neuroendocrine differentiation or neuroendocrine marker expression: If classic neuroendocrine morphology (organoid nesting, palisading, rosettes) is absent or very focal, and neuroendocrine marker expression is limited, it may be better classified as NSCLC with NE differentiation rather than LCNEC. LCNEC requires both NE morphology and IHC confirmation.
─ Metastatic Neuroendocrine Carcinoma from another site (e.g., high-grade neuroendocrine carcinoma from GI tract, pancreas): Clinical history is crucial. IHC for site-specific markers (CDX2, ISL1, PAX8, etc.) and TTF-1 (positivity favors lung primary for LCNEC/SCLC) can be helpful.
─ Basaloid Squamous Cell Carcinoma: Can have high mitotic rate and necrosis, but shows squamous differentiation (p40/p63 positive) and typically lacks significant neuroendocrine marker expression.
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Large Cell Carcinoma

An undifferentiated non-small cell carcinoma of the lung that, by definition, lacks the cytologic, architectural, or immunohistochemical features of small cell carcinoma, adenocarcinoma, or squamous cell carcinoma; it is largely a diagnosis of exclusion, and with modern ancillary techniques, most tumors previously classified as LCC can now be further categorized
Clinical ─
─ Symptoms, risk factors (strong association with smoking), and age distribution are generally similar to other common types of NSCLC
─ Typically presents as a large peripheral or sometimes central mass
─ Prognosis has historically been considered poor, similar to other poorly differentiated NSCLCs, but varies depending on whether it's a true "null" LCC or a poorly differentiated form of adeno/SCC that couldn't be fully classified
─ Historical context: In older classifications, LCC was a more common diagnosis, serving as a "wastebasket" category for NSCLCs that didn't fit neatly into adenocarcinoma or SCC. The current WHO classification emphasizes the need for thorough immunohistochemical workup to reclassify LCCs whenever possible.
Macro ─
─ Often presents as large, bulky tumors, frequently with areas of necrosis and hemorrhage
─ Can be peripheral or central
Micro ─
─ Composed of malignant epithelial cells that are "large" – typically with abundant cytoplasm, vesicular nuclei (pale chromatin), and prominent eosinophilic nucleoli
─ Cells usually grow in solid sheets, nests, or diffuse patterns without obvious glandular formation, keratinization, intercellular bridges, or definitive neuroendocrine morphology (organoid nesting, rosettes, palisading) on H&E microscopy
─ Cytologic pleomorphism is usually marked; mitotic figures are often frequent and may be atypical; necrosis is common
─ To make a diagnosis of Large Cell Carcinoma (current WHO definition):
─ ─ The tumor must be a non-small cell carcinoma (i.e., cells are large, not SCLC cytology).
─ ─ There must be NO morphological evidence of glandular differentiation (no acini, papillae, lepidic growth, or intracellular mucin obvious on H&E).
─ ─ There must be NO morphological evidence of squamous differentiation (no keratinization, no intercellular bridges).
─ ─ AND, immunohistochemical stains for adenocarcinoma markers (e.g., TTF-1, Napsin A; mucin stain if needed) and squamous markers (e.g., p40, CK5/6) must be NEGATIVE or show only focal, non-specific staining not meeting criteria for adeno or squamous differentiation.
─ ─ Neuroendocrine markers must also be negative to exclude LCNEC.
─ True "null" LCC, negative for all lineage markers, is rare with comprehensive IHC workup. Most cases previously called LCC are now reclassified as poorly differentiated adenocarcinoma or squamous cell carcinoma based on IHC or subtle H&E features.
Ancillary studies ─
─ Immunohistochemistry (IHC) panel is ESSENTIAL:
─ ─ To exclude adenocarcinoma: Stains for TTF-1 and Napsin A must be negative. Mucin stains (PAS-D, Alcian blue) should be negative for intracellular mucin.
─ ─ To exclude squamous cell carcinoma: Stains for p40 (or p63) and CK5/6 must be negative.
─ ─ To exclude neuroendocrine carcinoma: Stains for Chromogranin A, Synaptophysin, and CD56 must be negative.
─ ─ Broad-spectrum cytokeratins (e.g., AE1/AE3, CAM5.2) are usually positive, confirming epithelial nature, but without specific lineage.
DDx ─
─ Poorly Differentiated Adenocarcinoma: May require extensive sampling and IHC to identify focal glandular differentiation or mucin production, or TTF-1/Napsin A positivity.
─ Poorly Differentiated Squamous Cell Carcinoma (Non-keratinizing SCC): May require extensive sampling and IHC to identify focal squamous features or p40/p63/CK5/6 positivity.
─ Large Cell Neuroendocrine Carcinoma (LCNEC): Distinguished by positive neuroendocrine markers and neuroendocrine morphology (even if focal) on H&E.
─ Sarcomatoid Carcinoma (e.g., pleomorphic carcinoma, spindle cell carcinoma, giant cell carcinoma): Characterized by spindle and/or giant cells; cytokeratin positive. Some LCCs may have focal pleomorphic features.
─ Metastatic Undifferentiated Carcinoma or Melanoma: Clinical history is crucial. IHC for site-specific markers or melanoma markers (S100, SOX10, HMB-45) would be needed if suspected.
─ Undifferentiated Non-Small Cell Lung Carcinoma, Not Otherwise Specified (NSCLC-NOS): This term is preferred by some if a tumor lacks differentiation after IHC, rather than LCC, though LCC is still a WHO category.
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Large Cell Carcinoma with Rhabdoid Features

A rare, highly aggressive variant of large cell carcinoma (or other non-small cell lung carcinoma types if rhabdoid features are present as a component) characterized by the presence of a significant proportion of "rhabdoid" cells; these are large, pleomorphic cells with eccentric nuclei, prominent nucleoli, and abundant eosinophilic cytoplasm containing distinctive globular, hyaline-like paranuclear inclusions
Clinical ─
─ Highly aggressive tumor with a very poor prognosis, frequent early metastasis, and short survival
─ May affect younger patients compared to conventional lung cancers, and may or may not be strongly associated with smoking
─ Symptoms are similar to other aggressive lung cancers: cough, dyspnea, chest pain, hemoptysis, weight loss
Macro ─
─ Typically large, bulky, infiltrative masses, often with extensive necrosis and hemorrhage, similar to other high-grade lung cancers
Micro ─
─ Background features may resemble large cell carcinoma (undifferentiated large malignant cells) or, less commonly, other NSCLC types like adenocarcinoma or squamous cell carcinoma, with a superimposed or predominant component of rhabdoid cells.
─ Rhabdoid cells are the hallmark:
─ ─ Large, often discohesive or loosely cohesive malignant cells.
─ ─ Eccentrically placed, vesicular nuclei.
─ ─ Very prominent, often eosinophilic ("cherry-red") central nucleoli.
─ ─ Abundant, deeply eosinophilic cytoplasm containing a characteristic globular, hyaline-like, paranuclear inclusion that often indents or displaces the nucleus. This inclusion is composed of aggregates of intermediate filaments (cytokeratins and often vimentin).
─ The proportion of rhabdoid cells required for diagnosis is not strictly defined, but they should be a conspicuous component.
─ Marked nuclear pleomorphism, high mitotic rate, and atypical mitoses are common.
─ Extensive necrosis is frequently present.
Ancillary studies ─
─ IHC:
─ ─ Rhabdoid cells typically co-express broad-spectrum cytokeratins (e.g., AE1/AE3, CAM5.2, EMA), confirming their epithelial nature, and vimentin (reflecting their undifferentiated or mesenchymal-like state).
─ ─ Loss of nuclear expression of INI1 (SMARCB1/BAF47/SNF5) is characteristic of malignant rhabdoid tumors in other sites (e.g., kidney, soft tissue, CNS) and can be seen in a subset of pulmonary carcinomas with rhabdoid features, supporting true rhabdoid differentiation/phenotype. However, INI1 expression can be retained in some cases.
─ ─ Other NSCLC lineage markers (e.g., TTF-1 for adenocarcinoma component, p40 for squamous component) may be positive in the non-rhabdoid portion of the tumor if it arose from a specific NSCLC type, or sometimes focally in rhabdoid cells.
─ ─ Neuroendocrine markers are typically negative.
DDx ─
─ Malignant Rhabdoid Tumor (MRT), primary or metastatic: Primary MRT of the lung is exceedingly rare, more typically a tumor of infancy/early childhood (e.g., atypical teratoid/rhabdoid tumor of CNS, MRT of kidney). Metastatic MRT from another site should be considered. INI1 loss is a key feature of classic MRTs.
─ Epithelioid Sarcoma: Can have rhabdoid-like cells and often shows loss of INI1 expression; typically positive for cytokeratins and EMA, CD34 can be positive. Primary pulmonary epithelioid sarcoma is very rare.
─ Melanoma: Can have pleomorphic cells with prominent nucleoli and eosinophilic cytoplasm; S100, SOX10, HMB-45 positive.
─ Other poorly differentiated carcinomas with prominent eosinophilic cytoplasm or cytoplasmic inclusions (e.g., oncocytic carcinoma, carcinoma with hyaline globules). The specific nuclear features and paranuclear filamentous whorl of rhabdoid cells are distinctive.
─ True rhabdomyosarcomatous differentiation (seen in carcinosarcoma or primary rhabdomyosarcoma): Cells would show skeletal muscle differentiation with cross-striations (rarely seen) and positivity for muscle markers like desmin, myogenin, and MyoD1. Rhabdoid cells typically lack these muscle markers.
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Other Epithelial Malignancies

Adenosquamous Carcinoma

A malignant epithelial tumor of the lung that contains components of both squamous cell carcinoma and adenocarcinoma, with each component constituting at least 10% of the tumor mass
Clinical ─
─ Accounts for a small percentage (0.4-4%) of all lung cancers
─ Strongly associated with cigarette smoking, similar to pure squamous cell carcinoma and adenocarcinoma in smokers
─ Typically affects older individuals, with a male predominance
─ Clinical presentation is similar to other non-small cell lung carcinomas (NSCLC), including cough, dyspnea, chest pain, hemoptysis, or may be an incidental finding
─ Prognosis is generally considered to be poorer than that of pure adenocarcinoma or squamous cell carcinoma of comparable stage, though this is somewhat controversial and may depend on the predominant component or specific molecular features
Macro ─
─ Appearance is variable and may reflect the mixed nature; can be peripheral or central masses
─ Tumors are often firm, gray-white, and may show areas of necrosis, hemorrhage, or cavitation (if squamous component is large) or a more glandular/mucoid appearance (if adenocarcinoma component is prominent)
Micro ─
─ Two distinct malignant components must be clearly identifiable:
─ Squamous Cell Carcinoma component: Demonstrates unequivocal squamous differentiation, characterized by keratinization (e.g., keratin pearls, individual cell dyskeratosis) and/or intercellular bridges (desmosomes).
─ Adenocarcinoma component: Demonstrates unequivocal glandular differentiation, characterized by acinar, papillary, lepidic, or solid growth patterns with evidence of mucin production by tumor cells (either intracellular mucin or extracellular mucin associated with gland formation).
─ Diagnostic criterion: Each component (squamous and adenocarcinoma) must constitute at least 10% of the tumor volume. If one component is less than 10%, the tumor is classified as the predominant type with features of the minor component (e.g., adenocarcinoma with focal squamous differentiation).
─ The two components are often intermingled but can also be relatively discrete areas within the same tumor mass
─ The grade of differentiation can vary for each component
Ancillary studies ─
─ IHC is often crucial, especially in poorly differentiated tumors or when one component is subtle, to confirm the dual differentiation:
─ ─ Squamous component: Will be positive for squamous markers such as p40 (most specific), p63, and CK5/6. Typically negative for TTF-1 and Napsin A.
─ ─ Adenocarcinoma component: Will be positive for adenocarcinoma markers such as TTF-1 and Napsin A (for non-mucinous types). Mucin stains (e.g., PAS with diastase, Alcian blue) can confirm mucin production. Typically negative for p40 and CK5/6 (though p63 can be positive in some reactive or metaplastic glandular cells, p40 is more specific for squamous neoplasia).
─ A panel approach using markers for both lineages is recommended
DDx ─
─ Squamous Cell Carcinoma with pseudoglandular features (Acantholytic SCC): May mimic glandular spaces, but these are false lumens formed by acantholysis of squamous cells, lack true glandular lining, and are negative for mucin and adenocarcinoma IHC markers.
─ Adenocarcinoma with squamous metaplasia: The squamous component is metaplastic (benign or reactive change within an adenocarcinoma) and lacks the cytologic atypia and invasive features characteristic of a malignant squamous cell carcinoma component.
─ Collision tumor: Extremely rare, where two entirely separate primary tumors (e.g., an adenocarcinoma and a squamous cell carcinoma) grow into each other without true intermingling of components at the cellular level.
─ Mucoepidermoid Carcinoma (a salivary gland-type tumor): Contains squamous cells, mucous cells, and intermediate cells in characteristic architectural patterns; different IHC profile (e.g., p63 positive in basal/squamous cells, specific translocations like MAML2 fusions).
─ Poorly differentiated Non-Small Cell Carcinoma, NOS: If neither component reaches the 10% threshold or if differentiation is too poor to classify even with IHC.
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NUT Carcinoma (Midline Carcinoma, NUTM1-rearranged)

A rare, highly aggressive, and poorly differentiated carcinoma defined by the presence of a chromosomal rearrangement involving the NUTM1 (NUT Midline Carcinoma family member 1) gene, most commonly a t(15;19)(q14;p13.1) translocation resulting in a BRD4-NUTM1 fusion gene, or less commonly, fusions with BRD3 or other partners (e.g., NSD3)
Clinical ─
─ Affects individuals of all ages, including children, adolescents, and young adults, without a clear sex predilection
─ Very aggressive clinical course, characterized by rapid local progression, early metastasis, and poor response to conventional chemotherapy, leading to a dismal prognosis (median survival often <1 year)
─ Often arises in midline structures of the body, such as the head and neck (e.g., sinonasal tract, pharynx, salivary glands) and mediastinum (thymus, lungs), but can occur in other locations including the lungs (as primary pulmonary NUT carcinoma)
─ Symptoms depend on location but can include pain, mass effects, airway obstruction (if thoracic)
Macro ─
─ Typically presents as large, infiltrative, poorly-circumscribed masses, often with extensive necrosis and hemorrhage
Micro ─
─ Poorly differentiated or undifferentiated carcinoma with limited specific morphologic features on H&E alone, making it a challenging diagnosis without ancillary studies
─ Tumor cells are typically monomorphic, medium-sized, with round to oval nuclei, vesicular or open chromatin, often prominent eosinophilic nucleoli, and scant to moderate amounts of eosinophilic or amphophilic cytoplasm
─ Growth patterns are variable: often diffuse sheets, solid nests, or infiltrative cords and clusters
─ Abrupt, focal keratinization (squamous differentiation) in the form of small foci of squamous cells, individual dyskeratotic cells, or small "squamous pearls" within a sea of undifferentiated cells is a characteristic, though not invariably present, histologic clue
─ Brisk mitotic activity and extensive tumor necrosis (often comedo-like or geographic) are common
─ May have a prominent inflammatory infiltrate (neutrophils, lymphocytes)
Ancillary studies ─
─ IHC:
─ ─ Diagnosis is primarily confirmed by demonstrating nuclear expression of NUT protein using a specific monoclonal antibody (clone C52B1 or others). This staining is typically strong, diffuse, and speckled in the tumor cell nuclei and is highly specific.
─ ─ Tumor cells are usually positive for broad-spectrum cytokeratins (e.g., AE1/AE3, CAM5.2, CK7).
─ ─ May show focal or patchy positivity for p63 or p40, especially in areas with squamous differentiation, which can lead to misdiagnosis as poorly differentiated squamous cell carcinoma if NUT IHC is not performed.
─ ─ Typically negative for TTF-1, Napsin A, and definitive neuroendocrine markers (Chromogranin, Synaptophysin).
─ ─ CD34 expression has been reported in some cases.
─ Molecular studies: Definitive diagnosis can also be made by identifying the specific NUTM1 gene rearrangement using FISH (fluorescence in situ hybridization) with break-apart probes for NUTM1, RT-PCR, or next-generation sequencing (NGS) panels that include fusion detection.
DDx ─
─ Poorly Differentiated Squamous Cell Carcinoma (especially basaloid SCC or SCC with focal abrupt keratinization): NUT IHC is essential for distinction. SCC will be NUT negative.
─ Poorly Differentiated Adenocarcinoma or Non-Small Cell Carcinoma, NOS: NUT IHC negative; adeno markers (TTF-1, Napsin A) may be positive in adenocarcinoma.
─ Small Cell Carcinoma / Large Cell Neuroendocrine Carcinoma: NUT IHC negative; neuroendocrine markers positive.
─ Germ Cell Tumors (e.g., mediastinal primary with lung involvement, or metastatic): Specific germ cell markers (e.g., SALL4, OCT3/4, PLAP, AFP, HCG) would be positive; NUT IHC negative.
─ Ewing Sarcoma / PNET (especially if round cell morphology): CD99 positive, FLI1 positive, characteristic EWSR1 rearrangements; NUT IHC negative.
─ Lymphoma (e.g., diffuse large B-cell lymphoma, lymphoblastic lymphoma): CD45 positive, specific lymphoid markers positive; NUT IHC negative.
─ Sinonasal Undifferentiated Carcinoma (SNUC): Can have overlapping features if NUT carcinoma arises in sinonasal tract; NUT IHC/molecular is key.
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Thoracic SMARCA4-Deficient Undifferentiated Tumor (SMARCA4-DUT)

A recently recognized type of highly aggressive, undifferentiated malignant neoplasm occurring primarily in the thorax (lungs, pleura, or mediastinum), characterized by loss of protein expression of SMARCA4 (also known as BRG1), a critical ATPase subunit of the SWI/SNF chromatin remodeling complex, and often exhibiting rhabdoid or plasmacytoid cytomorphology
Clinical ─
─ Predominantly affects adult smokers, often heavy smokers, with a strong male predominance (M:F ratio ~4:1 or higher)
─ Characterized by a very aggressive clinical course with rapid disease progression, early metastasis, poor response to conventional therapies, and dismal prognosis (median survival often only a few months)
─ Typically presents with large thoracic masses, dyspnea, chest pain, cough, weight loss
─ Hypercalcemia of malignancy can occur in a subset of patients
Macro ─
─ Often presents as large, bulky, infiltrative masses within the lung parenchyma, pleura, or mediastinum
─ Cut surface frequently shows extensive necrosis and hemorrhage
Micro ─
─ Undifferentiated malignant neoplasm: Tumor cells typically grow in diffuse sheets, solid nests, or cohesive clusters, often with areas of necrosis
─ Cytology: Cells are usually medium to large, round to oval or polygonal, with vesicular or open chromatin, prominent eosinophilic nucleoli, and moderate to abundant eosinophilic cytoplasm
─ Rhabdoid or plasmacytoid cytomorphologic features are common and characteristic:
─ ─ Rhabdoid cells: Eccentrically placed nuclei, prominent nucleoli, and eosinophilic cytoplasm often containing paranuclear globular inclusions (composed of intermediate filaments)
─ ─ Plasmacytoid cells: Eccentric nuclei and more abundant amphophilic/eosinophilic cytoplasm resembling plasma cells
─ Brisk mitotic activity (numerous, often atypical mitoses) and extensive tumor necrosis are characteristic features
─ May have a significant inflammatory infiltrate (neutrophils, lymphocytes, eosinophils) within the tumor stroma
─ By definition, lacks clear glandular, squamous, or neuroendocrine differentiation on H&E microscopy
Ancillary studies ─
─ IHC:
─ ─ Hallmark diagnostic feature: Complete loss of nuclear expression of SMARCA4 (BRG1) in the tumor cells. It is crucial to confirm intact staining in internal positive controls (e.g., stromal cells, inflammatory cells, normal epithelium).
─ ─ Loss of SMARCA2 (BRM), another SWI/SNF complex component, is also frequently observed (often co-loss with SMARCA4).
─ ─ Tumor cells are usually positive for broad-spectrum cytokeratins (e.g., AE1/AE3, CAM5.2, CK7), but staining can be focal or weak.
─ ─ Often express SOX2 (a transcription factor involved in squamous differentiation and pluripotency).
─ ─ May show aberrant expression of other markers such as CD34, SALL4 (a germ cell tumor marker), Claudin-4, or focal p63/p40, but typically lack consistent expression of definitive lineage markers.
─ ─ Generally negative for TTF-1, Napsin A (adenocarcinoma markers), and definitive neuroendocrine markers (Chromogranin, Synaptophysin).
─ ─ INI1 (SMARCB1) expression is typically intact (retained nuclear staining), distinguishing these from classic INI1-deficient malignant rhabdoid tumors.
DDx ─
─ Poorly Differentiated Non-Small Cell Lung Carcinoma, NOS: If SMARCA4 expression is intact. SMARCA4 IHC is essential if morphology is undifferentiated with rhabdoid/plasmacytoid features.
─ Large Cell Carcinoma with Rhabdoid Features: Some of these cases may represent SMARCA4-DUT if SMARCA4 loss is demonstrated. If SMARCA4 is intact, INI1/SMARCB1 status should also be checked if rhabdoid features are prominent.
─ Malignant Rhabdoid Tumor (MRT), primary or metastatic: Classic MRTs are typically INI1/SMARCB1 deficient and more common in pediatric patients. Primary pulmonary MRT is exceedingly rare.
─ Germ Cell Tumors (especially Yolk Sac Tumor or Embryonal Carcinoma, if markers like SALL4, AFP, or Glypican-3 are positive): Clinical context (age, testicular/mediastinal primary), morphology, and a broader IHC panel are important. SMARCA4 loss is not typical of germ cell tumors.
─ NUT Carcinoma: Positive for NUT protein by IHC; SMARCA4 is usually intact.
─ Malignant Mesothelioma (Sarcomatoid or poorly differentiated epithelioid type): Would express mesothelial markers (e.g., calretinin, WT1, D2-40); SMARCA4 is usually intact.
─ Poorly differentiated Squamous Cell Carcinoma or Adenocarcinoma: If focal differentiation is missed on H&E, but IHC for lineage markers should clarify. SMARCA4 loss is not a defining feature of conventional SCC or adenocarcinoma.
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Salivary Gland-Type Tumors of the Lung

Mucoepidermoid Carcinoma (MEC)

A malignant epithelial neoplasm composed of a variable mixture of three cell types: mucinous (mucus-producing) cells, squamous (epidermoid) cells, and intermediate cells, arranged in cystic and solid patterns; it is the most common primary salivary gland-type tumor of the lung, typically arising in the trachea or main bronchi from submucosal glands
Clinical ─
─ Occurs over a wide age range, including children and adolescents, with peak incidence in 3rd to 5th decades
─ No sex predilection; generally not associated with smoking
─ Symptoms are often related to endobronchial obstruction: persistent cough, hemoptysis, wheezing, dyspnea, or recurrent post-obstructive pneumonia
─ Graded as low, intermediate, or high grade based on histologic features, which correlates with prognosis. Low-grade tumors have an excellent prognosis with complete resection; high-grade tumors are more aggressive and can metastasize.
Macro ─
─ Usually presents as a well-circumscribed, firm, lobulated, polypoid or exophytic endobronchial mass, often covered by intact respiratory mucosa
─ Cut surface is typically gray-white or tan, may have a glistening or mucoid appearance, and can show cystic spaces
─ Larger or higher-grade tumors may show infiltration into the bronchial wall and surrounding lung parenchyma
Micro ─
─ Composed of a variable admixture of three principal cell types:
─ ─ Mucinous cells: Columnar, cuboidal, or goblet-like cells containing intracytoplasmic mucin; often line cystic or glandular spaces.
─ ─ Squamous (epidermoid) cells: Polygonal cells with eosinophilic cytoplasm, intercellular bridges, and may show keratinization (individual cell or pearls), particularly in higher-grade tumors.
─ ─ Intermediate cells: Smaller, basaloid or ovoid to polygonal cells with scant cytoplasm and indistinct cell borders, often found in solid nests or sheets, and considered to be progenitor cells capable of differentiating into mucinous or squamous cells.
─ Architectural patterns: Tumors exhibit a combination of solid nests, sheets, glandular structures, and variably sized cystic spaces.
─ Grading (based on a point system or overall features – criteria vary slightly but generally consider):
─ Low-grade MEC: Predominantly cystic (<20% solid component), minimal cytologic atypia, rare mitoses (<4 per 10 high-power fields or per 2mm²), no necrosis, no neural invasion. Excellent prognosis.
─ Intermediate-grade MEC: More solid areas, mild to moderate cytologic atypia, increased mitotic activity, focal perineural invasion may be seen.
─ High-grade MEC: Predominantly solid growth pattern (>50% or >75% solid), significant cytologic atypia (pleomorphism, prominent nucleoli), frequent mitoses (often ≥4/10 HPF or higher thresholds), tumor necrosis, and often infiltrative growth. May closely resemble squamous cell carcinoma or adenosquamous carcinoma. Poorer prognosis with higher risk of recurrence and metastasis.
Ancillary studies ─
─ IHC:
─ ─ Squamous cells: Positive for p63, p40, and CK5/6.
─ ─ Mucinous cells: Positive for mucin stains (e.g., PAS with diastase, Alcian blue, mucicarmine). CK7 is often positive.
─ ─ Intermediate cells: Often positive for p63 and CK5/6.
─ ─ TTF-1 is characteristically negative (an important feature for distinguishing from primary lung adenocarcinoma with mucinous or squamous features).
─ ─ Ki-67 proliferation index: Low in low-grade MEC, increases with grade.
─ Molecular: Rearrangements of the MAML2 gene (most commonly t(11;19)(q21;p13) leading to a CRTC1-MAML2 fusion oncogene, less commonly CRTC3-MAML2) are characteristic and found in a majority of MECs, particularly low and intermediate-grade tumors. Detection of this fusion can be diagnostically helpful. High-grade MECs may lack this fusion and show other alterations (e.g., TP53 mutations, CDKN2A loss).
DDx ─
─ Adenosquamous Carcinoma: Composed of distinct malignant glandular (adenocarcinoma) and squamous components, each typically >10% of the tumor. Adenocarcinoma component is usually TTF-1 positive. Lacks the characteristic intermediate cells and MAML2 fusion of MEC.
─ Squamous Cell Carcinoma with mucinous metaplasia or pseudoglandular features: May have squamous and mucinous areas, but lacks the true mixture of cell types and architectural patterns of MEC. Predominantly squamous differentiation.
─ Adenocarcinoma with squamous metaplasia: Predominantly adenocarcinoma with benign-appearing squamous metaplasia.
─ Benign Mixed Tumor (Pleomorphic Adenoma): Rare in lung; characterized by epithelial/myoepithelial cells within a prominent chondromyxoid or hyalinized stroma; lacks the specific cell types and architecture of MEC.
─ Metastatic mucoepidermoid carcinoma from salivary glands or other sites (histologically indistinguishable; clinical history is key).
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Adenoid Cystic Carcinoma (ACC)

A malignant epithelial neoplasm composed of ductal (epithelial) and myoepithelial-like (basaloid) cells, characterized by one or more of three primary architectural patterns: cribriform ("Swiss cheese" pattern), tubular, or solid; it typically arises from tracheobronchial submucosal glands and is known for its slow but relentless growth, high propensity for perineural invasion, local recurrence, and late distant metastases
Clinical ─
─ Occurs in adults, typically between 40-60 years, with no strong sex predilection or association with smoking
─ Symptoms are often related to central airway involvement and insidious onset: persistent cough, dyspnea, wheezing, hemoptysis, chest pain (can be severe if perineural invasion is prominent)
─ Slow clinical course, but prone to extensive local infiltration and late recurrences (years or even decades after initial treatment) and distant metastases (most commonly to lungs, bone, liver, brain)
─ Prognosis is generally poor over the long term due to high rates of recurrence and metastasis, although 5-year survival can be relatively good. Solid pattern is associated with worse prognosis.
Macro ─
─ Usually arises in the trachea or main bronchi as a firm, gray-white, infiltrative submucosal mass that may narrow the airway lumen or extend extrabronchially
─ May appear relatively well-circumscribed but often shows microscopic infiltration beyond gross tumor margins
─ Cut surface is typically solid and homogenous
Micro ─
─ Biphasic tumor composed of two main cell types:
─ ─ Ductal cells (epithelial): Line true glandular lumens; cuboidal to columnar cells with eosinophilic cytoplasm and round, centrally located nuclei.
─ ─ Myoepithelial-like (basaloid) cells: Smaller cells with scant cytoplasm, dark (hyperchromatic) angular or ovoid nuclei; these cells often surround the ductal cells or form solid nests and sheets.
─ Three major architectural patterns (often admixed within the same tumor):
─ ─ Cribriform pattern: Most characteristic ("Swiss cheese" appearance). Nests of basaloid cells containing multiple, small, punched-out, rounded, cyst-like pseudoluminal spaces. These pseudolumens are often filled with hyaline eosinophilic basement membrane material (PAS-positive, collagen IV positive) or, less commonly, mucoid secretions.
─ ─ Tubular pattern: Composed of small ducts or tubules lined by an inner layer of ductal cells and an outer layer of myoepithelial-like cells, embedded in a hyalinized or fibrous stroma.
─ ─ Solid pattern: Sheets or large, solid nests of basaloid/myoepithelial-like cells with minimal or no true lumen or pseudolumen formation. Tumors with a significant solid component (>30-50%) are associated with a more aggressive clinical course and poorer prognosis.
─ Perineural invasion: A hallmark feature, seen in a high percentage of cases; tumor cells track along and encircle nerves. Lymphovascular invasion can also occur.
─ Stroma is often hyalinized or fibrotic. Mitotic activity is usually low, but can be higher in solid areas.
Ancillary studies ─
─ IHC:
─ ─ Ductal cells: Positive for cytokeratins (e.g., CK7, AE1/AE3, CAM5.2), EMA, CEA.
─ ─ Myoepithelial-like/basaloid cells: Positive for p63, p40, CK5/6, Smooth Muscle Actin (SMA, often focal), Calponin, S100 protein (variable).
─ ─ c-Kit (CD117): Often positive (membranous and/or cytoplasmic staining) in a majority of ACCs.
─ ─ SOX10: Can be positive in myoepithelial component.
─ ─ TTF-1: Negative.
─ Histochemical stains: PAS stain highlights basement membrane material in cribriform spaces.
─ Molecular: Characteristic gene fusions involving MYB (most common) or MYBL1 transcription factor genes (e.g., MYB-NFIB fusion) are found in many ACCs and can be diagnostically useful.
DDx ─
─ Basaloid Squamous Cell Carcinoma: Can have basaloid cells and nesting pattern, but will show squamous differentiation (keratinization, intercellular bridges, strong p40/p63 in most tumor cells) and lacks the true cribriform pattern with hyaline material, biphasic cell population, and MYB fusions of ACC.
─ Small Cell Carcinoma: High-grade neuroendocrine tumor with different cytology (small cells, scant cytoplasm, nuclear molding, "salt-and-pepper" chromatin) and positive for neuroendocrine markers.
─ Typical or Atypical Carcinoid Tumor: Neuroendocrine differentiation (Chromogranin, Synaptophysin positive), organoid patterns.
─ Pleomorphic Adenoma (Benign Mixed Tumor): Contains epithelial/myoepithelial cells but also a characteristic chondromyxoid or fibrous stroma.
─ Epithelial-Myoepithelial Carcinoma (rare in lung): Biphasic tumor with inner ductal cells and prominent outer clear myoepithelial cells, typically lacks cribriform pattern and MYB fusions.
─ Metastatic Adenoid Cystic Carcinoma from salivary glands or other sites (e.g., breast, cervix): Histologically indistinguishable from primary pulmonary ACC. Clinical history to exclude another primary is essential.
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Epithelial-Myoepithelial Carcinoma (EMC)

A rare malignant salivary gland-type tumor composed of a biphasic population of inner duct-lining epithelial cells and outer, often predominant, clear myoepithelial cells, typically arranged in tubules, ducts, or solid nests; very rare as a primary tumor in the lung, arising from tracheobronchial glands
Clinical ─
─ Usually considered a low-grade malignancy with potential for local recurrence and, less commonly, distant metastasis (prognosis is generally better than for high-grade salivary gland carcinomas)
─ Affects adults, with no clear sex predilection
─ Symptoms, if present, are often related to airway obstruction or a slowly growing mass (cough, dyspnea, hemoptysis)
Macro ─
─ Typically presents as a well-circumscribed, firm, grayish-white or tan nodule or mass, often endobronchial or involving the wall of a major airway
Micro ─
─ Biphasic architectural pattern is characteristic:
─ ─ Inner ductal (epithelial) cells: Form small tubules or ducts, often with distinct lumens. These cells are typically cuboidal or low columnar, with eosinophilic or amphophilic cytoplasm and round, centrally located nuclei.
─ ─ Outer myoepithelial cells: Usually the predominant component, surrounding the ductal structures in single or multiple layers, or forming solid sheets and nests. These cells are characteristically large, polygonal, with abundant clear or pale eosinophilic cytoplasm due to glycogen content (or sometimes empty-appearing if lipid washed out). Nuclei are often eccentrically placed.
─ The proportion of ductal to myoepithelial cells can vary.
─ Stroma is often scant but can be hyalinized or myxoid in areas.
─ Perineural invasion and vascular invasion can occur, indicating more aggressive potential.
─ Mitotic activity is generally low; cytologic atypia is usually mild to moderate.
Ancillary studies ─
─ IHC is essential to highlight the biphasic differentiation:
─ ─ Ductal cells: Positive for cytokeratins (e.g., CK7, AE1/AE3, CAM5.2), EMA.
─ ─ Myoepithelial cells: Positive for myoepithelial markers such as p63, p40, CK5/6, Smooth Muscle Actin (SMA), Calponin, S100 protein, GFAP (variable). The clear cytoplasm of myoepithelial cells is due to glycogen (PAS-positive, diastase-sensitive).
─ ─ TTF-1 is negative.
─ Molecular: Recurrent HRAS mutations and alterations in PI3K pathway genes have been reported in some EMCs, but specific recurrent fusions like those in MEC or ACC are less common or not well-defined for pulmonary EMC.
DDx ─
─ Adenoid Cystic Carcinoma (ACC): Also biphasic but has characteristic cribriform patterns with hyaline material, different myoepithelial cell morphology (more basaloid, less clear cytoplasm usually), and typically MYB fusions.
─ Clear Cell Adenocarcinoma of the lung: Monophasic proliferation of clear cells, typically TTF-1 positive, lacks the distinct biphasic ductal-myoepithelial architecture of EMC.
─ Metastatic Renal Cell Carcinoma, clear cell type: Monophasic clear cells, positive for PAX8 and often CD10/CAIX, negative for myoepithelial markers and TTF-1.
─ Mucoepidermoid Carcinoma with clear cell change: Would have areas of squamous and mucinous differentiation in addition to clear cells.
─ Pleomorphic Adenoma (Benign Mixed Tumor): Biphasic (epithelial/myoepithelial) but also contains a characteristic chondromyxoid or fibrous stromal component.
─ Other clear cell tumors (e.g., PEComa, sugar tumor – different IHC profile with melanocytic/smooth muscle markers).
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Pleomorphic Adenoma

A benign epithelial tumor of salivary gland type, characterized by a biphasic proliferation of epithelial (ductal) and myoepithelial cells embedded within a variably chondromyxoid, hyalinized, or fibrous stroma; it is very rare as a primary tumor in the lung, typically arising from the submucosal glands of the trachea or large bronchi
Clinical ─
─ Usually presents as an asymptomatic, slow-growing, solitary endobronchial or intramural nodule or polypoid mass, often discovered incidentally or causing symptoms of airway obstruction (cough, wheezing, dyspnea)
─ Affects adults, with no significant sex predilection; not associated with smoking
─ Excellent prognosis with complete surgical excision; recurrence is rare if completely excised. Malignant transformation (carcinoma ex pleomorphic adenoma) is extremely rare in pulmonary pleomorphic adenomas.
Macro ─
─ Typically a well-circumscribed, firm, often lobulated, grayish-white mass with a rubbery, glistening, or cartilaginous cut surface, reflecting the chondromyxoid stroma
─ Usually small (1-3 cm) and confined to the airway wall or protruding into the lumen
Micro ─
─ Biphasic tumor with intimately admixed epithelial and myoepithelial components within a characteristic mesenchymal-like stroma:
─ Epithelial component: Forms ducts, tubules, cords, strands, or solid sheets of cuboidal to columnar epithelial cells. These cells typically have eosinophilic cytoplasm and round, bland nuclei. Squamous metaplasia or keratin cyst formation can occur.
─ Myoepithelial component: Composed of cells with variable morphology – spindle-shaped, plasmacytoid (hyaline cells with eccentric nuclei and eosinophilic cytoplasm), or sometimes clear cells. These cells often surround the epithelial structures or are dispersed individually or in clusters within the stroma.
─ Stromal component: A hallmark feature, typically abundant and highly variable in appearance, often mesenchymal-like. It can be:
─ ─ Chondroid (cartilage-like): Areas of bluish-gray, hyaline matrix resembling cartilage.
─ ─ Myxoid (mucoid): Loose, basophilic, mucoid material.
─ ─ Hyalinized: Dense, eosinophilic, acellular collagenous tissue.
─ ─ Fibrous: Spindle cell fibroblastic stroma.
─ ─ This stroma is considered to be produced by the myoepithelial cells.
─ The tumor is usually well-demarcated or encapsulated
─ Cytologic atypia is generally minimal or absent; mitotic activity is low
Ancillary studies ─
─ IHC:
─ ─ Epithelial (ductal) cells: Positive for cytokeratins (e.g., CK7, AE1/AE3, CAM5.2), EMA.
─ ─ Myoepithelial cells: Positive for a range of myoepithelial markers, including p63, S100 protein, Smooth Muscle Actin (SMA, often focal), Calponin, CK5/6, GFAP (variable).
─ ─ Stromal component: Chondroid areas may stain with S100 protein; myxoid stroma stains with Alcian blue.
─ ─ TTF-1: Negative.
─ Molecular: Rearrangements of the PLAG1 gene (Pleiomorphic Adenoma Gene 1) or, less commonly, HMGA2, are characteristic genetic alterations found in a majority of salivary gland pleomorphic adenomas and may also be present in their pulmonary counterparts.
DDx ─
─ Other salivary gland-type tumors of the lung:
─ ─ Mucoepidermoid Carcinoma (MEC): Lacks the prominent chondromyxoid stroma; composed of mucinous, squamous, and intermediate cells; often has MAML2 fusions.
─ ─ Adenoid Cystic Carcinoma (ACC): Characteristic cribriform pattern, perineural invasion, different biphasic cytology (ductal and basaloid/myoepithelial cells), lacks chondromyxoid stroma; often has MYB fusions.
─ Pulmonary Hamartoma: Also benign and can contain cartilage, but hamartomas are disorganized proliferations of mature mesenchymal tissues (cartilage, fat, smooth muscle) admixed with entrapped benign respiratory epithelium, rather than a biphasic epithelial/myoepithelial tumor with neoplastic stroma.
─ Adenocarcinoma with chondroid metaplasia or prominent desmoplasia: Rare; the epithelial component would show malignant cytologic features of adenocarcinoma and be TTF-1 positive.
─ Carcinoma ex Pleomorphic Adenoma: Rare malignant transformation arising in a pleomorphic adenoma; would show areas of overt carcinoma (e.g., adenocarcinoma, SCC, or undifferentiated carcinoma) coexisting with recognizable pleomorphic adenoma.
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Myoepithelioma (Benign or Malignant)

A rare neoplasm composed predominantly or almost exclusively (>90%) of myoepithelial cells, exhibiting variable cytomorphology (spindle, epithelioid, plasmacytoid, clear cells) and architectural patterns; it can be benign or malignant (myoepithelial carcinoma/malignant myoepithelioma). Primary pulmonary myoepithelial tumors are extremely rare.
Clinical ─
─ Benign Myoepithelioma: Usually presents as a slow-growing, asymptomatic or minimally symptomatic mass. Excellent prognosis with complete excision.
─ Myoepithelial Carcinoma (Malignant Myoepithelioma): More aggressive, with potential for local recurrence, infiltrative growth, and distant metastasis. Prognosis is guarded.
─ Affects a wide age range; no clear sex predilection.
Macro ─
─ Benign: Typically a well-circumscribed, solid, firm, grayish-white nodule or mass.
─ Malignant: May be larger, infiltrative, with areas of necrosis or hemorrhage.
Micro ─
─ Predominantly or exclusively composed of myoepithelial cells (ductal/glandular differentiation, if present, is minimal, usually <5-10% of the tumor).
─ Myoepithelial cells can display a range of morphologies:
─ ─ Spindle cells: Arranged in fascicles, whorls, or a storiform pattern, resembling fibrosarcoma or leiomyosarcoma.
─ ─ Epithelioid cells: Polygonal cells with eosinophilic or amphophilic cytoplasm, often arranged in sheets, nests, or cords.
─ ─ Plasmacytoid cells: Eccentrically placed nuclei and abundant eosinophilic hyaline cytoplasm, resembling plasma cells.
─ ─ Clear cells: Abundant clear cytoplasm, often due to glycogen accumulation.
─ ─ A mixture of cell types is common.
─ Architectural patterns include solid, nested, reticular, trabecular, or myxoid.
─ Benign Myoepithelioma:
─ ─ Bland cytologic features: Uniform nuclei, inconspicuous nucleoli, minimal pleomorphism.
─ ─ Low mitotic activity (typically <3-5 mitoses per 10 high-power fields).
─ ─ No significant atypia, necrosis, or vascular invasion.
─ Myoepithelial Carcinoma (Malignant Myoepithelioma): Diagnosis requires one or more features of malignancy:
─ ─ Significant cytologic atypia: Marked nuclear pleomorphism, hyperchromasia, prominent irregular nucleoli.
─ ─ Increased mitotic activity: Often defined as >5-10 mitoses per 10 HPF, and/or presence of atypical mitoses.
─ ─ Infiltrative growth pattern into adjacent tissues.
─ ─ Tumor necrosis.
─ ─ Vascular invasion.
─ ─ May arise de novo or from a pre-existing benign myoepithelioma or pleomorphic adenoma.
Ancillary studies ─
─ IHC is crucial for confirming myoepithelial differentiation:
─ ─ Positive for a combination of myoepithelial markers: S100 protein (often strong and diffuse), p63 (nuclear), Smooth Muscle Actin (SMA), Calponin, CK5/6, GFAP (variable), SOX10 (variable).
─ ─ Usually positive for broad-spectrum cytokeratins (e.g., AE1/AE3, CAM5.2), EMA (variable).
─ ─ TTF-1 is negative.
─ Histochemical stains: PAS stain (with diastase) can highlight glycogen in clear cell variants.
─ Molecular: Rearrangements of the EWSR1 gene have been reported in a subset of myoepithelial tumors (especially those with clear cell features or arising in soft tissue/bone, less characterized in pulmonary primaries). PLAG1 or HMGA2 fusions may be seen if arising in the context of a pleomorphic adenoma.
DDx ─
─ Pleomorphic Adenoma: Distinguished by the presence of a significant (>10%) ductal epithelial component and characteristic chondromyxoid stroma.
─ Other Salivary Gland-Type Tumors (e.g., Epithelial-Myoepithelial Carcinoma – has a more prominent and organized biphasic ductal-myoepithelial pattern).
─ Spindle cell tumors of other lineages (if spindle cell predominant): Leiomyoma/leiomyosarcoma (desmin+, SMA diffuse+, S100-), schwannoma (S100 diffuse+, SOX10+), fibrosarcoma (markers negative).
─ Clear cell tumors (if clear cell predominant): Clear cell adenocarcinoma (TTF-1+), metastatic renal cell carcinoma (PAX8+, CD10+), sugar tumor/PEComa (HMB-45+).
─ Epithelioid Sarcoma (can have epithelioid cells, INI1 loss common, cytokeratin+, CD34 variable).
─ For malignant variants: Sarcomatoid carcinoma (co-expression of cytokeratins and vimentin, but lacks consistent myoepithelial marker profile).
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Hyalinizing Clear Cell Carcinoma (HCCC)

A rare, low-grade malignant salivary gland-type carcinoma characterized by nests, cords, or trabeculae of epithelial cells with predominantly clear to eosinophilic cytoplasm, embedded in a distinctively and often abundantly hyalinized stroma; it is defined by the presence of an EWSR1-ATF1 gene fusion in the majority of cases. Primary HCCC of the lung is extremely rare.
Clinical ─
─ Typically a slow-growing, locally infiltrative tumor with a potential for local recurrence and rare distant metastasis; generally considered a low-grade malignancy.
─ Usually affects adults; more common in minor salivary glands of the oral cavity (base of tongue, palate). Pulmonary primary is exceptional.
─ Symptoms depend on location and size; if endobronchial, may cause obstructive symptoms.
Macro ─
─ Presents as a firm, often unencapsulated or poorly circumscribed, grayish-white or tan, infiltrative mass.
─ Cut surface may appear solid and homogenous, possibly with a slightly gritty texture due to hyalinization.
Micro ─
─ Tumor cells are arranged in nests, cords, trabeculae, or sheets, often with an infiltrative pattern.
─ Cells are typically polygonal to ovoid, with predominantly clear or sometimes pale eosinophilic cytoplasm (clear appearance is usually due to glycogen).
─ Nuclei are generally round to oval, often eccentrically placed, with vesicular chromatin and inconspicuous or small nucleoli; cytologic atypia is usually mild.
─ Stroma is a characteristic feature: Typically abundant, densely hyalinized (glassy, eosinophilic collagen), and may surround individual cell nests or broad sheets of tumor. Myxoid change in stroma can also be seen.
─ Perineural invasion or vascular invasion can be present, even in tumors with bland cytology.
─ Mitotic activity is generally low. Necrosis is uncommon.
Ancillary studies ─
─ IHC:
─ ─ Tumor cells are positive for broad-spectrum cytokeratins (e.g., AE1/AE3, CAM5.2, CK7) and EMA.
─ ─ p63 and p40 are often positive (reflecting a basal/myoepithelial-like differentiation component or origin).
─ ─ S100 protein and Smooth Muscle Actin (SMA) may be focally positive in some cells.
─ ─ Mucin stains (PAS with diastase for intracellular mucin, Alcian blue) are typically negative or only very focally positive in scattered cells (helps distinguish from mucoepidermoid carcinoma).
─ ─ PAS stain (without diastase) is usually positive in the clear cytoplasm, and diastase-labile, confirming glycogen.
─ ─ TTF-1 is negative.
─ Molecular: Detection of the characteristic EWSR1-ATF1 gene fusion (resulting from t(12;22)(q13;q12)) or, less commonly, other EWSR1 fusions (e.g., with CREB1), by FISH, RT-PCR, or NGS is a key diagnostic feature and helps confirm the diagnosis, especially in difficult cases or unusual locations.
DDx ─
─ Mucoepidermoid Carcinoma, clear cell variant: MEC will have identifiable mucinous and squamous/intermediate cells in other areas, and often harbors MAML2 fusions, not EWSR1-ATF1. Mucin stains will be more prominent.
─ Squamous Cell Carcinoma with clear cell change: Will show more overt squamous differentiation (keratinization, intercellular bridges) in other areas and more significant cytologic atypia; typically lacks hyalinized stroma and EWSR1-ATF1 fusion.
─ Metastatic Clear Cell Renal Cell Carcinoma: A critical differential. ccRCC is positive for PAX8, CD10, and often CAIX; negative for p63/p40 and TTF-1; lacks EWSR1-ATF1 fusion.
─ Other primary lung clear cell tumors:
─ ─ Clear Cell Adenocarcinoma of lung: Typically TTF-1 positive, lacks hyalinized stroma and EWSR1-ATF1 fusion.
─ ─ Sugar Tumor (Benign Clear Cell Tumor) / PEComa: Positive for HMB-45 and SMA; lacks EWSR1-ATF1 fusion.
─ Myoepithelioma or Epithelial-Myoepithelial Carcinoma with prominent clear cells: EMC is biphasic with distinct ductal and myoepithelial components; myoepitheliomas show more diffuse myoepithelial markers; both usually lack the prominent hyalinized stroma and EWSR1-ATF1 fusion of HCCC (though some myoepithelial tumors can have EWSR1 fusions with other partners).
─ Metastatic clear cell tumors from other sites (e.g., clear cell odontogenic carcinoma, clear cell hidradenocarcinoma).
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Acinic Cell Carcinoma

A rare malignant epithelial neoplasm of salivary gland type characterized by tumor cells showing serous acinar differentiation, evidenced by cytoplasmic zymogen-like granules; it is extremely rare as a primary tumor in the lung, typically arising from submucosal glands of the trachea or major bronchi
Clinical ─
─ Occurs over a wide age range, including children and adults
─ Symptoms, if present, are often related to its endobronchial location, such as cough, dyspnea, hemoptysis, or post-obstructive pneumonia; may also be an asymptomatic incidental finding
─ Generally considered a low-grade malignancy with a relatively good prognosis after complete surgical resection, but has potential for local recurrence and rare distant metastasis (lymph nodes, distant organs) over a long period
Macro ─
─ Usually presents as a well-circumscribed, firm, solitary endobronchial or intramural nodule or mass
─ Cut surface is typically grayish-white, tan, or pinkish, and may appear solid or slightly lobulated
Micro ─
─ Tumor cells exhibit serous acinar differentiation and are arranged in various architectural patterns:
─ ─ Solid pattern: Sheets of tumor cells with minimal stroma.
─ ─ Microcystic pattern: Characterized by small, sieve-like cystic spaces or vacuoles within tumor cell nests.
─ ─ Follicular pattern: Resembles thyroid follicles, with spaces that may contain eosinophilic, colloid-like material.
─ ─ Papillary-cystic pattern: Papillary projections extending into cystic spaces.
─ ─ Acinar pattern: Well-formed acini resembling normal serous salivary glands (less common as a pure pattern).
─ Tumor cells are typically polygonal with basophilic, amphophilic, or sometimes clear cytoplasm.
─ Key diagnostic feature: Presence of zymogen-like cytoplasmic granules – these are coarse, eosinophilic to somewhat basophilic or purple (amphophilic) granules, best appreciated at the apical pole of cells lining glandular or cystic spaces, or diffusely in solid areas. Granules may be abundant or sparse.
─ Nuclei are usually round to oval, often eccentrically placed (especially if cytoplasm is granular), with inconspicuous or small nucleoli. Cytologic atypia is generally mild, but can be moderate in some cases.
─ Mitotic activity is generally infrequent. Necrosis is uncommon.
Ancillary studies ─
─ Histochemical stains:
─ ─ PAS (Periodic Acid-Schiff) stain with diastase digestion (PAS-D): The zymogen-like granules are typically PAS-positive and diastase-resistant, a helpful diagnostic feature.
─ IHC:
─ ─ Positive for cytokeratins (e.g., CK7, AE1/AE3, CAM5.2) and EMA.
─ ─ Markers of serous acinar differentiation:
─ ─ ─ DOG1 (Discovered on GIST 1, anoctamin-1): Often positive (membranous and/or cytoplasmic) and is a useful marker for acinic cell carcinoma.
─ ─ ─ Amylase, chymotrypsin, trypsin: May be positive but are less consistently expressed and less routinely used.
─ ─ S100 protein and SOX10 can be focally positive in some cases.
─ ─ p63 and other specific myoepithelial markers are typically negative in the neoplastic acinar cells (helping to distinguish from some other biphasic salivary gland tumors).
─ ─ TTF-1 is negative.
─ ─ Neuroendocrine markers are negative.
DDx ─
─ Metastatic Acinic Cell Carcinoma from salivary glands: Primary pulmonary acinic cell carcinoma is histologically indistinguishable from its salivary gland counterpart; clinical history and exclusion of a salivary gland primary are essential.
─ Other Salivary Gland-Type Tumors of the lung:
─ ─ Mucoepidermoid Carcinoma: Contains mucinous and squamous cells, lacks diffuse zymogen granules, DOG1 negative.
─ ─ Adenoid Cystic Carcinoma: Biphasic pattern, cribriform architecture, lacks zymogen granules.
─ Adenocarcinoma of the lung with granular or clear cell features: Would typically be TTF-1 positive and Napsin A positive (if non-mucinous), and would lack diffuse zymogen granules and DOG1 expression.
─ Carcinoid Tumor (Pulmonary Neuroendocrine Tumor): Positive for neuroendocrine markers (Chromogranin, Synaptophysin), different cytology ("salt-and-pepper" chromatin), lacks zymogen granules.
─ Oncocytic Adenocarcinoma or Oncocytic Carcinoid: Cells have abundant eosinophilic granular cytoplasm due to mitochondria, not zymogen granules.
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Sarcomatoid Carcinomas

Pleomorphic Carcinoma

A poorly differentiated non-small cell carcinoma (NSCLC) that contains at least 10% spindle cells and/or malignant giant cells, OR a tumor composed purely of malignant spindle and/or giant cells that is of epithelial origin (proven by immunohistochemistry or ultrastructure); it is a subtype of Sarcomatoid Carcinoma of the lung. If a specific type of NSCLC (adenocarcinoma, squamous cell carcinoma, or large cell carcinoma) is identifiable alongside the spindle/giant cell component and itself constitutes ≥10% of the tumor, then that NSCLC type is specified (e.g., "Adenocarcinoma with >10% spindle/giant cells" which would still fall under the pleomorphic carcinoma umbrella).
Clinical ─
─ Rare, accounting for a very small percentage of all lung cancers (<1%)
─ Highly aggressive tumors with a poor prognosis, often presenting at an advanced stage with early metastasis
─ Strong association with heavy cigarette smoking, predominantly affects older males
─ Typically presents as large peripheral masses, but can be central
─ Symptoms may include cough, dyspnea, chest pain, hemoptysis, weight loss; rapid tumor growth is common
Macro ─
─ Usually large, bulky, fleshy or firm masses, often with extensive areas of necrosis and hemorrhage
─ May show infiltrative borders into adjacent lung parenchyma or chest wall
Micro ─
─ Characterized by a biphasic appearance in many cases, or a monophasic appearance if composed purely of spindle or giant cells:
─ Malignant spindle cell component: Atypical fusiform (spindle-shaped) cells arranged in fascicles, storiform (cartwheel) patterns, or haphazardly, resembling fibrosarcoma or other sarcomas. Cells show elongated, pleomorphic, hyperchromatic nuclei and variable amounts of cytoplasm.
─ Malignant giant cell component: Large, bizarre, multinucleated or mononucleated tumor giant cells with abundant eosinophilic cytoplasm and highly pleomorphic, often multiple, nuclei. These are malignant epithelial giant cells, not osteoclast-like reactive giant cells (though reactive ones can also be present).
─ Conventional NSCLC component (if present): Can be squamous cell carcinoma, adenocarcinoma, or large cell carcinoma. If this component is <10% of the tumor, or if no specific conventional NSCLC component is identifiable and the tumor is composed of >10% spindle/giant cells, it is classified as pleomorphic carcinoma.
─ If the tumor is composed purely of malignant spindle cells and/or giant cells, immunohistochemistry for cytokeratins is essential to confirm epithelial origin and classify it as a carcinoma (specifically, pleomorphic carcinoma).
─ Marked cytologic atypia, high mitotic rate (often numerous and atypical mitoses), extensive tumor necrosis, and hemorrhage are common features throughout the tumor
Ancillary studies ─
─ IHC is crucial for diagnosis and classification:
─ ─ Tumor cells (both the spindle/giant cell components and any conventional NSCLC component) must show epithelial differentiation, typically by demonstrating positivity for broad-spectrum cytokeratins (e.g., AE1/AE3, CAM5.2, MNF116, OSCAR) or specific cytokeratins like CK7 or CK5/6 depending on the underlying NSCLC type if present. Staining can be focal in spindle cell areas.
─ ─ Spindle cell component often co-expresses vimentin (a mesenchymal marker), reflecting epithelial-mesenchymal transition or sarcomatoid differentiation.
─ ─ If an adenocarcinoma component is suspected or present, TTF-1 or Napsin A may be positive in that component and sometimes focally in the spindle/giant cells.
─ ─ If a squamous cell carcinoma component is suspected or present, p40 or p63 may be positive in that component and sometimes focally in the spindle/giant cells.
─ ─ Neuroendocrine markers (Chromogranin, Synaptophysin, CD56) are typically negative.
DDx ─
─ Other Sarcomatoid Carcinomas of the lung:
─ ─ Spindle Cell Squamous Cell Carcinoma: If the spindle cell component clearly arises from or is associated with a squamous cell carcinoma (often p40/p63 positive in spindle cells). This is essentially a subtype of pleomorphic carcinoma where squamous lineage is clear.
─ ─ Giant Cell Carcinoma: If the tumor is composed almost purely of malignant giant cells without a significant spindle cell or conventional NSCLC component.
─ ─ Carcinosarcoma: Contains both a malignant epithelial component (carcinoma) and a true malignant mesenchymal component with heterologous elements (e.g., malignant cartilage, bone, or skeletal muscle).
─ ─ Pulmonary Blastoma: A biphasic tumor with primitive epithelial glands (fetal adenocarcinoma-like) and a primitive mesenchymal (sarcomatous) stroma.
─ Primary Pulmonary Sarcoma (e.g., fibrosarcoma, leiomyosarcoma, undifferentiated pleomorphic sarcoma): These are purely mesenchymal tumors and will be negative for cytokeratins (or only very aberrantly focal) and will express specific mesenchymal lineage markers.
─ Metastatic Sarcoma or Sarcomatoid Carcinoma from another primary site: Clinical history is essential. Comparison with primary tumor histology if available.
─ Malignant Melanoma, spindle cell or pleomorphic type: Positive for S100 protein, SOX10, HMB-45/Melan-A.
─ Malignant Mesothelioma, sarcomatoid or biphasic type (if pleural-based): Positive for mesothelial markers (e.g., calretinin, WT1 in epithelioid component if present, D2-40 often in spindle cells); cytokeratins positive.
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Spindle Cell Carcinoma

A subtype of sarcomatoid carcinoma composed exclusively or almost exclusively (>90% or 100%) of malignant spindle-shaped epithelial cells that demonstrate epithelial differentiation by immunohistochemistry or ultrastructure; if a conventional non-small cell lung carcinoma (NSCLC) component (squamous, adenocarcinoma, or large cell) is present, it must constitute less than 10% of the tumor. If squamous differentiation is evident in the spindle cells or if the tumor arises from squamous carcinoma in situ, it may be specifically termed Spindle Cell Squamous Cell Carcinoma.
Clinical ─
─ Rare and aggressive malignant neoplasm, strongly associated with cigarette smoking
─ Predominantly affects older males
─ Generally carries a poor prognosis, similar to other sarcomatoid carcinomas
─ Often presents as large peripheral masses, but can also be central/endobronchial (then often polypoid)
─ Symptoms are similar to other NSCLCs: cough, dyspnea, chest pain, hemoptysis, weight loss
Macro ─
─ Typically large, fleshy, firm or friable masses, often with areas of necrosis and hemorrhage
─ Endobronchial lesions may appear polypoid or pedunculated
─ Peripheral tumors are often infiltrative
Micro ─
─ Predominantly or exclusively composed of malignant spindle cells:
─ ─ Cells are fusiform (elongated) with indistinct cell borders, arranged in fascicles, storiform (cartwheel) patterns, herringbone patterns, or haphazardly, often mimicking a sarcoma (e.g., fibrosarcoma, leiomyosarcoma)
─ ─ Nuclei are typically elongated, pleomorphic, hyperchromatic, with irregular contours; nucleoli may be prominent
─ ─ Cytoplasm is usually scant to moderate, eosinophilic or amphophilic
─ ─ Mitotic figures are generally frequent and can be atypical
─ No identifiable conventional NSCLC component (squamous, adenocarcinoma, large cell) or, if present, it constitutes <10% of the tumor
─ No significant malignant giant cell component (<10%)
─ No heterologous mesenchymal elements (e.g., malignant cartilage, bone, skeletal muscle)
─ Stroma is variable, can be desmoplastic, myxoid, or inflamed
─ Necrosis and hemorrhage are common
Ancillary studies ─
─ IHC is essential to confirm epithelial differentiation and exclude pure sarcoma:
─ ─ Must show positivity for broad-spectrum cytokeratins (e.g., AE1/AE3, CAM5.2, MNF116, OSCAR) at least focally within the spindle cells. High molecular weight cytokeratins (e.g., CK5/6) may also be positive.
─ ─ Squamous markers (p40 and/or p63) are often positive, at least focally, supporting a squamous lineage for many spindle cell carcinomas of the lung.
─ ─ Tumor cells frequently co-express vimentin (a mesenchymal marker), reflecting epithelial-mesenchymal transition or sarcomatoid differentiation.
─ ─ Typically negative for TTF-1 and Napsin A (unless an underlying adenocarcinoma lineage is present but not morphologically apparent and constitutes <10%).
─ ─ Negative for definitive neuroendocrine markers, melanoma markers (S100, SOX10), and specific sarcoma markers (e.g., desmin, myogenin for rhabdomyosarcoma; S100 for MPNST; CD34 for SFT).
DDx ─
─ Pleomorphic Carcinoma: If a significant malignant giant cell component (>10%) is present, or if an identifiable conventional NSCLC component (squamous, adeno, large cell) constitutes >10% of the tumor. Spindle cell carcinoma is essentially a monophasic variant of pleomorphic carcinoma.
─ Primary Pulmonary Sarcoma (e.g., fibrosarcoma, leiomyosarcoma, synovial sarcoma, undifferentiated pleomorphic sarcoma): These are purely mesenchymal tumors and will be negative for cytokeratins (or only very aberrantly focal) and will express specific mesenchymal lineage markers (e.g., SMA/desmin for leiomyosarcoma; specific translocations like SS18 for synovial sarcoma).
─ Metastatic Sarcoma or Sarcomatoid Carcinoma from another primary site: Clinical history is crucial. Comparison with primary tumor histology if available.
─ Malignant Melanoma, spindle cell type: Positive for S100 protein, SOX10, and other melanoma markers (e.g., HMB-45, Melan-A).
─ Inflammatory Myofibroblastic Tumor (IMT): Composed of bland spindle cells (myofibroblasts) admixed with a prominent inflammatory infiltrate (plasma cells, lymphocytes, eosinophils); often ALK-positive by IHC (due to ALK gene rearrangement); lacks the marked cytologic atypia and high mitotic rate of spindle cell carcinoma.
─ Solitary Fibrous Tumor (SFT), malignant variant: Can be spindle cell; STAT6 nuclear expression is characteristic; CD34 often positive.
─ Malignant Mesothelioma, sarcomatoid type (if pleural-based): Positive for mesothelial markers (e.g., calretinin can be focally positive, D2-40 often positive in spindle cells); cytokeratins positive.
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Giant Cell Carcinoma

A rare subtype of sarcomatoid carcinoma of the lung composed exclusively or almost exclusively (>90% or 100%) of large, bizarre, highly pleomorphic, multinucleated or mononucleated malignant giant cells; it should not have a significant spindle cell component or an identifiable conventional non-small cell lung carcinoma (NSCLC) component (each <10%)
Clinical ─
─ Highly aggressive malignant neoplasm with a very poor prognosis, characterized by rapid growth and early metastasis
─ Strong association with cigarette smoking; predominantly affects older males
─ Often presents as large peripheral masses, but can be central
─ Symptoms are similar to other aggressive NSCLCs: cough, dyspnea, chest pain, hemoptysis, weight loss; constitutional symptoms and leukocytosis (due to cytokine production by tumor) can occur
Macro ─
─ Typically large, fleshy, often friable masses with extensive necrosis and hemorrhage
─ May show infiltrative borders
Micro ─
─ Predominantly or exclusively composed of malignant giant cells:
─ ─ Cells are very large, bizarre, and highly pleomorphic, often discohesive or loosely cohesive, growing in sheets or clusters
─ ─ Can be mononucleated (with huge, irregular nuclei) or multinucleated (with multiple, often overlapping, pleomorphic nuclei)
─ ─ Cytoplasm is abundant, dense, and eosinophilic or amphophilic
─ ─ Nuclei are highly irregular in shape and contour, with coarse, clumped, or vesicular chromatin, and usually prominent, often irregular, eosinophilic nucleoli
─ Emperipolesis (engulfment of intact inflammatory cells, especially neutrophils, by the tumor giant cells, with the engulfed cells remaining viable within intracytoplasmic vacuoles) is a characteristic feature but is not always present and not entirely specific
─ Minimal or no spindle cell component (<10%)
─ No identifiable conventional NSCLC component (squamous, adenocarcinoma, large cell) or, if present, it constitutes <10% of the tumor
─ No heterologous mesenchymal elements
─ Brisk mitotic activity, often with numerous atypical mitoses, is characteristic
─ Extensive tumor necrosis and hemorrhage are common
─ Prominent inflammatory infiltrate, including neutrophils, may be present
Ancillary studies ─
─ IHC is essential to confirm epithelial differentiation and exclude other tumor types:
─ ─ Tumor cells must show epithelial differentiation by being positive for broad-spectrum cytokeratins (e.g., AE1/AE3, CAM5.2, MNF116, OSCAR), though staining can sometimes be focal or patchy.
─ ─ May co-express vimentin.
─ ─ Typically negative for TTF-1, Napsin A (adenocarcinoma markers), and p40/p63 (squamous markers), unless these represent focal retained expression from an underlying, poorly differentiated conventional NSCLC component that is <10%.
─ ─ Negative for definitive neuroendocrine markers, melanoma markers (S100, SOX10), and specific sarcoma markers.
─ ─ Beta-hCG (human chorionic gonadotropin) can be positive in some tumor giant cells and may be associated with paraneoplastic syndromes or leukocytosis (due to G-CSF production).
DDx ─
─ Pleomorphic Carcinoma: If a significant spindle cell component (>10%) is present, or if an identifiable conventional NSCLC component (squamous, adeno, large cell) constitutes >10% of the tumor. Giant cell carcinoma is essentially a monophasic variant of pleomorphic carcinoma dominated by giant cells.
─ Choriocarcinoma (primary pulmonary is extremely rare; usually metastatic from gonadal or gestational origin): Characterized by malignant syncytiotrophoblastic and cytotrophoblastic cells; markedly elevated serum hCG and IHC positivity for hCG in syncytiotrophoblasts.
─ Anaplastic Large Cell Lymphoma (ALCL): Composed of large, pleomorphic lymphoid cells (hallmark cells with eccentric, horseshoe-shaped nuclei); positive for CD30, often ALK (if ALK-positive ALCL), and CD45 (LCA); negative for cytokeratins.
─ Malignant Melanoma, pleomorphic type: Positive for S100 protein, SOX10, and other melanoma markers.
─ Metastatic undifferentiated carcinoma or sarcoma with giant cells from another primary site: Clinical history is crucial.
─ Reactive atypical histiocytes or osteoclast-like giant cells seen in other tumors or inflammatory conditions: These are benign cells, lack malignant nuclear features, and are not positive for cytokeratins (histiocytes are CD68/CD163 positive).
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Carcinosarcoma

A rare, aggressive biphasic malignant neoplasm composed of an intimate admixture of a malignant epithelial component (carcinoma) and a malignant mesenchymal component (sarcoma) that contains heterologous sarcomatous elements (e.g., malignant cartilage, bone, or skeletal muscle); it is considered a subtype of Sarcomatoid Carcinoma of the lung
Clinical ─
─ Very rare, accounting for <0.5% of all lung malignancies
─ Strong association with heavy cigarette smoking; predominantly affects older males
─ Highly aggressive with a poor prognosis; frequent local recurrence and early distant metastases
─ Often presents as large peripheral or central masses; symptoms are similar to other aggressive NSCLCs (cough, dyspnea, chest pain, hemoptysis, weight loss)
Macro ─
─ Typically large, bulky, fleshy or firm masses, often with extensive areas of necrosis and hemorrhage
─ May show grossly visible areas of cartilage or bone if these heterologous elements are present and substantial
─ Can be endobronchial (polypoid) or intraparenchymal with infiltrative growth
Micro ─
─ Two intimately admixed malignant components must be present:
─ Carcinoma component: Can be any type of NSCLC – most commonly squamous cell carcinoma, followed by adenocarcinoma or large cell carcinoma. This component must be unequivocally malignant, showing features of its respective type.
─ Sarcoma component: Shows malignant mesenchymal differentiation. For a diagnosis of carcinosarcoma (as traditionally defined and distinct from pleomorphic carcinoma which may have a homologous sarcomatoid stroma), this component should ideally exhibit identifiable heterologous differentiation, such as:
─ ─ Rhabdomyosarcoma (malignant spindle cells with eosinophilic cytoplasm, cross-striations rarely seen; confirmed by desmin, myogenin, MyoD1 IHC)
─ ─ Chondrosarcoma (lobules of atypical chondrocytes within a cartilaginous matrix; S100 positive)
─ ─ Osteosarcoma (malignant spindle cells producing osteoid or immature bone)
─ ─ Less commonly, liposarcoma or leiomyosarcoma.
─ ─ If the sarcomatous component is undifferentiated (e.g., resembling fibrosarcoma or undifferentiated pleomorphic sarcoma) without clear heterologous elements, the distinction from pleomorphic carcinoma can be challenging and depends on classification nuances (some definitions of carcinosarcoma are broader and include homologous sarcomatous stroma if clearly malignant and distinct from the carcinoma).
─ The carcinomatous and sarcomatous components are typically intermingled, but one may predominate.
─ Both components usually exhibit high-grade cytologic atypia, brisk mitotic activity, and necrosis.
Ancillary studies ─
─ IHC is essential to highlight and confirm the dual differentiation of the two components:
─ ─ Carcinoma component: Will be positive for broad-spectrum cytokeratins (e.g., AE1/AE3, CAM5.2) and specific lineage markers depending on its type (e.g., p40/p63 for squamous; TTF-1/Napsin A for adenocarcinoma).
─ ─ Sarcoma component: Typically positive for vimentin. Specific mesenchymal markers are key for identifying heterologous differentiation:
─ ─ ─ Desmin, myogenin, MyoD1 for rhabdomyosarcomatous differentiation.
─ ─ ─ S100 protein for chondrosarcomatous differentiation.
─ ─ ─ Smooth Muscle Actin (SMA), desmin for leiomyosarcomatous differentiation.
─ ─ ─ The sarcomatous component is generally negative for broad-spectrum cytokeratins, or only very focally positive if it represents a highly dedifferentiated sarcomatoid carcinoma rather than a true sarcoma with heterologous elements (this area can be controversial).
DDx ─
─ Pleomorphic Carcinoma: Composed of malignant spindle and/or giant cells of epithelial origin (cytokeratin-positive) admixed with or arising from a conventional NSCLC, but lacks true heterologous malignant mesenchymal elements. The "sarcomatoid" component in pleomorphic carcinoma represents dedifferentiated carcinoma.
─ Pulmonary Blastoma (Biphasic type): A distinct tumor composed of primitive epithelial glands (fetal adenocarcinoma-like) and a primitive mesenchymal (sarcomatous/blastemal-like) stroma; typically occurs in a different age group or context, though adult blastoma exists.
─ Metastatic Carcinosarcoma (Malignant Mixed Müllerian Tumor - MMMT from uterus/ovary; or carcinosarcoma from other sites like esophagus, bladder): Clinical history is crucial to exclude metastasis.
─ Teratoma with malignant transformation: A germ cell tumor containing elements from all three germ layers, one or more of which can undergo malignant transformation to carcinoma or sarcoma.
─ Synovial Sarcoma (Primary Pulmonary): Can be biphasic (epithelial and spindle cell components) or monophasic spindle cell; characterized by specific t(X;18) SS18-SSX gene fusion. Spindle cells are cytokeratin positive focally.
─ Epithelioid Sarcoma with rhabdoid features if the sarcomatous component is undifferentiated.
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Pulmonary Blastoma (Classic Biphasic Adult-type)

A rare, aggressive malignant tumor of the lung composed of a biphasic mixture of a malignant epithelial component, typically resembling fetal adenocarcinoma (low or high grade), and a primitive, malignant mesenchymal (sarcomatous) component resembling fetal lung mesenchyme or showing overt sarcomatous differentiation. This refers to the classic adult-type biphasic pulmonary blastoma.
Clinical ─
─ Rare, accounts for a very small fraction of lung malignancies (<0.5%)
─ Primarily affects adults (median age ~40-50 years), although cases in children can occur (pediatric forms, like pleuropulmonary blastoma, are distinct entities)
─ Often associated with cigarette smoking, particularly in adults
─ Symptoms are nonspecific and similar to other lung cancers: cough, hemoptysis, chest pain, dyspnea, weight loss
─ Prognosis is generally poor, with high rates of recurrence and metastasis, although it can be variable and somewhat better than other sarcomatoid carcinomas if completely resected at an early stage
Macro ─
─ Typically presents as a large, often well-circumscribed but potentially infiltrative, solitary peripheral or sometimes central lung mass
─ Cut surface is often fleshy, grayish-white or tan, and may show areas of necrosis, hemorrhage, or cystic change
─ May have a pseudoencapsulated appearance
Micro ─
─ Biphasic pattern is essential for diagnosis, consisting of intimately admixed malignant epithelial and malignant mesenchymal components:
─ Malignant Epithelial Component:
─ ─ Typically resembles fetal adenocarcinoma (low-grade or high-grade types).
─ ─ Forms glands, tubules, or papillary structures lined by glycogen-rich columnar or cuboidal epithelial cells. These cells often have clear or eosinophilic cytoplasm due to glycogen.
─ ─ Subnuclear or supranuclear glycogen vacuoles may be prominent.
─ ─ Morules (solid nests or whorls of cells with bland, ovoid nuclei and eosinophilic/clear cytoplasm, often showing biotin-rich optically clear nuclei) are a characteristic feature of the fetal adenocarcinoma component, especially in low-grade areas.
─ ─ Nuclear atypia in the epithelial component can range from low to high grade.
─ Malignant Mesenchymal (Stromal) Component:
─ ─ Composed of primitive, highly cellular, undifferentiated spindle cells (blastemal-like stroma) resembling fetal lung mesenchyme. These cells have scant cytoplasm, ovoid to spindle nuclei, and may show mitotic activity.
─ ─ OR, it may show overt sarcomatous differentiation, such as fibrosarcoma-like areas, rhabdomyosarcoma (strap cells, cross-striations), chondrosarcoma (malignant cartilage), or osteosarcoma (malignant osteoid).
─ ─ This mesenchymal component is clearly malignant and distinct from a reactive desmoplastic stroma.
─ The two components are intimately admixed, often with the stroma surrounding the epithelial glands.
Ancillary studies ─
─ IHC:
─ ─ Epithelial component: Positive for broad-spectrum cytokeratins (AE1/AE3, CAM5.2), EMA. TTF-1 is often positive. May express markers associated with fetal adenocarcinoma such as AFP (alpha-fetoprotein), SALL4, Glypican-3, and show nuclear accumulation of beta-catenin (especially in morules).
─ ─ Mesenchymal component: Positive for vimentin. May express specific mesenchymal markers depending on the type of sarcomatous differentiation (e.g., desmin, myogenin, MyoD1 for rhabdomyosarcomatous areas; S100 protein for chondrosarcomatous areas). The primitive spindle cell (blastemal) stroma may be relatively undifferentiated by IHC or show focal positivity for smooth muscle actin or desmin.
─ Histochemical stains: PAS stain (with diastase digestion) highlights glycogen in the epithelial cells of the fetal adenocarcinoma component.
─ Molecular: DICER1 mutations are characteristic of pleuropulmonary blastoma (a pediatric tumor) but are generally less common or well-characterized in classic adult-type biphasic pulmonary blastoma. CTNNB1 (beta-catenin) gene mutations are common in the epithelial component (fetal adenocarcinoma). TP53 mutations can occur in both components.
DDx ─
─ Carcinosarcoma: Also a biphasic tumor with malignant epithelial and mesenchymal components. However, in carcinosarcoma, the carcinoma component is usually a conventional NSCLC type (squamous cell carcinoma, adenocarcinoma NOS, or large cell carcinoma), not fetal adenocarcinoma. The sarcomatous component in carcinosarcoma is also typically more overtly differentiated (e.g., fibrosarcoma, osteosarcoma) without the primitive blastemal-like stroma often seen in blastoma.
─ Pleomorphic Carcinoma: A sarcomatoid carcinoma with malignant spindle and/or giant cells of epithelial origin (cytokeratin-positive), lacks the distinct primitive blastemal stroma and the characteristic fetal adenocarcinoma-like epithelial component of pulmonary blastoma.
─ Synovial Sarcoma (Primary Pulmonary): Can be biphasic (epithelial and spindle cell components) or monophasic spindle cell; characterized by specific t(X;18) SS18-SSX gene fusion. The epithelial component does not resemble fetal adenocarcinoma.
─ Metastatic Germ Cell Tumor with sarcomatous change (e.g., teratoma with malignant transformation): Clinical history of a primary germ cell tumor elsewhere is key.
─ Fetal Adenocarcinoma (monophasic): If only the fetal adenocarcinoma component is present without a malignant mesenchymal stroma, it is classified as fetal adenocarcinoma (low or high grade), not pulmonary blastoma.
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Benign Epithelial Tumors and Tumor-like Lesions

Squamous Cell Papilloma (Solitary, Multiple) and variants

A benign exophytic (outwardly growing) neoplasm of bronchial or bronchiolar epithelium characterized by papillary fronds lined by mature or mildly atypical squamous epithelium, overlying fibrovascular cores; it can occur as a solitary lesion or as multiple lesions (squamous papillomatosis)
Clinical ─
─ Solitary squamous papillomas: More common in adults, often associated with chronic irritation or cigarette smoking.
─ Multiple squamous papillomas (Pulmonary Squamous Papillomatosis): More common in children and young adults, strongly associated with Human Papillomavirus (HPV) infection, typically low-risk types HPV 6 and 11 (often related to maternal anogenital HPV infection and vertical transmission, or recurrent respiratory papillomatosis extending downwards).
─ Symptoms are often related to airway obstruction: cough, wheezing, dyspnea, hemoptysis, or post-obstructive pneumonia. Small or peripheral lesions may be asymptomatic.
─ Multiple papillomatosis can be recurrent, difficult to manage, and carries a small risk of malignant transformation to squamous cell carcinoma over time, especially if HPV-related or with continued irritation.
Macro ─
─ Typically appears as an exophytic, warty, cauliflower-like, or finger-like projection into the airway lumen (trachea, bronchus, or bronchiole)
─ Usually small (often <1-2 cm), soft, and pinkish-tan or white
Micro ─
─ Characterized by an exophytic papillary architecture: branching, finger-like fronds with central fibrovascular cores that contain connective tissue and blood vessels.
─ Epithelial lining: The papillae are lined by stratified squamous epithelium.
─ ─ In typical benign papillomas, the squamous epithelium is mature and well-differentiated, showing orderly maturation from basal cells to superficial flattened cells, with minimal or no cytologic atypia.
─ ─ Koilocytic atypia (perinuclear halos, wrinkled hyperchromatic nuclei) may be present if the papilloma is HPV-related.
─ ─ Mild cytologic atypia or dysplasia can sometimes be present, especially in adult solitary papillomas. If significant atypia amounting to carcinoma in situ (CIS) is present, the lesion is often termed "papilloma with carcinoma in situ" or "papillary squamous cell carcinoma in situ."
─ Variants:
─ ─ Inverted Squamous Papilloma: An uncommon variant characterized by an endophytic growth pattern, where the squamous epithelium grows downwards into the underlying stroma, forming nests and cords, but without true stromal invasion (the nests are usually surrounded by a basement membrane and lack infiltrative features). It is still considered benign.
─ ─ Keratinizing Squamous Papilloma: Shows prominent surface keratinization or keratin pearl formation within the benign squamous epithelium.
─ The basement membrane is intact, and there is no stromal invasion in benign papillomas.
Ancillary studies ─
─ IHC:
─ ─ Squamous epithelial cells are positive for squamous markers: p63, p40, CK5/6.
─ ─ Ki-67 proliferation index is generally low and confined to the basal layer in benign papillomas; may be increased if dysplasia is present.
─ In situ hybridization (ISH) or PCR for HPV DNA/RNA: Can detect HPV, especially in cases of multiple papillomatosis or if koilocytic features are suggestive. HPV types 6 and 11 are most common.
DDx ─
─ Papillary Squamous Cell Carcinoma (invasive or in situ): Distinguished by the presence of significant cytologic atypia (moderate to severe dysplasia or CIS) throughout much of the epithelium, disordered maturation, increased and atypical mitoses, and stromal invasion (for invasive forms).
─ Verrucous Carcinoma: A rare, very well-differentiated variant of squamous cell carcinoma with a warty appearance and pushing borders of invasion; typically lacks the significant cytologic atypia of conventional papillary SCC but is infiltrative.
─ Squamous metaplasia with papillary hyperplasia: A reactive process, often due to chronic inflammation or irritation, where the epithelium may show papillary folds but lacks the complex branching architecture of a true papilloma and the neoplastic nature.
─ Fibroepithelial polyp: A benign polypoid lesion with a prominent fibrovascular stromal core covered by benign respiratory or squamous metaplastic epithelium; the stroma is typically more abundant and less complexly papillary than in a papilloma.
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Glandular Papilloma

A benign exophytic (outwardly growing) neoplasm of bronchial or bronchiolar epithelium characterized by papillary fronds lined by benign glandular-type epithelial cells (e.g., ciliated columnar, non-ciliated cuboidal/columnar, or mucinous cells), overlying fibrovascular cores
Clinical ─
─ Rare benign tumors, typically occurring as solitary endobronchial lesions in adults
─ Symptoms, if present, are usually related to airway obstruction or irritation: cough, wheezing, dyspnea, hemoptysis
─ Generally has an excellent prognosis with complete local excision; recurrence is uncommon
─ The relationship with "exophytic papillary adenocarcinoma in situ" (as noted in the TOC) needs careful consideration: if there is significant cytologic atypia consistent with carcinoma in situ lining the papillae, then that diagnosis would be preferred over benign glandular papilloma. True glandular papilloma implies benign cytology.
Macro ─
─ Appears as a small (usually <2 cm), soft, exophytic, polypoid or papillary mass protruding into the airway lumen (trachea, bronchus, or bronchiole)
─ May be reddish, tan, or glistening depending on vascularity and cell type
Micro ─
─ Characterized by an exophytic papillary architecture: branching, finger-like fronds with central fibrovascular cores containing connective tissue and blood vessels.
─ Epithelial lining: The papillae are lined by a single layer or pseudostratified layer of benign glandular epithelial cells. The cell types can vary:
─ ─ Ciliated columnar cells (resembling normal respiratory epithelium).
─ ─ Non-ciliated cuboidal or columnar cells (sometimes referred to as "serous type" if cytoplasm is eosinophilic and granular, or "cuboidal type").
─ ─ Mucinous cells (goblet cells or columnar cells with abundant intracytoplasmic mucin).
─ ─ A mixture of these cell types can occur.
─ Cytologic atypia is minimal or absent; nuclei are generally bland, round to oval, with smooth contours and inconspicuous nucleoli. Mitotic figures are rare.
─ The basement membrane is intact, and there is no stromal invasion.
Ancillary studies ─
─ IHC:
─ ─ Epithelial cells are positive for cytokeratins (e.g., CK7, AE1/AE3).
─ ─ TTF-1 may be positive if the lining cells resemble pneumocytes or some types of respiratory epithelium.
─ ─ Mucin stains (PAS with diastase, Alcian blue) will be positive if mucinous cells are present.
─ ─ Ki-67 proliferation index is typically very low.
─ ─ Negative for squamous markers (p40, p63) unless focal squamous metaplasia is present (which should be minimal).
DDx ─
─ Papillary Adenocarcinoma (invasive or in situ): Distinguished by the presence of malignant cytologic features (nuclear atypia, pleomorphism, prominent nucleoli, increased/atypical mitoses), complex architectural patterns (e.g., fused glands, micropapillary tufts), and stromal invasion (for invasive forms). Exophytic papillary adenocarcinoma in situ would have neoplastic cytology confined to the papillae without invasion.
─ Inflammatory Polyp (Bronchial Polyp): A reactive lesion characterized by a prominent inflamed and often edematous fibrovascular stromal core, covered by benign respiratory epithelium which may show reactive atypia or squamous metaplasia; typically lacks the complex, uniform papillary architecture of a true papilloma.
─ Micropapillary Adenocarcinoma in Situ or invasive Micropapillary Adenocarcinoma: Characterized by small, cohesive tufts of tumor cells lacking true fibrovascular cores; different morphology and more aggressive implications.
─ Hamartoma with prominent epithelial invaginations (if polypoid).
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Mixed Squamous Cell and Glandular Papilloma

An extremely rare benign exophytic neoplasm of bronchial or bronchiolar epithelium characterized by papillary fronds lined by an intimate mixture of both benign squamous epithelial cells and benign glandular (columnar, cuboidal, or mucinous) epithelial cells, overlying fibrovascular cores
Clinical ─
─ Very rare, with only a few cases reported in the literature
─ Similar clinical presentation to solitary squamous or glandular papillomas if they cause airway obstruction (cough, wheezing, dyspnea)
─ Considered benign with an excellent prognosis following complete excision
Macro ─
─ Typically a small (usually <2 cm), exophytic, polypoid or papillary mass within the airway lumen
Micro ─
─ Exophytic papillary architecture: Branching fronds with central fibrovascular cores.
─ Epithelial lining shows a distinct and intimate admixture of both:
─ ─ Squamous epithelial component: Areas of mature, stratified squamous epithelium, typically without significant atypia.
─ ─ Glandular epithelial component: Areas lined by cuboidal, columnar, or mucinous cells, also without significant atypia.
─ Both components are cytologically bland, with minimal or no atypia and rare mitotic figures.
─ The two cell types may be sharply demarcated or intermingled along the same papillary frond or in different fronds.
─ No evidence of stromal invasion.
Ancillary studies ─
─ IHC can help highlight the two distinct epithelial populations:
─ ─ Squamous areas: Positive for squamous markers (p63, p40, CK5/6).
─ ─ Glandular areas: Positive for glandular markers (e.g., CK7). TTF-1 may be positive if lined by pneumocyte-like cells. Mucin stains positive if mucinous cells present.
─ ─ Ki-67 proliferation index is low in both components.
DDx ─
─ Adenosquamous Carcinoma: Distinguished by malignant cytologic features in both the squamous and glandular components, evidence of invasion, and each component typically constituting >10% of a malignant tumor.
─ Mucoepidermoid Carcinoma: A malignant tumor composed of mucinous, squamous, and intermediate cells in characteristic architectural patterns; typically lacks the simple papillary structure of a mixed papilloma and often has MAML2 fusions.
─ Squamous Papilloma with focal glandular metaplasia or Glandular Papilloma with focal squamous metaplasia: In these cases, one epithelial type is clearly dominant and neoplastic, while the other is a secondary metaplastic change. A true mixed papilloma implies that both epithelial components are integral parts of the benign neoplastic proliferation and are admixed.
─ Inflammatory Polyp with mixed epithelial metaplasia: Reactive lesion driven by inflammation.
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Sclerosing Pneumocytoma

A benign neoplasm of the lung, likely derived from primitive respiratory epithelium (type II pneumocytes and undifferentiated stromal cells), characterized by a biphasic proliferation of surface cuboidal epithelial cells and stromal round/oval cells, typically exhibiting a mixture of four main histologic patterns: papillary, solid, sclerotic (hemangioma-like), and hemorrhagic; formerly widely known as sclerosing hemangioma
Clinical ─
─ More common in women (F:M ratio ~4-5:1), particularly in middle-aged adults (median age ~50 years), with a higher incidence reported in Asian populations
─ Usually asymptomatic and discovered incidentally as a solitary, well-circumscribed peripheral pulmonary nodule or mass on chest imaging
─ Symptoms, if present, may include cough, chest pain, or hemoptysis (especially if large or hemorrhagic)
─ Excellent prognosis; it is considered benign with extremely rare reports of recurrence or metastasis after complete surgical excision
Macro ─
─ Typically a well-circumscribed, solitary, firm, round to oval nodule or mass, usually located in the peripheral lung parenchyma
─ Size ranges from <1 cm to several centimeters (most are 1-3 cm)
─ Cut surface is variable depending on the predominant histologic pattern: may be grayish-white, tan, yellowish, or reddish-brown (if hemorrhagic); areas of sclerosis or visible blood-filled spaces can be present
Micro ─
─ Characterized by a biphasic cell population and a combination of four main architectural patterns, which are often admixed within the same tumor:
─ Biphasic cell population:
─ ─ Surface cuboidal cells: Line papillary structures, alveolar-like spaces, and clefts. These cells are cuboidal to flattened, with bland, round to oval nuclei, inconspicuous nucleoli, and scant to moderate eosinophilic cytoplasm. They resemble reactive type II pneumocytes or club cells.
─ ─ Stromal round/oval cells: Monotonous cells with round to oval nuclei, finely granular or vesicular chromatin, inconspicuous nucleoli, and scant, pale eosinophilic or clear cytoplasm. These cells form sheets in solid areas or are interspersed within the sclerotic or hemorrhagic stroma. They are considered the main neoplastic component of the tumor.
─ Architectural patterns:
─ ─ Papillary pattern: Branching papillary fronds lined by surface cuboidal cells, overlying cores composed of stromal round/oval cells.
─ ─ Solid pattern: Sheets or nests of stromal round/oval cells with entrapped or overlying surface cuboidal cells lining cleft-like or alveolar-like spaces.
─ ─ Sclerotic (hemangioma-like) pattern: Characterized by dilated, blood-filled, cavernous vascular spaces or dense hyaline sclerosis with relatively sparse stromal and surface cells; this pattern can mimic a vascular neoplasm (hence the old term "sclerosing hemangioma").
─ ─ Hemorrhagic pattern: Large areas of fresh and old hemorrhage, with abundant hemosiderin-laden macrophages, often associated with the sclerotic pattern. Cholesterol clefts and foamy macrophages can also be seen.
─ Overall, the tumor lacks significant cytologic atypia, mitotic activity is very low or absent, and there is no evidence of invasion into adjacent structures
Ancillary studies ─
─ IHC is helpful in highlighting the biphasic cell population:
─ ─ Surface cuboidal cells: Positive for epithelial markers such as broad-spectrum cytokeratins (e.g., AE1/AE3, CAM5.2), CK7, and EMA. Also positive for pneumocyte markers TTF-1 (nuclear) and Napsin A (cytoplasmic).
─ ─ Stromal round/oval cells: Positive for TTF-1 (nuclear, sometimes also weak cytoplasmic staining) and EMA (often dot-like paranuclear or membranous). Usually negative or only focally positive for Napsin A and CK7. May express Progesterone Receptor (PR). Negative for vascular markers (e.g., CD31, CD34, ERG), S100 protein, and neuroendocrine markers.
DDx ─
─ Adenocarcinoma of the lung (especially lepidic-predominant or papillary types): Can be a major differential, but adenocarcinoma typically shows greater cytologic atypia, infiltrative growth, lacks the characteristic stromal round/oval cells of pneumocytoma, and the stromal cells in adenocarcinoma would not be TTF-1 positive in the same manner. Napsin A is usually strong in both components of adenocarcinoma.
─ Carcinoid Tumor (Pulmonary Neuroendocrine Tumor): Composed of cells with neuroendocrine morphology ("salt-and-pepper" chromatin) arranged in organoid patterns; positive for neuroendocrine markers (Chromogranin, Synaptophysin, CD56); lacks the biphasic pattern and other histologic features of pneumocytoma.
─ Metastatic tumors (e.g., metastatic papillary thyroid carcinoma – TTF-1 positive but thyroglobulin positive; metastatic renal cell carcinoma – PAX8 positive).
─ True vascular tumors (e.g., hemangioma, angiosarcoma): Would be positive for vascular markers (CD31, CD34, ERG) and lack the epithelial components of pneumocytoma.
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Alveolar Adenoma

A rare, benign glandular neoplasm of the peripheral lung, typically small (<1 cm), characterized by the formation of alveolar-like spaces or tubules lined by bland cuboidal to flattened epithelial cells, supported by a distinctive loose, hypocellular, edematous or myxoid stroma containing scattered benign spindle cells
Clinical ─
─ Usually an asymptomatic, incidental finding discovered as a small, solitary peripheral pulmonary nodule on chest imaging, typically in adults across a wide age range
─ No clear association with smoking or sex predilection
─ Considered benign with an excellent prognosis; local recurrence or malignant transformation has not been reported following complete excision
Macro ─
─ Typically a small (usually <1 cm, rarely up to 2 cm), well-circumscribed but unencapsulated, soft, grayish-white or translucent, sometimes partially cystic nodule, located in the peripheral lung parenchyma, often subpleurally
Micro ─
─ Well-demarcated from the surrounding lung parenchyma, though not truly encapsulated
─ Composed of numerous small, uniform, generally round to oval, alveolar-like cystic spaces or tubules
─ These spaces are lined by a single layer of bland cuboidal to flattened epithelial cells, resembling type II pneumocytes or attenuated alveolar lining cells. The cells have scant cytoplasm and round to oval nuclei with fine chromatin and inconspicuous nucleoli; cytologic atypia is minimal or absent.
─ The stroma separating these alveolar-like spaces is a characteristic feature: it is typically loose, edematous, or myxoid in appearance, and distinctly hypocellular. It contains scattered, bland, slender spindle cells, likely representing fibroblasts or myofibroblasts.
─ A sparse lymphoplasmacytic infiltrate may be present within the stroma
─ Mitotic figures are rare or absent; necrosis is not seen
─ No evidence of invasion into adjacent structures, lymphovascular invasion, or pleural involvement
Ancillary studies ─
─ IHC:
─ ─ Lining epithelial cells: Positive for epithelial markers (e.g., broad-spectrum cytokeratins, CK7, EMA) and pneumocyte markers TTF-1 (nuclear) and Napsin A (cytoplasmic).
─ ─ Stromal spindle cells: Positive for vimentin; may show focal SMA positivity. Negative for cytokeratins and TTF-1.
DDx ─
─ Atypical Adenomatous Hyperplasia (AAH): AAH is a preinvasive lesion characterized by atypical pneumocytes lining pre-existing alveolar walls, usually without the distinct cystic spaces or the characteristic loose, hypocellular stroma of alveolar adenoma. AAH cells may show more atypia.
─ Adenocarcinoma in Situ (AIS), non-mucinous type: AIS is a noninvasive carcinoma with neoplastic cells showing greater cytologic atypia and cellularity lining alveolar walls; it typically lacks the prominent loose stroma and distinct cystic spaces of alveolar adenoma.
─ Sclerosing Pneumocytoma: Also a benign tumor with pneumocytic differentiation, but sclerosing pneumocytoma is biphasic with distinct surface cuboidal cells and stromal round/oval cells, and often shows papillary, solid, sclerotic, or hemorrhagic patterns, different from the uniform cystic spaces and loose stroma of alveolar adenoma.
─ Lymphangioma: A benign lymphatic malformation composed of dilated lymphatic channels lined by D2-40 (podoplanin) positive endothelial cells; stroma is usually fibrous or contains lymphoid aggregates; epithelial markers negative in lining cells.
─ Peripheral carcinoid tumor (if forming small nests/acini): Would be positive for neuroendocrine markers.
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Papillary Adenoma

A rare benign exophytic or peripheral glandular neoplasm of the lung characterized by a predominantly or exclusively complex papillary architecture, lined by bland cuboidal, columnar, or sometimes hobnail or clear epithelial cells, overlying fibrovascular cores, and lacking stromal invasion or malignant cytologic features
Clinical ─
─ Can occur as an endobronchial lesion (presenting with symptoms of airway obstruction like cough, wheezing, or post-obstructive changes) or as an asymptomatic peripheral solitary pulmonary nodule
─ Affects adults over a wide age range; no clear sex predilection or strong association with smoking
─ Considered benign with an excellent prognosis following complete surgical excision; recurrences are rare
─ Distinction from "Glandular Papilloma" can be subtle; Papillary Adenoma often implies a more complex papillary architecture or specific cell types (like hobnail/clear cells) compared to simpler glandular papillomas lined by ciliated or mucinous cells. Some classifications may group them.
Macro ─
─ Endobronchial lesions: Appear as polypoid, papillary, or sessile masses protruding into the airway lumen.
─ Peripheral lesions: Present as well-circumscribed, solitary nodules, often small (<2-3 cm).
─ Cut surface may be tan, gray, or pink, and may appear granular or finely nodular.
Micro ─
─ Predominantly or exclusively papillary architecture: Consists of branching, finger-like or complex fronds with central fibrovascular cores.
─ The papillae are lined by a single layer or pseudostratified layer of epithelial cells, which can be:
─ ─ Cuboidal to columnar, with eosinophilic or amphophilic cytoplasm.
─ ─ Hobnail cells (cells with apically placed, protruding nuclei and bulbous cytoplasmic snouts) may be present.
─ ─ Clear cells (cells with abundant clear cytoplasm due to glycogen) can sometimes be a feature.
─ ─ Ciliated cells or mucinous cells are less typical of "papillary adenoma" as strictly defined by some, which might lean towards "glandular papilloma" if those are dominant, but overlap exists.
─ Cytologic atypia is minimal or absent: Nuclei are generally round to oval, uniform, with smooth contours and inconspicuous nucleoli. Mitotic figures are rare.
─ The basement membrane is intact, and there is no evidence of stromal invasion, significant pleomorphism, or tumor necrosis.
─ The stroma within the papillary cores is fibrovascular; the interpapillary stroma or base of the lesion may sometimes show sclerosis or chronic inflammation.
Ancillary studies ─
─ IHC:
─ ─ Epithelial cells are positive for broad-spectrum cytokeratins (e.g., AE1/AE3, CAM5.2) and often CK7.
─ ─ TTF-1 and Napsin A expression can be variable depending on the specific cell differentiation (may be positive if cells resemble pneumocytes or some types of bronchiolar epithelium, or negative).
─ ─ PAS stain (with diastase) can highlight glycogen in clear cell variants.
─ ─ Ki-67 proliferation index is typically very low.
DDx ─
─ Glandular Papilloma: As noted, distinction can be subtle. Glandular papillomas are often described with simpler architecture or predominant ciliated/mucinous lining. Papillary adenoma may imply more complex branching or specific cell types like hobnail/clear cells.
─ Papillary Adenocarcinoma (invasive or in situ): This is the most important differential. Papillary adenocarcinoma is distinguished by the presence of malignant cytologic features (nuclear atypia, pleomorphism, prominent nucleoli, increased/atypical mitoses), often more complex and fused glandular/papillary architecture, and stromal invasion (for invasive forms). Papillary adenocarcinoma in situ would have neoplastic cytology confined to the papillae without stromal invasion.
─ Adenocarcinoma in Situ (AIS), non-mucinous type with papillary features: AIS is non-invasive but composed of neoplastic cells with clear atypia.
─ Sclerosing Pneumocytoma: Also benign and can have a prominent papillary pattern, but is biphasic with characteristic surface cuboidal cells and stromal round/oval cells; different IHC profile of the stromal cells.
─ Inflammatory Polyp with papillary epithelial hyperplasia: A reactive lesion with a predominantly inflamed stromal core.
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Bronchiolar Adenoma / Ciliated Muconodular Papillary Tumor (CMPT)

A group of benign or low-malignant potential peripheral lung tumors, with "Ciliated Muconodular Papillary Tumor (CMPT)" being a more recently defined and specific entity within this spectrum, characterized by a complex papillary, glandular, and mucinous architecture with prominent ciliated cells, mucous cells, and often a basal cell layer. "Bronchiolar adenoma" is an older, less specific term that may have encompassed some lesions now classified as CMPT or other specific adenomas.
Clinical ─
─ CMPT is typically an asymptomatic, incidental finding discovered as a small, solitary peripheral pulmonary nodule (often subpleural) on imaging, usually in older adults (median age 60s-70s).
─ May have a higher incidence in Asian populations; association with smoking is variable, some studies suggest a link.
─ Generally considered benign or of very low malignant potential; recurrences or metastasis are exceptionally rare or not well documented for typical CMPT.
Macro ─
─ Usually a small (typically <1.5 cm, often <1 cm), well-circumscribed, grayish-white or tan nodule, often located in the peripheral lung, sometimes subpleurally.
─ Cut surface may appear solid, cystic, or mucoid/gelatinous.
Micro ─
─ Key features of Ciliated Muconodular Papillary Tumor (CMPT):
─ ─ Well-demarcated from surrounding lung parenchyma, though usually unencapsulated.
─ ─ Complex architectural patterns, often mixed:
─ ─ ─ Papillary structures: Exophytic and/or endophytic papillary fronds projecting into cystic spaces or alveolar lumens.
─ ─ ─ Glandular/acinar structures: Small to medium-sized glands or acini.
─ ─ ─ Muconodular areas: Pools of extracellular mucin, often containing detached epithelial cells or papillary fragments.
─ ─ Triphasic or biphasic cell population lining the structures is characteristic:
─ ─ ─ Ciliated columnar cells: Prominently line the surface of papillae or glands; these are a key feature.
─ ─ ─ Mucous cells (goblet cells or columnar mucin-producing cells): Interspersed among ciliated cells or forming clusters/lining glands, and contributing to extracellular mucin pools.
─ ─ ─ Basal-type cells (sometimes referred to as "reserve cells" or "scaffold cells"): A layer of small, cuboidal cells often present beneath the ciliated and mucous cells, particularly at the base of papillae or in solid areas. These are not always conspicuous.
─ ─ Stroma is often fibrotic, hyalinized, or may contain a mild chronic inflammatory infiltrate.
─ ─ Cytologic atypia is typically minimal to mild; nuclei are generally bland, and mitotic figures are rare.
─ ─ No destructive stromal invasion, lymphovascular invasion, or necrosis.
─ "Bronchiolar adenoma" as a broader term might include lesions with less complex architecture or lacking the full triphasic pattern of CMPT, but still benign and arising from bronchiolar epithelium.
Ancillary studies ─
─ IHC for CMPT:
─ ─ Ciliated and non-mucinous columnar cells: Usually positive for CK7 and TTF-1.
─ ─ Mucous cells: Positive for mucin stains (PAS with diastase, Alcian blue) and often MUC5AC. May be CK7 positive, TTF-1 variable/negative.
─ ─ Basal-type cells: Positive for p63, p40, and CK5/6.
─ ─ Ki-67 proliferation index is very low.
─ Molecular: BRAF V600E mutations and EGFR mutations have been reported in a subset of CMPTs, suggesting a neoplastic nature despite their benign behavior. ALK rearrangements also rarely reported.
DDx ─
─ Invasive Adenocarcinoma of the lung, particularly mucinous or papillary subtypes: Invasive adenocarcinoma will show clear evidence of stromal invasion, greater cytologic atypia, higher Ki-67, and typically lacks the consistent triphasic cell population (especially the distinct basal cell layer) and prominent ciliation seen in CMPT.
─ Adenocarcinoma in Situ (AIS) or Minimally Invasive Adenocarcinoma (MIA): These lack the complex papillary/muconodular architecture with triphasic cytology of CMPT. Mucinous AIS/MIA are composed of atypical mucinous cells, usually without cilia or a basal layer.
─ Other benign adenomas of the lung (e.g., mucous gland adenoma, papillary adenoma): Differ in their specific cell types, architecture, and IHC profile. Mucous gland adenoma is typically more solid/glandular and arises from bronchial glands. Papillary adenoma may lack the prominent mucin and ciliation of CMPT.
─ Inflammatory lesions with papillary change or mucinous metaplasia: Reactive lesions typically show more prominent inflammation and less complex, less organized epithelial proliferation than CMPT.
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Mucous Gland Adenoma (Bronchial Gland Adenoma)

A benign glandular neoplasm arising from the submucosal seromucinous glands of the trachea or bronchi, composed of mucus-producing cells and sometimes serous cells, forming glandular, tubular, cystic, or occasionally papillary structures, without significant cytologic atypia or evidence of invasion beyond the bronchial wall into lung parenchyma
Clinical ─
─ Rare benign tumors, typically occurring in adults
─ Usually located centrally in the trachea or main/lobar bronchi as an endobronchial or intramural lesion
─ Symptoms, if present, are often due to airway obstruction or irritation: cough, wheezing, dyspnea, hemoptysis, or post-obstructive pneumonia
─ Excellent prognosis following complete local excision (e.g., bronchoscopic resection or sleeve resection); recurrence is rare
Macro ─
─ Appears as a small (usually <2-3 cm), well-circumscribed, firm, polypoid or nodular endobronchial mass, often covered by intact respiratory mucosa
─ Cut surface may be solid, gray-white, tan, or glistening and mucoid if cysts containing mucus are present
Micro ─
─ Well-demarcated lesion, often appearing encapsulated or having pushing borders, arising from and expanding the submucosal bronchial glands
─ Composed of closely packed, variably sized glands, tubules, and often cystic spaces lined by bland epithelial cells:
─ ─ Predominantly mucus-producing cells: Cuboidal to columnar cells with abundant, pale, vacuolated or eosinophilic cytoplasm due to intracytoplasmic mucin; nuclei are typically small, round to oval, and basally located, without significant atypia. Goblet cells may be numerous.
─ ─ Serous acinar cells: Less commonly, areas resembling serous glands with cells having more granular eosinophilic cytoplasm and central nuclei may be seen.
─ ─ Oncocytic change can occur in some cells.
─ Architectural patterns can include simple tubular, complex glandular, microcystic, or occasionally cribriform or papillary structures, but these are lined by cytologically bland cells.
─ Mitotic figures are rare or absent; necrosis is not seen.
─ The stroma is usually scant and fibrovascular, separating the glandular elements.
─ No invasion into the surrounding cartilage of the bronchial wall or into adjacent lung parenchyma (beyond its origin within the bronchial wall).
Ancillary studies ─
─ IHC:
─ ─ Tumor cells are positive for cytokeratins (e.g., CK7, AE1/AE3).
─ ─ Mucin stains (PAS with diastase, Alcian blue, mucicarmine) highlight intracellular and intraluminal mucin.
─ ─ TTF-1 is typically negative (as these arise from bronchial glands, not alveolar or terminal bronchiolar epithelium).
─ ─ S100 protein may be positive in some ductal or myoepithelial-like cells if present at the periphery of glands (though true myoepithelial component is not a defining feature like in pleomorphic adenoma).
─ ─ Ki-67 proliferation index is very low.
DDx ─
─ Low-grade Mucoepidermoid Carcinoma (MEC): MEC is malignant and contains a mixture of mucinous, squamous, and intermediate cells, often with characteristic cystic and solid patterns; MAML2 fusions are common in MEC. Mucous gland adenoma lacks squamous and intermediate cells.
─ Adenoid Cystic Carcinoma (ACC): Biphasic tumor with ductal and myoepithelial/basaloid cells, characteristic cribriform pattern with hyaline material, perineural invasion; MYB fusions common.
─ Adenocarcinoma (especially mucinous types or those arising centrally): Adenocarcinoma shows malignant cytologic features (nuclear atypia, pleomorphism, prominent nucleoli, increased mitoses) and invasive growth patterns. TTF-1 may be positive in some adenocarcinomas.
─ Inflammatory Polyp with mucous gland hyperplasia: A reactive lesion with prominent inflammation and edema in the stroma, and hyperplastic but not neoplastic bronchial glands.
─ Bronchial gland cyst / Mucocele: Simple cyst lined by benign bronchial gland epithelium, usually due to duct obstruction, lacks the proliferative glandular architecture of an adenoma.
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Mucinous Cystadenoma

A benign cystic neoplasm of the lung characterized by one or more cysts lined by bland, non-ciliated, mucin-producing (goblet cell or tall columnar) epithelium, without stromal invasion, significant cytologic atypia, or the architectural complexity seen in borderline or malignant mucinous tumors; it is considered by some to be the benign end of the spectrum that includes mucinous adenocarcinoma in situ and invasive mucinous/colloid adenocarcinoma
Clinical ─
─ Rare, often discovered incidentally as a solitary, peripheral, well-circumscribed cystic lesion on chest imaging
─ Can occur in adults of any age; no clear sex predilection or strong association with smoking
─ Generally asymptomatic, unless very large or complicated by infection or rupture
─ Excellent prognosis with complete surgical excision; malignant transformation is considered exceptionally rare or not well documented for true benign mucinous cystadenomas
Macro ─
─ Typically a well-circumscribed, unilocular or, less commonly, multilocular cyst filled with thick, tenacious, gelatinous or mucoid material
─ Cyst lining is usually smooth, but may have focal irregularities or small septations if multilocular
─ Size can vary from small (<1 cm) to very large (several centimeters)
Micro ─
─ The cyst or cysts are lined by a single layer (or occasionally pseudostratified) of bland mucinous epithelium:
─ ─ Cells are typically tall columnar with abundant apical mucin and basally located small, uniform nuclei (goblet cell appearance), or cuboidal to columnar cells with pale eosinophilic or clear mucinous cytoplasm.
─ ─ Cilia are characteristically absent.
─ ─ Nuclear atypia is minimal or absent: Nuclei are small, round to oval, with smooth contours and inconspicuous nucleoli.
─ ─ Mitotic figures are rare or absent.
─ No complex papillary structures, significant epithelial tufting, or marked cellular stratification of the lining cells.
─ The cyst wall is typically composed of fibrous connective tissue, which may contain a mild chronic inflammatory infiltrate.
─ Crucially, there is no evidence of stromal invasion by the epithelial cells.
─ Rupture of the cyst can lead to extracellular mucin spillage into adjacent alveoli, potentially eliciting an inflammatory response or organizing pneumonia (mucin granulomas).
Ancillary studies ─
─ IHC:
─ ─ Epithelial lining cells are positive for cytokeratins (e.g., CK7 often positive, CK20 expression is variable but can be positive).
─ ─ Mucin stains (PAS with diastase, Alcian blue, mucicarmine) are strongly positive for intracellular and intraluminal mucin.
─ ─ TTF-1 is usually negative or only focally/weakly positive (consistent with mucinous lineage tumors of the lung which often lack strong TTF-1).
─ ─ Napsin A is typically negative.
─ ─ Ki-67 proliferation index is very low.
DDx ─
─ Mucinous Adenocarcinoma in Situ (AIS), mucinous type: AIS is also non-invasive and lined by atypical mucinous cells, but typically shows greater cytologic atypia, more cellular crowding, and may have a lepidic growth pattern along pre-existing alveolar walls rather than forming a primary large cyst structure (though AIS can arise in a cyst).
─ Minimally Invasive Adenocarcinoma (MIA), mucinous type, or Invasive Mucinous Adenocarcinoma / Colloid Adenocarcinoma: These are distinguished by the presence of stromal invasion, greater architectural complexity, or more significant cytologic atypia.
─ Congenital cysts of the lung:
─ ─ Bronchogenic cyst: Typically lined by ciliated pseudostratified columnar (respiratory) epithelium and its wall contains elements of bronchial wall (cartilage, smooth muscle, seromucinous glands).
─ ─ Congenital Pulmonary Airway Malformation (CPAM) Type 1: Can have large cysts lined by ciliated or mucinous epithelium, but has characteristic adenomatoid proliferation of bronchiolar structures and may have cartilage in walls.
─ Simple mucous retention cyst or mucocele: Usually smaller, often related to bronchial obstruction, lined by benign bronchial-type epithelium which may include ciliated cells.
─ Echinococcal (Hydatid) Cyst: Parasitic cyst with a characteristic laminated outer membrane and inner germinal layer producing scolices; serology positive.
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Mesenchymal Tumors of the Lung (Primary)

Pulmonary Hamartoma (Chondroid Hamartoma)

A benign tumor-like malformation (some consider it a true benign neoplasm) composed of a disorganized admixture of mature mesenchymal tissues normally found in the lung—most characteristically cartilage, but also fibrous connective tissue, fat, and smooth muscle—along with entrapped, benign respiratory epithelial elements forming clefts or tubules
Clinical ─
─ The most common benign tumor of the lung, accounting for ~75% of all benign lung neoplasms
─ Usually discovered incidentally as a solitary, well-circumscribed peripheral "coin lesion" on chest imaging in asymptomatic adults (peak incidence 50s-60s)
─ Slow-growing and rarely causes symptoms unless very large or endobronchial (which is less common)
─ No significant association with smoking; slightly more common in males
─ Excellent prognosis; malignant transformation is exceedingly rare
Macro ─
─ Typically a well-circumscribed, firm, lobulated, round or oval mass, usually <4 cm in diameter (can be larger)
─ Cut surface is often grayish-white, glistening, and may appear cartilaginous, fatty, or fibrous depending on the predominant mesenchymal component
─ "Popcorn calcification" on imaging (CT scan) is a characteristic but not invariably present feature, representing calcification within the cartilaginous component
Micro ─
─ Characterized by a disorganized ("hamartomatous") arrangement of various mature mesenchymal tissues, with entrapped benign epithelial elements:
─ Mesenchymal Components:
─ ─ Hyaline cartilage: This is the most common and characteristic mesenchymal component, often forming lobules or irregular islands. The chondrocytes within are bland, situated within lacunae, and may show focal calcification or ossification.
─ ─ Fibromyxoid stroma: Spindle cells (fibroblasts, myofibroblasts) embedded in a loose myxoid or more dense collagenous connective tissue matrix.
─ ─ Adipose tissue (fat): Mature adipocytes are frequently present, sometimes abundantly.
─ ─ Smooth muscle bundles: Less commonly, interlacing bundles of smooth muscle cells can be seen.
─ Epithelial Component:
─ ─ Entrapped benign respiratory epithelium lines cleft-like spaces, tubules, or small cystic structures within or between the mesenchymal components.
─ ─ The epithelium is typically ciliated pseudostratified columnar or cuboidal, and may show reactive hyperplasia or squamous metaplasia, but is cytologically bland.
─ All components are mature and show no significant cytologic atypia or mitotic activity
─ The lesion is usually well-demarcated from the surrounding lung parenchyma but lacks a true capsule
Ancillary studies ─
─ Generally not required for diagnosis, as H&E morphology is usually characteristic
─ IHC:
─ ─ Epithelial cells: Positive for cytokeratins (e.g., AE1/AE3, CK7) and TTF-1.
─ ─ Cartilage: Chondrocytes are S100 protein positive.
─ ─ Adipose tissue: Adipocytes are S100 protein positive.
─ ─ Smooth muscle: Positive for Smooth Muscle Actin (SMA) and desmin.
─ Molecular: Rearrangements involving the HMGA2 (High Mobility Group AT-hook 2) gene on chromosome 12q14-15 or, less commonly, HMGA1 on 6p21, are common in pulmonary hamartomas, supporting a neoplastic basis for many of these lesions despite their benign behavior.
DDx ─
─ Chondroma: A benign tumor composed purely of mature hyaline cartilage, without the other mesenchymal elements (fat, fibrous tissue) or the entrapped epithelial clefts seen in hamartoma.
─ Metastatic Chondrosarcoma or well-differentiated primary Chondrosarcoma (extremely rare in lung): Malignant cartilage with increased cellularity, cytologic atypia, pleomorphism, and mitotic figures.
─ Carcinosarcoma or Pulmonary Blastoma: Biphasic malignant tumors with both malignant epithelial and malignant mesenchymal components; clearly malignant cytology in both components.
─ Teratoma (Primary Pulmonary): A germ cell tumor containing elements derived from all three germ layers (e.g., skin, neural tissue, gastrointestinal epithelium, cartilage, bone, etc.). Hamartomas only contain elements native to the lung.
─ Organizing pneumonia or fibrotic nodules: May contain entrapped reactive epithelium but lack the characteristic disorganized mesenchymal elements, especially cartilage and fat.
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Chondroma

A benign cartilaginous tumor composed exclusively or almost exclusively of mature hyaline cartilage, without the admixture of other mesenchymal elements (fat, smooth muscle, fibrous tissue) or entrapped respiratory epithelium that characterizes a pulmonary hamartoma; primary pulmonary chondromas are very rare
Clinical ─
─ Can occur as an endobronchial lesion (arising from bronchial cartilage) or, less commonly, as a peripheral intraparenchymal nodule
─ Endobronchial chondromas may cause symptoms of airway obstruction (cough, wheezing, dyspnea, post-obstructive pneumonia)
─ Parenchymal chondromas are usually asymptomatic and discovered incidentally on imaging
─ Affects adults, with no clear sex predilection; not associated with smoking
─ Excellent prognosis with complete surgical excision; recurrence is rare
Macro ─
─ Typically a well-circumscribed, firm, lobulated, grayish-white or bluish-translucent, cartilaginous nodule or mass
─ Endobronchial lesions are often polypoid
─ Size is variable, usually small (<3 cm)
Micro ─
─ Composed of lobules of mature hyaline cartilage, similar in appearance to normal bronchial cartilage or articular cartilage
─ Chondrocytes are situated within lacunae and are typically small, bland, with round to oval, regular nuclei and clear or pale eosinophilic cytoplasm; binucleation of chondrocytes can occasionally be seen but is not a feature of malignancy in this context
─ No significant cytologic atypia, pleomorphism, or mitotic activity within the chondrocytes
─ The cartilaginous matrix is abundant, hyaline, and may show focal areas of calcification or, rarely, ossification
─ Crucially, lacks other mesenchymal tissues (such as fat, prominent fibrous stroma, or smooth muscle) and does not contain entrapped respiratory epithelial elements (this distinguishes it from a pulmonary hamartoma)
─ The lesion is usually well-demarcated from surrounding tissue
Ancillary studies ─
─ IHC:
─ ─ Chondrocytes are positive for S100 protein.
─ ─ Negative for cytokeratins (ruling out chondroid metaplasia in a carcinoma or hamartoma epithelium).
DDx ─
─ Pulmonary Hamartoma (Chondroid Hamartoma): This is the most important differential. Hamartomas contain cartilage but are defined by the presence of other mesenchymal elements (fat, fibrous tissue, smooth muscle) and entrapped benign respiratory epithelium. Pure chondromas lack these additional components.
─ Chondrosarcoma (Primary or Metastatic): A malignant cartilaginous tumor characterized by increased cellularity, significant cytologic atypia (pleomorphism, hyperchromasia, enlarged nuclei), mitotic figures, and often infiltrative growth. Distinguishing low-grade chondrosarcoma from a benign chondroma can sometimes be challenging, especially on small biopsies, and relies on assessing these features of malignancy. Clinical context (e.g., history of chondrosarcoma elsewhere) is vital for metastatic lesions.
─ Calcified Granuloma or other calcified/ossified benign lesions (e.g., old infarct): These may appear hard and gritty but will show histologic features of granulomatous inflammation or ischemic necrosis with dystrophic calcification/ossification, not viable neoplastic cartilage.
─ Tracheobronchopathia Osteochondroplastica: A rare, benign condition characterized by multiple submucosal cartilaginous and/or osseous nodules along the trachea and major bronchi, representing a diffuse process rather than a discrete tumor.
─ Chondroid metaplasia within another lesion (e.g., carcinoma, inflammatory lesion).
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Lipoma

A benign mesenchymal tumor composed entirely of mature adipose tissue (fat cells); it is rare as a primary tumor within the lung and can be endobronchial (arising from submucosal fat in airway walls) or intraparenchymal
Clinical ─
─ Endobronchial lipomas: More likely to be symptomatic due to airway obstruction, causing cough, wheezing, dyspnea, or post-obstructive pneumonia. Often seen in middle-aged to older adults, slight male predominance.
─ Intraparenchymal lipomas: Usually asymptomatic and discovered incidentally as well-circumscribed, low-density (fat density on CT) nodules or masses on chest imaging.
─ Excellent prognosis with complete surgical or bronchoscopic excision; recurrence is rare.
Macro ─
─ Endobronchial lipomas: Typically present as smooth, polypoid, yellowish, soft, and often encapsulated masses protruding into the airway lumen.
─ Intraparenchymal lipomas: Appear as well-circumscribed, soft, yellow, lobulated masses, clearly demarcated from surrounding lung tissue.
Micro ─
─ Well-circumscribed lesion composed predominantly or exclusively of sheets of mature adipocytes (fat cells).
─ Adipocytes are univacuolated cells with abundant clear cytoplasm (due to a single large lipid vacuole that is dissolved during routine processing, leaving an empty space) and small, flattened, eccentrically placed, bland nuclei.
─ A delicate fibrovascular stroma with thin capillaries typically separates lobules or clusters of adipocytes.
─ No significant cytologic atypia, pleomorphism, or hyperchromasia of adipocyte nuclei.
─ Lipoblasts (immature fat cells with atypical, scalloped nuclei and cytoplasmic lipid vacuoles) are absent (their presence would suggest liposarcoma).
─ Mitotic activity is absent or extremely rare. Necrosis is not a feature.
─ May possess a thin fibrous capsule, especially endobronchial variants.
Ancillary studies ─
─ Generally not required for diagnosis, as H&E morphology of mature adipose tissue is usually characteristic.
─ IHC:
─ ─ S100 protein can be positive in adipocytes (nuclear and cytoplasmic).
─ ─ Vimentin is positive.
─ ─ MDM2 and CDK4 IHC are negative (useful to exclude well-differentiated liposarcoma if there is any concern for atypia, though primary liposarcoma of lung is rare and usually metastatic or dedifferentiated).
DDx ─
─ Liposarcoma (Well-differentiated or Dedifferentiated): Metastatic liposarcoma is more common in the lung than primary. Well-differentiated liposarcoma shows atypical spindle cells and lipoblasts, often with MDM2/CDK4 amplification/overexpression. Dedifferentiated liposarcoma has a high-grade non-lipogenic sarcoma component adjacent to well-differentiated liposarcoma. Primary pulmonary liposarcoma is exceedingly rare.
─ Pulmonary Hamartoma with a predominant fatty component: Hamartomas are characterized by a mixture of mesenchymal tissues (cartilage, fat, fibrous tissue, smooth muscle) and entrapped benign respiratory epithelium. If fat is very dominant, it can resemble a lipoma, but careful search for other components (especially cartilage or epithelial clefts) is needed.
─ Pulmonary embolism with fat (Fat Embolism Syndrome): Characterized by fat globules within pulmonary capillaries and arterioles, often associated with trauma (long bone fractures) or orthopedic surgery, not a discrete tumor mass. Requires special stains (Oil Red O on frozen tissue) for definitive fat identification in vessels.
─ Lipoid Pneumonia (Exogenous): Accumulation of inhaled or aspirated lipid within alveolar spaces and interstitium, with associated inflammation and foamy macrophages; different clinical context and morphology (not a discrete mass of mature adipocytes).
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Leiomyoma

A benign mesenchymal tumor composed of mature smooth muscle cells; primary pulmonary leiomyomas are very rare and can arise from the smooth muscle of airways (endobronchial), lung parenchyma (intraparenchymal, possibly from vessel walls or interstitial smooth muscle), or pulmonary blood vessels
Clinical ─
─ Endobronchial leiomyomas: May cause symptoms of airway obstruction (cough, wheezing, dyspnea, hemoptysis, post-obstructive pneumonia).
─ Intraparenchymal leiomyomas: Usually asymptomatic and discovered incidentally as solitary, well-circumscribed nodules on chest imaging.
─ Occur over a wide age range, more common in adults; some studies suggest a female predominance.
─ Excellent prognosis for primary benign leiomyomas with complete surgical excision; recurrence is rare.
─ "Benign Metastasizing Leiomyoma": A rare condition seen in women, typically of reproductive age with a history of uterine leiomyomas (fibroids), where histologically benign-appearing smooth muscle tumors develop in the lungs (and sometimes other sites), representing metastases from a benign uterine primary. These are usually multiple.
Macro ─
─ Typically well-circumscribed, firm, grayish-white or tan, solid nodules or masses.
─ Cut surface often has a whorled, trabecular, or fascicular appearance, characteristic of smooth muscle tumors.
─ Endobronchial lesions may be polypoid.
Micro ─
─ Composed of interlacing fascicles or whorls of bland, spindle-shaped smooth muscle cells.
─ Tumor cells have elongated, eosinophilic, fibrillar cytoplasm and characteristic blunt-ended ("cigar-shaped") nuclei with fine chromatin and inconspicuous nucleoli.
─ Minimal or no cytologic atypia or pleomorphism.
─ Low mitotic activity: Generally defined as <2 mitoses per 10 high-power fields (HPF) or adhering to specific criteria for benign smooth muscle tumors (e.g., Stanford criteria for uterine smooth muscle tumors are sometimes referenced, though specific lung criteria are less defined due to rarity). No atypical mitoses.
─ No tumor necrosis (coagulative tumor cell necrosis). Hyalinization or myxoid change can occur in stroma.
Ancillary studies ─
─ IHC is crucial for confirming smooth muscle differentiation:
─ ─ Positive for smooth muscle markers: Smooth Muscle Actin (SMA, usually diffuse and strong), Desmin (often diffuse and strong), Caldesmon (h-caldesmon is a specific marker of smooth muscle differentiation).
─ ─ Negative for S100 protein, CD34, cytokeratins (AE1/AE3, CAM5.2), TTF-1, neuroendocrine markers.
─ ─ Estrogen Receptor (ER) and Progesterone Receptor (PR) may be positive, especially in tumors in females or benign metastasizing leiomyomas.
DDx ─
─ Leiomyosarcoma (primary or metastatic): Distinguished by the presence of significant cytologic atypia, increased mitotic activity (often >5-10 mitoses/10 HPF, depending on specific criteria and context), and/or tumor cell necrosis.
─ Benign Metastasizing Leiomyoma (from uterus): Histologically identical to benign uterine leiomyomas and primary pulmonary leiomyomas. Clinical history of uterine leiomyomas (often multiple, large, or with unusual growth patterns) and multiple lung nodules in a female patient is key. ER/PR positivity is common.
─ Pulmonary Hamartoma with a prominent smooth muscle component: Will also contain other mesenchymal elements (cartilage, fat, fibrous tissue) and entrapped respiratory epithelium.
─ Schwannoma: Also a spindle cell tumor, but S100 protein and SOX10 positive, negative for smooth muscle markers. Different nuclear morphology (wavy, pointed nuclei).
─ Solitary Fibrous Tumor (SFT): Spindle cell tumor with "patternless pattern," staghorn vasculature, positive for CD34, STAT6 (nuclear), and often BCL2; negative for smooth muscle markers.
─ Inflammatory Myofibroblastic Tumor (IMT): Spindle cell proliferation with a prominent inflammatory infiltrate (plasma cells, lymphocytes); often ALK-positive by IHC. Smooth muscle markers can be positive but ALK helps.
─ Spindle Cell Carcinoma (Sarcomatoid Carcinoma): Positive for cytokeratins and often p40/p63.
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Granular Cell Tumor (Endobronchial)

A benign mesenchymal neoplasm of probable Schwann cell origin (neural crest derivation), characterized by nests and sheets of large polygonal cells with abundant, distinctively coarse, granular, eosinophilic cytoplasm due to lysosomal accumulation; while it can occur in many sites, in the lung, it most commonly arises as an endobronchial lesion within the wall of larger bronchi or trachea
Clinical ─
─ Rare in the lung, typically affecting adults (30s-60s), with no clear sex predilection but some reports suggest slight female or Black patient predominance overall for granular cell tumors at all sites.
─ Endobronchial lesions (most common pulmonary presentation) can cause symptoms of airway irritation or obstruction: persistent cough, wheezing, dyspnea, hemoptysis, or post-obstructive atelectasis/pneumonia.
─ Generally considered benign with an excellent prognosis after complete local excision (e.g., bronchoscopic or surgical resection). Malignant granular cell tumors are extremely rare overall and exceptionally so in the lung.
Macro ─
─ Typically presents as a small (usually <2-3 cm), firm, yellowish-white, tan, or grayish, non-encapsulated but well-demarcated, sessile or polypoid submucosal nodule within the wall of a major airway (trachea, main bronchus, lobar bronchus).
─ Overlying respiratory mucosa is usually intact but may show pseudoepitheliomatous hyperplasia.
Micro ─
─ Composed of nests, sheets, cords, or alveolus-like clusters of large, polygonal to round or oval cells with abundant, strikingly granular, eosinophilic cytoplasm.
─ The cytoplasmic granules are coarse, variably sized, and give the cells a "muddy" or "dirty" eosinophilic appearance. These granules are lysosomes filled with cellular debris.
─ Nuclei are typically small, round to oval, centrally or eccentrically located, often vesicular with small, inconspicuous nucleoli. Significant nuclear atypia or pleomorphism is usually absent in benign lesions. Mitotic figures are rare.
─ Cell borders may be indistinct due to the granular cytoplasm, giving a syncytial appearance in some areas.
─ The tumor cells often show an infiltrative growth pattern into surrounding connective tissue, smooth muscle of the bronchial wall, or around nerves, but this infiltrative pattern does not necessarily imply malignancy in typical granular cell tumors.
─ Pseudoepitheliomatous hyperplasia (or pseudocarcinomatous hyperplasia) of the overlying bronchial squamous or respiratory epithelium is a common and important associated finding; it can be florid and mimic invasive squamous cell carcinoma if the underlying granular cell tumor is not well-sampled or recognized.
Ancillary studies ─
─ IHC:
─ ─ Characteristically positive for S100 protein (strong, diffuse nuclear and cytoplasmic staining).
─ ─ SOX10 (nuclear stain) is also typically positive.
─ ─ CD68 (a lysosomal marker, often KP1 clone): Usually positive within the cytoplasmic granules, reflecting their lysosomal nature.
─ ─ Inhibin-alpha can also be positive.
─ ─ Calretinin has been reported as positive in some cases.
─ ─ Negative for cytokeratins (AE1/AE3, CAM5.2) in the tumor cells (though the overlying hyperplastic epithelium will be cytokeratin positive).
─ ─ Negative for smooth muscle markers (SMA, desmin), neuroendocrine markers (Chromogranin, Synaptophysin), and TTF-1.
─ Histochemical stains:
─ ─ PAS (Periodic Acid-Schiff) stain: The cytoplasmic granules are typically PAS-positive and diastase-resistant.
DDx ─
─ Squamous Cell Carcinoma (if pseudoepitheliomatous hyperplasia is prominent and the granular cell tumor component is small or crushed): IHC for S100 and cytokeratins is crucial. Granular cells are S100+, keratin-.
─ Oncocytic tumors (e.g., oncocytic carcinoid, oncocytic adenocarcinoma): Cells have abundant granular eosinophilic cytoplasm due to mitochondria, not lysosomes. Oncocytic carcinoids are neuroendocrine marker positive, S100 negative. Oncocytic adenocarcinomas are TTF-1/Napsin A positive.
─ Rhabdomyoma: Composed of cells with skeletal muscle differentiation (cytoplasmic cross-striations may be seen); positive for desmin, myogenin, MyoD1; S100 negative.
─ Metastatic tumors with granular cytoplasm (e.g., some renal cell carcinomas, some melanomas): Clinical history and a broader IHC panel (PAX8 for renal, HMB-45/Melan-A for melanoma) would be needed.
─ Alveolar Soft Part Sarcoma (ASPS): Rare in lung; nests of cells with granular eosinophilic cytoplasm, characteristic crystalloids (PAS-positive, diastase-resistant); nuclear TFE3 positivity by IHC due to ASPSCR1-TFE3 fusion. S100 negative.
─ Accumulation of foamy macrophages (e.g., in obstructive pneumonia, lipoid pneumonia): Macrophages are CD68 positive but lack the distinct granular appearance and S100 positivity of granular cell tumor cells.
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Inflammatory Myofibroblastic Tumor (IMT)

A mesenchymal neoplasm of intermediate malignant potential (meaning it can recur locally and rarely metastasize, though most behave indolently if completely resected) composed of myofibroblastic spindle cells admixed with a prominent inflammatory infiltrate, typically rich in plasma cells, lymphocytes, and often eosinophils; formerly widely known as inflammatory pseudotumor or plasma cell granuloma
Clinical ─
─ Occurs over a wide age range, from children to older adults, with a peak in children and young adults. No clear sex predilection.
─ Can arise in various sites; in the lung, it typically presents as a solitary, well-circumscribed peripheral mass, but can also be endobronchial or multifocal.
─ Symptoms are variable: may be asymptomatic and found incidentally, or cause cough, dyspnea, chest pain, fever, weight loss, fatigue, hemoptysis. Paraneoplastic syndromes (e.g., fever, anemia, thrombocytosis, polyclonal hypergammaglobulinemia) can occur due to cytokine production.
─ Approximately 50-60% of IMTs harbor rearrangements of the ALK (Anaplastic Lymphoma Kinase) gene, leading to aberrant ALK protein expression.
─ Behavior is variable: Most are cured by complete surgical excision. Local recurrence can occur, especially if incompletely resected or with certain high-risk features. Distant metastases are rare (<5-10%) but can happen, particularly with larger, recurrent, or atypical tumors.
Macro ─
─ Usually a well-circumscribed or lobulated, firm, whorled, grayish-white, tan, or yellowish solid mass.
─ Size can vary from small nodules to very large masses (can exceed 10 cm).
─ Cut surface may show areas of hemorrhage, necrosis (uncommon in typical IMT), or myxoid/gelatinous change.
Micro ─
─ Composed of a proliferation of bland-appearing spindle cells (myofibroblasts) admixed with a significant inflammatory infiltrate.
─ Spindle cells: Fusiform or stellate cells with vesicular (open) nuclei, small, often inconspicuous nucleoli, and pale eosinophilic or amphophilic cytoplasm with ill-defined borders. Arranged in loose fascicles, a storiform pattern, or haphazardly.
─ Inflammatory infiltrate: Characteristically prominent and mixed, composed of numerous plasma cells (often forming sheets), lymphocytes (sometimes forming lymphoid follicles with germinal centers), eosinophils (can be abundant), neutrophils, and histiocytes.
─ Stroma: Variable; can be loose and edematous, myxoid (most common pattern), or more densely collagenous/fibrous (hypocellular fibrous pattern). Vascularity is often prominent, with thin-walled, branching vessels.
─ Three main histologic patterns are often described (frequently admixed):
─ ─ Myxoid/vascular pattern: Loose, edematous or myxoid stroma with prominent blood vessels and a rich inflammatory infiltrate. Spindle cells may be less conspicuous.
─ ─ Compact spindle cell pattern: Denser fascicles of spindle cells with less prominent stroma and inflammation. Nuclei may appear more plump.
─ ─ Hypocellular fibrous pattern: Dense, hyalinized collagenous stroma with relatively few spindle cells and scant inflammation, resembling a scar or desmoid-type fibromatosis.
─ Cytologic atypia in the spindle cells is usually minimal; mitotic activity is generally low (e.g., <1-3 mitoses per 10 HPF). Necrosis is uncommon. Atypical features (increased cellularity, atypia, mitoses, ganglion-like cells, necrosis) can occur and may be associated with more aggressive behavior ("atypical" or "epithelioid" IMT variants).
Ancillary studies ─
─ IHC:
─ ─ Spindle cells (myofibroblasts): Characteristically positive for Smooth Muscle Actin (SMA, often diffuse), Muscle-Specific Actin (MSA), and vimentin. Desmin expression is variable (often weaker, focal, or negative). Calponin can also be positive.
─ ─ ALK (Anaplastic Lymphoma Kinase): Aberrant cytoplasmic expression (granular or diffuse) is present in ~50-60% of IMTs due to ALK gene rearrangement (most commonly with partners like TPM3, TPM4, CLTC). This is a very useful diagnostic marker. ALK-negative IMTs exist.
─ ─ Cytokeratins (e.g., AE1/AE3, CAM5.2): Usually negative in the spindle cells, or only very focally positive in some cases (entrapped reactive epithelial cells will be positive).
─ ─ S100 protein, CD34, STAT6 are typically negative (helps distinguish from SFT, schwannoma).
─ ─ IgG4 staining may show increased IgG4+ plasma cells in some cases, but not meeting criteria for IgG4-related disease.
DDx ─
─ Sarcomatoid Carcinoma (especially Spindle Cell Carcinoma): Shows more significant cytologic atypia, higher mitotic rate, and more diffuse/strong cytokeratin positivity. ALK negative.
─ Primary Pulmonary Sarcoma (e.g., fibrosarcoma, leiomyosarcoma, undifferentiated pleomorphic sarcoma): Lacks the prominent inflammatory infiltrate of IMT, shows greater cytologic malignancy, and has a different IHC profile (e.g., leiomyosarcoma is desmin diffuse+, ALK neg).
─ Solitary Fibrous Tumor (SFT): Spindle cell tumor with "patternless pattern," staghorn vasculature, less inflammation; positive for CD34, STAT6 (nuclear), BCL2; ALK negative.
─ Organizing Pneumonia (Cryptogenic or Secondary): Predominantly intra-alveolar fibroblastic plugs (Masson bodies) with associated inflammation; not a discrete spindle cell mass like IMT.
─ Lymphoma (especially Hodgkin lymphoma or plasma cell rich types like plasmacytoma): Lymphoma cells would show specific lymphoid markers (CD45, CD20, CD3, CD30, CD15, CD138) and clonality. Plasma cells in IMT are polyclonal.
─ Fibrosing Pleuritis or Pseudotumor (if pleural based): Reactive fibrous proliferation with inflammation, less cellular and lacks ALK.
─ IgG4-Related Disease: Can form tumor-like masses with plasma cells and fibrosis, but typically shows storiform fibrosis, obliterative phlebitis, and a high IgG4+/IgG+ plasma cell ratio; ALK negative.
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PEComa (Perivascular Epithelioid Cell Tumor) - Benign

A mesenchymal neoplasm composed of distinctive perivascular epithelioid cells (PECs) that typically co-express melanocytic and smooth muscle markers; the PEComa family includes a spectrum from benign tumors (like the classic clear cell "sugar" tumor of the lung) to PEComas of uncertain malignant potential and malignant PEComas. This entry focuses on benign PEComa.
Clinical ─
─ Rare tumors in the lung; can occur at any age, with a slight female predominance for PEComas overall (though "sugar tumor" has no clear sex predilection)
─ Often an asymptomatic, incidental finding discovered as a solitary, well-circumscribed peripheral pulmonary nodule on imaging
─ Benign PEComas (including typical clear cell "sugar" tumor) have an excellent prognosis with complete surgical excision
─ May be associated with Tuberous Sclerosis Complex (TSC) in some cases, particularly when multifocal or involving other sites (e.g., renal angiomyolipoma, lymphangioleiomyomatosis - LAM, which is also a PEComatous lesion)
─ Clear Cell "Sugar" Tumor of the Lung: Considered a type of benign PEComa, characterized by prominent clear cytoplasm due to glycogen.
Macro ─
─ Typically a well-circumscribed, solid, firm or somewhat soft, grayish-white, tan, or reddish-brown (if vascular) nodule or mass
─ Size is variable, usually small (<3-4 cm) for benign lesions
Micro ─
─ Benign PEComa / Clear Cell "Sugar" Tumor:
─ ─ Composed of sheets, nests, or trabeculae of polygonal epithelioid cells, often with a prominent perivascular arrangement (cells clustering around numerous thin-walled, sinusoidal or staghorn-like blood vessels)
─ ─ Cells have abundant clear or eosinophilic granular cytoplasm:
─ ─ ─ In Clear Cell "Sugar" Tumor: Cytoplasm is predominantly clear due to abundant glycogen accumulation (PAS-positive, diastase-sensitive).
─ ─ ─ In other benign PEComas: Cytoplasm can be clear, eosinophilic granular, or mixed.
─ ─ Nuclei are typically round to oval, often centrally located, with bland, vesicular or finely granular chromatin and inconspicuous or small nucleoli; significant atypia is absent.
─ ─ Mitotic activity is very low or absent (e.g., <1 mitosis per 50 high-power fields for benign criteria).
─ ─ Tumor necrosis is absent. Vascular invasion is absent. Infiltrative growth is absent.
─ ─ Stroma is usually scant, delicate, and highly vascular.
Ancillary studies ─
─ IHC is characteristic and crucial for diagnosis:
─ ─ Co-expression of melanocytic markers:
─ ─ ─ HMB-45 (human melanoma black 45): Often strong and diffuse cytoplasmic positivity.
─ ─ ─ Melan-A / MART-1: Can be positive, often more focal or weaker than HMB-45.
─ ─ Co-expression of smooth muscle markers:
─ ─ ─ Smooth Muscle Actin (SMA): Often positive, can be diffuse or patchy.
─ ─ ─ Desmin: Expression is more variable, can be negative or focally positive.
─ ─ ─ Caldesmon: Can be positive.
─ ─ Cathepsin K: Often positive.
─ ─ TFE3 (nuclear staining): Can be positive in a subset of PEComas (associated with TFE3 gene fusions, more common in malignant PEComas but can be seen in benign).
─ ─ PAS stain (with diastase digestion): Highlights glycogen in the clear cytoplasm of "sugar tumor" cells (PAS-positive, diastase-sensitive).
─ ─ TTF-1, S100 protein, cytokeratins are typically negative.
DDx ─
─ Metastatic Clear Cell Renal Cell Carcinoma: A critical differential. ccRCC is positive for PAX8, CD10, and often CAIX; negative for HMB-45 and smooth muscle markers. TTF-1 negative.
─ Metastatic Malignant Melanoma (especially clear cell or epithelioid variants): Positive for S100 protein, SOX10, HMB-45, Melan-A; lacks smooth muscle marker expression.
─ Other primary lung clear cell tumors:
─ ─ Clear Cell Adenocarcinoma of lung: TTF-1 positive, HMB-45 negative.
─ Granular Cell Tumor: S100 positive, CD68 positive, distinct coarse granules (lysosomal); HMB-45 negative.
─ Oncocytic tumors (e.g., oncocytic carcinoid): Abundant granular eosinophilic cytoplasm due to mitochondria; neuroendocrine markers positive (for carcinoid); HMB-45 negative.
─ Malignant PEComa: Distinguished by features such as large size (>5 cm), infiltrative growth, high nuclear grade/pleomorphism, increased cellularity, high mitotic rate (>1/50 HPF), tumor necrosis, and vascular invasion.
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Solitary Fibrous Tumor (SFT)

A mesenchymal neoplasm of putative fibroblastic/myofibroblastic origin, characterized by a "patternless pattern" of spindle cells admixed with prominent, branching "staghorn" or hemangiopericytoma-like vasculature, and variable amounts of intervening collagen; most SFTs arise from the pleura (visceral or parietal), but they can also occur in intrapulmonary sites or virtually any other soft tissue or visceral location. Behavior ranges from benign to malignant.
Clinical ─
─ Pleural SFTs: Often present as asymptomatic, well-demarcated masses discovered incidentally on chest imaging. If large, can cause symptoms like cough, dyspnea, or chest pain. Paraneoplastic hypoglycemia (Doege-Potter syndrome, due to IGF2 production by the tumor) can occur with very large SFTs.
─ Intrapulmonary SFTs: Usually asymptomatic peripheral nodules.
─ Most SFTs are benign (~80-90%), but a subset (~10-20%) can behave aggressively, with local recurrence or distant metastasis (malignant SFT).
─ Occur in adults, typically middle-aged to older, with no clear sex predilection.
Macro ─
─ Usually well-circumscribed, firm, often lobulated, grayish-white or tan solid masses.
─ Can be pedunculated (especially pleural SFTs attached by a stalk) or sessile.
─ Size is highly variable, from small nodules to very large masses.
─ Cut surface may be fibrous, whorled, or somewhat gelatinous; areas of hemorrhage, necrosis, or cystic change may be seen, particularly in larger or malignant tumors.
Micro ─
─ Spindle cells: Relatively uniform, bland to moderately atypical, ovoid to spindle-shaped cells with scant, pale eosinophilic cytoplasm and indistinct cell borders. Nuclei are typically oval or fusiform with fine chromatin and inconspicuous nucleoli.
─ "Patternless pattern" (Storiform-like but less organized): Cells are arranged somewhat haphazardly, or in short, ill-defined fascicles, or storiform (cartwheel) patterns, often interspersed with dense, hyalinized collagenous stroma ("ropy collagen") or more myxoid areas.
─ Hemangiopericytoma-like vasculature: A characteristic feature is the presence of numerous, prominent, branching, thin-walled, "staghorn" or dilated, cavernous blood vessels.
─ Cellularity is variable: Can range from hypocellular and densely collagenous (fibrous SFT) to highly cellular (cellular SFT).
─ Mitotic activity: Generally low in benign SFTs (<4 mitoses per 10 high-power fields). Higher mitotic rates are a feature of malignant SFT.
─ Features suggesting malignant SFT (risk stratification is complex, often using a multi-parameter model):
─ ─ High mitotic rate (typically defined as ≥4 mitoses per 10 HPF)
─ ─ Increased cellularity and nuclear pleomorphism
─ ─ Tumor necrosis (especially spontaneous, not biopsy-related)
─ ─ Infiltrative margins (if assessable)
─ ─ Large tumor size (e.g., >10-15 cm)
Ancillary studies ─
─ IHC is crucial for diagnosis:
─ ─ STAT6 (Signal transducer and activator of transcription 6): Strong, diffuse nuclear positivity is a highly sensitive and specific marker for SFT, reflecting the underlying NAB2-STAT6 gene fusion. This is the most important diagnostic marker.
─ ─ CD34: Positive in most cases (membranous and/or cytoplasmic staining), but can be lost in some malignant SFTs or less cellular areas.
─ ─ BCL2: Often positive.
─ ─ CD99: Can be positive but is nonspecific.
─ ─ Cytokeratins, S100 protein, Smooth Muscle Actin (SMA), desmin are typically negative (helps distinguish SFT from other spindle cell tumors like sarcomatoid carcinoma, schwannoma, leiomyoma/sarcoma).
─ Molecular: The defining molecular alteration in SFT is a gene fusion involving NAB2 (NGFI-A binding protein 2) and STAT6, usually resulting from an intrachromosomal inversion on 12q13. Various fusion variants exist and may have prognostic implications.
DDx ─
─ Other spindle cell tumors of the lung/pleura:
─ ─ Fibrosarcoma (rare, diagnosis of exclusion, STAT6 negative)
─ ─ Synovial Sarcoma (can be biphasic or monophasic spindle cell; TLE1 positive, often focal cytokeratin positivity, characteristic SS18-SSX gene fusion, STAT6 negative)
─ ─ Leiomyoma or Leiomyosarcoma (positive for smooth muscle markers like SMA, desmin, caldesmon; STAT6 negative)
─ ─ Schwannoma or Malignant Peripheral Nerve Sheath Tumor (MPNST) (S100 protein and SOX10 positive; STAT6 negative)
─ ─ Sarcomatoid Carcinoma (spindle cell carcinoma component will be positive for cytokeratins, often p40/p63; STAT6 negative)
─ ─ Malignant Mesothelioma, sarcomatoid type (positive for mesothelial markers like calretinin (focal) or D2-40; cytokeratins positive; STAT6 negative)
─ ─ Inflammatory Myofibroblastic Tumor (IMT) (prominent inflammatory infiltrate, ALK positivity in many cases; STAT6 negative)
─ Benign fibrous pleurisy/plaque (acellular or paucicellular dense collagen, lacks the characteristic SFT morphology and STAT6 positivity)
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Hemangioma (various types)

A benign vascular neoplasm characterized by a proliferation of blood vessels; primary pulmonary hemangiomas are rare and can encompass various histologic types, with capillary and cavernous hemangiomas being recognized, though some consider many of these as vascular malformations rather than true neoplasms, especially arteriovenous malformations (AVMs)
Clinical ─
─ Often asymptomatic and discovered incidentally as solitary or multiple well-circumscribed nodules on chest imaging
─ Can occur at any age, including children
─ May cause symptoms such as hemoptysis (if endobronchial or eroding into an airway), dyspnea, or chest pain, especially if large or complicated by thrombosis/hemorrhage
─ Multiple pulmonary AVMs can occur in the context of hereditary hemorrhagic telangiectasia (HHT, Osler-Weber-Rendu syndrome), leading to right-to-left shunting, hypoxemia, paradoxical emboli, and brain abscesses
─ Prognosis for typical benign hemangiomas is excellent; AVMs carry risks related to shunting and hemorrhage
Macro ─
─ Usually well-circumscribed, soft, spongy, reddish-blue or dark red nodules or masses
─ Size is variable, from small to several centimeters
─ Cut surface may reveal blood-filled spaces
Micro ─
─ Capillary Hemangioma (Juvenile Hemangioma if in infants):
─ ─ Lobular proliferation of closely packed, small, capillary-sized blood vessels lined by bland, plump or flattened endothelial cells.
─ ─ Vessels are separated by scant connective tissue stroma, which may contain pericytes.
─ ─ Lumens may be inconspicuous or contain red blood cells. Mitotic activity is low.
─ ─ May show an initial proliferative phase (more cellular) followed by an involutional phase (more fibrotic, less cellular).
─ Cavernous Hemangioma:
─ ─ Composed of large, dilated, thin-walled vascular channels filled with blood, resembling cavernous erectile tissue.
─ ─ Channels are lined by a single layer of flattened, bland endothelial cells.
─ ─ Separated by fibrous stroma of variable thickness; thrombosis and phlebolith formation can occur within the vascular spaces.
─ Arteriovenous Malformation (AVM): (Often considered a developmental malformation rather than a true neoplasm)
─ ─ Characterized by a complex tangle of abnormal, thick-walled arteries and dilated, thin-walled veins with direct communication, bypassing an intervening capillary bed.
─ ─ Vessels are often dysplastic, with irregular wall thickness, intimal fibrosis, medial hypertrophy or attenuation, and elastic lamina abnormalities.
─ Other rare types: Epithelioid Hemangioma (Histiocytoid Hemangioma) – characterized by plump, epithelioid endothelial cells often with intracytoplasmic vacuoles, associated with lymphocytes and eosinophils; very rare in lung.
Ancillary studies ─
─ IHC is used to confirm endothelial differentiation of lining cells:
─ ─ Positive for vascular endothelial markers: CD31 (most sensitive and specific), CD34 (also positive in SFT and some other mesenchymal cells), ERG (nuclear stain, highly specific for endothelial differentiation), Factor VIII-related antigen (von Willebrand factor).
─ ─ Smooth Muscle Actin (SMA) can highlight pericytes or smooth muscle cells in the walls of larger vessels within AVMs or cavernous hemangiomas.
DDx ─
─ Angiosarcoma: A malignant vascular neoplasm characterized by atypical endothelial cells, infiltrative growth, anastomosing vascular channels, increased mitotic activity, and necrosis. Distinction from highly cellular or epithelioid hemangioma can sometimes be challenging on small biopsies.
─ Lymphangioma: A benign proliferation of lymphatic channels; channels are typically lined by D2-40 (podoplanin) positive endothelial cells and contain proteinaceous lymph fluid, not blood.
─ Kaposi Sarcoma: Spindle cell proliferation forming slit-like vascular spaces, associated with extravasated red blood cells and hemosiderin; HHV-8 (Human Herpesvirus 8) positive by IHC.
─ Sclerosing Pneumocytoma (hemorrhagic/hemangioma-like pattern): Can mimic a vascular lesion due to blood-filled spaces, but it is biphasic with TTF-1 positive epithelial and stromal cells, and negative for endothelial markers in these components.
─ Bacillary Angiomatosis: A reactive vascular proliferation caused by Bartonella species (often in immunocompromised individuals); characterized by lobular capillary proliferation with plump endothelial cells and numerous neutrophils; organisms can be seen with Warthin-Starry stain or IHC.
─ Organizing pneumonia or granulation tissue with prominent neovascularization: Reactive process, lacks the well-formed architecture of a hemangioma and associated with inflammation and fibrin.
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Angiosarcoma

A malignant mesenchymal neoplasm composed of atypical endothelial cells that form irregular, anastomosing vascular channels, or grow in solid sheets in poorly differentiated cases; primary pulmonary angiosarcoma is extremely rare, and most cases encountered in the lung represent metastases from other sites (e.g., skin, soft tissue, breast, heart)
Clinical ─
─ Highly aggressive malignancy with a very poor prognosis, characterized by rapid growth, local infiltration, and early distant metastases
─ Symptoms of pulmonary involvement (primary or metastatic) may include dyspnea, hemoptysis, chest pain, cough, pleural effusion; can present with diffuse alveolar hemorrhage
─ Often multifocal or diffuse within the lungs if metastatic
─ Primary pulmonary angiosarcoma can arise from pulmonary artery or parenchyma; risk factors are poorly defined but may include prior radiation or foreign bodies (e.g., old chest tubes - extremely rare).
Macro ─
─ Typically presents as hemorrhagic, ill-defined, spongy or fleshy nodules or masses, which can be solitary, multiple, or diffuse
─ Cut surface is often dark red, purple, or brown, reflecting extensive hemorrhage; areas of necrosis may be present
─ May extensively infiltrate lung parenchyma or pleura
Micro ─
─ Characterized by a proliferation of atypical endothelial cells lining or forming vascular spaces, or growing in solid sheets in poorly differentiated tumors.
─ Architectural patterns can vary widely, even within the same tumor:
─ ─ Well-differentiated areas: Show recognizable, irregular, anastomosing vascular channels lined by plump, atypical endothelial cells that may pile up, form small papillae, or show "hobnail" morphology (cells with apical nuclei bulging into lumen).
─ ─ Poorly differentiated areas: May consist of solid sheets of pleomorphic epithelioid or spindle cells with less obvious vascular channel formation. In these cases, IHC is essential to confirm endothelial differentiation.
─ Cytologic atypia: Endothelial cells show malignant features, including nuclear enlargement, hyperchromasia, pleomorphism, and often prominent nucleoli.
─ Mitotic activity is usually present and can be high; atypical mitoses may be seen.
─ Vascular channels often dissect through and infiltrate the surrounding stroma and lung parenchyma.
─ Extravasated red blood cells, hemosiderin deposition, and tumor necrosis are common findings.
Ancillary studies ─
─ IHC is essential for diagnosis, especially in poorly differentiated forms:
─ ─ Positive for vascular endothelial markers:
─ ─ ─ CD31 (PECAM-1): Generally considered the most sensitive and specific marker.
─ ─ ─ ERG (nuclear stain): Highly specific for endothelial differentiation (also positive in prostatic adenocarcinoma and some Ewing sarcomas, so use in panel).
─ ─ ─ CD34: Often positive but less specific than CD31 or ERG (can be positive in SFT, some other mesenchymal tumors, and hematopoietic precursors).
─ ─ ─ Factor VIII-related antigen (von Willebrand factor): Specific but less sensitive than CD31.
─ ─ ─ Fli-1 (Friend leukemia integration 1 site): Can also be positive but also stains lymphocytes.
─ ─ Cytokeratins (AE1/AE3, CAM5.2) are usually negative, which helps distinguish angiosarcoma from carcinomas with pseudoangiosarcomatous patterns or epithelioid carcinomas.
─ ─ S100 protein, HMB-45/Melan-A are negative (to exclude melanoma).
DDx ─
─ Benign Hemangioma (capillary or cavernous): Composed of bland endothelial cells lining well-formed vascular channels, without significant atypia, high mitotic activity, infiltrative growth, or necrosis.
─ Epithelioid Hemangioendothelioma (EHE): An intermediate-grade vascular neoplasm often characterized by epithelioid endothelial cells embedded in a distinctive hyaline or myxochondroid stroma; cells often have intracytoplasmic vacuoles (lumina). Specific translocations (WWTR1-CAMTA1 or YAP1-TFE3) are characteristic.
─ Kaposi Sarcoma: Spindle cell proliferation forming slit-like vascular spaces, associated with extravasated red blood cells ("promontory sign"), and positive for HHV-8 (Human Herpesvirus 8) by IHC.
─ Other sarcomas with prominent vascularity (e.g., some leiomyosarcomas or MPNSTs): These will be negative for definitive endothelial markers and positive for their respective lineage markers.
─ Metastatic Carcinoma with pseudoangiosarcomatous features or prominent vascularity: Will be positive for cytokeratins and potentially site-specific carcinoma markers (e.g., TTF-1, Napsin A for lung adeno; GATA3 for breast). Endothelial markers will highlight benign background vessels, not the tumor cells.
─ Malignant Melanoma (especially epithelioid or spindle cell variants): Can mimic poorly differentiated angiosarcoma; positive for S100 protein, SOX10, HMB-45/Melan-A.
─ Organizing pneumonia or diffuse alveolar damage (DAD) with prominent granulation tissue and capillary proliferation: These are reactive processes and lack the malignant cytologic atypia of endothelial cells seen in angiosarcoma.
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Leiomyosarcoma

A malignant mesenchymal neoplasm that exhibits smooth muscle differentiation; primary pulmonary leiomyosarcomas are rare and are thought to arise from the smooth muscle of bronchi, pulmonary blood vessels (arteries or veins), or interstitial smooth muscle. Metastatic leiomyosarcoma (e.g., from uterus, retroperitoneum, gastrointestinal tract, or soft tissues) is encountered more frequently in the lung than primary tumors.
Clinical ─
─ Occurs over a wide age range but is more common in adults; some studies suggest a slight female predominance for primary pulmonary leiomyosarcomas.
─ Symptoms depend on location and size: endobronchial tumors can cause cough, dyspnea, hemoptysis, or post-obstructive pneumonia; intraparenchymal tumors may be asymptomatic or cause chest pain or dyspnea if large.
─ These are aggressive tumors with a significant potential for local recurrence and distant metastasis (commonly to other parts of the lung, pleura, liver, bone). Prognosis is generally poor, particularly for high-grade tumors.
Macro ─
─ Often presents as a relatively well-circumscribed or sometimes infiltrative, firm, grayish-white, tan, or pinkish fleshy mass.
─ Cut surface typically has a whorled, trabecular, or fascicular appearance, characteristic of smooth muscle tumors.
─ Areas of hemorrhage, necrosis, or cystic degeneration may be present, especially in larger or higher-grade tumors.
─ Endobronchial lesions can be polypoid. Tumors arising from large pulmonary arteries can fill and expand the vessel lumen.
Micro ─
─ Composed of interlacing fascicles or whorls of spindle-shaped cells with eosinophilic, fibrillar cytoplasm and elongated, blunt-ended or "cigar-shaped" nuclei with fine to moderately coarse chromatin.
─ Diagnosis of malignancy (leiomyosarcoma vs. benign leiomyoma) is based on the presence of unequivocal malignant features, typically a combination of:
─ ─ Significant cytologic atypia: Nuclear pleomorphism, hyperchromasia, irregular nuclear contours, and often prominent nucleoli.
─ ─ High mitotic activity: Specific mitotic count thresholds vary by site (e.g., for uterine leiomyosarcomas), but for pulmonary leiomyosarcomas, often >5-10 mitoses per 10 high-power fields (HPF) is considered malignant, especially if accompanied by atypia or necrosis. Presence of atypical mitoses is a strong indicator of malignancy.
─ ─ Coagulative tumor cell necrosis: Necrosis not attributable to ischemia or ulceration.
─ Epithelioid or pleomorphic variants of leiomyosarcoma can occur but are less common.
Ancillary studies ─
─ IHC is essential for confirming smooth muscle differentiation and excluding other spindle cell malignancies:
─ ─ Positive for smooth muscle markers:
─ ─ ─ Smooth Muscle Actin (SMA): Usually diffuse and strong cytoplasmic staining.
─ ─ ─ Desmin: Often diffuse and strong cytoplasmic staining.
─ ─ ─ Caldesmon (h-caldesmon): A more specific marker of smooth muscle differentiation; usually positive.
─ ─ Muscle Specific Actin (MSA) may also be positive.
─ ─ Negative for S100 protein, SOX10 (to exclude neural tumors), CD34, STAT6 (to exclude SFT), cytokeratins (AE1/AE3, CAM5.2) (to exclude sarcomatoid carcinoma), TTF-1, and definitive neuroendocrine markers.
─ ─ Estrogen Receptor (ER) and Progesterone Receptor (PR) may be positive, particularly in tumors occurring in females or metastatic from uterine primary.
─ ─ Ki-67 proliferation index is typically elevated.
DDx ─
─ Leiomyoma (benign counterpart): Lacks significant cytologic atypia, has low mitotic activity (e.g., <2 mitoses/10 HPF or per specific criteria), and no tumor necrosis. Distinction can be challenging in borderline cases.
─ Benign Metastasizing Leiomyoma (from uterus): Multiple lung nodules in women with a history of uterine leiomyomas; these nodules are histologically benign-appearing smooth muscle tumors.
─ Other primary or metastatic spindle cell sarcomas:
─ ─ Fibrosarcoma: Herringbone pattern, negative for smooth muscle markers.
─ ─ Synovial Sarcoma: Can be monophasic spindle cell; TLE1 positive, often focal cytokeratin positivity, characteristic SS18-SSX fusion.
─ ─ Malignant Peripheral Nerve Sheath Tumor (MPNST): Associated with nerves or neurofibromatosis, S100/SOX10 often focally positive, loss of H3K27me3.
─ Sarcomatoid Carcinoma (Spindle Cell Carcinoma): Positive for cytokeratins and often p40/p63 if squamous lineage.
─ Solitary Fibrous Tumor (SFT): "Patternless pattern," staghorn vasculature, positive for CD34, STAT6 (nuclear).
─ Inflammatory Myofibroblastic Tumor (IMT): Prominent inflammatory infiltrate (plasma cells, lymphocytes), often ALK-positive by IHC. SMA can be positive but desmin usually weaker/focal.
─ Metastatic Leiomyosarcoma from an extrapulmonary primary (e.g., uterus, retroperitoneum, GI tract, soft tissues): Clinical history of a primary tumor elsewhere is crucial; histologically identical to primary pulmonary leiomyosarcoma.
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Synovial Sarcoma (Monophasic, Biphasic)

A malignant mesenchymal neoplasm of uncertain histogenesis (despite its name, it does not arise from synovium and is not related to synovial differentiation) characterized by specific chromosomal translocations involving the SS18 gene on chromosome 18 and one of the SSX genes (SSX1, SSX2, or rarely SSX4) on chromosome X. Primary pulmonary synovial sarcoma is rare but represents one of the more common primary lung sarcomas.
Clinical ─
─ Typically affects adolescents and young adults (peak incidence 15-40 years), but can occur at any age.
─ No clear sex predilection.
─ Symptoms are often nonspecific: chest pain, cough, dyspnea, hemoptysis; may be an incidental finding.
─ Aggressive tumor with a high rate of local recurrence and distant metastasis (commonly to lungs, bone, lymph nodes). Prognosis is generally poor, though can be variable.
Macro ─
─ Usually presents as a well-circumscribed or partially infiltrative solitary mass, which can be intraparenchymal, endobronchial, pleural, or mediastinal.
─ Size is variable, can be large.
─ Cut surface is typically grayish-white or tan, fleshy or firm, and may show areas of cystic change, necrosis, hemorrhage, or calcification (latter more common in biphasic type).
Micro ─
─ Two main histologic types (can coexist):
─ Monophasic Synovial Sarcoma (more common):
─ ─ Composed predominantly or exclusively of uniform, short spindle cells with scant, pale eosinophilic cytoplasm, ovoid to fusiform nuclei with fine chromatin, and inconspicuous nucleoli.
─ ─ Cells are arranged in dense, cellular, intersecting fascicles or sheets, often with a "herringbone" pattern in some areas.
─ ─ Mitotic activity is variable but usually present.
─ ─ A prominent hemangiopericytoma-like vascular pattern (branching, thin-walled vessels) is often seen. Mast cells are frequently present in the stroma.
─ ─ Stroma can be scant or focally myxoid or hyalinized.
─ Biphasic Synovial Sarcoma:
─ ─ Contains both a spindle cell (sarcomatous) component (as described above for monophasic type) and a distinct epithelial component.
─ ─ The epithelial component forms glands, nests, cords, or papillary structures lined by cuboidal to columnar epithelial cells with eosinophilic cytoplasm and round nuclei. These cells are malignant.
─ ─ The epithelial cells may show squamous metaplasia or clear cell change.
─ Poorly differentiated variants exist, characterized by sheets of round cells, high-grade spindle cells, or marked pleomorphism, which can make diagnosis challenging.
Ancillary studies ─
─ IHC:
─ ─ Both spindle cells and epithelial cells (in biphasic type) are often positive for cytokeratins (e.g., AE1/AE3, CAM5.2, CK7, CK19) and EMA, at least focally. This epithelial marker expression in a spindle cell tumor is a key diagnostic clue, especially for monophasic type.
─ ─ TLE1 (Transducin-Like Enhancer of split 1): Nuclear staining is a relatively sensitive marker for synovial sarcoma but is not entirely specific (can be seen in other spindle cell tumors like MPNST, SFT).
─ ─ BCL2: Often positive.
─ ─ CD99: Can be positive (membranous) but is nonspecific (also positive in Ewing sarcoma, some lymphomas, etc.).
─ ─ S100 protein, Smooth Muscle Actin (SMA), desmin are usually negative (helps exclude MPNST, leiomyosarcoma).
─ ─ CD34 is typically negative or only very focally positive (helps distinguish from SFT).
─ ─ Specific antibodies against SS18-SSX fusion proteins are being developed and may become diagnostically useful.
─ Molecular: Detection of the characteristic chromosomal translocation t(X;18)(p11.2;q11.2), resulting in SS18-SSX1, SS18-SSX2, or rarely SS18-SSX4 gene fusions, is considered the gold standard for diagnosis and is highly specific. This can be detected by FISH (break-apart or fusion probes for SS18 and/or SSX), RT-PCR, or NGS.
DDx ─
─ Other primary or metastatic spindle cell sarcomas:
─ ─ Fibrosarcoma (diagnosis of exclusion, lacks specific markers or fusions).
─ ─ Malignant Peripheral Nerve Sheath Tumor (MPNST) (often associated with NF1 or nerves, S100/SOX10 often focally positive, loss of H3K27me3).
─ ─ Leiomyosarcoma (positive for SMA, desmin, caldesmon).
─ Sarcomatoid Carcinoma (Spindle Cell Carcinoma): Usually more pleomorphic, cytokeratin expression often more diffuse and stronger, lacks SS18-SSX fusion.
─ Solitary Fibrous Tumor (SFT): STAT6 nuclear positive, CD34 positive, lacks SS18-SSX fusion.
─ Malignant Mesothelioma, sarcomatoid type (if pleural-based): Positive for mesothelial markers (e.g., calretinin, WT1 in epithelioid component if biphasic, D2-40), lacks SS18-SSX fusion.
─ If biphasic: Adenosarcoma (rare), carcinosarcoma, biphasic mesothelioma.
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Malignant PEComa

The malignant counterpart of a benign Perivascular Epithelioid Cell Tumor (PEComa), characterized by a proliferation of perivascular epithelioid cells (PECs) that co-express melanocytic and smooth muscle markers and exhibit one or more features of malignancy, such as large size, infiltrative growth, high nuclear grade/pleomorphism, increased cellularity, high mitotic rate, tumor necrosis, and/or vascular invasion. Primary malignant PEComa of the lung is very rare.
Clinical ─
─ More aggressive clinical behavior than benign PEComa, with a significant potential for local recurrence and distant metastasis (commonly to lung, liver, bone, lymph nodes).
─ Can occur at any age but often in adults.
─ Symptoms are variable and depend on tumor size and location; may include cough, dyspnea, chest pain, hemoptysis, or be an incidental finding.
─ Association with Tuberous Sclerosis Complex (TSC) is less common for malignant PEComas compared to benign angiomyolipomas or LAM.
Macro ─
─ Often presents as larger, more infiltrative, and less well-circumscribed masses compared to benign PEComas.
─ Cut surface may be fleshy, gray-white or tan, and frequently shows areas of hemorrhage or necrosis.
Micro ─
─ Composed of perivascular epithelioid cells (PECs) similar to benign PEComa, but with malignant features. PECs are typically polygonal to epithelioid, with clear, eosinophilic, or granular cytoplasm, often arranged in sheets, nests, or around blood vessels. Spindle cell areas can also be present.
─ Criteria for malignancy in PEComas are still evolving and not universally agreed upon, but generally include a combination of features (e.g., based on Folpe et al. criteria for soft tissue PEComas, adapted for other sites). Presence of ≥2 of the following is often used, or specific combinations:
─ ─ Tumor size >5 cm (or site-specific thresholds, e.g., >8 cm for retroperitoneal)
─ ─ Infiltrative growth pattern into adjacent tissues
─ ─ High nuclear grade and marked cellular pleomorphism
─ ─ Increased cellularity
─ ─ High mitotic activity (e.g., >1 mitosis per 50 high-power fields or specific thresholds like >2 or >5 mitoses/10 HPF have been proposed) and/or presence of atypical mitoses
─ ─ Tumor necrosis (coagulative type)
─ ─ Vascular invasion
Ancillary studies ─
─ IHC is crucial for diagnosis and lineage confirmation, similar to benign PEComa:
─ ─ Co-expression of melanocytic markers: HMB-45 (often strong), Melan-A/MART-1.
─ ─ Co-expression of smooth muscle markers: Smooth Muscle Actin (SMA), desmin (variable), caldesmon.
─ ─ Cathepsin K is often positive.
─ ─ TFE3 nuclear expression (due to TFE3 gene fusions) is seen in a subset of PEComas, and may be more common in malignant or atypical variants, but can also occur in benign lesions.
─ ─ Ki-67 proliferation index is usually elevated compared to benign PEComa.
─ ─ PAS stain (with diastase) for glycogen if clear cell features are prominent.
─ ─ Negative for TTF-1, S100 protein (or only very focal), broad-spectrum cytokeratins (usually).
DDx ─
─ Benign PEComa / Clear Cell "Sugar" Tumor of the lung: Lacks the malignant features listed above (size, infiltration, atypia, mitoses, necrosis). This is the most important differential.
─ Metastatic Malignant Melanoma (especially epithelioid or clear cell variants): Strong S100 and SOX10 positivity, typically lacks consistent smooth muscle marker expression. Clinical history of melanoma is key.
─ Metastatic Clear Cell Renal Cell Carcinoma: Positive for PAX8, CD10, and often CAIX; negative for melanocytic and smooth muscle markers.
─ Other high-grade sarcomas with epithelioid or clear cell features (e.g., epithelioid sarcoma, clear cell sarcoma of soft tissue - latter EWSR1 rearranged and S100/SOX10+, Alveolar Soft Part Sarcoma - TFE3 rearranged but different morphology). IHC panel is critical.
─ Epithelioid Angiosarcoma: Positive for vascular markers (CD31, ERG); negative for melanocytic/smooth muscle markers.
─ Large Cell Carcinoma with clear or eosinophilic cytoplasm / Sarcomatoid Carcinoma: Positive for cytokeratins; negative for HMB-45 and usually smooth muscle markers.
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Dedifferentiated Liposarcoma

A malignant adipocytic neoplasm composed of two distinct components: a well-differentiated liposarcoma (WDLPS) component (characterized by atypical adipocytes and spindle cells, often with lipoblasts, and amplification of MDM2 and CDK4 genes) that is juxtaposed with or transitions into a non-lipogenic sarcoma component of variable histologic grade (this dedifferentiated component is typically high-grade, resembling undifferentiated pleomorphic sarcoma or fibrosarcoma). Primary pulmonary dedifferentiated liposarcoma is extremely rare; most cases in the lung represent metastases from a retroperitoneal or soft tissue primary.
Clinical ─
─ An aggressive sarcoma with a high risk of local recurrence and distant metastasis; prognosis is largely dictated by the dedifferentiated component.
─ Typically affects older adults (50s-70s).
─ If primary in lung (exceptional), symptoms would be nonspecific (cough, dyspnea, chest pain). Metastatic lesions are more common.
Macro ─
─ Often presents as a large, bulky, multilobulated mass.
─ Cut surface typically shows a heterogeneous appearance: yellowish, fatty areas corresponding to the WDLPS component, and firm, fleshy, grayish-white, non-fatty areas corresponding to the dedifferentiated component. Necrosis and hemorrhage are common in the dedifferentiated areas.
Micro ─
─ Two distinct components are required for diagnosis:
─ Well-differentiated liposarcoma (WDLPS) component:
─ ─ Characterized by atypical adipocytes showing variation in size and shape, admixed with scattered atypical spindle cells within fibrous septa.
─ ─ Lipoblasts (immature fat cells with hyperchromatic, often scalloped or indented nuclei due to cytoplasmic lipid vacuoles) may be present but are not required for diagnosis if other features of WDLPS (atypical cells, MDM2/CDK4 amplification) are present.
─ ─ Subtypes of WDLPS include lipoma-like, sclerosing (prominent fibrous stroma), and inflammatory (prominent lymphoplasmacytic infiltrate).
─ Dedifferentiated component:
─ ─ An abrupt or gradual transition from the WDLPS component to a non-lipogenic sarcoma (i.e., a sarcoma that does not show adipocytic differentiation).
─ ─ This component is typically high-grade and most commonly resembles:
─ ─ ─ Undifferentiated Pleomorphic Sarcoma (UPS) (sheets or storiform pattern of highly pleomorphic spindle and polygonal cells).
─ ─ ─ Fibrosarcoma (herringbone pattern of spindle cells).
─ ─ ─ Myxofibrosarcoma-like areas can also be seen.
─ ─ Rarely, the dedifferentiated component can show heterologous differentiation (e.g., rhabdomyosarcomatous, osteosarcomatous, chondrosarcomatous elements) or be low-grade.
Ancillary studies ─
─ IHC:
─ ─ Well-differentiated liposarcoma component: Adipocytes are S100 protein positive. Spindle cells may be CD34 positive.
─ ─ Dedifferentiated component: Often less specific immunohistochemically; typically positive for vimentin. May show focal expression of other markers (e.g., SMA, desmin) depending on any minor lines of differentiation, but usually negative for S100 in the dedifferentiated areas.
─ ─ MDM2 and CDK4: Nuclear overexpression by IHC is characteristic of both the WDLPS and the dedifferentiated components and is a key diagnostic marker, reflecting underlying gene amplification. Strong, diffuse nuclear staining is supportive.
─ Molecular: Amplification of the 12q13-15 chromosomal region, which includes the MDM2 and CDK4 genes, is the hallmark genetic alteration of both WDLPS and dedifferentiated liposarcoma. This can be confirmed by FISH or NGS.
DDx ─
─ Other high-grade sarcomas (e.g., Undifferentiated Pleomorphic Sarcoma (UPS) not associated with WDLPS, fibrosarcoma, leiomyosarcoma, Malignant Peripheral Nerve Sheath Tumor - MPNST): These lack the WDLPS component and the characteristic MDM2/CDK4 amplification. IHC panel for specific sarcoma subtypes is needed.
─ Sarcomatoid Carcinoma: Will be positive for cytokeratins; negative for MDM2/CDK4 amplification usually.
─ Malignant Peripheral Nerve Sheath Tumor (MPNST): Can be pleomorphic; S100/SOX10 often focal/patchy, loss of H3K27me3 in some; lacks WDLPS and MDM2/CDK4 amplification.
─ Pleomorphic Lipoma: A benign adipocytic tumor that can show pleomorphic spindle cells and floret-like giant cells, but adipocytes are mature, lipoblasts are absent, and it lacks MDM2/CDK4 amplification; often CD34 positive. Usually in subcutaneous tissue of head/neck/shoulder.
─ Metastatic Dedifferentiated Liposarcoma from a retroperitoneal or other soft tissue primary: This is the most common scenario when encountered in the lung. Clinical history is crucial.
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Undifferentiated Pleomorphic Sarcoma (UPS) / Malignant Fibrous Histiocytoma (MFH)

A high-grade sarcoma composed of undifferentiated, pleomorphic spindle and/or polygonal cells arranged in sheets or a storiform pattern, which lacks any identifiable line of specific mesenchymal differentiation (e.g., lipogenic, myogenic, neurogenic, chondrogenic, osteogenic) by morphological or immunohistochemical analysis; "Malignant Fibrous Histiocytoma (MFH)" is an older, largely obsolete term for this entity, which is now classified as UPS. Primary pulmonary UPS is very rare; most cases represent metastases from soft tissue or other sites.
Clinical ─
─ An aggressive sarcoma with a high risk of local recurrence and distant metastasis, associated with a poor prognosis.
─ Typically affects older adults (peak incidence 50s-70s).
─ If primary in the lung (rare), symptoms may include chest pain, cough, dyspnea, or hemoptysis, often related to a large, rapidly growing mass.
Macro ─
─ Often presents as a large, fleshy, infiltrative mass, frequently with extensive areas of necrosis and hemorrhage.
─ Cut surface may be grayish-white, tan, or variegated.
Micro ─
─ Highly cellular, pleomorphic malignant mesenchymal tumor.
─ Tumor cells exhibit marked cytologic atypia:
─ ─ Bizarre spindle cells with large, hyperchromatic, irregular nuclei.
─ ─ Large, polygonal, epithelioid-like cells with abundant eosinophilic cytoplasm and pleomorphic nuclei.
─ ─ Multinucleated tumor giant cells are common.
─ Architectural patterns:
─ ─ Storiform (cartwheel) pattern: Spindle cells arranged in short, irregular fascicles radiating from a central point (less common as a dominant pattern in true UPS than historically thought for MFH).
─ ─ Fascicular or herringbone pattern (resembling fibrosarcoma).
─ ─ Sheet-like or haphazard growth of pleomorphic cells.
─ Mitotic activity is usually brisk, with numerous and often atypical mitotic figures.
─ Tumor necrosis is common and often extensive.
─ By definition, no specific line of mesenchymal differentiation is identifiable.
Ancillary studies ─
─ IHC is primarily a diagnosis of exclusion, used to rule out other specific types of sarcoma or poorly differentiated carcinoma/melanoma:
─ ─ Tumor cells are typically positive for vimentin.
─ ─ May show focal and nonspecific positivity for some markers like Smooth Muscle Actin (SMA) or CD68 (histiocytic marker, reflecting the "histiocytoma" part of the old MFH term, but not true histiocytic differentiation).
─ ─ Must be NEGATIVE for specific lineage markers:
─ ─ ─ Cytokeratins (AE1/AE3, CAM5.2) to exclude sarcomatoid carcinoma.
─ ─ ─ S100 protein, SOX10 to exclude malignant melanoma or Malignant Peripheral Nerve Sheath Tumor (MPNST).
─ ─ ─ Desmin, myogenin, MyoD1 to exclude rhabdomyosarcoma.
─ ─ ─ Desmin, SMA (diffuse), caldesmon to exclude leiomyosarcoma.
─ ─ ─ CD31, ERG to exclude angiosarcoma.
─ ─ ─ CD34, STAT6 to exclude Solitary Fibrous Tumor (SFT) or dermatofibrosarcoma protuberans.
─ ─ ─ HMB-45, Melan-A to exclude PEComa or melanoma.
─ ─ ─ MDM2, CDK4 to exclude dedifferentiated liposarcoma.
DDx ─
─ Sarcomatoid Carcinoma (Pleomorphic Carcinoma, Spindle Cell Carcinoma, Giant Cell Carcinoma): Must be excluded by negative or only very focally aberrant cytokeratin staining in UPS. Sarcomatoid carcinomas are cytokeratin positive.
─ Other specific types of high-grade sarcoma that can be pleomorphic (e.g., pleomorphic leiomyosarcoma, pleomorphic rhabdomyosarcoma, dedifferentiated liposarcoma, malignant peripheral nerve sheath tumor): These will show at least focal evidence of their specific line of differentiation by morphology or IHC (e.g., desmin+, MDM2+, S100+ respectively).
─ Metastatic Sarcoma or Carcinoma from another primary site: Clinical history is crucial.
─ Malignant Melanoma (especially desmoplastic or spindle cell variants): Positive for S100 protein, SOX10, and other melanoma markers.
─ Dedifferentiated Liposarcoma: Requires identification of a well-differentiated liposarcoma component and/or MDM2/CDK4 amplification.
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Rhabdomyosarcoma (RMS)

A malignant mesenchymal neoplasm that exhibits skeletal muscle differentiation, characterized by the presence of rhabdomyoblasts (cells with eosinophilic cytoplasm that may show cross-striations) and/or immunohistochemical evidence of myogenic differentiation. Primary pulmonary rhabdomyosarcoma is extremely rare; most cases encountered in the lung are metastatic, particularly from head/neck, genitourinary tract, or trunk/extremities in children and adolescents.
Clinical ─
─ Highly aggressive malignancy. Prognosis depends on subtype, stage, age, and location.
─ Primary pulmonary RMS is more common in children (often embryonal subtype, sometimes as a component of pleuropulmonary blastoma) than in adults (pleomorphic subtype is more typical in adults if primary).
─ Symptoms are nonspecific and depend on tumor location and size: cough, dyspnea, chest pain, hemoptysis.
Macro ─
─ Often presents as a fleshy, infiltrative, grayish-white or pinkish mass, frequently with areas of necrosis and hemorrhage.
─ Can be endobronchial, intraparenchymal, or involve the pleura or chest wall.
Micro ─
─ Histologic subtypes (WHO classification, primarily based on pediatric RMS but applicable):
─ Embryonal Rhabdomyosarcoma (most common type overall, especially in children):
─ ─ Composed of primitive-appearing small round blue cells, spindle cells, and scattered rhabdomyoblasts in varying stages of differentiation.
─ ─ Rhabdomyoblasts are the diagnostic cells: may be round, elongated ("strap" or "tadpole" cells) with eosinophilic cytoplasm; cross-striations are pathognomonic but rarely seen and not required for diagnosis if IHC is confirmatory. Nuclei are often eccentric.
─ ─ Stroma is typically loose and myxoid.
─ ─ Botryoid variant: Forms grape-like clusters beneath a mucosal surface (e.g., endobronchial).
─ Alveolar Rhabdomyosarcoma:
─ ─ Less common as a primary lung tumor. Characterized by nests or aggregates of primitive round cells separated by dense fibrous septa, resembling pulmonary alveoli. Tumor cells often show poor cohesion.
─ ─ Characteristic chromosomal translocations involving FOXO1 gene (e.g., t(2;13) producing PAX3-FOXO1 fusion, or t(1;13) producing PAX7-FOXO1 fusion) are present in most cases.
─ Pleomorphic Rhabdomyosarcoma:
─ ─ The most common type if primary RMS occurs in adults. A high-grade sarcoma composed of bizarre, pleomorphic spindle cells and large, multinucleated tumor giant cells, including large, atypical rhabdomyoblasts with abundant eosinophilic cytoplasm. Lacks the typical features of embryonal or alveolar RMS. Can be difficult to distinguish from other pleomorphic sarcomas without IHC.
─ Spindle Cell/Sclerosing Rhabdomyosarcoma: Rare variants.
Ancillary studies ─
─ IHC is essential for diagnosis, especially to confirm skeletal muscle differentiation:
─ ─ Positive for myogenic regulatory proteins (nuclear staining, highly specific): Myogenin (Myf4) and MyoD1.
─ ─ Positive for other muscle markers (cytoplasmic staining): Desmin (usually strong and diffuse), Muscle-Specific Actin (MSA, also known as HHF35).
─ ─ Vimentin is also usually positive.
─ ─ Cytokeratins are typically negative (helps distinguish from sarcomatoid carcinoma with rhabdoid features).
─ ─ S100 protein is negative.
─ Electron Microscopy (rarely needed): Can demonstrate sarcomeric structures (thick and thin filaments, Z-bands) in rhabdomyoblasts.
─ Molecular: Detection of FOXO1 gene fusions is characteristic of alveolar RMS.
DDx ─
─ Other small round blue cell tumors (for embryonal RMS): Lymphoma (CD45+, lymphoid markers), Ewing sarcoma/PNET (CD99+, FLI1+, EWSR1 fusion), Small Cell Lung Carcinoma (neuroendocrine markers+, TTF-1+), neuroblastoma (neuroendocrine markers, Homer-Wright rosettes).
─ Other pleomorphic sarcomas (for pleomorphic RMS): Undifferentiated Pleomorphic Sarcoma (UPS), leiomyosarcoma, malignant peripheral nerve sheath tumor. IHC for myogenic markers is key.
─ Sarcomatoid Carcinoma with rhabdoid features or giant cells: Will be positive for cytokeratins.
─ Malignant Rhabdoid Tumor: Different morphology, often INI1 (SMARCB1) loss by IHC, typically negative for definitive myogenic markers.
─ Granular Cell Tumor: S100 positive, CD68 positive, lacks myogenic markers.
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Hematolymphoid Tumors and Proliferations in the Lung

Reactive Lymphoid Hyperplasia (Nodular Lymphoid Hyperplasia, Follicular Bronchitis/Bronchiolitis)

Benign, reactive (non-neoplastic) proliferations of lymphoid tissue within the lung, which can form discrete nodules (Nodular Lymphoid Hyperplasia - NLH), be distributed along airways (Follicular Bronchitis/Bronchiolitis - FB), or present as diffuse interstitial infiltrates (covered under LIP if extensive and fitting that pattern)
Clinical ─
─ Often asymptomatic and discovered incidentally as solitary or multiple pulmonary nodules on chest imaging (for NLH), or as centrilobular nodules, tree-in-bud opacities, or bronchial wall thickening (for FB)
─ Can occur at any age, but NLH is more common in adults
─ May be associated with underlying conditions such as:
─ ─ Connective tissue diseases (especially rheumatoid arthritis, Sjögren syndrome)
─ ─ Immunodeficiency states (e.g., Common Variable Immunodeficiency - CVID, HIV infection)
─ ─ Recurrent infections or chronic inflammation
─ ─ Hypersensitivity reactions
─ ─ Can also be idiopathic (no identifiable underlying cause)
─ Generally has a benign course and good prognosis; not considered premalignant, though underlying immunodeficiency or autoimmune disease may carry its own risks
Macro ─
─ Nodular Lymphoid Hyperplasia (NLH): Typically presents as one or more well-circumscribed, firm, grayish-white or tan, fleshy nodules, ranging from a few millimeters to several centimeters in diameter.
─ Follicular Bronchitis/Bronchiolitis (FB): Usually not grossly distinct; airways may appear subtly thickened if involvement is extensive.
Micro ─
─ Nodular Lymphoid Hyperplasia (NLH):
─ ─ Well-demarcated, non-encapsulated nodules of mature-appearing lymphoid tissue.
─ ─ Composed of reactive lymphoid follicles, which often have prominent, well-formed germinal centers (displaying a "starry sky" pattern with tingible body macrophages, polarization of light and dark zones, and a normal follicular dendritic cell meshwork).
─ ─ Interfollicular areas consist of a mixed population of small mature lymphocytes (B and T cells), plasma cells (polyclonal), histiocytes, and sometimes scattered immunoblasts or eosinophils.
─ ─ No significant cytologic atypia of lymphocytes. No destructive infiltrates into adjacent structures (though can compress). No lymphoepithelial lesions (as seen in MALT lymphoma).
─ Follicular Bronchitis/Bronchiolitis (FB):
─ ─ Similar reactive lymphoid follicles with germinal centers, but these are characteristically distributed along and expand the walls of bronchi (bronchitis) and bronchioles (bronchiolitis).
─ ─ The lymphoid proliferation may cause narrowing of airway lumens.
─ ─ The interstitial inflammation may extend focally into adjacent alveolar septa.
Ancillary studies ─
─ IHC is crucial to confirm the reactive and polyclonal nature of the lymphoid infiltrate and to exclude lymphoma:
─ ─ Germinal centers: CD20+ B-cells, CD3+ T-cells (scattered), CD10+ and BCL6+ (germinal center B-cells), CD21+ or CD23+ highlighting follicular dendritic cell (FDC) meshworks. BCL2 protein is typically negative or weak in germinal center B-cells (positive in mantle zone B-cells and interfollicular T-cells). Ki-67 shows high proliferation within germinal centers.
─ ─ Interfollicular areas: Mixed population of CD20+ B-cells and CD3+ T-cells. Plasma cells are polyclonal (polytypic kappa and lambda light chain expression).
─ Flow cytometry (if fresh tissue available) can also confirm polyclonality.
─ Molecular studies (Ig gene rearrangement for B-cells, TCR gene rearrangement for T-cells) are typically negative for clonality (i.e., polyclonal).
DDx ─
─ Low-grade B-cell Lymphoma of MALT type (MALT Lymphoma): This is the most important differential. MALT lymphoma is a clonal B-cell neoplasm, often characterized by a denser, more monotonous infiltrate of small lymphoid cells (centrocyte-like cells, monocytoid B-cells, plasma cells), formation of lymphoepithelial lesions (infiltration and destruction of glandular/bronchial epithelium by neoplastic lymphocytes), and often lacks well-formed reactive germinal centers (or shows follicular colonization by neoplastic cells). MALT lymphoma will show B-cell monoclonality by IHC (light chain restriction) or molecular studies.
─ Lymphocytic Interstitial Pneumonia (LIP): Characterized by a more diffuse and extensive interstitial infiltrate of lymphocytes and plasma cells, which can include lymphoid follicles, but the overall pattern is more diffuse interstitial rather than nodular (NLH) or purely airway-centered (FB).
─ Metastatic lymphoma or leukemia to the lung: Clinical history of systemic lymphoma/leukemia; infiltrate is typically monoclonal and may show higher-grade features.
─ Inflammatory Myofibroblastic Tumor (IMT): A spindle cell proliferation with a prominent inflammatory infiltrate (plasma cells, lymphocytes, eosinophils); the spindle cell component and ALK positivity (in many cases) distinguish it from reactive lymphoid hyperplasia.
─ Granulomatous infections with lymphoid reaction (e.g., TB, fungal): Granulomas would be present; special stains for organisms positive.
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Lymphocytic Interstitial Pneumonia (LIP) - (Hematolymphoid context)

A rare form of interstitial lung disease characterized by diffuse infiltration of the pulmonary interstitium by mature lymphocytes, plasma cells, and other lymphoreticular cells, often with the formation of lymphoid follicles; while an idiopathic form is classified as an Idiopathic Interstitial Pneumonia, LIP frequently occurs in association with systemic autoimmune diseases (especially Sjögren syndrome, SLE), immunodeficiency states (e.g., HIV infection, Common Variable Immunodeficiency - CVID), or other conditions, highlighting its nature as a lymphoproliferative process.
Clinical ─
─ Insidious onset of progressive dyspnea on exertion and chronic non-productive cough, typically over months to years. Systemic symptoms like fever, weight loss, arthralgias may be present, especially if associated with an underlying systemic disease.
─ Pulmonary function tests usually show a restrictive pattern with impaired gas exchange.
─ High-resolution CT (HRCT) chest findings include bilateral, diffuse ground-glass opacities, reticulation, centrilobular nodules, peribronchovascular thickening, and often thin-walled cysts (which can be numerous and variable in size).
─ Associations:
─ ─ Autoimmune diseases: Most commonly Sjögren syndrome; also SLE, rheumatoid arthritis, myasthenia gravis, autoimmune thyroiditis, pernicious anemia.
─ ─ Immunodeficiency states: HIV infection (particularly in children, less common in adults on ART), CVID, agammaglobulinemia.
─ ─ Other: Can be associated with viral infections (e.g., EBV, HTLV-1), drug reactions, or be idiopathic (a diagnosis of exclusion).
─ There is an increased risk of progression to lymphoma (typically B-cell lymphoma, e.g., MALT lymphoma or DLBCL) in some patients with LIP, particularly those with Sjögren syndrome or long-standing immunodeficiency.
Macro ─
─ Lungs may appear diffusely firm, rubbery, or show a reticulonodular pattern on cut section. Cystic changes may be grossly apparent.
Micro ─
─ Diffuse, dense, or sometimes patchy interstitial infiltrates composed predominantly of small, mature-appearing lymphocytes (a mixture of T-cells and B-cells).
─ Significant numbers of plasma cells (polyclonal) are typically admixed within the infiltrate.
─ Other lymphoreticular cells may also be present, including macrophages, histiocytes, and occasional immunoblasts or eosinophils.
─ Lymphoid follicles, often with reactive germinal centers, are frequently seen along bronchovascular bundles, in interlobular septa, or within the expanded alveolar interstitium.
─ The interstitial infiltrates cause diffuse thickening of alveolar septa. Type II pneumocyte hyperplasia is common.
─ Interstitial fibrosis can develop in later stages, sometimes leading to architectural distortion and honeycombing, but is usually not the dominant feature in early or cellular LIP.
─ Cystic changes (dilated airspaces, thin-walled cysts) are common, particularly in advanced disease.
─ The infiltrate is generally non-destructive of overall lung architecture initially, but can be extensive and effacing.
─ Should lack significant cytologic atypia or features overtly diagnostic of lymphoma (e.g., sheets of atypical large cells, destructive infiltrates clearly effacing normal structures, unequivocal lymphoepithelial lesions of MALT lymphoma).
Ancillary studies ─
─ IHC:
─ ─ Demonstrates a mixed infiltrate of CD3+ T-lymphocytes and CD20+ B-lymphocytes.
─ ─ Plasma cells are polyclonal, showing a mixture of kappa and lambda light chain expression.
─ ─ Germinal centers show appropriate staining (CD20+, CD10+, BCL6+, Ki-67 high, BCL2-).
─ Flow cytometry (on BAL fluid or fresh tissue, if available): Can help confirm polyclonality of the lymphocyte population.
─ Molecular studies: Immunoglobulin (Ig) heavy and light chain gene rearrangements (for B-cell clonality) and T-cell receptor (TCR) gene rearrangements (for T-cell clonality) are typically negative for a dominant clonal population (i.e., polyclonal) in LIP. Detection of a clone would raise concern for lymphoma.
─ Special stains for microorganisms (GMS, AFB, Gram, viral IHC/ISH) are important to exclude an infectious cause for the lymphocytic infiltrates.
─ Serological tests for autoimmune diseases (e.g., ANA, anti-SSA/SSB for Sjögren's) and HIV testing are crucial given the strong associations.
DDx ─
─ Nonspecific Interstitial Pneumonia (NSIP), cellular variant: Also characterized by lymphocytic interstitial inflammation and preserved architecture. However, the infiltrate in LIP is typically denser, more polymorphous (with prominent plasma cells and often well-formed lymphoid follicles), and may be more destructive over time. Clinical associations also differ.
─ Hypersensitivity Pneumonitis (HP): Characterized by lymphocytic interstitial infiltrates, often airway-centered, and frequently associated with poorly formed granulomas or scattered multinucleated giant cells, which are not typical features of LIP. Exposure history is key for HP.
─ Low-grade B-cell Lymphoma of MALT type (MALT Lymphoma): This is a critical differential, as MALT lymphoma can arise in a background of LIP or mimic it. MALT lymphoma is a clonal B-cell neoplasm, often showing sheets of monotonous small lymphoid cells (centrocyte-like, monocytoid B-cells), characteristic lymphoepithelial lesions (infiltration of glandular/bronchial epithelium by neoplastic lymphocytes), and will demonstrate B-cell monoclonality by IHC (light chain restriction) or molecular studies.
─ Follicular Bronchiolitis/Bronchitis: Characterized by lymphoid follicles with germinal centers that are primarily restricted to the peribronchial and peribronchiolar tissue, without the significant diffuse interstitial extension seen in LIP.
─ Viral pneumonia (especially EBV or CMV): Can cause lymphocytic interstitial infiltrates, but often more acute, may show specific viral cytopathic effects, and viral markers would be positive.
─ Other lymphoproliferative disorders involving the lung (e.g., diffuse large B-cell lymphoma, T-cell lymphomas – these show overt malignant cytology and immunophenotype).
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MALT Lymphoma (Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue)

A low-grade B-cell lymphoma arising from mucosa-associated lymphoid tissue (MALT), characterized by a proliferation of neoplastic small B-cells (centrocyte-like cells, monocytoid B-cells, small lymphocytes, and plasma cells) that typically infiltrate reactive lymphoid follicles (follicular colonization) and form characteristic lymphoepithelial lesions; primary pulmonary MALT lymphoma is the most common type of primary lymphoma of the lung
Clinical ─
─ Often presents as an indolent, slow-growing tumor; may be asymptomatic and discovered incidentally on chest imaging, or cause nonspecific symptoms like chronic cough, dyspnea, or chest discomfort
─ Can occur over a wide age range, but more common in middle-aged to older adults
─ May be associated with underlying conditions causing chronic inflammation or immune stimulation, such as autoimmune diseases (e.g., Sjögren syndrome, rheumatoid arthritis), chronic infections, or smoking
─ Prognosis is generally good, with long survival; transformation to high-grade lymphoma (e.g., DLBCL) can occur but is uncommon
Macro ─
─ Can present as solitary or multiple nodules, areas of consolidation, or diffuse interstitial infiltrates
─ Lesions are typically grayish-white, tan, or fleshy on cut section
─ Endobronchial involvement can occur, sometimes appearing as a polypoid mass
Micro ─
─ Diffuse or nodular infiltrate of small, atypical B-lymphocytes that efface normal lung architecture to a variable extent
─ Neoplastic cells are heterogeneous and may include:
─ ─ Centrocyte-like cells: Small to medium-sized cells with irregular, cleaved, or indented nuclei, condensed chromatin, and scant pale cytoplasm (most common cell type)
─ ─ Monocytoid B-cells: Medium-sized cells with more abundant pale cytoplasm and distinct cell borders, often found in sheets or clusters
─ ─ Small lymphocytes resembling mature B-cells
─ ─ Plasmacytic differentiation: Variable numbers of mature-appearing plasma cells, which are part of the neoplastic clone (show light chain restriction)
─ Follicular colonization: Infiltration and expansion of reactive lymphoid follicles (germinal centers) by the neoplastic B-cells is a characteristic feature; neoplastic cells may surround or replace normal germinal center cells
─ Lymphoepithelial lesions: Infiltration and destruction of bronchial, bronchiolar, or alveolar duct epithelium by clusters of neoplastic lymphocytes; this is a hallmark feature of MALT lymphoma
─ Reactive lymphoid follicles are often present within or adjacent to the neoplastic infiltrate
─ Dutcher bodies (intranuclear PAS-positive immunoglobulin inclusions) may be seen in neoplastic plasma cells
─ Mitotic activity is generally low; cytologic atypia is mild
Ancillary studies ─
─ IHC:
─ ─ Neoplastic B-cells: Positive for pan-B-cell markers CD20 and CD79a; PAX5 (nuclear) is also positive.
─ ─ Typically negative or only weakly positive for CD5, CD10, CD23, and Cyclin D1 (helps distinguish from other small B-cell lymphomas like CLL/SLL, follicular lymphoma, mantle cell lymphoma).
─ ─ BCL2 protein is often expressed by the neoplastic cells, including those colonizing follicles (reactive germinal center B-cells are normally BCL2 negative).
─ ─ Plasma cell component will show light chain restriction (monoclonality for either kappa or lambda light chains), confirming their neoplastic nature.
─ ─ Cytokeratin (e.g., AE1/AE3, CAM5.2) immunohistochemistry can highlight the lymphoepithelial lesions by outlining the infiltrated epithelial structures.
─ ─ Ki-67 proliferation index is typically low.
─ Molecular:
─ ─ Clonality: Demonstration of monoclonal immunoglobulin gene rearrangements (e.g., IgH, IgK, IgL) by PCR is supportive of the diagnosis.
─ ─ Characteristic chromosomal translocations:
─ ─ ─ t(11;18)(q21;q21) resulting in the API2-MALT1 fusion gene (most common in gastric MALT lymphoma, less frequent in pulmonary MALT lymphoma; associated with resistance to H. pylori eradication therapy in gastric cases and may predict a more indolent course but also resistance to some chemotherapies).
─ ─ ─ Other translocations include t(1;14)(p22;q32) involving BCL10 and IGH, t(14;18)(q32;q21) involving MALT1 and IGH, and t(3;14)(p14.1;q32) involving FOXP1 and IGH.
DDx ─
─ Reactive Lymphoid Hyperplasia / Nodular Lymphoid Hyperplasia (NLH) / Follicular Bronchitis/Bronchiolitis: Composed of polyclonal lymphoid infiltrates with prominent, well-formed reactive germinal centers (BCL2 negative, high Ki-67 within GCs); lacks lymphoepithelial lesions and light chain restriction in plasma cells. This is a critical distinction.
─ Lymphocytic Interstitial Pneumonia (LIP): Characterized by a diffuse interstitial infiltrate of lymphocytes and plasma cells, often with lymphoid follicles; typically polyclonal and often associated with autoimmune diseases or immunodeficiency. Can be difficult to distinguish from MALT lymphoma, especially on small biopsies; clonality studies are key.
─ Other low-grade B-cell lymphomas that can involve the lung:
─ ─ Follicular Lymphoma: Composed of neoplastic follicles (CD10+, BCL6+, BCL2+); different morphology and immunophenotype.
─ ─ Small Lymphocytic Lymphoma (SLL) / Chronic Lymphocytic Leukemia (CLL): Monotonous infiltrate of small round lymphocytes; CD5+, CD23+.
─ ─ Mantle Cell Lymphoma: Monotonous small to medium-sized lymphocytes; CD5+, Cyclin D1+.
─ Diffuse Large B-cell Lymphoma (DLBCL): May arise from transformation of MALT lymphoma; composed of large atypical lymphoid cells with high proliferation rate.
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Diffuse Large B-cell Lymphoma (DLBCL), including intravascular large B-cell lymphoma

Diffuse Large B-cell Lymphoma (DLBCL) is a heterogeneous group of aggressive mature B-cell neoplasms characterized by a diffuse proliferation of large, atypical B-lymphoid cells that efface normal tissue architecture. Primary pulmonary DLBCL is rare. Intravascular Large B-cell Lymphoma (IVLBCL) is a rare subtype of extranodal DLBCL characterized by the selective growth of large neoplastic B-cells predominantly within the lumens of small blood vessels, often without forming obvious extravascular tumor masses.
Clinical ─
─ Primary Pulmonary DLBCL:
─ ─ Can occur at any age but more common in older adults.
─ ─ May present as a rapidly growing solitary or multiple lung masses or consolidations, causing symptoms like cough, dyspnea, chest pain, fever, weight loss.
─ ─ Aggressive but potentially curable with chemoimmunotherapy (e.g., R-CHOP).
─ Intravascular Large B-cell Lymphoma (IVLBCL):
─ ─ Typically affects middle-aged to older adults.
─ ─ Clinical presentation is highly variable and often perplexing ("the great mimicker") due to occlusion of small vessels in various organs. Common manifestations include fever of unknown origin, progressive neurologic deficits (CNS involvement is common), skin lesions (telangiectasias, nodules, ulcers), and less commonly, respiratory symptoms (dyspnea, hypoxemia, pulmonary hypertension) if lung involvement is significant.
─ ─ Often presents with B symptoms (fever, night sweats, weight loss) and elevated LDH or ESR.
─ ─ Diagnosis can be challenging due to lack of discrete tumor masses; random skin biopsies or biopsies of affected organs (including lung if involved) may be needed. Poor prognosis if untreated, but responds to DLBCL-type chemoimmunotherapy.
Macro ─
─ Primary Pulmonary DLBCL: Usually a solid, fleshy, grayish-white or tan tumor mass or area of consolidation, often with areas of necrosis.
─ Intravascular Large B-cell Lymphoma (IVLBCL): Lungs may appear grossly normal, congested, edematous, or show subtle interstitial thickening or petechial hemorrhages. Discrete tumor masses are characteristically absent.
Micro ─
─ Primary Pulmonary DLBCL:
─ ─ Diffuse growth pattern, effacing normal lung architecture.
─ ─ Composed of sheets or cohesive aggregates of large, atypical B-lymphoid cells.
─ ─ Cells typically have nuclei ≥2 times the size of a normal lymphocyte, or larger than a macrophage nucleus. Cytology is variable:
─ ─ ─ Centroblastic variant: Large cells with vesicular nuclei, distinct (often multiple) nucleoli, and moderate amounts of basophilic cytoplasm.
─ ─ ─ Immunoblastic variant: Large cells with prominent central eosinophilic nucleolus and more abundant basophilic cytoplasm.
─ ─ ─ Anaplastic variant: Very large, pleomorphic cells, may resemble Reed-Sternberg cells.
─ ─ High mitotic rate and apoptosis are common; tumor necrosis is frequently present.
─ Intravascular Large B-cell Lymphoma (IVLBCL):
─ ─ Large, atypical lymphoid cells (cytologically similar to DLBCL cells described above) are found predominantly or exclusively within the lumens of small blood vessels (alveolar capillaries, venules, arterioles).
─ ─ Minimal or no extravascular infiltration by tumor cells, especially in early stages or "classic" form.
─ ─ Vessels may be distended and occluded by the neoplastic cells, sometimes with associated fibrin thrombi.
─ ─ Secondary changes in the lung parenchyma can include interstitial edema, hemorrhage, diffuse alveolar damage (DAD), or organizing pneumonia due to vascular damage and ischemia.
Ancillary studies ─
─ IHC (for both Primary Pulmonary DLBCL and IVLBCL):
─ ─ Tumor cells are positive for pan-B-cell markers: CD20 (strong membranous), CD79a, PAX5 (nuclear).
─ ─ Often positive for BCL6, MUM1/IRF4. BCL2 expression is variable. CD10 expression is variable (used for Germinal Center B-cell like (GCB) vs. Non-GCB/Activated B-cell like (ABC) subtyping of DLBCL, which has prognostic and therapeutic implications, though subtyping is complex).
─ ─ Ki-67 proliferation index is characteristically high (often >40-50%, can be >90%).
─ ─ For IVLBCL: Endothelial markers (e.g., CD31, CD34, ERG) can be used to highlight the small blood vessels containing the intravascular tumor cells, making them easier to identify.
─ ─ Negative for T-cell markers (CD3), cytokeratins, S100, melanoma markers.
─ Molecular: Clonality studies (Ig gene rearrangements) confirm B-cell lineage and clonality. Chromosomal translocations (e.g., involving BCL2, BCL6, MYC) and gene mutations are common in DLBCL and can have prognostic significance.
DDx ─
─ For Primary Pulmonary DLBCL:
─ ─ Other high-grade lymphomas (e.g., Burkitt lymphoma, T-cell lymphomas – different morphology and immunophenotype).
─ ─ Poorly differentiated carcinoma (especially non-small cell lung carcinoma, large cell type, or sarcomatoid carcinoma): Positive for cytokeratins, negative for CD45 and B-cell markers.
─ ─ Malignant Melanoma: Positive for S100, SOX10, melanoma markers; negative for CD45 and B-cell markers.
─ ─ Transformed low-grade lymphoma (e.g., MALT lymphoma transforming to DLBCL).
─ For Intravascular Large B-cell Lymphoma (IVLBCL):
─ ─ Septic emboli or microthrombi within vessels: Contain bacteria/fungi or fibrin/platelets, not neoplastic lymphoid cells; associated with acute inflammation.
─ ─ Reactive intravascular histiocytosis or other benign intravascular cellular infiltrates (rare).
─ ─ Other conditions causing endothelial cell swelling or capillary congestion (e.g., DAD, severe infections, pulmonary edema).
─ ─ Diagnosis of IVLBCL often requires a high index of suspicion and careful examination of vessels, often aided by IHC for CD20 and endothelial markers.
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Lymphomatoid Granulomatosis (LYG)

An Epstein-Barr Virus (EBV)-driven, angiocentric and angiodestructive B-cell lymphoproliferative disorder characterized by a polymorphous lymphoid infiltrate containing scattered or clusters of large, atypical, EBV-positive B-lymphocytes admixed with numerous reactive T-lymphocytes and other inflammatory cells; it has a spectrum of histologic grades (1, 2, and 3) based on the proportion of large atypical EBV+ B-cells, with higher grades approaching or equivalent to EBV+ Diffuse Large B-cell Lymphoma (DLBCL)
Clinical ─
─ Primarily affects the lungs (often bilateral, multiple nodules), but can also involve extranodal sites such as skin, central nervous system (CNS), kidney, and liver. Lymph node involvement is uncommon.
─ Often occurs in the setting of immunodeficiency or immune dysregulation (e.g., congenital immunodeficiencies like Wiskott-Aldrich syndrome, post-transplantation, HIV infection, certain autoimmune diseases, or chemotherapy).
─ Symptoms are variable and may include cough, dyspnea, chest pain, fever, malaise, weight loss, skin lesions, or neurologic symptoms if CNS is involved.
─ Prognosis and treatment vary depending on the histologic grade; Grade 1/2 lesions may sometimes regress with reduction of immunosuppression or antiviral therapy, while Grade 3 lesions behave like aggressive lymphoma and require chemotherapy.
Macro ─
─ Typically presents as multiple, bilateral pulmonary nodules or masses, which can vary in size.
─ Lesions are often ill-defined and may show central necrosis or cavitation, especially in higher-grade forms.
Micro ─
─ Characterized by nodular, angiocentric (centered on blood vessels), and angiodestructive (invading and destroying vessel walls) lymphoid infiltrates.
─ The infiltrate is polymorphous, meaning it contains a mixture of cell types:
─ ─ Small, reactive lymphocytes (predominantly T-cells, often CD8+ cytotoxic T-cells).
─ ─ Plasma cells, histiocytes, and sometimes eosinophils.
─ ─ Atypical B-lymphocytes: These are the key neoplastic/proliferating cells. They are scattered individually or form small clusters or sheets (depending on grade). They are typically large, with vesicular nuclei, prominent (often eosinophilic) nucleoli, and features resembling immunoblasts or sometimes Reed-Sternberg-like cells. These large atypical B-cells are EBV-infected.
─ Grading (WHO classification, based on the number and cohesiveness of large atypical EBV+ B-cells):
─ ─ Grade 1: Rare, scattered large EBV+ B-cells within a predominantly T-cell rich reactive background.
─ ─ Grade 2: More numerous large EBV+ B-cells, often forming small clusters.
─ ─ Grade 3: Sheets or confluent aggregates of large EBV+ B-cells, essentially representing an EBV-positive Diffuse Large B-cell Lymphoma (DLBCL) arising in the context of LYG.
─ Vascular invasion and destruction by the lymphoid infiltrate are common and characteristic features, often leading to thrombosis and ischemic necrosis within the lesions.
─ Granulomatous inflammation is typically absent or minimal (distinguishes from GPA, though some overlap can be confusing).
Ancillary studies ─
─ IHC:
─ ─ Large atypical cells: Positive for B-cell markers (CD20, PAX5). Often positive for CD30. May be negative for CD15.
─ ─ Background infiltrate: Predominantly CD3+ T-cells (often CD8+ > CD4+).
─ In situ hybridization for EBV-encoded RNA (EBER): This is ESSENTIAL for diagnosis. EBER ISH demonstrates EBV within the nuclei of the large atypical B-cells.
─ Ki-67 proliferation index: Increases with grade; can be very high in Grade 3 lesions.
DDx ─
─ Vasculitis (especially Granulomatosis with Polyangiitis - GPA): GPA shows necrotizing granulomatous inflammation and vasculitis, typically ANCA-positive, and lacks the prominent EBV+ atypical B-cell infiltrate of LYG.
─ Hodgkin Lymphoma: Reed-Sternberg cells in classic Hodgkin lymphoma are CD30+, CD15+, PAX5+ (weak), CD20- (usually), and may be EBV+. However, the overall cellular milieu and specific immunophenotype differ. LYG lacks the typical polymorphous background of classic HL with numerous eosinophils/plasma cells in the same way.
─ T-cell lymphomas (especially Angioimmunoblastic T-cell Lymphoma - AITL, or Extranodal NK/T-cell lymphoma, nasal type if involving lung): AITL has a polymorphous T-cell infiltrate with clear cells, expanded FDC meshworks, often systemic symptoms. NK/T-cell lymphoma is CD56+, cytotoxic marker positive, EBV+ but involves T/NK cells.
─ Diffuse Large B-cell Lymphoma (DLBCL), not otherwise specified, or EBV+ DLBCL of the elderly: Grade 3 LYG is essentially an EBV+ DLBCL. If classic angiocentricity and polymorphous background are less apparent, it may be difficult to distinguish from de novo DLBCL. Clinical context (immunodeficiency) is important.
─ Infections causing angiitis and granulomas (e.g., fungal, mycobacterial): Special stains for organisms are crucial.
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Primary Pulmonary Hodgkin Lymphoma (rare)

Hodgkin lymphoma (HL) that arises primarily in the lung parenchyma or hilar/mediastinal lymph nodes directly draining the lung, without evidence of systemic disease at diagnosis or within a defined period (e.g., 3-6 months) following diagnosis; it is an extremely rare entity
Clinical ─
─ Can occur at any age, but often in young adults (for Nodular Sclerosis HL) or older adults (for Mixed Cellularity HL)
─ Symptoms are often nonspecific and may include cough, dyspnea, chest pain, fever, night sweats, weight loss (B symptoms)
─ Diagnosis requires thorough staging to exclude occult nodal or extranodal disease elsewhere, as metastatic HL to the lung is much more common than primary pulmonary HL
─ Prognosis is generally considered similar to nodal HL of the same subtype and stage if truly localized
Macro ─
─ May present as solitary or multiple pulmonary nodules or masses, areas of consolidation, or involvement of hilar/mediastinal lymph nodes
─ Cut surface is typically grayish-white or tan, firm, and may appear homogeneous or nodular
Micro ─
─ Diagnosis requires the identification of diagnostic Reed-Sternberg (RS) cells and their variants (e.g., Hodgkin cells, lacunar cells in Nodular Sclerosis type, LP cells/"popcorn cells" in Nodular Lymphocyte-Predominant Hodgkin Lymphoma - NLPHL) within an appropriate inflammatory cellular background.
─ Histologic subtypes are similar to those of nodal Hodgkin lymphoma:
─ ─ Nodular Sclerosis Classic Hodgkin Lymphoma (NSCHL): Most common subtype if primary HL occurs in the mediastinum/lung. Characterized by broad collagen bands dividing the lymphoid tissue into cellular nodules, containing lacunar-type RS cells within a mixed inflammatory background (lymphocytes, eosinophils, histiocytes, plasma cells).
─ ─ Mixed Cellularity Classic Hodgkin Lymphoma (MCCHL): Shows a heterogeneous inflammatory background (lymphocytes, eosinophils, plasma cells, histiocytes) with scattered classic RS cells and mononuclear Hodgkin cells.
─ ─ Lymphocyte-Rich Classic Hodgkin Lymphoma (LRCHL): Characterized by numerous small, mature lymphocytes and scattered classic RS cells or Hodgkin cells, often with a nodular or diffuse pattern.
─ ─ Lymphocyte-Depleted Classic Hodgkin Lymphoma (LDCHL): Rare; characterized by numerous RS cells and/or Hodgkin cells, a paucity of background lymphocytes, and often diffuse fibrosis or reticular pattern.
─ ─ Nodular Lymphocyte-Predominant Hodgkin Lymphoma (NLPHL): Very rare as a primary pulmonary lesion. Characterized by a nodular proliferation of small lymphocytes and histiocytes, with scattered large, atypical "popcorn" cells (LP cells).
Ancillary studies ─
─ IHC is essential for confirming the diagnosis and subtyping:
─ ─ Classic Reed-Sternberg (RS) cells and their variants (in NSCHL, MCCHL, LRCHL, LDCHL):
─ ─ ─ CD30: Strong membranous and Golgi staining (characteristic).
─ ─ ─ CD15: Often positive (membranous and/or Golgi staining), but can be negative in some cases.
─ ─ ─ PAX5 (BSAP): Weak to moderate nuclear staining (stronger staining would favor a B-cell NHL).
─ ─ ─ Usually negative for CD20 (or only weak/focal), CD45 (LCA), CD3, EMA.
─ ─ ─ Epstein-Barr Virus (EBV) association: EBV (LMP1 IHC or EBER ISH) is positive in RS cells in a proportion of classic HL cases (especially MCCHL and HL in immunocompromised settings).
─ ─ LP cells ("popcorn cells") in Nodular Lymphocyte-Predominant Hodgkin Lymphoma (NLPHL):
─ ─ ─ CD20: Strong positive.
─ ─ ─ BCL6: Positive.
─ ─ ─ EMA: Can be positive.
─ ─ ─ CD45 (LCA): Positive.
─ ─ ─ Typically negative for CD15 and CD30.
─ ─ ─ Surrounded by rosettes of CD3+/CD57+ T-cells.
─ Background inflammatory cells are as expected for the subtype.
DDx ─
─ Metastatic Hodgkin Lymphoma from nodal sites: This is much more common than primary pulmonary HL; thorough clinical staging is crucial to exclude.
─ Other lymphomas involving the lung:
─ ─ Non-Hodgkin Lymphomas (NHL), especially Diffuse Large B-cell Lymphoma (DLBCL) or Anaplastic Large Cell Lymphoma (ALCL): DLBCL cells are CD20+, CD30 variable. ALCL cells are CD30+, often ALK positive (if ALK+ ALCL), and typically express T-cell markers or are null phenotype; morphology differs (hallmark cells).
─ ─ T-cell lymphomas can have pleomorphic cells that might mimic RS cells but will have T-cell immunophenotype.
─ Reactive conditions with Reed-Sternberg-like cells: Can be seen in infectious mononucleosis (EBV-driven), some viral infections, or drug reactions. These RS-like cells may be CD30 positive, but the overall context and full immunophenotype of classic HL (e.g., CD15 positivity, lack of strong CD20/CD45) are usually absent.
─ Lymphoepithelioma-like Carcinoma (LELC): Composed of undifferentiated carcinoma cells (cytokeratin positive, CD45 negative) with a dense lymphoid stroma; may be EBV positive.
─ Germ cell tumors (e.g., mediastinal seminoma with lymphoid stroma): Seminoma cells are PLAP/OCT3-4/SALL4 positive.
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Erdheim-Chester Disease (ECD) (pulmonary involvement)

A rare systemic non-Langerhans cell histiocytosis characterized by the infiltration of tissues by foamy (lipid-laden) histiocytes (CD68+, CD1a-, Langerin-), often accompanied by fibrosis and a variable inflammatory infiltrate; pulmonary involvement is common and can manifest as interstitial lung disease
Clinical ─
─ Typically affects middle-aged to older adults (median age ~50-60 years), with a slight male predominance
─ Multisystemic disease; common sites of involvement include:
─ ─ Long bones (symmetric osteosclerosis, especially of diaphyses and metaphyses – "hairy kidney" appearance on X-ray is characteristic if kidneys are encased by retroperitoneal involvement) causing bone pain
─ ─ Cardiovascular system (e.g., "coated aorta," pericardial involvement, myocardial infiltration, valvular disease)
─ ─ Central nervous system (CNS) (e.g., diabetes insipidus due to pituitary stalk involvement, cerebellar ataxia, pyramidal signs)
─ ─ Retroperitoneum (perirenal and periureteral fibrosis – "hairy kidney")
─ ─ Skin (xanthelasmas, xanthomas)
─ Pulmonary involvement occurs in ~20-50% of cases, presenting with dyspnea, cough; imaging shows interstitial infiltrates, interlobular septal thickening, ground-glass opacities, pleural effusions, or nodules
─ Nearly all adult ECD patients harbor activating mutations in the MAPK pathway, most commonly BRAF V600E (~50-70%), or less frequently mutations in NRAS, KRAS, MAP2K1 (MEK1), etc.
─ Prognosis is variable; can be indolent or rapidly progressive and life-threatening depending on organ involvement (especially cardiac, CNS)
Macro ─
─ Lungs may show diffuse interstitial thickening, yellowish infiltrates or nodules, pleural thickening, or effusion
Micro ─
─ Interstitial infiltrates composed predominantly of foamy histiocytes (lipid-laden macrophages) with abundant, pale, multivacuolated or granular eosinophilic cytoplasm and small, often eccentric, bland nuclei
─ These histiocytes are admixed with a variable number of lymphocytes, plasma cells, and sometimes eosinophils and Touton-type giant cells (multinucleated giant cells with a peripheral wreath of nuclei and central eosinophilic cytoplasm surrounded by foamy cytoplasm)
─ Associated fibrosis is common and can be extensive, particularly involving interlobular septa, peribronchovascular bundles, and the pleura (lymphangitic distribution is characteristic)
─ The histiocytic infiltrate can encase and constrict vessels and airways
─ No Birbeck granules are seen on electron microscopy (distinguishing from Langerhans Cell Histiocytosis)
Ancillary studies ─
─ IHC:
─ ─ Histiocytes are positive for pan-macrophage markers: CD68 (strong cytoplasmic), CD163.
─ ─ Often positive for Factor XIIIa.
─ ─ Crucially, they are NEGATIVE for Langerhans cell markers: CD1a and Langerin (CD207).
─ ─ S100 protein expression is variable, often negative or only weakly/focally positive in histiocytes (Langerhans cells are strongly S100+).
─ ─ Cytokeratins are negative.
─ Molecular: Detection of BRAF V600E mutation (by IHC with VE1 antibody, or by PCR/NGS on tissue) is found in a majority of cases and is now considered a diagnostic criterion in many contexts, especially for initiating targeted therapy (BRAF/MEK inhibitors). Testing for other MAPK pathway mutations if BRAF is negative.
DDx ─
─ Langerhans Cell Histiocytosis (LCH), particularly pulmonary LCH (PLCH) if lung involvement: Langerhans cells are CD1a positive, Langerin positive, and strongly S100 positive; form characteristic nodular lesions with eosinophils, often cystic in lung, associated with smoking. Foamy histiocytes are less prominent.
─ Rosai-Dorfman Disease (Sinus Histiocytosis with Massive Lymphadenopathy): Histiocytes are S100 positive (strong), CD68 positive, but characteristically show emperipolesis (intact lymphocytes/plasma cells within cytoplasm); CD1a negative. Different clinical presentation usually (massive lymphadenopathy).
─ Xanthogranulomatous inflammation (e.g., xanthogranulomatous pyelonephritis, xanthogranulomatous cholecystitis extending locally): Sheets of foamy histiocytes with other inflammatory cells, but usually a destructive process related to infection or obstruction, lacks systemic features and BRAF mutation of ECD.
─ Storage diseases (e.g., Niemann-Pick disease, Gaucher disease): Accumulation of specific lipids due to enzyme deficiencies; different clinical context, specific enzyme assays or genetic testing.
─ Malakoplakia: Granulomatous inflammation with Michaelis-Gutmann bodies (calcified spherules within histiocytes), often related to bacterial infection (e.g., E. coli).
─ Diffuse lipoid pneumonia: Exogenous or endogenous lipid accumulation with foamy macrophages; different clinical history/context.
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Rosai-Dorfman Disease (Sinus Histiocytosis with Massive Lymphadenopathy - SHML) (pulmonary involvement)

A rare benign histiocytic proliferative disorder of unknown etiology, characterized by massive, painless cervical lymphadenopathy (classic presentation) and potential extranodal involvement in various sites, including the lung; histologically defined by sinusoidal or interstitial accumulation of large, distinctive histiocytes exhibiting emperipolesis (phagocytosis of intact hematopoietic cells, especially lymphocytes and plasma cells)
Clinical ─
─ Typically affects children and young adults, but can occur at any age; slight male predominance
─ Classic presentation: Bilateral, massive, painless cervical lymphadenopathy, often accompanied by fever, leukocytosis, elevated ESR, and polyclonal hypergammaglobulinemia
─ Extranodal involvement occurs in ~40% of cases, either with or without lymphadenopathy. Common extranodal sites include skin, bone, soft tissue, orbit, CNS, and less commonly, the respiratory tract (nasal cavity, larynx, trachea, lungs).
─ Pulmonary involvement can manifest as solitary or multiple nodules or masses, diffuse interstitial infiltrates, or endobronchial lesions. Symptoms may include cough, dyspnea, chest pain, or be asymptomatic.
─ The clinical course is often self-limiting and benign, with spontaneous remissions, but can be persistent, relapsing, or rarely life-threatening if critical organs are involved or due to immune dysregulation.
─ Some cases associated with mutations in MAPK pathway genes (e.g., NRAS, KRAS, MAP2K1) but less consistently than ECD with BRAF.
Macro ─
─ Lung lesions: May appear as solitary or multiple well-circumscribed or ill-defined nodules or masses, or as diffuse interstitial infiltrates or consolidation.
─ Cut surface is typically yellowish-white or tan, firm, and homogeneous.
Micro ─
─ Diffuse or nodular infiltrates composed of numerous large, pale histiocytes with abundant eosinophilic or sometimes foamy cytoplasm.
─ Hallmark feature: Emperipolesis – the presence of intact, viable lymphocytes, plasma cells, and occasionally neutrophils or red blood cells within the cytoplasm of these large histiocytes. The engulfed cells appear to reside within clear vacuoles and are not undergoing degradation.
─ The large histiocytes (Rosai-Dorfman cells or SHML cells) have round to oval, vesicular nuclei with smooth contours and often prominent, centrally located, eosinophilic nucleoli. Significant cytologic atypia and mitotic activity are typically absent.
─ Background polymorphous inflammatory infiltrate is usually present, consisting of numerous plasma cells (often forming sheets), lymphocytes, and sometimes neutrophils or eosinophils.
─ Fibrosis can be prominent, especially in chronic or treated lesions.
─ Vascular proliferation or sclerosis may be seen.
Ancillary studies ─
─ IHC:
─ ─ Characteristic large histiocytes are positive for:
─ ─ ─ S100 protein (strong nuclear and cytoplasmic staining – a key feature).
─ ─ ─ CD68 (pan-macrophage marker).
─ ─ ─ CD163 (macrophage marker).
─ ─ Crucially, they are NEGATIVE for CD1a and Langerin (CD207) (distinguishing from Langerhans Cell Histiocytosis).
─ ─ Fascin may also be positive in histiocytes.
─ Emperipolesis is a key morphological finding that should be actively sought.
DDx ─
─ Langerhans Cell Histiocytosis (LCH): Langerhans cells are CD1a positive, Langerin positive, S100 positive, and have characteristic grooved nuclei; Birbeck granules on EM. Lacks prominent emperipolesis by large S100+/CD1a- histiocytes.
─ Erdheim-Chester Disease (ECD): Histiocytes are foamy, CD68+/CD163+, CD1a negative, but S100 protein is usually negative or only weakly/focally positive (unlike strong S100 in RDD). ECD often shows prominent fibrosis, lymphangitic distribution, and BRAF V600E mutation is common. Emperipolesis is not a typical feature of ECD.
─ Lymphoma (especially Hodgkin lymphoma or some Non-Hodgkin Lymphomas with large cells): Malignant lymphoid cells would show specific immunophenotypes (e.g., CD30/CD15 for RS cells in HL; CD20 for B-cell NHL; CD3 for T-cell NHL) and often monoclonality. Emperipolesis is not a feature of lymphoma cells themselves.
─ Infectious granulomatous diseases (e.g., tuberculosis, fungal infections, rhinoscleroma, malakoplakia): May have histiocytes and plasma cells, but specific organisms should be identifiable with special stains or culture. Mikulicz cells in rhinoscleroma contain bacteria. Michaelis-Gutmann bodies in malakoplakia.
─ Metastatic carcinoma or melanoma with prominent histiocytic reaction: Tumor cells would be positive for cytokeratins or melanoma markers, respectively.
─ Hemophagocytic Lymphohistiocytosis (HLH): Systemic hyperinflammatory syndrome with cytopenias, fever, hepatosplenomegaly; histiocytes show hemophagocytosis (phagocytosis of RBCs, platelets, leukocytes), not typically emperipolesis of intact lymphocytes.
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Tumors of Childhood

Pleuropulmonary Blastoma (PPB) (Types I, Ir, II, III)

A rare and aggressive dysembryonic mesenchymal neoplasm of childhood, arising from primitive pleuropulmonary mesenchyme, characterized by a spectrum of cystic and solid patterns reflecting different stages of differentiation or progression, and strongly associated with germline or somatic mutations in the DICER1 gene
Clinical ─
─ Primarily affects infants and young children, typically before the age of 6 years (median age ~3 years); very rare in older children or adults.
─ Symptoms are often nonspecific and depend on the type and size of the tumor: respiratory distress, fever, cough, chest pain, or may be an incidental finding on imaging. Spontaneous pneumothorax is a common presentation for Type I PPB.
─ Part of the "DICER1 syndrome," an inherited cancer predisposition syndrome that also includes risk for other tumors (e.g., ovarian Sertoli-Leydig cell tumor, cystic nephroma, thyroid nodules/carcinoma, pineoblastoma). Family history may be relevant.
─ Prognosis varies by type: Type I generally has the best prognosis if completely resected; Type III has the worst. Overall survival has improved with multimodal therapy.
Macro ─
─ Type I (Cystic): Typically presents as a large, solitary or multilocular, thin-walled air-filled or fluid-filled cyst(s), resembling congenital pulmonary airway malformation (CPAM) or bronchogenic cyst.
─ Type Ir (Regressed): Represents a regressed or regressing form of Type I, often smaller, may be unilocular or fibrotic with residual cystic spaces.
─ Type II (Mixed Cystic and Solid): Contains both cystic components (similar to Type I) and solid, fleshy, sarcomatous areas.
─ Type III (Solid): Entirely solid, often large, fleshy, grayish-white or tan, aggressive-appearing mass, frequently with areas of necrosis and hemorrhage. May invade adjacent structures.
Micro ─
─ Type I (Purely Cystic) PPB:
─ ─ Characterized by single or multiple cysts lined by benign-appearing cuboidal to columnar respiratory epithelium.
─ ─ The key diagnostic feature (though can be focal and easily missed) is the presence of a variably cellular "cambium layer" of primitive, small, round to spindle-shaped mesenchymal cells beneath the epithelial lining of the cysts or within the cyst septa. These cells have scant cytoplasm, dark nuclei, and may show mitotic activity. No overt solid sarcomatous areas.
─ Type Ir (Regressed) PPB:
─ ─ Similar to Type I but often shows increased fibrosis in the cyst walls/septa, smaller or fewer cystic spaces, and a less prominent or absent primitive mesenchymal (cambium) layer. Represents probable regression or maturation of a Type I lesion.
─ Type II (Mixed Cystic and Solid) PPB:
─ ─ Contains both cystic areas (often with a cambium layer, similar to Type I) and solid areas composed of primitive mesenchymal cells (blastema) and/or overtly sarcomatous differentiation.
─ Type III (Purely Solid) PPB:
─ ─ Entirely solid tumor composed of primitive small round/spindle cells (blastemal component) and/or areas of overt sarcoma. No cystic component is present.
─ ─ Sarcomatous differentiation in Type II and Type III can be varied and may include:
─ ─ ─ Rhabdomyosarcoma (most common line of differentiation; presence of rhabdomyoblasts – strap cells, tadpole cells, cells with eosinophilic cytoplasm, cross-striations rarely seen).
─ ─ ─ Chondrosarcoma (nodules of atypical cartilage).
─ ─ ─ Undifferentiated sarcoma or fibrosarcoma-like areas.
─ ─ ─ Anaplastic cells with marked pleomorphism can be seen.
Ancillary studies ─
─ IHC:
─ ─ Primitive mesenchymal cells (blastema, cambium layer, sarcomatous areas): Typically positive for vimentin. May show variable expression of:
─ ─ ─ Desmin, myogenin, MyoD1 if rhabdomyoblastic differentiation is present.
─ ─ ─ S100 protein if chondroid differentiation is present.
─ ─ ─ Smooth Muscle Actin (SMA) can be positive in spindle cells.
─ ─ ─ CD99 can be positive but is nonspecific.
─ ─ Epithelial lining of cysts: Positive for cytokeratins (AE1/AE3, CAM5.2, CK7) and EMA. TTF-1 may be positive.
─ Molecular: Germline or somatic inactivating mutations in the DICER1 gene (an RNase III endonuclease involved in microRNA processing) are found in the majority of PPB cases across all types and are a defining feature of the DICER1 syndrome.
DDx ─
─ Congenital Pulmonary Airway Malformation (CPAM): Especially Type 4 CPAM, which can be cystic and also has an association with DICER1 mutations and a risk of developing PPB. Pure CPAM lacks the primitive mesenchymal cambium layer or sarcomatous stroma of PPB. The presence of a cambium layer, even focal, in a cystic lesion in a young child is highly suggestive of PPB Type I.
─ Bronchogenic cyst: Usually unilocular, lined by ciliated respiratory epithelium, wall contains cartilage and glands; lacks primitive mesenchyme.
─ Other pediatric sarcomas (e.g., primary embryonal rhabdomyosarcoma of lung if monophasic, infantile fibrosarcoma): Distinction from Type III PPB can be difficult without considering the possibility of PPB and DICER1 status, especially if only solid sarcoma is sampled.
─ Pulmonary Blastoma (classic adult-type biphasic): Contains a malignant epithelial component resembling fetal adenocarcinoma and a malignant mesenchymal stroma. Occurs in adults, different genetic profile typically (e.g., CTNNB1 mutations common in epithelial component, DICER1 mutations rare).
─ Cystic Hamartoma (rare in young children): Contains mature mesenchymal elements (cartilage, fat, smooth muscle) and benign entrapped epithelium; lacks primitive blastema/sarcoma.
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Infantile Fibrosarcoma (NTRK-rearranged)

A rare malignant spindle cell sarcoma occurring predominantly in infants and young children (typically <2 years of age, often congenital or presenting in the first year of life), characterized by a cellular proliferation of fibroblastic-like spindle cells, often with a prominent herringbone or fascicular pattern, and defined by recurrent gene fusions involving one of the neurotrophic tyrosine receptor kinase (NTRK) genes (most commonly ETV6-NTRK3 from t(12;15)(p13;q25), but also other NTRK1 or NTRK3 fusions)
Clinical ─
─ Usually presents as a rapidly growing, often large, soft tissue mass; can occur in extremities, trunk, head/neck. Primary pulmonary infantile fibrosarcoma is exceptionally rare.
─ Despite being histologically cellular and mitotically active, it generally has a better prognosis than its adult fibrosarcoma counterpart, particularly if completely resected.
─ Highly responsive to TRK inhibitors (e.g., larotrectinib, entrectinib) if an NTRK fusion is identified, leading to tumor-agnostic approvals for these drugs in NTRK fusion-positive cancers.
Macro ─
─ Typically a fleshy, infiltrative or sometimes well-circumscribed, grayish-white or tan mass.
─ Size is variable, can be large. Necrosis and hemorrhage may be present.
Micro ─
─ Highly cellular tumor composed of relatively uniform, primitive-appearing spindle cells.
─ Cells are arranged in long, intersecting fascicles, often forming a characteristic "herringbone" pattern, or may show more storiform or sheet-like areas.
─ Spindle cells have ovoid to fusiform nuclei with fine, vesicular chromatin and inconspicuous or small nucleoli; cytoplasm is scant and pale eosinophilic.
─ Mitotic activity is usually brisk, but atypical mitoses are not prominent.
─ Nuclear pleomorphism is generally minimal to moderate (significantly less than in adult high-grade fibrosarcoma or undifferentiated pleomorphic sarcoma).
─ Stroma is often scant; myxoid change or collagenous areas can be seen. A prominent hemangiopericytoma-like vascular pattern (branching, thin-walled vessels) may be present.
Ancillary studies ─
─ IHC:
─ ─ Spindle cells are typically positive for vimentin.
─ ─ Smooth Muscle Actin (SMA) may be focally positive in some cases.
─ ─ S100 protein, desmin, cytokeratins are characteristically negative.
─ ─ Pan-TRK immunohistochemistry (using antibodies that recognize the C-terminal portion of TRK proteins A, B, and C) can show cytoplasmic staining if an NTRK fusion leading to protein overexpression is present, serving as a useful screening tool.
─ Molecular: Detection of NTRK gene fusions is characteristic and diagnostically crucial. This can be achieved by:
─ ─ FISH (using break-apart probes for NTRK1, NTRK2, NTRK3 or specific fusion probes for common partners like ETV6).
─ ─ RT-PCR for specific known fusions (e.g., ETV6-NTRK3).
─ ─ Next-Generation Sequencing (NGS) panels (RNA-based or DNA-based) that can detect gene fusions.
DDx ─
─ Other spindle cell tumors of infancy and childhood:
─ ─ Myofibromatosis (infantile myofibromatosis): Often multiple nodules, characterized by a biphasic pattern with peripheral primitive ovoid/spindle cells and central more mature spindle cells, often with a hemangiopericytoma-like vasculature. Zonation can be seen. SMA positive. NTRK fusions absent.
─ ─ Congenital smooth muscle hamartoma: Disorganized bundles of mature smooth muscle; desmin/SMA positive.
─ ─ Rhabdomyosarcoma, spindle cell variant of embryonal type: Will be positive for myogenic markers (desmin, myogenin, MyoD1).
─ ─ Malignant Peripheral Nerve Sheath Tumor (MPNST): Rare in infants unless associated with NF1; S100/SOX10 often focally positive, loss of H3K27me3 in some.
─ ─ Primitive Myxoid Mesenchymal Tumor of Infancy (PMMTI): Characterized by primitive spindle and ovoid cells in a myxoid stroma; often involves BCOR internal tandem duplications.
─ ─ Fibrosarcoma, adult type (if occurring in an older child/adolescent): Lacks NTRK fusions, often more pleomorphic.
─ Cellular variants of other mesenchymal tumors.
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Metastatic Tumors to the Lung

Overview, Common Patterns, and Key Considerations

Neoplasms that spread to the lungs from a primary malignant tumor arising in another organ or tissue; the lungs are one of the most common sites for metastatic disease due to their extensive vascular supply (receiving the entire cardiac output via pulmonary arteries) and lymphatic drainage
Clinical ─
─ Can be asymptomatic and discovered incidentally on imaging, or present with a variety of symptoms such as persistent cough, dyspnea, hemoptysis, chest pain, or pleural effusion
─ A history of a known primary cancer elsewhere is crucial for diagnosis, but lung metastases can sometimes be the first clinical manifestation of an unknown primary malignancy
─ The presence of lung metastases usually signifies advanced stage disease (Stage IV) with significant prognostic implications
Macro ─
─ Appearance is highly variable depending on the primary tumor type, route of spread, and number/size of lesions:
─ Multiple, bilateral, well-circumscribed nodules of varying sizes scattered throughout all lung fields ("cannonball metastases") is a classic pattern for hematogenous spread, but not universal.
─ Solitary metastasis can occur and can be challenging to distinguish from a primary lung cancer.
─ Lymphangitic carcinomatosis: Diffuse permeation and thickening of pulmonary lymphatics by tumor cells, often leading to interstitial reticular patterns on imaging and prominent dyspnea. Lungs may appear firm, heavy, and show thickened interlobular septa and bronchovascular bundles.
─ Endobronchial metastases: Less common; present as polypoid or infiltrative lesions within the airway lumens, potentially causing obstruction.
─ Pleural metastases: May manifest as discrete pleural nodules, diffuse pleural thickening, or malignant pleural effusion.
─ Miliary pattern: Numerous tiny (1-2 mm) metastatic nodules diffusely scattered throughout the lungs, resembling miliary tuberculosis.
Micro ─
─ Histologic appearance of metastases typically reflects the morphology of the primary tumor, though a lesser degree of differentiation can sometimes be seen in metastases.
─ Common patterns of spread to the lung:
─ ─ Hematogenous spread: Tumor cells arrive via pulmonary arteries (most common route for parenchymal nodules) or less commonly bronchial arteries, lodge in small vessels, and then invade parenchyma to form discrete nodules.
─ ─ Lymphangitic spread (Lymphangitic carcinomatosis): Tumor cells infiltrate and proliferate within peribronchial, perivascular, interlobular septal, and pleural lymphatics. This often incites a desmoplastic stromal reaction and can cause significant respiratory compromise.
─ ─ Endobronchial/Endotracheal spread: Direct extension from adjacent structures, aspiration of tumor cells from upper airway primary, or hematogenous spread to bronchial wall with intraluminal growth.
─ ─ Pleural seeding: Direct extension from adjacent tumor, hematogenous spread to pleura, or lymphatic spread.
─ Specific considerations for common primary sites metastasizing to lung:
─ ─ Breast Carcinoma: Typically adenocarcinoma (ductal or lobular subtypes). Important IHC: ER, PR, GATA3, Mammaglobin positive. HER2 status.
─ ─ Colorectal Carcinoma: Adenocarcinoma, often with glandular/cribriform architecture and characteristic "dirty necrosis." Important IHC: CDX2 positive, SATB2 positive, CK20 positive, often CK7 negative.
─ ─ Renal Cell Carcinoma (especially Clear Cell type): Nests and sheets of cells with abundant clear cytoplasm and a rich vascular network. Important IHC: PAX8 positive, CD10 positive, CAIX positive; typically TTF-1 negative.
─ ─ Malignant Melanoma: Composed of epithelioid or spindle cells, often with prominent nucleoli and melanin pigment (if present). Important IHC: S100 protein positive, SOX10 positive, HMB-45 and/or Melan-A positive.
─ ─ Sarcomas (various types): Histology depends on the specific type of primary sarcoma (e.g., leiomyosarcoma, osteosarcoma, liposarcoma). Generally vimentin positive, and express specific mesenchymal markers depending on lineage; typically cytokeratin negative.
─ ─ Head and Neck Squamous Cell Carcinoma: Keratinizing or non-keratinizing squamous cell carcinoma. p16 IHC may be positive if HPV-related oropharyngeal primary.
─ ─ Thyroid Carcinoma: Papillary carcinoma (TTF-1 positive, PAX8 positive, thyroglobulin positive), follicular carcinoma (similar IHC), medullary carcinoma (calcitonin positive, chromogranin/synaptophysin positive).
─ ─ Prostate Carcinoma: Adenocarcinoma. PSA positive, PSAP positive, P501S (prostein) positive.
─ ─ Ovarian/Uterine Carcinoma: Serous, endometrioid, clear cell types. PAX8 positive, WT1 positive (for serous ovarian), ER/PR often positive.
─ Immunohistochemistry (IHC) is crucial for distinguishing a primary lung cancer from a metastatic tumor, especially in cases of a solitary lung nodule with an unknown or remote history of a primary cancer elsewhere, or if the morphology is unusual for a primary lung tumor. A panel approach is key, typically including markers for lung primary (TTF-1, Napsin A for adenocarcinoma; p40, CK5/6 for squamous) versus site-specific markers for common metastatic primaries (as listed above).
Ancillary studies ─
─ IHC: As detailed above, essential for determining the likely site of origin if unknown, or confirming metastatic nature if primary is known but morphology is ambiguous.
─ Molecular studies: Comparison of specific molecular alterations (e.g., EGFR, KRAS, BRAF mutations, gene fusions) between the lung lesion and a known or suspected primary tumor can definitively confirm a metastatic relationship if the profiles match.
DDx ─
─ Primary lung carcinoma (especially if presenting as a solitary nodule or with unusual morphology).
─ Benign lung tumors or tumor-like lesions (e.g., hamartoma, sclerosing pneumocytoma, inflammatory myofibroblastic tumor).
─ Infectious granulomas or other inflammatory processes that can form nodules or masses.
─ Distinguishing a solitary metastasis from a new primary lung cancer in a patient with a history of prior malignancy can be particularly challenging and often requires careful integration of clinical, radiological, morphological, immunohistochemical, and sometimes molecular data.
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Pleura

Normal Pleura

Normal Pleural Anatomy and Histology

An overview of the structure and composition of the pleura, the serous membrane that lines the thoracic cavity and covers the surfaces of the lungs, essential for understanding pleural pathology
Clinical ─ Serves as the baseline for interpreting pathological changes in pleural biopsies, effusions, and imaging; understanding normal fluid dynamics is key to effusion pathophysiology
Macro ─
─ Composed of two continuous layers:
─ ─ Parietal pleura: Lines the inner surface of the chest wall, the superior surface of the diaphragm, and the lateral aspects of the mediastinum.
─ ─ Visceral pleura: Directly covers the entire surface of each lung, including the interlobar fissures.
─ Pleural space (cavity): A potential space between the parietal and visceral pleura, which normally contains a very small amount (a few milliliters) of serous lubricating fluid that allows frictionless movement of the lungs during respiration.
Micro ─
─ Mesothelium: Both pleural layers are lined by a single, continuous layer of mesothelial cells.
─ ─ Mesothelial cells are specialized epithelial cells of mesenchymal origin, typically flattened (squamous-like) to cuboidal in shape, depending on their location and reactive state.
─ ─ They possess surface microvilli (best visualized by electron microscopy), intercellular junctions (desmosomes, tight junctions), and cytoplasmic intermediate filaments (cytokeratins).
─ Submesothelial connective tissue: A layer of connective tissue beneath the mesothelium, supporting it.
─ ─ Visceral pleura: Submesothelial layer is relatively thin and contains collagen, elastic fibers (forming distinct superficial and deep elastic layers), blood vessels (from bronchial and pulmonary circulation), lymphatics, and nerves. It is intimately adherent to the lung parenchyma.
─ ─ Parietal pleura: Submesothelial layer is generally thicker and looser, containing more collagen, adipose tissue, blood vessels (from systemic circulation, e.g., intercostal arteries), sensory nerves (pain-sensitive), and a rich network of lymphatics. Lymphatic stomata on the surface of the parietal pleura are important for pleural fluid drainage.
Ancillary studies ─
─ IHC (for identifying mesothelial cells):
─ ─ Positive markers: Calretinin (strong nuclear and cytoplasmic), WT1 (nuclear, Wilms Tumor 1 protein), CK5/6 (cytokeratin 5/6), D2-40 (podoplanin, also a lymphatic marker), HBME-1 (Hector Battifora Mesothelial-1), Thrombomodulin.
─ ─ Mesothelial cells are also positive for broad-spectrum cytokeratins (e.g., AE1/AE3, CAM5.2) and EMA (epithelial membrane antigen, often with a characteristic long microvillous/membranous pattern).
─ ─ Negative for markers typically associated with adenocarcinoma: TTF-1, Napsin A, CEA (monoclonal), MOC31, Ber-EP4, Claudin-4 (these are usually negative or only very focally positive in benign mesothelium).
DDx ─ N/A (This entry describes normal histology)
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Reactive Mesothelial Proliferation/Hyperplasia

A benign, non-neoplastic proliferation and hypertrophy of mesothelial cells, typically occurring in response to various forms of pleural irritation, inflammation, or fluid accumulation; it can sometimes mimic malignant mesothelioma, especially on small biopsy specimens, making distinction critical
Clinical ─
─ Commonly associated with a wide range of underlying conditions causing pleural injury or effusion:
─ ─ Pleural effusions of diverse etiologies (e.g., congestive heart failure, infection/parapneumonic effusion, empyema, pulmonary embolism, collagen vascular diseases, uremia, malignancy-associated non-neoplastic effusions)
─ ─ Pneumothorax, hemothorax
─ ─ Pleuritis (inflammatory conditions of the pleura)
─ ─ Trauma or surgical procedures involving the pleura
─ ─ Chronic lung diseases with pleural involvement (e.g., organizing pneumonia, interstitial fibrosis extending to pleura)
─ Usually resolves if the underlying cause is treated; not considered a premalignant lesion
Macro ─
─ Pleural surfaces may appear normal, dull, congested, or show varying degrees of thickening, granularity, nodularity, or a shaggy, villous appearance due to florid proliferation
Micro ─
─ Proliferation of mesothelial cells, which can exhibit a range of appearances:
─ ─ Single-layered (hypertrophic cuboidal cells) or multilayered (stratification) lining of the pleural surface.
─ ─ Formation of small papillary structures with or without fibrovascular cores.
─ ─ Formation of tubules, nests, or solid sheets of mesothelial cells.
─ Cytologic features of reactive mesothelial cells:
─ ─ Cells are typically bland or show only mild atypia: cuboidal to polygonal, with moderate amounts of eosinophilic cytoplasm.
─ ─ Nuclei are usually round to oval, with smooth nuclear contours, vesicular or finely granular chromatin, and often prominent but regular nucleoli (especially if reactive).
─ ─ Mitotic figures can be present, particularly in florid reactions, but are generally not atypical or numerous.
─ Often associated with underlying acute or chronic inflammation (neutrophils, lymphocytes, plasma cells, macrophages), edema, fibrin deposition, or granulation tissue formation in the submesothelial stroma.
─ Entrapment of reactive mesothelial cells or cell clusters within inflamed or fibrotic submesothelial connective tissue can occur, sometimes mimicking stromal invasion ("pseudoinvasion"). Features favoring reactive entrapment over true invasion include:
─ ─ Smooth, scalloped borders of cell clusters.
─ ─ Linear arrangement ("chaining" or "Indian filing") of cells within stroma, often separated by collagen.
─ ─ Lack of deep, destructive infiltrative growth into underlying adipose tissue or muscle (if present in biopsy).
─ ─ Absence of significant desmoplastic stromal reaction typically seen with invasive mesothelioma.
Ancillary studies ─
─ IHC:
─ ─ Reactive mesothelial cells show the same immunophenotype as normal mesothelial cells: Positive for Calretinin, WT1 (nuclear), CK5/6, D2-40 (podoplanin), HBME-1, Thrombomodulin, broad-spectrum cytokeratins, EMA.
─ ─ Markers favoring benign/reactive over malignant mesothelioma:
─ ─ ─ BAP1 (BRCA1 associated protein-1): Retained nuclear expression is characteristic of reactive mesothelial proliferation (loss of nuclear BAP1 is common in malignant mesothelioma).
─ ─ ─ MTAP (Methylthioadenosine phosphorylase): Retained expression (loss common with CDKN2A/p16 deletion in mesothelioma).
─ ─ ─ Desmin: Can be positive in reactive mesothelial cells (often lost in mesothelioma).
─ ─ ─ GLUT-1 and IMP3: Generally negative in reactive mesothelium (often positive in mesothelioma).
─ ─ Ki-67 proliferation index: Usually low (<5-10%) in reactive proliferations, though can be higher in florid reactions; significantly higher in most mesotheliomas.
─ Molecular: Deletion of CDKN2A/p16 (by FISH) or loss of BAP1 protein (by IHC due to mutation/deletion) strongly favors malignant mesothelioma over reactive proliferation.
DDx ─
─ Malignant Mesothelioma, epithelioid type: This is the most important differential. Mesothelioma typically shows more significant cytologic atypia, complex architectural patterns (tubulopapillary, solid, trabecular), true stromal invasion (into fat, muscle, or lung parenchyma), extensive desmoplastic stromal reaction, and often exhibits BAP1 loss or CDKN2A/p16 deletion.
─ Metastatic Adenocarcinoma involving the pleura: Adenocarcinoma cells form glands or sheets, produce mucin (sometimes), and are positive for adenocarcinoma markers (e.g., TTF-1, Napsin A for lung primary; site-specific markers for other primaries like PAX8, GATA3, CDX2) and negative or only weakly/aberrantly positive for mesothelial markers. Mesothelial cells may show reactive changes overlying metastatic tumor.
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Non-Neoplastic Pleural Lesions

Pleural Effusions (Transudate, Exudate; types)

An abnormal accumulation of fluid within the pleural space; effusions are broadly classified as transudates or exudates based on their biochemical composition (primarily protein content and LDH levels, often using Light's criteria), which reflects the underlying mechanism of fluid formation. Specific types are further characterized by their appearance and cellular content.
Clinical ─
─ Symptoms depend on the size and rate of accumulation of the effusion, as well as the underlying cause: dyspnea (most common), cough, pleuritic chest pain (if associated pleuritis)
─ Detected by physical examination (dullness to percussion, decreased breath sounds) and confirmed by imaging (chest X-ray, ultrasound, CT scan)
─ Thoracentesis (pleural fluid aspiration) is often performed for diagnostic (to determine cause) and sometimes therapeutic (to relieve dyspnea) purposes
Macro (Appearance of Pleural Fluid):
─ Transudate: Typically clear, pale yellow or straw-colored, and watery. Results from imbalances in hydrostatic or oncotic pressures (e.g., congestive heart failure, cirrhosis with ascites, nephrotic syndrome, hypoalbuminemia).
─ ─ Biochemical criteria (Light's criteria for exudate, if any one met): Pleural fluid protein/serum protein ratio >0.5; Pleural fluid LDH/serum LDH ratio >0.6; Pleural fluid LDH > two-thirds the upper limit of normal for serum LDH. Transudates do not meet these.
─ Exudate: Can be clear, cloudy, turbid, purulent, bloody, or milky. Results from increased capillary permeability or impaired lymphatic drainage due to inflammation, infection, or malignancy involving the pleura.
─ ─ Causes: Pneumonia (parapneumonic effusion, empyema), malignancy (lung cancer, mesothelioma, metastases), pulmonary embolism, viral pleuritis, tuberculosis, autoimmune diseases (e.g., rheumatoid arthritis, lupus), pancreatitis, post-cardiac injury syndrome.
─ Specific Types of Effusions based on appearance/content:
─ ─ Serous: Clear or pale yellow (can be transudate or mild exudate).
─ ─ Chylous (Chylothorax): Milky white, opalescent. Due to leakage or obstruction of the thoracic duct, leading to accumulation of chyle (lymph fluid rich in triglycerides/chylomicrons). Triglyceride level in fluid >110 mg/dL is characteristic.
─ ─ Pseudochylous (Cholesterol Effusion): Turbid, often golden-brown or opalescent, with a shimmering or satiny sheen due to high cholesterol content (cholesterol crystals). Occurs in long-standing chronic effusions (e.g., old tuberculous pleurisy, rheumatoid pleuritis).
─ ─ Hemorrhagic (Hemothorax if significant): Bloody appearance. If pleural fluid hematocrit is >50% of the peripheral blood hematocrit, it's considered a hemothorax (usually due to trauma, malignancy, or vascular rupture). Lesser amounts of blood can be seen in various exudates.
─ ─ Purulent (Empyema): Turbid, thick, pus-like fluid containing numerous neutrophils and bacteria; indicates infection of the pleural space.
─ ─ Eosinophilic Pleural Effusion: Defined by >10% eosinophils in the pleural fluid differential cell count. Common causes include air or blood in the pleural space (e.g., post-pneumothorax, post-traumatic), infections (parasitic, fungal), drug reactions, malignancy (lymphoma, carcinoma), asbestos exposure.
Micro (Cytologic Examination of Pleural Fluid):
─ Cellular components include:
─ ─ Mesothelial cells: Benign reactive mesothelial cells are commonly present (single or in clusters, variable atypia). Distinguishing reactive from malignant mesothelial cells can be challenging.
─ ─ Inflammatory cells: Neutrophils (predominate in empyema, acute parapneumonic effusions), lymphocytes (predominate in tuberculosis, malignancy, viral pleuritis, autoimmune diseases, chylothorax), eosinophils (in eosinophilic effusions), macrophages.
─ ─ Malignant cells: If the effusion is due to metastatic carcinoma, lymphoma, leukemia, or malignant mesothelioma. Cytology is crucial for detecting these.
─ Other elements: Red blood cells, lipid globules (in chylous effusion), cholesterol crystals (in pseudochylous effusion), fibrin.
Ancillary studies ─
─ Pleural fluid analysis: Cell count and differential, total protein, LDH, glucose, pH, amylase (if pancreatitis suspected), triglycerides and cholesterol (for chylous/pseudochylous).
─ Cytology: Microscopic examination for malignant cells, differential inflammatory cell count, and identification of mesothelial cells. Cell block preparation with IHC can be very helpful.
─ Microbiology: Gram stain, bacterial culture and sensitivity, AFB smear and culture (for tuberculosis), fungal smear and culture.
─ Specific markers: Adenosine deaminase (ADA) or interferon-gamma for tuberculous pleurisy. Tumor markers (e.g., CEA) have limited diagnostic value in fluid alone.
DDx ─ The differential diagnosis is for the underlying cause of the effusion, based on clinical context and comprehensive pleural fluid analysis.
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Pleuritis/Pleurisy (Acute, Chronic, Fibrinous, Organizing)

Inflammation of the pleura (both visceral and parietal layers), which can be acute or chronic and is often categorized by the nature of the inflammatory exudate and the reactive changes observed; frequently associated with pleural effusion and pleuritic chest pain
Clinical ─
─ Pleuritic chest pain is a common symptom: sharp, localized pain that is exacerbated by deep inspiration, coughing, or movement.
─ Other symptoms may include cough, dyspnea (especially if a significant effusion is present), fever (if infectious cause).
─ A pleural friction rub (a creaking or grating sound heard on auscultation during respiration) may be present.
─ Numerous underlying causes, including:
─ ─ Infections (most common): Viral (e.g., Coxsackie B, influenza), bacterial (pneumonia extending to pleura – parapneumonic pleuritis, empyema), tuberculosis, fungal, parasitic.
─ ─ Pulmonary embolism with infarction.
─ ─ Autoimmune diseases (e.g., Systemic Lupus Erythematosus - SLE, Rheumatoid Arthritis - RA).
─ ─ Malignancy (primary pleural tumors like mesothelioma, or metastatic tumors to the pleura).
─ ─ Trauma or surgery involving the chest.
─ ─ Drug reactions.
─ ─ Uremia, pancreatitis, post-myocardial infarction syndrome (Dressler's syndrome).
Macro ─
─ Acute Pleuritis: Pleural surfaces appear dull, roughened, and congested (hyperemic). A fibrinous or purulent exudate may cover the pleural surfaces.
─ Chronic Pleuritis: Pleural surfaces may be thickened, opaque, and fibrotic, with formation of adhesions between visceral and parietal pleura, potentially leading to obliteration of the pleural space or fibrothorax (if extensive and constricting).
Micro ─
─ Acute Pleuritis:
─ ─ Characterized by vascular congestion and edema within the submesothelial connective tissue of the pleura.
─ ─ Infiltration by acute inflammatory cells, predominantly neutrophils, but also macrophages and lymphocytes.
─ ─ Fibrinous Pleuritis: A common form of acute pleuritis where there is deposition of abundant eosinophilic fibrin strands and meshwork on the pleural surfaces. Fibrin may contain entrapped inflammatory cells and mesothelial cells.
─ ─ Suppurative Pleuritis / Empyema: If the acute inflammation is predominantly neutrophilic and forms frank pus (a collection of neutrophils, necrotic debris, and bacteria) within the pleural space. Bacteria may be identifiable on Gram stain.
─ Chronic Pleuritis:
─ ─ Characterized by infiltration of the pleura by chronic inflammatory cells: lymphocytes (often forming aggregates or follicles), plasma cells, and macrophages (histiocytes).
─ ─ Proliferation of fibroblasts and capillaries (granulation tissue formation) is common as part of the healing and organization process.
─ ─ Organizing Pleuritis: The fibrinous exudate from acute pleuritis is gradually replaced by granulation tissue, which matures into fibrous connective tissue (collagen deposition), leading to pleural thickening or fibrous adhesions.
─ ─ Mesothelial cell hyperplasia (see previous entry) is a common reactive change overlying areas of pleuritis.
─ Specific types of pleuritis based on etiology:
─ ─ Tuberculous pleuritis: Often shows granulomatous inflammation (caseating or non-caseating epithelioid granulomas) within a background of lymphocytic and plasmacytic inflammation. AFB may be demonstrable.
─ ─ Rheumatoid pleuritis: Typically chronic inflammation with lymphocytes, plasma cells, fibrin deposition, cholesterol clefts, and sometimes characteristic rheumatoid nodules (central fibrinoid necrosis surrounded by palisading histiocytes and granulation tissue – rarely seen on pleural biopsy).
Ancillary studies ─
─ Special stains for microorganisms (Gram stain for bacteria, GMS for fungi, AFB for mycobacteria) on pleural biopsy tissue or pleural fluid are crucial if an infectious etiology is suspected.
─ Culture of pleural fluid and/or pleural biopsy tissue for bacteria, mycobacteria, and fungi.
─ Cytologic examination of any associated pleural effusion for inflammatory cells, mesothelial cells, and malignant cells.
─ IHC for mesothelial markers (Calretinin, WT1, etc.) can help identify reactive mesothelial cells; BAP1 IHC can help distinguish reactive from malignant mesothelial proliferation if mesothelioma is a concern.
DDx ─
─ Malignant Mesothelioma: Can be associated with pleuritis and pleural effusion, but is distinguished by the presence of neoplastic mesothelial cells showing invasion, significant atypia, and specific IHC/molecular features (e.g., BAP1 loss).
─ Metastatic Carcinoma involving the pleura: Can cause pleuritis and effusion; malignant epithelial cells identified by morphology and IHC (positive for adenocarcinoma markers like TTF-1, Napsin A for lung primary, or site-specific markers for other primaries; negative for mesothelial markers).
─ Reactive mesothelial hyperplasia versus epithelioid mesothelioma (see previous entry).
─ Specific infectious etiologies need to be identified or excluded based on special stains, cultures, and clinical context.
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Pleural Fibrosis and Fibrothorax (Diffuse Pleural Thickening)

Pleural fibrosis is the thickening of the visceral and/or parietal pleura by fibrous connective tissue; Fibrothorax refers to extensive, dense pleural fibrosis that encases a significant portion or all of a lung, leading to restricted lung expansion and impaired pulmonary function. Diffuse Pleural Thickening (DPT) is a descriptive term often used, particularly in the context of asbestos exposure, for widespread involvement.
Clinical ─
─ Can be asymptomatic if mild, or cause progressive dyspnea (especially on exertion), restrictive ventilatory defect on pulmonary function tests, and sometimes chest pain or discomfort
─ Numerous potential causes:
─ ─ Post-inflammatory: Complication of healed empyema, tuberculous pleurisy, bacterial pneumonia with complicated parapneumonic effusion, hemothorax, fungal pleuritis
─ ─ Asbestos exposure: A common cause of DPT, often bilateral, may involve visceral pleura and extend into fissures (distinct from circumscribed pleural plaques)
─ ─ Trauma or surgery (e.g., post-thoracotomy, post-CABG)
─ ─ Drug-induced (e.g., methysergide, ergotamine, amiodarone, practolol)
─ ─ Uremia (uremic pleuritis can lead to fibrosis)
─ ─ Connective tissue diseases (e.g., rheumatoid arthritis, SLE)
─ ─ Radiation therapy to the chest
─ ─ Idiopathic
Macro ─
─ Pleura appears thickened, opaque, and whitish-gray or pearly white, and feels firm or leathery
─ Can be focal or diffuse; in fibrothorax, it forms a thick, inelastic "peel" or "rind" encasing the lung, which may be visibly trapped or compressed
─ Adhesions between visceral and parietal pleura are common and can be extensive, sometimes obliterating the pleural space
─ Calcification may occur within the fibrotic areas, especially in long-standing cases
Micro ─
─ Characterized by the deposition of dense, often paucicellular or acellular, hyalinized collagenous connective tissue within the pleural layers (visceral and/or parietal)
─ The fibrous tissue typically contains elongated spindle cells (fibroblasts, myofibroblasts) which may be sparse in mature, hyalinized fibrosis
─ Elastic layers of the visceral pleura may be involved, duplicated, or disrupted by the fibrotic process
─ Chronic inflammatory infiltrates (lymphocytes, plasma cells) may be present, particularly in earlier stages or if the underlying inflammatory cause is ongoing, but are often scant in established, "burnt-out" fibrosis
─ Blood vessels within the fibrotic pleura may show thickened walls or hyalinization
─ Dystrophic calcification can be present
─ In fibrothorax, the fibrous tissue is extensive and forms a thick, constricting layer over the lung surface
─ Asbestos-related Diffuse Pleural Thickening (DPT): Often involves the visceral pleura, can be extensive and bilateral, may extend into interlobar fissures, and is sometimes associated with rounded atelectasis of the underlying lung parenchyma. Asbestos bodies are usually found in the lung parenchyma, not typically within the pleural fibrosis itself.
Ancillary studies ─
─ Generally not required for the diagnosis of fibrosis itself, as H&E morphology is usually characteristic
─ Trichrome stain (e.g., Masson's trichrome) can highlight the collagenous nature of the fibrosis
─ Elastic stains (e.g., Verhoeff-Van Gieson - VVG) can help assess involvement of pleural elastic layers and distinguish visceral from parietal pleural fibrosis in some contexts
─ Clinical history, imaging findings (e.g., extent and distribution of thickening, presence of calcification, associated lung disease), and exclusion of malignancy are key for determining etiology and significance
DDx ─
─ Desmoplastic Malignant Mesothelioma: A key differential, especially if fibrosis is extensive and cellularity/atypia is present. Mesothelioma is characterized by malignant spindle cells infiltrating stroma, often with a storiform or fascicular pattern, showing invasion into underlying structures (fat, muscle, lung), and positive for mesothelial markers (though can be challenging in desmoplastic type); BAP1 loss or CDKN2A/p16 deletion favors mesothelioma.
─ Pleural Plaques (Asbestos-related): Circumscribed, paucicellular, hyalinized collagenous lesions, typically on the parietal pleura, with a characteristic "basket-weave" pattern of collagen; distinct from diffuse pleural thickening.
─ Organizing Pleuritis: Represents an earlier stage of pleural healing, characterized by more cellular granulation tissue (proliferating fibroblasts, capillaries, inflammatory cells) organizing a fibrinous exudate; may progress to mature fibrosis.
─ Sarcomatoid Carcinoma or Sarcoma involving the pleura: Malignant spindle cell tumors with greater atypia, mitotic activity, necrosis, and specific IHC profiles.
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Pleural Plaques (Asbestos-related and other)

Circumscribed, often elevated, fibrohyaline lesions that primarily develop on the parietal pleura, and less commonly on the diaphragmatic pleura or visceral pleura over interlobar fissures; they are strongly associated with asbestos exposure and are considered a key marker of such exposure, though they can rarely have other non-asbestos related causes or be idiopathic
Clinical ─
─ Usually asymptomatic and discovered incidentally on chest radiography or CT scans
─ Typically appear 20-30 years or more after initial asbestos exposure (long latency period)
─ Generally do not cause significant pulmonary function impairment unless extremely extensive and confluent (which would then constitute diffuse pleural thickening)
─ Not considered premalignant lesions for mesothelioma or lung cancer, but their presence indicates asbestos exposure, which is a risk factor for those malignancies
─ Bilateral plaques are more specific for asbestos exposure than unilateral ones
Macro ─
─ Appear as irregular, well-demarcated, pearly white, ivory-colored, or grayish, firm, raised plaques on the pleural surfaces
─ Typically found on the posterolateral chest wall (often along ribs), dome of the diaphragm, and pericardium
─ Size and thickness are variable, from small flecks to large confluent plaques several centimeters across and up to 1 cm thick
─ May become calcified (especially with increasing age and duration of exposure), appearing very hard and radiopaque
Micro ─
─ Composed of dense, paucicellular or acellular, hyalinized collagen arranged in a characteristic "basket-weave" or laminated pattern, with fibers often running parallel to the pleural surface
─ Elastic fibers may be present within the plaque but are usually not prominent
─ The plaque is typically covered by a single layer of flattened or attenuated mesothelial cells on its free surface
─ Minimal or no inflammatory infiltrate is usually present within established plaques
─ Dystrophic calcification is common, appearing as basophilic, amorphous, or crystalline deposits
─ Asbestos bodies are usually not found within the plaques themselves (they are typically located in the lung parenchyma if asbestosis is also present)
Ancillary studies ─
─ Diagnosis is generally made based on characteristic radiological appearance in the context of a history of asbestos exposure; biopsy is rarely performed or indicated for typical pleural plaques
─ If biopsied, H&E morphology is usually diagnostic
DDx ─
─ Diffuse Pleural Thickening (DPT): More extensive, widespread pleural fibrosis, often involving visceral pleura, less demarcated than plaques, and can cause restrictive lung function. DPT can also be asbestos-related.
─ Malignant Mesothelioma (especially early or localized forms): Mesothelioma is a cellular, malignant neoplasm with atypia and invasion; plaques are paucicellular and non-invasive.
─ Metastatic Carcinoma to the pleura: Forms nodules or diffuse thickening composed of malignant epithelial cells; IHC for carcinoma markers positive.
─ Old, healed pleuritis with focal scarring or calcification: May resemble plaques if very localized and hyalinized, but often associated with underlying lung changes or adhesions, and may lack the classic basket-weave collagen.
─ Other rare pleural lesions (e.g., amyloidosis if forming plaques – Congo red positive).
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Pneumothorax (Spontaneous, Traumatic, Iatrogenic, Tension)

The presence of air or gas in the pleural space (between the visceral and parietal pleura), leading to partial or complete collapse (atelectasis) of the ipsilateral lung due to loss of negative intrapleural pressure
Clinical ─
─ Sudden onset of acute pleuritic chest pain (sharp, localized, worse with inspiration or cough) and dyspnea are common symptoms; severity depends on the size of the pneumothorax and the patient's underlying lung function
─ Physical examination may reveal decreased or absent breath sounds, hyperresonance to percussion on the affected side, and decreased chest expansion
─ Types:
─ ─ Spontaneous Pneumothorax:
─ ─ ─ Primary Spontaneous Pneumothorax (PSP): Occurs in individuals without clinically apparent underlying lung disease; often affects tall, thin young males (20s-30s) and is typically due to rupture of small apical subpleural blebs or bullae. Smoking is a major risk factor.
─ ─ ─ Secondary Spontaneous Pneumothorax (SSP): Occurs as a complication of pre-existing underlying lung disease, such as COPD (most common cause of SSP), asthma, cystic fibrosis, tuberculosis, lung cancer, interstitial lung diseases (e.g., Pulmonary Langerhans Cell Histiocytosis, Lymphangioleiomyomatosis, Birt-Hogg-Dubé syndrome – all associated with cysts/bullae).
─ ─ Traumatic Pneumothorax: Results from penetrating (e.g., stab wound, gunshot) or non-penetrating (e.g., rib fracture lacerating pleura, blunt trauma) chest injury.
─ ─ Iatrogenic Pneumothorax: Occurs as a complication of medical or surgical procedures (e.g., thoracentesis, central venous catheter insertion, lung biopsy, mechanical ventilation – barotrauma).
─ ─ Tension Pneumothorax: A life-threatening emergency where air enters the pleural space on inspiration but cannot exit on expiration (one-way valve effect), leading to progressive accumulation of air under positive pressure. This causes complete lung collapse, mediastinal shift to the contralateral side, impaired venous return to the heart, and cardiovascular compromise (hypotension, tachycardia). Requires immediate decompression.
Macro (Pathologic findings are usually not the primary diagnostic modality unless surgery or autopsy is performed for other reasons or complications):
─ Air within the pleural space.
─ Ipsilateral lung is partially or completely collapsed (atelectatic).
─ The underlying cause may be visible, such as ruptured apical blebs or bullae (in PSP or emphysema), cysts (in LAM, PLCH, BHD), or evidence of trauma or underlying lung disease.
Micro (Of resected lung tissue, e.g., blebectomy, or pleural biopsy if performed):
─ Histologic findings may reveal the underlying cause of the pneumothorax:
─ ─ Ruptured blebs (small subpleural air cysts within visceral pleura) or bullae (larger emphysematous spaces >1 cm).
─ ─ Features of emphysema, cystic lung diseases (LAM, PLCH, BHD), interstitial fibrosis, or other underlying lung pathology.
─ Pleural reaction can occur, especially with recurrent or complicated pneumothorax:
─ ─ Acute inflammation (neutrophils, fibrin) if associated with irritation or infection.
─ ─ Mesothelial cell hyperplasia.
─ ─ Chronic inflammation and fibrosis (pleural thickening, adhesions) with recurrent episodes.
Ancillary studies ─
─ Diagnosis of pneumothorax is primarily clinical and radiological (chest X-ray – shows visceral pleural line, absence of lung markings peripherally; CT scan is more sensitive for small pneumothoraces and underlying lung disease).
─ Pathologic examination is usually focused on any resected lung tissue (e.g., during VATS bullectomy and pleurodesis) to identify the cause of spontaneous pneumothorax or assess for other pathology.
DDx (Clinical differential for symptoms):
─ Other causes of acute dyspnea and/or chest pain: Pulmonary embolism, myocardial infarction, acute pericarditis, pneumonia, aortic dissection, musculoskeletal pain.
─ Radiological differential: Large emphysematous bulla (can mimic pneumothorax by appearing as a lucent area, but will have a thin wall and compressed lung around it, not a visible visceral pleural line of a collapsed lung), diaphragmatic hernia, cystic lung disease without pneumothorax.
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Pleural Endometriosis

The presence of endometrial glands and endometrial stroma on or within the pleural surfaces (visceral, parietal, or diaphragmatic pleura); it is a rare manifestation of extragenital endometriosis
Clinical ─
─ Affects women of reproductive age, typically between 30-40 years.
─ Symptoms are often catamenial (occurring cyclically in relation to the menstrual cycle) and may include:
─ ─ Catamenial pneumothorax: Recurrent pneumothorax occurring within 24-72 hours of the onset of menstruation; most common manifestation, usually right-sided. Thought to be due to air passage through diaphragmatic defects or rupture of endometrial blebs.
─ ─ Catamenial hemothorax or bloody pleural effusion.
─ ─ Catamenial chest pain (pleuritic pain).
─ ─ Catamenial hemoptysis (rare, implies parenchymal endometrial implants).
─ Thoracic endometriosis syndrome (TES) encompasses these manifestations.
─ Pathogenesis is debated: theories include retrograde menstruation with transdiaphragmatic passage of endometrial cells, lymphatic or hematogenous embolization of endometrial cells, or coelomic metaplasia.
Macro (Usually identified during thoracoscopy or surgery):
─ Typically appears as small (millimeters to a few centimeters), discrete, reddish-blue, brown, black, or puckered nodules, plaques, blebs, or patches on the pleural surfaces, most commonly on the diaphragmatic pleura (especially right hemidiaphragm) or visceral pleura.
─ Fenestrations or defects in the diaphragm may be seen, particularly in cases of catamenial pneumothorax.
─ May be associated with old hemorrhage (hemosiderin staining) or fibrous adhesions.
Micro ─
─ Definitive diagnosis requires the presence of both endometrial-type glands and endometrial stroma:
─ Endometrial glands: Lined by cuboidal to columnar epithelial cells, which may be ciliated or non-ciliated. Glands can show cyclic changes (proliferative or secretory features depending on the phase of the menstrual cycle) if hormonally responsive, but are often inactive or atrophic.
─ Endometrial stroma: A specialized, cellular stroma composed of small, compact spindle to ovoid cells with scant cytoplasm and dark nuclei, typically surrounding the endometrial glands. This stroma is crucial for diagnosis.
─ Hemosiderin-laden macrophages are usually present within or adjacent to the endometrial implants, indicating previous hemorrhage.
─ Fibrosis and a mild chronic inflammatory infiltrate (lymphocytes, plasma cells) may be associated with the implants.
─ Decidual change (large polygonal cells with abundant eosinophilic cytoplasm) can occur in endometrial stroma during pregnancy or progestin therapy.
Ancillary studies ─
─ IHC can be very helpful in confirming the diagnosis, especially on small biopsies:
─ ─ Endometrial stromal cells: Characteristically positive for CD10 (a sensitive and relatively specific marker for endometrial stroma). Also often positive for ER (Estrogen Receptor) and PR (Progesterone Receptor).
─ ─ Endometrial epithelial cells: Positive for cytokeratins (e.g., CK7 often positive, AE1/AE3), EMA. Also usually positive for ER and PR. WT1 can be positive in the epithelial cells (similar to ovarian serous tumors or normal Müllerian epithelium, so interpret with caution and in panel).
─ ─ Calretinin, WT1 (nuclear in mesothelial cells), D2-40 should be negative in endometrial components (to exclude mesothelial origin).
DDx ─
─ Metastatic Adenocarcinoma (especially endometrioid adenocarcinoma from uterus/ovary, or serous carcinoma from ovary/peritoneum): Malignant tumors will show greater cytologic atypia, infiltrative growth, and a different IHC profile (e.g., PAX8 is often positive in Müllerian metastases, but can also be positive in some endometrial implants; CD10 positivity of stroma is key for endometriosis).
─ Endosalpingiosis: Presence of benign fallopian tube-type epithelium (ciliated cells, intercalary/peg cells, psammoma bodies may be present) on peritoneal or pleural surfaces, but characteristically LACKS endometrial stroma. CD10 negative stroma.
─ Malignant Mesothelioma: Neoplastic proliferation of mesothelial cells; positive for mesothelial markers (calretinin, WT1, CK5/6, D2-40).
─ Organizing hemorrhage or pleuritis with hemosiderin deposition and reactive changes: May contain hemosiderin-laden macrophages but lacks endometrial glands and stroma.
─ Deciduosis (ectopic decidual reaction): Presence of decidualized stromal cells without glands, typically occurs during pregnancy.
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Pleural Splenosis

Acquired autotransplantation of splenic tissue onto pleural surfaces, typically following thoracoabdominal trauma with diaphragmatic and splenic rupture
Clinical ─ Often asymptomatic and discovered incidentally years after trauma (average 20 years), more common in males, history of splenic injury/splenectomy and diaphragmatic rupture is key, usually no specific lab findings, generally benign with no malignant potential but can mimic malignancy
Macro ─ Multiple, small (can grow large), sessile or rounded, reddish-blue nodules on the pleural surfaces, most commonly in the left hemithorax
Micro ─ Histologically normal splenic tissue is present, including:
─ Red pulp (venous sinusoids and cords of Billroth)
─ White pulp (lymphoid follicles, periarteriolar lymphoid sheaths)
─ Capsule may be absent or poorly formed as implants derive blood supply from surrounding pleura
Ancillary studies ─ ─ IHC (+) Typically not required for diagnosis if histology is classic; splenic tissue markers can be used if needed (e.g CD8 for sinusoids, CD20/CD3 for lymphoid components) but are often not specific in this context
─ IHC (-) Markers to exclude malignancy if morphology is atypical (e.g cytokeratins for mesothelioma/carcinoma)
─ Imaging ─ Tc-99m sulfur colloid scan or Tc-99m-tagged heat-damaged red blood cell (DRBC) scan is highly specific, showing uptake in the ectopic splenic tissue
DDx ─ ─ Metastatic disease (most important differential)
─ Malignant mesothelioma
─ Endometriosis (if female with pelvic symptoms, though morphology is distinct)
─ Hemangioma
─ Lymphoma
─ Accessory spleen (congenital, usually near splenic hilum, has own hilar vasculature)
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Calcifying Fibrous Tumor of the Pleura

A rare, benign mesenchymal neoplasm characterized by hyalinized collagen, bland spindle cells, psammomatous or dystrophic calcifications, and a lymphoplasmacytic infiltrate
Clinical ─ Affects a wide age range including children and young adults, no clear sex predilection, usually asymptomatic and found incidentally on imaging; may cause chest pain or dyspnea if large, excellent prognosis with complete surgical excision, recurrence is rare
Macro ─ Well-circumscribed, firm, unencapsulated, white-tan, lobulated mass; cut surface may be gritty due to calcifications, variable size (can be very large)
Micro ─ Key features include:
─ Hypocellular to moderately cellular bland spindle cells with ovoid to elongated nuclei and inconspicuous nucleoli, embedded in a densely hyalinized collagenous stroma
─ Prominent psammomatous and/or dystrophic calcifications
─ A variable chronic inflammatory infiltrate, often rich in plasma cells and lymphocytes, sometimes forming lymphoid aggregates or germinal centers
─ No significant cytologic atypia, necrosis, or high mitotic activity
Ancillary studies ─ ─ IHC (+) Vimentin, Factor XIIIa (variable), CD34 (can be focally positive in some cases), IgG4 (plasma cells may be positive, raising consideration for IgG4-related disease context in some cases, but not specific for CFT itself)
─ IHC (-) ALK1 (usually negative, helps distinguish from inflammatory myofibroblastic tumor), S100 protein, desmin, smooth muscle actin (SMA) (usually negative or only focally positive), cytokeratins, CD117 (c-kit), DOG1
─ Molecular ─ Generally no specific recurrent molecular alterations identified; ALK rearrangements are absent
DDx ─ ─ Solitary fibrous tumor (SFT) (more cellular, "patternless pattern", staghorn vessels, STAT6 positive, CD34 often positive)
─ Inflammatory myofibroblastic tumor (IMT) (more cellular, fascicular spindle cells, prominent plasma cells and eosinophils, ALK positive in ~50%)
─ Desmoplastic mesothelioma (more infiltrative, atypical mesothelial cells, positive for mesothelial markers)
─ Hyalinizing granuloma / Sclerosing pneumocytoma (if intrapulmonary involvement considered, but different histology)
─ Reactive pleural fibrosis/plaque (often paucicellular, lacks prominent calcifications and the specific inflammatory infiltrate of CFT, may be asbestos-related)
─ IgG4-related disease (may show storiform fibrosis and IgG4+ plasma cells, but CFT has more prominent hyalinization and calcification typically)
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Pleural Effusions

An abnormal accumulation of fluid in the pleural space
Clinical ─ Symptoms vary with size and cause; dyspnea, cough, pleuritic chest pain; detected by physical exam, imaging (X-ray, CT, ultrasound); thoracentesis for diagnosis and therapy; classified as transudate or exudate based on fluid analysis (Light's criteria commonly used: fluid/serum protein ratio >0.5, fluid/serum LDH ratio >0.6, or fluid LDH >2/3 upper limit of normal serum LDH suggest exudate)
Types of Effusions:
─ Transudate
─ Pathophysiology: Due to increased hydrostatic pressure or decreased oncotic pressure
─ Common causes: Congestive heart failure (most common), cirrhosis with ascites, nephrotic syndrome, hypoalbuminemia, peritoneal dialysis
─ Fluid characteristics: Clear, pale yellow, low protein (<3 g/dL), low LDH, low specific gravity, few cells
─ Exudate
─ Pathophysiology: Due to increased capillary permeability or decreased lymphatic drainage, often from inflammation or malignancy
─ Common causes: Pneumonia (parapneumonic effusion), malignancy, viral infection, pulmonary embolism, tuberculosis, autoimmune disease (e.g RA, SLE), pancreatitis, trauma
─ Fluid characteristics: Cloudy, turbid, higher protein (>3 g/dL), higher LDH, variable cell counts (neutrophils in acute inflammation, lymphocytes in chronic inflammation/TB/malignancy, eosinophils in specific conditions)
Specific Types of Exudative Effusions:
─ Serous Effusion: Clear, straw-colored; can be transudate or exudate
─ Fibrinous/Serofibrinous Effusion: Contains fibrin, often seen with pleuritis; common in autoimmune diseases, infection, post-MI
─ Suppurative Effusion (Empyema): Contains pus (frank neutrophils, necrotic debris); due to bacterial or fungal infection
─ Hemorrhagic Effusion: Bloody; causes include trauma, malignancy (most common cause of large bloody effusions), pulmonary infarction, pancreatitis, tuberculosis; hematocrit of pleural fluid >50% of peripheral blood indicates hemothorax
─ Chylous Effusion (Chylothorax): Milky white fluid rich in triglycerides (>110 mg/dL) and chylomicrons; due to disruption or obstruction of thoracic duct (e.g trauma, surgery, malignancy like lymphoma, congenital malformations)
─ Pseudochylous Effusion (Cholesterol Effusion): Turbid, milky, or shimmering gold-paint appearance with high cholesterol content (often >200-250 mg/dL) and cholesterol crystals; typically seen in long-standing chronic effusions (e.g rheumatoid arthritis, tuberculosis, trapped lung)
─ Eosinophilic Pleural Effusion: Defined by pleural fluid eosinophils >10% of total nucleated cells; common causes include air or blood in pleural space (pneumothorax, hemothorax, trauma, surgery), infections (parasitic, fungal, sometimes bacterial/viral), malignancy, drug reactions, asbestos exposure, idiopathic
Micro ─ (Cytology or cell block of pleural fluid)
Depends on the nature and cause of the effusion:
─ Transudates: Paucity of cells, mainly mesothelial cells, macrophages
─ Exudates: Variable cellularity
─ Neutrophils: Prominent in acute inflammation (parapneumonic effusions, empyema)
─ Lymphocytes: Prominent in chronic inflammation, tuberculosis, malignancy (lymphoma, carcinoma), viral pleuritis, autoimmune diseases
─ Eosinophils: In eosinophilic effusions
─ Mesothelial cells: Single or in flat sheets, bland nuclei, prominent nucleoli, "windows" between cells; can be reactive and atypical, posing diagnostic challenge
─ Malignant cells: Clusters or single atypical cells (e.g adenocarcinoma, squamous cell carcinoma, mesothelioma, lymphoma/leukemia cells)
─ Other findings: Cholesterol crystals (rhomboid, notched plates in pseudochylous effusion), hemosiderin-laden macrophages (previous hemorrhage), LE cells (SLE), rheumatoid nodules/necrotic background (rheumatoid pleuritis)
Ancillary studies ─ (On pleural fluid/cell block)
─ Biochemical analysis: Protein, LDH, glucose, amylase, triglycerides, cholesterol, pH, adenosine deaminase (ADA for TB)
─ Microbiology: Gram stain, cultures (bacterial, fungal, mycobacterial), AFB stain
─ Cytology: Papanicolaou and Giemsa stains for cell morphology and malignancy detection
─ IHC (on cell block): To differentiate reactive mesothelial cells from adenocarcinoma (e.g Calretinin, WT1, CK5/6, D2-40 for mesothelial; MOC31, CEA, BerEP4, TTF-1, Napsin A for adenocarcinoma) or characterize lymphoid infiltrates
─ Flow cytometry: For suspected lymphoma/leukemia
DDx ─ (Clinically, and for cytologic interpretation)
─ For specific fluid types: Various causes listed above
─ Cytologic DDx: Reactive mesothelial hyperplasia vs Malignant mesothelioma vs Adenocarcinoma
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Pleuritis/Pleurisy

Inflammation of the pleura
Clinical ─ Characteristic symptom is pleuritic chest pain (sharp, localized pain worse with deep inspiration, coughing, or movement); may be associated with pleural friction rub on auscultation, dyspnea, cough, fever depending on underlying cause; numerous causes including infection, autoimmune disease, malignancy, trauma, pulmonary embolism
Micro ─ Histologic appearance evolves over time:
─ Acute Pleuritis:
─ Vascular congestion and edema of the submesothelial connective tissue
─ Infiltration by neutrophils, later by macrophages and lymphocytes
─ Mesothelial cells may become reactive, swollen, or sloughed
─ Fibrinous exudate on pleural surfaces (fibrinous pleuritis): eosinophilic meshwork of fibrin, may contain trapped inflammatory cells; can lead to adhesions if not resolved
─ Chronic Pleuritis:
─ Predominance of lymphocytes, plasma cells, and macrophages in thickened pleura
─ Fibroblastic proliferation and collagen deposition leading to pleural thickening/fibrosis
─ Vascular proliferation
─ Can result in fibrous adhesions or diffuse pleural fibrosis
─ Organizing Pleuritis:
─ Fibrin is replaced by granulation tissue (capillaries, fibroblasts, myofibroblasts)
─ Eventually matures into fibrous tissue (collagen)
Specific Patterns:
─ Suppurative Pleuritis (Empyema): Gross pus in pleural space; histologically shows sheets of neutrophils, necrotic debris, bacteria; often walled off by granulation tissue and fibrous tissue (pyogenic membrane)
─ Granulomatous Pleuritis: Presence of granulomas (epithelioid histiocytes, multinucleated giant cells, lymphocytes); causes include tuberculosis (often caseating), fungal infections, sarcoidosis, rheumatoid disease (necrotizing granulomas near surface)
Ancillary studies ─ ─ IHC (+) Not typically primary for diagnosis of pleuritis itself, but can help identify underlying causes in biopsy (e.g specific organisms, markers for malignancy if present)
─ Special stains: For organisms (Gram, GMS, AFB) if infection suspected
DDx ─ ─ Reactive mesothelial hyperplasia (can be florid in pleuritis) vs Malignant mesothelioma
─ Specific causes of pleuritis need to be differentiated based on clinical context and specific histologic clues (e.g granulomas for TB/fungus, malignant cells for cancer)
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Pleural Fibrosis and Fibrothorax

Deposition of collagenous tissue in the pleura leading to thickening, adhesions, or encasement of the lung
Clinical ─ Can be asymptomatic if mild; extensive fibrosis (fibrothorax) can cause restrictive lung disease, dyspnea, chest pain, decreased chest wall movement; may follow various insults like infection (empyema, TB), hemothorax, asbestos exposure, uremia, autoimmune diseases, radiation, drugs, or be idiopathic
Macro ─ ─ Localized or diffuse pleural thickening; can be smooth or nodular
─ Fibrous adhesions between visceral and parietal pleura, potentially obliterating the pleural space
─ Fibrothorax: Thick, dense, inelastic fibrous peel encasing the lung, restricting its expansion
Micro ─ ─ Paucicellular or variably cellular proliferation of bland spindle cells (fibroblasts, myofibroblasts) in a dense, collagenous stroma
─ Collagen can be arranged in thick, hyalinized bundles
─ Minimal to mild chronic inflammatory infiltrate (lymphocytes, plasma cells) may be present
─ Blood vessels may be sparse or prominent depending on stage
─ Calcification can occur in long-standing fibrosis
─ No significant atypia, necrosis, or high mitotic activity to suggest malignancy
─ Diffuse Pleural Thickening (DPT): A specific form often related to asbestos exposure, involving visceral pleura, often extensive, can lead to restrictive physiology
Ancillary studies ─ ─ IHC (+) Vimentin; spindle cells may show variable SMA or muscle actin if myofibroblastic
─ IHC (-) Cytokeratins (to exclude desmoplastic mesothelioma), STAT6 (to exclude solitary fibrous tumor if nodular)
DDx ─ ─ Desmoplastic mesothelioma (infiltrative growth, entrapment of structures, atypical mesothelial cells which may be subtle, positive for mesothelial markers like calretinin, WT1, CK5/6 in cellular areas)
─ Solitary fibrous tumor (more cellular, distinct architecture often with "patternless pattern" and hemangiopericytoma-like vessels, STAT6 positive)
─ Calcifying fibrous tumor (distinct hyalinized collagen, psammomatous calcifications, prominent lymphoplasmacytic infiltrate)
─ Pleural plaques (typically discrete, hyalinized, basket-weave collagen, often parietal)
─ Organizing pleuritis/empyema (more inflammatory cells, granulation tissue in earlier stages)
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Pleural Plaques

Circumscribed, localized areas of pleural thickening, typically composed of dense, hyalinized collagen; most commonly associated with asbestos exposure
Clinical ─ Usually asymptomatic, discovered incidentally on chest imaging (X-ray, CT); considered a marker of asbestos exposure but not pre-malignant themselves; typically appear 10-30 years after initial exposure, bilateral involvement is common
Macro ─ ─ Raised, well-demarcated, pearly white to gray-white, smooth or slightly nodular plaques
─ Most commonly on the parietal pleura, especially posterolaterally, along ribs, over the diaphragm, and on the pericardium
─ Visceral pleura is rarely primarily involved, though plaques may extend to it
─ May become calcified, especially with longer duration
Micro ─ ─ Relatively acellular or hypocellular
─ Composed of dense, hyalinized collagen bundles, often arranged in a characteristic "basket-weave" pattern
─ Minimal to no inflammatory cells or spindle cell atypia
─ May show focal calcification
─ Covered by a single layer of flattened or attenuated mesothelial cells, or mesothelial cells may be absent
─ Distinct from underlying fatty tissue or muscle of the chest wall
─ Non-asbestos related plaques can occur (e.g after infection, trauma, hemothorax) but are often unilateral or have different distribution/morphology
Ancillary studies ─ ─ Generally not required for diagnosis if classic imaging and/or history of asbestos exposure is present
─ IHC (-) Not typically performed; negative for mesothelial markers and STAT6 if DDx with mesothelioma or SFT is considered in atypical biopsy presentations
DDx ─ ─ Diffuse pleural thickening (more extensive, often involves visceral pleura, symptomatic)
─ Malignant mesothelioma (cellular, atypical mesothelial cells, infiltrative, positive for mesothelial markers)
─ Solitary fibrous tumor (cellular spindle cell neoplasm, STAT6 positive)
─ Pleural fibrosis from other causes (e.g post-infectious, post-traumatic – may lack classic basket-weave and location)
─ Metastatic carcinoma (nodular, cellular, atypical epithelial cells, positive for carcinoma markers)
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Rounded Atelectasis

(Blesovsky Syndrome, Folded Lung Syndrome) A form of peripheral lung collapse where a portion of lung parenchyma rounds up and becomes trapped by thickened, infolded visceral pleura, often associated with asbestos-related pleural disease
Clinical ─ Often asymptomatic and discovered incidentally on chest imaging; may cause mild dyspnea or chest pain; strongly associated with asbestos exposure and benign pleural effusions/thickening, but can occur with other causes of pleural inflammation or scarring (e.g tuberculosis, histoplasmosis, post-cardiac surgery, uremic pleuritis); usually stable but can slowly progress; important to differentiate from lung cancer
Macro ─ Grossly, the lesion appears as a rounded or oval subpleural mass with thickened, retracted visceral pleura; characteristic "comet tail" sign on CT (bronchovascular bundles sweeping into the rounded mass)
Micro ─ ─ Compressed and collapsed lung parenchyma (atelectasis) with crowded alveoli and approximated bronchioles
─ Overlying visceral pleura is markedly thickened and fibrotic, often hyalinized, and may show chronic inflammation
─ The thickened pleura typically folds inwards, invaginating into the lung parenchyma and trapping portions of it
─ Entrapped lung tissue may show non-specific changes like alveolar septal fibrosis, inflammation, or entrapped airspaces
─ No evidence of neoplastic cells; bland cytology of entrapped pneumocytes and bronchial epithelium
Ancillary studies ─ ─ IHC (+) Not usually required for diagnosis; IHC can confirm epithelial nature of entrapped lung (e.g TTF-1, Napsin A in pneumocytes) and mesothelial nature of overlying pleura (e.g calretinin, WT1) if there's diagnostic confusion with a neoplasm on a small biopsy, but morphology and imaging are key
─ IHC (-) Markers for malignancy would be negative
DDx ─ ─ Peripheral lung carcinoma (most important DDx; shows malignant cytology, infiltrative growth, desmoplasia different from pleural fibrosis)
─ Localized fibrous tumor of the pleura (solitary fibrous tumor) (spindle cell neoplasm, STAT6 positive, arises from pleura not collapsed lung)
─ Malignant mesothelioma (neoplastic mesothelial cells, more diffuse pleural involvement typically, positive mesothelial markers)
─ Inflammatory pseudotumor (myofibroblastic proliferation, more cellular, often ALK positive)
─ Organizing pneumonia (intraluminal plugs of granulation tissue within alveoli, different pattern)
─ Pulmonary infarct (coagulative necrosis, hemorrhage, different clinical context)
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Pneumothorax

Presence of air or gas in the pleural cavity, leading to partial or complete collapse of the lung
Clinical ─ Symptoms vary from asymptomatic (small pneumothorax) to severe dyspnea, acute chest pain (often pleuritic, sudden onset), and respiratory distress; decreased breath sounds and hyperresonant percussion on affected side; Tension pneumothorax is a medical emergency with hemodynamic compromise (hypotension, tachycardia, tracheal deviation away from affected side)
Types and Etiology:
─ Spontaneous Pneumothorax
─ ─ Primary Spontaneous Pneumothorax (PSP): Occurs without underlying lung disease; typically in tall, thin young males (20-40 yrs); associated with rupture of apical subpleural blebs or bullae
─ ─ Secondary Spontaneous Pneumothorax (SSP): Occurs as a complication of underlying lung disease (e.g COPD (most common), asthma, cystic fibrosis, tuberculosis, interstitial lung disease, lung cancer, catamenial pneumothorax in endometriosis)
─ Traumatic Pneumothorax: Due to penetrating or non-penetrating chest trauma (e.g rib fracture, stab wound, gunshot wound)
─ Iatrogenic Pneumothorax: Resulting from medical procedures (e.g transthoracic needle aspiration, central line placement, thoracentesis, mechanical ventilation (barotrauma))
─ Tension Pneumothorax: Air enters pleural space during inspiration but cannot exit during expiration (one-way valve effect), leading to progressive accumulation of air, increased intrapleural pressure, lung collapse, mediastinal shift, and impaired venous return to the heart
Micro ─ (Pathologic findings are often of the underlying cause or complications, rather than pneumothorax itself, unless pleural tissue is resected)
─ Ruptured blebs or bullae (thin-walled, dilated airspaces, often subpleural; blebs are intrapleural, bullae are intraparenchymal) may be seen if tissue is resected
─ Underlying lung disease pathology (e.g emphysema in COPD, granulomas in TB)
─ Pleural reaction may occur with inflammation, mesothelial cell reactivity, or fibrosis, especially in recurrent or chronic cases
─ Eosinophilic pleural inflammation can be seen, particularly in recurrent spontaneous pneumothorax
Ancillary studies ─ ─ Imaging (Chest X-ray, CT scan) is primary for diagnosis, showing visceral pleural line and absence of lung markings peripherally
─ Pathologic examination of resected blebs/bullae or pleura in surgical cases (e.g VATS pleurectomy or bullectomy)
DDx ─ (Clinical diagnosis primarily)
─ Myocardial infarction
─ Pulmonary embolism
─ Pericarditis
─ Musculoskeletal chest pain
─ Large bulla (can mimic pneumothorax on X-ray)
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Mesothelial Tumors and Proliferations

Well-Differentiated Papillary Mesothelial Tumor (WDPMT)

A rare mesothelial proliferation characterized by a superficial, non-invasive papillary architecture and bland cytology, with a generally indolent clinical course
Clinical ─ Often an incidental finding, typically in the peritoneum of women of reproductive age, but can occur in the pleura (and pericardium, tunica vaginalis) in both sexes and wide age range; usually asymptomatic, can be associated with asbestos exposure in some pleural cases; recurrence is uncommon but can occur, malignant transformation is very rare but reported
Macro ─ Usually small (<2 cm), multiple, discrete, gray-white, wart-like or papillary nodules on the serosal surface; can be solitary
Micro ─ ─ Exophytic papillary structures with fibrovascular cores lined by a single layer of bland, cuboidal to flattened mesothelial cells
─ Mesothelial cells show minimal to no cytologic atypia, uniform nuclei, inconspicuous nucleoli, and low mitotic activity (typically <1 mitosis/10 HPF, often none)
─ No stromal invasion; the proliferation is confined to the serosal surface
─ Psammoma bodies may be present
─ Stroma of papillae is usually paucicellular and fibrous, may be edematous or hyalinized
─ Simple tubular structures or small solid nests may be present but are not predominant
Ancillary studies ─ ─ IHC (+) Calretinin, WT1 (nuclear), CK5/6, D2-40 (podoplanin), EMA (epithelial membrane antigen), Cytokeratin (AE1/AE3, CAM5.2) – consistent with mesothelial origin
─ IHC (-) Markers of adenocarcinoma (e.g MOC31, BerEP4, CEA, TTF-1, Napsin A) are negative
─ IHC (Prognostic/Invasion markers): BAP1 expression is typically retained (loss is common in malignant mesothelioma); MTAP expression retained; CDKN2A (p16) typically not deleted by FISH (homozygous deletion common in malignant mesothelioma); Ki-67 proliferation index is low
─ Molecular ─ Most cases lack BAP1 mutations and CDKN2A homozygous deletion, which are common in epithelioid malignant mesothelioma
DDx ─ ─ Malignant epithelioid mesothelioma (shows frank invasion, greater cytologic atypia, higher mitotic activity, necrosis, complex architecture, often BAP1 loss and/or CDKN2A homozygous deletion)
─ Reactive mesothelial hyperplasia (often flatter, more admixed inflammation, typically in response to irritation/effusion; can be very difficult to distinguish from WDPMT if floridly papillary, but WDPMT is generally more structured and clonal)
─ Papillary carcinoma metastatic to pleura (e.g ovarian, thyroid, lung adenocarcinoma; positive for carcinoma markers like PAX8, TTF-1, Napsin A, etc, and negative for most mesothelial markers)
─ Adenomatoid tumor (rare in pleura, more common in genital tract; has glandular/tubular/cord-like patterns, but is also a benign mesothelial proliferation)
─ Mesothelioma in situ (proposed entity; flat or micropapillary proliferation of atypical mesothelial cells without invasion but with molecular alterations of mesothelioma like BAP1 loss or CDKN2A deletion)
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Adenomatoid Tumor

A rare, benign mesothelial proliferation typically found in the genital tract, but occasionally occurs in the pleura, characterized by glandular, tubular, or cord-like structures lined by flattened to cuboidal cells
Clinical ─ Most pleural cases are incidental findings in asymptomatic individuals; can occur over a wide age range, no clear sex predilection for pleural lesions; extremely rare in the pleura compared to genital tract; generally considered benign with an excellent prognosis after complete surgical excision
Macro ─ Usually a small, solitary, well-circumscribed, firm, gray-white nodule on the pleural surface, typically <2 cm
Micro ─ Consists of variably sized tubules, cords, and microcysts lined by flattened, cuboidal, or vacuolated cells resembling endothelial or mesothelial cells, set in a fibrous or hyalinized stroma:
─ Architectural patterns: Glandular/tubular, angiomatoid, solid, cystic, or mixed
─ Cells have bland, vesicular nuclei, inconspicuous nucleoli, and eosinophilic or vacuolated cytoplasm (signet-ring like cells can be seen but are not true mucin-containing)
─ Minimal to no cytologic atypia or mitotic activity
─ Stroma can be fibrous, hyalinized, or edematous, and may contain smooth muscle or lymphoid aggregates
─ No invasion into underlying tissue
Ancillary studies ─ ─ IHC (+) Calretinin, WT1 (nuclear), CK5/6, D2-40 (podoplanin), HBME-1, EMA, pan-cytokeratin (AE1/AE3, CAM5.2) – confirms mesothelial origin
─ IHC (-) CEA, MOC31, BerEP4, Claudin-4 (typically negative or weak, helping to distinguish from adenocarcinoma)
─ Special stains: Mucicarmine or PAS-D negative (vacuoles are not mucin)
DDx ─ ─ Malignant mesothelioma, epithelioid type (invasive growth, cytologic atypia, higher mitotic rate, complex architecture, potential BAP1 loss or CDKN2A deletion)
─ Metastatic adenocarcinoma (especially signet ring cell carcinoma; positive for adenocarcinoma markers like CEA, MOC31, CDX2, TTF-1 depending on origin, negative for most mesothelial markers)
─ Reactive mesothelial hyperplasia (often flatter, associated with inflammation/effusion, less architectural complexity)
─ Well-differentiated papillary mesothelial tumor (WDPMT) (distinctly papillary architecture)
─ Angiosarcoma (more atypical endothelial cells, complex vascular channels, positive for endothelial markers like CD31, ERG)
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Malignant Mesothelioma

An aggressive malignant neoplasm arising from mesothelial cells lining the pleura, peritoneum, pericardium, or tunica vaginalis, strongly associated with asbestos exposure, especially in the pleura
Clinical ─ Pleural mesothelioma is most common; long latency after asbestos exposure (20-50+ years); symptoms include insidious onset of dyspnea, non-pleuritic chest pain, weight loss, fatigue; often presents with large unilateral pleural effusion; prognosis is generally poor, though variable by histologic type and stage
Macro ─ ─ Diffuse thickening of the pleura, encasing the lung like a rind ("sheet-like growth")
─ Multiple nodules or masses on pleural surfaces
─ Obliteration of the pleural space by tumor and effusion
─ May invade chest wall, diaphragm, mediastinal structures, or lung parenchyma
Micro ─ Histologic Types:
─ Epithelioid Mesothelioma (50-70% of cases):
─ ─ Composed of cells resembling normal mesothelial cells, but with malignant features
─ ─ Architectural patterns: Tubulopapillary, trabecular, acinar, solid/sheet-like, micropapillary, adenomatoid-like, clear cell, deciduoid, small cell
─ ─ Cells are cuboidal, polygonal, or oval with eosinophilic cytoplasm, round to oval nuclei, vesicular chromatin, and variably prominent nucleoli
─ ─ Cytologic atypia can range from bland to markedly pleomorphic
─ ─ Mitotic activity is variable
─ Sarcomatoid Mesothelioma (10-20% of cases):
─ ─ Composed of spindle cells resembling fibrosarcoma or other sarcomas
─ ─ Cells are elongated, with tapered nuclei, and arranged in fascicles or storiform patterns
─ ─ May have marked pleomorphism, high mitotic activity, and necrosis
─ ─ May produce collagen or osteoid/chondroid matrix (rare)
─ Biphasic (Mixed) Mesothelioma (20-30% of cases):
─ ─ Contains distinct components of both epithelioid and sarcomatoid mesothelioma
─ ─ Diagnosis requires at least 10% of each component
─ ─ Prognosis is intermediate, often closer to sarcomatoid type depending on proportion
─ Desmoplastic Mesothelioma:
─ ─ A rare, paucicellular variant of sarcomatoid mesothelioma (<5% of cases)
─ ─ Characterized by dense, hyalinized collagenous stroma with bland-appearing, often sparse spindle cells that deeply invade adipose tissue or skeletal muscle of the chest wall
─ ─ Often has a "patternless" pattern of fibrosis
─ ─ Diagnosis can be challenging on small biopsies due to bland cytology and paucicellularity; deep invasion is a key feature
Rare Variants (often considered within epithelioid or sarcomatoid categories):
─ Lymphohistiocytoid Mesothelioma: Predominantly inflammatory infiltrate rich in lymphocytes and histiocytes, obscuring a smaller population of neoplastic mesothelial cells; generally considered a variant of epithelioid mesothelioma with a better prognosis
─ Small Cell Mesothelioma: Composed of small, round blue cells with scant cytoplasm, mimicking small cell carcinoma; very rare, aggressive
─ Deciduoid Mesothelioma: A variant of epithelioid mesothelioma with large, discohesive cells with abundant glassy eosinophilic cytoplasm and prominent nucleoli, resembling decidual cells
Grading of Epithelioid Mesothelioma:
─ Nuclear atypia and mitotic count are used in some proposed grading systems for epithelioid mesothelioma to predict prognosis (e.g low grade vs high grade)
─ High grade features: Moderate to severe nuclear atypia, high mitotic rate (e.g ≥5 mitoses/10 HPF or per 2 mm²), presence of necrosis
Ancillary studies ─ ─ IHC (+) (Confirm mesothelial origin and malignancy)
─ ─ Pan-Mesothelial markers: Calretinin (nuclear and cytoplasmic), WT1 (nuclear), CK5/6 (cytoplasmic/membranous), D2-40 (podoplanin, membranous) – a panel of at least two is recommended
─ ─ Other positive markers: EMA (membranous, often thick), HBME-1 (membranous), Thrombomodulin
─ ─ Markers of malignancy/prognosis: BAP1 (loss of nuclear expression in ~60-70% of mesotheliomas, supports malignancy over reactive hyperplasia), MTAP (loss of expression, correlated with CDKN2A deletion), GLUT1 (membranous staining supports malignancy), Desmin (often positive in sarcomatoid type)
─ IHC (-) (To exclude other tumors, especially adenocarcinoma and synovial sarcoma)
─ ─ Adenocarcinoma markers: Claudin-4 (usually negative/weak focal in mesothelioma, strong/diffuse in adenocarcinoma), MOC31 (similar to Claudin-4), BerEP4 (similar), CEA, TTF-1, Napsin A, PAX8, GATA3, ER, PR, PSA, etc (depending on suspected primary)
─ ─ Synovial sarcoma (for spindle cell lesions): TLE1, CK7, EMA (can be shared), CD99, BCL2 (less specific for SS)
─ Molecular ─
─ ─ BAP1 mutation/loss: Common in epithelioid and biphasic types, associated with familial mesothelioma predisposition (germline mutations)
─ ─ CDKN2A (p16) homozygous deletion (by FISH): Common, associated with poor prognosis, helps distinguish malignant from reactive mesothelial proliferations
─ ─ NF2 mutations: Also common
─ ─ TP53 mutations: More frequent in sarcomatoid mesothelioma
Staging ─ (AJCC TNM Classification, 8th Edition is current)
─ Based on extent of primary tumor (T), nodal involvement (N), and distant metastasis (M)
─ T categories describe invasion into pleura, lung, diaphragm, chest wall, mediastinal structures
─ N categories describe ipsilateral or contralateral lymph node involvement
─ M categories describe distant metastases
─ Stage groupings (I-IV) combine T, N, M information
DDx ─ Epithelioid Mesothelioma vs:
─ Reactive mesothelial hyperplasia (bland cytology, no BAP1 loss, no CDKN2A deletion, lacks deep invasion, often zonal phenomenon)
─ Adenocarcinoma metastatic to pleura (positive for adenocarcinoma IHC markers, negative for most mesothelial markers)
─ Well-differentiated papillary mesothelial tumor (WDPMT) (non-invasive, bland papillary architecture)
Sarcomatoid Mesothelioma vs:
─ Other spindle cell sarcomas (e.g fibrosarcoma, synovial sarcoma, MPNST; require specific IHC/molecular markers for distinction)
─ Solitary fibrous tumor (STAT6 positive)
─ Organizing pleuritis/fibrosis (paucicellular, lacks significant atypia or invasiveness of desmoplastic mesothelioma)
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Mesothelioma in situ (MIS)

A proposed pre-invasive lesion characterized by a flat or micropapillary proliferation of atypical mesothelial cells confined to the surface epithelium, without stromal invasion, but possessing molecular alterations found in invasive mesothelioma
Clinical ─ Currently a controversial entity, not yet universally accepted or formally classified in WHO; may be an incidental finding or found adjacent to invasive mesothelioma; natural history and risk of progression to invasive disease are not fully understood
Macro ─ No specific macroscopic lesion; pleural surface may appear normal or show subtle granularity or erythema
Micro ─ ─ Atypical mesothelial cells arranged in a single layer (flat) or forming small, simple micropapillary tufts without fibrovascular cores, confined to the pleural surface
─ Cells show cytologic atypia (nuclear pleomorphism, hyperchromasia, prominent nucleoli, increased N/C ratio) exceeding reactive changes
─ No evidence of stromal invasion into underlying connective tissue
─ Mitotic figures may be present but are typically infrequent
Ancillary studies ─ ─ IHC (+) Positive for mesothelial markers (Calretinin, WT1, CK5/6)
─ IHC (Malignancy-associated): May show loss of BAP1 nuclear expression
─ Molecular ─ May show CDKN2A (p16) homozygous deletion by FISH or other molecular alterations characteristic of invasive mesothelioma (e.g BAP1 mutation)
DDx ─ ─ Reactive mesothelial hyperplasia (lacks significant cytologic atypia and molecular alterations like BAP1 loss or CDKN2A deletion)
─ Invasive malignant mesothelioma (epithelioid type, especially superficial spreading) (shows evidence of stromal invasion)
─ Well-differentiated papillary mesothelial tumor (WDPMT) (more complex papillary architecture, typically bland cytology, BAP1 retained, no CDKN2A deletion)
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Other Primary Tumors of the Pleura

Solitary Fibrous Tumor (SFT) of the Pleura

A mesenchymal neoplasm, usually benign but with a potential for aggressive behavior, characterized by a "patternless" arrangement of bland spindle cells in a collagenous stroma with prominent hemangiopericytoma-like (staghorn) vessels
Clinical ─ Can occur at any age, typically in adults; no sex predilection; may be asymptomatic and found incidentally, or cause symptoms due to mass effect (cough, chest pain, dyspnea); paraneoplastic hypoglycemia (Doege-Potter syndrome due to IGF2 production) occurs in <5% of cases, usually with large tumors; most are benign, but ~10-20% can recur or metastasize (malignant SFT)
Macro ─ Usually a well-circumscribed, often pedunculated mass attached to visceral (most common) or parietal pleura; can be very large; cut surface is firm, gray-white, whorled, may show cystic change or hemorrhage, especially in malignant variants
Micro ─ ─ Variable cellularity, ranging from hypocellular and densely collagenous to hypercellular areas
─ Classic "patternless pattern" of ovoid to spindle cells with scant cytoplasm and bland, vesicular nuclei, arranged haphazardly or in short fascicles
─ Stroma is typically collagenous, can be myxoid or hyalinized
─ Characteristic branching, thin-walled, dilated (staghorn) hemangiopericytoma-like vessels are common
─ Mitotic activity is generally low in benign SFTs (<4 mitoses/10 HPF or per 2 mm²); higher in malignant SFTs
─ Malignant features (predictive of aggressive behavior): Increased cellularity, nuclear pleomorphism, high mitotic rate (≥4 mitoses/10 HPF or per 2 mm²), tumor necrosis, infiltrative margins
Ancillary studies ─ ─ IHC (+) STAT6 (strong nuclear positivity, highly sensitive and specific, reflects NAB2-STAT6 fusion), CD34 (strong and diffuse in most cases), BCL2, CD99 (often positive but non-specific)
─ IHC (-) Cytokeratins (usually negative, distinguishes from sarcomatoid mesothelioma or carcinoma), S100 protein, desmin, SMA (usually negative or focal)
─ Molecular ─ NAB2-STAT6 gene fusion resulting from intrachromosomal inversion inv(12)(q13q13) is the pathognomonic molecular alteration, present in virtually all SFTs regardless of location or behavior
DDx ─ ─ Sarcomatoid malignant mesothelioma (positive for mesothelial markers, negative for STAT6, CD34 often negative)
─ Other spindle cell sarcomas (e.g fibrosarcoma, synovial sarcoma, MPNST; require specific IHC profiles, STAT6 negative)
─ Desmoplastic mesothelioma (paucicellular, infiltrative, STAT6 negative, positive for mesothelial markers)
─ Calcifying fibrous tumor (distinct hyalinization, psammomatous calcifications, prominent lymphoplasmacytic infiltrate, STAT6 negative)
─ Cellular variant of organizing pleuritis/fibrosis (lacks characteristic SFT architecture and STAT6 positivity)
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Primary Pleural Sarcomas

A heterogeneous group of rare malignant mesenchymal tumors arising directly from the pleura, excluding sarcomatoid mesothelioma and SFT with malignant features
Clinical ─ Very rare; occur in adults, symptoms are non-specific (chest pain, dyspnea, mass effect); aggressive behavior with high rates of recurrence and metastasis; prognosis is generally poor
Macro ─ Typically large, fleshy masses involving the pleura, may invade chest wall or lung
Micro ─ Histologic features depend on the specific sarcoma type; examples include:
─ Synovial Sarcoma:
─ ─ Monophasic (spindle cells) or Biphasic (spindle cells and epithelial glandular component)
─ ─ Spindle cells are uniform, ovoid to plump, with scant cytoplasm, arranged in dense fascicles
─ ─ Often shows focal expression of cytokeratins (CK7, AE1/AE3) and EMA, TLE1 positive
─ ─ Characterized by SS18-SSX (SYT-SSX) gene fusion
─ Angiosarcoma:
─ ─ Malignant endothelial proliferation forming irregular vascular channels or solid sheets of atypical cells
─ ─ Cells are pleomorphic with hyperchromatic nuclei and prominent nucleoli
─ ─ Positive for endothelial markers (CD31, ERG, Factor VIII)
─ Leiomyosarcoma:
─ ─ Spindle cells with blunt-ended (cigar-shaped) nuclei, eosinophilic cytoplasm, arranged in intersecting fascicles
─ ─ Positive for smooth muscle markers (SMA, desmin, caldesmon)
─ Liposarcoma:
─ ─ Various subtypes (e.g well-differentiated, dedifferentiated, myxoid, pleomorphic)
─ ─ Presence of atypical lipoblasts is key for diagnosis in some types
─ ─ MDM2 amplification in well-differentiated/dedifferentiated types
─ Undifferentiated Pleomorphic Sarcoma (UPS):
─ ─ High-grade sarcoma with marked pleomorphism, no specific line of differentiation
─ ─ Diagnosis of exclusion
Ancillary studies ─ ─ IHC (+) Panel tailored to suspected sarcoma type (e.g see specific examples above)
─ IHC (-) Mesothelial markers (Calretinin, WT1, CK5/6) and STAT6 to exclude mesothelioma and SFT
─ Molecular ─ Specific translocations or mutations can confirm diagnosis for certain types (e.g SS18-SSX for synovial sarcoma, MDM2 amplification for dedifferentiated liposarcoma)
DDx ─ ─ Sarcomatoid malignant mesothelioma (may express some cytokeratins, positive for mesothelial markers)
─ Malignant solitary fibrous tumor (STAT6 positive)
─ Metastatic sarcoma from another site (clinical history crucial)
─ Spindle cell/sarcomatoid carcinoma metastatic to pleura (positive for cytokeratins, specific carcinoma markers depending on origin)
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A rare malignancy representing lymphoma arising primarily in the pleural space, not secondary to systemic lymphoma; includes specific types like Pyothorax-Associated Lymphoma and primary Diffuse Large B-cell Lymphoma of the pleura
Clinical ─ Rare; symptoms can include chest pain, dyspnea, pleural effusion, fever, weight loss; prognosis varies by lymphoma type and stage
Types and Specific Features:
─ Pyothorax-Associated Lymphoma (PAL):
─ ─ A type of Diffuse Large B-cell Lymphoma (DLBCL), strongly associated with Epstein-Barr Virus (EBV) infection
─ ─ Arises in the context of long-standing chronic pyothorax (20+ years), often secondary to artificial pneumothorax for tuberculosis treatment or chronic empyema
─ ─ More common in Japan
─ ─ Prognosis is generally poor
─ Primary Effusion Lymphoma (PEL) can involve the pleura (though more classic in body cavities of HIV+ patients, HHV8-associated), but PAL is distinct
─ Other Primary Pleural DLBCL, NOS: Occurs without chronic pyothorax or known immunodeficiency, extremely rare
─ Extranodal Marginal Zone Lymphoma of MALT type (MALT Lymphoma): Can rarely arise primarily in the pleura
Macro ─ May present as pleural thickening, nodules, masses, or a dominant pleural effusion
Micro ─ (Varies by lymphoma type)
─ Pyothorax-Associated Lymphoma (PAL):
─ ─ Diffuse infiltrate of large, atypical lymphoid cells with features of centroblasts or immunoblasts
─ ─ Background may show chronic inflammation, fibrosis, and necrosis related to the pre-existing pyothorax
─ ─ EBV infection is demonstrable in tumor cells (EBER ISH)
─ Primary Pleural DLBCL, NOS: Sheets of large atypical lymphocytes
─ MALT Lymphoma: Infiltrate of small to medium-sized lymphocytes with lymphoepithelial lesions if it infiltrates lung tissue, often plasmacytic differentiation
Ancillary studies ─ ─ IHC (+) (Depends on lymphoma type)
─ ─ PAL/DLBCL: CD20, CD79a, PAX5 (B-cell markers); MUM1/IRF4 often positive; CD30 can be positive; EBV markers (LMP1, EBER ISH) are positive in PAL
─ ─ MALT Lymphoma: CD20, CD79a, PAX5; often CD21/CD35 highlights follicular dendritic cell meshworks; negative for CD5, CD10, BCL6 (usually)
─ IHC (-) Markers for mesothelioma (Calretinin, WT1), carcinoma (cytokeratins, specific markers)
─ Flow Cytometry: Can confirm clonality and immunophenotype on fresh tissue or effusion fluid
─ Molecular ─ Clonal immunoglobulin gene rearrangements (B-cell lymphomas); specific translocations for some lymphoma types (e.g t(11;18)(q21;q21) in some MALT lymphomas)
DDx ─ ─ Reactive lymphoid hyperplasia/Pleuritis with extensive lymphoid infiltrates (polyclonal, lacks atypia of lymphoma, no destructive infiltrates)
─ Secondary involvement of the pleura by systemic lymphoma (clinically more common)
─ Malignant mesothelioma (especially lymphohistiocytoid variant vs lymphoma; mesothelioma markers positive, lymphoma markers negative)
─ Metastatic carcinoma (especially poorly differentiated or small cell carcinoma; cytokeratin positive, lymphoma markers negative)
─ Thymoma extending to pleura (thymic markers like TdT (for lymphoblastic), p40/p63, CD5, CD117 in some thymic carcinomas)
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Desmoplastic Small Round Cell Tumor (DSRCT) involving pleura

A rare and highly aggressive mesenchymal neoplasm typically arising in the abdominal or pelvic peritoneum of young males, characterized by nests of small round blue cells in a dense desmoplastic stroma and a specific EWSR1-WT1 gene fusion
Clinical ─ Extremely rare in the pleura, usually representing metastasis from an abdominal primary, but primary pleural DSRCT has been reported; affects predominantly adolescent and young adult males; symptoms include chest pain, dyspnea, cough; aggressive course with poor prognosis
Macro ─ Multiple firm, gray-white nodules or masses on pleural surfaces, often associated with extensive desmoplasia; may cause diffuse pleural thickening
Micro ─ ─ Characteristic triphasic pattern (though not always all present or prominent):
─ ─ Nests and cords of small, undifferentiated round cells with scant cytoplasm, hyperchromatic nuclei, and inconspicuous nucleoli
─ ─ Dense, desmoplastic (hyalinized) collagenous stroma surrounding the tumor nests
─ ─ Angiomatoid or myxoid areas may be present
─ Mitotic figures and apoptotic bodies are common within tumor cell nests
Ancillary studies ─ ─ IHC (+)
─ ─ Polyphenotypic differentiation is characteristic: Cytokeratin (AE1/AE3, CAM5.2, CK7 - often dot-like perinuclear staining), EMA, Desmin (strong dot-like perinuclear positivity is very typical), Vimentin
─ ─ WT1 (nuclear staining, C-terminus antibody, e.g WT1-C)
─ ─ Neuron-specific enolase (NSE), FLI1 (nuclear, can be positive reflecting EWSR1 involvement, but also in Ewing)
─ IHC (-) CD45 (leukocyte common antigen), S100 protein, Myogenin, Chromogranin, Synaptophysin (usually negative, though focal staining can occur)
─ Molecular ─ EWSR1-WT1 gene fusion t(11;22)(p13;q12) is pathognomonic and present in almost all cases
DDx ─ ─ Other small round blue cell tumors involving the pleura:
─ ─ Ewing Sarcoma/Primitive Neuroectodermal Tumor (PNET) (CD99 positive, FLI1 positive, often EWSR1-FLI1 or other EWSR1 fusions, lacks desmin and broad cytokeratin expression)
─ ─ Lymphoma (CD45 positive, specific lymphoid markers)
─ ─ Small cell carcinoma (neuroendocrine markers like chromogranin/synaptophysin positive, TTF-1 in pulmonary origin, different cytokeratin pattern)
─ ─ Sarcomatoid mesothelioma, small cell variant (mesothelial markers like calretinin/WT1 N-terminus positive, lacks EWSR1-WT1 fusion and desmin dot-positivity)
─ ─ Rhabdomyosarcoma (myogenin, MyoD1 positive)
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Primary Pleural Adenocarcinoma

A very rare malignant epithelial neoplasm arising directly from the pleura, with glandular differentiation, diagnosed after rigorous exclusion of metastatic adenocarcinoma and epithelioid malignant mesothelioma
Clinical ─ Extremely rare, diagnosis of exclusion; patients are often elderly; symptoms include chest pain, dyspnea, pleural effusion; prognosis is generally poor, similar to metastatic adenocarcinoma to the pleura
Macro ─ May present as localized nodules, diffuse pleural thickening, or pleural effusion; indistinguishable from metastatic adenocarcinoma or mesothelioma macroscopically
Micro ─ ─ Shows features of adenocarcinoma, e.g glandular formation, papillary structures, mucin production (intra or extracellular), or solid sheets of malignant epithelial cells with at least focal glandular differentiation
─ Cytologic atypia is present (pleomorphism, hyperchromasia, prominent nucleoli, increased mitoses)
─ Invasion into underlying stroma or structures is seen
Ancillary studies ─ ─ IHC (+) Cytokeratin 7 (often positive), Cytokeratin 20 (variable, depends on presumed differentiation if any), EMA
─ ─ Markers suggesting potential primary sites if metastatic must be thoroughly evaluated (e.g TTF-1 and Napsin A for lung primary; PAX8 for gynecologic/renal; CDX2, SATB2 for colorectal; GATA3, ER/PR for breast; PSA/PSAP for prostate etc) – these should be NEGATIVE to consider primary pleural adenocarcinoma, or a pattern inconsistent with common metastases
─ IHC (-) Consistent panel of mesothelial markers (Calretinin, WT1-nuclear, CK5/6, D2-40, HBME-1) to exclude epithelioid mesothelioma
─ IHC (-) Absence of markers for common primary sites of metastasis (e.g TTF-1, Napsin A, PAX8, CDX2, GATA3 etc) is crucial for the diagnosis of exclusion
─ Molecular ─ No specific molecular signature for primary pleural adenocarcinoma; molecular testing may help identify a primary site if it's a metastasis (e.g EGFR, ALK for lung)
DDx ─ ─ Metastatic adenocarcinoma to the pleura (most important and common differential; requires extensive clinical and radiological investigation to exclude an occult primary elsewhere; IHC panel is key)
─ Epithelioid malignant mesothelioma (positive for mesothelial markers, negative for adenocarcinoma markers like MOC31, BerEP4, Claudin-4, and specific site markers)
─ Well-differentiated papillary mesothelial tumor (WDPMT) (non-invasive, bland cytology, mesothelial phenotype)
─ Adenomatoid tumor (benign mesothelial lesion, distinct morphology, mesothelial phenotype)
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Thymoma or Thymic Carcinoma extending to or primary in pleura

Rare instances of thymic epithelial neoplasms (thymoma or thymic carcinoma) that involve the pleura either by direct extension from a mediastinal primary or, exceptionally rarely, as a primary pleural tumor
Clinical ─ Primary pleural thymoma/thymic carcinoma is exceedingly rare; more commonly, pleural involvement is secondary to direct invasion or metastasis from an anterior mediastinal thymic primary; symptoms depend on extent (chest pain, dyspnea); paraneoplastic syndromes (e.g myasthenia gravis) may be present if related to thymoma
Macro ─ Pleural nodules, masses, or diffuse thickening; may be associated with a visible mediastinal mass
Micro ─ (Histology mirrors that of the thymic primary)
─ Thymoma:
─ ─ Composed of neoplastic epithelial cells admixed with variable numbers of non-neoplastic lymphocytes (T-cells)
─ ─ Types A, AB, B1, B2, B3 based on epithelial cell morphology and lymphocyte ratio
─ ─ Epithelial cells are bland to mildly atypical, with vesicular nuclei and inconspicuous nucleoli (except Type B3)
─ ─ Hassall's corpuscles may be present, perivascular spaces
─ Thymic Carcinoma:
─ ─ Overtly malignant cytology, often resembling squamous cell carcinoma (most common type), basaloid carcinoma, mucoepidermoid carcinoma, or other carcinoma types
─ ─ Lacks the organotypical features of thymoma (e.g prominent immature T-lymphocytes, Hassall's corpuscles) and shows frank atypia, higher mitotic activity, and infiltrative growth
Ancillary studies ─ ─ IHC (+) (For thymic epithelial origin)
─ ─ Thymoma: Epithelial cells positive for pan-cytokeratin (AE1/AE3, CAM5.2), CK5/6, p63/p40, PAX8 (often); variable CD205 (thymic epithelial marker); Lymphocytes are TdT positive (immature T-cells, especially in Type B thymomas)
─ ─ Thymic Carcinoma: Cytokeratins, p63/p40, PAX8; CD5 and CD117 (c-kit) are often positive in thymic carcinomas (less so or negative in thymomas), helping distinguish from thymoma and some other carcinomas; GLUT1 often positive
─ IHC (-) Mesothelial markers (Calretinin, WT1) to exclude mesothelioma; TTF-1 (usually negative, to help exclude lung primary); specific markers for other carcinomas depending on context
DDx ─ ─ Malignant mesothelioma (positive for mesothelial markers)
─ Metastatic carcinoma to pleura (especially squamous cell carcinoma or adenocarcinoma from lung or other sites; requires careful IHC panel)
─ Lymphoma (especially T-lymphoblastic lymphoma if rich in lymphocytes, but tumor cells are CD45 positive; thymoma epithelial cells are CD45 negative)
─ Solitary fibrous tumor or other sarcomas (STAT6 for SFT, specific sarcoma markers)
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Metastatic Tumors to the Pleura

The most common malignant neoplasms involving the pleura, originating from cancers at distant sites
Clinical ─ Pleural metastases are common and a significant cause of malignant pleural effusions; primary sites frequently metastasizing to pleura include lung (most common), breast, ovary, gastrointestinal tract (stomach, colorectum, pancreas), kidney, and lymphoma/leukemia; symptoms include dyspnea (due to effusion), cough, chest pain; prognosis is generally poor, dependent on primary tumor type and extent of disease
Macro ─ Patterns of pleural metastasis:
─ Pleural effusion (often large, recurrent, and hemorrhagic)
─ Multiple discrete pleural nodules or plaques scattered over visceral and/or parietal pleura
─ Diffuse pleural thickening mimicking mesothelioma (e.g lymphangitic spread within pleura)
─ Endobronchial metastasis extending to visceral pleura
─ Direct invasion from adjacent primary lung cancer or chest wall tumors
Micro ─ ─ Histology mirrors the primary tumor (e.g adenocarcinoma, squamous cell carcinoma, small cell carcinoma, melanoma, sarcoma cells)
─ Tumor cells may be found in pleural fluid cytology, as deposits on pleural surfaces, or infiltrating pleural connective tissue and lymphatics
─ Desmoplastic stromal reaction is common
─ Specific patterns:
─ ─ Adenocarcinoma: Gland formation, papillary structures, mucin production, signet ring cells
─ ─ Squamous Cell Carcinoma: Keratinization, intercellular bridges, nests of polygonal cells with glassy eosinophilic cytoplasm
─ ─ Small Cell Carcinoma: Sheets of small blue cells with scant cytoplasm, nuclear molding, high mitotic rate
─ ─ Lymphoma/Leukemia: Atypical lymphoid or hematopoietic cells
Ancillary studies ─ ─ IHC (+) Panel tailored to suspected primary site based on clinical history and morphology:
─ ─ Lung adenocarcinoma: TTF-1, Napsin A, CK7
─ ─ Breast carcinoma: GATA3, ER, PR, HER2, GCDFP-15
─ ─ Ovarian serous carcinoma: PAX8, WT1 (cytoplasmic/nuclear in tumor cells, distinct from nuclear-only in mesothelial cells), CA125
─ ─ Colorectal adenocarcinoma: CDX2, CK20, SATB2 (often CK7 negative)
─ ─ Renal cell carcinoma: PAX8, RCCma, CD10
─ ─ Melanoma: S100, SOX10, HMB-45, Melan-A
─ ─ Thyroid carcinoma: TTF-1, PAX8, Thyroglobulin
─ IHC (-) Mesothelial markers (Calretinin, WT1-nuclear, CK5/6, D2-40) to exclude mesothelioma (though some carcinomas like ovarian serous can be WT1 positive, pattern and panel are key)
DDx ─ ─ Malignant mesothelioma (positive for mesothelial markers, typically negative for specific lineage markers of carcinomas)
─ Primary pleural tumors (e.g primary pleural adenocarcinoma – diagnosis of exclusion)
─ Reactive mesothelial hyperplasia (bland cytology, lacks overt malignancy)
─ Specific benign pleural lesions depending on morphology (e.g endometriosis, splenosis)
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MEDIASTINUM (Including Thymus)

Mediastinal Compartments

Anatomical divisions of the mediastinum, the central thoracic cavity between the pleural sacs, used to localize and characterize mediastinal lesions; definitions vary slightly (e.g anatomic vs radiologic) but generally include Superior, Anterior, Middle, and Posterior compartments
Clinical ─ The location of a mediastinal mass within a specific compartment narrows the differential diagnosis as different lesions have predilections for certain compartments
Compartment Definitions and Common Contents/Pathologies:
─ Superior Mediastinum:
─ ─ Boundaries (anatomic): Superior thoracic aperture to transverse thoracic plane (sternal angle to T4-T5 intervertebral disc)
─ ─ Contents: Thymus (upper portion), trachea, esophagus, aortic arch and major branches, superior vena cava, brachiocephalic veins, thoracic duct, phrenic/vagus/recurrent laryngeal nerves, lymph nodes
─ ─ Common Pathologies: Thymoma, lymphoma, germ cell tumors, thyroid lesions (goiter, carcinoma), parathyroid adenoma, cysts
─ Anterior Mediastinum:
─ ─ Boundaries (radiologic/Felson): Posterior to sternum, anterior to pericardium and great vessels; extends from thoracic inlet to diaphragm
─ ─ Contents: Thymus (lower portion, especially in children/young adults), lymph nodes, adipose tissue, internal mammary vessels
─ ─ Common Pathologies ("4 T's"): Thymoma (and other thymic neoplasms/cysts), Teratoma (and other Germ Cell Tumors), Thyroid lesions (intrathoracic goiter, ectopic thyroid), Terrible Lymphoma; also mesenchymal tumors (lipoma, liposarcoma)
─ Middle Mediastinum:
─ ─ Boundaries (radiologic/Felson): Bounded by pericardium; contains heart and great vessels
─ ─ Contents: Heart, pericardium, ascending aorta, pulmonary trunk, superior and inferior vena cava, main bronchi, phrenic nerves, lymph nodes (tracheobronchial, hilar)
─ ─ Common Pathologies: Lymphadenopathy (sarcoidosis, lymphoma, metastatic carcinoma), pericardial cysts, bronchogenic cysts, vascular lesions, cardiac tumors
─ Posterior Mediastinum:
─ ─ Boundaries (radiologic/Felson): Posterior to pericardium and trachea, anterior to vertebral column
─ ─ Contents: Esophagus, descending thoracic aorta, azygos and hemiazygos veins, thoracic duct, vagus nerves, sympathetic chain, lymph nodes
─ ─ Common Pathologies: Neurogenic tumors (schwannoma, neurofibroma, ganglioneuroma - most common), esophageal lesions (tumors, cysts, diverticula), bronchogenic cysts (can also be middle), extramedullary hematopoiesis, meningocele, vascular lesions
Micro ─ N/A (This entity describes anatomical divisions)
Ancillary studies ─ N/A
DDx ─ N/A
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Normal Thymus Anatomy and Histology

The thymus is a primary lymphoid organ essential for T-cell development and maturation, located in the anterior-superior mediastinum, which undergoes significant age-related changes including involution
Clinical ─ Most active during neonatal period and childhood, gradually involutes with age, replaced by adipose tissue; thymic tissue can be ectopic (e.g neck, thyroid, lung)
Macro ─ ─ Bilobed organ, pinkish-gray in youth, yellowish with increasing adipose tissue in adults
─ Weight: ~10-15g at birth, peaks at ~20-40g during puberty, then declines to ~5-15g in older adults
─ Encapsulated, with fibrous septa dividing lobes into lobules
Micro ─ Each lobule is divided into two distinct zones:
─ Cortex (Outer zone):
─ ─ Densely cellular, stains darkly basophilic
─ ─ Predominantly populated by immature T-lymphocytes (thymocytes), which are small with scant cytoplasm and condensed chromatin (positive for TdT)
─ ─ Scattered thymic epithelial cells (reticular epithelial cells) with pale cytoplasm and oval nuclei, forming a supportive meshwork
─ ─ Tingible body macrophages are common (phagocytosing apoptotic thymocytes)
─ Medulla (Inner zone):
─ ─ Less cellular, stains paler eosinophilic
─ ─ Contains more mature T-lymphocytes (TdT negative or weakly positive), fewer than in cortex
─ ─ Prominent spindle-shaped and plump thymic epithelial cells
─ ─ Hassall's Corpuscles: Pathognomonic structures found only in the medulla; concentrically laminated, keratinized whorls of epithelial cells, often with central calcification or cystic change; function not fully clear, may relate to T-regulatory cell development
─ Thymic Epithelial Cells: Diverse population providing structural support and secreting hormones/cytokines essential for T-cell maturation; express cytokeratins
Involution:
─ Age-related process beginning around puberty
─ Progressive depletion of thymocytes, particularly in the cortex
─ Widening of interlobular septa with increased fibrous tissue and adipose tissue infiltration (lipomatous atrophy)
─ Hassall's corpuscles may appear more prominent or cystic due to loss of surrounding parenchyma
─ Eventually, the thymus may be largely replaced by fat, with only small islands of residual thymic tissue
Ancillary studies ─ (Immunohistochemistry of normal components)
─ Thymocytes (lymphocytes):
─ ─ Cortex: TdT (+), CD1a (+), CD3 (+, often cytoplasmic in immature cells), CD4/CD8 double positive
─ ─ Medulla: TdT (- or weak), CD3 (+, surface), mixtures of CD4 single positive and CD8 single positive cells
─ Thymic Epithelial Cells: Pan-Cytokeratin (AE1/AE3, CAM5.2) (+), CK5/6 (+), p63/p40 (+), PAX8 (+)
DDx ─ (For histologic sections)
─ Thymic hyperplasia (distinction based on size/weight and architecture)
─ Lymphoma (especially T-lymphoblastic lymphoma, which resembles cortical thymocytes but is a neoplastic proliferation)
─ Thymoma (neoplastic proliferation of thymic epithelial cells)
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Thymic Hyperplasia

An increase in thymic volume or weight beyond that expected for age, encompassing true thymic hyperplasia and follicular (lymphoid) hyperplasia
Clinical ─ May be asymptomatic and detected incidentally, or cause compressive symptoms if massive; follicular hyperplasia is often associated with autoimmune diseases, especially Myasthenia Gravis
Types:
─ True Thymic Hyperplasia (Massive Thymic Hyperplasia):
─ ─ Definition: Diffuse, symmetric enlargement of the thymus with preserved normal architecture (distinct cortex and medulla, Hassall's corpuscles) but increased overall size and weight for age (e.g >40g in young adults, or significantly above age-adjusted norms)
─ ─ Clinical: Rare; can occur in infants/children or adults (e.g "rebound" hyperplasia after chemotherapy, radiation, burns, or corticosteroids withdrawal, or idiopathic)
─ ─ Imaging: Diffuse symmetric enlargement, smooth contour, normal density
─ ─ Micro: Normal histologic components (cortex, medulla, Hassall’s corpuscles) are present and appear qualitatively normal but expanded in volume; no neoplastic cells
─ Follicular (Lymphoid) Hyperplasia:
─ ─ Definition: Presence of reactive B-cell germinal centers (lymphoid follicles) within the thymic medulla and sometimes cortex; thymus may be normal sized, enlarged, or atrophic
─ ─ Clinical: Strongly associated with autoimmune diseases, particularly Myasthenia Gravis (MG) (~65% of MG patients have follicular hyperplasia, ~10-15% have thymoma); also seen in Graves' disease, SLE, rheumatoid arthritis, Addison's disease, HIV infection
─ ─ Micro: Key feature is the presence of lymphoid follicles with well-formed germinal centers (CD20+ B-cells, CD21/CD35+ FDC networks, Ki67+ proliferating cells, tingible body macrophages) within the thymic parenchyma, primarily in the medulla and perivascular spaces; remainder of thymus may be normal or involuted
Macro ─ ─ True Hyperplasia: Thymus is enlarged but retains normal shape and lobulation
─ Follicular Hyperplasia: Thymus may be normal size, enlarged, or atrophic; cut surface may appear more nodular or fleshy if follicles are numerous/large
Micro ─ (See descriptions under Types above)
Ancillary studies ─ ─ IHC (Follicular Hyperplasia):
─ ─ Germinal centers: CD20+, BCL6+, Ki67+ (in B-cells); CD21+ or CD35+ (follicular dendritic cell meshworks); BCL2 negative in germinal center B-cells
─ ─ Surrounding T-cells are polyclonal (CD3+, CD5+)
─ IHC (True Hyperplasia): Shows normal distribution of thymic epithelial cells and thymocytes (TdT+ cortical thymocytes)
DDx ─ ─ Normal thymus (especially in children where thymus is normally large; true hyperplasia implies size beyond normal for age)
─ Thymoma (neoplastic proliferation of thymic epithelial cells; follicular hyperplasia can coexist with thymoma, especially Type B1 or AB)
─ Lymphoma involving the thymus (especially T-lymphoblastic lymphoma, Hodgkin lymphoma, or MALT lymphoma which can form follicles; lymphoma shows monoclonal atypical lymphoid cells)
─ Rebound hyperplasia vs Thymoma (imaging and sometimes biopsy needed)
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Thymic Cysts

Cystic lesions arising within or in association with the thymus, which can be congenital/developmental or acquired
Clinical ─ Often asymptomatic and discovered incidentally on imaging; may cause symptoms due to compression of adjacent structures if large (e.g cough, dyspnea, chest pain); most are benign
Types:
─ Congenital/Developmental Thymic Cysts:
─ ─ Origin: Thought to arise from persistent remnants of the thymopharyngeal duct or cystic degeneration of Hassall's corpuscles
─ ─ Location: Can occur anywhere along the path of thymic descent from neck to mediastinum (cervical or mediastinal)
─ ─ Structure: Typically unilocular, thin-walled, filled with clear serous fluid
─ ─ Lining: Lined by cuboidal, columnar, squamous, or transitional epithelium; thymic tissue (cortex, medulla, Hassall's corpuscles) is usually present in the cyst wall
─ Acquired Thymic Cysts:
─ ─ Origin: Develop secondary to various processes including inflammation, infection, trauma, post-radiation/chemotherapy, or associated with neoplasms (e.g thymoma, Hodgkin lymphoma, seminoma)
─ ─ Structure: Can be unilocular or multilocular; cyst contents may be serous, hemorrhagic, or purulent
─ ─ Lining: Variable, may be flattened epithelium, granulation tissue, or fibrous tissue; chronic inflammation, hemorrhage, cholesterol clefts, and calcification are common in the wall
─ ─ Multilocular Thymic Cyst with Prominent Lymphoid Hyperplasia:
─ ─ ─ Often associated with HIV infection ("HIV-associated multilocular thymic cyst") or other autoimmune/inflammatory conditions (e.g Sjögren syndrome, SLE)
─ ─ ─ Characterized by multiple cysts separated by fibrous septa containing dense lymphoid tissue with florid follicular hyperplasia (numerous germinal centers)
─ ─ ─ Epithelial lining can be squamous, cuboidal, or columnar, often with reactive atypia or squamous metaplasia
Macro ─ ─ Variable size, from small to very large
─ Unilocular or multilocular; thin or thick-walled
─ Cyst fluid can be clear, cloudy, bloody, or gelatinous
Micro ─ ─ Cyst lining: Squamous, cuboidal, columnar, pseudostratified, or transitional epithelium; may be denuded or replaced by granulation tissue/fibrosis
─ Cyst wall: May contain thymic tissue (cortex, medulla, Hassall's corpuscles - key for diagnosing thymic origin, especially in congenital type), fibrous tissue, smooth muscle, lymphoid aggregates/follicles, cholesterol granulomas, hemosiderin, calcification
─ Acquired cysts often show more inflammation and reactive changes
─ Multilocular cysts associated with HIV/autoimmune disease show prominent follicular hyperplasia in the septa/wall
Ancillary studies ─ ─ IHC: Can help identify thymic elements in the wall (e.g cytokeratins, p63 for epithelial cells; TdT for immature thymocytes if present); markers for lymphoid hyperplasia (CD20, CD3, CD21) if prominent
─ Special stains for organisms if infection suspected as a cause
DDx ─ ─ Other mediastinal cysts:
─ ─ Bronchogenic cyst (lined by ciliated pseudostratified columnar respiratory epithelium, cartilage and smooth muscle in wall)
─ ─ Pericardial cyst (lined by single layer of flat mesothelial cells, thin fibrous wall, typically near cardiophrenic angle)
─ ─ Esophageal duplication cyst (lined by squamous or glandular esophageal/gastric mucosa, smooth muscle layers in wall)
─ ─ Lymphangioma/Cystic hygroma (endothelial-lined channels containing lymph, positive for D2-40, CD31)
─ Cystic degeneration in a neoplasm (e.g cystic thymoma, germ cell tumor with cystic areas, lymphoma with cystic change); careful examination of the entire lesion is crucial to exclude underlying tumor
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Rebound Hyperplasia (Thymus)

A diffuse enlargement of the thymus that occurs as a recovery phenomenon following periods of stress, such as chemotherapy, radiation therapy, corticosteroid therapy, or severe systemic illness (e.g burns, surgery)
Clinical ─ Typically seen in children and young adults a few weeks to months after the stressful event or cessation of therapy; usually asymptomatic and detected incidentally on follow-up imaging; can be mistaken for recurrent malignancy or new thymic neoplasm, necessitating awareness of this phenomenon; generally self-limiting
Macro ─ Diffuse, symmetric enlargement of the thymus; the gland may appear larger than its pre-stress baseline but retains a normal shape and smooth contour
Micro ─ ─ Histologically similar to True Thymic Hyperplasia, showing an increase in thymic parenchymal volume with preserved corticomedullary differentiation
─ Both cortex and medulla are expanded but maintain their normal cellular components and architecture
─ Increased numbers of thymocytes and epithelial cells
─ Hassall's corpuscles are present and may appear prominent
─ No atypical cells or features of neoplasia
─ The key is the clinical context of recent stress or recovery from cytotoxic therapy
Ancillary studies ─ ─ IHC: Shows normal immunophenotype of thymic components (e.g TdT+ cortical thymocytes, cytokeratin+ epithelial cells)
─ Imaging: FDG-PET scans can show increased uptake in rebound hyperplasia, which can also mimic malignancy; correlation with clinical history and prior imaging is crucial
DDx ─ ─ True thymic hyperplasia (idiopathic or massive; rebound is specifically post-stress)
─ Thymoma (neoplastic epithelial proliferation, distinct architectural types)
─ Lymphoma involving the thymus (e.g T-lymphoblastic lymphoma shows a monotonous infiltrate of atypical lymphocytes, often TdT+)
─ Normal thymus in a child (thymus is normally proportionally larger in children)
─ Metastatic disease to the thymus (rare)
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Ectopic Thymic Tissue

Presence of thymic tissue outside its normal anterior mediastinal location, resulting from aberrancies during embryologic development and migration of the thymus from the third pharyngeal pouch
Clinical ─ Can be found anywhere along the descent pathway, most commonly in the neck (cervical ectopic thymus, often as a lateral neck mass in children), but also reported in thyroid gland, parathyroid, base of skull, trachea, lung, pleura, or posterior mediastinum; usually asymptomatic and discovered incidentally or as a palpable mass; rarely, can give rise to thymic neoplasms (e.g thymoma, thymic carcinoma) or cysts in ectopic locations
Macro ─ Appears as a well-circumscribed, lobulated, soft, tan-pink nodule or mass, resembling normal thymic tissue; size is variable
Micro ─ ─ Histologically identical to normal thymus, containing:
─ ─ Lobules with distinct cortical (darker, cellular) and medullary (paler, less cellular) areas
─ ─ Normal thymocytes (lymphocytes) and thymic epithelial cells
─ ─ Hassall's corpuscles within the medullary regions
─ May show age-appropriate involution with fatty infiltration if the individual is older
─ If cystic change occurs, it resembles a thymic cyst
Ancillary studies ─ ─ IHC: Confirms thymic origin with positivity for thymic epithelial markers (pan-cytokeratin, p63, PAX8) and presence of TdT+ cortical thymocytes
DDx ─ (Depends on location)
─ In the neck: Branchial cleft cyst, lymph node (reactive or neoplastic), thyroid nodule, parathyroid adenoma/hyperplasia, soft tissue tumors
─ In other locations: Specific differential for that anatomic site; biopsy with characteristic thymic histology is diagnostic
─ Thymoma or other thymic neoplasm arising in ectopic tissue (will show features of the specific neoplasm)
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Thymoma

A neoplasm of thymic epithelial cells, representing the most common primary tumor of the anterior mediastinum in adults
Clinical ─ Peak incidence 40-60 years, no strong sex predilection; ~30-50% are asymptomatic, discovered incidentally; symptomatic patients may present with local compressive symptoms (cough, dyspnea, chest pain, SVC syndrome); ~30-45% are associated with paraneoplastic syndromes, most commonly:
─ Myasthenia Gravis (MG): (~30-50% of thymoma patients develop MG; conversely ~10-15% of MG patients have thymoma); autoimmune disorder targeting acetylcholine receptors at neuromuscular junction
─ Pure Red Cell Aplasia: (~5% of thymoma patients)
─ Hypogammaglobulinemia (Good Syndrome): (~5-10% of thymoma patients); increased susceptibility to infections
─ Other autoimmune conditions (e.g SLE, polymyositis, pemphigus) occur less frequently
─ Prognosis is generally good for non-invasive thymomas, dependent on stage and histologic type; recurrence or metastasis can occur, even years later
Macro ─ Usually well-circumscribed, encapsulated, lobulated, firm, gray-white to tan-yellow mass; cystic changes, hemorrhage, or calcification may be present; invasive thymomas may show infiltration into adjacent structures (mediastinal fat, pleura, lung)
Micro ─ (WHO Classification is key, based on epithelial cell morphology and lymphocyte proportion)
─ General features: Composed of neoplastic thymic epithelial cells admixed with a variable number of non-neoplastic T-lymphocytes (thymocytes); presence of fibrous septa dividing tumor into lobules, perivascular spaces (dilated spaces around blood vessels containing lymphocytes and proteinaceous fluid) are common
─ WHO Classification (2021/2015):
─ Type A Thymoma (~5-20%):
─ ─ Spindle cell or oval cell thymoma; neoplastic epithelial cells are bland, elongated or oval, with inconspicuous nucleoli and scant cytoplasm, forming fascicles or storiform patterns
─ ─ Very few or no immature T-lymphocytes (<10% of tumor area)
─ ─ Medullary or cortico-medullary differentiation common
─ ─ Excellent prognosis
─ ─ Atypical Type A Thymoma: Retains Type A morphology but has increased atypia (hypercellularity, nuclear crowding, mild pleomorphism, scattered nucleoli) or increased mitotic activity (>0 and <4 mitoses/2 mm²), or focal necrosis. Higher risk of recurrence. (WHO 2021 considers it a distinct subtype; some earlier classifications linked it to B3 behavior if atypia was marked)
─ Type AB Thymoma (~20-35%):
─ ─ Mixed spindle cell and lymphocyte-rich thymoma
─ ─ Composed of a mixture of lymphocyte-poor areas resembling Type A thymoma and lymphocyte-rich areas resembling Type B1 or B2 thymoma
─ ─ Good prognosis, similar to Type A
─ Type B1 Thymoma (~10-25%):
─ ─ Lymphocyte-rich thymoma, resembles normal functional thymus with prominent cortex and medulla-like areas
─ ─ Neoplastic epithelial cells are scattered, plump, with vesicular nuclei and inconspicuous nucleoli, outnumbered by abundant immature T-lymphocytes (cortical thymocytes, TdT+)
─ ─ Medullary islands or Hassall's corpuscle-like structures may be present
─ ─ Good prognosis
─ Type B2 Thymoma (~20-35%):
─ ─ Cortical type thymoma; neoplastic epithelial cells are plump, polygonal, with vesicular nuclei and distinct nucleoli, arranged in clusters or sheets, more numerous than in B1
─ ─ Abundant immature T-lymphocytes are present, but epithelial cells are more easily identified and form cohesive groups
─ ─ Perivascular spaces are common
─ ─ Intermediate prognosis
─ Type B3 Thymoma (~10-20%):
─ ─ Epithelial-rich thymoma, atypical thymoma, or well-differentiated thymic carcinoma (older terms)
─ ─ Predominantly composed of sheets of relatively large, polygonal or rounded epithelial cells with mild to moderate atypia, vesicular or eosinophilic cytoplasm, and distinct nucleoli
─ ─ Few lymphocytes (<10-20% of tumor area)
─ ─ Represents a step towards thymic carcinoma in terms of atypia but lacks overt carcinomatous features
─ ─ Higher risk of invasion and recurrence; intermediate to guarded prognosis
Ancillary studies ─ ─ IHC (Epithelial cells): Pan-Cytokeratin (AE1/AE3, CAM5.2) (+), CK5/6 (+), p63/p40 (+), PAX8 (+)
─ IHC (Lymphocytes):
─ ─ Immature T-lymphocytes (in Type A (scant), AB, B1, B2): TdT (+), CD1a (+), CD3 (+), CD4/CD8 double positive
─ ─ Mature T-lymphocytes (in Type A, AB, medullary areas of B1): TdT (-), CD3 (+), single positive CD4 or CD8
─ IHC (Distinction from Thymic Carcinoma):
─ ─ Thymomas are generally CD5 (-) and CD117 (c-kit) (-), whereas these are often positive in thymic carcinomas
─ ─ GLUT1 is typically negative or weak in thymomas, often strong in thymic carcinomas
Staging ─ (Masaoka-Koga staging system is widely used; AJCC TNM staging (8th ed.) also exists)
─ Masaoka-Koga Staging:
─ ─ Stage I: Macroscopically completely encapsulated, no microscopic capsular invasion
─ ─ Stage IIA: Microscopic transcapsular invasion
─ ─ Stage IIB: Macroscopic invasion into surrounding fatty tissue or adherent pleura/pericardium
─ ─ Stage III: Macroscopic invasion into adjacent organs (e.g pericardium, great vessels, lung)
─ ─ Stage IVA: Pleural or pericardial dissemination (implants)
─ ─ Stage IVB: Lymphogenous or hematogenous metastasis
─ AJCC TNM Staging: Based on tumor size/invasion (T), nodal status (N), and distant metastasis (M)
DDx ─ ─ Thymic carcinoma (overt malignant cytology, often CD5/CD117 positive)
─ Lymphoma (T-lymphoblastic lymphoma for lymphocyte-rich thymomas – lymphoma cells are neoplastic, TdT+ but lack epithelial component; Hodgkin lymphoma – Reed-Sternberg cells)
─ Germ cell tumor (seminoma, teratoma – specific markers like OCT3/4, SALL4, AFP, HCG)
─ Thymic hyperplasia (preserved architecture, no neoplastic epithelial cells)
─ Metastatic carcinoma (negative for thymic epithelial markers, positive for site-specific markers)
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Micronodular Thymoma with Lymphoid Stroma (MNTLS)

A rare variant of thymoma characterized by multiple, discrete, small nodules of bland spindle epithelial cells (similar to Type A thymoma) embedded in a prominent B-cell rich lymphoid stroma that forms reactive germinal centers
Clinical ─ Typically occurs in older adults; generally asymptomatic or discovered incidentally; not typically associated with Myasthenia Gravis or other autoimmune syndromes seen with conventional thymomas; considered to have a very good prognosis, behaves indolently
Macro ─ Usually a well-circumscribed, firm, lobulated mass; cut surface may show subtle nodularity and a yellowish or tan appearance
Micro ─ ─ Biphasic pattern:
─ ─ Epithelial component: Multiple, small, discrete, well-demarcated nodules or islands composed of bland spindle to oval epithelial cells with pale eosinophilic cytoplasm and inconspicuous nucleoli, resembling Type A thymoma cells
─ ─ Lymphoid stroma: Abundant, dense polyclonal B-cell lymphoid infiltrate surrounding the epithelial nodules, with numerous large, reactive germinal centers (follicular hyperplasia)
─ No immature T-lymphocytes (TdT negative) associated with the epithelial nodules (unlike conventional Type A or AB thymoma which may have scant TdT+ cells)
─ Epithelial nodules do not show atypia or significant mitotic activity
Ancillary studies ─ ─ IHC (Epithelial nodules): Pan-Cytokeratin (+), p63 (+), PAX8 (+)
─ IHC (Lymphoid stroma):
─ ─ B-cells: CD20 (+), PAX5 (+) forming follicles
─ ─ Germinal centers: BCL6 (+), Ki67 (high proliferation in GCs), CD21/CD35 (follicular dendritic cell meshworks)
─ ─ T-cells: CD3 (+), CD5 (+) T-cells are present between follicles and around epithelial nodules, polyclonal
─ ─ TdT (-), distinguishing from thymomas with immature T-cell components
DDx ─ ─ Type AB thymoma (has lymphocyte-rich areas with TdT+ thymocytes, not prominent B-cell follicles; Type A component present)
─ Type A thymoma with reactive lymphoid hyperplasia (lymphoid component might not be as organized into follicles or as B-cell rich as in MNTLS)
─ Follicular hyperplasia of the thymus (lacks the distinct spindle cell epithelial nodules of MNTLS)
─ Lymphoma with sclerotic nodules (e.g Hodgkin lymphoma, nodular sclerosis type – Reed-Sternberg cells present; some B-cell lymphomas)
─ Castleman disease, hyaline-vascular type (if mediastinal lymph node; different morphology with regressed germinal centers, hyalinized vessels)
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Metaplastic Thymoma

A rare, benign thymic epithelial neoplasm characterized by a biphasic pattern with areas resembling low-grade spindle cell sarcoma (fibrosarcoma-like) and islands of epithelial cells that can show squamous or glandular differentiation, often with cystic changes
Clinical ─ Typically occurs in adults, wide age range; generally asymptomatic or presents with non-specific symptoms due to mass effect; not associated with Myasthenia Gravis or other autoimmune syndromes; considered benign with excellent prognosis after complete excision; recurrences are exceptional
Macro ─ Usually a well-circumscribed, firm, solitary mass; may be partially cystic; cut surface can be heterogeneous, gray-white to tan, with solid and cystic areas
Micro ─ ─ Distinctly biphasic:
─ ─ Spindle cell component: Predominant component, composed of bland spindle cells arranged in fascicles or storiform patterns, often with a collagenous or myxoid stroma, resembling low-grade fibrosarcoma or solitary fibrous tumor; mitotic activity is typically very low
─ ─ Epithelial component: Islands, nests, cords, or gland-like structures of epithelial cells embedded within the spindle cell stroma; epithelial cells can be polygonal, cuboidal, or squamoid; may show squamous metaplasia (keratinization, intercellular bridges), glandular differentiation (true gland formation with mucin is rare), or form solid nests
─ Cystic changes are common within the epithelial islands
─ No significant cytologic atypia or necrosis in either component
─ No immature T-lymphocytes (TdT negative)
Ancillary studies ─ ─ IHC (Epithelial component): Pan-Cytokeratin (AE1/AE3, CAM5.2) (+), CK5/6 (+), p63/p40 (+), EMA (+)
─ IHC (Spindle cell component): Often Vimentin (+); variable, often focal or weak positivity for cytokeratins (can be difficult to interpret due to intermingling with epithelial islands); typically negative for S100, desmin, SMA, CD34, STAT6
DDx ─ ─ Carcinosarcoma (malignant epithelial and malignant mesenchymal components; metaplastic thymoma is bland)
─ Synovial sarcoma, biphasic type (malignant spindle cells and epithelial glands; SS18-SSX fusion positive, TLE1 positive)
─ Solitary fibrous tumor (monophasic spindle cell tumor, STAT6 positive, CD34 positive, lacks distinct epithelial islands)
─ Spindle cell thymic carcinoma (malignant spindle cells, invasive, cytologically atypical, CD5/CD117 may be positive)
─ Type A thymoma (monophasic spindle epithelial cells, lacks the distinct biphasic pattern with metaplastic epithelial islands seen in metaplastic thymoma)
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Lipofibroadenoma of the Thymus (Thymic Hamartoma)

A very rare, benign lesion of the thymus characterized by a haphazard proliferation of mature adipose tissue, fibrous connective tissue, and entrapped or hyperplastic thymic epithelial elements including Hassall's corpuscles
Clinical ─ Extremely rare, usually discovered incidentally in adults; asymptomatic or may cause compressive symptoms if large; considered a benign hamartomatous lesion with no malignant potential; complete surgical excision is curative
Macro ─ Typically a large, well-circumscribed, encapsulated mass; cut surface is predominantly fatty (yellow) with interspersed gray-white fibrous areas and visible thymic tissue remnants
Micro ─ ─ Composed of a disorganized mixture of mature tissues:
─ ─ Adipose tissue: Mature adipocytes, often the most abundant component
─ ─ Fibrous connective tissue: Bands of collagenous tissue, sometimes hyalinized, traversing the lesion
─ ─ Thymic elements: Entrapped or hyperplastic islands of thymic epithelium, including squamous nests, duct-like structures, and Hassall's corpuscles (which may be cystic or calcified); lymphocytes (thymocytes) are associated with these epithelial elements
─ No cellular atypia, necrosis, or significant mitotic activity in any component
─ The proportions of fat, fibrous tissue, and thymic elements vary considerably between cases
Ancillary studies ─ ─ IHC: Thymic epithelial elements are positive for cytokeratins (AE1/AE3, CAM5.2), p63, and PAX8; associated lymphocytes may show TdT positivity if immature cortical thymocytes are present. Adipose tissue is S100 positive.
DDx ─ ─ Lipoma of the thymus (composed purely of mature adipose tissue, without significant fibrous or thymic epithelial components)
─ Liposarcoma involving the mediastinum (malignant features, lipoblasts, MDM2 amplification in well-differentiated/dedifferentiated types)
─ Invasive thymoma with fatty ingrowth (thymoma will have its characteristic epithelial neoplasm, not just entrapped elements)
─ Teratoma with prominent adipose tissue (will contain other germ cell elements like cartilage, glandular epithelium from other lineages)
─ Normal involuted thymus (predominantly fat but retains organized lobular architecture with shrunken thymic lobules, not a discrete mass of haphazard tissues)
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Sclerosing Thymoma

A rare variant of thymoma characterized by extensive stromal sclerosis or hyalinization that partially or largely obscures the underlying thymic epithelial proliferation
Clinical ─ Rare; may occur at any age typical for thymomas; clinical presentation similar to other thymomas, can be incidental or symptomatic; association with Myasthenia Gravis is less clear than for other types; behavior is generally considered indolent, similar to Type A thymoma, if the underlying epithelial component is bland
Macro ─ Firm to hard, well-circumscribed mass; cut surface is typically gray-white and very fibrous, may mimic a desmoid tumor or scar tissue
Micro ─ ─ Predominant feature is extensive, dense collagenous stroma, often paucicellular and hyalinized
─ Entrapped within the sclerotic stroma are sparse nests, cords, or single cells of neoplastic thymic epithelial cells
─ Epithelial cells are typically bland, resembling Type A thymoma (spindle or oval cells) or sometimes Type AB or B-type epithelial cells, but their features may be distorted by the sclerosis
─ Lymphocytes are usually scant
─ Foci of more cellular thymoma may be present, aiding in diagnosis
─ No significant cytologic atypia or high mitotic activity in the epithelial component if it's a pure sclerosing variant of a typically benign thymoma type
Ancillary studies ─ ─ IHC: Crucial to highlight the entrapped epithelial cells within the dense stroma.
─ ─ Epithelial cells: Pan-Cytokeratin (AE1/AE3, CAM5.2) (+), p63 (+), PAX8 (+)
─ Special stains: Trichrome stain can highlight the collagenous stroma
DDx ─ ─ Desmoplastic mesothelioma involving mediastinum (if extensive pleural/pericardial involvement; mesothelial markers positive)
─ Solitary fibrous tumor with extensive hyalinization (STAT6 positive)
─ Desmoid fibromatosis involving mediastinum (beta-catenin nuclear positivity in many cases; lacks thymic epithelial cells)
─ Nodular sclerosis Hodgkin lymphoma (sclerotic bands, but Reed-Sternberg cells and characteristic inflammatory background present; CD30+, CD15+)
─ IgG4-related disease with mediastinal fibrosis (storiform fibrosis, obliterative phlebitis, prominent IgG4+ plasma cells; lacks neoplastic epithelial component)
─ Primary sclerosing/desmoplastic carcinoma of the mediastinum (more atypical epithelial cells, infiltrative growth beyond typical thymoma patterns)
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Thymic Carcinoma

Thymic Squamous Cell Carcinoma

The most common type of thymic carcinoma, an overtly malignant epithelial neoplasm showing squamous differentiation, distinguished from Type B3 thymoma by greater cytologic atypia and carcinomatous features
Clinical ─ Rare but aggressive; typically affects middle-aged to older adults; male predominance; symptoms often related to local invasion (chest pain, dyspnea, cough, SVC syndrome); paraneoplastic syndromes are uncommon compared to thymoma; prognosis is generally poor, with high rates of recurrence and metastasis (lymph nodes, lung, bone)
Macro ─ Usually a large, firm, infiltrative mass in the anterior mediastinum; cut surface is gray-white, often with areas of necrosis and hemorrhage; may grossly invade adjacent structures
Micro ─ ─ Shows features typical of squamous cell carcinoma seen elsewhere:
─ ─ Infiltrating nests, sheets, or trabeculae of polygonal epithelial cells with eosinophilic cytoplasm, distinct cell borders
─ ─ Variable degrees of squamous differentiation: keratinization (keratin pearls, individual cell keratinization), intercellular bridges
─ ─ Nuclear atypia is overt: pleomorphism, hyperchromasia, irregular nuclear contours, coarse chromatin, prominent nucleoli
─ ─ Mitotic activity is usually brisk, atypical mitoses may be present
─ ─ Stromal desmoplasia is common
─ ─ Necrosis is often seen
─ Grading: Can be graded as well, moderately, or poorly differentiated based on extent of keratinization and atypia
─ Lacks the organotypical features of thymoma (e.g admixed TdT+ lymphocytes, Hassall's corpuscles, perivascular spaces)
Ancillary studies ─ ─ IHC (+) Pan-Cytokeratin (AE1/AE3, CAM5.2) (+), CK5/6 (+), p63/p40 (strong, diffuse nuclear staining is characteristic)
─ ─ CD5 and CD117 (c-kit) are often positive (in ~70-80% and ~80-90% respectively), which helps distinguish from most thymomas (usually negative) and metastatic SCC from some sites (e.g lung SCC often CD5/CD117 negative)
─ ─ PAX8 may be positive (also positive in thymoma)
─ ─ GLUT1 often positive
─ IHC (-) TdT (negative for immature lymphocytes), mesothelial markers (Calretinin, WT1), TTF-1 (usually negative, helps exclude lung primary SCC, though focal TTF-1 in thymic SCC is rarely reported)
DDx ─ ─ Metastatic squamous cell carcinoma to mediastinum (from lung, head and neck, esophagus; clinical history and correlation with primary site morphology/IHC crucial; e.g lung SCC is often TTF-1 negative, p63/CK5/6 positive, but CD5/CD117 negative)
─ Type B3 thymoma (less cytologic atypia, lacks overt carcinomatous features like extensive necrosis or high-grade nuclear features; usually CD5/CD117 negative)
─ Other thymic carcinomas with squamous differentiation (e.g mucoepidermoid carcinoma, adenosquamous carcinoma)
─ Germ cell tumor with somatic-type malignancy (squamous carcinoma arising in a teratoma; look for other teratomatous elements, GCT markers may be positive in other components)
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Basaloid Carcinoma (Thymus)

A rare variant of thymic carcinoma characterized by a predominantly basaloid cytoarchitecture, resembling basal cell carcinoma of the skin or basaloid squamous cell carcinoma of other sites
Clinical ─ Extremely rare, aggressive malignancy; occurs in adults; may present with local invasion or metastases; prognosis is generally poor
Macro ─ Infiltrative mass in the anterior mediastinum, similar to other thymic carcinomas; gray-white, firm, may have necrosis
Micro ─ ─ Composed of nests, islands, or trabeculae of small to medium-sized cells with scant cytoplasm, hyperchromatic nuclei with coarse chromatin, and inconspicuous nucleoli (basaloid appearance)
─ Peripheral palisading of nuclei at the edge of tumor nests is often prominent
─ Abrupt keratinization or small foci of squamous differentiation may be present within the tumor nests (distinguishing from pure basal cell carcinoma)
─ Areas of stromal hyalinization or desmoplasia are common
─ High mitotic rate and apoptotic bodies are frequently seen
─ Necrosis, including comedo-type necrosis, may be present
Ancillary studies ─ ─ IHC (+) Pan-Cytokeratin (AE1/AE3, CAM5.2) (+), CK5/6 (+), p63/p40 (strong and diffuse)
─ ─ BerEP4 often positive (can also be positive in basal cell carcinoma)
─ ─ CD5 and CD117 (c-kit) are frequently positive, similar to thymic squamous cell carcinoma
─ ─ SOX2 may be positive
─ IHC (-) Neuroendocrine markers (Synaptophysin, Chromogranin), TdT, TTF-1 (usually)
DDx ─ ─ Thymic squamous cell carcinoma, poorly differentiated or with basaloid features (distinction can be difficult, basaloid carcinoma has predominant basaloid pattern)
─ Metastatic basaloid squamous cell carcinoma (from head and neck, esophagus, lung; clinical history and IHC essential)
─ Adenoid cystic carcinoma involving mediastinum (cribriform pattern, dual cell population with myoepithelial cells, specific IHC like c-Kit positive, S100 positive in ductal cells, MYB alterations)
─ Small cell carcinoma of the thymus (neuroendocrine markers positive, different cytology – nuclear molding, salt-and-pepper chromatin)
─ Type A or AB thymoma with prominent basaloid epithelial cells (thymoma lacks overt malignant cytology, typically CD5/CD117 negative, TdT+ lymphocytes may be present)
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Mucoepidermoid Carcinoma (Thymus)

A rare type of thymic carcinoma composed of a mixture of mucin-producing (mucous) cells, squamous cells, and intermediate cells, similar to its counterpart in salivary glands
Clinical ─ Very rare, occurs in adults; behavior can range from low-grade (indolent) to high-grade (aggressive) depending on histologic features; may present with local symptoms or be an incidental finding; complete surgical resection is the primary treatment
Macro ─ Usually a relatively well-circumscribed or infiltrative mass in the anterior mediastinum; may have cystic areas due to mucin production
Micro ─ ─ Triad of cell types:
─ ─ Mucous cells: Glandular or goblet-like cells containing intracellular mucin (stains with mucicarmine or PAS-D)
─ ─ Squamous (epidermoid) cells: Polygonal cells with eosinophilic cytoplasm, may form nests, show keratinization or intercellular bridges
─ ─ Intermediate cells: Smaller, basaloid, or transitional-type cells, thought to be precursor cells, often found between mucous and squamous components
─ Cells are arranged in solid nests, glandular structures, cysts, or sheets
─ Stroma is typically fibrous
─ Grading (based on features similar to salivary gland MEC):
─ ─ Low-grade: Prominent cystic component, bland cytology, low mitotic rate, pushing borders
─ ─ High-grade: Predominantly solid growth, significant cytologic atypia, high mitotic rate, necrosis, infiltrative growth; resembles squamous cell carcinoma or adenocarcinoma with focal mucinous/squamous elements
Ancillary studies ─ ─ IHC (+) Pan-Cytokeratin (AE1/AE3, CAM5.2) (+), CK5/6 (+ in squamous areas), CK7 (often positive in glandular/intermediate cells), p63/p40 (positive in squamous and basal/intermediate cells)
─ ─ Mucin stains (Mucicarmine, PAS with diastase) highlight intracellular mucin in mucous cells
─ ─ CD117 (c-kit) and CD5 may be positive, especially in higher-grade tumors
─ Molecular ─ MAML2 gene rearrangements (CRTC1-MAML2 or CRTC3-MAML2 fusions) are characteristic of mucoepidermoid carcinomas in salivary glands and other sites, and have been reported in thymic MEC, supporting the diagnosis and distinguishing from adenosquamous carcinoma or SCC with mucinous change
DDx ─ ─ Thymic squamous cell carcinoma with mucinous metaplasia or degeneration (MEC has distinct admixture of cell types and often MAML2 fusion)
─ Adenosquamous carcinoma of the thymus (distinct separate components of adenocarcinoma and squamous cell carcinoma, not intimately admixed like MEC; MAML2 fusion usually absent)
─ Metastatic mucoepidermoid carcinoma (from salivary gland, lung, bronchus; clinical history crucial, morphology and MAML2 status may be identical)
─ Cystic thymoma (thymoma types A, AB, or B can have cystic change, but lack true mucous cells and squamous differentiation of MEC)
─ Teratoma with glandular and squamous elements (will have other germ cell components)
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Lymphoepithelioma-like Carcinoma of Thymus

A rare type of thymic carcinoma morphologically similar to undifferentiated nasopharyngeal carcinoma (lymphoepithelioma), characterized by syncytial sheets of large, undifferentiated malignant epithelial cells with vesicular nuclei and prominent nucleoli, admixed with a dense, non-neoplastic lymphoplasmacytic infiltrate
Clinical ─ Rare, occurs in adults; may be associated with Epstein-Barr Virus (EBV) infection in a subset of cases (variable by geographic region); aggressive clinical course with frequent local invasion and distant metastases; prognosis is generally poor
Macro ─ Large, fleshy, infiltrative mass in the anterior mediastinum; cut surface is typically gray-white to tan, may show necrosis
Micro ─ ─ Sheets, nests, or trabeculae of large, undifferentiated malignant epithelial cells
─ Epithelial cells have indistinct cell borders (syncytial appearance), vesicular nuclei, prominent eosinophilic nucleoli, and moderate amounts of eosinophilic cytoplasm
─ A prominent, non-neoplastic inflammatory infiltrate composed of mature lymphocytes, plasma cells, and sometimes eosinophils is intimately admixed with the tumor cells
─ High mitotic activity and necrosis are common
─ Lacks features of thymoma (e.g organotypical architecture, TdT+ immature lymphocytes as the primary lymphoid component)
Ancillary studies ─ ─ IHC (+) Pan-Cytokeratin (AE1/AE3, CAM5.2) (+, often highlighting the syncytial epithelial cells amidst the lymphocytes), EMA (+), p63/p40 (+)
─ ─ CD5 and CD117 (c-kit) may be positive (similar to other thymic carcinomas)
─ IHC (-) TdT (- in neoplastic cells), markers for lymphoma (e.g CD45, CD20, CD3 on the neoplastic epithelial cells, though the infiltrate is positive), S100 (usually negative)
─ EBV EBER in-situ hybridization: Positive in a variable percentage of cases (more common in Asian populations), staining the nuclei of the malignant epithelial cells
DDx ─ ─ Lymphoma involving the thymus (especially Hodgkin lymphoma or T-cell rich large B-cell lymphoma; lymphoma cells are CD45+, specific lymphoid markers positive; Reed-Sternberg cells in Hodgkin)
─ Type B1 or B2 thymoma (thymoma has bland epithelial cells, immature TdT+ lymphocytes, and organotypical features; lacks the high-grade malignant cytology of LELC)
─ Metastatic lymphoepithelioma-like carcinoma (from nasopharynx or other sites; clinical history is crucial)
─ Germ cell tumor (seminoma can have lymphocytic infiltrate; seminoma cells are OCT3/4+, SALL4+, PLAP+)
─ Inflammatory myofibroblastic tumor (spindle cell proliferation, ALK positive in a subset, lacks malignant epithelial cells)
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Clear Cell Carcinoma of Thymus

An extremely rare variant of thymic carcinoma characterized by a predominant population of malignant epithelial cells with abundant clear cytoplasm due to glycogen accumulation
Clinical ─ Exceedingly rare, aggressive malignancy with limited case reports; occurs in adults; poor prognosis with tendency for local recurrence and distant metastasis
Macro ─ Infiltrative mass in the anterior mediastinum, often large; cut surface may appear yellowish or gray-white
Micro ─ ─ Sheets, nests, or solid alveolar structures of polygonal to rounded malignant epithelial cells
─ Cells have distinct cell borders and abundant, clear cytoplasm that is rich in glycogen (stains positive with PAS, sensitive to diastase)
─ Nuclei are typically centrally located, vesicular or hyperchromatic, with prominent nucleoli; varying degrees of nuclear pleomorphism and atypia
─ Mitotic activity is variable but often present
─ Stroma is typically delicate and vascular; necrosis may be present
─ May show focal areas of squamous or glandular differentiation in some cases
Ancillary studies ─ ─ IHC (+) Pan-Cytokeratin (AE1/AE3, CAM5.2) (+), EMA (+), p63/p40 (often positive, especially if squamous elements present)
─ ─ CD5 and CD117 (c-kit) may be positive
─ ─ PAX8 may be positive
─ IHC (-) TTF-1 (helps exclude metastatic clear cell carcinoma from lung), RCCma (helps exclude metastatic renal cell carcinoma), S100 (negative, unlike clear cell melanoma or some clear cell sarcomas), HMB-45, Melan-A
─ Special Stains: PAS stain positive for intracytoplasmic glycogen, which is digested by diastase (PAS-D negative)
DDx ─ ─ Metastatic clear cell carcinoma (most important differential, especially from kidney, lung, thyroid, ovary, or other gynecologic sites; requires thorough clinical workup and broad IHC panel)
─ ─ Renal cell carcinoma, clear cell type: PAX8 (+), CD10 (+), RCCma (+), CAIX (+)
─ ─ Lung adenocarcinoma with clear cell features: TTF-1 (+), Napsin A (+)
─ Clear cell change in other thymic neoplasms (e.g thymoma with clear cell features – lacks overt malignant cytology, typically CD5/CD117 negative; other thymic carcinoma subtypes with focal clear cell change)
─ Parathyroid carcinoma with clear cells (PTH positive)
─ PEComa (clear cell "sugar" tumor) (HMB-45, Melan-A, SMA positive)
─ Adrenal cortical carcinoma, clear cell type (SF-1, Melan-A, inhibin positive)
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Sarcomatoid Carcinoma of Thymus (Spindle Cell Carcinoma)

A rare, aggressive variant of thymic carcinoma characterized by a predominant or exclusive proliferation of malignant spindle cells that may or may not show overt epithelial differentiation by light microscopy, but demonstrate epithelial origin by immunohistochemistry or ultrastructure
Clinical ─ Very rare, affects adults; highly aggressive with poor prognosis, frequent local invasion, recurrence, and distant metastases
Macro ─ Large, infiltrative, fleshy, gray-white mass in the anterior mediastinum, often with areas of necrosis and hemorrhage
Micro ─ ─ Predominantly composed of malignant spindle cells arranged in fascicles, storiform patterns, or sheets, resembling a sarcoma (e.g fibrosarcoma, malignant fibrous histiocytoma/undifferentiated pleomorphic sarcoma)
─ Spindle cells exhibit marked cytologic atypia: nuclear pleomorphism, hyperchromasia, irregular nuclear contours, prominent nucleoli, and frequent, often atypical, mitotic figures
─ Necrosis is common
─ Foci of overt carcinomatous differentiation (e.g squamous cell carcinoma, adenocarcinoma) may be present (biphasic pattern), confirming the diagnosis as sarcomatoid carcinoma; if absent, IHC is crucial
─ Stroma can be collagenous or myxoid
Ancillary studies ─ ─ IHC (+) Pan-Cytokeratin (AE1/AE3, CAM5.2) (+, may be focal or patchy in spindle cell areas, but crucial for diagnosis), EMA (+), p63/p40 (often positive, especially if squamous elements are hinted at)
─ ─ Vimentin is usually co-expressed with cytokeratins in the spindle cells
─ ─ CD5 and CD117 (c-kit) may be positive
─ IHC (-) S100 protein, desmin, SMA (usually negative, to exclude true sarcoma types like MPNST or leiomyosarcoma), STAT6 (to exclude SFT)
DDx ─ ─ True sarcoma of the mediastinum (e.g synovial sarcoma, leiomyosarcoma, fibrosarcoma, UPS; cytokeratin negative or only very rarely focally positive in some sarcoma types like synovial sarcoma, which has other specific markers like TLE1 and SS18 fusion)
─ Sarcomatoid mesothelioma involving mediastinum (positive for mesothelial markers like calretinin, WT1, often more diffuse cytokeratin)
─ Solitary fibrous tumor, malignant variant (STAT6 positive, CD34 positive)
─ Spindle cell melanoma metastatic to mediastinum (S100, SOX10, HMB-45 positive)
─ Type A or B3 thymoma with prominent spindle cells (thymomas lack the high-grade malignant cytology and infiltrative sarcomatoid growth of sarcomatoid carcinoma; typically CD5/CD117 negative)
─ Metaplastic thymoma (bland spindle cell component and distinct benign-appearing epithelial islands)
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Adenocarcinoma of Thymus (Papillary, Mucinous, NOS)

A rare form of thymic carcinoma showing glandular differentiation, including subtypes such as papillary adenocarcinoma, mucinous adenocarcinoma, or adenocarcinoma not otherwise specified (NOS)
Clinical ─ Extremely rare, aggressive malignancy; occurs in adults; prognosis is generally poor; may present with local invasion or metastatic disease
Macro ─ Infiltrative mass in the anterior mediastinum; appearance depends on subtype (e.g mucinous types may be gelatinous)
Micro ─ (Varies by subtype)
─ General features: Malignant epithelial cells forming glandular structures, tubules, papillae, or producing mucin
─ Papillary Adenocarcinoma: Predominantly papillary architecture with fibrovascular cores lined by atypical cuboidal to columnar epithelial cells
─ Mucinous Adenocarcinoma (Colloid Carcinoma): Characterized by abundant extracellular mucin pools containing floating clusters or single atypical epithelial cells, often with signet-ring cell features; must be distinguished from metastatic mucinous adenocarcinoma
─ Adenocarcinoma, NOS: Glandular differentiation without specific features of papillary or mucinous types; may be tubular, acinar, or solid with focal gland formation
─ Cells show overt malignant cytologic features: nuclear atypia, pleomorphism, prominent nucleoli, increased mitoses
Ancillary studies ─ ─ IHC (+) Pan-Cytokeratin (AE1/AE3, CAM5.2) (+), CK7 (often positive), EMA (+)
─ ─ CD5 and CD117 (c-kit) may be positive (as in other thymic carcinomas)
─ ─ PAX8 may be positive
─ IHC (-) TTF-1 (usually negative, important to exclude lung primary adenocarcinoma, though rare focal positivity in thymic adenocarcinoma has been described), Napsin A (usually negative), CDX2 (usually negative, to exclude GI primary), ER/PR (usually negative, to exclude breast/gyn primary), PSA (to exclude prostate primary)
─ ─ Mesothelial markers (Calretinin, WT1) are negative
─ Special Stains: Mucicarmine or PAS-D to highlight mucin in mucinous adenocarcinoma
DDx ─ ─ Metastatic adenocarcinoma (most important differential; from lung, breast, GI tract, pancreas, ovary, etc.; extensive clinical workup and comprehensive IHC panel needed to exclude metastasis; TTF-1/Napsin A for lung, GATA3/ER for breast, CDX2/SATB2 for colorectal, PAX8 for Gyn/Renal)
─ Thymoma with glandular differentiation or cystic change (thymomas have bland cytology, characteristic architecture, often TdT+ lymphocytes, and are CD5/CD117 negative)
─ Mucoepidermoid carcinoma of thymus (has squamous and intermediate cells in addition to mucous cells; MAML2 fusion)
─ Salivary gland-type tumors of the thymus (other types like adenoid cystic carcinoma)
─ Mesothelioma with glandular features (positive for mesothelial markers)
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Undifferentiated Carcinoma of Thymus

A high-grade malignant epithelial neoplasm of the thymus that lacks specific morphologic features of differentiation (e.g squamous, glandular, neuroendocrine), diagnosed after exclusion of other poorly differentiated thymic carcinomas and metastatic undifferentiated carcinoma
Clinical ─ Very rare and highly aggressive; poor prognosis with early local invasion and distant metastases; occurs in adults
Macro ─ Large, infiltrative, fleshy, gray-white mass, often with extensive necrosis and hemorrhage
Micro ─ ─ Sheets, nests, or diffuse infiltrates of highly pleomorphic malignant epithelial cells
─ Cells typically have large, vesicular or hyperchromatic nuclei, prominent nucleoli, and variable amounts of cytoplasm
─ High mitotic rate, frequent atypical mitoses, and extensive necrosis are common
─ No discernible squamous, glandular, or convincing neuroendocrine differentiation by light microscopy
─ May have a vaguely epithelioid, rhabdoid, or plasmacytoid appearance in some areas
Ancillary studies ─ ─ IHC (+) Pan-Cytokeratin (AE1/AE3, CAM5.2) (+, confirms epithelial nature), EMA (+)
─ ─ p63/p40 may be positive, but often weaker or more focal than in SCC
─ ─ CD5 and CD117 (c-kit) may be positive
─ ─ PAX8 may be positive
─ IHC (-) Markers for specific differentiation (e.g extensive TTF-1, Napsin A for lung adeno; strong diffuse p63/CK5/6 for SCC; Synaptophysin/Chromogranin for neuroendocrine; S100/SOX10 for melanoma; CD45 for lymphoma; germ cell markers like OCT3/4, SALL4) must be largely negative or unconvincing for a specific lineage to classify as undifferentiated
DDx ─ ─ Other poorly differentiated thymic carcinomas (e.g poorly differentiated SCC, adenocarcinoma, neuroendocrine carcinoma – careful search for focal differentiation and specific markers is key)
─ Metastatic undifferentiated carcinoma or sarcoma from another site (clinical history and broader IHC panel essential)
─ Large cell lymphoma (CD45 positive, specific lymphoid markers)
─ Melanoma (S100, SOX10, HMB-45 positive)
─ Poorly differentiated germ cell tumor (e.g embryonal carcinoma; OCT3/4, SALL4 positive)
─ Sarcomatoid carcinoma of thymus (if spindle cell component is significant)
─ NUT carcinoma (if relevant morphology and NUTM1 IHC is available/considered)
─ SMARCA4-deficient undifferentiated thoracic tumor (SMARCA4/BRG1 loss by IHC)
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NUT Carcinoma (Midline Carcinoma) involving Thymus

A highly aggressive and rare carcinoma defined by NUTM1 gene rearrangement, typically arising in midline structures including the thymus and upper aerodigestive tract, characterized by poorly differentiated monomorphic cells with abrupt squamous differentiation in some cases
Clinical ─ Extremely rare, affects children and adults; highly aggressive with rapid progression, widespread metastases, and very poor prognosis despite intensive therapy; often presents as a large, locally advanced mass
Macro ─ Large, infiltrative, gray-white mass, frequently with necrosis and hemorrhage
Micro ─ ─ Monomorphic population of primitive, round to oval undifferentiated cells growing in sheets or nests
─ Cells have scant cytoplasm, round nuclei with vesicular or fine chromatin, and often prominent nucleoli
─ High mitotic activity and extensive necrosis are characteristic
─ Abrupt, focal squamous differentiation (keratinization, intercellular bridges) is a common and distinctive feature, often appearing as small "pearls" or islands within the undifferentiated component
─ Minimal stromal desmoplasia is typical; inflammatory infiltrate is variable
Ancillary studies ─ ─ IHC (+) NUT (Nuclear protein in testis) (nuclear staining is pathognomonic, using a NUTM1-specific antibody)
─ ─ Cytokeratin (AE1/AE3, CAM5.2) (+, often diffuse)
─ ─ p63/p40 (often positive, especially in areas with squamous differentiation)
─ ─ CD34 can be positive in some cases (unusual for carcinoma)
─ ─ Other markers: Variable positivity for EMA, CK5/6, CEA; MyoD1, desmin, S100 are negative
─ IHC (-) CD45, CD99, FLI1, OCT3/4, SALL4, TTF-1, neuroendocrine markers (Synaptophysin, Chromogranin)
─ Molecular ─ Demonstration of NUTM1 gene rearrangement (most commonly t(15;19)(q14;p13.1) leading to BRD4-NUTM1 fusion, or other NUTM1 fusion partners like BRD3, NSD3) by FISH, RT-PCR, or sequencing is confirmatory
DDx ─ ─ Poorly differentiated squamous cell carcinoma of thymus (lacks NUTM1 rearrangement; NUT IHC negative)
─ Undifferentiated carcinoma of thymus (lacks NUTM1 rearrangement; NUT IHC negative)
─ Germ cell tumor (especially embryonal carcinoma or yolk sac tumor; positive for OCT3/4, SALL4, AFP, etc.; NUT IHC negative)
─ Ewing sarcoma/PNET (CD99 positive, FLI1 positive, characteristic EWSR1 rearrangement; NUT IHC negative)
─ Lymphoma (CD45 positive; NUT IHC negative)
─ Other small round blue cell tumors
─ SMARCA4-deficient undifferentiated thoracic tumor (loss of SMARCA4/BRG1; NUT IHC negative)
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Neuroendocrine Neoplasms of the Thymus (Thymic NETs)

Well-differentiated Neuroendocrine Tumor (Carcinoid Tumor) of Thymus

A rare neuroendocrine neoplasm arising in the thymus, morphologically similar to carcinoid tumors of other sites, divided into typical and atypical carcinoid subtypes based on mitotic activity and presence of necrosis
Clinical ─ Rare, <5% of mediastinal tumors; occurs mainly in adults (mean age ~50 years), male predominance; ~25-40% associated with Multiple Endocrine Neoplasia type 1 (MEN1) syndrome; ~30-50% may produce ectopic hormones (e.g ACTH leading to Cushing syndrome, ADH, GHRH); symptoms can be due to mass effect, hormone production, or MEN1 manifestations; prognosis is better for typical carcinoid than atypical, but overall more aggressive than pulmonary counterparts; metastases (lymph node, distant) can occur even with typical carcinoids
Macro ─ Usually a well-circumscribed, encapsulated or partially encapsulated, firm, lobulated mass; tan, yellow, or reddish-brown cut surface; hemorrhage or necrosis more common in atypical variant
Micro ─ General neuroendocrine features:
─ Organoid, trabecular, nesting, gyriform, or sheet-like growth patterns
─ Cells are relatively uniform, polygonal or spindle-shaped, with moderate amounts of eosinophilic granular cytoplasm
─ Nuclei are round to oval with characteristic "salt-and-pepper" stippled chromatin; nucleoli are usually inconspicuous
─ Stroma is often highly vascular
Subtypes:
─ Typical Carcinoid (Low-grade):
─ ─ Mitotic count <2 mitoses per 2 mm² (or per 10 HPF using 40x objective) AND
─ ─ Lacks necrosis (focal punctate necrosis may be acceptable if minimal)
─ ─ Cytology is generally bland
─ Atypical Carcinoid (Intermediate-grade):
─ ─ Mitotic count 2-10 mitoses per 2 mm² OR
─ ─ Presence of necrosis (usually punctate or focal, not extensive)
─ ─ May show increased cellularity, disorganization, or more prominent nucleoli compared to typical carcinoid
Ancillary studies ─ ─ IHC (+) Neuroendocrine markers: Synaptophysin (+, diffuse), Chromogranin A (+, often focal/patchy), CD56 (NCAM) (+)
─ ─ Cytokeratins (AE1/AE3, CAM5.2, CK8/18) (+)
─ ─ TTF-1 is usually negative (helps distinguish from pulmonary carcinoid if metastasis is a concern)
─ ─ Ki-67 proliferation index: Typically low (<2-5%) in typical carcinoids, higher (5-20%) in atypical carcinoids (variable cutoffs reported)
─ IHC (-) CD5, CD117 (usually negative, helps distinguish from thymic carcinoma)
DDx ─ ─ Thymoma (especially Type A or B variants; thymomas have neoplastic epithelial cells, often TdT+ lymphocytes, lack strong diffuse neuroendocrine marker expression; PAX8 positive, neuroendocrine markers negative)
─ Paraganglioma of mediastinum (zellballen pattern, S100+ sustentacular cells around chief cell nests, GATA3 positive, chromogranin/synaptophysin positive)
─ Metastatic well-differentiated NET (from lung, GI tract, pancreas; clinical history, TTF-1 for lung, CDX2/ISL1 for GI/pancreas can be helpful)
─ Thymic carcinoma with neuroendocrine features (higher grade cytology, often positive for CD5/CD117, higher Ki-67)
─ Poorly-differentiated neuroendocrine carcinoma (small cell or large cell; high grade cytology, extensive necrosis, high Ki-67)
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Poorly-differentiated Neuroendocrine Carcinoma of Thymus

A high-grade malignant neoplasm with neuroendocrine differentiation, encompassing Small Cell Carcinoma and Large Cell Neuroendocrine Carcinoma of the thymus
Clinical ─ Rare, highly aggressive tumors; occur in adults, often associated with smoking history (especially small cell); symptoms are typically due to rapid growth, local invasion, or paraneoplastic syndromes (e.g SIADH, Cushing syndrome, Lambert-Eaton myasthenic syndrome); early metastasis is common; very poor prognosis; association with MEN1 is less common than with thymic carcinoids
Macro ─ Large, infiltrative, gray-white to tan masses, often with extensive necrosis and hemorrhage
Micro ─ Subtypes:
─ Small Cell Carcinoma (SCLC) of Thymus:
─ ─ Morphologically identical to SCLC of the lung
─ ─ Sheets, nests, or diffuse infiltrates of small, round, oval, or spindle-shaped cells with scant cytoplasm
─ ─ Nuclei have finely granular (salt-and-pepper) chromatin, inconspicuous or absent nucleoli, and exhibit significant nuclear molding
─ ─ High mitotic rate (typically >10 mitoses per 2 mm²), abundant apoptosis (crush artifact common)
─ ─ Extensive necrosis
─ Large Cell Neuroendocrine Carcinoma (LCNEC) of Thymus:
─ ─ Composed of large polygonal cells with lower nuclear-to-cytoplasmic ratios than SCLC, more abundant cytoplasm (can be eosinophilic)
─ ─ Nuclei are vesicular or coarsely granular, often with prominent nucleoli
─ ─ Neuroendocrine architectural features (organoid nesting, trabeculae, rosettes, peripheral palisading)
─ ─ High mitotic rate (typically >10 mitoses per 2 mm²), frequent necrosis (often large, geographic areas)
Ancillary studies ─ ─ IHC (+) Neuroendocrine markers: Synaptophysin (+, usually strong and diffuse), Chromogranin A (+, can be focal), CD56 (NCAM) (+)
─ ─ Cytokeratins (AE1/AE3, CAM5.2) (+, often dot-like perinuclear in SCLC)
─ ─ TTF-1: Can be positive in a subset of thymic SCLC and LCNEC (similar to pulmonary counterparts), making distinction from metastasis challenging without clinical correlation
─ ─ Ki-67 proliferation index: Very high (typically >50-70%)
─ IHC (Differential markers):
─ ─ CD5 and CD117 (c-kit) can be positive, but less consistently than in some other thymic carcinomas
─ ─ p63/p40 usually negative or only focally positive (helps distinguish from squamous cell carcinoma)
─ ─ CD45 negative (to exclude lymphoma)
DDx ─ ─ Metastatic poorly-differentiated neuroendocrine carcinoma (especially from lung; clinical history and comparison with primary is crucial if known; TTF-1 positivity is not definitive for lung origin in this context)
─ Well-differentiated NET (carcinoid tumor) of thymus (lower grade cytology, lower mitotic rate/Ki-67, less necrosis)
─ Other thymic carcinomas (e.g squamous cell, basaloid, undifferentiated; distinguished by morphology and lack of definitive neuroendocrine marker expression)
─ Lymphoma (especially diffuse large B-cell or T-lymphoblastic lymphoma; CD45 positive, specific lymphoid markers)
─ Ewing sarcoma/PNET (CD99 positive, FLI1 positive, lacks definitive neuroendocrine markers)
─ NUT Carcinoma (NUT IHC positive, characteristic morphology)
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Combined Neuroendocrine Neoplasms of Thymus

Rare thymic tumors composed of a combination of a neuroendocrine neoplasm component (well-differentiated NET or poorly-differentiated neuroendocrine carcinoma) and a non-neuroendocrine carcinoma component (e.g squamous cell carcinoma, adenocarcinoma)
Clinical ─ Extremely rare; clinical behavior and prognosis are generally driven by the higher-grade or more aggressive component; occur in adults
Macro ─ Similar to other large, infiltrative thymic malignancies; appearance may be heterogeneous depending on the components
Micro ─ ─ Two distinct malignant components intimately admixed or clearly demarcated:
─ ─ Neuroendocrine Component: Can be typical carcinoid, atypical carcinoid, small cell carcinoma, or large cell neuroendocrine carcinoma, showing characteristic morphology and neuroendocrine marker expression
─ ─ Non-Neuroendocrine Carcinoma Component: Most commonly squamous cell carcinoma or adenocarcinoma; can also be other types of thymic carcinoma
─ Each component must constitute a significant proportion (e.g at least 10% or 30% depending on definition, though no strict consensus for thymus) and be identifiable as malignant
─ It is important to distinguish from a single carcinoma type with focal neuroendocrine differentiation or a neuroendocrine neoplasm with focal non-neuroendocrine features if those features are not clearly malignant or extensive
Ancillary studies ─ ─ IHC: Essential to confirm the dual differentiation.
─ ─ Neuroendocrine markers (Synaptophysin, Chromogranin A, CD56) will be positive in the neuroendocrine component
─ ─ Markers for the non-neuroendocrine component (e.g p63/p40/CK5/6 for squamous; mucin stains, CK7, or site-associated markers for adenocarcinoma if applicable, though often non-specific in primary thymic adenocarcinoma) will be positive in their respective areas
─ ─ Ki-67 can show different proliferation rates in the two components
DDx ─ ─ Poorly-differentiated neuroendocrine carcinoma with divergent differentiation (if the non-NE component is minor or less distinct)
─ Thymic carcinoma (e.g SCC or adenocarcinoma) with reactive entrapped or hyperplastic neuroendocrine cells (neuroendocrine cells are not neoplastic)
─ Collision tumor (two separate primary tumors growing into each other; rare)
─ Thymoma with neuroendocrine differentiation (neuroendocrine cells are usually scattered and not forming a distinct malignant NE component; thymoma has characteristic epithelial cells and often TdT+ lymphocytes)
─ Metastatic combined carcinoma (e.g from lung)
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Germ Cell Tumors of the Mediastinum

Teratoma (Mediastinum)

A type of germ cell tumor composed of tissues derived from two or more of the three embryonic germ layers (ectoderm, mesoderm, endoderm), which can be mature, immature, or exhibit somatic-type malignancy
Clinical ─ Most common mediastinal germ cell tumor (~50-70% of mediastinal GCTs); typically occurs in young adults (20s-30s), slight male predominance for mediastinal location; usually located in the anterior mediastinum; symptoms vary from asymptomatic (especially mature teratomas) to chest pain, cough, dyspnea due to mass effect or rupture; mature teratomas are benign, immature teratomas have malignant potential based on grade, and teratomas with somatic-type malignancy are overtly malignant
Macro ─ Variable appearance:
─ Mature Cystic Teratoma: Often large, well-circumscribed, multiloculated cyst; contains sebaceous material, hair, teeth, cartilage, bone; cut surface shows heterogeneous mixture of tissues
─ Solid Teratoma (Mature or Immature): More solid, fleshy components, may have cystic areas; immature teratomas often larger with areas of necrosis or hemorrhage
Micro ─ Composed of a variety of tissues from different germ layers:
─ Ectodermal derivatives: Squamous epithelium (keratinizing, skin appendages like hair follicles, sebaceous glands), neural tissue (glial tissue, choroid plexus, neuroblasts if immature), dental structures
─ Mesodermal derivatives: Cartilage, bone, adipose tissue, smooth muscle, striated muscle, fibrous tissue
─ Endodermal derivatives: Respiratory or gastrointestinal epithelium (glandular or cystic structures), pancreatic tissue, thyroid tissue
Subtypes:
─ Mature Teratoma:
─ ─ Composed exclusively of mature, well-differentiated tissues from at least two germ layers
─ ─ No immature or embryonal components
─ ─ May be cystic (dermoid cyst if predominantly skin elements) or solid
─ ─ Benign clinical course
─ Immature Teratoma:
─ ─ Contains immature or embryonal tissues, most commonly immature neuroepithelium (primitive neuroectodermal tubules, rosettes, sheets of small blue cells resembling neuroblasts)
─ ─ Other immature tissues (e.g immature cartilage, mesenchyme) can be present but grading primarily relies on immature neuroepithelium
─ ─ Graded based on the quantity of immature neuroepithelium (e.g Grade 1: <1 low power field (LPF) of immature neuroepithelium in any slide; Grade 2: 1-3 LPFs; Grade 3: >3 LPFs); higher grade correlates with worse prognosis, especially in post-pubertal patients
─ ─ Malignant potential, particularly Grades 2 and 3
─ Teratoma with Somatic-Type Malignancy:
─ ─ Development of a non-germ cell malignancy (carcinoma or sarcoma) within a teratoma (usually mature teratoma background)
─ ─ Most common somatic malignancies: Squamous cell carcinoma, adenocarcinoma, sarcoma (e.g rhabdomyosarcoma, angiosarcoma, leiomyosarcoma), primitive neuroectodermal tumor (PNET, distinct from immature neuroepithelium)
─ ─ The somatic malignancy determines the behavior and prognosis, often aggressive
Ancillary studies ─ ─ IHC: Generally not needed for mature teratoma; can be used to characterize components in immature teratoma or somatic malignancy (e.g GFAP for glia, cytokeratins for epithelial elements, specific markers for sarcomas or carcinomas in somatic malignancy)
─ Serum tumor markers (AFP, HCG): Usually normal in pure mature teratoma; may be slightly elevated with immature components or significantly elevated if mixed with yolk sac tumor or choriocarcinoma elements (then classified as mixed GCT), or in some somatic malignancies
DDx ─ ─ Other germ cell tumors (seminoma, yolk sac tumor, embryonal carcinoma, choriocarcinoma – if these are present, it's a mixed GCT)
─ Thymic cyst or other mediastinal cysts (if teratoma is predominantly cystic; presence of multiple germ layer derivatives confirms teratoma)
─ Thymoma (epithelial neoplasm, lacks diverse germ layer components)
─ Primary mediastinal sarcoma or carcinoma (if teratoma has somatic malignancy; look for teratomatous background)
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Seminoma (Mediastinum)

A malignant germ cell tumor composed of primitive, uniform cells resembling gonadal seminoma (testis) or dysgerminoma (ovary), representing the most common type of malignant germ cell tumor in the mediastinum
Clinical ─ Primarily affects young men (peak age 20-40 years); rare in women; almost exclusively in anterior mediastinum; symptoms include chest pain, cough, dyspnea, SVC syndrome; may be associated with Klinefelter syndrome; generally good prognosis, highly sensitive to radiation and chemotherapy; serum HCG may be mildly elevated in ~10-15% due to syncytiotrophoblastic giant cells, AFP is typically normal (if elevated, suspect mixed GCT)
Macro ─ Large, bulky, well-circumscribed or lobulated, fleshy, homogeneous, gray-white to tan-pink mass; areas of necrosis may be present, hemorrhage is less common than in NSGCTs
Micro ─ ─ Diffuse sheets, nests, or lobules of uniform, large, round to polygonal cells ("seminoma cells" or "germinoma cells")
─ Cells have distinct cell membranes, abundant clear or pale eosinophilic cytoplasm (rich in glycogen), and large central nuclei with prominent, often bar-like or eosinophilic nucleoli, and vesicular chromatin
─ Fibrous septa containing a prominent lymphocytic infiltrate (T-cells) are characteristic, often with associated granulomatous reaction (non-caseating granulomas)
─ Mitotic figures are usually readily identifiable
─ Syncytiotrophoblastic giant cells (STGCs), which are HCG-positive, may be scattered within the tumor
Ancillary studies ─ ─ IHC (+) OCT3/4 (nuclear, strong and diffuse), SALL4 (nuclear), PLAP (placental-like alkaline phosphatase, membranous, often focal/variable), D2-40 (podoplanin, membranous), KIT (CD117, membranous, in majority)
─ ─ Cytokeratin (AE1/AE3, CAM5.2) can show variable focal positivity, often dot-like or perinuclear (beware of strong diffuse positivity which would suggest embryonal carcinoma)
─ ─ HCG (in syncytiotrophoblastic giant cells if present)
─ IHC (-) AFP, CD30 (usually negative or weak/focal, strong CD30 suggests embryonal carcinoma), EMA (usually negative), SOX2 (usually negative)
─ Special Stains: PAS stain highlights glycogen in cytoplasm (diastase sensitive)
DDx ─ ─ Embryonal carcinoma (more pleomorphic, irregular nuclei, indistinct cell borders, often CD30 strong positive, cytokeratin strong positive, OCT3/4 & SALL4 positive)
─ Lymphoma (especially large B-cell lymphoma or Hodgkin lymphoma; CD45+, specific lymphoid markers positive; OCT3/4 negative)
─ Thymic carcinoma (especially clear cell or lymphoepithelioma-like; cytokeratin strong positive, CD5/CD117 may be positive, specific GCT markers negative)
─ Thymoma (especially Type B variants; thymic epithelial cells with associated lymphocytes, PAX8 positive, GCT markers negative)
─ Yolk sac tumor (if only scattered STGCs in seminoma raise AFP concern; YST has distinct patterns and AFP positivity)
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Non-Seminomatous Germ Cell Tumors (NSGCTs) of Mediastinum

A heterogeneous group of malignant germ cell tumors other than seminoma, including embryonal carcinoma, yolk sac tumor, choriocarcinoma, and mixed germ cell tumors; these are generally more aggressive than seminoma
Clinical ─ Primarily affect young men (peak age 20-30 years); almost exclusively in anterior mediastinum; often present with symptoms due to rapid growth, local invasion, or metastases (chest pain, dyspnea, cough, SVC syndrome, fever, weight loss); serum tumor markers (AFP, HCG) are frequently elevated depending on components; generally more aggressive than seminoma, but respond to chemotherapy; may be associated with Klinefelter syndrome
Macro ─ Typically large, infiltrative masses with heterogeneous cut surface, often showing extensive necrosis, hemorrhage, and cystic changes
Micro ─ (Can be composed of one or more of the following types)
─ Embryonal Carcinoma:
─ ─ Highly malignant, composed of primitive epithelial-appearing cells growing in sheets, nests, cords, papillary, or glandular patterns
─ ─ Cells are large, pleomorphic, with indistinct cell borders, amphophilic cytoplasm, large irregular nuclei with coarse chromatin and prominent nucleoli
─ ─ High mitotic activity and necrosis are common
─ ─ IHC: OCT3/4 (+), SALL4 (+), SOX2 (+), CD30 (+, strong membranous), Cytokeratin (AE1/AE3, CAM5.2) (+, strong diffuse), PLAP (+/-)
─ ─ IHC (-): KIT (CD117) often negative or weaker than in seminoma, AFP (-), HCG (-) (unless STGCs present)
─ Yolk Sac Tumor (Endodermal Sinus Tumor):
─ ─ Characterized by a variety of architectural patterns: reticular/microcystic (most common), macrocystic, papillary, solid, glandular-alveolar, polyvesicular vitelline, hepatoid
─ ─ Schiller-Duval bodies (pathognomonic): perivascular structures with a central vessel surrounded by tumor cells, resembling a primitive glomerulus, within a cystic space
─ ─ Cells are cuboidal to flattened, may have clear or eosinophilic cytoplasm
─ ─ Hyaline globules (PAS-positive, diastase-resistant) containing AFP are often present intracellularly or extracellularly
─ ─ IHC: AFP (+, strong cytoplasmic/globular), SALL4 (+), Glypican-3 (+), Cytokeratin (+), OCT3/4 (- or weak/focal), CD30 (-)
─ Choriocarcinoma:
─ ─ Highly aggressive, composed of a biphasic population of malignant trophoblastic cells:
─ ─ ─ Syncytiotrophoblasts: Large, multinucleated giant cells with abundant eosinophilic or vacuolated cytoplasm, pleomorphic hyperchromatic nuclei; produce HCG
─ ─ ─ Cytotrophoblasts: Smaller, mononucleated polygonal cells with clear cytoplasm and distinct cell borders, often underlying or capping syncytiotrophoblasts
─ ─ Extensive hemorrhage and necrosis are characteristic; vascular invasion is common
─ ─ Pure choriocarcinoma is very rare; more often a component of mixed GCT
─ ─ IHC: HCG (+, strong in syncytiotrophoblasts), SALL4 (+), GATA3 (+), Cytokeratin (+), OCT3/4 (-), AFP (-)
─ Mixed Germ Cell Tumors:
─ ─ Composed of two or more GCT components (e.g teratoma + embryonal carcinoma + yolk sac tumor; seminoma + embryonal carcinoma etc)
─ ─ Most common type of NSGCT in the mediastinum
─ ─ Prognosis and treatment depend on the types and proportions of components, and presence of chemoresistant elements like mature teratoma post-chemotherapy
─ ─ Serum markers reflect the components present (e.g AFP from YST, HCG from choriocarcinoma/STGCs)
Ancillary studies ─ (See individual components above)
─ Serum Tumor Markers: AFP (elevated in YST), HCG (elevated in choriocarcinoma, seminoma with STGCs, some embryonal carcinomas), LDH (non-specific marker of tumor burden/turnover)
DDx ─ ─ Seminoma (if NSGCT has clear cell features or lymphocytic infiltrate; seminoma is OCT3/4+, KIT+, CD30-)
─ Thymic carcinoma (especially poorly differentiated types; cytokeratin+, but GCT markers like OCT3/4, SALL4, AFP, HCG are negative or different profile; CD5/CD117 common in thymic Ca)
─ Metastatic carcinoma or sarcoma (clinical history, specific lineage markers)
─ Lymphoma (CD45+, specific lymphoid markers)
─ Teratoma (if NSGCT elements are focal within a teratoma, it becomes a mixed GCT)
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Germ Cell Tumors associated with Hematologic Malignancies (Mediastinum)

A rare phenomenon where patients with mediastinal germ cell tumors (most often NSGCTs) develop concurrent or subsequent hematologic malignancies, particularly acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), or systemic mastocytosis
Clinical ─ Almost exclusively occurs in young males with primary mediastinal NSGCTs (especially those with yolk sac tumor components or prominent isochromosome 12p (i12p) abnormality); hematologic malignancy usually develops within months to a few years of GCT diagnosis, often refractory to treatment and carries a very poor prognosis; Klinefelter syndrome is a predisposing factor for both mediastinal GCTs and this association
Pathogenesis ─ Thought to involve a common clonal origin or shared progenitor cell for both the GCT and the hematologic malignancy, possibly related to i12p or other genetic abnormalities in the GCT cells that confer hematopoietic potential or predisposition; GCT cells may differentiate along hematopoietic lines or induce malignant transformation in host hematopoietic cells
Micro ─ (Of the GCT and the hematologic malignancy)
─ Mediastinal GCT: Typically a non-seminomatous GCT, often with yolk sac tumor, embryonal carcinoma, or teratomatous elements; may show i(12p)
─ Hematologic Malignancy: Bone marrow and peripheral blood will show features of AML (e.g acute megakaryoblastic leukemia is common), MDS, or less commonly other myeloid or lymphoid neoplasms; features are typical for de novo hematologic malignancies
Ancillary studies ─ ─ For GCT: Standard GCT markers (AFP, HCG, OCT3/4, SALL4, etc)
─ For Hematologic Malignancy: Cytogenetics on bone marrow (may show abnormalities similar to those in the GCT, like i(12p), or other myeloid-specific changes), flow cytometry, specific leukemia/MDS markers
─ Molecular: i(12p) or 12p overrepresentation in GCT cells is a common finding; shared clonal markers between GCT and hematologic malignancy if demonstrable
DDx ─ ─ Therapy-related myeloid neoplasm (if patient received chemotherapy/radiotherapy for GCT; however, this association can occur pre-therapy or with specific cytogenetic links suggesting common origin)
─ Coincidental occurrence of two separate malignancies (less likely given the strong association and specific GCT subtypes involved)
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Regressed ("Burned-out") Germ Cell Tumors (Mediastinum)

A rare phenomenon where a malignant germ cell tumor, typically a non-seminomatous GCT, undergoes extensive necrosis or differentiation (e.g into mature teratoma) following or even prior to therapy, leaving behind a residual scar, fibrous tissue, calcification, or mature teratomatous elements, with little or no viable malignant GCT identifiable
Clinical ─ May present as a mediastinal mass with elevated serum tumor markers (AFP, HCG) that subsequently normalize, or with symptoms from metastases despite a small or fibrotic primary mediastinal lesion; can occur spontaneously or after chemotherapy; important to recognize as metastases may still be viable and require treatment; prior history of GCT or elevated markers is key
Macro ─ The residual mediastinal lesion may be small, irregular, firm, fibrotic, and calcified; may contain cystic areas if mature teratoma is present; gross evidence of viable tumor may be absent
Micro ─ ─ Predominantly dense, hyalinized fibrous scar tissue, often with chronic inflammation, hemosiderin-laden macrophages, dystrophic calcification, and cholesterol clefts
─ Scattered, atypical, degenerating cells may be present but difficult to classify
─ Foci of mature teratomatous elements (cartilage, glands, squamous cysts) may be found within the scar, representing differentiation of the original GCT
─ Viable malignant germ cell tumor (seminoma, embryonal carcinoma, YST, choriocarcinoma) is absent or very sparse; extensive sampling is crucial
─ Evidence of prior GCT may include "ghosts" of seminoma cells, vascular scarring, or specific structures related to YST or teratoma
Ancillary studies ─ ─ IHC: May be difficult to interpret on degenerating cells.
─ ─ If sparse atypical cells are present, GCT markers (OCT3/4, SALL4, AFP, HCG, cytokeratins) can be attempted but may be negative or non-specific in necrotic/regressed cells
─ ─ If mature teratoma is present, markers for differentiated tissues can be used if needed
─ Serum Tumor Markers: Current levels should be correlated; if previously elevated, their decline supports regression, but persistent elevation suggests viable tumor elsewhere
DDx ─ ─ Fibrosing mediastinitis (idiopathic or secondary to infection e.g histoplasmosis; lacks history/markers of GCT, no atypical cells or teratomatous elements)
─ Treated lymphoma with sclerosis (history of lymphoma, specific lymphoma markers might be demonstrable on residual cells if any)
─ Post-inflammatory scar from other causes
─ Thymoma with extensive sclerosis/cyst formation (thymic epithelial markers positive in residual thymoma cells)
─ Mature teratoma (if only mature elements are found, and no history of prior malignancy or elevated markers, it’s simply mature teratoma)
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Lymphomas of the Mediastinum

Hodgkin Lymphoma of the Mediastinum

A group of lymphoid neoplasms defined by the presence of neoplastic Reed-Sternberg (RS) cells or their variants (e.g Hodgkin cells, lacunar cells, LP cells) in an appropriate cellular background; the mediastinum, particularly the anterior compartment, is a common site of involvement, especially for Nodular Sclerosis Classical Hodgkin Lymphoma
Clinical ─ Bimodal age distribution (young adulthood and older age); symptoms include B symptoms (fever, night sweats, weight loss), painless lymphadenopathy, cough, chest pain, dyspnea if large mediastinal mass; generally good prognosis with modern therapy, depending on type and stage
Macro ─ Involved lymph nodes are often enlarged, firm, matted; cut surface may be homogeneous gray-white or show nodularity and fibrosis, especially in Nodular Sclerosis type
Micro ─ Diagnosis relies on identifying neoplastic cells within a characteristic inflammatory background:
─ Reed-Sternberg (RS) cells (classic): Large cells (>20-50 µm) with abundant amphophilic or eosinophilic cytoplasm, bilobed or multilobed (mirror-image) nuclei, prominent eosinophilic nucleoli resembling viral inclusions
─ Variants of RS cells:
─ ─ Hodgkin cells (mononuclear variant): Single large nucleus with prominent eosinophilic nucleolus
─ ─ Lacunar cells (characteristic of Nodular Sclerosis CHL): Large cells with pale, abundant cytoplasm that retracts during fixation, creating an empty space ("lacuna") around the nucleus; nuclei are often lobated
─ ─ LP cells ("popcorn cells," characteristic of NLPHL): Large cells with delicate, folded or "popcorn-shaped" nuclei, inconspicuous nucleoli, and pale cytoplasm
─ Background infiltrate: Variable mixture of non-neoplastic lymphocytes (mostly T-cells in CHL, B-cells in NLPHL), eosinophils, neutrophils, plasma cells, histiocytes, and fibroblasts; pattern of fibrosis varies by type
Mediastinal Subtypes:
─ Classical Hodgkin Lymphoma (CHL): RS cells are CD30+, CD15+, PAX5 (weak)+, OCT2/BOB1 variable/weak, CD45-, EBV variable (positive in ~40-50% of Mixed Cellularity and Lymphocyte Depleted CHL, less common in Nodular Sclerosis CHL in Western populations)
─ ─ Nodular Sclerosis Classical Hodgkin Lymphoma (NSCHL):
─ ─ Most common type of CHL overall and most common Hodgkin Lymphoma in the mediastinum
─ ─ Characterized by broad collagen bands originating from a thickened lymph node capsule, dividing the lymphoid tissue into cellular nodules
─ ─ Lacunar cells are typically present within the nodules, admixed with lymphocytes, eosinophils, and histiocytes
─ ─ Classic RS cells may also be seen
─ ─ Other types of Classical Hodgkin Lymphoma (less commonly primary in mediastinum but can involve it):
─ ─ ─ Mixed Cellularity CHL (MCCHL): Diffuse or vaguely nodular infiltrate with classic RS cells and Hodgkin cells in a heterogeneous inflammatory background; EBV often positive
─ ─ ─ Lymphocyte-Rich CHL (LRCHL): Nodular or diffuse pattern with scattered RS cells/Hodgkin cells and a predominance of small lymphocytes; background lacks numerous eosinophils/neutrophils
─ ─ ─ Lymphocyte-Depleted CHL (LDCHL): Rare, aggressive; diffuse fibrosis and paucity of lymphocytes with numerous RS cells or sarcomatoid variants; often associated with HIV
─ Nodular Lymphocyte-Predominant Hodgkin Lymphoma (NLPHL):
─ ─ Rare in the mediastinum as a primary site
─ ─ Characterized by a nodular or nodular and diffuse proliferation of LP cells within a background of small B-lymphocytes, follicular dendritic cell meshworks, and epithelioid histiocytes; eosinophils and plasma cells are typically sparse
─ ─ LP cells are CD20+, CD45+, BCL6+, EMA+/-, PAX5+, OCT2/BOB1+, CD30-, CD15-, EBV-
Ancillary studies ─ (See IHC markers under subtypes above)
DDx ─ ─ Non-Hodgkin Lymphoma (e.g Primary Mediastinal Large B-cell Lymphoma, T-cell lymphomas; different morphology and IHC profile)
─ Thymoma (especially lymphocyte-rich types like B1; thymoma has neoplastic epithelial cells, often TdT+ lymphocytes, lacks RS cells)
─ Germ cell tumors (seminoma can have lymphocytic infiltrate and granulomas; seminoma cells are OCT3/4+, SALL4+)
─ Inflammatory/reactive conditions (e.g Castleman disease, sarcoidosis, infectious mononucleosis; lack true RS cells and their specific IHC profile)
─ Thymic carcinoma (lymphoepithelioma-like variant has prominent lymphocytes but malignant epithelial cells are EBV+ or show cytokeratin, p63)
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Primary Mediastinal (Thymic) Large B-cell Lymphoma (PMBCL)

An aggressive diffuse large B-cell lymphoma subtype arising in the mediastinum (thymic B-cells of putative origin), with distinct clinical, immunophenotypic, and molecular features
Clinical ─ Predominantly affects young adults (peak age 30-40 years), slight female predominance; presents as a bulky anterior mediastinal mass, often with local compressive symptoms (SVC syndrome, cough, dyspnea); B symptoms may be present; extranodal spread is uncommon at diagnosis but can occur later; good response to modern chemoimmunotherapy and consolidative radiation, with cure rates >70-80%
Macro ─ Large, fleshy, infiltrative mass in the anterior mediastinum, often with extensive fibrosis/sclerosis; necrosis can be present
Micro ─ ─ Diffuse proliferation of medium to large-sized atypical B-lymphoid cells (centroblast-like or immunoblast-like) with vesicular nuclei, prominent nucleoli, and variably abundant cytoplasm
─ Cells may appear clear or pale due to glycogen or cytoplasmic retraction
─ Compartmentalizing fibrosis/sclerosis is a characteristic feature, leading to cells entrapped in fibrous bands or a "starry sky" appearance due to interspersed histiocytes, though less prominent than Burkitt's
─ Infiltrative growth pattern into surrounding thymic tissue or mediastinal structures
─ Necrosis is common
Ancillary studies ─ ─ IHC (+) CD20 (+, strong), CD79a (+), PAX5 (+), OCT2 (+), BOB1 (+) (B-cell markers)
─ ─ CD30 (often positive, but usually weaker/more heterogeneous than in Hodgkin lymphoma or ALCL)
─ ─ MAL (mediastinal B-cell lymphoma associated molecule) is often positive (cytoplasmic/membranous)
─ ─ TRAF1, c-REL, PD-L1/PD-L2 often expressed
─ ─ BCL2 expression variable (~50%), BCL6 expression variable (~60-70%)
─ ─ CD10 usually negative or weak, MUM1/IRF4 often positive
─ IHC (-) CD15 (-), CD3 (-), TdT (-), ALK (-)
─ Molecular ─
─ ─ Frequent gains/amplifications of 9p24.1 (encoding PD-L1, PD-L2, JAK2) and 2p16.1 (encoding REL)
─ ─ SOCS1 and PTPN1 mutations common
─ ─ Gene expression profiling shows similarity to Hodgkin lymphoma and overlap with DLBCL, GCB-type (though immunophenotypically often non-GCB)
─ ─ No BCL2 or MYC translocations typically found in other DLBCLs (though rearrangements can occur)
DDx ─ ─ Classical Hodgkin Lymphoma, Nodular Sclerosis type (RS/lacunar cells, CD30 strong+, CD15+, CD20 usually -, different morphology and broader IHC)
─ Diffuse Large B-cell Lymphoma, NOS (may be morphologically similar but PMBCL has distinct clinical presentation, immunophenotype, and molecular features; PMBCL typically mediastinal primary)
─ Mediastinal gray zone lymphoma (B-cell lymphoma with features intermediate between PMBCL and classical Hodgkin lymphoma, NS type; often CD20+, CD30+, CD15 variable)
─ T-lymphoblastic lymphoma (TdT+, CD3+, CD1a+, immature T-cell markers)
─ Thymic carcinoma (cytokeratin+, p63+, CD5/CD117+, GATA3-; lymphoid markers negative)
─ Germ cell tumor (seminoma is OCT3/4+, SALL4+; NSGCTs have other markers like AFP/HCG)
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T-Lymphoblastic Lymphoma/Leukemia (T-LBL) of Mediastinum

An aggressive neoplasm of immature T-cells (lymphoblasts), often presenting as a bulky anterior mediastinal (thymic) mass with frequent progression to T-cell acute lymphoblastic leukemia (T-ALL); distinction between T-LBL and T-ALL is based on bone marrow involvement (>25% blasts for T-ALL)
Clinical ─ Primarily affects children, adolescents, and young adults; male predominance; presents with rapidly enlarging anterior mediastinal mass, leading to respiratory distress, SVC syndrome, pleural effusions; B symptoms common; high peripheral blood blast count and bone marrow involvement (T-ALL) are frequent at diagnosis or develop soon after; CNS involvement can occur; aggressive but curable with intensive chemotherapy
Macro ─ Large, fleshy, infiltrative mass in the anterior mediastinum (thymus); may replace normal thymic architecture; cut surface is typically homogeneous, gray-white
Micro ─ ─ Diffuse, monotonous infiltrate of small to medium-sized lymphoblasts with scant cytoplasm
─ Nuclei are round, oval, or convoluted, with finely dispersed ("blastic") chromatin and inconspicuous or small nucleoli
─ High mitotic rate and apoptotic bodies are characteristic ("starry sky" pattern due to tingible body macrophages may be seen)
─ Infiltration of perivascular spaces, surrounding fat, and residual thymic tissue
Ancillary studies ─ ─ IHC (+) TdT (terminal deoxynucleotidyl transferase) (strong nuclear positivity, key marker of immaturity)
─ ─ Pan T-cell markers: Cytoplasmic CD3 (+, often earliest T-cell marker), CD2 (+), CD5 (+), CD7 (+)
─ ─ Immature T-cell markers: CD1a (+, often strong), CD4/CD8 (can be double positive, double negative, or single positive reflecting stages of T-cell development)
─ ─ CD34 (variable positivity, stem/progenitor cell marker)
─ ─ Ki-67 proliferation index is very high (>90%)
─ IHC (-) B-cell markers (CD20, CD79a, PAX5), myeloid markers (MPO), CD30, ALK
─ Flow Cytometry: Essential for immunophenotyping, confirming T-lineage and immaturity (expression of TdT, CD1a, various CD markers)
─ Cytogenetics/Molecular: Clonal T-cell receptor (TCR) gene rearrangements; various chromosomal abnormalities and gene mutations (e.g NOTCH1, FBXW7, PTEN) are common and may have prognostic significance
DDx ─ ─ Thymoma (especially lymphocyte-rich types like B1 or cortical B2; thymoma has neoplastic epithelial cells (cytokeratin+, p63+, PAX8+), lymphoblasts are TdT+ but non-neoplastic background; T-LBL lacks the epithelial network and is a monotonous blast population)
─ Other non-Hodgkin lymphomas (e.g Burkitt lymphoma – different morphology, B-cell markers, MYC translocation; DLBCL – larger cells, B-cell markers)
─ Classical Hodgkin Lymphoma (RS cells, different IHC profile CD30+, CD15+)
─ Myeloid sarcoma (granulocytic sarcoma) involving mediastinum (MPO+, other myeloid markers positive)
─ Normal thymus or rebound hyperplasia (preserved architecture, no monotonous sheet of blasts)
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Diffuse Large B-cell Lymphoma, NOS, involving mediastinum

The most common type of non-Hodgkin lymphoma overall, which can involve mediastinal lymph nodes or structures as part of systemic disease or, rarely, as a primary extranodal site without features of PMBCL
Clinical ─ Can occur at any age, but more common in older adults; mediastinal involvement can be from contiguous spread from lymph nodes or primary extranodal disease; symptoms depend on location and extent of involvement (e.g lymphadenopathy, compressive symptoms); prognosis is variable, dependent on molecular subtype, stage, and host factors
Macro ─ Enlarged lymph nodes or infiltrative mass; cut surface is typically homogeneous, gray-white, fleshy
Micro ─ ─ Diffuse proliferation of large, atypical B-lymphoid cells with nuclear size equal to or exceeding that of a macrophage nucleus, or more than twice the size of a small lymphocyte
─ Cells typically have features of centroblasts (round/oval vesicular nuclei, 2-4 membrane-bound nucleoli, scant cytoplasm), immunoblasts (single large central eosinophilic nucleolus, more abundant basophilic cytoplasm), or anaplastic cells
─ Growth pattern obliterates normal lymph node architecture or infiltrates extranodal tissue
─ Variable stromal fibrosis or necrosis
Ancillary studies ─ ─ IHC (+) CD20 (+, strong), CD79a (+), PAX5 (+), (B-cell markers)
─ ─ Subtyping by Hans algorithm (or similar) using CD10, BCL6, MUM1/IRF4 to classify into Germinal Center B-cell like (GCB) or Activated B-cell like (ABC)/non-GCB subtypes, which has prognostic implications
─ ─ BCL2 (often positive), BCL6 (often positive), MYC (expression variable, co-expression with BCL2 – "double expressor" – has worse prognosis)
─ ─ Ki-67 proliferation index is usually high
─ IHC (-) CD3, CD5 (usually), CD15, CD30 (usually negative or weak, unlike PMBCL or CHL), TdT
─ Molecular:
─ ─ Clonal immunoglobulin gene rearrangements
─ ─ FISH for translocations involving BCL2 (t(14;18)), BCL6 (3q27), MYC (8q24) – "double hit" (MYC + BCL2 and/or BCL6) or "triple hit" lymphomas have poor prognosis
DDx ─ ─ Primary Mediastinal (Thymic) Large B-cell Lymphoma (PMBCL) (distinct clinicopathologic entity, often younger patients, anterior mediastinal mass, characteristic IHC/molecular profile; DLBCL NOS usually lacks strong PMBCL features if primary in mediastinum outside thymus)
─ Classical Hodgkin Lymphoma (RS cells, CD30+/CD15+)
─ Other aggressive B-cell lymphomas (e.g Burkitt lymphoma – MYC translocation, very high Ki67, characteristic morphology; B-cell lymphoma unclassifiable with features intermediate between DLBCL and CHL)
─ T-cell/histiocyte-rich large B-cell lymphoma (variant of DLBCL with scattered large neoplastic B-cells in a background of T-cells and histiocytes)
─ Transformed follicular lymphoma or other low-grade B-cell lymphomas
─ Undifferentiated carcinoma or sarcoma (cytokeratin or sarcoma markers positive, B-cell markers negative)
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Follicular Lymphoma involving mediastinum

A common indolent B-cell lymphoma characterized by a follicular (nodular) growth pattern of neoplastic germinal center B-cells (centrocytes and centroblasts); primary mediastinal follicular lymphoma is rare, more often mediastinal involvement is part of systemic disease
Clinical ─ Typically affects older adults; often presents with disseminated painless lymphadenopathy; mediastinal involvement (hilar, paratracheal nodes) may be seen with advanced stage systemic disease; primary mediastinal FL is uncommon and may behave more aggressively or have unusual features; indolent course, but can transform to DLBCL
Macro ─ Involved lymph nodes are enlarged, with a vaguely nodular or effaced cut surface; may form conglomerate masses
Micro ─ ─ Nodular (follicular) proliferation of neoplastic B-cells, often effacing normal lymph node architecture
─ Follicles are typically crowded, variable in size and shape, lack well-defined mantle zones, and may show "back-to-back" arrangement
─ Neoplastic follicles are composed of a monotonous population of:
─ ─ Centrocytes: Small to medium-sized cleaved cells with irregular/indented nuclei, condensed chromatin, scant cytoplasm
─ ─ Centroblasts: Larger non-cleaved cells with round/oval vesicular nuclei, 1-3 prominent nucleoli, moderate cytoplasm
─ Grading (WHO): Based on the number of centroblasts per high power field (HPF) in neoplastic follicles:
─ ─ Grade 1: 0-5 centroblasts/HPF
─ ─ Grade 2: 6-15 centroblasts/HPF
─ ─ Grade 3: >15 centroblasts/HPF
─ ─ Grade 3A: Centrocytes still present
─ ─ Grade 3B: Follicles consist almost entirely of centroblasts (may behave like DLBCL)
─ Diffuse areas of involvement can be present, especially in higher grades or transformed disease
─ Lack of tingible body macrophages and polarization within follicles compared to reactive follicles
Ancillary studies ─ ─ IHC (+) CD20 (+), CD79a (+), PAX5 (+), CD10 (+, in neoplastic follicles), BCL6 (+, in neoplastic follicles)
─ ─ BCL2 (+, strong staining in neoplastic germinal centers, whereas reactive GCs are BCL2 negative or weak) – key diagnostic feature
─ ─ CD21 or CD23 highlights follicular dendritic cell meshworks within neoplastic follicles
─ IHC (-) CD3 (-), CD5 (-), Cyclin D1 (-)
─ Molecular ─ Characteristic t(14;18)(q32;q21) involving IGH-BCL2 fusion is present in ~80-90% of cases, leading to BCL2 overexpression
DDx ─ ─ Reactive follicular hyperplasia (preserved nodal architecture, follicles vary in size/shape, have distinct mantle zones, tingible body macrophages, polarized germinal centers, BCL2 negative in GCs, polyclonal B-cells)
─ Other B-cell lymphomas with follicular pattern (e.g Mantle cell lymphoma with nodular pattern – Cyclin D1+, CD5+; Marginal zone lymphoma with follicular colonization – different immunophenotype)
─ Nodular Lymphocyte-Predominant Hodgkin Lymphoma (LP cells are CD20+, BCL6+, but CD10-, BCL2-, different morphology and background)
─ Diffuse Large B-cell Lymphoma (if FL transforms or has large diffuse areas)
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MALT Lymphoma involving thymus or mediastinum

An extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) that can rarely arise primarily in the thymus or other mediastinal sites, often associated with underlying autoimmune conditions like Sjögren syndrome or Hashimoto thyroiditis when in thymus/thyroid
Clinical ─ Rare in the mediastinum; typically occurs in older adults; often indolent clinical course, may be an incidental finding or present with symptoms of a slow-growing mass; can remain localized for long periods but may disseminate or transform to diffuse large B-cell lymphoma
Macro ─ May present as a localized mass, diffuse infiltration, or multiple nodules within the thymus or mediastinal soft tissues/lymph nodes; cut surface is usually homogeneous, gray-white to tan
Micro ─ ─ Diffuse or vaguely nodular proliferation of small to medium-sized atypical B-cells (marginal zone cells/centrocyte-like cells) with irregular nuclear contours, condensed chromatin, and moderate amounts of pale cytoplasm
─ Plasmacytic differentiation is common, with mature plasma cells present in variable numbers
─ Characteristic lymphoepithelial lesions (infiltration and destruction of epithelial structures, e.g thymic ducts or glands, by neoplastic lymphocytes) are a hallmark feature, especially when involving epithelial-rich tissues like thymus or salivary gland type tissue
─ Reactive lymphoid follicles are often present, which may be colonized by the neoplastic marginal zone cells
─ No significant number of large transformed blasts (unless transformation has occurred)
Ancillary studies ─ ─ IHC (+) CD20 (+), CD79a (+), PAX5 (+) (B-cell markers)
─ ─ BCL2 (+) in neoplastic cells (unlike reactive marginal zone B-cells)
─ ─ CD43 (often co-expressed)
─ IHC (-) CD5 (-), CD10 (-), BCL6 (- or weak in marginal zone cells, can be positive in reactive follicle centers), Cyclin D1 (-)
─ Cytokeratin stains can highlight lymphoepithelial lesions by outlining the infiltrated epithelial structures
─ Molecular ─
─ ─ Clonal immunoglobulin gene rearrangements (IgH, IgK, IgL)
─ ─ Specific translocations associated with MALT lymphoma include t(11;18)(q21;q21) resulting in API2-MALT1 fusion (most common, associated with resistance to Helicobacter pylori eradication therapy elsewhere), t(14;18)(q32;q21) involving IGH-MALT1, t(1;14)(p22;q32) involving BCL10-IGH, and t(3;14)(p14.1;q32) involving FOXP1-IGH
DDx ─ ─ Reactive lymphoid hyperplasia with prominent marginal zones or plasma cells (polyclonal, lacks destructive lymphoepithelial lesions, no clonal gene rearrangement)
─ Follicular hyperplasia in thymus or lymph node (reactive follicles, BCL2 negative in GCs)
─ Small lymphocytic lymphoma/chronic lymphocytic leukemia (CD5+, CD23+)
─ Mantle cell lymphoma (CD5+, Cyclin D1+)
─ Follicular lymphoma (CD10+, BCL6+, often t(14;18) IGH-BCL2 but different morphology)
─ Thymoma with prominent lymphoid infiltrate (thymoma has neoplastic epithelial cells, MALT lymphoma has neoplastic B-cells invading epithelium)
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Anaplastic Large Cell Lymphoma (ALK+ or ALK-) involving mediastinum

A T-cell lymphoma characterized by proliferation of large lymphoid cells with strong CD30 expression and often anaplastic morphology (pleomorphic, horseshoe or kidney-shaped nuclei – "hallmark cells"); can be ALK-positive (due to ALK gene rearrangement) or ALK-negative, with distinct clinical and prognostic implications
Clinical ─ Mediastinal involvement can occur, more common in ALK-positive ALCL which often affects children and young adults with systemic disease; ALK-negative ALCL typically affects older adults and has a more variable prognosis; B symptoms common; extranodal involvement is frequent
Macro ─ May involve mediastinal lymph nodes or thymus, presenting as a mass; cut surface is often fleshy, gray-white, may show necrosis or hemorrhage
Micro ─ ─ Cohesive proliferation of large, atypical lymphoid cells, often with anaplastic cytology:
─ ─ "Hallmark cells": Large cells with eccentric, pleomorphic, horseshoe-shaped or kidney-shaped nuclei, prominent eosinophilic nucleoli, and abundant cytoplasm
─ ─ Sinusoidal growth pattern is common in lymph nodes
─ ─ May have a variable number of smaller reactive lymphocytes, histiocytes, eosinophils
─ ─ Necrosis can be extensive
─ ALK-positive ALCL: Tumor cells show nuclear and/or cytoplasmic ALK protein expression due to ALK gene rearrangement (most commonly t(2;5)(p23;q35) resulting in NPM1-ALK fusion)
─ ALK-negative ALCL: Morphologically similar but lacks ALK protein expression and ALK gene rearrangement; genetically more heterogeneous
Ancillary studies ─ ─ IHC (+) CD30 (+, strong and diffuse membranous and Golgi pattern is characteristic)
─ ─ ALK (+ in ALK-positive ALCL; nuclear and/or cytoplasmic staining pattern depends on fusion partner)
─ ─ T-cell markers: Variable expression; CD3 (often cytoplasmic or negative), CD2 (+), CD4 (+), CD5 (- or weak), CD7 (- or weak), CD8 (-)
─ ─ Cytotoxic markers (Granzyme B, Perforin, TIA1) are often positive
─ ─ EMA (epithelial membrane antigen) can be positive
─ IHC (-) B-cell markers (CD20, PAX5), CD15 (usually negative, helps distinguish from Hodgkin)
─ Molecular: ALK gene rearrangement (by FISH or RT-PCR) in ALK-positive ALCL; TCR gene rearrangements confirm T-cell lineage
DDx ─ ─ Classical Hodgkin Lymphoma (RS cells are CD30+, but also CD15+; ALK-; different morphology)
─ Peripheral T-cell lymphoma, NOS (lacks strong uniform CD30 and ALK expression, morphology differs)
─ Primary Mediastinal Large B-cell Lymphoma (PMBCL) (B-cell markers positive, CD30 can be positive but usually weaker, ALK negative)
─ Metastatic carcinoma or melanoma (cytokeratin or S100/melanoma markers positive, CD30/ALK negative)
─ Germ cell tumors (seminoma is OCT3/4+, ALK-; embryonal carcinoma can be CD30+)
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Other Non-Hodgkin Lymphomas involving mediastinum (e.g., Mantle Cell, Burkitt)

An overview of less common NHLs that can involve mediastinal structures, typically as part of systemic disease, each with unique clinicopathologic features
Clinical ─ Mantle Cell Lymphoma (MCL) and Burkitt Lymphoma (BL) are aggressive B-cell NHLs that can involve mediastinal lymph nodes or thymus, though primary mediastinal presentation is rare for BL and uncommon for MCL; patients often present with advanced stage disease
Micro ─ ─ Mantle Cell Lymphoma (MCL):
─ ─ Monotonous proliferation of small to medium-sized atypical lymphocytes with irregular, cleaved nuclei, condensed chromatin, and inconspicuous nucleoli
─ ─ Growth patterns can be diffuse, nodular, or mantle zone (around reactive germinal centers)
─ ─ Hyalinized vessels may be prominent
─ ─ Blastoid variant is more aggressive, with larger cells resembling lymphoblasts
─ ─ IHC: CD20 (+), CD5 (+), Cyclin D1 (nuclear, +, key marker), SOX11 (+), BCL2 (+); CD10 (-), CD23 (-), BCL6 (-)
─ ─ Molecular: t(11;14)(q13;q32) involving CCND1-IGH genes is pathognomonic
─ Burkitt Lymphoma (BL):
─ ─ Diffuse, monotonous infiltrate of medium-sized atypical lymphocytes with round nuclei, vesicular chromatin, multiple small basophilic nucleoli, and basophilic cytoplasm often containing lipid vacuoles
─ ─ Very high mitotic rate and abundant apoptotic bodies, leading to a "starry sky" appearance due to numerous tingible body macrophages phagocytosing debris
─ ─ IHC: CD20 (+), CD10 (+), BCL6 (+), c-MYC (+, high expression), Ki-67 (~100% proliferation index); BCL2 (-), TdT (-)
─ ─ Molecular: MYC gene rearrangement t(8;14)(q24;q32) or variants (t(2;8), t(8;22)) is pathognomonic
Ancillary studies ─ (See individual lymphoma types above)
DDx ─ (For mediastinal involvement)
─ Other B-cell lymphomas (e.g DLBCL, Follicular lymphoma, MALT lymphoma)
─ T-cell lymphomas (e.g T-LBL)
─ Acute leukemias involving mediastinum
─ Thymoma (especially if lymphocyte-rich)
─ Reactive lymphoid hyperplasia (polyclonal, lacks specific markers/translocations)
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Neurogenic Tumors of the Mediastinum (Primarily Posterior Mediastinum)

Peripheral Nerve Sheath Tumors of Mediastinum

A group of tumors arising from Schwann cells or other cells of the nerve sheath, commonly found in the posterior mediastinum where sympathetic ganglia and nerve roots are located; includes benign (Schwannoma, Neurofibroma) and malignant (MPNST) types
Clinical ─ Most are benign and asymptomatic, discovered incidentally; symptoms can arise from compression of adjacent structures (e.g cough, pain, neurologic symptoms); association with neurofibromatosis type 1 (NF1) for neurofibromas and MPNSTs, and schwannomatosis for multiple schwannomas
Macro ─ Usually well-circumscribed, encapsulated (Schwannoma) or infiltrative (some Neurofibromas, MPNST) masses; cut surface varies (yellow-tan, fleshy, cystic, hemorrhagic)
Micro ─ Subtypes:
─ Schwannoma (Neurilemmoma):
─ ─ Benign, encapsulated tumor composed entirely of Schwann cells
─ ─ Biphasic pattern:
─ ─ ─ Antoni A areas: Dense, cellular regions with spindle cells arranged in fascicles, palisades (Verocay bodies – nuclear palisades surrounding acellular eosinophilic zones), and hyalinized blood vessels
─ ─ ─ Antoni B areas: Loose, hypocellular, myxoid regions with microcystic changes and scattered Schwann cells
─ ─ Nuclei are typically wavy or buckled; no significant atypia or mitoses
─ ─ Variants: Ancient schwannoma (degenerative atypia, hyalinization, calcification, but benign), Cellular schwannoma (predominantly Antoni A, can be mistaken for MPNST but lacks overt malignant features), Melanotic schwannoma (pigmented, psammoma bodies, can be associated with Carney complex)
─ ─ IHC: S100 (+, strong diffuse), SOX10 (+), GFAP (variable)
─ Neurofibroma:
─ ─ Benign tumor composed of a mixed proliferation of Schwann cells, perineurial-like cells, and fibroblasts, embedded in a loose, collagenous, or myxoid stroma, with entrapped axons
─ ─ Less cellular and less well-demarcated than schwannoma
─ ─ Cells are slender, spindle-shaped with wavy nuclei and scant cytoplasm
─ ─ Mast cells are often present
─ ─ Types:
─ ─ ─ Localized Neurofibroma: Most common, well-circumscribed or diffuse but localized
─ ─ ─ Diffuse Neurofibroma: Infiltrative growth in skin/subcutis, less common in mediastinum
─ ─ ─ Plexiform Neurofibroma: Infiltrates and expands multiple nerve fascicles ("bag of worms" appearance); pathognomonic for NF1, carries risk of MPNST transformation
─ ─ IHC: S100 (+, often more patchy than schwannoma), SOX10 (+), CD34 (+ in some stromal cells), Neurofilament (highlights entrapped axons), EMA (+ in perineurial-like cells)
─ Malignant Peripheral Nerve Sheath Tumor (MPNST):
─ ─ Aggressive sarcoma arising from a peripheral nerve or pre-existing neurofibroma (especially plexiform in NF1 patients), or de novo
─ ─ Highly cellular spindle cell neoplasm with features of malignancy: nuclear pleomorphism, hyperchromasia, high mitotic rate (often >10/10 HPF), necrosis
─ ─ Cells often arranged in fascicles, may show "marbled" appearance (alternating cellularity)
─ ─ Heterologous differentiation (e.g rhabdomyoblastic – "Triton tumor", chondroid, osseous) can occur
─ ─ IHC: S100 and SOX10 positivity is variable and often focal/weak (loss of S100 common compared to benign PNSTs), GFAP (variable); H3K27me3 loss is common, especially in NF1-associated MPNSTs
Ancillary studies ─ (See individual subtypes above)
DDx ─ (For mediastinal spindle cell tumors)
─ Solitary fibrous tumor (STAT6+, CD34+)
─ Sarcomatoid carcinoma or mesothelioma (cytokeratin positive)
─ Other sarcomas (e.g fibrosarcoma, leiomyosarcoma – specific markers)
─ Ganglioneuroma (if ganglion cells present)
─ For MPNST vs Cellular Schwannoma: MPNST has overt malignancy (mitoses, necrosis, pleomorphism); Cellular Schwannoma lacks these despite high cellularity
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Sympathetic Ganglia Tumors of Mediastinum

A spectrum of neuroblastic tumors arising from primitive sympathetic ganglion cells, typically in the posterior mediastinum (paravertebral region); includes benign Ganglioneuroma, intermediate Ganglioneuroblastoma, and malignant Neuroblastoma
Clinical ─ Primarily tumors of infancy and childhood, but ganglioneuroma can occur in older children/adults; symptoms depend on size, location, and functional activity (e.g catecholamine secretion causing hypertension, diarrhea – rare in mediastinal tumors compared to adrenal); prognosis varies from excellent (Ganglioneuroma) to poor (high-risk Neuroblastoma)
Macro ─ Tumors vary from well-circumscribed, firm, gray-white (Ganglioneuroma) to large, heterogeneous, hemorrhagic, necrotic masses (Neuroblastoma)
Micro ─ (Spectrum based on differentiation towards mature ganglion cells and Schwannian stroma)
─ Ganglioneuroma (GN):
─ ─ Benign, fully differentiated tumor
─ ─ Composed of mature ganglion cells (large cells with abundant eosinophilic cytoplasm, eccentric large vesicular nucleus, prominent nucleolus), satellite cells, and abundant Schwannian stroma (neuropil-like spindle cells similar to neurofibroma or schwannoma)
─ ─ No neuroblasts, minimal to no mitotic activity
─ Ganglioneuroblastoma (GNB):
─ ─ Intermediate malignancy, composite tumor with features of both Ganglioneuroma and Neuroblastoma
─ ─ Subtypes:
─ ─ ─ Intermixed GNB: Ganglion cells and differentiating neuroblasts are intimately mixed with Schwannian stroma throughout the tumor; favorable prognosis if stroma-rich
─ ─ ─ Nodular GNB (Composite GNB): One or more discrete nodules of Neuroblastoma within a predominantly Ganglioneuroma background; behavior dictated by the neuroblastoma component, often less favorable
─ Neuroblastoma (NB):
─ ─ Malignant, primitive tumor composed of small, round blue cells (neuroblasts) with scant cytoplasm, hyperchromatic nuclei, and inconspicuous nucleoli
─ ─ Neuroblasts often form Homer Wright rosettes (neuroblasts surrounding fibrillary neuropil)
─ ─ Background may be fibrillary (neuropil) or relatively stroma-poor
─ ─ Grading (Shimada system for NB): Based on age, degree of differentiation (stroma-rich vs stroma-poor, differentiation towards ganglion cells), mitosis-karyorrhexis index (MKI)
Ancillary studies ─ ─ IHC (Neuroblastic cells in NB/GNB): Synaptophysin (+), Chromogranin A (+/-), PGP9.5 (+), Neuron-Specific Enolase (NSE) (+), CD56 (+)
─ ─ Phox2B (nuclear, specific for neuroblastic lineage)
─ IHC (Ganglion cells in GN/GNB): Similar to neuroblasts but also positive for neurofilament protein
─ IHC (Schwannian stroma in GN/GNB): S100 (+), SOX10 (+)
─ IHC (NB): Ki-67 high in neuroblastoma component
─ Molecular (NB): N-MYC (MYCN) amplification is a key adverse prognostic factor in neuroblastoma and is assessed by FISH or other methods
─ Urine/Serum catecholamine metabolites (VMA, HVA): Often elevated in Neuroblastoma and some Ganglioneuroblastomas
DDx ─ ─ Other small round blue cell tumors (for Neuroblastoma): Ewing sarcoma/PNET (CD99+, FLI1+), lymphoma (CD45+), rhabdomyosarcoma (myogenin/MyoD1+)
─ Peripheral nerve sheath tumors (for Ganglioneuroma, if ganglion cells are not apparent; PNSTs lack neuroblastic component)
─ Paraganglioma (zellballen pattern, S100+ sustentacular cells around chief cells; GATA3+, synaptophysin/chromogranin+)
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Mesenchymal Tumors of the Mediastinum (Non-Thymic, Non-Neurogenic)

Lipoma and Liposarcoma of Mediastinum

Adipocytic tumors arising in the mediastinum, ranging from benign Lipoma to malignant Liposarcoma with various subtypes
Clinical ─ Lipomas are benign, often asymptomatic, and may be found incidentally; Liposarcomas are malignant, can be large, cause compressive symptoms, and have potential for recurrence and metastasis depending on subtype and grade; mediastinum is a rare site for primary liposarcoma
Macro ─ ─ Lipoma: Well-circumscribed, encapsulated, soft, yellow, greasy mass, identical to lipomas elsewhere
─ Liposarcoma: Often large, lobulated, variably fleshy, yellow, or white-gray depending on subtype and differentiation; may show areas of necrosis or hemorrhage
Micro ─ ─ Lipoma:
─ ─ Composed entirely of mature adipocytes (univacuolated fat cells) with small, eccentric, bland nuclei
─ ─ Fine fibrous septa with thin-walled capillaries may be present
─ ─ No lipoblasts, atypia, or significant mitotic activity
─ Liposarcoma: (Subtypes relevant to mediastinum)
─ ─ Well-differentiated Liposarcoma (WDLPS) / Atypical Lipomatous Tumor (ALT):
─ ─ ─ Composed of mature adipocytes with significant variation in cell size, scattered atypical spindle cells within fibrous septa, and often enlarged, hyperchromatic stromal cells; lipoblasts may be present but are not required if other features are diagnostic
─ ─ ─ Lacks overt dedifferentiation; locally recurrent but does not metastasize unless it dedifferentiates
─ ─ Dedifferentiated Liposarcoma (DDLPS):
─ ─ ─ Development of a non-lipogenic sarcoma (usually high-grade, pleomorphic, or resembling fibrosarcoma/UPS) arising from or adjacent to WDLPS
─ ─ ─ The transition between WDLPS and DDLPS can be abrupt
─ ─ ─ Carries significant risk of recurrence and metastasis
─ ─ Myxoid Liposarcoma:
─ ─ ─ Composed of bland, uniform, round to oval non-lipogenic mesenchymal cells and scattered small signet-ring lipoblasts in a prominent myxoid stroma with a rich, plexiform capillary network ("chicken-wire" vasculature)
─ ─ ─ Round cell component (>5%) indicates higher grade and worse prognosis
─ ─ ─ Characterized by FUS-DDIT3 or EWSR1-DDIT3 fusion
─ ─ Pleomorphic Liposarcoma:
─ ─ ─ Rare, high-grade sarcoma with sheets of pleomorphic, bizarre cells and numerous multivacuolated lipoblasts
─ ─ ─ Lacks features of WDLPS or DDLPS; aggressive with high metastatic potential
Ancillary studies ─ ─ Lipoma: Generally none needed
─ Liposarcoma:
─ ─ IHC (WDLPS/DDLPS): MDM2 (+, nuclear), CDK4 (+, nuclear) are highly sensitive and specific for WDLPS and both components of DDLPS
─ ─ IHC (Myxoid LPS): S100 (+/- in lipoblasts), variable other markers; diagnosis often relies on morphology and molecular
─ ─ IHC (Pleomorphic LPS): S100 (+ in lipoblasts)
─ ─ Molecular (WDLPS/DDLPS): MDM2 and CDK4 gene amplification by FISH or other methods
─ ─ Molecular (Myxoid LPS): FUS-DDIT3 (t(12;16)) or EWSR1-DDIT3 (t(12;22)) fusion
DDx ─ ─ Lipoma vs Well-differentiated Liposarcoma: WDLPS has atypical cells, hyperchromatic stromal cells, size variation of adipocytes, and MDM2/CDK4 positivity/amplification
─ Liposarcoma subtypes from each other (based on morphology, IHC, molecular)
─ Other sarcomas with fatty change or myxoid stroma (e.g myxofibrosarcoma, MPNST with myxoid change – specific markers for these entities, lack MDM2 amplification or liposarcoma-specific fusions)
─ Thymolipoma (thymic tissue admixed with mature fat; distinct from pure lipoma or liposarcoma arising in thymus)
─ Normal mediastinal fat or thymic involution (not a discrete mass)
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Solitary Fibrous Tumor (SFT) of mediastinum

A mesenchymal neoplasm with fibroblastic differentiation, similar to SFTs in pleura and other locations, characterized by a "patternless pattern" of spindle cells, hemangiopericytoma-like vessels, and NAB2-STAT6 gene fusion
Clinical ─ Rare in the mediastinum (less common than pleural SFT); occurs in adults, no sex predilection; can be asymptomatic or cause symptoms due to mass effect; most are benign, but a subset can be malignant based on histologic features, with risk of recurrence or metastasis
Macro ─ Usually a well-circumscribed, solid, firm, lobulated mass; gray-white to tan cut surface; may show cystic change, hemorrhage, or necrosis, especially in malignant variants
Micro ─ ─ Varied cellularity, from hypocellular and collagenous to hypercellular areas
─ "Patternless pattern" (storiform or haphazard arrangement) of ovoid to spindle cells with scant cytoplasm and bland, vesicular nuclei
─ Stroma is typically collagenous, can be myxoid or hyalinized
─ Prominent, branching, thin-walled, dilated (staghorn) hemangiopericytoma-like vessels are characteristic
─ Mitotic activity is generally low in benign SFTs (<4 mitoses per 2 mm² or per 10 HPF); higher in malignant SFTs
─ Malignant features include: Increased cellularity, nuclear pleomorphism, high mitotic rate (≥4 mitoses per 2 mm²), tumor necrosis, infiltrative margins
Ancillary studies ─ ─ IHC (+) STAT6 (strong nuclear positivity, reflects NAB2-STAT6 fusion, highly sensitive and specific), CD34 (strong and diffuse in most cases), BCL2 (+), CD99 (+, often)
─ IHC (-) Cytokeratins (usually), S100 protein (usually), Desmin (usually), SMA (usually), EMA (usually)
─ Molecular ─ NAB2-STAT6 gene fusion is pathognomonic
DDx ─ ─ Other spindle cell tumors of the mediastinum:
─ ─ Schwannoma (S100+, SOX10+, lacks STAT6/CD34)
─ ─ Neurofibroma (S100 variable, SOX10+, lacks STAT6)
─ ─ Leiomyoma/Leiomyosarcoma (smooth muscle markers positive, STAT6-)
─ ─ Fibromatosis (desmoid tumor) (beta-catenin nuclear positive in many, STAT6-)
─ ─ Sarcomatoid carcinoma or mesothelioma (cytokeratin positive, STAT6-)
─ ─ Malignant Peripheral Nerve Sheath Tumor (MPNST) (S100/SOX10 often lost or focal, H3K27me3 loss common, STAT6-)
─ ─ Thymoma Type A (cytokeratin+, PAX8+, TdT+ lymphocytes may be present, STAT6-)
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Hemangioma and Angiosarcoma of Mediastinum

Vascular tumors arising in the mediastinum, ranging from benign Hemangioma to highly malignant Angiosarcoma
Clinical ─ Hemangiomas are rare, usually congenital or found in children/young adults, often asymptomatic or cause symptoms due to mass effect/bleeding; Angiosarcomas are very rare, highly aggressive, affect adults, present with chest pain, dyspnea, hemoptysis, or SVC syndrome, poor prognosis with rapid local invasion and distant metastasis
Macro ─ ─ Hemangioma: Well-circumscribed or infiltrative, red-purple, spongy or firm mass; cavernous types have large dilated vascular spaces, capillary types are more solid
─ Angiosarcoma: Poorly defined, infiltrative, hemorrhagic mass; may be multifocal; cut surface is often hemorrhagic and necrotic
Micro ─ ─ Hemangioma:
─ ─ Composed of benign vascular channels lined by bland, flattened endothelial cells without atypia or significant mitotic activity
─ ─ Types:
─ ─ ─ Cavernous Hemangioma: Large, dilated, thin-walled vascular spaces filled with blood, separated by fibrous stroma
─ ─ ─ Capillary Hemangioma: Lobules of small, closely packed capillary-sized vessels
─ ─ ─ Arteriovenous Malformation (AVM) / Hemangioma: More complex, with thick-walled arteries and veins as well as capillary channels
─ Angiosarcoma:
─ ─ Malignant proliferation of atypical endothelial cells forming irregular, anastomosing vascular channels, solid sheets, or papillary structures
─ ─ Endothelial cells show nuclear pleomorphism, hyperchromasia, prominent nucleoli, and increased mitotic activity (often atypical mitoses)
─ ─ Lumen formation may be subtle or absent in poorly differentiated areas (epithelioid or spindle cell morphology)
─ ─ Hemorrhage and necrosis are common
Ancillary studies ─ ─ IHC (Both Hemangioma and Angiosarcoma show endothelial differentiation):
─ ─ CD31 (+, strong membranous), ERG (+, nuclear, very sensitive and specific), CD34 (+, variable), Factor VIII-related antigen (FVIII-RA) (+)
─ ─ FLI1 (+, nuclear)
─ IHC (Angiosarcoma): Ki-67 proliferation index is high; cytokeratins can be positive in epithelioid angiosarcoma, potentially causing confusion with carcinoma if vascular markers are not performed
DDx ─ ─ For Hemangioma:
─ ─ Lymphangioma (lined by D2-40+ lymphatic endothelium, usually contains lymph not blood)
─ ─ Vascular malformation
─ ─ Well-differentiated Angiosarcoma (look for any atypia, mitoses, infiltrative growth)
─ For Angiosarcoma:
─ ─ Hemangioma (benign features)
─ ─ Other sarcomas with prominent vasculature or hemorrhage (e.g Kaposi sarcoma – HHV8+)
─ ─ Poorly differentiated carcinoma or melanoma with epithelioid or spindle cell features (vascular markers negative, specific carcinoma/melanoma markers positive)
─ ─ Organizing hematoma or granulation tissue (reactive, lacks malignant endothelial atypia)
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Lymphangioma (Cystic Hygroma) of Mediastinum

Benign congenital malformation of lymphatic vessels, characterized by localized proliferation of dilated lymphatic channels; often presents in infancy or childhood but can be found in adults
Clinical ─ Most common in the neck (cervical cystic hygroma) but can extend into or arise primarily in the mediastinum (usually anterior or superior); often asymptomatic, discovered incidentally, or presents as a slow-growing, soft, compressible mass; may cause compressive symptoms if large (dyspnea, cough, dysphagia); generally benign but can infiltrate surrounding tissues, making complete resection difficult and leading to recurrence
Macro ─ Usually a multiloculated, cystic mass (cystic hygroma); cysts are thin-walled, filled with clear, straw-colored, or chylous-appearing (milky) lymphatic fluid; can be large and infiltrative; less commonly, may be a more solid-appearing cavernous or capillary lymphangioma (lymphangioma circumscriptum if superficial)
Micro ─ ─ Composed of variably sized, dilated lymphatic channels lined by a single layer of flattened, bland endothelial cells
─ Lymphatic channels are often irregular and anastomosing, separated by fibrous connective tissue stroma that may contain lymphoid aggregates (often prominent), smooth muscle bundles, and adipose tissue
─ Lumen contains proteinaceous lymph fluid, lymphocytes, and occasionally red blood cells; true blood vessels are present in the stroma but not forming the primary channels
─ No significant endothelial atypia or mitotic activity
Ancillary studies ─ ─ IHC (Endothelial lining of lymphatic channels): D2-40 (podoplanin) (+, strong membranous), LYVE-1 (+), Prox1 (+)
─ ─ Other vascular endothelial markers: CD31 (+), ERG (+), CD34 (often weaker or negative compared to blood vessel endothelium)
DDx ─ ─ Hemangioma (especially cavernous) (vascular channels filled with blood, endothelial cells D2-40 negative or only focally)
─ Cystic teratoma (contains derivatives of multiple germ layers like skin, cartilage, glandular epithelium)
─ Bronchogenic, pericardial, or thymic cysts (lined by specific epithelium relevant to origin – respiratory, mesothelial, thymic; D2-40 negative lining)
─ Venous malformation (dilated vascular channels with thicker, more muscular walls, contain blood)
─ Angiosarcoma with cystic change (malignant endothelial cells, atypia, mitoses)
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Leiomyoma and Leiomyosarcoma of Mediastinum

Smooth muscle tumors arising in the mediastinum, ranging from benign Leiomyoma to malignant Leiomyosarcoma; primary mediastinal smooth muscle tumors are rare
Clinical ─ Leiomyomas are very rare, typically occur in adults, often asymptomatic or slow-growing; may arise from esophageal wall, tracheobronchial tree, or blood vessels. Leiomyosarcomas are also rare, more common in adults, aggressive with symptoms of local invasion or metastasis (chest pain, dyspnea, cough); can arise de novo or from pre-existing leiomyoma (rarely); prognosis for leiomyosarcoma is generally poor
Macro ─ ─ Leiomyoma: Well-circumscribed, firm, gray-white, whorled mass
─ Leiomyosarcoma: Larger, often poorly marginated, fleshy, gray-white mass with areas of hemorrhage, necrosis, and cystic degeneration
Micro ─ ─ Leiomyoma:
─ ─ Intersecting fascicles of bland, elongated spindle cells with eosinophilic cytoplasm and blunt-ended (cigar-shaped) nuclei
─ ─ Minimal to no cytologic atypia, very low mitotic activity (<1-2 mitoses/10 HPF), no tumor necrosis
─ Leiomyosarcoma:
─ ─ Cellular spindle cell neoplasm with features of smooth muscle differentiation and malignancy
─ ─ Cells have eosinophilic cytoplasm and elongated, blunt-ended nuclei, but show significant cytologic atypia (pleomorphism, hyperchromasia)
─ ─ High mitotic rate (often ≥10 mitoses/10 HPF, including atypical mitoses)
─ ─ Tumor cell necrosis is common
─ ─ Infiltrative growth pattern
─ ─ Epithelioid variant can occur (polygonal cells with eosinophilic cytoplasm)
Ancillary studies ─ ─ IHC (Both Leiomyoma and Leiomyosarcoma show smooth muscle differentiation):
─ ─ Smooth Muscle Actin (SMA) (+, strong diffuse)
─ ─ Desmin (+, strong diffuse)
─ ─ Caldesmon (h-caldesmon) (+, specific for smooth muscle)
─ IHC (Leiomyosarcoma): Ki-67 proliferation index is high
─ IHC (-) S100, SOX10, CD34, STAT6, cytokeratins (usually)
DDx ─ ─ Other spindle cell tumors of the mediastinum:
─ ─ Schwannoma/Neurofibroma (S100+, SOX10+)
─ ─ Solitary fibrous tumor (STAT6+, CD34+)
─ ─ Fibromatosis (desmoid) (beta-catenin nuclear+, SMA variable, desmin often negative)
─ ─ Sarcomatoid carcinoma or mesothelioma (cytokeratin positive)
─ ─ MPNST (S100/SOX10 variable/lost, H3K27me3 loss)
─ For Leiomyoma vs Leiomyosarcoma: Key features for LMS are cytologic atypia, mitotic activity, and tumor necrosis
─ Gastrointestinal Stromal Tumor (GIST) metastatic or extending to mediastinum (CD117+, DOG1+)
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Rhabdomyoma and Rhabdomyosarcoma of Mediastinum

Tumors showing skeletal muscle differentiation, ranging from benign Rhabdomyoma to malignant Rhabdomyosarcoma; primary mediastinal involvement is rare for both
Clinical ─ Rhabdomyomas are exceedingly rare in the mediastinum, more common in head/neck or heart (cardiac rhabdomyomas often in tuberous sclerosis). Rhabdomyosarcomas (RMS) are aggressive sarcomas, more common in children and adolescents but can occur in adults; mediastinal RMS is rare and carries a poor prognosis.
Macro ─ ─ Rhabdomyoma: Usually well-circumscribed, firm, pink-tan to red-brown mass
─ Rhabdomyosarcoma: Often large, infiltrative, fleshy, gray-white mass with hemorrhage and necrosis
Micro ─ ─ Rhabdomyoma:
─ ─ Composed of large, polygonal cells with abundant, deeply eosinophilic, granular or vacuolated cytoplasm (spider cells due to glycogen), and eccentrically or centrally placed nuclei
─ ─ Cross-striations may be visible but can be difficult to find
─ ─ Minimal atypia, no significant mitotic activity
─ ─ Adult type (more common extracardiac) vs Fetal type
─ Rhabdomyosarcoma (RMS):
─ ─ Malignant mesenchymal tumor with evidence of skeletal muscle differentiation (rhabdomyoblasts)
─ ─ Main subtypes:
─ ─ ─ Embryonal RMS: Most common type in children; composed of primitive round to spindle cells in a myxoid stroma, with scattered rhabdomyoblasts (strap cells, tadpole cells, or round cells with eosinophilic cytoplasm and cross-striations); botryoid variant has subepithelial cambium layer
─ ─ ─ Alveolar RMS: Composed of nests of primitive round cells separated by fibrous septa, resembling pulmonary alveoli; cells often discohesive in the center of nests; characteristic PAX3-FOXO1 or PAX7-FOXO1 fusions; more aggressive
─ ─ ─ Pleomorphic RMS: Rare, occurs in adults; high-grade pleomorphic sarcoma with large, bizarre rhabdomyoblasts; lacks typical features of embryonal or alveolar RMS
─ ─ ─ Spindle Cell/Sclerosing RMS: Spindle cell fascicles or prominent sclerosis; variable aggressiveness
Ancillary studies ─ ─ IHC (Both Rhabdomyoma and Rhabdomyosarcoma show skeletal muscle markers):
─ ─ Myogenin (nuclear, highly specific for rhabdomyoblastic differentiation)
─ ─ MyoD1 (nuclear, highly specific)
─ ─ Desmin (+, cytoplasmic)
─ ─ Muscle Specific Actin (MSA) / Smooth Muscle Actin (SMA) (can be positive)
─ IHC (RMS): Ki-67 high; Myogenin/MyoD1 are key for confirming rhabdomyoblastic nature in poorly differentiated RMS
─ Molecular (Alveolar RMS): PAX3-FOXO1 or PAX7-FOXO1 fusions
DDx ─ ─ For Rhabdomyoma: Granular cell tumor (S100+), adult Rhabdomyosarcoma (if atypia is subtle in rhabdomyoma)
─ For Rhabdomyosarcoma:
─ ─ Other small round blue cell tumors (Ewing sarcoma, lymphoma, neuroblastoma – specific markers for each)
─ ─ Other sarcomas (e.g Leiomyosarcoma, MPNST, Undifferentiated Pleomorphic Sarcoma – lack Myogenin/MyoD1)
─ ─ Germ cell tumors (especially if pleomorphic RMS resembles pleomorphic YST or choriocarcinoma; GCT markers positive)
─ ─ Malignant Triton Tumor (MPNST with rhabdomyoblastic differentiation – look for nerve sheath tumor background)
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Fibromatosis (Desmoid Tumor) of Mediastinum

A rare, locally aggressive (non-metastasizing) fibroblastic/myofibroblastic neoplasm arising in the soft tissues of the mediastinum, characterized by an infiltrative proliferation of bland spindle cells in a collagenous stroma
Clinical ─ Can occur at any age, often young to middle-aged adults; may be sporadic or associated with Gardner syndrome (familial adenomatous polyposis, APC gene mutation) or trauma/surgery; presents as a firm, fixed mass, may cause compressive symptoms due to infiltrative growth (e.g SVC syndrome, airway compromise); locally recurrent if incompletely excised, but does not metastasize
Macro ─ Firm, rubbery, poorly circumscribed, infiltrative mass; cut surface is typically gray-white, trabeculated, resembling scar tissue or tendon
Micro ─ ─ Composed of elongated, slender, bland spindle cells (fibroblasts/myofibroblasts) with pale eosinophilic cytoplasm and uniform, tapering nuclei with fine chromatin and inconspicuous nucleoli
─ Cells are arranged in sweeping fascicles or a vaguely storiform pattern, embedded in an abundant collagenous stroma (can be myxoid in areas)
─ Infiltrative growth into adjacent soft tissues, muscle, or around vessels/nerves is characteristic
─ Mitotic activity is typically low (<1-2 mitoses/10 HPF), no atypical mitoses or significant cytologic atypia
─ Prominent, thin-walled, elongated blood vessels are often present
Ancillary studies ─ ─ IHC (+) Nuclear Beta-catenin (in ~80-90% of sporadic desmoids, reflects CTNNB1 mutation or APC pathway dysregulation)
─ ─ Smooth Muscle Actin (SMA) (variable, often patchy), Muscle Specific Actin (MSA) (variable)
─ ─ Desmin (usually negative or focal)
─ IHC (-) S100, SOX10, CD34 (usually), STAT6, cytokeratins, h-caldesmon
─ Molecular: CTNNB1 (beta-catenin gene) mutations are common in sporadic cases; APC gene germline mutations in Gardner syndrome
DDx ─ ─ Solitary fibrous tumor (STAT6+, CD34+, well-circumscribed, different vascular pattern)
─ Low-grade fibromyxoid sarcoma or low-grade myofibroblastic sarcoma (may require molecular to exclude if atypia/mitoses are borderline; desmoids lack specific sarcoma translocations)
─ Sarcomatoid carcinoma or mesothelioma with prominent spindle cells (cytokeratin positive)
─ Sclerosing thymoma or other sclerosing mediastinal lesions (look for entrapped epithelial or specific elements)
─ Reactive fibrosis/scar tissue (less cellular, more organized collagen, history of injury/inflammation, no beta-catenin nuclear staining)
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Other Rare Mesenchymal Tumors of Mediastinum (e.g., Synovial Sarcoma, Chondrosarcoma)

An overview of uncommon primary mesenchymal malignancies of the mediastinum beyond the more frequently encountered types, each with distinct histopathology and molecular features
Clinical ─ These are individually very rare in the mediastinum; typically affect adults; presentation and prognosis vary widely depending on the specific sarcoma type and grade; often present with symptoms of a growing mass, local invasion, or metastases
Micro ─ (Features depend on specific sarcoma type)
─ Synovial Sarcoma:
─ ─ Can be monophasic (spindle cells only, most common), biphasic (spindle cells and epithelial glandular component), or poorly differentiated
─ ─ Spindle cells are uniform, ovoid to plump, with scant cytoplasm, arranged in dense fascicles; may have ropey collagen or hyalinized stroma; mast cells often present
─ ─ Epithelial component (in biphasic) forms glands, nests, or cords of cuboidal to columnar cells
─ ─ IHC: Cytokeratin (+, often focal in spindle cells, strong in epithelial component), EMA (+), TLE1 (+, nuclear), BCL2 (+), CD99 (+, often); S100 (-), smooth muscle markers (-)
─ ─ Molecular: Characteristic SS18-SSX (SYT-SSX) gene fusion (t(X;18)(p11;q11)) is pathognomonic
─ Chondrosarcoma:
─ ─ Malignant cartilaginous tumor, very rare as primary in mediastinum (may arise from chest wall, sternum, or vertebrae and extend, or de novo)
─ ─ Composed of atypical chondrocytes within a cartilaginous matrix; features of malignancy include hypercellularity, nuclear atypia, pleomorphism, binucleation/multinucleation of chondrocytes, and mitotic activity
─ ─ Graded (1, 2, 3) based on cellularity, atypia, and mitotic activity; higher grade indicates worse prognosis
─ ─ Myxoid change, calcification, or ossification can be present
─ ─ IHC: S100 (+ in chondrocytes), SOX9 (+)
Ancillary studies ─ (Tailored to suspected sarcoma type, see examples above)
DDx ─ (Broad, depends on morphology)
─ Metastatic sarcoma from another site (most common scenario for sarcomas in mediastinum)
─ Other primary mediastinal sarcomas (e.g liposarcoma, leiomyosarcoma, angiosarcoma, MPNST)
─ Sarcomatoid carcinoma or mesothelioma (cytokeratin positive)
─ Solitary fibrous tumor (STAT6+)
─ Germ cell tumor with somatic sarcomatous transformation (look for teratomatous elements or GCT markers)
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Endocrine Tumors/Lesions in the Mediastinum (Non-Thymic NETs)

Ectopic Thyroid Tissue / Intrathoracic Goiter (Substernal Goiter)

Presence of thyroid tissue within the mediastinum, either as truly ectopic developmental rests or, more commonly, as a downward extension (cervicothoracic or substernal goiter) of a cervical thyroid gland
Clinical ─ Intrathoracic goiters are common, especially in older adults, females > males; usually arise from inferior poles of cervical thyroid extending into superior/anterior mediastinum; truly ectopic thyroid tissue is rare. Most are asymptomatic, found incidentally on imaging; can cause compressive symptoms (dyspnea, cough, dysphagia, SVC syndrome) if large; may be associated with hyperthyroidism, hypothyroidism, or be euthyroid; risk of malignant transformation is similar to cervical thyroid
Macro ─ ─ Intrathoracic Goiter: Often multinodular, enlarged thyroid tissue extending from neck; may be encapsulated or ill-defined; cut surface shows colloid-filled nodules, cystic change, hemorrhage, calcification (typical goiter appearance)
─ Ectopic Thyroid Tissue: Discrete nodule or mass of thyroid tissue separate from cervical thyroid, usually in anterior mediastinum; resembles normal thyroid or goiter
Micro ─ ─ Histology mirrors that of normal thyroid gland or various thyroid pathologies:
─ ─ Benign colloid nodules: Large follicles filled with colloid, lined by flattened to cuboidal follicular epithelium
─ ─ Follicular hyperplasia, adenomatoid nodules
─ ─ Hashimoto thyroiditis (lymphocytic infiltrate, Hürthle cell change, germinal centers) may be present
─ ─ Degenerative changes: Cystic degeneration, hemorrhage, fibrosis, calcification
─ ─ Normal thyroid follicles if it's simple ectopic tissue
Ancillary studies ─ ─ IHC (To confirm thyroid origin if needed): Thyroglobulin (+, in colloid and follicular cells), TTF-1 (thyroid transcription factor-1, nuclear +), PAX8 (nuclear +)
─ Thyroid function tests (TSH, T3, T4) to assess functional status
─ Radioactive iodine uptake scan can confirm thyroidal nature and extent
DDx ─ ─ Thymic lesions (e.g thymoma, thymic cyst; thymic markers positive, thyroid markers negative)
─ Parathyroid adenoma/hyperplasia (if inferior mediastinum; PTH positive)
─ Lymphadenopathy (reactive or neoplastic)
─ Metastatic carcinoma to mediastinum (especially if thyroid lesion shows atypia; thyroid markers help confirm thyroid origin if primary vs met is unclear)
─ Ectopic Thyroid Carcinoma (see next entry; look for malignant features)
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Ectopic Thyroid Carcinoma (e.g., Papillary Thyroid Carcinoma arising in mediastinum)

Malignant transformation within ectopic thyroid tissue located in the mediastinum, or rarely, metastasis from an occult or known cervical thyroid carcinoma presenting as a primary mediastinal mass
Clinical ─ Rare; Papillary Thyroid Carcinoma (PTC) is the most common type to arise in ectopic mediastinal thyroid tissue or to metastasize to mediastinal lymph nodes; other types (follicular, medullary, anaplastic) are even rarer primarily in mediastinum; symptoms may be due to mass effect or found during workup for metastases; prognosis depends on tumor type, stage, and extent of disease
Macro ─ Solid or cystic mass in the mediastinum, may be infiltrative; appearance similar to primary thyroid carcinomas
Micro ─ (Histology of the specific thyroid carcinoma type)
─ Papillary Thyroid Carcinoma (PTC):
─ ─ Papillary architecture, follicular variants, or solid patterns
─ ─ Characteristic nuclear features: Enlarged, overlapping nuclei ("Orphan Annie eye" nuclei due to chromatin clearing), nuclear grooves, intranuclear pseudoinclusions
─ ─ Psammoma bodies may be present
─ Other carcinoma types (Follicular, Medullary, Anaplastic) will show their respective characteristic morphologies
─ Important to assess if tumor arises in a background of benign ectopic thyroid tissue or if it represents a lymph node metastasis (capsule, subcapsular sinus, residual lymphoid tissue)
Ancillary studies ─ ─ IHC (+) Thyroglobulin (+, often less intense or focal in poorly differentiated or some PTC variants), TTF-1 (+), PAX8 (+) – confirm thyroid origin
─ ─ For PTC: HBME-1 (+), Galectin-3 (+), CK19 (+) (variable utility)
─ ─ For Medullary Carcinoma: Calcitonin (+), Chromogranin A (+), CEA (+)
─ Molecular (For PTC): BRAF V600E mutation is common; RET/PTC rearrangements can occur
DDx ─ ─ Benign ectopic thyroid tissue / Intrathoracic goiter (lacks malignant cytologic and architectural features)
─ Metastatic carcinoma from non-thyroid primary to mediastinum (e.g lung adenocarcinoma can be TTF-1+ but PAX8 usually negative or different staining, thyroglobulin negative; other primaries negative for thyroid markers)
─ Primary mediastinal tumors mimicking thyroid carcinoma:
─ ─ Thymic carcinoma (some subtypes can have papillary or clear cell features; PAX8 can be positive in both thymic and thyroid neoplasms, so panel is crucial; TTF-1 usually neg in thymic Ca, thyroglobulin neg)
─ ─ Parathyroid carcinoma (PTH positive)
─ ─ Germ cell tumor with papillary features (YST, embryonal; specific GCT markers positive)
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Ectopic Parathyroid Adenoma / Carcinoma (Mediastinum)

Parathyroid neoplasms (adenoma or, rarely, carcinoma) arising from ectopic parathyroid tissue located within the mediastinum, typically due to aberrant migration of parathyroid glands during embryogenesis
Clinical ─ Most ectopic parathyroid glands are found in the anterior or superior mediastinum, often near the thymus or thyroid; ectopic adenomas are a cause of primary hyperparathyroidism (elevated serum calcium and PTH), especially persistent or recurrent hyperparathyroidism after neck exploration; ectopic parathyroid carcinoma is exceedingly rare but highly malignant if it occurs
Macro ─ ─ Adenoma: Usually a solitary, well-circumscribed, encapsulated, soft, tan to red-brown nodule, typically 1-3 cm
─ Carcinoma: Larger, often invasive, firm, gray-white mass; adherence to surrounding structures is common
Micro ─ ─ Ectopic Parathyroid Adenoma:
─ ─ Composed predominantly of chief cells (small polygonal cells with round, central nuclei and clear to eosinophilic cytoplasm) arranged in sheets, nests, cords, or follicular patterns
─ ─ Oxyphil cells (larger cells with abundant granular eosinophilic cytoplasm) may be present in clusters or scattered
─ ─ Adipose tissue is typically scant or absent within the adenoma (unlike normal parathyroid gland)
─ ─ A rim of compressed normal parathyroid tissue or a fibrous capsule is usually present
─ ─ Minimal atypia, low mitotic activity, no vascular or capsular invasion (key to distinguish from carcinoma if atypical features are present)
─ Ectopic Parathyroid Carcinoma:
─ ─ Malignant features are essential for diagnosis: Trabecular growth pattern, thick fibrous bands, mitotic activity (>5 mitoses/10 HPF is suggestive but not absolute), capsular invasion, vascular invasion, perineural invasion, or documented metastasis
─ ─ Cells are often larger, more pleomorphic, with prominent nucleoli compared to adenoma
─ ─ Necrosis can be present
Ancillary studies ─ ─ IHC (+) Parathyroid Hormone (PTH) (+, confirms parathyroid origin), GATA3 (+, nuclear), Chromogranin A (+/-)
─ ─ PAX8 (can be positive, but also in thyroid/thymic lesions)
─ ─ Parafibromin (loss of nuclear expression, due to HRPT2/CDC73 mutation, is suggestive of carcinoma or HPT-JT syndrome-associated adenomas, but not entirely specific for sporadic carcinoma)
─ ─ Ki-67 proliferation index: Higher in carcinoma than adenoma
─ IHC (-) Thyroglobulin (-), TTF-1 (-) (to exclude thyroid lesions); Cytokeratins (may be positive but pattern differs from thymic or other carcinomas)
DDx ─ ─ Ectopic thyroid tissue / Intrathoracic goiter / Thyroid carcinoma (Thyroglobulin+, TTF-1+)
─ Thymoma or thymic carcinoma (Thymic markers like p63/p40, PAX8 can overlap; PTH negative, specific thymoma architecture or carcinoma features)
─ Neuroendocrine tumor (carcinoid) of thymus (Synaptophysin/Chromogranin+, but PTH negative; different morphology)
─ Paraganglioma (S100+ sustentacular cells, GATA3 often strong+, Chromogranin/Synaptophysin+, PTH negative)
─ Lymph node metastasis from a parathyroid primary (if carcinoma)
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Mediastinal Cysts (Non-Thymic)

Bronchogenic Cyst (Mediastinal)

A congenital benign cyst arising from abnormal budding or branching of the primitive tracheobronchial tree (foregut duplication cyst), most commonly located in the middle mediastinum but can occur in posterior mediastinum or rarely within lung parenchyma or other sites
Clinical ─ Often asymptomatic and discovered incidentally on imaging at any age; can cause symptoms due to compression of adjacent structures (e.g cough, dyspnea, dysphagia, chest pain), infection, or rupture; generally does not communicate with the tracheobronchial tree postnatally
Macro ─ Typically a solitary, unilocular, spherical or oval, well-circumscribed cyst; thin-walled, filled with clear, mucoid, or gelatinous fluid (rarely hemorrhagic or purulent if infected); size varies from small to very large
Micro ─ ─ Cyst wall is composed of several layers characteristic of a bronchus:
─ ─ Lining: Ciliated pseudostratified columnar (respiratory) epithelium is pathognomonic; squamous metaplasia or denudation can occur, especially with inflammation
─ ─ Submucosa: Loose connective tissue, often with seromucinous bronchial glands
─ ─ Cartilage: Plates or islands of hyaline cartilage are present in the wall in ~50-75% of cases (key diagnostic feature)
─ ─ Smooth Muscle: Bundles of smooth muscle are typically present between the cartilage and fibrous outer layer
─ ─ Fibrous connective tissue outer layer
─ Inflammatory infiltrates (acute or chronic) may be present if the cyst is infected or inflamed
Ancillary studies ─ ─ IHC: Generally not required if classic histologic features are present. Epithelial lining is cytokeratin positive; cartilage is S100 positive.
DDx ─ ─ Esophageal duplication cyst (lined by squamous or glandular esophageal/gastric mucosa, two well-defined smooth muscle layers, often lacks cartilage and respiratory epithelium)
─ Pericardial cyst (lined by flat mesothelial cells, thin fibrous wall, typically lacks cartilage, smooth muscle, glands, and respiratory epithelium)
─ Thymic cyst (may contain thymic tissue in wall, Hassall's corpuscles, variable epithelial lining, lacks cartilage)
─ Enteric cyst (lined by intestinal-type mucosa, may have Peyer's patches, lacks cartilage)
─ Lymphangioma (multicystic, lined by D2-40+ lymphatic endothelium, lacks cartilage and respiratory epithelium)
─ Teratoma, cystic (contains derivatives of multiple germ layers e.g skin, neural tissue, fat, in addition to cartilage or respiratory elements)
─ Neuroenteric cyst (associated with vertebral anomalies, may have neural and GI elements)
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Esophageal Duplication Cyst (Mediastinal)

A congenital benign cyst representing a duplication of a segment of the esophagus (foregut duplication cyst), typically located in the posterior mediastinum, often intimately associated with or attached to the native esophageal wall
Clinical ─ Can present at any age, often in childhood; may be asymptomatic or cause symptoms due to compression (dysphagia, dyspnea, pain), bleeding, or infection; rare malignant transformation has been reported in adults
Macro ─ Solitary, unilocular or occasionally multilocular, spherical or tubular cyst; wall is typically thicker than bronchogenic or pericardial cysts due to well-developed muscle layers; contains clear, milky, or mucoid fluid
Micro ─ ─ Cyst wall characteristically has two well-defined layers of smooth muscle, analogous to the muscularis propria of the esophagus (inner circular, outer longitudinal arrangements may be discernible)
─ Lining epithelium varies:
─ ─ Stratified squamous epithelium (most common, resembling esophageal mucosa)
─ ─ Ciliated columnar (respiratory-type) epithelium (can occur, leading to overlap with bronchogenic cyst if other features are not definitive)
─ ─ Gastric-type glandular mucosa (can be present, may lead to peptic ulceration within the cyst)
─ ─ Intestinal-type mucosa (less common)
─ Submucosal glands (esophageal-type) may be present
─ Cartilage is typically absent (key feature distinguishing from bronchogenic cyst if respiratory epithelium is present)
─ No complex organoid structures from other germ layers (unlike teratoma)
Ancillary studies ─ ─ IHC: Cytokeratins highlight epithelial lining; smooth muscle markers (SMA, desmin) highlight muscle layers. If gastric mucosa present, specific markers (e.g MUC5AC, MUC6) could be used.
DDx ─ ─ Bronchogenic cyst (presence of cartilage and/or bronchial glands in wall, predominantly respiratory lining)
─ Pericardial cyst (mesothelial lining, thin fibrous wall, lacks muscle layers and specific GI/respiratory epithelium)
─ Thymic cyst (thymic tissue in wall)
─ Enteric cyst (if lined by intestinal mucosa, distinction can be subtle; esophageal duplication cyst is specifically related to esophagus)
─ Neuroenteric cyst (associated with vertebral anomalies, may have neural elements)
─ Leiomyoma of esophagus with cystic degeneration (solid tumor of smooth muscle, cystic change secondary)
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Pericardial Cyst (Mesothelial Cyst)

A benign congenital or acquired cyst typically located in the cardiophrenic angles (most commonly right), arising from persistence of an isolated coelomic remnant or secondary to pericardial inflammation/effusion; lined by mesothelial cells
Clinical ─ Usually asymptomatic and discovered incidentally on chest imaging in adults (3rd-4th decade); rarely cause symptoms (atypical chest pain, dyspnea) due to large size or compression; generally considered benign with no malignant potential; may change in size or rarely resolve spontaneously
Macro ─ Typically a unilocular, thin-walled, translucent cyst filled with clear, watery ("spring water") fluid; usually 2-10 cm in diameter; attached to the parietal pericardium but does not communicate with the pericardial cavity
Micro ─ ─ Cyst wall is composed of a thin layer of dense to loose collagenous connective tissue, sometimes with a mild chronic inflammatory infiltrate or focal adipose tissue
─ Lined by a single layer of flattened to cuboidal, bland mesothelial cells
─ No cartilage, smooth muscle layers (other than associated vessels), respiratory epithelium, or glandular structures
Ancillary studies ─ ─ IHC (Lining cells): Positive for mesothelial markers such as Calretinin (nuclear and cytoplasmic), WT1 (nuclear), CK5/6 (cytoplasmic/membranous), D2-40 (podoplanin, membranous)
─ IHC (-): Negative for markers of other epithelial types (e.g CEA, TTF-1)
DDx ─ ─ Bronchogenic cyst (respiratory lining, cartilage, smooth muscle, glands in wall)
─ Esophageal duplication cyst (GI-type lining, two smooth muscle layers in wall)
─ Thymic cyst (thymic tissue in wall, variable epithelial lining)
─ Lymphangioma (multicystic, D2-40+ lymphatic endothelium lines channels, often contains lymphoid aggregates)
─ Cystic teratoma (derivatives of multiple germ layers)
─ Hydatid cyst (parasitic, specific internal structures and hooklets)
─ Malignant mesothelioma with cystic change (rare; would show malignant cytologic features, invasion)
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Enteric Cyst (Mediastinal)

A type of foregut duplication cyst lined by intestinal-type mucosa, typically located in the posterior mediastinum; represents a developmental anomaly of the primitive foregut
Clinical ─ Rare, usually presents in infancy or childhood, but can be found in adults; may be asymptomatic or cause symptoms due to compression (dysphagia, dyspnea, vomiting), bleeding (if gastric mucosa causes ulceration), or infection
Macro ─ Solitary, unilocular or occasionally septated, spherical or tubular cyst; wall structure similar to intestinal wall, may be thick due to muscle layers; contains mucoid, serous, or hemorrhagic fluid
Micro ─ ─ Cyst wall typically shows features resembling intestinal wall:
─ ─ Lining: Intestinal-type epithelium, which can be small intestinal (with villi, goblet cells, Paneth cells) or large intestinal (crypts, abundant goblet cells); gastric mucosa (with parietal and chief cells) can also be present, leading to potential for peptic ulceration
─ ─ Submucosa: May contain Brunner's glands or lymphoid aggregates (Peyer's patches if small intestinal differentiation)
─ ─ Muscularis propria: Usually two well-defined layers of smooth muscle are present
─ No cartilage or definitive respiratory structures (unlike bronchogenic cyst)
─ No complex organoid structures from other germ layers (unlike teratoma)
Ancillary studies ─ ─ IHC: Can confirm intestinal differentiation if needed (e.g CDX2 for intestinal epithelium, MUC2 for goblet cells, specific gastric mucins like MUC5AC/MUC6 if gastric mucosa is present). Smooth muscle markers for muscle layers.
DDx ─ ─ Esophageal duplication cyst (distinction can be challenging if enteric cyst is high in posterior mediastinum and esophageal duplication cyst has gastric/intestinal metaplasia; true enteric cyst implies more definitive intestinal differentiation rather than esophageal origin with metaplasia)
─ Bronchogenic cyst (respiratory lining, cartilage, bronchial glands)
─ Neuroenteric cyst (associated with vertebral anomalies, may contain neural elements in addition to GI mucosa)
─ Teratoma with prominent gastrointestinal differentiation (will have other germ layer derivatives)
─ Pancreatic pseudocyst extending into mediastinum (history of pancreatitis, lined by granulation tissue/fibrosis, not true epithelium, high amylase in fluid)
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Neuroenteric Cyst (Mediastinal)

A rare congenital cyst resulting from incomplete separation of the neural tube and primitive foregut (notochordal remnant theory), characterized by a cyst lined by gastrointestinal or respiratory-type epithelium and often associated with vertebral anomalies
Clinical ─ Typically located in the posterior mediastinum, may be intramural within the esophagus or extend into the spinal canal (causing neurologic symptoms); often presents in infancy or childhood, but can be diagnosed in adults; symptoms include pain, dysphagia, dyspnea, or neurologic deficits if spinal involvement; associated vertebral anomalies (e.g hemivertebrae, spina bifida, scoliosis, Klippel-Feil syndrome) are common
Macro ─ Solitary, unilocular or multilocular cyst, often attached to the esophagus, vertebrae, or extending through an intervertebral foramen; wall may be thick; contents vary (clear, mucoid, hemorrhagic)
Micro ─ ─ Cyst lining is variable:
─ ─ Gastrointestinal-type mucosa (most common): Gastric (with parietal/chief cells, risk of peptic ulceration), small intestinal (with villi, goblet cells), or colonic type
─ ─ Respiratory-type epithelium (ciliated columnar) can also occur, or a mix of GI and respiratory types
─ Wall structure:
─ ─ Smooth muscle layers (often two, like muscularis propria) are usually present
─ ─ Neural tissue (glial cells, nerve fibers, ganglion cells) may be present within the cyst wall or in associated stalk connecting to meninges/spinal cord (key distinguishing feature if present)
─ ─ Cartilage is typically absent (unlike bronchogenic cysts)
─ Vertebral anomalies are often associated but not seen in the cyst wall itself
Ancillary studies ─ ─ IHC: Can confirm epithelial lineage (cytokeratins) and specific differentiation if needed (e.g CDX2 for intestinal, MUC5AC for gastric foveolar, S100/GFAP for neural elements if present). Smooth muscle markers highlight muscle layers.
DDx ─ ─ Esophageal duplication cyst (lacks neural elements and usually no direct connection/association with spinal canal/vertebral anomalies, though both have GI lining and muscle coats)
─ Enteric cyst (similar GI lining, but typically lacks neural elements and strong association with vertebral defects unless it is truly a neuroenteric cyst)
─ Bronchogenic cyst (respiratory lining, cartilage in wall, lacks neural elements and typical GI lining)
─ Teratoma (contains derivatives of all three germ layers, including more complex organoid structures like skin, mature brain tissue, bone)
─ Meningocele (protrusion of meninges, lined by arachnoid cells, contains CSF, direct connection to spinal canal, lacks GI lining)
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Thoracic Duct Cyst (Mediastinal)

A very rare cystic dilation of the thoracic duct or its major tributaries, typically located in the posterior or superior mediastinum, lined by endothelial cells and containing chyle
Clinical ─ Extremely rare, can occur at any age; often asymptomatic and discovered incidentally; may present with symptoms due to compression (dyspnea, chest pain, cough) or chylothorax if it ruptures or leaks; may be congenital (due to ductal atresia or weakness) or acquired (due to trauma, inflammation, or obstruction)
Macro ─ Usually a solitary, unilocular or occasionally multilocular, thin-walled cyst; typically elongated or tubular, following the path of the thoracic duct; contains milky white or serous (if patient fasting) chylous fluid rich in triglycerides and lymphocytes
Micro ─ ─ Cyst wall is composed of fibrous connective tissue, often with scattered smooth muscle bundles (which may be sparse or disorganized compared to a true vessel wall) and lymphoid aggregates
─ Lined by a single layer of flattened, bland endothelial cells (lymphatic endothelium)
─ Lumen contains eosinophilic, proteinaceous material (lymph), numerous small lymphocytes, and lipid globules (chyle)
─ No cartilage, respiratory epithelium, or complex GI mucosal lining
Ancillary studies ─ ─ IHC (Lining endothelial cells): D2-40 (podoplanin) (+), LYVE-1 (+), Prox1 (+), CD31 (+), ERG (+) – confirms lymphatic endothelial origin
─ Fluid analysis (if aspirated): High triglyceride levels (>110 mg/dL or higher than serum), presence of chylomicrons, and predominance of lymphocytes confirm chylous nature
DDx ─ ─ Lymphangioma (cystic hygroma) (often more multicystic and infiltrative, but histologically similar lymphatic channels; distinction can be difficult, thoracic duct cyst is a specific dilation of the main duct)
─ Pericardial cyst (mesothelial lining, typically cardiophrenic angle, clear serous fluid)
─ Bronchogenic cyst (respiratory lining, cartilage)
─ Esophageal duplication cyst / Enteric cyst (GI lining, muscular wall)
─ Thymic cyst (thymic tissue in wall)
─ Chylous pleural effusion (if cyst ruptures; cyst itself is the origin)
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Pancreatic Pseudocyst extending into mediastinum

A collection of amylase-rich fluid, debris, and inflammatory exudate contained by a non-epithelialized fibrous wall, arising from pancreatitis and dissecting superiorly through the esophageal or aortic hiatus into the mediastinum
Clinical ─ Rare complication of acute or chronic pancreatitis (especially alcohol-related or traumatic); usually presents with chest pain, dyspnea, dysphagia, or signs of sepsis if infected; history of pancreatitis is key; high mortality if not recognized and treated
Macro ─ Ill-defined or encapsulated fluid collection in the posterior mediastinum, often connected via a tract to the pancreas; may contain necrotic debris, hemorrhagic fluid
Micro ─ ─ Cyst wall is composed of granulation tissue, fibrous connective tissue, and chronic inflammatory cells (macrophages, lymphocytes, plasma cells)
─ Lacks a true epithelial lining (hence "pseudo"cyst); the inner surface may have fibrin, necrotic debris, and hemosiderin-laden macrophages
─ Fat necrosis may be present in or around the pseudocyst wall
─ No cartilage, respiratory epithelium, complex GI mucosa, or mesothelium (unless it erodes into a pre-existing structure)
Ancillary studies ─ ─ Fluid analysis (if aspirated from mediastinal collection): Markedly elevated amylase and lipase levels are diagnostic (much higher than serum levels)
─ Imaging (CT/MRI/ERCP/EUS): Demonstrates pancreatic inflammation/pseudocyst and its extension into the mediastinum
─ IHC: Not typically used for diagnosis; focus is on absence of epithelial lining and presence of inflammatory/fibrous wall
DDx ─ ─ True cysts of the mediastinum (bronchogenic, esophageal, pericardial, enteric, thymic – all have epithelial or mesothelial linings)
─ Esophageal perforation or Boerhaave syndrome (can lead to mediastinal fluid collections/inflammation, but different clinical context and fluid content typically not high amylase unless pancreas also involved)
─ Mediastinal abscess from other causes (purulent material, cultures positive, different underlying cause)
─ Necrotic tumor with cystic degeneration (presence of viable malignant cells)
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Metastatic Tumors to the Mediastinum/Thymus

Secondary malignancies involving mediastinal structures (lymph nodes, thymus, soft tissues) from primary cancers elsewhere, representing a common cause of mediastinal masses, especially in adults
Clinical ─ Metastases are more common than primary mediastinal malignancies overall; common primary sites include lung, breast, esophagus, kidney, melanoma, gastrointestinal tract (stomach, colon, pancreas), testis (germ cell tumors), and thyroid; lymphoma can also involve mediastinal nodes extensively as secondary spread. Symptoms depend on location and extent of involvement (e.g lymphadenopathy, cough, dyspnea, SVC syndrome, chest pain, or related to primary cancer); prognosis depends on primary tumor type, burden of disease, and treatment options
Patterns of Spread and Macro Appearance:
─ Lymph node metastases: Most common pattern; mediastinal lymph nodes (paratracheal, hilar, subcarinal, paraesophageal, anterior mediastinal) become enlarged, matted, may show central necrosis. Specific nodal groups are often involved depending on primary tumor drainage (e.g lung cancer to hilar/mediastinal nodes)
─ Direct invasion: Tumors from adjacent organs (e.g lung, esophagus, pleura, thyroid) can directly invade mediastinal structures
─ Hematogenous spread: Can lead to discrete nodules in thymus or soft tissues, though less common than nodal spread for carcinomas
─ Thymic metastases: Relatively uncommon but can occur from lung, breast, melanoma, kidney etc, appearing as single or multiple nodules within the thymus
Micro ─ ─ Histology mirrors the primary tumor:
─ ─ Carcinomas: Adenocarcinoma (gland formation, mucin), squamous cell carcinoma (keratinization, intercellular bridges), small cell carcinoma, neuroendocrine carcinoma, urothelial carcinoma, etc.
─ ─ Sarcomas: Various types reflecting primary sarcoma histology
─ ─ Melanoma: Nests of atypical melanocytes, pigment may or may not be present
─ ─ Germ Cell Tumors: Seminoma or NSGCT components if from testis (mediastinal primary GCTs also occur, see previous section)
─ Tumor cells are found within lymph node sinuses, parenchyma, or infiltrating mediastinal soft tissues/thymus
Ancillary studies ─ ─ IHC: Crucial for confirming metastatic nature and suggesting/confirming primary site, especially if primary is unknown or if morphology is poorly differentiated. Panel should be guided by morphology and clinical context. Examples:
─ ─ Lung adenocarcinoma: TTF-1 (+), Napsin A (+), CK7 (+)
─ ─ Breast carcinoma: GATA3 (+), ER (+/-), PR (+/-), GCDFP-15 (+/-), Mammaglobin (+/-)
─ ─ Colorectal adenocarcinoma: CDX2 (+), CK20 (+), SATB2 (+), CK7 (-)
─ ─ Renal cell carcinoma: PAX8 (+), RCCma (+), CD10 (+)
─ ─ Melanoma: S100 (+), SOX10 (+), HMB-45 (+), Melan-A (+)
─ ─ Thyroid carcinoma: TTF-1 (+), PAX8 (+), Thyroglobulin (+)
─ ─ Squamous Cell Carcinoma: p63/p40 (+), CK5/6 (+) (need to correlate with site, e.g TTF-1 for lung vs other)
─ IHC (-) Markers for primary mediastinal tumors (e.g OCT3/4, SALL4 for primary GCTs; extensive panel of mesothelial markers for mesothelioma if pleura involved; specific thymic markers if thymic primary is in DDx and morphology is ambiguous)
DDx ─ ─ Primary mediastinal malignancies (thymoma, thymic carcinoma, primary mediastinal GCT, lymphoma, primary mediastinal sarcoma, neurogenic tumors, paraganglioma – require specific markers and exclusion of metastasis)
─ Reactive lymphadenopathy (e.g sarcoidosis, infections – specific granulomatous or inflammatory features, no malignant cells)
─ Benign mediastinal lesions (cysts, goiter – characteristic benign histology)
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HEART AND PERICARDIUM

Normal Heart

Normal Cardiac Anatomy and Histology

A foundational understanding of the heart's structure, including its chambers, valves, conduction system, and coronary arteries, and their normal microscopic appearances
Clinical ─ Normal structure is essential for proper cardiac function; deviations underlie various cardiac diseases; imaging (echocardiography, MRI, CT) and electrophysiology studies assess anatomy and function
Anatomy and Histology:
─ Chambers:
─ ─ Four chambers: Right atrium (RA), right ventricle (RV), left atrium (LA), left ventricle (LV)
─ ─ Atria: Thin-walled receiving chambers; RA receives deoxygenated blood from body (SVC, IVC, coronary sinus), LA receives oxygenated blood from lungs (pulmonary veins); pectinate muscles in auricles
─ ─ Ventricles: Thicker-walled pumping chambers; RV pumps deoxygenated blood to lungs (pulmonary artery), LV pumps oxygenated blood to body (aorta); LV wall is much thicker (~3x) than RV wall due to higher pressure system; trabeculae carneae, papillary muscles, chordae tendineae
─ ─ Myocardium: Cardiac muscle tissue; composed of cardiomyocytes (striated muscle cells with centrally located nuclei, intercalated discs for cell-cell communication and electrical coupling, abundant mitochondria)
─ ─ Endocardium: Inner lining of chambers and valves; single layer of flat endothelial cells overlying thin connective tissue and smooth muscle cells
─ ─ Epicardium (Visceral Pericardium): Outer layer of heart; single layer of mesothelial cells overlying connective tissue, adipose tissue, coronary vessels, and nerves
─ Valves:
─ ─ Four valves ensure unidirectional blood flow: Tricuspid (RA to RV), Pulmonic (RV to pulmonary artery), Mitral (LA to LV, bicuspid), Aortic (LV to aorta)
─ ─ Composed of three layers: Fibrosa (dense collagenous core, provides structural integrity, continuous with cardiac skeleton), Spongiosa (loose connective tissue, shock absorber), and Ventricularis/Atrialis (elastic fibers, endothelium-lined)
─ ─ Avascular structures (nourished by diffusion)
─ Conduction System:
─ ─ Specialized cardiac muscle cells that initiate and propagate electrical impulses for coordinated contraction
─ ─ Sinoatrial (SA) node: Pacemaker, located in RA near SVC entrance
─ ─ Atrioventricular (AV) node: Located in interatrial septum, near tricuspid valve
─ ─ Bundle of His (AV bundle): Descends from AV node into interventricular septum
─ ─ Right and Left Bundle Branches: Extend down interventricular septum
─ ─ Purkinje fibers: Terminal fibers spreading throughout ventricular myocardium; larger cells, pale cytoplasm (glycogen-rich), peripheral myofibrils
─ Coronary Arteries:
─ ─ Supply oxygenated blood to myocardium; Right Coronary Artery (RCA) and Left Main Coronary Artery (LMCA), which divides into Left Anterior Descending (LAD) and Left Circumflex (LCx) arteries
─ ─ Arise from aortic root, run on epicardial surface, give off penetrating branches into myocardium
─ ─ Histology: Typical muscular arteries (intima, media, adventitia); prone to atherosclerosis
Micro ─ (Key features of cardiomyocytes)
─ Striated (sarcomeres), branched cells with 1-2 centrally located nuclei
─ Intercalated discs: Specialized junctions (gap junctions, desmosomes, fascia adherens) connecting cardiomyocytes, visible as dark transverse lines
─ Abundant mitochondria, sarcoplasmic reticulum for calcium handling
─ Lipofuscin pigment (wear-and-tear) accumulates with age
Ancillary studies ─ N/A (for normal histology)
DDx ─ N/A
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Basic Myocardial Responses to Injury

The myocardium exhibits a limited repertoire of responses to various injurious stimuli, including hypertrophy, atrophy, necrosis, fibrosis, and inflammation
Clinical ─ These responses underlie the pathophysiology of most cardiac diseases (e.g heart failure, arrhythmias, ischemic heart disease); understanding these changes is crucial for interpreting cardiac pathology
Myocardial Responses:
─ Hypertrophy:
─ ─ Increase in cardiomyocyte size (not number, as adult cardiomyocytes have limited regenerative capacity) leading to increased heart muscle mass and wall thickness
─ ─ Physiologic (e.g athlete's heart) or Pathologic (e.g due to pressure overload like hypertension/aortic stenosis, or volume overload like valvular regurgitation, or genetic mutations in HCM)
─ ─ Micro: Enlarged cardiomyocytes (>15 µm diameter), "boxcar" shaped enlarged hyperchromatic nuclei, increased myofibrils; may eventually lead to degenerative changes (myofiber disarray in HCM, interstitial fibrosis)
─ Atrophy:
─ ─ Decrease in cardiomyocyte size, leading to reduced heart muscle mass
─ ─ Causes: Disuse (prolonged bed rest), cachexia (cancer, malnutrition), senile atrophy, some chronic diseases
─ ─ Micro: Smaller cardiomyocytes, often with increased lipofuscin pigment around nucleus (brown atrophy)
─ Necrosis:
─ ─ Cardiomyocyte death due to irreversible injury, most commonly ischemia (myocardial infarction)
─ ─ Types of Necrosis:
─ ─ ─ Coagulation Necrosis: Characteristic of ischemia; eosinophilic cytoplasm, loss of nuclei (karyolysis), preserved cell outlines initially; inflammatory response follows (neutrophils, then macrophages)
─ ─ ─ Contraction Band Necrosis: Occurs with reperfusion of ischemic myocardium or exposure to high catecholamines; hypercontracted sarcomeres form dense eosinophilic transverse bands, often with cell rupture
─ ─ ─ Myocytolysis (Vacuolar Degeneration): Colliquative necrosis with cell swelling, vacuolization, and myofibrillar dissolution; seen in severe ischemia, electrolyte imbalance, some toxic states
─ Fibrosis (Scarring):
─ ─ Replacement of necrotic cardiomyocytes with collagenous connective tissue by fibroblasts/myofibroblasts
─ ─ Reparative Fibrosis (Replacement Fibrosis): Forms a scar in areas of prior infarction or significant myocyte loss
─ ─ Reactive Interstitial Fibrosis (Perivascular or Interstitial): Diffuse increase in collagen in the spaces between cardiomyocytes or around vessels; common in chronic pressure/volume overload, aging, cardiomyopathies
─ ─ Micro: Acellular collagen (mature scar) or more cellular granulation tissue (healing phase with neovascularization, fibroblasts, inflammatory cells)
─ Inflammation (Myocarditis):
─ ─ Infiltration of the myocardium by inflammatory cells (lymphocytes, macrophages, neutrophils, eosinophils, giant cells) often accompanied by myocyte injury/necrosis
─ ─ Causes: Infections (viral, bacterial, fungal, parasitic), autoimmune diseases, toxins, hypersensitivity reactions, idiopathic (see Myocarditis entry)
Macro ─ Variable; hypertrophy (thickened walls), atrophy (thinned walls), necrosis (pale or hemorrhagic infarcts), fibrosis (white scar tissue)
Micro ─ (See descriptions above)
Ancillary studies ─ Special stains (e.g Masson trichrome for fibrosis), IHC (for inflammatory cells, markers of injury if needed)
DDx ─ Specific etiologies based on pattern of injury and clinical context
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Endocardial and Pericardial Reactions

Pathologic responses of the endocardium and pericardium to injury or inflammation, contributing to various cardiac conditions
Clinical ─ Endocardial reactions can lead to valvular dysfunction, thrombus formation, or restrictive physiology. Pericardial reactions can cause acute pericarditis, pericardial effusion, tamponade, or constrictive pericarditis.
Endocardial Reactions:
─ Endocardial Fibroelastosis (EFE):
─ ─ Diffuse or patchy thickening of the endocardium due to proliferation of collagen and elastic fibers
─ ─ Primary EFE: Idiopathic, occurs in infants/young children, often leads to restrictive cardiomyopathy
─ ─ Secondary EFE: Response to chronic stress, pressure/volume overload, inflammation (e.g in dilated cardiomyopathy, congenital heart disease, post-myocarditis)
─ ─ Micro: Thickened endocardium with layers of collagen and elastic fibers (highlighted by elastic stains e.g Verhoeff-Van Gieson); underlying myocardium may be normal or show hypertrophy/fibrosis
─ Nonbacterial Thrombotic Endocarditis (NBTE) / Marantic Endocarditis:
─ ─ Deposition of sterile platelet-fibrin thrombi (vegetations) on cardiac valves (typically aortic or mitral, along lines of closure), usually in patients with hypercoagulable states, malignancy (especially mucinous adenocarcinomas), or severe chronic illness
─ ─ Micro: Bland vegetations of fibrin and platelets, minimal inflammation, valves are often normal underlying
─ Infective Endocarditis: (See Valvular Heart Disease section for detail)
─ ─ Microbial infection of valves or endocardium leading to bulky, friable vegetations (bacteria, fibrin, inflammatory cells), valvular destruction, and systemic complications
─ Jet Lesions: Endocardial thickening or plaques caused by turbulent blood flow hitting the endocardial surface (e.g in valvular regurgitation or septal defects)
Pericardial Reactions:
─ Pericarditis: Inflammation of the pericardium
─ ─ Acute Pericarditis:
─ ─ ─ Serous Pericarditis: Thin, watery exudate; often viral, autoimmune (SLE, RF), uremia; mild inflammation
─ ─ ─ Fibrinous/Serofibrinous Pericarditis: Most common type; fibrinous exudate on pericardial surfaces ("bread and butter" appearance); causes include MI (Dressler syndrome), uremia, radiation, trauma, viral/bacterial infection, autoimmune disease; resolves by fibrinolysis or organizes
─ ─ ─ Suppurative/Purulent Pericarditis: Gross pus (neutrophils, necrotic debris); bacterial, fungal, or parasitic infection; can lead to scarring/constriction
─ ─ ─ Hemorrhagic Pericarditis: Bloody exudate; often due to malignancy, tuberculosis, trauma, bleeding diathesis
─ ─ Chronic Pericarditis: Long-standing inflammation, may lead to:
─ ─ ─ Adhesive Mediastinopericarditis: Obliteration of pericardial sac by fibrous adhesions, heart may be tethered to surrounding structures
─ ─ ─ Constrictive Pericarditis: Dense fibrous scarring and thickening of pericardium (often calcified – "concretio cordis") encasing the heart, impairing diastolic filling; can follow suppurative, tuberculous, or hemorrhagic pericarditis, cardiac surgery, radiation
─ Pericardial Effusion: Abnormal accumulation of fluid in pericardial sac (serous, chylous, cholesterol, hemorrhagic); can lead to cardiac tamponade if rapid or large
Macro ─ EFE (opaque, thickened endocardium); NBTE (small, sterile vegetations); Pericarditis (fibrin, pus, adhesions, thickened pericardium)
Micro ─ EFE (collagen/elastic fibers); NBTE (platelet/fibrin thrombi); Pericarditis (inflammatory cells, fibrin, granulation tissue, fibrosis, calcification)
Ancillary studies ─ Special stains for organisms (pericarditis), elastic stains (EFE)
DDx ─ Based on morphology and clinical context
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Non-Neoplastic Myocardial Diseases

Myocarditis

Inflammation of the myocardium, often associated with cardiomyocyte injury or necrosis, caused by a wide range of infectious and non-infectious etiologies
Clinical ─ Highly variable presentation: asymptomatic, flu-like illness, chest pain (pericarditic or ischemic-like), palpitations, arrhythmias, heart failure (fulminant or chronic dilated cardiomyopathy), sudden cardiac death; diagnosis aided by clinical picture, ECG changes, elevated cardiac biomarkers (troponin), imaging (CMR), and endomyocardial biopsy (EMB, though sensitivity can be limited by sampling error and patchy nature of disease)
Micro ─ (Dallas Criteria historically used for EMB diagnosis of active myocarditis: inflammatory infiltrate + associated myocyte necrosis/damage not characteristic of ischemia)
Etiologic Classification and Histologic Features:
─ Lymphocytic Myocarditis:
─ ─ Most common pattern in North America/Europe
─ ─ Etiology: Often viral (Coxsackie B, adenovirus, parvovirus B19, influenza, HIV, CMV, EBV), post-viral autoimmune reaction, or idiopathic
─ ─ Micro: Predominantly lymphocytic infiltrate (mainly T-cells, some B-cells and macrophages) with associated myocyte necrosis or degeneration; infiltrate can be focal, diffuse, or multifocal
─ Eosinophilic Myocarditis:
─ ─ Etiology: Hypersensitivity reactions (drugs like sulfonamides, methyldopa, penicillin), parasitic infections (e.g Trichinella, Toxocara), Churg-Strauss syndrome (Eosinophilic Granulomatosis with Polyangiitis), Idiopathic Hypereosinophilic Syndrome, certain malignancies
─ ─ Micro: Prominent myocardial and often perivascular infiltrate of eosinophils, usually mixed with lymphocytes and macrophages; myocyte necrosis; vasculitis or granulomas may be present depending on cause (e.g Churg-Strauss)
─ Giant Cell Myocarditis (GCM):
─ ─ Etiology: Idiopathic, aggressive, often fulminant autoimmune disorder; may be associated with other autoimmune diseases (e.g thymoma, inflammatory bowel disease)
─ ─ Micro: Widespread inflammatory infiltrate with lymphocytes, eosinophils, plasma cells, macrophages, and characteristic multinucleated giant cells (histiocytic origin); extensive myocyte necrosis; often poor prognosis, requiring urgent immunosuppression or transplantation
─ Infectious Myocarditis (Non-viral):
─ ─ Bacterial: Direct bacterial invasion (e.g Staphylococcus aureus, Streptococcus pneumoniae, Borrelia burgdorferi in Lyme carditis – often spirochetes in tissue with lymphoplasmacytic infiltrate and AV block) or toxin-mediated (e.g Diphtheria); often suppurative inflammation with neutrophils and abscess formation
─ ─ Fungal: (e.g Candida, Aspergillus, Cryptococcus) usually in immunocompromised patients; may show yeast/hyphae with mixed inflammation or granulomas
─ ─ Parasitic:
─ ─ ─ Chagas Disease (Trypanosoma cruzi): Endemic in South/Central America; acute phase with trypomastigotes in myocytes, inflammation; chronic phase with dilated cardiomyopathy, fibrosis, destruction of cardiac ganglia, few parasites (amastigotes in myocytes)
─ ─ ─ Toxoplasmosis (Toxoplasma gondii): Usually in immunocompromised (AIDS) or congenital; parasitic cysts (bradyzoites) or free tachyzoites in myocytes with focal inflammation/necrosis
─ ─ ─ Trichinellosis (Trichinella spiralis): Larvae encyst in skeletal muscle, can involve myocardium causing eosinophilic and lymphocytic inflammation
─ Sarcoid Myocarditis (Cardiac Sarcoidosis):
─ ─ Myocardial involvement by sarcoidosis, a multisystem granulomatous disease of unknown etiology
─ ─ Micro: Non-caseating epithelioid granulomas (collections of epithelioid histiocytes, multinucleated giant cells, lymphocytes) within the myocardium, often patchy, involving conduction system, ventricular free walls, septum; can lead to arrhythmias, heart block, heart failure, sudden death; associated fibrosis is common
─ Myocarditis in Systemic Diseases:
─ ─ Systemic Lupus Erythematosus (SLE): Can cause pericarditis (most common), myocarditis (lymphocytic), Libman-Sacks endocarditis, coronary arteritis
─ ─ Scleroderma (Systemic Sclerosis): Myocardial fibrosis (patchy or diffuse, often contraction band necrosis related ischemia from small vessel disease), less commonly true myocarditis
─ ─ Rheumatoid Arthritis: Granulomatous myocarditis (rheumatoid nodules), non-specific lymphocytic infiltrates, pericarditis
Ancillary studies ─ ─ IHC: To characterize inflammatory infiltrate (e.g CD3, CD4, CD8 for T-cells; CD20 for B-cells; CD68 for macrophages; MBP/ECP for eosinophils); C4d/C3d for antibody-mediated rejection if transplant context (not primary myocarditis)
─ Special Stains: Gram, GMS, PAS for organisms; Congo red for amyloid if suspected (can mimic or coexist)
─ PCR/ISH: For viral genomes (e.g PVB19, CMV, EBV) in EMB (clinical significance can be complex) or specific microbes
DDx ─ ─ Myocardial infarction (ischemic necrosis with neutrophils initially, then macrophages and granulation tissue; specific distribution related to coronary territories)
─ Arrhythmogenic Cardiomyopathy (fibrofatty replacement, inflammation can be present but usually lymphocytic and related to myocyte injury in that context)
─ Dilated cardiomyopathy (may be end-stage of some myocarditis, but often idiopathic with hypertrophy, fibrosis, no active inflammation)
─ Cardiac transplant rejection (specific patterns of cellular or antibody-mediated rejection)
─ Toxic effects on myocardium (e.g anthracyclines – vacuolar degeneration; catecholamines – contraction band necrosis)
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Cardiomyopathies

A heterogeneous group of diseases of the myocardium associated with mechanical and/or electrical dysfunction, which usually (but not invariably) exhibit inappropriate ventricular hypertrophy or dilatation and are due to a variety of causes, frequently genetic; cardiomyopathies either are confined to the heart or are part of generalized systemic disorders, often leading to cardiovascular death or progressive heart failure-related disability (adapted from AHA/ESC definitions)
Clinical ─ Presentations vary widely depending on type: heart failure symptoms (dyspnea, fatigue, edema), arrhythmias, syncope, chest pain, sudden cardiac death; diagnosis involves echocardiography, cardiac MRI, genetic testing, ECG, and sometimes endomyocardial biopsy
Classification and Features:
─ Dilated Cardiomyopathy (DCM):
─ ─ Characterized by ventricular chamber enlargement and systolic dysfunction (impaired contractility) of one or both ventricles, with normal or reduced wall thickness
─ ─ Etiology: Idiopathic (~50%), genetic/familial (~20-35%, mutations in genes for cytoskeletal, sarcomeric, nuclear envelope proteins e.g TTN, LMNA, MYH7), alcoholic, post-myocarditis, peripartum, toxic (e.g doxorubicin, cocaine), metabolic (e.g thyroid disease, hemochromatosis), tachycardia-induced
─ ─ Macro: Enlarged, heavy, flabby heart; all four chambers often dilated; mural thrombi common, especially at apex
─ ─ Micro: Non-specific; cardiomyocyte hypertrophy (often attenuated/stretched cells), interstitial and perivascular fibrosis, myocyte vacuolization, nuclear atypia; minimal or no inflammation if not related to ongoing myocarditis
─ Hypertrophic Cardiomyopathy (HCM):
─ ─ Characterized by unexplained left ventricular hypertrophy (often asymmetric, involving septum – Asymmetric Septal Hypertrophy, ASH), with preserved or increased ejection fraction, often associated with diastolic dysfunction
─ ─ Etiology: Primarily genetic (~60-70%), autosomal dominant mutations in genes encoding sarcomeric proteins (e.g MYH7 (β-myosin heavy chain), MYBPC3 (myosin-binding protein C), TNNT2 (troponin T), TNNI3 (troponin I))
─ ─ Macro: Massive myocardial hypertrophy, typically LV and septum, without ventricular dilatation (unless end-stage); narrowed LV outflow tract may occur due to septal bulge and systolic anterior motion (SAM) of mitral valve
─ ─ Micro: Pathognomonic feature is myofiber disarray (haphazard arrangement of cardiomyocytes); cardiomyocyte hypertrophy with bizarre, enlarged, hyperchromatic nuclei; interstitial and replacement fibrosis; small intramural coronary arteries may show thickened walls and narrowed lumens
─ Restrictive Cardiomyopathy (RCM):
─ ─ Characterized by impaired ventricular filling and diastolic dysfunction with normal or near-normal systolic function and ventricular wall thickness (or mildly increased); atria are often dilated
─ ─ Etiology:
─ ─ ─ Infiltrative: Amyloidosis (most common cause of RCM in Western countries; deposition of amyloid protein – AL or ATTR type), Sarcoidosis (non-caseating granulomas)
─ ─ ─ Storage Diseases: Hemochromatosis (iron deposition), Fabry disease (glycosphingolipid accumulation), Glycogen storage diseases
─ ─ ─ Endomyocardial Fibrosis: Tropical regions; dense fibrosis of endocardium and subendocardium, often involving AV valves and apices
─ ─ ─ Loeffler Endocarditis / Hypereosinophilic Syndrome: Endomyocardial fibrosis with prominent eosinophilic infiltrates and thrombus formation
─ ─ ─ Radiation-induced heart disease (can cause restrictive physiology due to fibrosis)
─ ─ ─ Idiopathic RCM
─ ─ Macro: Ventricles normal or mildly thickened, firm; atria often markedly dilated
─ ─ Micro: Varies with cause (e.g amyloid deposits – Congo red positive with apple-green birefringence; iron deposition – Prussian blue positive; endomyocardial fibrosis; granulomas in sarcoidosis); interstitial fibrosis is common
─ Arrhythmogenic Cardiomyopathy (ACM) / Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia (ARVC/D):
─ ─ Characterized by progressive fibrofatty replacement of the right ventricular (RV) myocardium, leading to RV dilatation, dysfunction, and life-threatening ventricular arrhythmias; can also involve LV (Arrhythmogenic Left Ventricular Cardiomyopathy or biventricular forms)
─ ─ Etiology: Primarily genetic, autosomal dominant (some recessive forms), mutations in genes encoding desmosomal proteins (e.g Plakoglobin (JUP), Plakophilin-2 (PKP2), Desmoplakin (DSP), Desmoglein-2 (DSG2), Desmocollin-2 (DSC2))
─ ─ Macro: RV dilatation, thinning of RV free wall, fatty infiltration, aneurysms; "triangle of dysplasia" (RV inflow, outflow, apex) often affected
─ ─ Micro: Transmural or patchy replacement of RV myocytes by mature adipose tissue and fibrous tissue; residual myocytes may show atrophy or hypertrophy; inflammatory infiltrates (lymphocytic) can be present, especially in areas of active myocyte injury
─ Left Ventricular Noncompaction Cardiomyopathy (LVNC):
─ ─ Congenital cardiomyopathy characterized by a thickened LV wall with prominent trabeculations and deep intertrabecular recesses, creating a "spongy" appearance; thought to be due to arrest of normal myocardial compaction during embryogenesis
─ ─ Associated with arrhythmias, heart failure, thromboembolism
─ ─ Micro: Prominent trabeculae lined by endothelium, continuous with ventricular cavity; deep recesses; may have associated fibrosis or EFE
─ Specific Cardiomyopathies (Secondary cardiomyopathies or those with distinct causes):
─ ─ Toxic Cardiomyopathy: e.g Doxorubicin (anthracycline) cardiotoxicity (myocyte vacuolization, myofibrillar loss); Cocaine (can cause MI, arrhythmias, myocarditis, chronic DCM)
─ ─ Metabolic Cardiomyopathy: e.g Hemochromatosis (iron in myocytes); Fabry disease (lysosomal globotriaosylceramide accumulation in myocytes, vascular endothelium)
─ ─ Tachycardia-induced Cardiomyopathy: Reversible LV dysfunction due to chronic rapid heart rates
─ ─ Stress-induced (Takotsubo) Cardiomyopathy: Transient LV apical (or other segments) ballooning and dysfunction, often precipitated by intense emotional or physical stress, mimicking MI but usually with normal coronary arteries; mechanism likely catecholamine surge
Ancillary studies ─ ─ Special Stains: Masson trichrome (fibrosis), Congo red (amyloid), Prussian blue (iron), PAS (glycogen)
─ IHC: For specific infiltrates or deposits if indicated (e.g CD68 for macrophages, TTR for transthyretin amyloid)
─ Electron Microscopy (EM): Historically used for some storage diseases or mitochondrial cardiomyopathies; can show myofibrillar disarray in HCM, specific inclusions in Fabry disease
─ Genetic Testing: Increasingly important for inherited cardiomyopathies (HCM, DCM, ARVC, LVNC, some RCMs)
DDx ─ (Often broad, overlaps between types or with other cardiac conditions)
─ Ischemic heart disease (can lead to dilated phenotype, "ischemic cardiomyopathy")
─ Hypertensive heart disease (can cause hypertrophy, fibrosis, diastolic dysfunction)
─ Valvular heart disease (can cause volume/pressure overload leading to hypertrophy/dilation)
─ Myocarditis (can be a precursor to DCM)
─ Pericardial disease (constrictive pericarditis can mimic RCM)
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Ischemic Heart Disease (IHD)

A group of related syndromes resulting from myocardial ischemia, an imbalance between myocardial oxygen supply and demand, most commonly due to atherosclerotic coronary artery disease (CAD)
Clinical ─ Leading cause of death globally; manifestations include angina pectoris (stable, unstable), myocardial infarction (MI), chronic IHD with heart failure, and sudden cardiac death (SCD)
Pathology of Myocardial Infarction (MI): Cell death (necrosis) of cardiac myocytes due to prolonged ischemia. Sequence of changes:
─ Acute MI (0-24 hours):
─ ─ 0-4 hrs: Minimal to no gross changes; microscopically, early features include wavy fibers, myocyte swelling, eosinophilia (may be subtle); electron microscopy shows mitochondrial swelling, glycogen depletion
─ ─ 4-12 hrs: Grossly, infarct may appear pale or mottled; microscopically, established coagulation necrosis (eosinophilic myocytes, pyknotic nuclei then karyolysis), edema, hemorrhage
─ ─ 12-24 hrs: Grossly, infarct is reddish-blue (stagnant blood) or more clearly demarcated pale/yellow area; microscopically, ongoing coagulation necrosis, marginal contraction band necrosis, beginning of neutrophil infiltration from periphery
─ Healing MI (Subacute, 1 day - weeks):
─ ─ 1-3 days: Grossly, infarct is yellow-tan, soft; microscopically, dense neutrophilic infiltrate, myocyte nuclei disappear, interstitial edema prominent
─ ─ 3-7 days: Grossly, infarct center is yellow and soft, with hyperemic (red) border; microscopically, disintegration of necrotic myocytes, phagocytosis by macrophages begins from periphery, early granulation tissue formation at edges
─ ─ 7-10 days: Grossly, infarct is depressed, yellow-tan, with soft center and firm reddish-purple margins; microscopically, prominent macrophage infiltration and phagocytosis, well-developed granulation tissue (capillaries, fibroblasts, myofibroblasts) at periphery, collagen deposition starts
─ ─ 10-14 days: Grossly, infarct margins are gray-white due to fibrosis; microscopically, established granulation tissue with ingrowth of new blood vessels and fibroblasts, progressive collagen deposition
─ Healed MI (Chronic, >2-8 weeks):
─ ─ Grossly, infarct is a dense, gray-white fibrous scar, often thinned and firm; ventricular remodeling (dilation, hypertrophy of non-infarcted areas) may occur
─ ─ Microscopically, dense collagenous scar replacing necrotic myocardium; remaining myocytes may be hypertrophied; chronic inflammation may be minimal
Complications of MI:
─ Arrhythmias (most common cause of death in early post-MI period)
─ Myocardial Rupture:
─ ─ Ventricular free wall rupture (3-7 days post-MI, leads to hemopericardium and cardiac tamponade, often fatal)
─ ─ Interventricular septal rupture (leads to VSD, acute right heart failure)
─ ─ Papillary muscle rupture (leads to acute severe mitral regurgitation)
─ Ventricular Aneurysm: Late complication; thinned scar tissue bulges paradoxically during systole; risk of mural thrombus, arrhythmias, heart failure (but rupture is rare once fully formed scar)
─ Mural Thrombus: Develops over damaged endocardium in infarct area (especially aneurysms or large akinetic segments); risk of systemic embolism
─ Pericarditis (Dressler Syndrome): Fibrinous or serofibrinous pericarditis, typically 1 day to several weeks post-MI (early form due to inflammation over infarct; late form Dressler's is autoimmune)
─ Progressive Heart Failure (Chronic IHD)
Chronic Ischemic Heart Disease:
─ Progressive heart failure due to ischemic myocardial damage, often in patients with prior MI(s) or severe multivessel CAD without discrete large infarcts
─ Macro: Enlarged heart (cardiomegaly), ventricular dilation, hypertrophy of remaining viable myocardium, discrete scars from prior infarcts, diffuse subendocardial fibrosis, coronary atherosclerosis
─ Micro: Myocyte hypertrophy, diffuse interstitial fibrosis, patchy replacement fibrosis (healed infarcts), vacuolization of subendocardial myocytes
Ancillary studies ─ ─ Special Stains: Triphenyltetrazolium chloride (TTC) stain on gross slices (colors viable myocardium red, infarct remains pale/unstained, useful in early hours); Masson trichrome (highlights fibrosis blue)
─ IHC: Can demonstrate early myocyte injury (e.g complement deposition, fibronectin) but not routine for MI diagnosis
DDx ─ ─ Myocarditis (inflammatory infiltrate as primary pathology, necrosis often patchy, not typically transmural in coronary distribution)
─ Cardiomyopathy (various types, different primary mechanisms of injury/hypertrophy/fibrosis)
─ Non-ischemic causes of chest pain or sudden death (e.g aortic dissection, pulmonary embolism)
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Hypertensive Heart Disease (Systemic, Pulmonary)

Cardiac pathology resulting from sustained elevation of blood pressure, leading to adaptive changes (hypertrophy) and eventual maladaptive remodeling and heart failure
Clinical ─ Systemic hypertension is very common, major risk factor for IHD, stroke, renal failure; Pulmonary hypertension can be primary or secondary to lung disease, left heart disease, or thromboembolism
Systemic Hypertensive Heart Disease:
─ Pathophysiology: Increased systemic arterial pressure imposes increased afterload on the left ventricle (LV), leading to compensatory concentric LV hypertrophy (LVH) to maintain wall stress and cardiac output
─ Macro: Thickened LV free wall and septum (often >1.5 cm, normal up to 1.2-1.3 cm), increased heart weight; LV chamber size may be normal or reduced initially, but can dilate in late stages (decompensated hypertensive heart disease leading to heart failure with preserved or reduced ejection fraction)
─ Micro: Cardiomyocyte hypertrophy (enlarged cells, "boxcar" nuclei); increased interstitial fibrosis (perivascular and interstitial); small intramyocardial arteries and arterioles may show medial hypertrophy, intimal thickening (arteriolosclerosis), and hyalinization
Pulmonary Hypertensive Heart Disease (Cor Pulmonale):
─ Pathophysiology: Increased pulmonary arterial pressure imposes increased afterload on the right ventricle (RV), leading to RV hypertrophy and/or dilatation
─ Acute Cor Pulmonale: RV dilatation without significant hypertrophy, typically due to massive pulmonary embolism
─ Chronic Cor Pulmonale: RV hypertrophy (wall thickness >0.5 cm, normal up to 0.3-0.4 cm), often with RV dilatation, secondary to chronic lung diseases (COPD, interstitial lung disease), primary pulmonary hypertension, recurrent pulmonary emboli, or left-sided heart disease causing pulmonary venous hypertension
─ Macro: RV wall thickening, trabecular prominence, dilatation of RV chamber; right atrium may also be dilated; main pulmonary artery may be dilated
─ Micro: RV cardiomyocyte hypertrophy; interstitial fibrosis in RV; changes in pulmonary arteries/arterioles reflecting cause of pulmonary hypertension (e.g medial hypertrophy, intimal fibrosis, plexiform lesions in some forms of PAH)
Ancillary studies ─ Measurements of wall thickness and heart weight at autopsy; microscopy to assess hypertrophy, fibrosis, and vascular changes
DDx ─ ─ For LVH: Aortic stenosis, hypertrophic cardiomyopathy (HCM has myofiber disarray, often asymmetric septal hypertrophy, genetic basis), athlete's heart (physiologic hypertrophy)
─ For RVH: Congenital heart disease (e.g pulmonic stenosis, atrial septal defect), arrhythmogenic cardiomyopathy (fibrofatty replacement of RV)
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Cardiac Amyloidosis (AL, ATTR - wild-type and hereditary, AA)

A form of restrictive cardiomyopathy caused by extracellular deposition of amyloid fibrils in the myocardium and other cardiac structures, leading to diastolic dysfunction, arrhythmias, and heart failure
Clinical ─ Symptoms include dyspnea, fatigue, edema, orthostatic hypotension, arrhythmias (atrial fibrillation common), conduction abnormalities; diagnosis suspected by echocardiography (thickened ventricles, biatrial enlargement, diastolic dysfunction, "sparkling" myocardium), cardiac MRI (diffuse late gadolinium enhancement), and confirmed by biopsy (endomyocardial, fat pad, or other involved organ) showing amyloid deposits, and typing of amyloid
Types and Pathogenesis:
─ AL (Light Chain) Amyloidosis:
─ ─ Most common systemic amyloidosis; due to deposition of monoclonal immunoglobulin light chains (lambda > kappa) produced by a clonal plasma cell dyscrasia (e.g multiple myeloma, MGUS)
─ ─ Rapidly progressive, often severe cardiac involvement, poor prognosis if untreated
─ ATTR (Transthyretin) Amyloidosis:
─ ─ Deposition of transthyretin (TTR), a protein produced by the liver
─ ─ ATTRwt (wild-type ATTR) / Senile Cardiac Amyloidosis: Affects older individuals (typically men >70-80 yrs) due to age-related misfolding of normal TTR; slowly progressive
─ ─ ATTRm (mutant/hereditary ATTR): Autosomal dominant; due to mutations in TTR gene, leading to unstable TTR prone to misfolding; variable age of onset and organ involvement (cardiac, neurologic) depending on mutation
─ AA (Reactive) Amyloidosis:
─ ─ Deposition of serum amyloid A (SAA) protein, an acute phase reactant; occurs in context of chronic inflammatory conditions (e.g rheumatoid arthritis, IBD, chronic infections)
─ ─ Cardiac involvement is less common and usually less severe than in AL or ATTR
Macro ─ Heart is often enlarged, firm, waxy, rubbery consistency; ventricular walls are typically thickened (concentrically), chambers may be normal sized or small (restrictive pattern); atria often dilated; endocardial surfaces may have a granular or ground-glass appearance; deposits can also occur in valves and pericardium
Micro ─ ─ Extracellular deposition of amorphous, eosinophilic, hyaline material (amyloid) in the interstitium, surrounding cardiomyocytes, around blood vessels, and in valvular/endocardial/pericardial tissue
─ Cardiomyocytes may be compressed, atrophied, or separated by amyloid deposits
─ Small intramyocardial arteries and arterioles often show amyloid in their walls
─ Minimal to no inflammatory infiltrate (unless related to underlying cause of AA amyloid)
Ancillary studies ─ ─ Special Stains: Congo Red stain shows characteristic apple-green birefringence under polarized light (pathognomonic for amyloid)
─ IHC / Immunofluorescence: Used for amyloid typing on tissue biopsies (crucial for guiding therapy)
─ ─ Antibodies against Kappa and Lambda light chains (for AL)
─ ─ Antibodies against Transthyretin (TTR) (for ATTR)
─ ─ Antibodies against Serum Amyloid A (SAA) (for AA)
─ Mass Spectrometry-based Proteomics: Considered gold standard for amyloid typing on tissue if IHC is equivocal
─ Scintigraphy (e.g Technetium pyrophosphate scan): Useful for non-invasively detecting ATTR cardiac amyloidosis (uptake in ATTR, not usually in AL)
DDx ─ ─ Other causes of restrictive cardiomyopathy (e.g endomyocardial fibrosis, sarcoidosis, storage diseases – specific histologic features and stains)
─ Hypertensive heart disease (LVH due to pressure, no amyloid deposits)
─ Hypertrophic cardiomyopathy (myofiber disarray, sarcomeric mutations, no amyloid)
─ Interstitial fibrosis (collagen deposition, Congo red negative)
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Cardiac Involvement in Systemic Diseases

The heart can be affected by a variety of systemic disorders, including metabolic diseases, storage diseases, inflammatory conditions, and neuromuscular disorders, leading to diverse cardiac manifestations
Clinical ─ Cardiac symptoms may be the presenting feature or develop during the course of the systemic illness; manifestations include cardiomyopathies (dilated, hypertrophic, restrictive), arrhythmias, valvular dysfunction, and heart failure
Examples of Systemic Diseases and Cardiac Manifestations:
─ Hemochromatosis:
─ ─ Autosomal recessive disorder of iron metabolism (HFE gene mutations) or secondary to iron overload (e.g multiple transfusions)
─ ─ Cardiac: Iron deposition (hemosiderin) in cardiomyocytes (especially ventricular) leading to dilated cardiomyopathy, restrictive physiology, arrhythmias, heart failure ("ferruginous heart")
─ ─ Micro: Golden-brown hemosiderin granules within sarcoplasm of cardiomyocytes (best seen with Prussian blue stain); myocyte hypertrophy, degeneration, interstitial fibrosis
─ Fabry Disease:
─ ─ X-linked lysosomal storage disease due to alpha-galactosidase A deficiency, leading to accumulation of globotriaosylceramide (Gb3)
─ ─ Cardiac: Progressive Gb3 accumulation in cardiomyocytes, valvular fibroblasts, conduction system cells, vascular endothelium/smooth muscle; leads to concentric LVH (mimicking HCM), valvular abnormalities, arrhythmias, heart failure, MI
─ ─ Micro: Cardiomyocytes appear vacuolated (glycosphingolipid accumulation, removed during processing); characteristic lamellar bodies (myelin figures, "zebra bodies") seen on electron microscopy; PAS stain may be positive; specific IHC for Gb3 possible
─ Glycogen Storage Diseases (GSDs):
─ ─ Group of genetic disorders affecting glycogen synthesis or breakdown; several types can involve heart
─ ─ Pompe Disease (GSD Type II, acid maltase/alpha-glucosidase deficiency): Accumulation of glycogen in lysosomes of all tissues, especially heart, skeletal muscle, liver; massive cardiomegaly in infantile form (mimicking HCM or RCM), heart failure
─ ─ Micro (Pompe): Cardiomyocytes markedly enlarged, cytoplasm filled with clear vacuoles of glycogen (PAS positive, diastase sensitive); minimal fibrosis initially
─ Mitochondrial Diseases:
─ ─ Genetically diverse group affecting mitochondrial structure/function (mtDNA or nuclear DNA mutations)
─ ─ Cardiac: Can cause hypertrophic or dilated cardiomyopathy, conduction defects, arrhythmias (e.g Kearns-Sayre syndrome, MELAS, MERRF)
─ ─ Micro: Variable; "ragged red fibers" (abnormal mitochondria accumulation, seen with Gomori trichrome stain) may be present but often less prominent than in skeletal muscle; myocyte vacuolization, fibrosis
─ Muscular Dystrophies:
─ ─ Inherited disorders characterized by progressive muscle weakness and degeneration
─ ─ Duchenne Muscular Dystrophy (DMD) & Becker Muscular Dystrophy (BMD) (X-linked, dystrophin deficiency/abnormality): Dilated cardiomyopathy is common, especially in DMD, often affecting posterobasal LV; fibrosis, myocyte atrophy/hypertrophy
─ ─ Myotonic Dystrophy (DM1, DM2) (autosomal dominant): Conduction abnormalities (heart block, arrhythmias) are very common; cardiomyopathy (dilated or hypertrophic) can occur; myofiber degeneration, fibrosis, fatty infiltration
Macro & Micro ─ Vary widely depending on specific disease (see descriptions above)
Ancillary studies ─ ─ Special Stains: Prussian blue (iron), PAS (glycogen), Congo red (amyloid if coexisting), Gomori trichrome (mitochondria)
─ IHC: For specific protein deficiencies (e.g dystrophin) or accumulated substances (e.g Gb3) if available
─ Electron Microscopy (EM): Can be diagnostic for some storage diseases (Fabry, some GSDs, mitochondrial abnormalities)
─ Genetic Testing: For definitive diagnosis of inherited systemic diseases
DDx ─ ─ Idiopathic or other forms of cardiomyopathy (DCM, HCM, RCM)
─ Ischemic heart disease
─ Myocarditis
─ Other causes of specific organ damage seen in these systemic diseases (e.g liver cirrhosis for hemochromatosis)
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Diseases of the Conduction System

Pathologic abnormalities affecting the specialized cardiac tissues responsible for initiation and propagation of electrical impulses (SA node, AV node, His-Purkinje system), leading to arrhythmias, heart block, or sudden cardiac death
Clinical ─ Symptoms include palpitations, syncope, dizziness, bradycardia, tachycardia, heart block (first, second, or third degree), bundle branch blocks, sudden cardiac death; diagnosis often relies on ECG, Holter monitoring, electrophysiology studies
Pathology: (Often subtle or requires specialized examination of conduction system, which is not routinely done in standard autopsy unless specifically indicated)
─ Common Pathologic Processes:
─ ─ Fibrosis: Progressive age-related fibrosis (sclerosis) of the conduction system is a common cause of heart block in the elderly (e.g Lenègre-Lev disease – idiopathic fibrosis affecting distal conduction system)
─ ─ Ischemia/Infarction: Can damage SA node (often RCA supplied), AV node (often RCA supplied), or bundle branches (often LAD supplied for LBB, RCA for RBB)
─ ─ Inflammation (Myocarditis): Viral, Lyme carditis, sarcoidosis, Chagas disease can directly involve conduction tissues
─ ─ Infiltrative Diseases: Amyloidosis, hemochromatosis, sarcoidosis, tumors (primary or metastatic) can infiltrate/damage conduction system
─ ─ Degenerative Changes: Fatty infiltration, calcification (e.g calcification of aortic valve extending into conduction system)
─ ─ Trauma/Iatrogenic: Surgical injury (e.g valve replacement, septal myectomy), catheter ablation complications
─ ─ Genetic/Congenital Abnormalities: Channelopathies (e.g Long QT syndrome, Brugada syndrome – structurally normal heart but ion channel dysfunction), congenital heart block (e.g associated with maternal SLE), accessory pathways (e.g Wolff-Parkinson-White syndrome – bundle of Kent)
Macro ─ Heart may appear normal or show underlying cardiac disease (e.g IHD, cardiomyopathy, valvular disease); gross lesions directly involving conduction system are rare unless large tumor or infarct
Micro ─ (Requires meticulous dissection and sampling of conduction system for detailed histology)
─ SA Node: Atrophy of nodal cells, fibrosis, fatty infiltration, amyloid deposition, inflammation
─ AV Node/His Bundle/Bundle Branches: Fibrosis, fatty infiltration, calcification, inflammation, necrosis, amyloid, granulomas (sarcoid), tumor infiltration, developmental abnormalities (e.g Mahaim fibers, AV nodal disarray)
─ Purkinje Fibers: Degeneration, fibrosis
Ancillary studies ─ ─ Special Stains: Masson trichrome (fibrosis), Congo red (amyloid), Prussian blue (iron)
─ IHC: To characterize infiltrates or identify specific cell types if needed (e.g inflammatory markers, tumor markers)
─ Genetic testing for channelopathies or inherited arrhythmia syndromes if suspected
DDx ─ ─ Primary cause of underlying heart disease (e.g if conduction defect is secondary to MI or cardiomyopathy)
─ Specific infiltrative or inflammatory diseases identified by their characteristic histology
─ Normal age-related changes (mild fibrosis/fatty change can be seen, distinction from pathologic levels can be difficult)
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Non-Neoplastic Pericardial Diseases

Pericarditis

Inflammation of the pericardium, which can be acute, subacute, or chronic, and caused by a wide variety of infectious and non-infectious etiologies
Clinical ─ Acute pericarditis often presents with sharp, pleuritic chest pain (relieved by sitting up/leaning forward, worsened by lying down/inspiration), pericardial friction rub, diffuse ST segment elevation on ECG; chronic pericarditis can lead to pericardial effusion, constrictive pericarditis, or be asymptomatic; causes include viral infections (most common idiopathic/viral), bacterial/fungal/parasitic infections, uremia, autoimmune diseases (SLE, rheumatoid arthritis), post-myocardial infarction (Dressler syndrome), trauma, cardiac surgery, radiation, malignancy
Types and Microscopic Features:
─ Acute Pericarditis:
─ ─ Serous Pericarditis:
─ ─ ─ Thin, watery or straw-colored exudate (serous fluid, few cells) in pericardial sac
─ ─ ─ Mild inflammatory infiltrate in epicardium/pericardium (lymphocytes, macrophages)
─ ─ ─ Causes: Non-infectious inflammatory diseases (rheumatic fever, SLE, scleroderma), viral infections, uremia (early)
─ ─ Fibrinous and Serofibrinous Pericarditis:
─ ─ ─ Most common type of acute pericarditis
─ ─ ─ Pericardial surfaces are erythematous, granular, coated with a shaggy or "bread-and-butter" fibrinous exudate (fibrin mixed with plasma proteins, inflammatory cells)
─ ─ ─ Micro: Eosinophilic meshwork of fibrin, neutrophils, lymphocytes, macrophages on pericardial surfaces; underlying pericardium shows vascular congestion and inflammation
─ ─ ─ Causes: Uremia (most common cause of fibrinous), acute MI (Dressler syndrome, early pericarditis over infarct), post-cardiac surgery (postcardiotomy syndrome), radiation, rheumatic fever, SLE, trauma, viral/bacterial infections
─ ─ Suppurative (Purulent) Pericarditis:
─ ─ ─ Gross pus (thick, creamy exudate of neutrophils, necrotic debris, bacteria) in pericardial sac
─ ─ ─ Micro: Intense neutrophilic infiltrate, fibrin, necrotic debris, microorganisms often visible (bacteria, fungi)
─ ─ ─ Causes: Bacterial infection (Staph, Strep, Pneumococcus via direct extension, hematogenous spread, or penetrating injury), fungal, parasitic; serious, can lead to constrictive pericarditis if not drained/treated
─ ─ Hemorrhagic Pericarditis:
─ ─ ─ Bloody or blood-tinged pericardial exudate
─ ─ ─ Causes: Malignancy (primary or metastatic to pericardium), tuberculosis, bleeding diatheses, trauma, post-cardiac surgery, uremia
─ ─ Caseous Pericarditis:
─ ─ ─ Uncommon, usually due to tuberculosis; caseous (cheesy, necrotic) material in pericardium
─ ─ ─ Micro: Granulomatous inflammation with central caseous necrosis, Langhans giant cells, epithelioid histiocytes, lymphocytes; AFB stain may show bacilli
─ Chronic Pericarditis:
─ ─ Long-standing inflammation leading to pericardial thickening, fibrosis, and adhesions
─ ─ Adhesive Mediastinopericarditis: Pericardial sac obliterated by fibrous adhesions, heart may be adherent to sternum, pleura, diaphragm, impairing cardiac motion
─ ─ Constrictive Pericarditis:
─ ─ ─ Dense, rigid, thickened (often calcified – "concretio cordis") fibrous pericardium encases the heart, severely restricting diastolic filling
─ ─ ─ Micro: Dense hyalinized collagen, chronic inflammation (lymphocytes, plasma cells), dystrophic calcification; may follow suppurative, tuberculous, hemorrhagic pericarditis, cardiac surgery, radiation, or be idiopathic
Macro ─ Variable: "Bread-and-butter" appearance (fibrinous), pus (suppurative), thickened/calcified pericardium (constrictive)
Ancillary studies ─ Pericardial fluid analysis (cell count, chemistry, cytology, microbiology); special stains for organisms (Gram, AFB, GMS) on tissue; viral PCR/serology if suspected
DDx ─ Myocardial infarction (chest pain, ECG changes, but different pain character, troponin elevation more specific for myocyte necrosis)
─ Other causes of chest pain (pulmonary embolism, aortic dissection, pleuritis)
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Pericardial Effusion and Cardiac Tamponade

Abnormal accumulation of fluid in the pericardial sac (Pericardial Effusion), which, if significant or rapid, can impair diastolic filling of the heart and lead to life-threatening Cardiac Tamponade
Clinical ─ Small effusions may be asymptomatic; larger or rapidly accumulating effusions cause dyspnea, chest pain/pressure, tachycardia; Cardiac Tamponade presents with Beck's triad (hypotension, muffled heart sounds, jugular venous distension), pulsus paradoxus, and cardiogenic shock; diagnosis by echocardiography, pericardiocentesis for diagnosis and therapy
Types of Pericardial Fluid:
─ Serous Effusion (Transudate or Exudate):
─ ─ Clear, straw-colored fluid
─ ─ Transudate: Due to increased hydrostatic pressure or decreased oncotic pressure (e.g congestive heart failure, nephrotic syndrome, cirrhosis, hypoalbuminemia)
─ ─ Exudate: Due to inflammation or impaired lymphatic drainage (e.g pericarditis – viral, autoimmune; hypothyroidism, radiation)
─ Hemorrhagic Effusion (Hemopericardium):
─ ─ Bloody fluid; indicates bleeding into pericardial sac
─ ─ Causes: Trauma (blunt or penetrating), iatrogenic (cardiac surgery, catheter procedures), aortic dissection rupturing into pericardium, myocardial rupture post-MI, malignancy, tuberculosis, bleeding diathesis, anticoagulant therapy
─ Chylous Effusion (Chylopericardium):
─ ─ Milky white fluid rich in triglycerides and chylomicrons
─ ─ Due to obstruction or damage to thoracic duct or other major lymphatic channels (e.g malignancy, surgery, trauma, congenital lymphatic anomalies)
─ Cholesterol Effusion ("Gold Paint" Pericarditis – see separate entry for this specific chronic form)
─ Pyopericardium (Purulent Effusion): Pus; due to bacterial, fungal infection (suppurative pericarditis)
Cardiac Tamponade:
─ Pathophysiology: Increased intrapericardial pressure exceeds ventricular diastolic pressures, impairing venous return and ventricular filling, leading to decreased stroke volume and cardiac output
─ Amount of fluid and rate of accumulation determine severity; rapid accumulation of small amounts (e.g 150-200 mL) can cause tamponade, while slow accumulation of larger amounts (>1 L) may be tolerated better due to pericardial stretching
Macro ─ Distended pericardial sac filled with fluid of varying character
Micro ─ (Of pericardial fluid cytology or pericardial biopsy)
─ Fluid cytology: Can identify inflammatory cells (neutrophils, lymphocytes, eosinophils), mesothelial cells (reactive or malignant), malignant cells (metastatic carcinoma, lymphoma), or microorganisms
─ Pericardial biopsy: Shows features of underlying cause (e.g inflammation, infection, malignancy, fibrosis)
Ancillary studies ─ Pericardial fluid analysis: Cell count, differential, protein, LDH, glucose, triglycerides, cholesterol, cytology, Gram stain, cultures (bacterial, fungal, AFB), PCR for viruses/TB
DDx ─ (Clinical DDx for chest pain/dyspnea)
─ Myocardial infarction, pulmonary embolism, aortic dissection, constrictive pericarditis (can follow effusion or occur de novo, causes diastolic dysfunction but different mechanism than tamponade)
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Cholesterol Pericarditis ("Gold Paint" Pericarditis)

A rare form of chronic pericardial effusion characterized by the presence of abundant cholesterol crystals in the pericardial fluid, giving it a shimmering, golden-brown ("gold paint") appearance
Clinical ─ Typically develops in the setting of long-standing, slow-accumulating pericardial effusions where cholesterol from degenerating cells (e.g red blood cells, inflammatory cells) precipitates out; often associated with hypothyroidism (myxedema), rheumatoid arthritis, tuberculosis, idiopathic chronic effusions, or prior hemopericardium; usually asymptomatic or mild symptoms unless effusion becomes very large or causes tamponade/constriction
Macro ─ Pericardial sac contains thick, often turbid, golden-brown or yellowish fluid with a shimmering or iridescent quality due to suspended cholesterol crystals; pericardium may be thickened and fibrotic
Micro ─ ─ Pericardial fluid: Numerous cholesterol crystals (rhomboid, plate-like, often with notched corners), foamy macrophages (lipid-laden), chronic inflammatory cells (lymphocytes, plasma cells), red blood cell breakdown products (hemosiderin)
─ Pericardial biopsy: Thickened, fibrotic pericardium with chronic inflammation, cholesterol clefts (empty spaces where crystals were dissolved during processing), foreign body giant cell reaction to cholesterol crystals, hemosiderin deposition, and granulation tissue
Ancillary studies ─ ─ Pericardial fluid analysis: High cholesterol content (often >200-250 mg/dL, much higher than serum); cytology shows cholesterol crystals and inflammatory cells
─ Thyroid function tests (to exclude hypothyroidism)
DDx ─ ─ Other types of chronic pericardial effusion (e.g tuberculous, uremic, malignant – fluid has different characteristics and cytology)
─ Chylous effusion (milky white, high triglycerides, chylomicrons, but not typically cholesterol crystals as the primary feature)
─ Pseudochylous effusion (can also have high cholesterol and milky appearance, but "gold paint" and abundant crystals are more specific for cholesterol pericarditis; distinction can be semantic, both related to chronic effusions)
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Non-Neoplastic Valvular Heart Disease (Brief Overview)

Degenerative Valve Disease

A group of common valvular abnormalities primarily caused by age-related wear and tear, mechanical stress, or intrinsic connective tissue defects, leading to stenosis or regurgitation; includes Calcific Aortic Stenosis, Mitral Annular Calcification, and Mitral Valve Prolapse
Clinical ─ Manifestations depend on valve(s) affected and severity: dyspnea, fatigue, chest pain, syncope, arrhythmias, heart failure; diagnosis by auscultation (murmurs), echocardiography
Types and Pathologic Features:
─ Calcific Aortic Stenosis (Senile type):
─ ─ Most common valvular abnormality; age-related (typically >65-70 yrs), progressive calcification and stiffening of a previously normal (tricuspid) or congenitally bicuspid aortic valve, leading to obstruction of left ventricular outflow
─ ─ Pathogenesis: Chronic mechanical stress, endothelial dysfunction, lipid accumulation, inflammation, active fibrocalcific process (similar to atherosclerosis, involving osteoblast-like cells)
─ ─ Macro: Irregular, heaped-up calcific masses within the aortic valve cusps (primarily at bases, on aortic side), restricting cusp mobility; commissural fusion is usually absent (unlike rheumatic aortic stenosis)
─ ─ Micro: Dystrophic calcification, fibrosis, chronic inflammation (lymphocytes, macrophages), ossification may occur; underlying cusp architecture may be disrupted
─ Mitral Annular Calcification (MAC):
─ ─ Age-related (common in elderly, especially women >60 yrs, and those with hypertension, diabetes, chronic kidney disease) deposition of calcium in the fibrous annulus (ring) of the mitral valve, typically at the base of the posterior leaflet
─ ─ Usually asymptomatic and of little hemodynamic consequence, but can: impair mitral valve function (stenosis or regurgitation if severe), predispose to infective endocarditis, be a source of emboli, or interfere with prosthetic valve implantation; can extend into myocardium causing conduction defects
─ ─ Macro: Hard, irregular, stony nodules or ring of calcium in mitral annulus
─ ─ Micro: Dystrophic calcification, hyalinization, chronic inflammation in the fibrous tissue of the annulus
─ Mitral Valve Prolapse (MVP) / Myxomatous Degeneration of Mitral Valve:
─ ─ Common condition (2-3% of population, F>M), characterized by bulging (prolapse) of one or both mitral valve leaflets (typically posterior or both) into the left atrium during systole; may lead to mitral regurgitation, arrhythmias, infective endocarditis, rarely sudden death
─ ─ Etiology: Often idiopathic or familial (autosomal dominant with variable penetrance, associated with connective tissue disorders like Marfan syndrome, Ehlers-Danlos); can be secondary to other conditions
─ ─ Macro: Enlarged, thickened, redundant, "floppy" mitral valve leaflets and chordae tendineae; leaflets may be hooded or interchordal scalloping exaggerated; chordae are elongated, thinned, or may rupture; annulus may be dilated
─ ─ Micro: Pathognomonic feature is myxomatous (mucoid) degeneration of the spongiosa layer of the valve leaflet, with marked thickening due to deposition of acid mucopolysaccharides (glycosaminoglycans); attenuation or disruption of the fibrosa layer; collagen disarray; secondary changes include fibrosis, calcification, thrombi on atrial surface
Ancillary studies ─ Echocardiography is key for diagnosis and assessing severity. Pathologic examination of excised valves confirms diagnosis.
DDx ─ ─ For Aortic Stenosis: Rheumatic aortic stenosis (commissural fusion, often involves mitral valve too), congenital bicuspid aortic valve (prone to earlier calcification)
─ For Mitral Regurgitation: Rheumatic heart disease, infective endocarditis, ischemic papillary muscle dysfunction, dilated cardiomyopathy causing annular dilatation
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Rheumatic Heart Disease (Acute Rheumatic Fever, Chronic RHD)

A systemic inflammatory disease, primarily affecting children (5-15 yrs), that occurs as a delayed, non-suppurative sequela of group A streptococcal (GAS) pharyngitis, leading to pancarditis (myocarditis, pericarditis, endocarditis/valvulitis) in the acute phase and potentially progressive, deforming fibrotic valvular disease (especially mitral stenosis) in the chronic phase
Clinical ─ Acute Rheumatic Fever (ARF): Diagnosed by Jones criteria (migratory polyarthritis, carditis, subcutaneous nodules, erythema marginatum, Sydenham chorea) following GAS infection; recurrent episodes common without antibiotic prophylaxis. Chronic RHD: Develops years to decades after ARF, primarily manifesting as valvular stenosis and/or regurgitation. Incidence has declined in developed countries but remains significant in developing nations.
Pathology:
─ Acute Rheumatic Fever (ARF) Carditis:
─ ─ Pancarditis (inflammation of all three heart layers)
─ ─ Myocarditis: Aschoff bodies are pathognomonic; focal interstitial inflammatory lesions composed of a central area of fibrinoid necrosis surrounded by lymphocytes (mainly T-cells), plasma cells, and characteristic Anitschkow cells (plump macrophages with vesicular nuclei and distinctive wavy, caterpillar-like chromatin bar) and Aschoff giant cells (multinucleated Anitschkow cells). Aschoff bodies are found in interstitium, often perivascular.
─ ─ Pericarditis: Fibrinous or serofibrinous ("bread-and-butter") pericarditis
─ ─ Endocarditis/Valvulitis: Inflammation of valve leaflets (especially mitral and aortic) with edema, fibrinoid necrosis, and small, warty, sterile vegetations (verrucae) composed of fibrin and platelets along lines of valve closure; chordae tendineae may also be involved (thickening, fusion)
─ Chronic Rheumatic Heart Disease (Chronic RHD):
─ ─ Primarily affects valves, leading to progressive fibrosis, thickening, calcification, and distortion
─ ─ Mitral Valve: Most commonly affected (often with aortic valve); characteristic "fish-mouth" or "buttonhole" stenosis due to commissural fusion, leaflet thickening/retraction, chordae tendineae thickening, fusion, and shortening; mitral regurgitation can also occur
─ ─ Aortic Valve: Leaflet thickening, commissural fusion (leading to stenosis), cusp retraction (leading to regurgitation)
─ ─ Tricuspid and Pulmonic Valves: Less commonly and usually less severely affected, typically in conjunction with left-sided valve disease
─ ─ Micro (Chronic): Fibrous thickening and neovascularization of valve leaflets, hyalinization, dystrophic calcification; Aschoff bodies are rare in chronic stage (may see old, hyalinized scars); MacCallum plaques (irregular thickenings in LA endocardium due to regurgitant jet)
Macro ─ ARF: Small vegetations on valves, fibrinous pericarditis. Chronic RHD: Thickened, calcified, stenotic/regurgitant valves (e.g "fish-mouth" mitral valve)
Ancillary studies ─ ─ ARF: Elevated anti-streptolysin O (ASO) titers, throat culture for GAS (often negative by time ARF develops)
─ Histology: H&E for Aschoff bodies, Anitschkow cells, valvular changes. Elastic/Trichrome stains for fibrosis/valve structure.
DDx ─ ─ For Acute Valvulitis: Infective endocarditis (larger, destructive vegetations with bacteria), Nonbacterial thrombotic endocarditis (NBTE - bland vegetations, no inflammation), Libman-Sacks endocarditis (in SLE, vegetations on both sides of leaflets)
─ For Chronic Valvular Disease: Degenerative calcific aortic stenosis (no commissural fusion usually), mitral valve prolapse (myxomatous change), congenital valvular anomalies
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Infective Endocarditis (Native and Prosthetic Valve)

A microbial infection of the heart valves or mural endocardium, leading to formation of vegetations (thrombus, microorganisms, inflammatory cells) and often associated with valvular destruction and systemic complications
Clinical ─ Highly variable presentation: fever, chills, fatigue, new or changed heart murmur, embolic phenomena (stroke, splenic/renal infarcts), Janeway lesions (painless erythematous macules on palms/soles), Osler nodes (painful nodules on fingers/toes), Roth spots (retinal hemorrhages); diagnosis aided by blood cultures, echocardiography (vegetations, valvular dysfunction), Duke criteria; predisposing factors include pre-existing valvular disease (RHD, MVP, bicuspid aortic valve), prosthetic valves, intravenous drug use (IVDU often right-sided, esp. tricuspid), immunosuppression, dental procedures
Types and Causative Organisms:
─ Acute Infective Endocarditis:
─ ─ Rapid onset, high fever, fulminant course, often involves a previously normal valve, caused by highly virulent organisms (e.g Staphylococcus aureus – most common overall and in IVDU; Streptococcus pneumoniae, Streptococcus pyogenes, Neisseria gonorrhoeae)
─ ─ Can cause rapid valve destruction, abscess formation, early embolization
─ Subacute Infective Endocarditis:
─ ─ Insidious onset, low-grade fever, slower course, typically involves a previously damaged valve, caused by less virulent organisms (e.g Viridans group streptococci – common after dental procedures; Enterococcus faecalis; HACEK group organisms – Haemophilus, Aggregatibacter, Cardiobacterium, Eikenella, Kingella)
─ Prosthetic Valve Endocarditis (PVE):
─ ─ Early PVE (<2 months post-op): Often due to Staphylococci (coagulase-negative like S. epidermidis, or S. aureus), gram-negative bacilli, fungi (Candida) – often nosocomial
─ ─ Late PVE (>2 months post-op): Similar organisms to native valve endocarditis (Streptococci, S. aureus, Enterococci)
─ Culture-Negative Endocarditis: Due to prior antibiotic therapy, or fastidious organisms (e.g Coxiella burnetii, Bartonella, Brucella, Tropheryma whipplei, fungi)
Macro ─ ─ Vegetations: Friable, bulky, often destructive lesions on valve cusps/leaflets (typically atrial surface of AV valves, ventricular surface of semilunar valves), chordae tendineae, or mural endocardium; variable size (mm to cm); may be single or multiple; color varies (gray, tan, reddish)
─ Valvular destruction: Erosion, ulceration, perforation of leaflets/cusps, rupture of chordae tendineae or papillary muscles
─ Ring abscess: Extension of infection into perivalvular tissue (annulus, adjacent myocardium), common with S. aureus and prosthetic valves
Micro ─ ─ Vegetations: Composed of fibrin, platelets, numerous microorganisms (bacteria often visible as basophilic colonies, fungi as yeasts/hyphae), acute and chronic inflammatory cells (neutrophils, macrophages, lymphocytes, plasma cells), and granulation tissue at the base
─ Underlying valve: Shows inflammation, edema, destruction of valve tissue (collagen, elastin), neovascularization; calcification may be present in chronically damaged valves
─ Myocardial abscesses or septic emboli in coronary arteries can occur
Complications:
─ Cardiac: Valvular stenosis or regurgitation, heart failure, ring abscess, myocardial abscess, purulent pericarditis, conduction abnormalities
─ Embolic: Systemic emboli (brain – stroke, spleen, kidney, extremities) from left-sided endocarditis; pulmonary emboli from right-sided endocarditis
─ Immunologic: Glomerulonephritis (immune complex deposition), vasculitis
─ Metastatic infection: Abscesses in distant organs
Ancillary studies ─ ─ Gram stain, GMS stain, PAS stain on vegetations to identify microorganisms
─ Blood cultures (before antibiotics if possible)
─ PCR for specific organisms on valve tissue if culture-negative
DDx ─ ─ Nonbacterial Thrombotic Endocarditis (NBTE) / Marantic Endocarditis (sterile, bland fibrin-platelet vegetations, minimal inflammation, no organisms)
─ Libman-Sacks Endocarditis (in SLE; sterile vegetations, often on both sides of leaflets, associated with fibrinoid necrosis and hematoxylin bodies)
─ Rheumatic valvulitis (acute phase has small, warty verrucae, Aschoff bodies)
─ Mitral valve prolapse with superimposed thrombus (myxomatous valve)
─ Papillary fibroelastoma (benign tumor, can mimic vegetation on echo)
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Libman-Sacks Endocarditis (in SLE)

A form of sterile, non-infective endocarditis characterized by small to medium-sized warty vegetations, typically occurring on either or both surfaces of heart valves (especially mitral and aortic), and also on chordae tendineae or mural endocardium, in patients with Systemic Lupus Erythematosus (SLE)
Clinical ─ Occurs in ~10-50% of SLE patients, though often clinically silent; may be associated with valvular regurgitation or, rarely, stenosis or embolism; can coexist with other cardiac manifestations of SLE (pericarditis, myocarditis, coronary artery disease); associated with antiphospholipid antibodies
Macro ─ Small (1-4 mm) to medium-sized, single or multiple, granular, pink or tan, warty (verrucous) vegetations; can occur on atrial or ventricular surfaces of AV valves, or aortic/pulmonary surfaces of semilunar valves, also on valve pockets, chordae, or mural endocardium; lesions may be friable
Micro ─ ─ Vegetations are composed of finely granular, eosinophilic material (fibrinoid necrosis, fibrin, immune complexes, platelet thrombi) admixed with mononuclear inflammatory cells (lymphocytes, histiocytes, plasma cells)
─ Hematoxylin bodies (DNA-anti-DNA immune complexes appearing as amorphous, smudgy, hematoxyphilic aggregates, pathognomonic for SLE) may be present within vegetations or inflamed valve tissue, but are often difficult to find
─ Underlying valve tissue often shows fibrinoid necrosis, inflammation, fibrosis, and neovascularization; valvulitis can lead to scarring and deformity with chronic or recurrent episodes
Ancillary studies ─ ─ IHC: Can demonstrate immunoglobulins (IgG, IgM, IgA) and complement components (C3, C1q) within vegetations, consistent with immune complex deposition
─ Special Stains: Feulgen stain can highlight DNA in hematoxylin bodies
DDx ─ ─ Infective endocarditis (larger, more destructive vegetations with microorganisms and prominent neutrophils)
─ Nonbacterial Thrombotic Endocarditis (NBTE) / Marantic Endocarditis (bland fibrin-platelet vegetations, minimal inflammation, no hematoxylin bodies, often on lines of closure)
─ Acute Rheumatic Valvulitis (small verrucae along lines of closure, Aschoff bodies in myocardium/pericardium)
─ Mitral valve prolapse (myxomatous degeneration of valve)
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Carcinoid Heart Disease (Plaques on right-sided valves)

A cardiac manifestation of metastatic carcinoid tumors (neuroendocrine tumors, typically from GI tract or lung that have metastasized to liver), characterized by deposition of fibrous plaques on the endocardium, predominantly affecting right-sided heart valves (tricuspid and pulmonic) and chambers
Clinical ─ Occurs in ~20-50% of patients with carcinoid syndrome (flushing, diarrhea, bronchospasm due to vasoactive substances like serotonin, bradykinin, histamine released by tumor, which are not inactivated by liver due to hepatic metastases); leads to tricuspid regurgitation and/or stenosis, and pulmonic stenosis and/or regurgitation, eventually right heart failure; left-sided valves usually spared unless right-to-left shunt or primary lung carcinoid
Macro ─ ─ Distinctive, firm, pearly white, fibrous plaques deposited on endocardial surfaces of:
─ ─ Tricuspid valve leaflets (typically on ventricular aspect, causing thickening, fusion, retraction, leading to regurgitation and/or stenosis)
─ ─ Pulmonic valve cusps (typically on arterial aspect, causing thickening, fusion, stenosis and/or regurgitation)
─ ─ Right atrial and right ventricular endocardium, chordae tendineae, pulmonary artery intima
─ Valves themselves are intrinsically normal (plaques are "stuck on")
Macro ─ Valves themselves are intrinsically normal (plaques are "stuck on")
Micro ─ ─ Plaques are composed of bland, spindle-shaped smooth muscle cells and myofibroblasts embedded in an abundant, dense collagenous and myxoid stroma, with sparse elastic fibers
─ No significant inflammation or foreign body reaction
─ Plaques are located on the endocardial surface, without destroying the underlying valve architecture (though function is impaired)
─ No tumor cells are present within the cardiac plaques
Ancillary studies ─ ─ Special Stains: Masson trichrome (highlights collagen in blue), Alcian blue (highlights myxoid stroma)
─ IHC: Smooth muscle actin (SMA) positive in spindle cells
DDx ─ ─ Rheumatic heart disease (affects primarily left-sided valves, characteristic Aschoff bodies in acute phase, different valvular deformity)
─ Other causes of valvular fibrosis or endocardial thickening (e.g ergot alkaloid-induced valvulopathy, endomyocardial fibrosis – different distribution and histology)
─ Myxomatous degeneration (mitral valve prolapse – affects valve leaflets themselves with myxoid change in spongiosa)
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Pathology of Prosthetic Heart Valves (Bioprosthetic, Mechanical)

Complications and pathologic changes associated with surgically implanted artificial heart valves, which can be bioprosthetic (tissue-based) or mechanical (made of pyrolytic carbon, metal, polymers)
Clinical ─ Prosthetic valves improve hemodynamics and survival but are prone to complications: structural valve deterioration (SVD), thrombosis, embolism, pannus formation, endocarditis, paravalvular leak, hemolysis; require lifelong monitoring and often anticoagulation (especially mechanical valves)
Pathology:
─ Bioprosthetic Valves (e.g porcine aortic, bovine pericardial, homografts):
─ ─ Structural Valve Deterioration (SVD):
─ ─ ─ Calcification: Most common cause of late failure; dystrophic calcification of cusps leads to stiffening, stenosis, or regurgitation
─ ─ ─ Tears/Perforations: Due to mechanical stress, cusp fatigue, calcification, or infection
─ ─ ─ Cusp thickening and fibrosis (non-calcific)
─ ─ ─ Stent creep or frame fracture (less common)
─ ─ Thrombosis: Formation of blood clot on valve components, can cause obstruction or embolism; less common than with mechanical valves if anticoagulation is appropriate for underlying conditions
─ ─ Endocarditis (Prosthetic Valve Endocarditis - PVE): Microbial infection of valve components, often leading to vegetations, dehiscence, ring abscess; can be early or late (see Infective Endocarditis)
─ ─ Pannus Formation: Ingrowth of host fibrous tissue onto valve sewing ring or cusps, can cause stenosis or regurgitation; smooth, white, firm tissue
─ Mechanical Valves (e.g bileaflet tilting disc, caged-ball, single tilting disc):
─ ─ Thrombosis: Major complication, especially with subtherapeutic anticoagulation; thrombus can obstruct valve motion (stenosis) or embolize
─ ─ Thromboembolism: Embolization of thrombus material to systemic circulation (stroke, peripheral embolism)
─ ─ Pannus Formation: Similar to bioprosthetic valves, host fibrous tissue ingrowth can impede occluder motion
─ ─ Structural Failure: Rare with modern valves; occluder escape, strut fracture, disc wear/fracture
─ ─ Hemolysis: Mechanical trauma to red blood cells, can lead to anemia, especially with paravalvular leak or older valve designs
─ ─ Endocarditis (PVE): Infection can affect sewing ring, occluder, or lead to perivalvular abscess
─ Common Complications for Both Types:
─ ─ Paravalvular Leak: Suture dehiscence or incomplete sealing at sewing ring, leading to regurgitation around the prosthesis; can predispose to hemolysis and endocarditis
─ ─ Disproportion (Patient-Prosthesis Mismatch): Effective prosthetic valve area is too small for patient's body surface area, leading to high transvalvular gradients despite normal valve function
Macro ─ Examination of explanted valves: assess occluder mobility, presence of thrombus, vegetations, pannus, calcification, tears, wear, suture integrity
Micro ─ (Of valve components and associated tissues)
─ Bioprosthetic: Cusp calcification, fibrosis, collagen degeneration, tears, inflammatory infiltrates (in endocarditis or immune reactions), thrombus, pannus (fibroblasts, collagen, chronic inflammation)
─ Mechanical: Thrombus (fibrin, platelets, RBCs), pannus, inflammatory cells in endocarditis
Ancillary studies ─ Radiography of explanted valve (for calcification, metallic components); microbiology of vegetations/thrombi if infection suspected
DDx ─ Based on type of valve and specific findings
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Cardiac Tumors and Tumor-like Lesions

Cardiac Myxoma

The most common primary tumor of the heart in adults, a benign neoplasm of putative multipotent mesenchymal (endocardial-derived) cells, typically arising in the atria (left > right) from the interatrial septum near the fossa ovalis
Clinical ─ Can occur at any age, peak 30-60 years, slight female predominance for sporadic cases; symptoms depend on size, location, mobility: constitutional (fever, weight loss, arthralgia – "tumor plop" on auscultation if pedunculated and mobile, mimicking mitral stenosis); embolic (fragments to systemic or pulmonary circulation – stroke, peripheral emboli); or intracardiac obstruction (mimicking valvular stenosis or causing heart failure); ~10% associated with Carney complex (autosomal dominant: myxomas, spotty skin pigmentation, endocrine overactivity, schwannomas)
Macro ─ Typically a solitary, pedunculated (attached by a stalk) or sessile, gelatinous, glistening, often friable mass; variable size (1-15 cm or more); color ranges from pale gray-white to yellow, tan, or hemorrhagic (red-brown); surface can be smooth, lobulated, or papillary/villous; may show areas of hemorrhage, necrosis, or calcification
Micro ─ ─ Myxoma cells (lepidic cells): Characteristic neoplastic cells, stellate, spindle-shaped, polygonal, or globular, with scant to moderate eosinophilic cytoplasm and indistinct cell borders; often arranged singly, in small clusters, cords, or forming syncytial rings around small blood vessels (perivascular cuffing) within an abundant myxoid stroma
─ Stroma: Rich in acid mucopolysaccharides (glycosaminoglycans), appears loose, basophilic, or myxoid; contains delicate capillaries and variable amounts of collagen and elastic fibers
─ Other features:
─ ─ Hemorrhage (fresh and old, with hemosiderin-laden macrophages – "Gamna-Gandy bodies" or siderotic nodules can form)
─ ─ Inflammation (lymphocytes, plasma cells, histiocytes) can be present
─ ─ Thrombosis on surface
─ ─ Calcification (dystrophic, can be extensive)
─ ─ Extramedullary hematopoiesis (rare)
─ ─ Glandular structures (rare, "myxoma with glands")
─ Myxoma cells are generally bland with minimal atypia and low mitotic activity
Ancillary studies ─ ─ IHC: Myxoma cells are often positive for Calretinin (can be strong, potential pitfall if mesothelioma considered in unusual location, but context is key), CD31, CD34 (variable), Smooth Muscle Actin (SMA, variable), Vimentin
─ ─ Negative for cytokeratins (usually), S100 (usually), desmin (usually), Factor VIII
─ Special Stains: Alcian blue or colloidal iron highlights myxoid stroma; Trichrome can show collagen
DDx ─ ─ Mural thrombus (especially organizing thrombus, can have myxoid areas; lacks true myxoma cells and characteristic architecture, often laminated, associated with underlying myocardial injury or atrial fibrillation)
─ Papillary fibroelastoma (avascular papillary fronds on valve surfaces, different histology with dense collagen core and elastic fibers)
─ Myxoid sarcoma (e.g myxoid liposarcoma, myxofibrosarcoma – these are malignant, show atypia, specific molecular findings, very rare as primary cardiac)
─ Angiosarcoma (malignant endothelial cells, vascular channels, significant atypia)
─ Metastatic carcinoma with myxoid stroma (look for epithelial atypia, specific carcinoma markers)
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Papillary Fibroelastoma

The most common primary tumor of cardiac valves in adults, a benign avascular papillary mesenchymal neoplasm resembling a sea anemone, typically an incidental finding but can cause embolic events
Clinical ─ Usually asymptomatic; can occur at any age but more common in older adults (mean age ~60 years); most commonly found on aortic and mitral valves, but can occur on any valve or endocardial surface (e.g ventricular septum, papillary muscles); potential complications include stroke, transient ischemic attack, myocardial infarction, or peripheral embolism due to fragmentation of papillary fronds or associated thrombus; surgical excision is curative if symptomatic or high embolic risk
Macro ─ Characteristic "sea anemone" appearance: a small (<1.5 cm, usually <1 cm), glistening, gelatinous, pedunculated or sessile lesion with numerous delicate, branching papillary fronds attached to the valve surface by a short stalk; may be single or multiple
Micro ─ ─ Avascular papillary fronds lined by a single layer of flat to plump endothelial cells
─ Each frond has a central core composed of:
─ ─ Dense collagenous connective tissue (Type I collagen)
─ ─ Abundant elastic fibers (radially arranged)
─ ─ Variable amounts of loose myxoid stroma rich in acid mucopolysaccharides (hyaluronic acid)
─ Scant spindle cells (fibroblast-like) within the stroma
─ Surface may have adherent fibrin/platelet thrombi, but no inflammation or organisms (unlike endocarditis)
─ No significant atypia or mitotic activity
Ancillary studies ─ ─ Special Stains: Elastic stain (e.g Verhoeff-Van Gieson) highlights abundant elastic fibers in cores; Trichrome stain (collagen); Alcian blue (myxoid stroma)
─ IHC (Endothelial lining): CD31 (+), CD34 (+), ERG (+)
DDx ─ ─ Lambl's excrescences (age-related, small filiform projections on lines of valve closure, considered organized thrombi or wear-and-tear lesions; PFE are generally larger and more complex)
─ Myxoma (atrial location common, different histology with myxoma cells in myxoid stroma, vascularized)
─ Thrombus (organizing thrombus can have papillary surface but different underlying structure, lacks characteristic PFE architecture)
─ Infective endocarditis vegetations (contain microorganisms, fibrin, inflammatory cells, destructive)
─ Nonbacterial thrombotic endocarditis (NBTE) (bland fibrin-platelet vegetations, often on damaged valves or in hypercoagulable states)
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Rhabdomyoma (Cardiac)

The most common primary cardiac tumor in infants and children, a benign hamartoma of cardiac myocytes, strongly associated with Tuberous Sclerosis Complex (TSC1/TSC2 gene mutations)
Clinical ─ Often multiple, typically presents in fetal life, infancy, or early childhood (most diagnosed by age 1); can cause arrhythmias, obstruction of blood flow (mimicking valvular stenosis), or heart failure depending on size and location; may spontaneously regress in some cases; ~50-80% of patients with cardiac rhabdomyomas have Tuberous Sclerosis Complex (TSC), and conversely, ~50-80% of TSC patients have cardiac rhabdomyomas
Macro ─ Well-circumscribed, firm, gray-white, lobulated nodules or masses, typically intramural (within ventricular walls or septum), but can be intracavitary or epicardial; size ranges from millimeters to several centimeters; often multiple
Micro ─ ─ Composed of large, polygonal to rounded cells (rhabdomyocytes) with abundant, clear or eosinophilic, granular cytoplasm rich in glycogen
─ Characteristic "spider cells": Pathognomonic feature; large cells with central nucleus and fine strands of cytoplasm radiating towards the cell membrane, separated by clear spaces filled with glycogen (glycogen dissolves during processing, leaving empty vacuoles)
─ Cells may show cross-striations, though often poorly formed or difficult to see
─ Nuclei are usually central, round to oval, with vesicular chromatin; minimal to no atypia or mitotic activity
─ Interstitial stroma is scant
─ No encapsulation, but tumor is well-demarcated from surrounding normal myocardium
Ancillary studies ─ ─ IHC: Positive for muscle markers such as Desmin, Muscle Specific Actin (MSA), Smooth Muscle Actin (SMA, variable); Myogenin and MyoD1 are typically negative or only very focally positive (unlike rhabdomyosarcoma)
─ Special Stains: PAS stain highlights abundant glycogen (diastase sensitive)
DDx ─ ─ Cardiac fibroma (collagenous, spindle cells, lacks spider cells and glycogen)
─ Glycogen storage disease involving heart (e.g Pompe disease; diffuse glycogen accumulation in all myocytes, not a discrete tumor mass)
─ Hypertrophic cardiomyopathy (myofiber disarray, hypertrophy, lacks spider cells)
─ Metastatic rhabdomyosarcoma (very rare in this age group in heart; shows malignant features, high mitotic rate, Myogenin/MyoD1 positive)
─ Histiocytoid cardiomyopathy (arrhythmogenic disorder in infants, sheets of cells with oncocytic/histiocytoid appearance, not true rhabdomyoma)
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Fibroma (Cardiac)

A benign mesenchymal tumor composed of fibroblasts and collagen, the second most common primary cardiac tumor in children (after rhabdomyoma), but can occur at any age
Clinical ─ Usually solitary, most commonly located in the ventricular septum or free wall of the left ventricle; can be large and cause obstruction, arrhythmias, heart failure, or sudden death; not typically associated with spontaneous regression; may be associated with Gorlin syndrome (Nevoid Basal Cell Carcinoma Syndrome, PTCH1 gene mutation) in a small subset of cases
Macro ─ Solitary, firm, well-circumscribed (though often unencapsulated and infiltrative at edges), gray-white, whorled mass, resembling a desmoid tumor or scar; may have central calcification or cystic degeneration, especially in larger tumors
Micro ─ ─ Composed of bland, spindle-shaped fibroblasts and myofibroblasts embedded in an abundant collagenous stroma (can be hyalinized)
─ Cells have uniform, elongated nuclei with fine chromatin and inconspicuous nucleoli; scant cytoplasm
─ Low cellularity overall, though cellularity can vary
─ Minimal to no cytologic atypia, very low mitotic activity (typically <1 mitosis/10 HPF)
─ Entrapped cardiac myocytes may be present at the periphery or within the tumor, distinguishing it from a scar
─ Elastic fibers are often prominent within the tumor (elastofibromatous change)
─ Calcification is common; ossification or cystic change can occur
Ancillary studies ─ ─ IHC: Vimentin (+); Smooth Muscle Actin (SMA) (often positive in myofibroblastic cells); Desmin (usually negative, or positive in entrapped myocytes only)
─ ─ Negative for S100, Myogenin/MyoD1, cytokeratins
─ Special Stains: Masson trichrome highlights collagen; Elastic stains (Verhoeff-Van Gieson) highlight elastic fibers
DDx ─ ─ Myocardial scar (healed infarct; history of ischemia, less well-circumscribed, often associated with coronary artery disease, lacks prominent elastic fibers throughout)
─ Hypertrophic cardiomyopathy (focal septal bulge; shows myofiber disarray and hypertrophy, not a discrete fibroblastic mass)
─ Rhabdomyoma (glycogen-rich spider cells, different IHC)
─ Inflammatory myofibroblastic tumor (more cellular, prominent inflammatory infiltrate especially plasma cells, ALK positive in a subset)
─ Desmoid-type fibromatosis (histologically very similar, may be indistinguishable; nuclear beta-catenin can be positive in desmoids)
─ Low-grade fibrosarcoma or myofibroblastic sarcoma (rare; would show more cellularity, atypia, mitoses)
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Lipoma and Lipomatous Hypertrophy of Atrial Septum (Cardiac)

Adipose tissue lesions of the heart, including benign encapsulated Lipomas and a non-neoplastic accumulation of fat in the atrial septum known as Lipomatous Hypertrophy of the Atrial Septum
Clinical ─ Cardiac Lipomas are rare, can occur at any age, in any location (subepicardial, intramyocardial, subendocardial, valvular); usually asymptomatic, may cause arrhythmias or obstruction if large. Lipomatous Hypertrophy of Atrial Septum (LHAS) is more common, typically in older, obese individuals, usually an incidental finding on imaging, can be associated with atrial arrhythmias or SVC obstruction if very large.
Macro ─ ─ Cardiac Lipoma: Well-circumscribed, encapsulated, soft, yellow, greasy mass of mature adipose tissue; size varies
─ Lipomatous Hypertrophy of Atrial Septum (LHAS): Non-encapsulated, bi-lobed or "dumbbell-shaped" fatty thickening of the interatrial septum, characteristically sparing the fossa ovalis; cut surface is yellow, fatty, may contain visible brown fat areas
Micro ─ ─ Cardiac Lipoma:
─ ─ Composed entirely of mature univacuolated adipocytes with eccentric, bland nuclei
─ ─ Fine fibrous septa with capillaries may be present
─ ─ No atypia, lipoblasts, or significant mitoses
─ Lipomatous Hypertrophy of Atrial Septum (LHAS):
─ ─ Non-neoplastic accumulation of mature adipose tissue (univacuolated adipocytes) within the interatrial septum
─ ─ Characteristic feature is the presence of entrapped, hypertrophied cardiac myocytes within the adipose tissue
─ ─ Variable amounts of fetal-type (brown) fat cells (multivacuolated cells with granular eosinophilic cytoplasm and central nuclei) may be present, especially in adults
─ ─ Fibrosis can be seen
─ ─ No true capsule
Ancillary studies ─ ─ Lipoma: Generally none needed
─ LHAS: IHC can highlight entrapped myocytes (Desmin, MSA) or brown fat cells (UCP1 if available, though not routine)
DDx ─ ─ For Cardiac Lipoma:
─ ─ Well-differentiated Liposarcoma (rare in heart; shows atypical stromal cells, lipoblasts, MDM2 amplification)
─ ─ Normal epicardial fat (not a discrete mass)
─ ─ Cardiac rhabdomyoma with fatty change (uncommon)
─ For Lipomatous Hypertrophy of Atrial Septum:
─ ─ Atrial septal defect (imaging distinction)
─ ─ Myxoma involving septum (gelatinous, myxoid stroma, myxoma cells)
─ ─ Liposarcoma involving septum (very rare; would show malignant features)
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Hemangioma (Cardiac)

Benign congenital vascular tumors composed of blood-filled channels, which are rare as primary cardiac tumors but can occur in any part of the heart (epicardium, myocardium, endocardium, valves)
Clinical ─ Can occur at any age, often found in children or incidentally in adults; symptoms depend on size and location: asymptomatic, arrhythmias, chest pain, obstruction, heart failure, pericardial effusion (if epicardial and bleeding); most are small and hemodynamically insignificant
Macro ─ Variable appearance: well-circumscribed or poorly defined, red-purple to dark blue, spongy or firm mass; size ranges from millimeters to several centimeters; may be solitary or multiple; cavernous types have larger, visible vascular spaces
Micro ─ ─ Composed of benign vascular channels lined by a single layer of bland, flattened endothelial cells without atypia or significant mitotic activity
─ Vascular channels vary in size and shape, filled with blood
─ Stroma between channels is usually fibrous, may contain smooth muscle or adipose tissue
─ Types (similar to extracardiac hemangiomas):
─ ─ Cavernous Hemangioma: Large, dilated, thin-walled vascular spaces, often back-to-back with minimal intervening stroma
─ ─ Capillary Hemangioma: Lobules of small, closely packed capillary-sized vessels
─ ─ Arteriovenous Hemangioma (Malformation): More complex, with thick-walled arterial and venous structures in addition to capillary channels
─ ─ Epithelioid Hemangioma (Angiolymphoid Hyperplasia with Eosinophilia): Rare in heart; plump epithelioid endothelial cells, often with lymphocytic and eosinophilic infiltrate (less common in deep visceral locations)
Ancillary studies ─ ─ IHC (Endothelial cells): CD31 (+), ERG (+, nuclear), CD34 (+, often), Factor VIII-related antigen (+)
─ IHC (-) Markers of malignancy or other lineages
DDx ─ ─ Angiosarcoma (malignant endothelial cells, atypia, mitoses, infiltrative growth, necrosis, complex anastomosing channels)
─ Lymphangioma (lymphatic channels lined by D2-40+ endothelial cells, typically contain lymph not blood)
─ Vascular malformation (distinction from hemangioma can be difficult, often based on clinical behavior and growth pattern; malformations are errors of morphogenesis, hemangiomas are true neoplasms that may proliferate)
─ Papillary fibroelastoma (if valvular, characteristic papillary fronds with avascular collagen/elastic cores)
─ Cardiac myxoma with prominent vascularity (myxoma cells in myxoid stroma are key)
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Mesothelial/Monocytic Incidental Cardiac Excrescences (MICME) / Cardiac Lambl's Excrescences

Benign, small, filiform or papillary projections found on cardiac valves or endocardial surfaces, representing either organized thrombi (Lambl's excrescences) or reactive proliferations of mesothelial cells and histiocytes (MICME)
Clinical ─ Usually incidental findings at autopsy, cardiac surgery, or on high-resolution echocardiography, particularly in older individuals; generally considered clinically insignificant but rarely can be a source of microemboli; Lambl's excrescences are more common on lines of valve closure due to wear and tear
Macro ─ ─ Lambl's Excrescences: Fine, thread-like or filiform strands, typically on the lines of closure of aortic and mitral valves; may be single or multiple
─ MICME: Small (<2-3 mm), irregular, often multiple, grayish-white, glistening, sessile or slightly raised papillary projections or clusters, can occur on valves, chordae, endocardium, or epicardial surface (if related to pericardial procedures)
Micro ─ ─ Lambl's Excrescences:
─ ─ Composed of dense, avascular, hyalinized collagenous tissue covered by endothelium
─ ─ Thought to represent organized small thrombi or result from age-related endothelial damage and repair along valve closure lines
─ Mesothelial/Monocytic Incidental Cardiac Excrescences (MICME):
─ ─ Small papillary or flat aggregates of cells loosely attached to endocardial or epicardial surfaces
─ ─ Composed of a variable mixture of:
─ ─ ─ Mesothelial cells: Plump cells with eosinophilic cytoplasm, round nuclei, often forming small clusters or lining micropapillae (Calretinin+, WT1+, CK5/6+)
─ ─ ─ Monocytes/Histiocytes: CD68+ cells, may be foamy
─ ─ ─ Fibrin and entrapped blood cells often present
─ ─ Lack true fibrovascular cores seen in papillary fibroelastoma
─ ─ Often associated with prior cardiac surgery, catheterization, or inflammation where mesothelial cells might be shed or proliferate
Ancillary studies ─ ─ IHC (for MICME): Calretinin, WT1, CK5/6 (to confirm mesothelial cells); CD68 (for histiocytes); CD31/CD34 (for endothelial covering)
DDx ─ ─ Papillary Fibroelastoma (true benign neoplasm, larger, more complex papillary fronds with distinct avascular collagen/elastic cores, "sea anemone" appearance)
─ Infective endocarditis vegetations (contain microorganisms, fibrin, prominent acute inflammation, destructive)
─ Nonbacterial Thrombotic Endocarditis (NBTE) (bland fibrin-platelet vegetations, minimal inflammation, often on lines of closure but generally larger and more organized than Lambl's excrescences, though can overlap)
─ Small organizing thrombi
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Histiocytoid Cardiomyopathy (infancy, ?hamartoma)

A rare and often fatal arrhythmogenic disorder of infancy and early childhood, characterized by multifocal myocardial infiltrates of large, polygonal cells with granular eosinophilic (histiocytoid or oncocytic) cytoplasm, possibly representing a developmental anomaly or hamartoma of Purkinje-like cells
Clinical ─ Presents in infants (typically <2 years old) with intractable arrhythmias (ventricular tachycardia, supraventricular tachycardia), cardiomegaly, heart failure, or sudden death; female predominance; may be associated with other congenital anomalies (e.g ophthalmic, CNS); familial cases reported; also known as oncocytic cardiomyopathy or Purkinje cell hamartoma
Macro ─ Heart may be enlarged; discrete, yellowish-tan or pale nodules or diffuse infiltrates may be seen in the myocardium, often involving ventricular walls and septum, sometimes subendocardial
Micro ─ ─ Nodular or diffuse infiltrates of distinctive large, polygonal to round cells with sharply defined cell borders and abundant, granular, eosinophilic cytoplasm (due to numerous mitochondria)
─ Nuclei are usually central, round to oval, with vesicular chromatin and prominent nucleoli; binucleation or multinucleation can occur
─ Cells may appear vacuolated if lipid or glycogen is present (though mitochondria are the main feature)
─ Minimal to no interstitial stroma or fibrosis within the nodules; cells are often closely packed
─ No significant inflammation, necrosis, or mitotic activity
─ Cells resemble histiocytes or oncocytes, but are thought to be of Purkinje cell or modified cardiomyocyte lineage
Ancillary studies ─ ─ IHC: Cells are typically positive for Desmin, Vimentin; may be focally positive for Muscle Specific Actin (MSA) or Smooth Muscle Actin (SMA). Usually negative for true histiocytic markers (CD68), S100 protein, cytokeratins, and neuroendocrine markers. Some Purkinje cell markers (e.g connexins) may be positive.
─ Special Stains: PTAH may show cytoplasmic granularity or cross-striations (rarely); PAS (for glycogen) may be positive but often weak/variable.
─ Electron Microscopy: Cytoplasm packed with abundant, often abnormal, mitochondria; rudimentary myofibrils and intercalated disc-like structures may be seen
DDx ─ ─ Rhabdomyoma (cardiac) (also occurs in infants, associated with TSC; "spider cells" with clear cytoplasm due to glycogen, Myogenin/MyoD1 negative or focal)
─ Glycogen storage disease (e.g Pompe; diffuse glycogen accumulation in all myocytes, not discrete nodules of histiocytoid cells)
─ Mitochondrial cardiomyopathy (can have oncocytic change, but usually more diffuse myocardial involvement and clinical picture of mitochondrial disease)
─ Endocardial fibroelastosis (diffuse endocardial thickening, no histiocytoid cell infiltrates)
─ Myocarditis with prominent histiocytes (would have other inflammatory cells, myocyte necrosis)
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Pericardial Lipoma

A benign mesenchymal tumor composed of mature adipose tissue, arising within or on the surface of the pericardium; distinct from epicardial fat or cardiac lipoma by its specific pericardial origin and encapsulation
Clinical ─ Very rare; can occur at any age but more common in adults; usually asymptomatic and discovered incidentally on imaging or at autopsy; may cause symptoms if very large due to compression of cardiac chambers or adjacent structures (dyspnea, arrhythmias, chest discomfort); excellent prognosis with complete surgical excision
Macro ─ Typically a solitary, well-circumscribed, encapsulated, soft, lobulated, yellow mass located within the pericardial sac, attached to the parietal or visceral pericardium, or in the cardiophrenic angle; size varies from small to very large (can weigh several kilograms)
Micro ─ ─ Composed entirely of mature univacuolated adipocytes with small, eccentric, bland nuclei
─ Fine fibrous septa containing thin-walled capillaries may traverse the tumor
─ No lipoblasts, significant cellular atypia, hyperchromasia, or mitotic activity
─ Identical histologically to lipomas in other locations
─ May be surrounded by a thin fibrous capsule
Ancillary studies ─ Generally not required for diagnosis if histology is typical
DDx ─ ─ Normal epicardial or mediastinal adipose tissue (not a discrete, encapsulated mass)
─ Lipomatous hypertrophy of atrial septum (specific location, non-encapsulated infiltration of atrial septum with mature and brown fat, entrapped myocytes)
─ Cardiac lipoma (arising from myocardium or endocardium, rather than pericardium)
─ Well-differentiated liposarcoma (rare in pericardium; shows atypical stromal cells, variation in adipocyte size, MDM2/CDK4 positivity/amplification)
─ Pericardial cyst with fatty content (rare, cystic structure)
─ Teratoma with prominent adipose component (would have other germ cell derivatives)
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Angiosarcoma (Cardiac)

The most common primary malignant tumor of the heart in adults, an aggressive sarcoma of endothelial differentiation, typically arising in the right atrium
Clinical ─ Rare overall, but accounts for ~30-40% of primary cardiac sarcomas; affects adults (mean age 40-50 years), male predominance; most commonly arises in the right atrium or pericardium; presents with rapidly progressive symptoms: dyspnea, chest pain, signs of right heart failure (edema, ascites), pericardial effusion/tamponade, hemoptysis, SVC syndrome; early and widespread metastases (lungs, liver, bone, brain) are common; very poor prognosis despite therapy
Macro ─ Often a large, ill-defined, infiltrative, hemorrhagic, necrotic mass; may be fungating or nodular, extending into cardiac chambers, pericardial space, or great vessels; cut surface is typically dark red-brown, spongy, or fleshy with areas of hemorrhage and necrosis
Micro ─ ─ Malignant proliferation of atypical endothelial cells forming irregular, anastomosing vascular channels, solid sheets, papillary structures, or spindle cell areas
─ Endothelial cells show significant cytologic atypia: nuclear pleomorphism, hyperchromasia, prominent nucleoli, increased N/C ratio
─ Mitotic activity is usually brisk, atypical mitoses may be present
─ Lumen formation may be well-developed ("vascular angiosarcoma") or abortive/absent in poorly differentiated areas ("solid" or "epithelioid" angiosarcoma)
─ "Hobnail" endothelial cells (cells bulge into lumen) can be seen
─ Hemorrhage, necrosis, and inflammatory infiltrates are common
─ Infiltration into surrounding myocardium, pericardium, and vessels
Ancillary studies ─ ─ IHC (Endothelial markers are key for diagnosis):
─ ─ CD31 (+, strong membranous, most sensitive and specific)
─ ─ ERG (+, nuclear, very sensitive and specific)
─ ─ CD34 (+, variable, can be lost in poorly differentiated areas)
─ ─ Factor VIII-related antigen (FVIII-RA) (+, often focal)
─ ─ FLI1 (+, nuclear)
─ ─ Cytokeratins (AE1/AE3, CAM5.2) can be positive in epithelioid variants, potentially causing confusion with carcinoma if a full vascular panel is not done
─ IHC (-): Markers for other lineages (e.g S100 for melanoma, specific carcinoma markers, lymphoid markers)
─ Ki-67 proliferation index is high
DDx ─ ─ Hemangioma (benign endothelial proliferation, lacks atypia, mitoses, infiltrative growth)
─ Organizing thrombus with prominent granulation tissue (reactive endothelial proliferation, lacks malignant atypia)
─ Kaposi sarcoma (HHV8 positive, different morphology with slit-like spaces and spindle cells)
─ Other primary cardiac sarcomas (e.g undifferentiated pleomorphic sarcoma, leiomyosarcoma – negative for endothelial markers, positive for other lineage markers if differentiated)
─ Metastatic angiosarcoma (rare to metastasize to heart unless widespread disease; clinical history important)
─ Metastatic carcinoma or melanoma with epithelioid or spindle cell features (negative for endothelial markers, positive for specific carcinoma/melanoma markers)
─ Reactive vascular proliferations (e.g papillary endothelial hyperplasia/Masson tumor – intravascular, organized, lacks atypia)
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Other Sarcomas (Primary Cardiac)

A heterogeneous group of rare malignant mesenchymal tumors arising primarily in the heart, excluding angiosarcoma (the most common type); these include undifferentiated pleomorphic sarcoma, leiomyosarcoma, rhabdomyosarcoma, fibrosarcoma, synovial sarcoma, etc.
Clinical ─ Extremely rare, collectively less common than angiosarcoma; occur in adults, though some types (e.g rhabdomyosarcoma) can occur in children; symptoms depend on location, size, and infiltrative nature (e.g heart failure, arrhythmias, obstruction, embolic events, constitutional symptoms); generally aggressive with poor prognosis due to late diagnosis, difficulty of complete resection, and high metastatic potential
Macro ─ Typically large, fleshy, infiltrative masses, often involving left atrium or ventricles (unlike angiosarcoma which favors right atrium); may show hemorrhage, necrosis, cystic change; can involve any cardiac chamber, valves, or pericardium
Micro ─ (Histologic features depend on the specific sarcoma type)
─ Undifferentiated Pleomorphic Sarcoma (UPS) (formerly Malignant Fibrous Histiocytoma - MFH):
─ ─ High-grade sarcoma composed of highly pleomorphic spindle and polygonal cells arranged in sheets or storiform patterns, with no specific line of differentiation identifiable by IHC/EM
─ ─ Numerous bizarre tumor giant cells, high mitotic rate, extensive necrosis
─ ─ Diagnosis of exclusion
─ Leiomyosarcoma:
─ ─ Malignant spindle cells with features of smooth muscle differentiation (elongated, blunt-ended nuclei, eosinophilic cytoplasm) arranged in intersecting fascicles
─ ─ Significant atypia, high mitotic rate, necrosis
─ ─ IHC: SMA (+), Desmin (+), Caldesmon (+)
─ Rhabdomyosarcoma:
─ ─ Presence of rhabdomyoblasts is diagnostic
─ ─ IHC: Myogenin (+), MyoD1 (+)
─ Fibrosarcoma:
─ ─ Malignant spindle cell sarcoma with fibroblastic differentiation, arranged in herringbone pattern or intersecting fascicles
─ ─ Variable cellularity and atypia; diagnosis requires exclusion of other spindle cell sarcomas
─ ─ IHC: Vimentin (+), variable SMA; negative for S100, desmin, cytokeratins, endothelial markers
─ Synovial Sarcoma:
─ ─ Rare in heart; can be monophasic (spindle cells) or biphasic (spindle cells and epithelial glands)
─ ─ IHC: Cytokeratin (+, often focal), EMA (+), TLE1 (+), BCL2 (+), CD99 (+); S100 (-)
─ ─ Molecular: SS18-SSX fusion is pathognomonic
─ Others: Osteosarcoma, chondrosarcoma, liposarcoma (all exceedingly rare as primary cardiac)
Ancillary studies ─ ─ IHC: Extensive panel is crucial to determine line of differentiation and exclude other tumor types (e.g endothelial markers for angiosarcoma; S100 for MPNST/melanoma; cytokeratins for sarcomatoid carcinoma; lymphoid markers for lymphoma; GCT markers)
─ Molecular: Specific translocations or mutations can confirm diagnosis for certain types (e.g SS18-SSX for synovial sarcoma; MDM2 amplification for well-diff/dediff liposarcoma if that component is suspected)
DDx ─ ─ Angiosarcoma (most common primary cardiac sarcoma; endothelial markers positive)
─ Metastatic sarcoma from an extracardiac primary (more common than primary cardiac sarcoma; clinical history crucial)
─ Sarcomatoid carcinoma or mesothelioma (cytokeratin positive)
─ Myxoma with atypical features (rare, myxoid background, characteristic myxoma cells, generally bland)
─ Spindle cell melanoma (S100/SOX10/melanoma markers positive)
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Primary Cardiac Lymphoma

A rare extranodal lymphoma arising primarily within the heart or pericardium, most commonly Diffuse Large B-cell Lymphoma (DLBCL), often occurring in immunocompromised individuals (e.g HIV/AIDS, post-transplant) but can affect immunocompetent patients
Clinical ─ Extremely rare, but incidence increasing, especially in immunocompromised; affects adults; symptoms are often non-specific and depend on location/extent of involvement: dyspnea, chest pain, arrhythmias, heart failure, pericardial effusion/tamponade, constitutional symptoms (fever, weight loss); prognosis is generally poor due to late diagnosis and aggressive nature, though chemoimmunotherapy can be effective in some
Macro ─ Typically presents as an infiltrative mass or multiple nodules within the myocardium (often right atrium or ventricle), pericardium, or rarely valves; may cause chamber obliteration or wall thickening; cut surface is fleshy, gray-white, may show necrosis or hemorrhage
Micro ─ ─ Diffuse Large B-cell Lymphoma (DLBCL) is the most common histologic type:
─ ─ Sheets of large, atypical lymphoid cells (centroblasts, immunoblasts) with vesicular nuclei, prominent nucleoli, and moderate cytoplasm, diffusely infiltrating myocardial fibers or pericardial tissue
─ ─ High mitotic rate, apoptosis, and necrosis are common
─ Other less common types include Burkitt lymphoma, T-cell lymphomas, or low-grade B-cell lymphomas (e.g MALT lymphoma of pericardium)
─ Angiocentric/angiodestructive growth pattern may be seen
─ Pericardial involvement often presents as lymphomatous effusion
Ancillary studies ─ ─ IHC (For DLBCL type): CD20 (+, strong), CD79a (+), PAX5 (+) (B-cell markers)
─ ─ MUM1/IRF4 (often positive), BCL6 (variable), CD10 (variable) – for subtyping (GCB vs non-GCB)
─ ─ BCL2 (often positive)
─ ─ Ki-67 proliferation index is high
─ ─ EBV (EBER ISH) may be positive, especially in immunocompromised-associated cases
─ IHC (-): Cytokeratins, melanoma markers, sarcoma markers, CD3 (for most cases unless T-cell lymphoma), CD30 (usually negative unless specific subtype)
─ Flow Cytometry (on fresh tissue or effusion): Confirms B-cell lineage, clonality, and immunophenotype
─ Molecular: Clonal immunoglobulin gene rearrangements; FISH for MYC, BCL2, BCL6 translocations if DLBCL
DDx ─ ─ Metastatic lymphoma to the heart (more common than primary cardiac lymphoma; history of systemic lymphoma)
─ Myocarditis with prominent lymphoid infiltrate (inflammatory cells are polyclonal, lack significant atypia, no destructive sheets of blasts)
─ Other primary cardiac malignancies (e.g angiosarcoma, undifferentiated sarcoma – specific sarcoma markers positive, lymphoid markers negative)
─ Reactive lymphoid hyperplasia in pericardium or associated with other cardiac conditions (polyclonal, lacks atypia)
─ Undifferentiated carcinoma (cytokeratin positive)
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Malignant Mesothelioma of Pericardium

A rare and highly aggressive primary malignancy arising from the mesothelial cells lining the pericardium, similar in histology and behavior to pleural malignant mesothelioma
Clinical ─ Extremely rare, accounts for <1% of all mesotheliomas; affects adults, often older individuals; association with asbestos exposure is less clear/strong than for pleural mesothelioma; presents with chest pain, dyspnea, pericardial effusion (often large, hemorrhagic, leading to tamponade), constrictive pericarditis, arrhythmias, or signs of heart failure; prognosis is very poor
Macro ─ Diffuse, nodular, or sheet-like thickening of the pericardium, encasing the heart; may directly invade myocardium, great vessels, or adjacent structures; pericardial effusion is common
Micro ─ (Histologic types similar to pleural mesothelioma)
─ Epithelioid Mesothelioma (most common pericardial type):
─ ─ Tubulopapillary, trabecular, acinar, or solid/sheet-like patterns of cuboidal, polygonal, or oval cells with eosinophilic cytoplasm, round to oval nuclei, and variably prominent nucleoli
─ ─ Cytologic atypia can range from bland to pleomorphic
─ Sarcomatoid Mesothelioma:
─ ─ Spindle cells resembling fibrosarcoma or other sarcomas, arranged in fascicles or storiform patterns
─ Biphasic (Mixed) Mesothelioma:
─ ─ Contains distinct components of both epithelioid and sarcomatoid mesothelioma (each >10%)
─ Desmoplastic Mesothelioma (rare variant of sarcomatoid): Paucicellular, dense collagenous stroma with bland spindle cells, deeply invasive
Ancillary studies ─ ─ IHC (+) (Panel of mesothelial markers is crucial): Calretinin (nuclear & cytoplasmic), WT1 (nuclear), CK5/6 (cytoplasmic/membranous), D2-40 (podoplanin, membranous) – at least two positive mesothelial markers recommended
─ ─ Other positive markers: EMA (membranous), Thrombomodulin
─ ─ Markers of malignancy: BAP1 (loss of nuclear expression), MTAP (loss), GLUT1 (+)
─ IHC (-) (To exclude other tumors, especially adenocarcinoma): Claudin-4 (usually negative/weak focal), MOC31 (similar), BerEP4 (similar), CEA, TTF-1, Napsin A, PAX8 (except some GYN tumors)
─ Molecular: BAP1 mutation/loss, CDKN2A (p16) homozygous deletion, NF2 mutations (similar to pleural mesothelioma)
DDx ─ ─ Metastatic adenocarcinoma to pericardium (most important differential; positive for adenocarcinoma markers, negative for most mesothelial markers)
─ Reactive mesothelial hyperplasia (often in response to inflammation/effusion; lacks deep invasion, significant atypia, BAP1 loss, or CDKN2A deletion)
─ Other primary cardiac/pericardial sarcomas (e.g angiosarcoma – endothelial markers positive)
─ Thymic carcinoma invading pericardium (thymic markers positive)
─ Fibrosing pericarditis (chronic inflammation, fibrosis, no malignant mesothelial cells)
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Metastatic Tumors to the Heart and Pericardium

Secondary malignancies involving the heart or pericardium from primary cancers elsewhere; metastases are significantly more common than primary cardiac tumors
Clinical ─ Incidence varies with primary tumor type and stage; common primary sites include lung, breast, esophagus, melanoma, leukemia, lymphoma, kidney, and GI tract; often asymptomatic or symptoms are non-specific (dyspnea, arrhythmias, chest pain, heart failure, pericardial effusion/tamponade) and may be attributed to primary cancer or its treatment; usually indicates advanced disease and poor prognosis
Patterns of Spread and Macro Appearance:
─ Pericardial Metastases (more common than myocardial):
─ ─ Often present as pericardial effusion (serous, hemorrhagic, or malignant cytology)
─ ─ Discrete tumor nodules or plaques on pericardial surfaces
─ ─ Diffuse pericardial thickening mimicking constrictive pericarditis
─ Myocardial Metastases:
─ ─ Usually multifocal, small, discrete nodules within the myocardium of any chamber
─ ─ Less commonly, diffuse infiltrative growth
─ ─ Rarely, solitary large mass
─ Endocardial/Intracavitary Metastases: Rare, can embolize or cause obstruction
─ Routes of spread: Hematogenous (most common for myocardial), lymphatic (to pericardium/epicardium), direct extension from adjacent tumors (e.g lung, esophagus, breast)
Micro ─ ─ Histology mirrors the primary tumor (e.g adenocarcinoma, squamous cell carcinoma, melanoma, sarcoma, lymphoma/leukemia cells)
─ Tumor cells are found within pericardial fluid, on pericardial surfaces, or infiltrating pericardial/myocardial tissue and lymphatics
─ May elicit a desmoplastic stromal reaction or inflammatory response
Ancillary studies ─ ─ IHC: Crucial for confirming metastatic nature and suggesting/confirming primary site, especially if primary is unknown or morphology is poorly differentiated. Panel guided by morphology and clinical history
─ IHC (-) Markers for primary cardiac tumors (e.g mesothelial markers for pericardial mesothelioma if morphology is epithelioid; specific sarcoma markers if spindle cell)
─ Cytology of pericardial fluid: Can identify malignant cells
DDx ─ ─ Primary cardiac or pericardial malignancies (e.g angiosarcoma, mesothelioma, lymphoma – require specific markers and exclusion of metastasis from elsewhere)
─ Benign cardiac tumors or tumor-like lesions (e.g myxoma, rhabdomyoma, fibroma – characteristic benign histology)
─ Non-neoplastic conditions (e.g pericarditis, myocarditis, organizing thrombus – inflammatory or reactive features, no malignant cells)
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Heart Transplant Pathology

Donor Heart Evaluation (Heart Transplant Pathology)

Pathologic assessment of hearts from potential organ donors to determine suitability for transplantation, identify pre-existing conditions that might affect allograft function or recipient outcome, and for procurement quality control
Clinical ─ Critical step in heart transplantation process; involves review of donor medical history, serologies, hemodynamic status, cardiac function (echo, angiogram if indicated); gross and microscopic examination of the heart if procured or at time of implantation biopsy
Pathologic Assessment Aspects:
─ Donor History Review: Age, cause of death (e.g head trauma vs anoxia), comorbidities (hypertension, diabetes, hyperlipidemia, smoking), infections, drug use, family history of cardiac disease, prior cardiac interventions
─ Gross Examination (if heart available pre-transplant, or from unused donor hearts):
─ ─ Heart weight and chamber dimensions (hypertrophy, dilation)
─ ─ Valvular morphology (stenosis, regurgitation, calcification, vegetations)
─ ─ Coronary arteries (atherosclerosis – extent, severity, location of plaques; anomalies, dissection, thrombus)
─ ─ Myocardium (infarct scars, fibrosis, contusions, color, consistency)
─ ─ Congenital anomalies
─ ─ Aorta and great vessels (atherosclerosis, dissection)
─ Microscopic Examination (often from implantation biopsy or unused donor hearts):
─ ─ Myocardium: Myocyte hypertrophy, atrophy, disarray, fibrosis (interstitial, replacement), inflammation (myocarditis – type, extent), necrosis (ischemic, contraction band), fatty infiltration, small vessel disease (arteriolosclerosis), iron/amyloid deposits (rarely screened for routinely unless suspected)
─ ─ Coronary arteries: Atherosclerosis (plaque morphology, inflammation, calcification), vasculitis, thrombosis
─ ─ Valves: Degenerative changes, inflammation
─ ─ Conduction system: Not usually assessed in detail unless specific indication
─ Implantation ("Time Zero") Biopsy: Endomyocardial biopsy taken from donor heart immediately after reperfusion in recipient; serves as baseline for future surveillance biopsies; may show procurement/preservation injury (e.g contraction band necrosis, interstitial edema, early ischemic changes) or pre-existing donor pathology
Contraindications (Relative or Absolute, based on findings):
─ Significant coronary artery disease (uncorrectable or high risk)
─ Severe unexplained ventricular hypertrophy
─ Valvular heart disease requiring repair/replacement (unless donor valve also used)
─ Active infection involving heart
─ Cardiac malignancy (primary or metastatic)
─ Irreversible cardiac damage from trauma or prolonged ischemia
─ Certain cardiomyopathies in donor
Ancillary studies ─ Special stains (e.g Trichrome for fibrosis, Congo red for amyloid if suspected), IHC (for inflammation if myocarditis questioned) on biopsy material
DDx ─ N/A (focus is on detection of any pathology)
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Ischemia-Reperfusion Injury (Heart Transplant Pathology)

Myocardial damage that occurs when blood flow is restored to previously ischemic tissue, a common phenomenon in heart transplantation due to procurement, cold storage, and revascularization of the donor heart
Clinical ─ Can contribute to early allograft dysfunction (ranging from mild stunning to primary graft failure); manifests as arrhythmias, myocardial edema, impaired contractility, elevated cardiac enzymes post-transplant; severity depends on duration of ischemia, preservation techniques, and reperfusion conditions
Pathophysiology ─ Complex, involves multiple mechanisms:
─ Oxidative stress: Generation of reactive oxygen species (ROS) upon reintroduction of oxygen
─ Calcium overload: Intracellular calcium accumulation during ischemia, exacerbated by reperfusion, leading to hypercontracture and mitochondrial damage
─ Endothelial dysfunction: Swelling, increased permeability, impaired vasodilation
─ Inflammatory response: Activation of neutrophils, macrophages, complement system, release of cytokines
─ Mitochondrial dysfunction: Damage to mitochondria, impaired ATP production, opening of mitochondrial permeability transition pore (MPTP) leading to cell death
─ Apoptosis and Necrosis of cardiomyocytes
Macro ─ Heart may appear edematous, congested, with patchy areas of hemorrhage or pallor, especially in severe cases; difficult to assess grossly in mild forms
Micro ─ (Features often seen in early post-transplant endomyocardial biopsies, including "time-zero" biopsy)
─ Contraction Band Necrosis: Characteristic feature; hypercontracted sarcomeres form dense eosinophilic transverse bands in cardiomyocytes, often with disruption of cell membrane and pyknotic nuclei; typically subendocardial or patchy distribution
─ Myocyte vacuolization (hydropic change) and swelling
─ Interstitial edema and hemorrhage
─ Endothelial cell swelling and capillary congestion/sludging
─ Neutrophil infiltration: Can occur within hours, usually mild to moderate unless severe injury
─ Apoptosis of cardiomyocytes (less prominent than necrosis usually)
─ Subendocardial myocyte necrosis (if ischemia was prolonged)
Ancillary studies ─ ─ IHC: Can demonstrate markers of oxidative stress, complement deposition (C4d can be positive due to ischemia-reperfusion, not necessarily AMR in this early context), or apoptosis (e.g TUNEL, Caspase-3) but not routinely used for diagnosis
─ Electron Microscopy: Shows mitochondrial swelling, disruption of cristae, sarcolemmal breaks, myofibrillar hypercontraction
DDx ─ ─ Hyperacute rejection (rare with current crossmatching; diffuse microvascular thrombosis, hemorrhage, severe edema, rapid graft failure within minutes to hours; C4d deposition)
─ Acute cellular rejection (ACR) or Antibody-mediated rejection (AMR) (typically occur later, days to weeks post-transplant, though early AMR can overlap; specific histologic criteria and C4d for AMR – see respective entries)
─ Procurement injury (mechanical trauma, or effects of brain death in donor – e.g catecholamine surge causing contraction bands unrelated to reperfusion itself)
─ Pre-existing donor heart pathology (e.g underlying ischemia, myocarditis if not fully recognized pre-transplant)
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Hyperacute Rejection (Heart Transplant Pathology)

A rare and devastating form of allograft rejection occurring minutes to hours after transplantation, mediated by pre-existing donor-specific antibodies (DSAs) in the recipient against donor endothelial antigens (e.g ABO blood group antigens, HLA class I antigens)
Clinical ─ Extremely rare with current pre-transplant crossmatching techniques; manifests as rapid cyanosis, mottling, and failure of the transplanted heart immediately upon reperfusion or within the first 24-48 hours; leads to irreversible graft loss
Pathophysiology ─ Pre-formed recipient antibodies bind to donor endothelial cells, activating complement and coagulation cascades, leading to widespread endothelial injury, microvascular thrombosis, interstitial hemorrhage, and ischemic necrosis of the graft
Macro ─ Heart becomes swollen, dusky, cyanotic, and flaccid; fails to contract effectively shortly after reperfusion
Micro ─ ─ Widespread endothelial cell injury and necrosis in capillaries, venules, and arterioles
─ Fibrin-platelet thrombi occluding small vessels (microvascular thrombosis)
─ Interstitial edema and hemorrhage
─ Neutrophil margination within capillaries and venules, often with interstitial infiltration
─ Ischemic necrosis of cardiomyocytes (coagulation necrosis, contraction bands) develops rapidly
─ Immunofluorescence or IHC may show deposition of immunoglobulins (IgG, IgM) and complement components (C3, C4d) along endothelial surfaces (though C4d can also be seen in ischemia-reperfusion or AMR)
Ancillary studies ─ ─ Serologic: Detection of pre-formed DSAs in recipient serum (retrospective confirmation if not done prospectively, or if unexpected HAR occurs)
─ IHC/IF: C4d deposition in microvasculature (strong, diffuse staining is supportive but not solely diagnostic of HAR vs other early injury)
DDx ─ ─ Severe ischemia-reperfusion injury (can also cause early graft dysfunction, edema, some necrosis, and C4d deposition; HAR is typically more rapid, diffuse, and associated with widespread microvascular thrombosis due to pre-formed antibodies)
─ Early, severe antibody-mediated rejection (AMR) (mechanism is similar, but HAR is immediate due to pre-existing high-titer antibodies; AMR often develops days to weeks later, though an early fulminant form can occur)
─ Technical complications of surgery (e.g vascular anastomotic problems)
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Acute Cellular Rejection (ACR) - Myocardial and Vascular (ISHLT Grading) (Heart Transplant Pathology)

An adaptive immune response mediated by recipient T-lymphocytes sensitized to donor antigens, primarily HLA, leading to inflammation and damage of the cardiac allograft; typically occurs weeks to months post-transplant but can occur at any time
Clinical ─ May be asymptomatic (detected on surveillance endomyocardial biopsies - EMBs) or present with signs of heart failure (dyspnea, fatigue, edema), arrhythmias, or general malaise; severity graded by ISHLT classification on EMBs; responsive to immunosuppressive therapy
ISHLT 2004 Grading System for Acute Cellular Rejection (based on EMB findings):
─ Grade 0R: No rejection (normal histology or changes of ischemia-reperfusion injury, Quilty effect)
─ Grade 1R (Mild ACR):
─ ─ Interstitial and/or perivascular lymphoid infiltrate
─ ─ Infiltrate is focal or diffuse but without associated myocyte damage
─ ─ Myocytes appear viable
─ Grade 2R (Moderate ACR):
─ ─ Single focus of aggressive lymphocytic infiltration with associated myocyte damage (necrosis, degeneration, phagocytosis of myocyte debris by macrophages) OR
─ ─ Multiple foci of less aggressive infiltrates with associated myocyte damage
─ ─ Eosinophils and neutrophils may be present
─ Grade 3R (Severe ACR):
─ ─ Diffuse, extensive, aggressive polymorphic infiltrate (lymphocytes, eosinophils, neutrophils) with multifocal or extensive myocyte damage and necrosis
─ ─ May also involve hemorrhage, edema, and endothelialitis (vascular rejection)
Vascular Rejection (often accompanies moderate to severe myocardial ACR, or can be isolated):
─ Lymphocytic infiltration of small intramyocardial arterioles or venules, with endothelial swelling, inflammation within the vessel wall (endotheliitis/intimal arteritis), and sometimes luminal occlusion or fibrinoid necrosis in severe cases
Micro ─ (Features depend on grade, see ISHLT above)
─ Lymphocytic infiltrate: Predominantly T-lymphocytes (CD3+, CD4+, CD8+), often activated (larger, more irregular nuclei)
─ Myocyte damage: Eosinophilia of cytoplasm, vacuolization, pyknosis, karyolysis, frank necrosis, apoptosis; phagocytosis of damaged myocytes by macrophages
─ Endothelialitis: Swollen endothelial cells, subendothelial lymphocytic infiltration, lifting of endothelium from basement membrane
─ Quilty effect: Endocardial lymphocytic infiltrates (often B-cell rich peripherally, T-cell rich centrally), sometimes extending into adjacent myocardium; considered a benign finding, not rejection, but can be confused with mild ACR if infiltrates are extensive or myopericardial
Ancillary studies ─ ─ IHC: Can help characterize infiltrate (CD3, CD4, CD8 for T-cells; CD68 for macrophages; CD20 for B-cells, especially in Quilty lesions). Not routinely required for grading ACR if H&E is clear.
DDx ─ ─ Ischemia-reperfusion injury (contraction band necrosis, edema, early neutrophil infiltrate, typically in first week)
─ Infection-related myocarditis (e.g viral myocarditis like CMV; specific organisms or viral inclusions may be seen, PCR/ISH for viruses)
─ Antibody-mediated rejection (AMR) (microvascular inflammation with neutrophils/macrophages, endothelial swelling, C4d deposition, often less prominent lymphocytic infiltrate directly damaging myocytes compared to ACR)
─ Post-transplant lymphoproliferative disorder (PTLD) (atypical, often monomorphic lymphoid infiltrate, EBV+ usually)
─ Quilty effect (endocardial based, often B-cell component, no significant myocyte damage)
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Antibody-Mediated Rejection (AMR) - Pathologic criteria (Endothelial swelling, Macrophages, C4d, DSA) (Heart Transplant Pathology)

Allograft rejection mediated by donor-specific antibodies (DSAs) directed against donor HLA or non-HLA antigens on endothelial cells, leading to microvascular injury and inflammation
Clinical ─ Can occur early or late post-transplant; may be acute (sudden graft dysfunction, hemodynamic compromise) or chronic (contributing to cardiac allograft vasculopathy); symptoms include heart failure, arrhythmias, cardiogenic shock; diagnosis integrates histopathology from EMB, immunopathology (C4d, C3d staining), and DSA detection in serum
ISHLT 2013 Pathologic Criteria for Antibody-Mediated Rejection (pAMR):
─ pAMR 0: No evidence of AMR
─ pAMR 1 (Suspicious for AMR): Requires meeting at least one of the following categories (histologic or immunopathologic):
─ ─ pAMR 1 (H+): Histologic evidence of microvascular inflammation (intracapillary activated mononuclear cells – lymphocytes/macrophages, endothelial swelling, +/- neutrophils) without immunopathologic evidence (C4d negative)
─ ─ pAMR 1 (I+): Immunopathologic evidence (C4d deposition in capillaries – diffuse linear or granular staining) without histologic evidence of microvascular inflammation
─ pAMR 2 (Pathologic AMR): Requires both histologic evidence of microvascular inflammation AND immunopathologic evidence (C4d deposition); OR strong immunopathologic evidence (C4d or C3d) with specific DSA, even if histology is minimal
─ pAMR 3 (Severe Pathologic AMR): Diffuse, severe microvascular inflammation, capillary fragmentation, hemorrhage, edema, +/- widespread myocyte necrosis, endothelial cell necrosis/pyknosis, intravascular thrombi, marked C4d deposition
Micro ─ (Key features for histologic component of pAMR)
─ Microvascular inflammation:
─ ─ Endothelial cell swelling and activation (enlarged, prominent nuclei) in capillaries and venules
─ ─ Intracapillary activated mononuclear cells (lymphocytes with irregular nuclei, macrophages, sometimes neutrophils) filling or marginating in capillaries/venules
─ Interstitial edema and hemorrhage (in more severe cases)
─ Myocyte injury (necrosis, apoptosis) may be present but is often less prominent or secondary to microvascular damage compared to ACR
Ancillary studies ─ ─ Immunofluorescence (IF) or Immunohistochemistry (IHC) for C4d:
─ ─ Diffuse, strong, linear or granular C4d deposition along capillary endothelium is a key marker of antibody-mediated complement activation
─ ─ IF is generally considered more sensitive than IHC for C4d
─ IHC for CD68: Highlights intracapillary macrophages, contributing to assessment of microvascular inflammation
─ Serum DSA testing: Detection of antibodies against donor HLA class I or II antigens, or non-HLA antigens (e.g AT1R, MICA)
DDx ─ ─ Acute cellular rejection (ACR) (predominantly T-cell lymphocytic infiltrate directly damaging myocytes; AMR has more microvascular focus) – ACR and AMR can coexist
─ Ischemia-reperfusion injury (can cause C4d deposition and endothelial swelling early post-transplant; typically resolves, lacks sustained microvascular inflammation and prominent macrophage/lymphocyte margination of AMR)
─ Quilty effect (endocardial lymphocytic infiltrate, usually C4d negative within the Quilty lesion itself)
─ Capillary injury due to other causes (e.g infection, thrombotic microangiopathy – clinical context and other findings important)
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Cardiac Allograft Vasculopathy (CAV) - Chronic rejection, concentric intimal thickening (Heart Transplant Pathology)

An accelerated form of coronary artery disease occurring in transplanted hearts, a major cause of late allograft failure and mortality; considered a manifestation of chronic rejection involving both immune (alloantibody, T-cell mediated) and non-immune mechanisms (ischemia-reperfusion injury, CMV infection, dyslipidemia, hypertension)
Clinical ─ Often clinically silent until advanced stages due to denervation of the donor heart (lack of angina); may present with atypical symptoms, heart failure, arrhythmias, myocardial infarction, or sudden cardiac death; diagnosis by coronary angiography (shows diffuse narrowing, distal pruning), intravascular ultrasound (IVUS, more sensitive for intimal thickening), or non-invasive imaging; surveillance is crucial
Macro ─ Diffuse, concentric thickening of coronary artery walls (both epicardial arteries and intramyocardial arterioles); lumens are narrowed; discrete atheromatous plaques may be present but CAV is often more diffuse and less lipid-rich than typical atherosclerosis
Micro ─ ─ Characteristic lesion is diffuse, concentric intimal thickening (fibrocellular or fibromuscular proliferation) in epicardial coronary arteries and intramyocardial arterioles/small arteries
─ Intimal proliferation composed of smooth muscle cells, myofibroblasts, extracellular matrix (collagen, proteoglycans), and variable numbers of lymphocytes, macrophages (foam cells may be present but less prominent than typical atherosclerosis)
─ Internal elastic lamina may be intact or fragmented/reduplicated
─ Medial involvement is variable (atrophy, fibrosis, inflammation)
─ Unlike typical atherosclerosis:
─ ─ CAV is often diffuse and circumferential, affecting entire length of vessels
─ ─ Less prominent lipid cores, cholesterol clefts, and calcification (though these can occur, especially in later stages or if superimposed atherosclerosis)
─ ─ More prominent involvement of smaller intramyocardial arteries and veins (venous CAV can also occur)
─ Endothelialitis (lymphocytic infiltration of intima/endothelium) may be seen, suggesting active immune component
Ancillary studies ─ ─ Special Stains: Elastic stains (e.g Verhoeff-Van Gieson) highlight intimal thickening and internal elastic lamina changes; Trichrome (fibrosis)
─ IHC: Can demonstrate smooth muscle cells (SMA), macrophages (CD68), lymphocytes (CD3, CD20) in intimal lesions
DDx ─ ─ Native atherosclerosis in donor heart (pre-existing disease; can be difficult to distinguish if advanced, but CAV often more diffuse and concentric, less eccentric/lipid-rich)
─ Arterial changes due to other causes (e.g hypertension – hyaline arteriolosclerosis; vasculitis – transmural inflammation, fibrinoid necrosis)
─ Post-intervention changes (e.g restenosis after angioplasty/stenting if applicable)
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Post-Transplant Lymphoproliferative Disorders (PTLD) in cardiac allografts

A spectrum of lymphoid proliferations or lymphomas that occur in recipients of solid organ (including heart) or hematopoietic stem cell transplantation due to immunosuppression, most commonly driven by Epstein-Barr Virus (EBV) infection or reactivation
Clinical ─ Can occur at any time post-transplant, but more common in first year or with high levels of immunosuppression; presentation is variable: localized tumor masses (in allograft, lymph nodes, or extranodal sites), diffuse lymphadenopathy, or systemic B symptoms (fever, weight loss, night sweats); risk factors include EBV seronegativity of recipient pre-transplant (primary EBV infection post-transplant), intensity of immunosuppression
WHO Classification of PTLD (simplified):
─ Early Lesions:
─ ─ Plasmacytic hyperplasia: Polyclonal or oligoclonal plasma cell proliferation
─ ─ Infectious mononucleosis-like PTLD: Polymorphic B-cell hyperplasia resembling IM
─ Polymorphic PTLD:
─ ─ Destructive lymphoid proliferation with a spectrum of cell sizes/types (small lymphocytes, plasma cells, immunoblasts, Reed-Sternberg-like cells) but lacks features of overt lymphoma; often EBV+
─ ─ May regress with reduction of immunosuppression, but can progress to monomorphic PTLD
─ Monomorphic PTLD (Overt Lymphoma):
─ ─ Meets criteria for a specific B-cell or T-cell/NK-cell lymphoma subtype
─ ─ Most common are B-cell lymphomas: Diffuse Large B-cell Lymphoma (DLBCL, most frequent), Burkitt lymphoma, plasmablastic lymphoma, plasma cell myeloma
─ ─ T-cell/NK-cell PTLDs are much rarer and often have worse prognosis
─ Classical Hodgkin Lymphoma PTLD (rare)
Macro ─ Can present as discrete tumor masses within the heart (myocardium, pericardium), enlarged lymph nodes, or involve other organs; lesions are often fleshy, gray-white
Micro ─ (Varies by PTLD type, see WHO classification above)
─ Cardiac allograft involvement: May show diffuse or nodular infiltrates of atypical lymphoid cells in endomyocardial biopsies or explanted hearts; can be difficult to distinguish from severe rejection or infection on small biopsies without appropriate ancillary studies
─ Atypical lymphoid cells, often with plasmacytoid differentiation, immunoblasts, or features of specific lymphoma subtype in monomorphic PTLD
Ancillary studies ─ ─ IHC: Crucial for diagnosis and classification.
─ ─ B-cell markers (CD20, CD79a, PAX5), T-cell markers (CD3, CD5)
─ ─ Markers of activation/proliferation (CD30, Ki-67)
─ ─ Plasma cell markers (CD138, MUM1, immunoglobulins kappa/lambda for clonality)
─ ─ Specific lymphoma markers depending on suspected subtype (e.g BCL6, CD10 for DLBCL/Burkitt; Cyclin D1 for Mantle Cell (very rare PTLD))
─ EBV EBER in-situ hybridization: Positive in neoplastic cells in most PTLDs (especially B-cell types), helps support diagnosis
─ Clonality studies: Immunoglobulin gene rearrangements (for B-cell PTLD), T-cell receptor (TCR) gene rearrangements (for T-cell PTLD)
DDx ─ ─ Acute cellular rejection (predominantly T-cell infiltrate, myocyte damage, lacks features of lymphoma, EBV negative in rejecting cells)
─ Antibody-mediated rejection (microvascular inflammation, C4d, lacks atypical lymphoid sheets)
─ Myocarditis due to infection (e.g CMV, other viruses; specific viral inclusions or PCR/ISH positive, lymphoid infiltrate typically reactive)
─ Benign lymphoid aggregates (e.g Quilty effect in heart transplant – endocardial, typically CD20+ B-cells peripherally and CD3+ T-cells, EBV negative)
─ De novo lymphoma unrelated to transplant (rare, may be EBV negative)
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Infections in Cardiac Transplant Recipients (CMV, Fungal, Bacterial)

opportunistic and common infections that occur in heart transplant recipients due to long-term immunosuppression, significantly impacting morbidity and mortality
Clinical ─ Risk of infection is highest in the first few months post-transplant when immunosuppression is most intense, but can occur at any time; type of infection varies with time post-transplant and net state of immunosuppression; symptoms can be non-specific (fever, malaise) or organ-specific (e.g pneumonitis, myocarditis, GI symptoms, CNS changes); prophylactic antimicrobial regimens are standard
Common Pathogens and Pathologic Features:
─ Cytomegalovirus (CMV):
─ ─ Most common opportunistic viral infection; can be primary infection (donor seropositive to recipient seronegative) or reactivation
─ ─ Manifestations: CMV pneumonitis, hepatitis, colitis, retinitis, myocarditis (less common but can mimic rejection)
─ ─ Micro (CMV Myocarditis/Vasculitis): Endothelial cell tropism; characteristic enlarged cells with large eosinophilic or amphophilic intranuclear inclusions ("owl's eye" appearance) and smaller basophilic intracytoplasmic inclusions; may see focal lymphocytic infiltrates, myocyte necrosis, or vasculitis
─ Fungal Infections:
─ ─ Aspergillus species: Invasive aspergillosis is life-threatening; often involves lungs (pneumonia, fungus balls), can disseminate to brain, heart (myocardial abscesses, endocarditis, pericarditis), or other organs
─ ─ Micro (Aspergillus): Septate hyphae with acute angle branching, invading tissues, often with associated necrosis, hemorrhage, and angioinvasion
─ ─ Candida species: Can cause esophagitis, bloodstream infections, endocarditis (especially on valves or devices), myocardial abscesses
─ ─ Micro (Candida): Yeast forms, pseudohyphae, and true hyphae; often associated with neutrophilic infiltrates and necrosis
─ ─ Pneumocystis jirovecii Pneumonia (PJP): Though primarily a lung infection, important in transplant recipients; prophylaxis is key
─ Bacterial Infections:
─ ─ Common early post-transplant (wound infections, pneumonia, line sepsis – often Staph, Strep, Gram-negatives)
─ ─ Nocardia: Can cause pulmonary or disseminated disease (brain abscesses, skin lesions)
─ ─ Listeria monocytogenes: Meningitis, sepsis
─ ─ Legionella: Pneumonia
─ ─ Mycobacteria (Tuberculosis and Nontuberculous Mycobacteria): Can reactivate or be newly acquired
─ ─ Micro (Bacterial Myocarditis/Pericarditis/Endocarditis): Typically neutrophilic inflammation, abscess formation, organisms may be visible on Gram stain
Ancillary studies ─ ─ Special Stains: GMS, PAS (fungi); Gram stain (bacteria); AFB/Ziehl-Neelsen (mycobacteria)
─ IHC/ISH: CMV immunohistochemistry or in-situ hybridization (for CMV inclusions)
─ Cultures (blood, tissue, BAL fluid), PCR assays for specific pathogens
DDx ─ ─ Allograft rejection (ACR, AMR – histologic features of rejection, C4d for AMR, lack of overt organisms) – infection can sometimes trigger or coexist with rejection
─ Post-transplant lymphoproliferative disorder (PTLD) (atypical lymphoid infiltrates, EBV EBER ISH positive)
─ Drug toxicity affecting heart
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Complications of Endomyocardial Biopsy (Heart Transplant Pathology)

Potential adverse events associated with the endomyocardial biopsy (EMB) procedure, which is routinely performed for surveillance of acute rejection in heart transplant recipients
Clinical ─ EMB is generally safe but carries small risks; complications are infrequent but can be serious; common access sites are right internal jugular or femoral vein to sample RV septum
Types of Complications:
─ Arrhythmias:
─ ─ Most common complication; usually transient (e.g premature ventricular contractions, atrial arrhythmias, transient right bundle branch block) during catheter manipulation; rarely sustained or life-threatening arrhythmias
─ Vascular Access Site Complications:
─ ─ Hematoma, arterial puncture, pneumothorax (with subclavian/jugular approach), nerve injury, deep vein thrombosis, arteriovenous fistula
─ Cardiac Perforation / Tamponade:
─ ─ Rare but life-threatening; puncture of RV free wall by bioptome or catheter, leading to hemopericardium and cardiac tamponade; requires urgent pericardiocentesis or surgical repair
─ Tricuspid Valve Damage:
─ ─ Avulsion or tearing of tricuspid valve leaflets or chordae tendineae by bioptome, can lead to acute or chronic tricuspid regurgitation
─ Myocardial Biopsy Site Issues:
─ ─ Small areas of hemorrhage, myocyte damage, and subsequent fibrosis at biopsy sites are expected and usually subclinical ("biopsy tracks")
─ ─ Extensive scarring with repeated biopsies is rare
─ Systemic Complications:
─ ─ Infection (rare), air embolism (very rare), vasovagal reactions
─ Inadequate Sampling / Sampling Error:
─ ─ Biopsy may not be representative of overall myocardial status due to patchy nature of rejection or other pathologies; obtaining sufficient tissue (typically 3-5 adequate pieces) is important
Histologic Artifacts related to EMB:
─ Crush artifact: Distortion of cells due to bioptome jaws
─ Contraction bands: Due to catecholamine release or mechanical stimulation
─ Telescoping artifact: Endocardium invaginates into myocardium
─ Endocardial denudation or thrombus at biopsy site
Macro ─ (If perforation occurs leading to explant/autopsy) Site of perforation, hemopericardium
Micro ─ (At biopsy sites in subsequent biopsies or explant) Hemorrhage, fibrin, hemosiderin, granulation tissue, fibrosis (scar) marking prior biopsy locations
Ancillary studies ─ N/A for the complications themselves, but understanding these helps in interpreting EMB findings for rejection/other pathology
DDx ─ (For histologic findings in biopsy)
─ True pathology (rejection, infection, ischemia) vs artifact or biopsy site reaction
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Pathology of Cardiac Devices

Pathology of Pacemakers and Implantable Cardioverter-Defibrillators (ICDs)

Complications and tissue reactions associated with implanted cardiac rhythm management devices, including pulse generators and transvenous leads
Clinical ─ Widely used for bradyarrhythmias (pacemakers) and tachyarrhythmias/sudden death prevention (ICDs); complications include lead dislodgement/fracture, insulation break, infection (pocket or systemic), thrombosis, venous occlusion, inappropriate shocks (ICDs), device failure
Pathologic Findings:
─ Lead-Related Issues:
─ ─ Fibrous Sheath Formation: Leads become encapsulated by a layer of fibrous connective tissue along their intravascular course and at the lead-myocardial interface; normal host response, can make lead extraction difficult
─ ─ Thrombosis: Thrombus formation around leads (especially in right atrium or ventricle) or within veins (e.g subclavian vein stenosis/occlusion); can lead to pulmonary embolism or SVC syndrome
─ ─ Endocardial/Myocardial Changes at Lead Tip:
─ ─ ─ Fibrosis/Scarring at implantation site (tip of lead screwed or tined into myocardium); pressure necrosis initially, then chronic inflammation and fibrosis
─ ─ ─ Myocardial perforation by lead (acute or chronic), can lead to pericardial effusion/tamponade
─ ─ ─ Endocardial irritation/thickening, valvular damage (if lead impinges on tricuspid valve causing regurgitation or vegetations)
─ ─ Lead Fracture or Insulation Break: Can lead to device malfunction; insulation breaks can expose conductor coil, leading to current leakage or tissue reaction
─ Pulse Generator (Pocket) Issues:
─ ─ Pocket Infection: Inflammation, purulence, sinus tract formation at generator implantation site (subcutaneous or submuscular pocket); common organisms S. aureus, S. epidermidis
─ ─ Pocket Hematoma: Bleeding at implantation site
─ ─ Device Migration or Erosion through skin
─ ─ Allergic reaction to device components (rare)
Macro ─ Examination of explanted devices and associated tissues: fibrosis around leads, thrombus, vegetations (if endocarditis), evidence of infection at pocket site, lead integrity
Micro ─ ─ Fibrous sheath around lead: Dense collagenous tissue, may have chronic inflammation
─ Thrombus: Fibrin, platelets, entrapped blood cells
─ Myocardial implantation site: Fibrosis, chronic inflammation, foreign body giant cell reaction (to lead materials), hemosiderin
─ Pocket infection: Acute and chronic inflammation, granulation tissue, abscess formation, microorganisms on special stains
Ancillary studies ─ Cultures (for infection); examination of device for mechanical failure
DDx ─ ─ Bland thrombus vs infected thrombus/vegetation (presence of organisms, prominent inflammation)
─ Normal healing response vs problematic fibrosis (e.g causing venous occlusion or lead entrapment)
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Pathology of Ventricular Assist Devices (VADs)

Complications and tissue reactions associated with mechanical circulatory support devices used in end-stage heart failure as a bridge to transplant, destination therapy, or bridge to recovery
Clinical ─ VADs (e.g Left Ventricular Assist Device - LVAD) improve survival and quality of life but are associated with significant complications: bleeding (especially GI), thromboembolism (stroke, device thrombosis), infection (driveline, pump pocket, bloodstream), right heart failure, hemolysis, device malfunction/failure
Pathologic Findings:
─ Device Thrombosis:
─ ─ Formation of thrombus within pump housing, inflow/outflow cannulas, or on rotors/bearings; can lead to pump dysfunction, hemolysis, embolic events
─ ─ Micro: Laminated thrombus (fibrin, platelets, RBCs), may show organization
─ Infection:
─ ─ Driveline Infection: Most common type; infection along percutaneous driveline tract, can extend to pump pocket or bloodstream; often S. aureus, S. epidermidis, Pseudomonas
─ ─ Pump Pocket Infection: Infection around implanted pump
─ ─ Bloodstream Infection / Sepsis: Often related to driveline or device infection, or other sources
─ ─ Micro: Acute and chronic inflammation, abscesses, granulation tissue, biofilm formation on device components, organisms on special stains/cultures
─ Hemorrhage:
─ ─ Related to anticoagulation, acquired von Willebrand syndrome (due to shear stress on vWF), GI arteriovenous malformations
─ ─ Pathologic exam may show sites of bleeding if relevant to autopsy (e.g GI tract, intracranial)
─ Thromboembolism: Embolization of thrombus from device or cardiac chambers to brain, lungs, or other organs
─ Myocardial Response to VAD Unloading:
─ ─ LV unloading can lead to myocyte atrophy, decreased fibrosis in some cases, or reverse remodeling; however, changes are variable
─ ─ Apical core tissue (removed at VAD implantation): Shows underlying cardiomyopathy (e.g dilated CM, ischemic CM features)
─ Device-Related Mechanical Issues:
─ ─ Cannula malposition, kinking, obstruction
─ ─ Pump wear, seal failure, component fracture (rare with modern devices)
─ Right Heart Failure: Can develop post-LVAD due to increased preload or underlying RV dysfunction
Macro ─ Examination of explanted VAD components (pump, cannulas) for thrombus, infection, wear; heart for underlying pathology, cannula sites, evidence of complications
Micro ─ Biofilm on device surfaces, thrombus, inflammatory infiltrates in tissues adjacent to device; myocardial biopsies may show changes related to unloading or underlying disease
Ancillary studies ─ Cultures (device components, driveline swabs, blood); microscopic examination of thrombi/biofilms; engineering analysis of failed devices
DDx ─ Differentiating causes of device dysfunction (thrombus vs mechanical failure vs infection)
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Pathology of Artificial Hearts

Complications and tissue responses associated with Total Artificial Hearts (TAHs), devices that replace native ventricles and are used as a bridge to transplantation in patients with biventricular end-stage heart failure
Clinical ─ TAHs provide complete circulatory support but are complex and associated with significant risks: thromboembolism, infection, bleeding, hemolysis, device malfunction, multiorgan failure; require external console for power and control
Pathologic Findings (similar to VADs but involve biventricular replacement):
─ Thromboembolism:
─ ─ Major complication; thrombus formation within TAH chambers, valves (if mechanical), or connections, leading to systemic or pulmonary embolism (stroke is a major concern)
─ ─ Micro: Laminated thrombus
─ Infection:
─ ─ Driveline infections (similar to VADs), device pocket infections, bloodstream infections, endocarditis-like infection of internal TAH surfaces or valves
─ ─ Biofilm formation on device surfaces is common
─ ─ Micro: Acute/chronic inflammation, abscesses, organisms
─ Bleeding: Due to anticoagulation, acquired coagulopathies
─ Hemolysis: Mechanical trauma to red blood cells by device components
─ Device Malfunction/Failure:
─ ─ Component wear, valve dysfunction (if applicable), diaphragm rupture, seal failure, electrical or mechanical failure
─ Tissue Reactions at Anastomotic Sites:
─ ─ Fibrous tissue ingrowth (pannus) at connections to native atria, aorta, pulmonary artery; can cause obstruction or interfere with device function
─ ─ Suture line dehiscence or pseudoaneurysm formation
─ Organ Damage Secondary to TAH support: e.g renal insufficiency, hepatic dysfunction, related to non-pulsatile flow (in some older designs), hemodynamic effects, or complications like sepsis/emboli
Macro ─ Examination of explanted TAH, anastomotic sites, native atria/great vessels; search for thrombus, infection, pannus, component wear/failure
Micro ─ Thrombus, biofilm, inflammatory infiltrates in adjacent tissues, pannus (fibrous tissue), foreign body reaction
Ancillary studies ─ Cultures, microscopic examination of thrombi/biofilms, engineering analysis of device components
DDx ─ Differentiating cause of TAH dysfunction or patient deterioration (e.g infection vs thrombosis vs mechanical failure)
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Pathology of Complications related to Catheters and Cannulas (Cardiac)

Adverse events and tissue reactions associated with intravascular catheters and cannulas used for diagnostic (e.g cardiac catheterization, electrophysiology studies) or therapeutic purposes (e.g cardiopulmonary bypass, ECMO, central venous lines, arterial lines) in cardiac patients
Clinical ─ Common procedures, generally safe but with potential complications depending on type, duration, and insertion site; complications include vascular injury, thrombosis, embolism (air, thrombus, particulate), infection, hematoma, arrhythmia, perforation
Pathologic Findings:
─ Vascular Injury at Insertion Site or Along Catheter/Cannula Tract:
─ ─ Endothelial denudation, intimal tears, medial dissection, vessel perforation, pseudoaneurysm formation, arteriovenous fistula
─ ─ Hematoma formation at puncture site or retroperitoneally
─ Thrombosis:
─ ─ Catheter-related thrombosis: Thrombus formation on catheter surface or in vessel lumen around catheter, can lead to venous obstruction (e.g SVC syndrome with central lines) or arterial occlusion
─ ─ Embolization of thrombus fragments
─ Infection:
─ ─ Catheter-related bloodstream infection (CRBSI): Microorganisms colonize catheter surface (biofilm), leading to bacteremia/fungemia; common with central venous catheters
─ ─ Local site infection: Cellulitis, abscess at insertion site
─ ─ Septic thrombophlebitis
─ Embolism:
─ ─ Thromboembolism (see above)
─ ─ Air embolism (if air enters system, can be catastrophic if arterial or large venous)
─ ─ Particulate embolism (e.g from catheter fragmentation, guidewire coating, dislodged atherosclerotic plaque during angiography)
─ ─ Cholesterol embolism (atheroembolism from aortic manipulation during catheterization)
─ Cardiac Complications (from intracardiac catheters):
─ ─ Arrhythmias (mechanical irritation)
─ ─ Myocardial perforation, leading to tamponade
─ ─ Valvular damage (trauma to leaflets or chordae)
─ ─ Endocardial injury, mural thrombus formation
─ ─ Coronary artery dissection or spasm (during coronary angiography/intervention)
─ Complications of Cardiopulmonary Bypass (CPB) / ECMO Cannulas:
─ ─ Similar to other large cannulas (vascular injury, thrombosis, infection)
─ ─ Specific issues related to circuit: hemolysis, systemic inflammatory response, particulate or gaseous microemboli to brain/other organs
Macro ─ Site of vascular injury, thrombus in vessels, vegetations on catheters (if infected), evidence of perforation/hemorrhage
Micro ─ Thrombus (fibrin, platelets, RBCs); inflammation (acute/chronic at infection sites, foreign body reaction to catheter material); biofilm on catheter surfaces; evidence of endothelial injury/repair; embolic material in target organs
Ancillary studies ─ Cultures (catheter tip, blood); microscopic examination of thrombi/emboli; imaging to identify vascular complications
DDx ─ Distinguishing catheter-related thrombus/infection from underlying disease process
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