Feature	Description
Structure	Muscular tube (~25 cm) from pharynx (at level of C6 vertebra) to stomach.
Compartments	Neck, Thorax (posterior mediastinum), Abdomen.
Sphincters	UES: Cricopharyngeus muscle. LES: Functional high-pressure zone at GE junction.
Anatomic Narrowings	1. UES (cricopharyngeal) 2. Thoracic (aortic arch/left bronchus crossing) 3. Diaphragmatic hiatus.
Wall Layers	Mucosa, Submucosa, Muscularis Propria, Adventitia (most) / Serosa (intra-abdominal segment).
Blood Supply	Cervical: Inferior thyroid a. Thoracic: Aortic/bronchial branches Abdominal: Left gastric a. / left inferior phrenic a.
Venous Drainage	Upper 2/3 to SVC. Lower 1/3 to portal vein (site of varices).
Lymphatics	Extensive longitudinal network; minimal invasion allows lymphatic access. Upper 1/3: Cervical nodes. Middle 1/3: Mediastinal nodes. Lower 1/3: Celiac/gastric nodes.

Esophagus Histology

Layer	Components & Features
Mucosa	Epithelium: Nonkeratinized stratified squamous. Basal layer is 1-3 cells thick. Papillae extend <2/3 of epithelial thickness. Lamina Propria: Loose CT, lymphatics, few immune cells. Muscularis Mucosae: Longitudinal smooth muscle, relatively thick.
Submucosa	Dense irregular CT, larger vessels, Meissner's plexus. Esophageal glands proper & Ducts: Tubuloacinar mucous glands for lubrication. Ducts confirm esophageal origin.
Muscularis Propria	Inner circular & outer longitudinal muscle layers with Auerbach's plexus. Composition: Upper 1/3 striated, Middle 1/3 mixed, Lower 1/3 smooth muscle.
Adventitia / Serosa	Adventitia: Covers thoracic portion (lacks a mesothelial lining). Serosa: Covers short intra-abdominal portion.
GE Junction	Abrupt transition (Z-line) from stratified squamous epithelium to simple columnar (gastric cardia) epithelium.

Esophagitis

Reflux esophagitis

A common condition resulting from injury to the esophageal mucosa due to recurrent exposure to gastric acid and/or duodenal contents

Clinical ─ Also known as gastroesophageal reflux disease (GERD)
─ Affects individuals of any age; more common in males
─ Key symptoms include heartburn (pyrosis), dysphagia, and regurgitation
─ Risk factors: hiatal hernia, obesity, smoking, alcohol, certain medications (e-g-, NSAIDs, bisphosphonates), pregnancy, delayed gastric emptying
─ Complications: ulceration, stricture, Barrett esophagus, adenocarcinoma
─ Proton pump inhibitors (PPIs) are the mainstay of treatment

Macro ─ Mucosal erythema, edema, erosions, or ulcerations, typically in the distal esophagus
─ Strictures may be present in chronic cases

Micro ─
─ Basal cell hyperplasia: >15-20% of total epithelial thickness or >3-4 cell layers
─ Papillary elongation: lamina propria papillae extend into the upper third of the squamous epithelium (nl ≤ 2/3 thickness)
─ Intraepithelial eosinophils: often the earliest and most specific sign; number can vary, some use >1-2/hpf as significant, others >5-15/hpf, especially if isolated away from GEJ
─ Intraepithelial neutrophils: indicate more severe injury, often with erosion or ulceration
─ Dilated intercellular spaces (spongiosis) and balloon cells are non-specific but common
─ Superficial necrosis and erosions may be present
─ In chronic cases: fibrosis of lamina propria and submucosa

Ancillary studies ─
─ Generally not required for diagnosis
─ IHC (-): CMV, HSV (to exclude infectious causes if clinically suspected)

DDx ─
─ Eosinophilic esophagitis: significantly higher numbers of eosinophils, often >15-20/hpf throughout the epithelium, eosinophilic microabscesses, superficial layering of eosinophils, often proximal involvement
─ Pill-induced esophagitis: history of specific medication, localized ulceration, possible pill remnants
─ Infectious esophagitis (Candida, HSV, CMV): specific cytopathic changes or organisms identified
─ Crohn's disease: granulomas (rare in esophagus)

Prognosis ─ Generally good with medical management (PPIs) and lifestyle modifications
─ Risk of complications like Barrett esophagus and adenocarcinoma in a subset of patients with chronic, severe GERD

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Radiation esophagitis

Esophageal mucosal injury resulting from therapeutic radiation to the chest, neck, or upper abdomen

Clinical ─ Occurs in patients undergoing radiotherapy for malignancies such as lung cancer, breast cancer, lymphoma, or esophageal cancer itself
─ Symptoms typically begin 2-3 weeks after initiation of radiation, including odynophagia, dysphagia, and chest pain
─ Severity depends on radiation dose, volume of esophagus irradiated, and concurrent chemotherapy

Macro ─ Mucosal erythema, edema, erosions, and ulcerations in the irradiated field
─ Strictures can develop as a late complication due to fibrosis

Micro ─
─ Acute changes: mucosal inflammation (neutrophils, eosinophils, lymphocytes), epithelial necrosis, ulceration, vascular endothelial swelling, fibrin thrombi in small vessels
─ Subacute/Chronic changes: atypical reactive epithelial cells with enlarged, hyperchromatic nuclei and smudged chromatin; bizarre stromal fibroblasts with similar atypia
─ Squamous epithelial atypia can be marked and may mimic dysplasia or carcinoma
─ Submucosal and mural fibrosis, vascular sclerosis (intimal thickening, hyalinization) are late findings
─ Absence of viral inclusions or fungal elements helps distinguish from infectious causes

Ancillary studies ─
─ Generally not required; diagnosis is often clinical based on history of radiation
─ IHC (-): CMV, HSV (to exclude superimposed infection in immunocompromised patients)

DDx ─
─ Reflux esophagitis: typically distal, characteristic basal cell hyperplasia and papillary elongation may be less prominent or altered by radiation
─ Infectious esophagitis: presence of organisms or viral cytopathic effects
─ Chemotherapy-induced esophagitis: can be histologically similar; clinical history is key
─ Squamous dysplasia/carcinoma: true neoplastic cells show more definitive features of malignancy beyond reactive atypia (e-g-, loss of maturation, high N/C ratio throughout, abnormal mitoses); radiation atypia typically involves both epithelium and stroma

Prognosis ─ Acute symptoms usually resolve weeks to months after radiation completion
─ Chronic complications like strictures or fistulas can occur and may require intervention
─ Small increased risk of secondary esophageal carcinoma years after radiation

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Chemical esophagitis

Esophageal injury due to ingestion of corrosive substances, such as strong acids or alkalis

Clinical ─ Also known as corrosive esophagitis
─ Accidental ingestion (especially in children) or suicidal intent
─ Alkalis (e-g-, lye, drain cleaners) cause liquefaction necrosis, leading to deeper penetration and more severe injury
─ Acids (e-g-, battery acid, toilet bowl cleaners) cause coagulation necrosis, forming an eschar that may limit deeper penetration but can still be severe
─ Symptoms: severe odynophagia, dysphagia, hematemesis, chest/abdominal pain, potential for perforation and systemic toxicity
─ Site: depends on agent and contact time; alkalis often affect esophagus more diffusely, acids may spare esophagus or affect it and stomach

Macro ─ Findings vary with severity and timing: erythema, edema, blistering, erosions, deep ulcerations, necrosis, hemorrhage, pseudomembrane formation
─ Strictures are a common long-term complication

Micro ─
─ Acute phase: extensive coagulative or liquefactive necrosis of mucosa and potentially deeper layers, intense acute inflammation, edema, hemorrhage, thrombosis of small vessels
─ Ulcer bed shows necrotic debris, fibrin, and acute inflammatory cells
─ Repair phase (days to weeks): granulation tissue formation, re-epithelialization, chronic inflammation
─ Chronic phase (weeks to months): fibrosis leading to stricture formation, residual chronic inflammation, squamous regeneration which may be atypical
─ Absence of viral inclusions or fungal elements

DDx ─
─ Severe reflux esophagitis: usually distal, less extensive full-thickness necrosis
─ Pill-induced esophagitis: localized injury, history of specific medication
─ Infectious esophagitis: specific organisms or viral changes present
─ Ischemic esophagitis: rare, often in critically ill patients, may show full-thickness necrosis but different clinical context

Prognosis ─ Highly variable depending on the agent, amount ingested, and promptness of treatment
─ High risk of acute complications (perforation, mediastinitis, sepsis) and long-term sequelae (strictures, dysphagia)
─ Increased long-term risk of esophageal squamous cell carcinoma (especially after lye ingestion), typically decades later

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Herpes Esophagitis

Esophagitis caused by Herpes Simplex Virus (HSV), most commonly HSV-1

Clinical ─ Also known as HSV esophagitis
─ Often occurs in immunocompromised individuals (e-g-, HIV/AIDS, transplant recipients, chemotherapy patients), but can affect immunocompetent persons
─ Symptoms: acute onset odynophagia, dysphagia, chest pain; fever may be present
─ Site: typically mid to lower esophagus, but can be diffuse

Macro ─ Multiple, small, discrete, "punched-out" or "volcano-like" ulcers, often with raised erythematous or yellowish edges
─ Ulcers may coalesce to form larger denuded areas in severe cases
─ Vesicles may be seen in early stages but are rarely biopsied

Micro ─ ─ Biopsies should be taken from the ulcer edge for optimal diagnostic yield, not the necrotic base ─ Characteristic viral cytopathic changes in squamous epithelial cells at the ulcer margin: ─ ─ Multinucleation (syncytia formation) ─ ─ Margination of chromatin (peripheral condensation against the nuclear membrane) ─ ─ Molding of nuclei (adjacent nuclei conform to each other's contours) ─ ─ Ground-glass appearance of nuclei due to viral inclusions (Cowdry type A inclusions are eosinophilic and intranuclear, surrounded by a halo, but may not always be prominent) ─ Acute inflammation, necrosis, and ulceration are present ─ Key negative findings: absence of CMV-infected endothelial/stromal cells; absence of fungal hyphae

Ancillary studies ─
─ IHC (+): HSV-1 or HSV-2 specific antibodies can confirm the diagnosis, especially if cytopathic changes are equivocal
─ Molecular ─ PCR for HSV DNA can be performed on biopsy tissue or brushings if diagnosis is uncertain

DDx ─
─ CMV esophagitis: typically involves endothelial and stromal cells in the ulcer base, not squamous epithelium at the edge; characteristic large "owl-eye" nuclear inclusions and smaller cytoplasmic inclusions
─ Varicella-Zoster Virus (VZV) esophagitis: histologically indistinguishable from HSV; clinical correlation (e-g-, dermatomal zoster) or specific IHC/PCR needed if distinction is critical (rarely)
─ Aphthous ulcers / non-specific ulceration: lack viral cytopathic changes
─ Pill-induced esophagitis: localized ulcer, no viral changes
─ Crohn's disease: granulomas, chronicity (though acute ulcers can occur)

Prognosis ─ In immunocompetent individuals, usually self-limited, resolving in 1-2 weeks; antiviral therapy (e-g-, acyclovir) can shorten duration
─ In immunocompromised patients, can be more severe, prolonged, and may disseminate; requires antiviral therapy

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Candida Esophagitis

The most common type of infectious esophagitis, caused by an overgrowth of Candida species, usually Candida albicans

Clinical ─ Most common in immunocompromised patients (HIV/AIDS, chemotherapy, organ transplant recipients, corticosteroid use)
─ Other risk factors include diabetes mellitus, elderly, adrenal insufficiency, esophageal stasis (e-g-, achalasia, scleroderma), and broad-spectrum antibiotic use
─ Symptoms include odynophagia, dysphagia, and retrosternal pain; oral thrush is often, but not always, present

Macro ─ Endoscopy shows characteristic white to yellowish, adherent, cottage cheese-like plaques or pseudomembranes on the esophageal mucosa
─ Underlying mucosa may be erythematous and friable
─ Plaques can be focal or diffuse

Micro ─
─ Biopsies show squamous epithelial cells admixed with necrotic debris, acute inflammatory cells (neutrophils), and fibrin
─ Identification of fungal elements is key:
─ ─ Yeast forms: oval, budding single cells
─ ─ Pseudohyphae: chains of budding yeast cells that remain attached, forming elongated structures with constrictions at septation points
─ ─ True hyphae: less common in Candida esophagitis, parallel-sided, septate, branching fungal filaments (more typical of Aspergillus, but can be seen)
─ Fungal elements are typically found within the desquamated superficial layers or pseudomembranes; invasion into deeper viable epithelium or lamina propria can occur, especially in severely immunocompromised patients
─ Parakeratosis, acanthosis, and intraepithelial neutrophils may be present in the underlying squamous epithelium

Ancillary studies ─
─ Special stains: Periodic acid-Schiff (PAS) with diastase and Grocott-Gomori methenamine silver (GMS) highlight fungal elements, appearing magenta with PAS and black with GMS
─ Fungal culture can be done but is usually not necessary if organisms are seen histologically
─ IHC (-): HSV, CMV (to exclude co-infection if suspected)

DDx ─
─ Reflux esophagitis with exudate: may have whitish exudate but lacks fungal elements
─ Sloughing esophagitis: shows sloughed strips of squamous epithelium, often without significant inflammation or organisms
─ Glycogenic acanthosis: whitish plaques, but histologically shows squamous cells filled with glycogen, no fungal elements
─ Leukoplakia: rare in esophagus, shows hyperkeratosis and dysplasia, no fungal elements

Prognosis ─ Excellent with antifungal therapy (e-g-, fluconazole) in most cases
─ Recurrence is possible, especially if underlying immunosuppression persists
─ Severe cases in immunocompromised hosts can lead to complications like stricture, perforation (rare), or systemic dissemination (rare)

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CMV Esophagitis

Esophagitis caused by Cytomegalovirus (CMV), typically occurring in severely immunocompromised individuals

Clinical ─ Primarily affects patients with HIV/AIDS (especially with low CD4 counts), organ transplant recipients (especially bone marrow and solid organ), and those on high-dose corticosteroids or other immunosuppressive drugs
─ Symptoms include odynophagia (often severe), dysphagia, chest pain, nausea, and vomiting; fever and weight loss may occur
─ Site: often involves the mid to distal esophagus

Macro ─ Endoscopy typically reveals one or more large, relatively deep, linear or ovoid ulcers; smaller, shallow ulcers or erosions can also occur
─ Ulcers may have a yellowish exudate

Micro ─
─ Biopsies should ideally be taken from the ulcer base, as CMV infects mesenchymal cells (endothelial cells, fibroblasts, macrophages) rather than squamous epithelial cells directly
─ Characteristic viral cytopathic changes are diagnostic:
─ ─ Enlarged cells (cytomegaly)
─ ─ Large, eosinophilic or amphophilic intranuclear inclusions, often with a surrounding clear halo ("owl's eye" appearance)
─ ─ Smaller, granular basophilic cytoplasmic inclusions may also be present
─ Infected cells are typically found in the granulation tissue at the ulcer base, within vascular endothelium, or among stromal fibroblasts
─ Ulceration, necrosis, acute and chronic inflammation are present
─ Key negative findings: absence of HSV-type viral changes in squamous cells; absence of fungal elements

Ancillary studies ─
─ IHC (+): CMV specific antibodies can confirm the diagnosis, especially if viral inclusions are sparse or atypical; stains endothelial and stromal cells
─ Molecular ─ PCR for CMV DNA can be performed on biopsy tissue, but positive result may indicate latent virus or viremia without active esophagitis, so correlation with histology/IHC is important
─ Special stains (PAS, GMS) are useful to exclude fungal co-infection

DDx ─
─ HSV esophagitis: viral changes in squamous cells at ulcer edge (multinucleation, molding, margination)
─ Other infectious esophagitis (e-g-, Candida): specific organisms identified
─ Pill-induced esophagitis: history of offending medication, localized ulceration without viral inclusions
─ Idiopathic esophageal ulcers (especially in HIV patients): lack specific viral inclusions, diagnosis of exclusion
─ Crohn's disease: granulomas, aphthous ulcers (can mimic early CMV)

Prognosis ─ Depends on the severity of immunosuppression and response to antiviral therapy (e-g-, ganciclovir, foscarnet)
─ Can lead to severe complications like hemorrhage, perforation, or stricture if untreated or in very immunocompromised patients
─ Improvement of underlying immune status is crucial for long-term control

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Lymphocytic Esophagitis

A chronic inflammatory condition of the esophagus characterized by a dense intraepithelial lymphocytic infiltrate, often associated with dysphagia and reflux-like symptoms

Clinical ─ Can affect both children and adults; some studies show a female predominance in adults
─ Symptoms are often non-specific and include dysphagia (most common), heartburn, chest pain, and food impaction
─ Associated conditions: Crohn's disease (especially in children), celiac disease, atopic conditions, connective tissue diseases; however, many cases are idiopathic
─ Endoscopic findings are variable and can be normal, or show rings, furrows, linear streaks, plaques, or strictures, sometimes mimicking eosinophilic esophagitis

Macro ─ Endoscopic appearance can be normal in many cases
─ May show subtle mucosal changes like erythema, edema, or loss of vascular pattern
─ More pronounced findings can include linear furrows, concentric rings ("trachealization"), white plaques, or strictures, especially in the proximal or mid esophagus

Micro ─
─ Diagnostic hallmark: increased number of intraepithelial lymphocytes (IELs), typically CD3+ T cells (often CD8+ predominant)
─ IELs are usually numerous, often >20-30 per high-power field (hpf), and characteristically cluster around papillae (peripapillary accentuation) and in the superficial layers of the epithelium
─ Spongiosis (intercellular edema) is common, often prominent in areas with high IEL density
─ Basal cell hyperplasia and papillary elongation may be present but are often less pronounced than in reflux esophagitis
─ Eosinophils are typically sparse or absent; if numerous, consider eosinophilic esophagitis or GERD with eosinophils
─ Neutrophils are generally absent, unless there is superimposed acute injury or ulceration
─ Epithelial desquamation or erosions are uncommon in uncomplicated cases
─ Key negative findings: absence of significant eosinophilia, granulomas, viral inclusions, or fungal elements

Ancillary studies ─
─ IHC: CD3 and CD8 stains can highlight T-lymphocytes and confirm increased IELs, but are not always necessary if H&E is clear
─ Special stains (PAS, GMS) to exclude Candida if plaques are seen endoscopically

DDx ─
─ Reflux esophagitis (GERD): IELs can be increased but usually not as densely or with peripapillary accentuation; eosinophils and neutrophils often more prominent, along with more consistent basal cell hyperplasia/papillary elongation, typically distal
─ Eosinophilic esophagitis (EoE): predominant intraepithelial eosinophils (>15-20/hpf), eosinophilic microabscesses, superficial layering of eosinophils
─ Crohn's disease involving the esophagus: may show lymphocytic infiltrates, but often has aphthous ulcers, granulomas (rare), or transmural inflammation
─ Graft-versus-host disease (GVHD) of the esophagus: history of transplant, epithelial apoptosis is a key feature along with IELs
─ Lichen planus: band-like lymphocytic infiltrate in the lamina propria hugging the basal layer, Civatte bodies, sawtooth rete ridges (more common in oral/skin but can affect esophagus)

Prognosis ─ Natural history is not fully understood; often a chronic condition with fluctuating symptoms
─ Response to PPIs is variable; some patients may respond to swallowed topical corticosteroids or dietary modifications, similar to EoE
─ Stricture formation is a potential long-term complication in some cases

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Eosinophilic Esophagitis

A chronic, immune/antigen-mediated esophageal disease characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominant inflammation

Clinical ─ Affects both children and adults; more common in males
─ Symptoms in adults: dysphagia (especially with solid foods), food impaction (hallmark), chest pain, heartburn (often PPI-refractory)
─ Symptoms in children: feeding difficulties, vomiting, abdominal pain, failure to thrive, reflux-like symptoms
─ Strong association with atopic conditions (asthma, eczema, allergic rhinitis, food allergies)
─ Diagnosis requires ≥15 eosinophils per high-power field (eos/hpf) in at least one esophageal biopsy, after excluding other causes of esophageal eosinophilia (especially GERD)
─ PPI trial (typically 8 weeks) is often used to exclude PPI-responsive esophageal eosinophilia (PPI-REE) before confirming EoE diagnosis, though this distinction is evolving

Macro ─ Endoscopic findings are variable and can include:
─ ─ Fixed rings (concentric, "trachealization" or "corrugated esophagus")
─ ─ Linear furrows (vertical lines)
─ ─ White exudates or plaques (eosinophilic abscesses)
─ ─ Edema or pallor of the mucosa
─ ─ Strictures, narrowing, or small-caliber esophagus
─ ─ Normal-appearing esophagus in a subset of patients (especially children)
─ Crepe-paper esophagus (mucosal fragility) may be noted during procedure

Micro ─
─ Diagnostic threshold: ≥15 intraepithelial eosinophils per hpf (peak count)
─ Eosinophils often found throughout the squamous epithelium, not just distally
─ Superficial layering or clustering of eosinophils near the luminal surface is characteristic
─ Eosinophilic microabscesses: collections of ≥4-5 eosinophils
─ Eosinophil degranulation: release of eosinophilic granules into the extracellular space, appearing as pink, granular material
─ Basal cell hyperplasia and papillary elongation are common
─ Lamina propria fibrosis and thickened muscularis mucosae may be seen in chronic cases
─ Marked intercellular edema (spongiosis)
─ Epithelial desquamation or sloughing may be present
─ Biopsies from both proximal and distal esophagus are recommended as eosinophilia can be patchy or more prominent proximally

Ancillary studies ─
─ Generally not required for diagnosis if H&E is characteristic and clinical criteria are met
─ Special stains (PAS, GMS) can exclude Candida if whitish plaques are seen

DDx ─
─ Gastroesophageal reflux disease (GERD): eosinophils usually <15/hpf, more prominent distally, often respond to PPIs; lacks diffuse eosinophilia, microabscesses, or superficial layering typical of EoE
─ PPI-Responsive Esophageal Eosinophilia (PPI-REE): histologically indistinguishable from EoE but symptoms and eosinophilia resolve with PPIs; now considered by some to be part of the EoE spectrum
─ Other causes of esophageal eosinophilia: infections (fungal, parasitic - rare in developed countries), pill esophagitis, Crohn's disease, GVHD, hypereosinophilic syndrome, connective tissue diseases, vasculitis
─ Lymphocytic esophagitis: predominant lymphocytes, few eosinophils

Prognosis ─ Chronic relapsing-remitting condition if untreated
─ Treatment aims to control symptoms and inflammation, and prevent complications (food impaction, strictures)
─ Mainstay treatments: dietary elimination (elemental or targeted based on allergy testing), topical swallowed corticosteroids (e-g-, fluticasone, budesonide), esophageal dilation for strictures
─ Generally does not lead to Barrett esophagus or adenocarcinoma

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Pill induced esophagitis

Esophageal mucosal injury caused by direct contact with a medication, typically when a pill is swallowed with insufficient water or by a recumbent patient

Clinical ─ Many medications can cause pill esophagitis; common culprits include:
─ ─ Doxycycline and other tetracyclines
─ ─ NSAIDs (e-g-, aspirin, ibuprofen)
─ ─ Bisphosphonates (e-g-, alendronate)
─ ─ Potassium chloride
─ ─ Iron supplements
─ ─ Quinidine, Ascorbic acid (Vitamin C), Theophylline
─ Symptoms: acute onset odynophagia, dysphagia, retrosternal chest pain, often localized
─ Site: typically occurs at sites of normal esophageal narrowing (e-g-, near aortic arch, left mainstem bronchus, or gastroesophageal junction) or areas of stasis

Macro ─ Endoscopy usually reveals a discrete, localized ulcer or erosion, sometimes with surrounding inflammation or exudate
─ Kissing ulcers on opposing esophageal walls may be seen

Micro ─
─ Focal ulceration with underlying granulation tissue and acute/chronic inflammation
─ Eosinophils may be prominent in the inflammatory infiltrate, especially with certain drugs
─ Presence of foreign material (pill fragments) is diagnostic but not always seen:
─ ─ Sevelamer (Renagel/Renvela): crystalline material, may appear "tree-bark" like, broad fish scales, can be two-toned (pink/purple on H&E)
─ ─ Kayexalate (sodium polystyrene sulfonate): distinctive violet, refractile, non-polarizable crystalline material with a mosaic or "fish-scale" pattern
─ ─ Cholestyramine: angulated, glassy, homogenous pink fragments
─ ─ Iron sulfate: rusty brown, refractile granular pigment, stains with iron stain (Prussian blue)
─ Epithelial regenerative changes, squamous hyperplasia at ulcer margins
─ Absence of viral inclusions, fungal elements, or features of severe reflux (unless coexisting)

Ancillary studies ─
─ Special stains: Iron stain (Prussian blue) for suspected iron pill injury
─ Polarization microscopy may help identify some crystalline drug remnants but many are non-polarizable

DDx ─
─ Reflux esophagitis: usually more diffuse or linear erosions/ulcers in distal esophagus; characteristic basal cell hyperplasia and papillary elongation
─ Infectious esophagitis (HSV, CMV, Candida): specific organisms or viral cytopathic changes
─ Crohn's disease: aphthous ulcers, granulomas (rare in esophagus)
─ Caustic injury: history of ingestion, more extensive necrosis

Prognosis ─ Generally excellent with discontinuation of the offending medication and supportive care (e-g-, sucralfate, PPIs)
─ Healing usually occurs within days to weeks
─ Strictures are a rare complication of severe, deep ulceration

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Lichenoid esophagitis

A rare inflammatory condition of the esophagus, often considered a manifestation of esophageal lichen planus, characterized by a band-like lymphocytic infiltrate in the superficial lamina propria and basal epithelium

Clinical ─ Often associated with cutaneous or oral lichen planus (up to 50% of cases)
─ Can also be idiopathic or associated with other conditions like chronic hepatitis C, GVHD, or medications
─ More common in middle-aged to older women
─ Symptoms: dysphagia, odynophagia, heartburn, chest pain
─ Site: typically involves the proximal or mid esophagus, but can be diffuse

Macro ─ Endoscopic findings can be variable:
─ ─ Mucosal friability, erythema, erosions, or superficial ulcerations
─ ─ Whitish papules, plaques, or reticular (lace-like) patterns (Wickham's striae, though less common than in oral lichen planus)
─ ─ Strictures or web-like narrowing in chronic cases

Micro ─
─ Band-like (lichenoid) lymphocytic infiltrate in the upper lamina propria, hugging and infiltrating the basal squamous epithelium
─ Intraepithelial lymphocytosis, predominantly T-lymphocytes (often CD8+)
─ Basal cell hydropic degeneration (vacuolization) and necrosis
─ Civatte bodies (colloid bodies): apoptotic keratinocytes, appear as eosinophilic globules in the basal epithelium or superficial lamina propria
─ Acanthosis (epithelial thickening) and parakeratosis may be present
─ Sawtooth appearance of rete ridges (less common than in cutaneous lichen planus)
─ Subepithelial clefting or separation at the epithelium-lamina propria junction can occur in severe cases
─ Key negative findings: absence of significant neutrophils or eosinophils; no granulomas, viral inclusions, or fungal elements

Ancillary studies ─
─ IHC: CD3, CD8 can highlight the T-cell nature of the infiltrate but are not essential for diagnosis
─ Direct immunofluorescence (DIF) on fresh tissue may show shaggy fibrinogen deposition along the basement membrane zone (similar to cutaneous lichen planus), but is not routinely performed and may be negative
─ Special stains (PAS, GMS) to exclude Candida if white plaques are seen

DDx ─
─ Reflux esophagitis: more neutrophils/eosinophils, basal cell hyperplasia without prominent hydropic change or Civatte bodies, typically distal
─ Lymphocytic esophagitis: dense intraepithelial lymphocytosis often with peripapillary accentuation, but typically lacks the band-like subepithelial infiltrate, basal hydropic change, and Civatte bodies
─ Sloughing esophagitis: intraepithelial splitting and superficial necrosis, but lacks the dense lichenoid infiltrate
─ Bullous diseases (e-g-, pemphigoid, epidermolysis bullosa acquisita): subepithelial or intraepithelial blisters, DIF is key for diagnosis
─ Graft-versus-host disease (GVHD): history of transplant, prominent epithelial apoptosis, lymphocytic infiltrate may be present but often not as band-like or with prominent Civatte bodies

Prognosis ─ Chronic condition, may have a relapsing-remitting course
─ Treatment often involves systemic or topical corticosteroids; response can be variable
─ Esophageal strictures are a significant complication
─ There is a potential, though not well-quantified, increased risk of developing squamous cell carcinoma in long-standing esophageal lichen planus, similar to oral lichen planus

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Sloughing esophagitis

A condition characterized by desquamation or sloughing of large fragments of the superficial esophageal squamous epithelium, often presenting with dysphagia or odynophagia

Clinical ─ Also known as esophagitis dissecans superficialis
─ Can occur at any age, but more common in adults, particularly elderly or debilitated patients
─ Associated with various factors: medications (especially NSAIDs, bisphosphonates), hot beverages, caustic ingestions (mild), bullous dermatoses (e-g-, pemphigus vulgaris), celiac disease, polypharmacy, and idiopathic cases
─ Symptoms: odynophagia, dysphagia, hematemesis (rare); some patients may be asymptomatic and sloughing is an incidental finding
─ Patients may report expectorating strips of esophageal tissue

Macro ─ Endoscopy may show whitish mucosal plaques or membranes that can be easily dislodged, revealing an underlying erythematous or eroded surface
─ Long strips or sheets of sloughed epithelium may be seen
─ Esophagus may otherwise appear normal or show mild inflammation

Micro ─
─ Characteristic finding is intraepithelial or subepithelial splitting, leading to detachment of the superficial layers of the squamous epithelium
─ Sloughed fragments consist of parakeratotic and viable squamous cells, often with a "two-tone" appearance due to superficial necrosis/debris and underlying intact epithelium
─ Prominent parakeratosis is common in the sloughed fragments and remaining epithelium
─ Intraepithelial cystic degeneration or bullae may be present
─ Basal cell hyperplasia can be seen in the remaining attached epithelium
─ Inflammatory infiltrate is usually mild and composed of lymphocytes and eosinophils; neutrophils may be present if there is associated ulceration
─ Key negative findings: absence of significant viral cytopathic changes, fungal elements, or features of lichen planus (unless coexisting)

Ancillary studies ─
─ Generally not required for diagnosis; H&E is usually sufficient
─ Special stains (PAS, GMS) to exclude Candida if extensive white plaques are noted

DDx ─
─ Candida esophagitis: presence of yeast and pseudohyphae within the plaques/pseudomembranes
─ Reflux esophagitis with exudate: exudate is more fibrinous and neutrophilic, lacks large cohesive strips of squamous epithelium
─ Chemical/caustic esophagitis: more extensive necrosis and inflammation, history of ingestion
─ Bullous dermatoses involving esophagus (e-g-, pemphigus, pemphigoid): may show similar splitting, but DIF on fresh tissue is diagnostic for these conditions; clinical history of skin lesions is usually present
─ Eosinophilic esophagitis: marked eosinophilic infiltrate, microabscesses, superficial layering of eosinophils

Prognosis ─ Generally benign and self-limited, especially if an offending agent (e-g-, medication) is identified and discontinued
─ Recurrences are possible if the underlying cause is not addressed
─ Complications such as stricture are rare

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Benign Epithelial Tumors

Squamous Papilloma

A benign exophytic proliferation of squamous epithelium with a fibrovascular core, occurring in the esophagus

Clinical ─ Relatively uncommon, often an incidental finding during endoscopy
─ Etiology is thought to be related to chronic irritation (e-g-, GERD, alcohol, smoking) or human papillomavirus (HPV), though the role of HPV is controversial and varies by geographic region and papilloma subtype
─ Can occur at any age, but more common in adults
─ Usually asymptomatic, but large papillomas can cause dysphagia
─ Site: most commonly found in the distal esophagus in Western populations; mid-esophagus reported more in some Asian studies
─ Multiple papillomas may be associated with Goltz-Gorlin syndrome (focal dermal hypoplasia) or other rare syndromes

Macro ─ Typically small (<1 cm), solitary, sessile or pedunculated, warty or polypoid, pinkish-white lesions

Micro ─
─ Exophytic papillary fronds lined by hyperplastic, mature squamous epithelium
─ Each papilla contains a central fibrovascular core derived from the lamina propria
─ Acanthosis (thickening of squamous epithelium) and parakeratosis are common
─ Koilocytic atypia (perinuclear halo, wrinkled nuclei) suggestive of HPV may be present but is not a constant feature and its significance is debated
─ No significant cytologic atypia or features of dysplasia (e-g-, loss of polarity, marked nuclear pleomorphism, abnormal mitoses extending superficially)
─ Underlying stroma may show mild chronic inflammation

Ancillary studies ─
─ IHC for p16 may be positive in HPV-associated cases but is not routinely performed or required for diagnosis
─ Molecular: HPV DNA detection (e-g-, PCR, ISH) can be performed but clinical utility is limited as most are benign regardless of HPV status; low-risk HPV types (e-g-, 6, 11) are more commonly implicated than high-risk types when HPV is present

DDx ─
─ Verrucous carcinoma: a well-differentiated variant of squamous cell carcinoma; larger, more infiltrative with a broad "pushing" base, bulbous rete ridges, and more cytologic atypia/dyskeratosis than a papilloma
─ Squamous cell carcinoma, conventional: invasive nests of malignant squamous cells with desmoplasia
─ Fibrovascular polyp: typically larger, arises in upper esophagus, composed mainly of fibrovascular stroma and adipose tissue covered by non-papillary squamous epithelium
─ Glycogenic acanthosis: flat or slightly raised plaques, histologically shows acanthosis with abundant intracytoplasmic glycogen, lacks papillary architecture
─ Inflammatory polyp (reflux polyp): often at GEJ, may have papillary surface but more prominent inflammation and granulation tissue, often with features of reflux esophagitis

Prognosis ─ Excellent; these are benign lesions with very low to negligible risk of malignant transformation
─ Recurrence after removal is uncommon
─ Management is usually endoscopic removal if symptomatic or for definitive diagnosis; small, asymptomatic lesions may be observed

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Barrett’s Esophagus (BE)

Replacement of the normal stratified squamous epithelium of the distal esophagus with metaplastic columnar epithelium containing goblet cells, predisposing to adenocarcinoma

Clinical ─ Primarily a complication of chronic gastroesophageal reflux disease (GERD)
─ Risk factors: long duration of GERD symptoms, older age (typically >50 years), male sex, Caucasian race, hiatal hernia, obesity (especially central adiposity), smoking, family history of BE or esophageal adenocarcinoma
─ Most patients with BE are asymptomatic or have typical GERD symptoms; specialized intestinal metaplasia itself does not cause symptoms
─ Endoscopic surveillance is recommended to detect dysplasia or early carcinoma
─ Management of dysplasia may include endoscopic eradication therapies (e-g-, radiofrequency ablation, endoscopic mucosal resection) or esophagectomy for high-grade dysplasia or early cancer
─ American College of Gastroenterology (ACG) defines BE as >1 cm of columnar epithelium above the gastric folds with histologic evidence of intestinal metaplasia (goblet cells)
─ British Society of Gastroenterology defines BE as ≥1 cm of columnar-lined esophagus (CLE) endoscopically, intestinal metaplasia not strictly required for diagnosis but its presence signifies higher risk

Macro ─ Endoscopically, appears as tongues or patches of salmon-pink, velvety mucosa extending proximally from the gastroesophageal junction (GEJ) into the normally pale, glossy squamous mucosa of the esophagus
─ Classified by length: Short segment BE (<3 cm), Long segment BE (≥3 cm)
─ Prague C & M criteria (Circumferential and Maximal extent) used for standardized endoscopic description
─ May be associated with other signs of GERD like erosions, ulcers, or strictures
─ Dysplasia or early carcinoma may appear as subtle mucosal irregularities, plaques, nodules, or ulcers within the Barrett's segment

Micro ─
Barrett's Esophagus without Dysplasia (Non-dysplastic BE):
─ Presence of metaplastic columnar epithelium with goblet cells (intestinal metaplasia) is required for diagnosis in the US
─ Other cell types in metaplastic epithelium can include gastric-type foveolar cells (mucin-rich, clear cytoplasm) and, less commonly, oxyntic glands (parietal and chief cells) or Paneth cells
─ Architecturally, the glands are usually regularly spaced and crypts are relatively uniform, though some villiform change can be seen
─ Chronic inflammation (lymphocytes, plasma cells) in the lamina propria is common due to underlying GERD
─ Neutrophils and eosinophils may be present, indicating active esophagitis
─ Duplication of the muscularis mucosae is a common finding, with a superficial, disorganized layer of smooth muscle within the lamina propria, above the original, deeper muscularis mucosae; this is important for staging intramucosal carcinoma
─ Key negative findings: absence of cytologic atypia beyond reactive changes, no significant architectural distortion indicative of dysplasia

Dysplasia in Barrett's Esophagus:
─ Defined as unequivocal neoplastic epithelium confined within the basement membrane
─ Characterized by cytologic and architectural abnormalities beyond those attributable to inflammation or regeneration
─ Indefinite for Dysplasia (IND):
─ ─ Atypia present that is not definitively reactive nor unequivocally dysplastic
─ ─ Often occurs in the setting of active inflammation, ulceration, or prominent regenerative changes
─ ─ Cytologic features may include nuclear crowding, hyperchromasia, some loss of polarity, but not meeting criteria for LGD
─ ─ Architectural changes are usually minimal or obscured by inflammation
─ ─ Recommendation is typically to optimize anti-reflux therapy and re-biopsy in 3-6 months
─ Low-Grade Dysplasia (LGD):
─ ─ Cytologic atypia: enlarged, hyperchromatic, elongated/pencillate nuclei, typically maintaining polarity (oriented perpendicular to basement membrane), often pseudostratified, extending to the luminal surface; nucleoli usually not prominent; mitotic figures may be present, usually basal
─ ─ Architectural atypia: glands may be mildly crowded or show slight villiform configuration; overall architecture generally preserved without complex patterns like cribriforming or extensive fusion
─ ─ Abrupt transition from non-dysplastic BE is often seen
─ ─ Surface maturation (mucin preservation at surface with atypia confined to crypts) is generally absent in true LGD; atypia involves both crypts and surface epithelium
─ High-Grade Dysplasia (HGD):
─ ─ Cytologic atypia: marked nuclear pleomorphism, irregular nuclear contours, vesicular chromatin, prominent nucleoli, loss of nuclear polarity (nuclei become rounded, haphazardly arranged); increased and often atypical mitotic figures, may be seen at all levels of the epithelium
─ ─ Architectural atypia: significant glandular complexity including crowding, branching, budding, gland fusion, cribriforming, or micropapillary patterns; glands may be irregular in size and shape
─ ─ Severe atypia involving both crypts and surface epithelium
─ ─ May include "carcinoma in situ" by some definitions, though this term is less favored
─ ─ Foveolar (gastric-type) dysplasia can occur, characterized by cells with more eosinophilic cytoplasm, rounder nuclei, and often prominent nucleoli, forming tufted or papillary surface structures
─ ─ Crypt dysplasia (atypia confined to crypts with surface maturation) is controversial; some consider it indefinite, others LGD or HGD depending on severity of atypia; its biologic significance is still debated, but high-grade atypia in crypts is concerning

Ancillary studies ─
─ Special Stains: Alcian blue (pH 2-5) or PAS-Alcian blue highlights goblet cell mucin (acidic mucin)
─ IHC (for dysplasia):
─ ─ p53: Overexpression (strong, diffuse nuclear staining) or complete absence (null pattern) in dysplastic cells, compared to wild-type (patchy, weak to moderate) staining in non-dysplastic BE or reactive atypia; can be helpful in LGD vs IND, or confirming HGD
─ ─ AMACR (alpha-methylacyl-CoA racemase): Cytoplasmic staining may be increased in dysplasia (especially HGD) and adenocarcinoma, but utility is limited by background staining and interpretation challenges
─ ─ Ki-67: Increased proliferation index in dysplasia, with staining extending to the surface, but overlap exists with reactive atypia

DDx ─
Non-dysplastic BE vs- Reactive atypia/GERD changes:
─ Reactive atypia: typically shows surface maturation (nuclei smaller, more mucin at surface), atypia more basal, inflammation often prominent; lacks abrupt clonal demarcation of dysplasia
─ Gastric cardia intestinal metaplasia: indistinguishable histologically from BE if goblet cells are present; diagnosis of BE requires endoscopic evidence of columnar lining >1cm above gastric folds
Dysplasia vs- Reactive atypia:
─ As above, reactive atypia shows surface maturation, less severe cytologic changes, and often prominent inflammation; dysplasia shows atypia extending to surface, clonal appearance, and more significant architectural changes in HGD
LGD vs- HGD:
─ Degree of cytologic pleomorphism, loss of polarity, and architectural complexity are key distinguishing features (see Micro section)
HGD vs- Intramucosal Adenocarcinoma:
─ Intramucosal adenocarcinoma shows invasion of neoplastic cells/glands into the lamina propria, often with desmoplastic response (though this can be subtle or absent in mucosa), single cells, or complex fused glands clearly separate from overlying dysplastic epithelium; HGD is confined by the glandular basement membrane
─ Duplication of muscularis mucosae can make invasion assessment tricky; true invasion must be beyond the deeper, true muscularis mucosae to be considered submucosal (pT1b)

Prognosis ─ Risk of progression to adenocarcinoma from non-dysplastic BE is ~0-2-0-5% per year
─ LGD: risk of progression to HGD/cancer is variable, reported ~0-5-13% per year; many cases regress or remain stable, interobserver variability in LGD diagnosis is high
─ HGD: significant risk of progression to adenocarcinoma (~6-19% per year or higher in some series) or harboring occult invasive cancer at time of HGD diagnosis

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Squamous Dysplasia (Esophageal)

A pre-malignant lesion characterized by neoplastic alteration of the esophageal squamous epithelium, representing a precursor to squamous cell carcinoma

Clinical ─ Risk factors are similar to those for esophageal squamous cell carcinoma: smoking, excessive alcohol consumption, history of head and neck squamous cell carcinoma, achalasia, caustic esophageal injury (e-g-, lye ingestion), Plummer-Vinson syndrome, tylosis, and dietary factors (e-g-, nitrosamines, nutritional deficiencies) in high-risk geographic areas (e-g-, parts of Asia, Africa, South America)
─ Often asymptomatic and detected during surveillance endoscopy in high-risk individuals or incidentally
─ Not typically associated with GERD or Barrett esophagus (which is glandular metaplasia)
─ HPV is not considered a major etiologic factor in most Western countries, unlike anal or cervical squamous dysplasia

Macro ─ Endoscopically, squamous dysplasia can be subtle and appear as:
─ ─ Flat, slightly erythematous or discolored patches
─ ─ Leukoplakia (whitish plaques)
─ ─ Subtle mucosal irregularities or erosions
─ ─ Lugol's iodine staining can help highlight dysplastic areas (dysplastic epithelium fails to stain or stains lightly due to glycogen depletion)
─ Advanced imaging techniques (e-g-, narrow-band imaging) improve detection

Micro ─
─ Characterized by cytologic and architectural abnormalities of squamous cells
─ Low-Grade Squamous Dysplasia (LGSD):
─ ─ Architectural changes: disordered maturation, mild basal cell hyperplasia extending into the lower one-third to one-half of the epithelium
─ ─ Cytologic atypia: mild to moderate nuclear enlargement, hyperchromasia, and pleomorphism, primarily in the basal and parabasal layers; increased nuclear-to-cytoplasmic (N/C) ratio; mitotic figures may be increased but are typically basal and not atypical
─ ─ Surface maturation is generally preserved
─ High-Grade Squamous Dysplasia (HGSD):
─ ─ Architectural changes: marked disorganization, loss of normal maturation sequence, with atypical cells extending into the upper half or full thickness of the epithelium; rete pegs may be irregular or bulbous
─ ─ Cytologic atypia: severe nuclear enlargement, hyperchromasia, pleomorphism, and irregular nuclear contours; high N/C ratio throughout much of the epithelium; mitotic figures are often numerous, may be present in superficial layers, and can be atypical
─ ─ Loss of nuclear polarity is common
─ ─ Includes lesions previously termed "carcinoma in situ"
─ Keratinization (dyskeratosis, parakeratosis, or hyperkeratosis) can be variable in both grades
─ Underlying lamina propria may show chronic inflammation

Ancillary studies ─
─ IHC for p53: Overexpression or null pattern can be seen in dysplastic cells, more commonly in HGSD, supporting neoplastic nature
─ IHC for Ki-67: Increased proliferation, with positive cells extending into suprabasal layers, more extensively in HGSD

DDx ─
─ Reactive atypia/Reparative changes (e-g-, due to reflux, infection, radiation): inflammation often prominent; atypia is usually more uniform, confined to basal/parabasal layers with preserved surface maturation; nuclei may be enlarged but often have smooth contours and prominent nucleoli rather than coarse chromatin of dysplasia; radiation atypia can affect stromal cells as well
─ Acanthosis/Glycogenic acanthosis: epithelial thickening, but cells are mature and lack significant atypia; glycogenic acanthosis has abundant clear cytoplasm due to glycogen
─ Pseudoepitheliomatous hyperplasia: often adjacent to an ulcer or granular cell tumor; shows downgrowth of irregular but cytologically bland squamous epithelium into the lamina propria, lacks significant atypia of dysplasia
─ Invasive squamous cell carcinoma: nests or single malignant cells infiltrating beyond the basement membrane into the lamina propria or deeper, often with desmoplastic stromal reaction

Prognosis ─ LGSD has a risk of progression to HGSD or invasive SCC, but many lesions may regress or remain stable; surveillance is warranted
─ HGSD has a significantly higher risk of progression to invasive SCC and often coexists with occult carcinoma; typically managed with endoscopic resection or ablation, or esophagectomy in select cases

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Malignant epithelial tumours

Esophageal Adenocarcinoma

A malignant glandular neoplasm arising in the esophagus, most commonly in the distal third and often from a background of Barrett esophagus

Clinical ─ Incidence has been rising dramatically in Western countries over the past few decades
─ Strong association with Barrett esophagus (long-segment > short-segment) and chronic GERD
─ Other risk factors include obesity, smoking, male sex, and Caucasian race
─ Symptoms: progressive dysphagia (solids then liquids), weight loss, odynophagia, chest pain, hematemesis, or melena; often asymptomatic until advanced
─ Tumors located at or involving the GEJ are staged as esophageal if the epicenter is in the esophagus or within the proximal 2 cm of the cardia and extends into the esophagus

Macro ─ Most common in the distal esophagus
─ May appear as an exophytic mass, an ulcerated lesion, a diffusely infiltrative thickening (linitis plastica-like), or a stricture
─ Underlying Barrett esophagus is often visible adjacent to the tumor

Micro ─
─ Majority are intestinal-type adenocarcinomas, forming glands, tubules, or papillary structures
─ Tumor cells are columnar or cuboidal with varying degrees of nuclear atypia, pleomorphism, hyperchromasia, and prominent nucleoli
─ Mitotic activity is usually evident
─ Glandular differentiation can range from well-formed glands to poorly differentiated sheets or cords of cells
─ Mucinous adenocarcinoma (extracellular mucin >50% of tumor volume) and signet-ring cell carcinoma (intracellular mucin displacing nucleus, >50% of tumor cells) variants occur and are often associated with a worse prognosis
─ Poorly cohesive carcinoma (other than signet-ring cell type) can also occur
─ Background Barrett esophagus with or without dysplasia is frequently present
─ Invasion into lamina propria, submucosa, muscularis propria, adventitia, or adjacent structures defines T stage
─ Lymphovascular invasion is common and an adverse prognostic factor
─ Treatment effect (e-g-, after neoadjuvant chemoradiation) should be assessed: fibrosis, inflammation, acellular mucin pools, and residual viable tumor cells (often with marked cytologic atypia)

Ancillary studies ─
─ IHC (+): Cytokeratins (AE1/AE3, CAM5-2, CK7, CK19), CDX2 (often positive, indicating intestinal differentiation), Villin
─ IHC (-): CK20 (can be positive but less consistently than CDX2), p63, CK5/6 (to exclude squamous differentiation)
─ HER2 (ERBB2) overexpression/amplification: Present in 10-30% of cases; testing is mandatory for advanced/metastatic disease to guide trastuzumab therapy; typically assessed by IHC, with FISH for equivocal (2+) cases
─ Mismatch Repair (MMR) protein IHC/Microsatellite Instability (MSI) testing: MSI-High is uncommon in esophageal adenocarcinoma (~5-15%), but may have prognostic/predictive implications (e-g-, for immunotherapy)
─ PD-L1 IHC: May be tested in advanced disease to guide immunotherapy

DDx ─
─ High-grade dysplasia in Barrett esophagus: lacks invasion into lamina propria; complex architecture but glands generally remain confined by basement membranes
─ Gastric cardia adenocarcinoma extending into esophagus: distinction can be difficult, relies on tumor epicenter and staging rules; immunoprofile may overlap
─ Adenosquamous carcinoma: requires distinct components of both adenocarcinoma and squamous cell carcinoma
─ Mucoepidermoid carcinoma: rare, mixture of squamoid, mucous, and intermediate cells
─ Adenoid cystic carcinoma: rare, cribriform pattern, dual epithelial-myoepithelial population
─ Metastatic adenocarcinoma: clinical history, morphology, and IHC panel (e-g-, TTF-1 for lung, GATA3 for breast) crucial

Prognosis ─ Generally poor, as many patients present with advanced-stage disease
─ Stage (TNM) is the most important prognostic factor
─ Other adverse factors: poor differentiation, signet-ring cells, lymphovascular invasion, positive margins, HER2 amplification (controversial, but may indicate more aggressive biology)
─ Response to neoadjuvant therapy is also a key prognostic indicator

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Esophageal squamous cell carcinoma (SCC)

A malignant epithelial neoplasm with squamous differentiation, arising from the esophageal squamous mucosa

Clinical ─ Historically the most common type of esophageal cancer worldwide, though adenocarcinoma is now more common in some Western countries
─ High incidence in specific geographic regions ("esophageal cancer belt" in Asia, parts of Africa and South America)
─ Major risk factors: tobacco smoking (any form), excessive alcohol consumption (especially synergistic with smoking)
─ Other risk factors: achalasia, history of caustic esophageal injury (e-g-, lye), Plummer-Vinson syndrome, tylosis (howel-evans syndrome), previous radiation to the mediastinum, dietary factors (e-g-, nitrosamines, betel nut chewing, hot beverages), poor oral hygiene, low socioeconomic status
─ HPV infection is not a major established risk factor in most Western populations, unlike SCC in other sites (e-g-, oropharynx, anus, cervix)
─ Symptoms: progressive dysphagia (solids then liquids), weight loss, odynophagia, retrosternal pain, cough (due to tracheoesophageal fistula), hoarseness (recurrent laryngeal nerve involvement)
─ Site: most commonly in the middle third of the esophagus, followed by lower third, then upper third

Macro ─ Appearance varies with stage:
─ ─ Early lesions: plaques, nodules, superficial erosions, or reddish patches
─ ─ Advanced lesions: exophytic (fungating) masses, ulcerative lesions, diffusely infiltrative (stenosing) tumors

Micro ─
─ Invasive nests, sheets, or cords of malignant squamous cells infiltrating the stroma
─ Squamous differentiation is characterized by:
─ ─ Keratinization (keratin pearls, individual cell keratinization/dyskeratosis)
─ ─ Intercellular bridges (desmosomes)
─ Tumor cells show varying degrees of nuclear atypia, pleomorphism, hyperchromasia, prominent nucleoli, and increased/abnormal mitotic figures
─ Grading (well, moderately, poorly differentiated) is based on the degree of squamous differentiation (keratinization) and cytologic atypia; poorly differentiated tumors may show minimal keratinization and be difficult to recognize as squamous without IHC
─ Stroma is often desmoplastic
─ Lymphovascular and perineural invasion are common
─ Background squamous mucosa may show dysplasia (low-grade or high-grade)
─ Variants:
─ ─ Basaloid squamous cell carcinoma: Composed of nests and lobules of small, basaloid cells with scant cytoplasm, hyperchromatic nuclei, and peripheral palisading; often shows comedo-like necrosis; may have areas of conventional SCC; aggressive behavior
─ ─ Verrucous (squamous cell) carcinoma: Exceedingly well-differentiated, exophytic, warty tumor with bulbous rete ridges and a broad "pushing" invasive front rather than infiltrative nests; minimal cytologic atypia; locally destructive but rarely metastasizes; diagnosis on superficial biopsy can be challenging
─ ─ Spindle cell (sarcomatoid) carcinoma and Adenosquamous carcinoma are discussed as separate entities

Ancillary studies ─
─ IHC (+): High molecular weight cytokeratins (e-g-, CK5/6), p63, p40 (more specific for squamous differentiation than p63)
─ IHC (-): CK7, CK20, CDX2 (to exclude adenocarcinoma)
─ p16 IHC: Can be positive, but its role as a surrogate for HPV is not as established or clinically relevant in esophageal SCC as in oropharyngeal SCC in most regions
─ PD-L1 IHC: May be tested in advanced disease to guide immunotherapy

DDx ─
─ Squamous dysplasia (high-grade): lacks invasion beyond the basement membrane
─ Pseudoepitheliomatous hyperplasia: reactive proliferation of squamous epithelium, often over a granular cell tumor or ulcer; lacks significant atypia and invasive features of SCC
─ Adenocarcinoma with squamous metaplasia: rare; glandular component should be evident
─ Adenosquamous carcinoma: distinct malignant glandular and squamous components
─ Undifferentiated carcinoma: lacks clear squamous or glandular differentiation; IHC needed
─ Metastatic SCC (e-g-, from lung, head/neck): clinical history is crucial; morphology and IHC usually indistinguishable from primary esophageal SCC
─ Basaloid SCC vs Adenoid cystic carcinoma: ACC is very rare, shows true glandular lumina and myoepithelial component (S100+, SMA+); Basaloid SCC is p63/p40+

Prognosis ─ Generally poor, similar to esophageal adenocarcinoma, as many present at advanced stage
─ Stage (TNM) is the most critical prognostic factor
─ Poor differentiation, deep invasion, lymph node metastasis, and positive margins are adverse prognostic indicators
─ Verrucous carcinoma has a better prognosis due to its locally aggressive but rarely metastasizing nature
─ Basaloid SCC is considered aggressive

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Esophageal sarcomatoid carcinoma

A rare, biphasic malignant neoplasm of the esophagus composed of both carcinomatous (usually squamous) and sarcomatous (spindle cell and/or pleomorphic) components

Clinical ─ Also known as spindle cell carcinoma, carcinosarcoma, or pseudosarcoma
─ Accounts for <2% of esophageal malignancies
─ Typically affects older males (6th-7th decades)
─ Risk factors are similar to those for conventional SCC (smoking, alcohol)
─ Symptoms: dysphagia, odynophagia, weight loss, chest pain; often presents with symptoms of obstruction due to its typically polypoid growth
─ Site: most common in the mid-esophagus, followed by distal then proximal

Macro ─ Characteristically forms a large, bulky, polypoid, intraluminal mass that may be pedunculated
─ Surface may be ulcerated or covered by intact squamous epithelium
─ Cut surface is often fleshy, may show areas of hemorrhage or necrosis

Micro ─
─ Biphasic tumor with intimately mixed or distinct areas of:
─ ─ Epithelial (carcinomatous) component: Most commonly squamous cell carcinoma (in situ or invasive), but can be adenocarcinoma or undifferentiated carcinoma; this component may be focal and require extensive sampling to identify, especially in biopsy specimens
─ ─ Mesenchymal (sarcomatoid) component: Composed of spindle cells, pleomorphic cells, or giant cells resembling various sarcomas (e-g-, fibrosarcoma, malignant fibrous histiocytoma-like, osteosarcoma, chondrosarcoma, rhabdomyosarcoma); spindle cells often arranged in fascicles or storiform patterns
─ The spindle cell component often predominates
─ Mitotic activity is usually high in the sarcomatoid component
─ Heterologous elements like malignant bone, cartilage, or muscle can be present
─ The two components may be intermingled or show a collision-like pattern
─ Current understanding is that this is a monoclonal tumor with divergent differentiation (metaplastic carcinoma) rather than a true collision of two separate neoplasms

Ancillary studies ─
─ IHC:
─ ─ Carcinomatous component: Positive for cytokeratins (AE1/AE3, CAM5-2, CK5/6), p63, p40 if squamous
─ ─ Sarcomatoid component: Often positive for vimentin; may show variable and focal cytokeratin positivity (especially broad-spectrum keratins like AE1/AE3 or CAM5-2), EMA, and sometimes p63, supporting its epithelial origin despite mesenchymal appearance; specific mesenchymal markers (e-g-, SMA, desmin, S100) are usually negative unless there is true heterologous differentiation
─ Molecular: Both components typically share similar genetic alterations (e-g-, TP53 mutations), supporting a monoclonal origin

DDx ─
─ True primary esophageal sarcoma (e-g-, leiomyosarcoma, GIST with anaplasia): extremely rare; lacks an epithelial component (requires thorough sampling); specific sarcoma markers would be positive (e-g-, desmin/SMA for leiomyosarcoma, CD117/DOG1 for GIST)
─ Squamous cell carcinoma with extensive spindle cell change (without true sarcomatoid morphology): spindle cells are clearly squamous and keratin positive
─ Melanoma: can be spindled and pleomorphic; S100, SOX10, Melan-A, HMB45 positive; cytokeratin negative
─ Reactive spindle cell proliferations (e-g-, inflammatory myofibroblastic tumor, postoperative spindle cell nodule): lack severe atypia and malignant epithelial component; IMT may be ALK positive
─ Polypoid well-differentiated SCC: lacks the overtly sarcomatous spindle cell component

Prognosis ─ Controversial; some studies suggest a better prognosis than conventional SCC of similar stage, possibly due to earlier presentation from obstructive symptoms caused by polypoid growth and less tendency for deep infiltration or early nodal metastasis
─ Other studies report similar or worse prognosis
─ Stage remains the most important prognostic factor
─ Depth of invasion and lymph node status are key
─ The sarcomatoid component is thought to be responsible for metastases in many cases

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Esophageal adenoid cystic carcinoma

A rare malignant epithelial neoplasm of the esophagus, histologically similar to adenoid cystic carcinoma (ACC) of the salivary glands, characterized by a dual population of ductal and myoepithelial-like cells arranged in cribriform, tubular, or solid patterns

Clinical ─ Extremely rare, representing <1% of all esophageal malignancies
─ Tends to occur in older adults (mean age ~60 years), slight male predominance
─ No specific known risk factors, not clearly associated with smoking, alcohol, or GERD
─ Symptoms are similar to other esophageal cancers: progressive dysphagia, odynophagia, weight loss
─ Site: can occur anywhere in the esophagus, but some reports suggest a predilection for the middle or upper thirds, possibly arising from submucosal esophageal glands or their ducts

Macro ─ Typically presents as an infiltrative, firm, submucosal mass, often with mucosal ulceration
─ May cause circumferential thickening and stenosis

Micro ─
─ Histologic patterns are similar to ACC in salivary glands:
─ ─ Cribriform pattern: nests of cells with multiple, rounded, "punched-out" spaces containing hyaline eosinophilic or basophilic mucoid material (pseudolumens)
─ ─ Tubular pattern: small, angulated tubules lined by ductal cells, surrounded by myoepithelial-like cells
─ ─ Solid pattern: sheets of basaloid cells with minimal lumen formation; often associated with more aggressive behavior
─ Composed of two cell types:
─ ─ Inner ductal cells: cuboidal to columnar, eosinophilic cytoplasm, line true lumens
─ ─ Outer myoepithelial-like (basaloid) cells: smaller, darker nuclei, scant cytoplasm, surround ductal cells and line pseudolumens
─ Perineural invasion is a characteristic and frequent finding, even in small tumors
─ Lymphovascular invasion can also occur
─ Stroma is often hyalinized

Ancillary studies ─
─ IHC:
─ ─ Ductal cells: Positive for cytokeratins (e-g-, CK7, AE1/AE3), EMA, CEA
─ ─ Myoepithelial-like cells: Positive for p63, p40, CK5/6, S100 (variable), SMA (variable), calponin (variable)
─ ─ KIT (CD117) is often positive in ACC (membranous/cytoplasmic), which can be a diagnostic pitfall if GIST is considered (though GIST is exceptionally rare as a primary esophageal ACC mimic)
─ ─ MYB IHC: Nuclear MYB overexpression is seen in a majority of ACCs across sites, reflecting underlying MYB-NFIB fusion or MYB activation
─ Molecular: MYB-NFIB gene fusion is characteristic of ACC in salivary glands and other sites; its presence in esophageal ACC supports the diagnosis

DDx ─
─ Basaloid squamous cell carcinoma (BSCC): most important differential; BSCC is more common, often shows connection to surface squamous epithelium or dysplasia, lacks true biphasic pattern with myoepithelial differentiation, shows more overt squamous features (keratinization, intercellular bridges) focally, and is typically negative for S100/SMA in the basaloid component; p63/p40 positive in both, but diffuse in BSCC vs peripheral in ACC myoepithelial cells
─ Mucoepidermoid carcinoma: contains mucous, intermediate, and squamoid cells; lacks the classic cribriform pattern and distinct myoepithelial component of ACC
─ Small cell neuroendocrine carcinoma: high-grade neuroendocrine morphology (nuclear molding, salt-and-pepper chromatin, high mitoses/apoptosis), positive for neuroendocrine markers (synaptophysin, chromogranin)
─ Adenocarcinoma, poorly differentiated: forms glands, lacks myoepithelial component and cribriform pattern with hyaline material
─ Metastatic ACC (e-g-, from salivary gland, lung): clinical history essential; histologically indistinguishable

Prognosis ─ Generally considered an aggressive malignancy with a poor prognosis
─ Characterized by slow but relentless growth, frequent local recurrence, and perineural spread
─ Distant metastases (commonly to lungs, liver, bone) can occur late in the course
─ Solid pattern may be associated with worse outcome
─ Long-term survival is low, though some patients may have prolonged survival despite recurrences

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Esophageal mucoepidermoid carcinoma

A rare malignant tumor of the esophagus composed of a mixture of mucus-producing cells, squamous cells, and intermediate cells, similar to its salivary gland counterpart

Clinical ─ Extremely rare in the esophagus, comprising a very small fraction of esophageal cancers
─ Can occur over a wide age range, but typically in older adults; some reports suggest male predominance
─ Symptoms are similar to other esophageal cancers: dysphagia, odynophagia, weight loss, chest pain
─ Site: most commonly reported in the mid to distal esophagus
─ Thought to arise from submucosal esophageal gland ducts

Macro ─ May present as a polypoid, ulcerated, or infiltrative mass
─ Size is variable at presentation

Micro ─
─ Triad of cell types:
─ ─ Squamoid (epidermoid) cells: polygonal cells, may show keratinization or intercellular bridges
─ ─ Mucus-producing (mucous) cells: columnar or cuboidal cells with intracytoplasmic mucin, often lining glandular or cystic structures
─ ─ Intermediate cells: smaller, basaloid, or ovoid cells with scant cytoplasm, considered pluripotential and can differentiate into squamoid or mucous cells
─ Cells are arranged in nests, islands, cords, or lining cystic spaces; solid areas may also be present
─ Stroma is often fibrous or desmoplastic
─ Grading (low, intermediate, high) is based on architectural features (cystic component vs solid growth), anaplasia, mitotic activity, and necrosis, similar to salivary gland mucoepidermoid carcinoma:
─ ─ Low-grade: predominantly cystic, minimal atypia, few mitoses
─ ─ High-grade: predominantly solid, significant atypia, increased mitoses, necrosis; may resemble squamous cell carcinoma or adenocarcinoma
─ Perineural and lymphovascular invasion can occur, especially in higher-grade tumors

Ancillary studies ─
─ IHC:
─ ─ Squamoid cells: Positive for p63, p40, high molecular weight cytokeratins (e-g-, CK5/6)
─ ─ Mucous cells: Positive for mucicarmine or PAS-diastase stains; may express cytokeratins like CK7
─ ─ Intermediate cells: May be positive for pan-cytokeratin
─ Molecular: CRTC1-MAML2 fusion (or less commonly CRTC3-MAML2) is characteristic of mucoepidermoid carcinoma in salivary glands and other sites, and its presence can confirm the diagnosis in esophageal cases, particularly distinguishing high-grade forms from adenosquamous or squamous cell carcinoma

DDx ─
─ Adenosquamous carcinoma: composed of two distinct, well-defined malignant components of adenocarcinoma and squamous cell carcinoma, rather than the intimate admixture of three cell types seen in mucoepidermoid carcinoma
─ Squamous cell carcinoma with mucinous differentiation: predominantly SCC with focal mucin production, lacks the distinct intermediate cell type and cystic structures of mucoepidermoid carcinoma
─ Adenocarcinoma with squamous metaplasia: predominantly adenocarcinoma with benign-appearing squamous metaplasia
─ Adenoid cystic carcinoma: characterized by cribriform pattern and dual population of ductal and myoepithelial-like cells; different immunoprofile (e-g-, S100, SMA in myoepithelial component)

Prognosis ─ Highly dependent on tumor grade and stage at diagnosis
─ Low-grade tumors generally have a better prognosis with surgical resection
─ High-grade tumors are aggressive, with a high rate of recurrence and metastasis, similar to other high-grade esophageal carcinomas
─ Due to rarity, large outcome studies are limited

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Esophageal adenosquamous carcinoma

A malignant epithelial tumor of the esophagus composed of two distinct malignant components: adenocarcinoma and squamous cell carcinoma

Clinical ─ Rare, accounting for approximately 1-4% of esophageal cancers
─ Typically affects older adults, with a male predominance, similar to both esophageal adenocarcinoma and SCC
─ Risk factors may overlap with both adenocarcinoma (e-g-, Barrett esophagus, GERD) and SCC (e-g-, smoking, alcohol), though specific etiology is unclear
─ Symptoms are typical of esophageal cancer: dysphagia, weight loss, odynophagia
─ Site: can occur throughout the esophagus, but may be more common in the mid to distal portions where both adenocarcinoma and SCC are prevalent

Macro ─ Tumors are often large and may appear as ulcerated, infiltrative, or exophytic masses
─ Gross appearance may not distinguish it from pure adenocarcinoma or SCC

Micro ─
─ Definitive diagnosis requires the presence of both unequivocal malignant glandular (adenocarcinomatous) and malignant squamous (squamous cell carcinomatous) components
─ Each component must constitute a significant portion of the tumor (e-g-, some definitions require at least 10% or 25% of each, though this is not universally standardized); focal metaplastic changes are insufficient
─ The two components can be intermingled or be present as distinct separate areas within the same tumor
─ Adenocarcinomatous component: forms glands, tubules, or papillary structures; cells are columnar or cuboidal with mucin production
─ Squamous cell carcinomatous component: shows keratinization (pearls, dyskeratosis) and/or intercellular bridges
─ Both components must exhibit malignant cytologic features (nuclear atypia, pleomorphism, high N/C ratio, abnormal mitoses)
─ The grade of each component can vary
─ An origin from Barrett esophagus or squamous dysplasia may be identifiable

Ancillary studies ─
─ IHC can help confirm the dual differentiation:
─ ─ Adenocarcinomatous component: Positive for cytokeratins (e-g-, CK7, CAM5-2), CEA, CDX2 (if intestinal type), MUC5AC (if gastric type)
─ ─ Squamous component: Positive for p63, p40, high molecular weight cytokeratins (e-g-, CK5/6)
─ Double-labeling IHC or careful interpretation of serial sections may be needed in intermingled areas

DDx ─
─ Adenocarcinoma with squamous metaplasia: squamous component is benign-appearing (metaplastic), not malignant
─ Squamous cell carcinoma with glandular differentiation or mucin production: predominantly SCC, glandular elements are focal or represent entrapped benign glands, or mucin is intracellular in squamous cells; lacks a distinct malignant adenocarcinoma component
─ Mucoepidermoid carcinoma: contains mucous, squamoid, and intermediate cells in an intimate admixture, not two distinct malignant populations; often has cystic components
─ Collision tumor: two separate, distinct primary tumors (adenocarcinoma and SCC) that have grown into each other; extremely rare, requires evidence of separate origins

Prognosis ─ Generally considered aggressive with a poor prognosis, often worse than pure adenocarcinoma or SCC of similar stage
─ Tends to present at an advanced stage
─ High rates of lymph node metastasis and distant spread
─ Treatment typically involves multimodality therapy similar to other esophageal cancers (surgery, chemotherapy, radiation)

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Esophageal undifferentiated carcinoma

A malignant epithelial neoplasm of the esophagus that shows no discernible squamous, glandular, or neuroendocrine differentiation by light microscopy and conventional IHC

Clinical ─ Very rare, accounting for a small percentage of esophageal cancers
─ Can occur in adults, often older individuals; male predominance similar to other esophageal cancers
─ Symptoms are non-specific and typical of esophageal malignancy: dysphagia, weight loss, pain
─ May arise anywhere in the esophagus
─ Diagnosis is one of exclusion after ruling out poorly differentiated forms of SCC, adenocarcinoma, and neuroendocrine carcinoma

Macro ─ Often presents as a large, infiltrative, and frequently ulcerated mass
─ May cause significant stenosis

Micro ─
─ Composed of sheets, nests, or diffuse infiltrates of highly atypical, pleomorphic cells
─ Cells may be round, ovoid, spindled, or anaplastic with large, bizarre nuclei and prominent nucleoli
─ Cytoplasm is variable, often scant to moderate, eosinophilic or amphophilic
─ No clear evidence of keratin pearl formation, intercellular bridges, gland formation, or mucin production by routine H&E
─ Mitotic activity is usually high, and atypical mitoses are common
─ Extensive necrosis and hemorrhage are frequent features
─ Lymphovascular and perineural invasion are often present
─ Some cases may have a prominent inflammatory infiltrate or a desmoplastic stromal response
─ Variants may include those with rhabdoid features or osteoclast-like giant cells, though these are exceptionally rare and may overlap with sarcomatoid carcinoma if any epithelial component is found

Ancillary studies ─
─ IHC is crucial for diagnosis by exclusion:
─ ─ Positive for pan-cytokeratin (e-g-, AE1/AE3, CAM5-2) confirming epithelial origin, though staining can sometimes be focal or weak in very poorly differentiated tumors
─ ─ Negative for markers of squamous differentiation (p63, p40, CK5/6)
─ ─ Negative for markers of glandular differentiation (CDX2, CK7 - though CK7 can be non-specific, villin, MUCs)
─ ─ Negative for neuroendocrine markers (synaptophysin, chromogranin, CD56)
─ ─ Negative for melanoma markers (S100, SOX10, Melan-A, HMB45)
─ ─ Negative for lymphoma markers (CD45, CD20, CD3)
─ ─ Negative for specific sarcoma markers (unless considering sarcomatoid carcinoma)
─ Electron microscopy (rarely used now) would show epithelial features (e-g-, desmosomes, tonofilaments) but lack specific differentiation

DDx ─
─ Poorly differentiated squamous cell carcinoma: may show focal keratinization or intercellular bridges on careful search or with IHC (p40, CK5/6)
─ Poorly differentiated adenocarcinoma: may show focal gland formation or mucin (PAS-D, Alcian blue) or IHC markers (CDX2, MUCs)
─ Sarcomatoid carcinoma: biphasic pattern with identifiable carcinomatous component (even if focal) and a sarcomatoid spindle/pleomorphic component; sarcomatoid part may be keratin positive
─ High-grade neuroendocrine carcinoma (small cell or large cell): shows neuroendocrine morphology (molding, salt & pepper chromatin, high mitoses/apoptosis) and positive for neuroendocrine markers
─ Malignant melanoma: S100, SOX10, Melan-A, HMB45 positive
─ Lymphoma (e-g-, diffuse large B-cell lymphoma): CD45 positive; specific lymphoid markers
─ True sarcoma: extremely rare in esophagus; expresses mesenchymal markers, negative for keratins
─ Metastatic undifferentiated carcinoma: clinical history is paramount

Prognosis ─ Generally very poor due to aggressive behavior, high grade, and often advanced stage at presentation
─ High rates of local recurrence, lymph node involvement, and distant metastases
─ Treatment options are limited and often palliative; may involve chemotherapy and/or radiation

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Esophageal neuroendocrine neoplasms (NENs)

A heterogeneous group of neoplasms arising from neuroendocrine cells within the esophageal mucosa or submucosal glands, ranging from well-differentiated neuroendocrine tumors (NETs) to poorly differentiated neuroendocrine carcinomas (NECs)

Clinical ─ Rare, comprising <1-2% of all esophageal malignancies
─ Can occur at any age, but more common in older adults (median age 60s)
─ Slight male predominance reported for some types (e-g-, small cell carcinoma)
─ Risk factors are not well-defined; unlike SCC and adenocarcinoma, clear associations with smoking, alcohol, or GERD are not consistently established for all NEN types, though some NECs may arise in association with these
─ Symptoms depend on tumor size, location, and type: dysphagia, odynophagia, weight loss, chest pain; hormone-related syndromes (e-g-, carcinoid syndrome) are exceptionally rare from primary esophageal NETs
─ Site: can occur anywhere in the esophagus; NECs (especially small cell) may favor mid to lower esophagus

Macro ─ Well-differentiated NETs (carcinoids): often small, submucosal nodules or polyps, may have yellowish cut surface; can be incidental findings
─ Poorly differentiated NECs (small cell, large cell): typically larger, infiltrative, ulcerated masses, similar to other advanced esophageal cancers

Micro ─
1- Well-differentiated Neuroendocrine Tumor (NET G1, G2): (Formerly "carcinoid tumor")
─ Cells arranged in nests, trabeculae, glands, or solid sheets within a vascular stroma
─ Tumor cells are relatively uniform, polygonal, with round to oval nuclei, "salt-and-pepper" (stippled) chromatin, and inconspicuous nucleoli
─ Cytoplasm is typically eosinophilic and granular
─ Mitotic activity is low: G1 (<2 mitoses/2 mm² or <2 mitoses/10 HPF, and Ki-67 index ≤2%); G2 (2-20 mitoses/2 mm² or 2-20 mitoses/10 HPF, or Ki-67 index 3-20%)
─ Necrosis is usually absent or minimal
2- Poorly differentiated Neuroendocrine Carcinoma (NEC G3):
─ Small cell carcinoma: Sheets of small, round, oval, or spindle-shaped cells with scant cytoplasm, ill-defined cell borders, finely granular (salt-and-pepper) chromatin, nuclear molding, and inconspicuous nucleoli; high mitotic rate (>20 mitoses/2 mm² or >20 mitoses/10 HPF); extensive necrosis and apoptosis (karyorrhexis) are characteristic; prominent Azzopardi effect (DNA encrustation of blood vessels)
─ Large cell neuroendocrine carcinoma (LCNEC): Nests, trabeculae, or sheets of large polygonal cells with abundant cytoplasm, vesicular nuclei, and prominent nucleoli; organoid patterns may be evident; high mitotic rate and frequent necrosis; must demonstrate neuroendocrine differentiation by IHC as morphology can overlap with other poorly differentiated non-neuroendocrine carcinomas
─ Ki-67 index is high (>20%) for all NEC G3
3- Mixed Neuroendocrine-Non-Neuroendocrine Neoplasm (MiNEN): (Formerly MANEC)
─ Contains both NEN and non-NEN (e-g-, adenocarcinoma or SCC) components, with each comprising at least 30% of the tumor; prognosis often driven by the NEC component or the higher-grade component

Ancillary studies ─
─ IHC (for all NENs):
─ ─ Positive for neuroendocrine markers: Synaptophysin (most sensitive), Chromogranin A (more specific, but may be negative in poorly differentiated or some NETs), CD56 (less specific)
─ ─ Positive for cytokeratins (e-g-, AE1/AE3, CAM5-2), often with a dot-like perinuclear pattern in NECs
─ ─ Ki-67 index is essential for grading (G1, G2, G3)
─ ─ Small cell carcinoma: May be TTF-1 positive (similar to lung small cell)
─ ─ Specific hormone stains (e-g-, serotonin, gastrin) are generally not useful as functional syndromes are rare from esophageal primaries

DDx ─
Well-differentiated NET vs-:
─ Granular cell tumor: S100 positive, neuroendocrine markers negative
─ Metastatic NET (e-g-, from lung, pancreas, GI tract): clinical history, IHC for site-specific markers (e-g-, TTF-1 for lung, CDX2/ISL1 for GI/pancreas) if applicable
Poorly differentiated NEC vs-:
─ Basaloid squamous cell carcinoma: p63/p40 positive, neuroendocrine markers negative
─ Poorly differentiated adenocarcinoma or SCC: lack diffuse neuroendocrine marker expression
─ Lymphoma: CD45 positive, specific lymphoid markers
─ Melanoma: S100/SOX10 positive, neuroendocrine markers negative
─ Metastatic NEC (especially from lung): often indistinguishable morphologically and immunophenotypically; clinical correlation is critical; TTF-1 positivity in a small cell carcinoma strongly suggests lung primary but can be seen in primary esophageal small cell carcinoma

Prognosis ─ Well-differentiated NETs (G1, G2): generally indolent if small and localized; larger or invasive tumors have metastatic potential (lymph nodes, liver); overall better prognosis than NECs
─ Poorly differentiated NECs (Small cell carcinoma, LCNEC): highly aggressive with early and widespread metastases; very poor prognosis, similar to small cell lung cancer
─ Stage at diagnosis is a major prognostic factor for all types

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Congenital malformations

Duplication Cyst (Esophageal)

A rare congenital anomaly consisting of a cyst lined by esophageal or other gastrointestinal-type epithelium, typically located in the esophageal wall or mediastinum adjacent to the esophagus

Clinical ─ Often asymptomatic and discovered incidentally on imaging or endoscopy
─ Symptoms, if present, depend on size and location; may include dysphagia, chest pain, cough, or respiratory distress due to compression of adjacent structures
─ Can occur at any age, but often diagnosed in infancy or childhood; some present in adulthood
─ Usually solitary; multiple cysts are rare
─ Site: most commonly in the distal esophagus, can occur anywhere along its length

Macro ─ Well-circumscribed, spherical or tubular cystic structure
─ May be intramural (within the esophageal wall, often submucosal or within muscularis propria) or extramural (mediastinal, attached to esophagus)
─ Cyst contains clear, mucoid, or hemorrhagic fluid
─ Size varies from small to very large

Micro ─
─ Cyst wall typically contains two layers of smooth muscle (muscularis propria), though this may be attenuated or incomplete
─ Lining epithelium varies:
─ ─ Most commonly stratified squamous epithelium (like normal esophagus)
─ ─ Can also be lined by ciliated columnar (respiratory-type) epithelium, gastric-type columnar epithelium (foveolar or oxyntic), or intestinal-type epithelium (rarely)
─ Submucosal glands may be present beneath the lining epithelium
─ The cyst does not typically communicate with the esophageal lumen, though rare communicating duplications exist
─ Inflammatory changes or ulceration of the lining can occur, especially if ectopic gastric mucosa is present and secretes acid

Ancillary studies ─
─ Generally not required for diagnosis if characteristic histologic features are present
─ IHC for smooth muscle markers (e-g-, SMA, desmin) can highlight the muscular wall layers if obscured
─ IHC for cytokeratins can help characterize the lining epithelium if unclear (e-g-, CK7/CK20 for intestinal vs- gastric)

DDx ─
─ Bronchogenic cyst: typically mediastinal, lined by respiratory epithelium, contains cartilage and seromucinous glands in the wall; usually lacks a double muscle layer
─ Pericardial cyst: thin-walled, lined by mesothelium, typically located in cardiophrenic angle
─ Lymphangioma: composed of dilated lymphatic channels lined by endothelium, D2-40 positive
─ Acquired esophageal diverticulum (e-g-, Zenker's, traction, epiphrenic): outpouching of esophageal lumen, lacks complete muscular wall in pulsion diverticula
─ Leiomyoma with cystic degeneration: solid tumor with secondary cystic change, lacks epithelial lining characteristic of duplication cyst

Prognosis ─ Benign condition
─ Surgical excision is curative and often performed if symptomatic or for definitive diagnosis to exclude malignancy (though malignant transformation is exceedingly rare)
─ Complications are rare but can include bleeding, infection, perforation, or malignant change (very rare, usually adenocarcinoma or SCC arising in the lining)

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Stomach

Stomach Anatomy

Feature	Description
Structure	J-shaped organ between esophagus and duodenum.
Regions	Cardia: Surrounds esophageal opening. Fundus: Dome-shaped, superior to cardia. Body (Corpus): Large central portion. Antrum & Pylorus: Distal funnel-shaped portion connecting to duodenum.
Curvatures	Lesser: Medial, concave. Greater: Lateral, convex.
Rugae	Longitudinal folds of mucosa/submucosa that allow for expansion.
Wall Layers	Mucosa, Submucosa, Muscularis Propria (3 layers: inner oblique, middle circular, outer longitudinal), Serosa.
Blood Supply	Celiac trunk (left gastric, common hepatic, splenic arteries).
Venous Drainage	Drains into the portal venous system.
Lymphatics	To gastric, gastro-omental, pyloric, pancreaticosplenic, and celiac nodes.

Stomach Histology

Layer / Region	Components & Features
Mucosa	Surface Epithelium: Simple columnar surface mucous cells (foveolar cells) secreting alkaline mucus; form gastric pits (foveolae). Lamina Propria: Loose CT with gastric glands, few immune cells. Muscularis Mucosae: Thin smooth muscle layer.
Cardiac Glands	Coiled tubular mucous glands. Pits are relatively shallow.
Oxyntic Glands (Fundus/Body)	Long, straight glands with shallow pits (<25% of mucosal thickness). - Parietal (Oxyntic) cells: Eosinophilic; secrete HCl and intrinsic factor. - Chief cells: Basophilic; secrete pepsinogen. - Mucous neck cells and Neuroendocrine cells (ECL cells).
Pyloric Glands (Antrum)	Branched, coiled mucous glands with deep pits (>50% of mucosal thickness). Contain G-cells that secrete gastrin.
Muscularis Propria	Three layers: Inner oblique, Middle circular, Outer longitudinal. Contains Auerbach's plexus.
Serosa	Outermost layer of connective tissue covered by mesothelium.

Gastritis

Reactive Gastropathy / Chemical Gastritis

Gastric mucosal injury and reactive changes due to chemical irritants, most commonly NSAIDs, alcohol, or bile reflux

Clinical ─ Often asymptomatic or associated with vague dyspeptic symptoms, epigastric pain, nausea, or vomiting
─ Common causes: Nonsteroidal anti-inflammatory drugs (NSAIDs), alcohol, bile reflux (e-g-, post-gastrectomy, cholecystectomy, or due to duodenogastric reflux), other medications (e-g-, iron, potassium chloride)
─ Symptoms may not correlate well with histologic severity
─ Site: can be diffuse or localized depending on the irritant; bile reflux typically affects antrum and pre-pyloric region; NSAID injury can be multifocal

Macro ─ Endoscopic findings are variable:
─ ─ May appear normal, or show erythema, edema, petechiae, erosions, or ulcers
─ ─ Bile staining of the mucosa may be seen in bile reflux gastropathy

Micro ─
─ Foveolar hyperplasia: elongated, tortuous, or corkscrew-shaped gastric pits lined by hyperplastic mucinous foveolar cells; cytoplasm is often depleted of mucin
─ Surface epithelial damage: degeneration, sloughing, or erosion of surface mucous cells
─ Lamina propria edema and congestion of capillaries are common
─ Smooth muscle fiber proliferation from the muscularis mucosae extending upwards between glands in the lamina propria ("fibromuscular proliferation")
─ Minimal to no significant neutrophilic or lymphocytic inflammation in the lamina propria or epithelium is characteristic of pure reactive/chemical gastropathy (hence "gastropathy" rather than "gastritis" is preferred by some if inflammation is absent)
─ If inflammation is present, it's usually mild and consists of scattered lymphocytes and plasma cells; neutrophils suggest superimposed acute gastritis (e-g-, H- pylori) or severe chemical injury
─ Intestinal metaplasia or pyloric gland metaplasia may be present if chronic injury
─ Key negative findings: absence of H- pylori organisms (unless coexisting), granulomas, significant eosinophilia, or viral inclusions

Ancillary studies ─
─ Special stains for H- pylori (e-g-, Giemsa, Warthin-Starry, or IHC) are important to exclude coexisting infection, which can cause similar foveolar hyperplasia
─ Iron stain if iron pill-induced injury is suspected

DDx ─
─ Helicobacter pylori gastritis: shows more prominent chronic inflammation (lymphocytes, plasma cells, lymphoid follicles) and often active inflammation (neutrophils in pits/epithelium); organisms identifiable with special stains/IHC
─ Portal hypertensive gastropathy: similar foveolar hyperplasia and vascular congestion, but specifically shows dilated, tortuous capillaries and venules in the superficial lamina propria without significant inflammation; clinical history of portal hypertension
─ Gastric antral vascular ectasia (GAVE): prominent fibrin thrombi within dilated superficial mucosal capillaries, along with foveolar hyperplasia and fibromuscular proliferation; characteristic "watermelon stomach" endoscopically
─ Hyperplastic polyp: a focal, polypoid lesion with exaggerated foveolar hyperplasia and edematous, often inflamed stroma
─ Menetrier disease: massive foveolar hyperplasia with cystic dilation of glands, affecting gastric body/fundus predominantly, leading to protein-losing gastropathy

Prognosis ─ Generally reversible if the offending chemical agent is removed or reduced
─ Chronic injury can lead to erosions, ulcers, and bleeding
─ Long-term bile reflux is a risk factor for intestinal metaplasia and gastric adenocarcinoma

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Portal Hypertensive Gastropathy

Gastric mucosal abnormalities, primarily vascular ectasia and congestion, occurring in patients with portal hypertension

Clinical ─ Develops in patients with portal hypertension, most commonly due to liver cirrhosis of any cause (e-g-, alcohol, viral hepatitis, NASH)
─ Can also occur with non-cirrhotic portal hypertension (e-g-, portal vein thrombosis)
─ Often asymptomatic, but can cause chronic or acute gastrointestinal bleeding (oozing or more significant hemorrhage)
─ Severity of gastropathy often correlates with the severity of portal hypertension
─ Site: predominantly affects the gastric fundus and body; antrum is typically spared or less involved

Macro ─ Endoscopic findings are characteristic:
─ ─ "Mosaic pattern" or "snake-skin" appearance: fine, reticular network of erythematous areas separated by whitish depressed lines, due to congested and edematous gastric areas (areolae)
─ ─ Red spots: small, flat or slightly raised cherry-red spots (dilated venules) or larger, more diffuse erythematous areas
─ ─ Gastric varices may also be present, especially in the fundus

Micro ─
─ Hallmark feature: marked dilation and tortuosity of capillaries and venules in the superficial lamina propria (mucosal and superficial submucosal vessels)
─ Vessels often appear congested with red blood cells
─ Foveolar hyperplasia, edema of the lamina propria, and proliferation of smooth muscle fibers from the muscularis mucosae may be present (features of reactive gastropathy)
─ Minimal or no significant inflammation (lymphocytes, plasma cells, neutrophils) is typical of pure portal hypertensive gastropathy; if present, consider coexisting gastritis (e-g-, H- pylori)
─ Fibrin thrombi in capillaries are typically absent (unlike GAVE)
─ Key negative findings: absence of significant inflammation, H- pylori, or fibrin thrombi in capillaries

Ancillary studies ─
─ Generally not required; diagnosis is based on endoscopic findings in a patient with known portal hypertension, supported by histology
─ Special stains for H- pylori if coexisting gastritis is suspected

DDx ─
─ Gastric Antral Vascular Ectasia (GAVE): predominantly antral ("watermelon stomach"), histologically shows fibrin thrombi in dilated capillaries, more prominent fibromuscular hyperplasia, and often more inflammation; not necessarily associated with portal hypertension (though can coexist)
─ Reactive gastropathy (chemical gastropathy): foveolar hyperplasia and edema, but lacks the marked, specific vascular dilation of PHG; caused by irritants like NSAIDs or bile
─ Other causes of gastric bleeding/red spots (e-g-, angiodysplasia, hereditary hemorrhagic telangiectasia): clinical context and specific vascular morphology differ

Prognosis ─ Related to the underlying cause and severity of portal hypertension
─ Risk of bleeding is significant, especially with more severe endoscopic findings
─ Management focuses on reducing portal pressure (e-g-, beta-blockers, TIPS) and treating underlying liver disease; endoscopic therapy for bleeding may be needed

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Gastric Antral Vascular Ectasia (GAVE)

A condition characterized by stripes of ectatic and thrombosed mucosal blood vessels in the gastric antrum, leading to chronic gastrointestinal bleeding and anemia

Clinical ─ Also known as "watermelon stomach" due to its characteristic endoscopic appearance of longitudinal red stripes radiating from the pylorus
─ More common in older women
─ Associated with various systemic conditions, including autoimmune diseases (especially scleroderma/CREST syndrome), chronic liver disease/cirrhosis (though portal hypertension is not a prerequisite), chronic renal failure, and bone marrow transplantation
─ Presents with chronic iron deficiency anemia due to occult blood loss; can occasionally cause acute, more severe bleeding
─ Site: almost exclusively affects the gastric antrum; rarely can involve the gastric body or duodenum

Macro ─ Endoscopy shows distinctive longitudinal erythematous stripes or columns of dilated blood vessels converging on the pylorus, resembling the stripes of a watermelon
─ Diffuse punctate red spots without clear stripes can also occur (diffuse antral vascular ectasia)

Micro ─
─ Key histologic features are found in the superficial mucosa (lamina propria):
─ ─ Dilated and tortuous mucosal capillaries and venules, often containing fibrin thrombi (microthrombi) – this is a hallmark feature
─ ─ Spindle cell proliferation (fibromuscular hyperplasia) in the lamina propria surrounding the ectatic vessels, derived from smooth muscle of muscularis mucosae or myofibroblasts
─ ─ Foveolar hyperplasia and edema of the lamina propria are common (features of reactive gastropathy)
─ Minimal to mild chronic inflammation (lymphocytes, plasma cells) may be present
─ Key negative findings: absence of significant acute inflammation (neutrophils), vasculitis, or features of portal hypertensive gastropathy (though PHG can coexist if patient has cirrhosis)

Ancillary studies ─
─ Generally not required for diagnosis if classic endoscopic and histologic features are present
─ Trichrome stain can highlight the fibromuscular hyperplasia
─ Special stains for H- pylori if coexisting gastritis is suspected

DDx ─
─ Portal Hypertensive Gastropathy (PHG): affects fundus/body more than antrum, "snake-skin" or mosaic pattern endoscopically, dilated vessels lack fibrin thrombi, associated with portal hypertension
─ Reactive gastropathy (chemical): foveolar hyperplasia and edema, but lacks the prominent vascular ectasia with fibrin thrombi and characteristic endoscopic appearance of GAVE
─ Angiodysplasia: typically isolated, larger, more malformed vessels, often in right colon or small intestine, though can occur in stomach; lacks the organized stripes of GAVE
─ Hereditary Hemorrhagic Telangiectasia (Osler-Weber-Rendu syndrome): multiple telangiectasias throughout GI tract and other organs, family history

Prognosis ─ Chronic condition that often requires ongoing management for anemia and bleeding
─ Does not typically resolve spontaneously
─ Treatment options include iron supplementation, endoscopic ablation (e-g-, argon plasma coagulation - APC, laser therapy, band ligation), and less commonly, antrectomy for refractory cases
─ Not considered a premalignant lesion

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Acute Gastritis

A condition characterized by acute inflammation of the gastric mucosa, often with epithelial injury or erosion, typically due to infectious agents or chemical irritants

Clinical ─ Common causes include Helicobacter pylori infection (initial phase), other infections (e-g-, viral like CMV, bacterial phlegmonous gastritis), NSAID use, excessive alcohol consumption, severe stress (e-g-, burns, trauma, surgery - "stress ulcers"), radiation, and chemotherapy
─ Symptoms can range from asymptomatic to epigastric pain, nausea, vomiting, and hematemesis (especially with erosions/ulcers)
─ "Focally enhanced gastritis" is a specific pattern of acute (often chronic active) gastritis with prominent pit abscesses and foveolar damage, sometimes seen in pediatric Crohn's disease or associated with H- pylori

Macro ─ Endoscopic findings may include mucosal erythema, edema, petechiae, erosions (superficial mucosal defects), or ulcers (deeper defects)
─ Hemorrhagic gastritis shows prominent submucosal hemorrhages

Micro ─
─ Hallmark is the presence of neutrophils within the gastric mucosa, particularly infiltrating the lamina propria, surface epithelium, and crypt/pit epithelium (cryptitis, pititis, pit abscesses)
─ Surface epithelial damage, degeneration, and sloughing are common
─ Erosions are characterized by loss of superficial mucosa, often with an overlying fibrinopurulent exudate and granulation tissue at the base if older
─ Lamina propria edema and vascular congestion are often present
─ In H- pylori-associated acute gastritis, organisms may be visible on the surface or within mucus, and a background chronic inflammatory infiltrate (lymphocytes, plasma cells) may also be present if transitioning to chronic phase
─ NSAID-induced acute gastritis may show more prominent erosions, hemorrhage, and relatively less inflammation initially, but can progress to ulceration; foveolar hyperplasia and paucity of inflammation can be features of NSAID gastropathy
─ CMV gastritis shows viral inclusions in endothelial or stromal cells, typically at the base of ulcers

Ancillary studies ─
─ Special stains for H- pylori (e-g-, Giemsa, Steiner, or IHC) if suspected
─ IHC for CMV if viral inclusions are suspected, especially in immunocompromised patients

DDx ─
─ Reactive gastropathy: foveolar hyperplasia, edema, smooth muscle proliferation, but minimal to no neutrophilic inflammation
─ Chronic gastritis: predominant lymphocytes and plasma cells, with or without activity (neutrophils); architectural changes like atrophy or intestinal metaplasia if long-standing
─ Lymphocytic gastritis: marked increase in intraepithelial lymphocytes, often with surface epithelial damage, but neutrophils are typically sparse
─ Eosinophilic gastritis: prominent eosinophilic infiltrate in mucosa and sometimes deeper layers, often without significant neutrophilic component

Prognosis ─ Generally good if the underlying cause is identified and removed/treated (e-g-, H- pylori eradication, NSAID withdrawal)
─ Can lead to complications like ulceration, bleeding, or perforation if severe or untreated
─ Stress ulcers can be life-threatening in critically ill patients

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Chronic Gastritis

A condition characterized by chronic inflammation of the gastric mucosa, primarily involving lymphocytes and plasma cells, which may lead to mucosal atrophy and metaplasia over time

Clinical ─ The most common cause worldwide is chronic infection with Helicobacter pylori
─ Other causes include autoimmune gastritis (targeting parietal cells), chemical irritants (long-term NSAID use, chronic bile reflux), radiation, granulomatous conditions (e-g-, Crohn's disease, sarcoidosis), and some systemic diseases
─ Often asymptomatic for long periods
─ Symptoms, when present, are non-specific: dyspepsia, epigastric pain, nausea, bloating
─ Complications depend on etiology and severity: peptic ulcer disease, mucosal atrophy, intestinal metaplasia, dysplasia, and increased risk of gastric adenocarcinoma and MALT lymphoma (especially with H- pylori and autoimmune gastritis)

Macro ─ Endoscopic findings can be variable:
─ ─ Normal appearance
─ ─ Mucosal erythema, edema, friability
─ ─ Nodularity (e-g-, antral nodular gastritis in H- pylori infection)
─ ─ Atrophic changes: pale mucosa, visible submucosal vessels, loss of rugal folds (especially in corpus/fundus with autoimmune gastritis or long-standing H- pylori)
─ ─ Intestinal metaplasia may appear as whitish, slightly raised patches

Micro ─
─ Hallmark: increased chronic inflammatory cells (lymphocytes and plasma cells) in the lamina propria
─ Lymphoid aggregates or follicles with germinal centers are common, especially in H- pylori gastritis
─ Activity: Presence of neutrophils indicates active inflammation (chronic active gastritis); neutrophils may infiltrate lamina propria, surface epithelium, or crypt/pit epithelium (cryptitis, pit abscesses)
─ Chronicity features (if present):
─ ─ Mucosal atrophy: loss of appropriate glands for the site (e-g-, oxyntic gland loss in corpus/fundus, or antral gland loss); replaced by fibrous tissue or metaplastic epithelium
─ ─ Intestinal metaplasia (IM): replacement of gastric epithelium by intestinal-type epithelium, characterized by goblet cells; may be complete (small intestinal type with brush border, Paneth cells) or incomplete (colonic type, lacking brush border, variable Paneth cells); incomplete IM may carry higher cancer risk
─ ─ Pyloric (pseudopyloric) metaplasia: replacement of oxyntic glands by mucus-secreting glands resembling antral/pyloric glands; occurs in corpus/fundus
─ ─ Pancreatic acinar metaplasia: foci of pancreatic acinar cells, usually in antrum or cardia
─ Surface epithelial changes: mucin depletion, reactive atypia, erosions (if active and severe)
─ Specific etiologic clues: H- pylori organisms, granulomas (Crohn's, sarcoid), viral inclusions (CMV), prominent eosinophils (eosinophilic gastritis)

Ancillary studies ─
─ Special stains or IHC for H- pylori are crucial if suspected
─ IHC for gastrin, chromogranin A, synaptophysin may show endocrine cell hyperplasia (e-g-, ECL cell hyperplasia in autoimmune gastritis)
─ Special stains for other organisms (e-g-, AFB for tuberculosis, GMS for fungi) if granulomatous or unusual inflammation is seen

DDx ─
─ Reactive gastropathy: foveolar hyperplasia, edema, smooth muscle proliferation, minimal to no chronic inflammation
─ Acute gastritis: predominantly neutrophilic infiltrate, may lack significant chronic inflammation or architectural changes (unless superimposed on chronic gastritis)
─ Lymphocytic gastritis: marked increase in intraepithelial lymphocytes (>25/100 epithelial cells)
─ Eosinophilic gastritis: dense eosinophilic infiltrate
─ Gastric lymphoma (especially MALT lymphoma): atypical lymphoid infiltrate, lymphoepithelial lesions; clonality studies may be needed

Prognosis ─ Depends on etiology, severity, and presence of complications like atrophy, IM, or dysplasia
─ Eradication of H- pylori can lead to resolution of inflammation and may halt or partially reverse atrophic changes if treated early
─ Autoimmune gastritis is a lifelong condition requiring B12 supplementation and surveillance for NENs and adenocarcinoma
─ Patients with extensive atrophy and intestinal metaplasia are at increased risk for gastric adenocarcinoma and require endoscopic surveillance

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Autoimmune Gastritis (Autoimmune Metaplastic Atrophic Gastritis - AMAG)

A chronic, corpus-restricted inflammatory disease where the immune system targets gastric parietal cells, leading to their destruction, loss of intrinsic factor, and profound hypochlorhydria/achlorhydria.

Clinical ─ Often asymptomatic until complications arise; may present with symptoms of pernicious anemia (a megaloblastic anemia due to B12 deficiency) such as fatigue, weakness, pallor, or neurological symptoms (peripheral neuropathy, subacute combined degeneration of the spinal cord). Can also cause iron deficiency anemia due to achlorhydria impairing iron absorption. Strongly associated with other autoimmune diseases (e.g., Hashimoto thyroiditis, type 1 diabetes). Hypergastrinemia develops as a compensatory response to achlorhydria. Increased risk of gastric neuroendocrine tumors (NETs, formerly carcinoids) and intestinal-type gastric adenocarcinoma.

Macro ─ Endoscopic findings can be subtle but often show loss of rugal folds in the body and fundus (atrophy), with preserved antral rugae. The mucosa may appear pale and thin. Polyps (hyperplastic or NETs) may be present.

Micro ─

─ Corpus/Fundus (Oxyntic Mucosa): ─ Deep, lamina propria lymphoplasmacytic infiltrate, often centered on remaining glands. Eosinophils can be prominent.

─ Destruction and marked loss of parietal and chief cells (oxyntic atrophy).

─ Metaplastic changes are key:

─ Pseudopyloric metaplasia: Oxyntic glands are replaced by mucus-secreting glands resembling antral pyloric glands.

─ Intestinal metaplasia: Replacement with goblet cells and absorptive cells.

─ Enterochromaffin-like (ECL) cell hyperplasia: Driven by chronic hypergastrinemia. Ranges from linear chains to micronodules; precursor to gastric NETs.

─ Antrum: ─ Typically shows minimal or no inflammation and is histologically spared from the primary autoimmune attack.

─ G-cell (gastrin-producing cell) hyperplasia is present due to lack of negative feedback from stomach acid.

Ancillary studies ─

─ IHC (+): Chromogranin A or Synaptophysin highlights linear and nodular ECL cell hyperplasia in the body/fundus. Gastrin IHC shows G-cell hyperplasia in the antrum.

─ IHC (-): The atrophic corpus/fundus mucosa will be negative for Gastrin. H. pylori stain should be negative (though prior infection can coexist).

─ Serology: Anti-parietal cell antibodies (APCA) are sensitive but not specific. Anti-intrinsic factor antibodies (IFA) are highly specific but less sensitive. Markedly elevated serum gastrin is characteristic.

DDx ─

─ Multifocal Atrophic Gastritis (Environmental/H. pylori-associated): Involves both antrum and corpus, typically antrum-predominant. Inflammation is more superficial and active (neutrophils). Lacks diffuse ECL hyperplasia and serologic markers of autoimmunity.

─ Chemical/Reactive Gastropathy: Foveolar hyperplasia is prominent, inflammation is scant, and there is no significant oxyntic atrophy or metaplasia.

Atrophic gastritis

A form of chronic gastritis characterized by the loss of native gastric glandular epithelium, which may be replaced by metaplastic epithelium or fibrosis

Clinical ─ Two main types:
─ ─ Environmental Metaplastic Atrophic Gastritis (EMAG): Most common type, usually caused by chronic H- pylori infection; can also be due to other chronic irritants (diet, smoking, bile reflux); typically multifocal, affecting antrum and corpus (pangastritis) or predominantly antral
─ ─ Autoimmune Metaplastic Atrophic Gastritis (AMAG): Less common, caused by autoantibodies against parietal cells and/or intrinsic factor, leading to destruction of oxyntic glands; primarily affects gastric corpus and fundus, usually spares antrum; associated with pernicious anemia (B12 deficiency), other autoimmune diseases (e-g-, Hashimoto's thyroiditis), and increased risk of Type 1 gastric neuroendocrine tumors (ECLomas) and adenocarcinoma
─ Often asymptomatic or presents with non-specific dyspeptic symptoms
─ AMAG may present with symptoms of pernicious anemia (megaloblastic anemia, neurological symptoms)
─ Both types are significant risk factors for gastric adenocarcinoma

Macro ─ Endoscopically, atrophic mucosa appears pale, thinned, with visible submucosal blood vessels and loss of rugal folds
─ Intestinal metaplasia may appear as whitish patches
─ In AMAG, antral mucosa may appear normal or even hyperplastic (due to G-cell hyperplasia) in contrast to atrophic corpus/fundus

Micro ─
─ General features of atrophy: Reduction in the volume or complete loss of native gastric glands appropriate for the biopsy site (e-g-, loss of oxyntic glands in corpus/fundus, or antral glands in antrum)
─ Glandular loss is often accompanied by lamina propria fibrosis and increased inflammatory infiltrate (lymphocytes, plasma cells)
─ Metaplastic changes are common:
─ ─ Intestinal Metaplasia (IM): Replacement of gastric epithelium by intestinal-type epithelium with goblet cells; may be complete (small intestinal type with brush border, absorptive cells, Paneth cells) or incomplete (colonic type with distorted crypts, variable Paneth cells, no brush border); often graded as mild, moderate, severe based on extent
─ ─ Pyloric (Pseudopyloric) Metaplasia: In the corpus/fundus, oxyntic glands are replaced by mucus-secreting glands resembling antral/pyloric glands
─ ─ Pancreatic Acinar Metaplasia: Foci of cells resembling pancreatic acini
─ Specific features of AMAG:
─ ─ Corpus/fundus shows marked loss of oxyntic glands, often with prominent pyloric metaplasia and intestinal metaplasia
─ ─ Lamina propria infiltrate often rich in lymphocytes and plasma cells; eosinophils can be prominent
─ ─ Deep lymphocytic infiltrates around residual glands may be seen
─ ─ Enterochromaffin-like (ECL) cell hyperplasia (linear or micronodular) is characteristic, driven by hypergastrinemia (due to achlorhydria and G-cell hyperplasia in the spared antrum)
─ ─ Antral biopsies in AMAG typically show preserved antral glands, G-cell hyperplasia, and minimal or no atrophy/inflammation (unless coexistent H- pylori)
─ Specific features of EMAG (often H- pylori related):
─ ─ Atrophy and IM can be patchy or extensive, involving antrum, corpus, or both (multifocal atrophic gastritis)
─ ─ Active inflammation (neutrophils) and lymphoid follicles suggest ongoing H- pylori infection
─ Dysplasia can arise in areas of atrophy and metaplasia, and should be carefully searched for

Ancillary studies ─
─ Special stains/IHC for H- pylori to identify or exclude infection
─ IHC for gastrin can demonstrate G-cell hyperplasia in antral biopsies in AMAG
─ IHC for synaptophysin or chromogranin A can highlight ECL cell hyperplasia in corpus/fundus biopsies in AMAG
─ Serology for anti-parietal cell antibodies and anti-intrinsic factor antibodies for AMAG diagnosis
─ Serum gastrin levels (elevated in AMAG) and pepsinogen I/II ratio (low in corpus atrophy)

DDx ─
─ Chronic gastritis without atrophy: inflammation present, but glands are preserved
─ Reactive gastropathy: foveolar hyperplasia, edema, but no significant gland loss or chronic inflammation (unless coexisting)
─ Gastric adenocarcinoma: invasive neoplastic glands, desmoplasia
─ Lymphoma: diffuse atypical lymphoid infiltrate, may cause gland destruction but different cell type

Prognosis ─ Increased risk of gastric adenocarcinoma for both EMAG and AMAG, particularly with extensive atrophy and intestinal metaplasia (especially incomplete type)
─ AMAG also carries risk for Type 1 gastric neuroendocrine tumors (ECLomas)
─ Endoscopic surveillance is recommended for patients with extensive atrophic gastritis and/or intestinal metaplasia (Operative Link on Gastritis Assessment - OLGA, or Operative Link on Gastric Intestinal Metaplasia Assessment - OLGIM staging systems can risk stratify)

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Lymphocytic Gastritis

A distinct type of chronic gastritis characterized by a marked increase in intraepithelial lymphocytes (IELs) in the surface and foveolar epithelium

Clinical ─ Relatively uncommon, but recognized more frequently
─ Etiology is often unknown (idiopathic), but associations include:
─ ─ Celiac disease (strong association, ~25-40% of lymphocytic gastritis patients may have or develop celiac disease)
─ ─ Helicobacter pylori infection (some cases, inflammation may resolve after eradication)
─ ─ HIV infection
─ ─ Crohn's disease
─ ─ Medications (e-g-, ticlopidine, olmesartan)
─ ─ Other autoimmune conditions
─ Can affect adults and children; some studies show female predominance
─ Symptoms are often non-specific: epigastric pain, dyspepsia, nausea, vomiting, anemia; can be asymptomatic
─ Site: typically involves the entire stomach (pangastritis), but can be corpus-predominant or antral-predominant

Macro ─ Endoscopic appearance is variable:
─ ─ "Varioliform gastritis": thickened rugal folds with central erosions or aphthous ulcers (classic but not always present)
─ ─ Nodular gastritis, mucosal erythema, erosions, or normal appearance

Micro ─
─ Diagnostic hallmark: increased number of intraepithelial lymphocytes (IELs) in surface and foveolar epithelium, typically defined as >25-30 IELs per 100 epithelial cells
─ IELs are small, mature lymphocytes with dark, round nuclei and scant cytoplasm, usually CD3+ and CD8+ T-cells
─ Surface epithelium often shows damage: vacuolization, mucin depletion, flattening, reactive atypia, increased apoptosis
─ Lamina propria contains a chronic inflammatory infiltrate, usually composed of lymphocytes and plasma cells, which can be mild to moderate; eosinophils may be slightly increased
─ Neutrophils (activity) are typically sparse or absent, unless there is coexisting H- pylori infection or erosions
─ Gastric pits may be elongated or show foveolar hyperplasia
─ Mucosal atrophy and intestinal metaplasia are generally not prominent features of uncomplicated lymphocytic gastritis (unless related to long-standing H- pylori or celiac disease)
─ Key negative findings: absence of granulomas, viral inclusions, significant neutrophilic activity (unless co-infection), or atypical lymphoid infiltrates suggestive of lymphoma

Ancillary studies ─
─ IHC for CD3 and CD8 can help quantify IELs and confirm their T-cell lineage if diagnosis is uncertain on H&E
─ Special stains/IHC for H- pylori to exclude co-infection
─ Serologic testing for celiac disease (anti-tissue transglutaminase, anti-endomysial antibodies) should be considered given the strong association

DDx ─
─ Chronic gastritis (e-g-, H- pylori associated): IELs may be mildly increased but usually <25/100 epithelial cells; other features like prominent plasma cells, lymphoid follicles, and neutrophils (if active) are more typical
─ Celiac disease-associated gastritis: indistinguishable histologically from idiopathic lymphocytic gastritis; clinical correlation and duodenal biopsies are key
─ Reactive gastropathy: foveolar hyperplasia, edema, minimal inflammation, IELs not significantly increased
─ Early MALT lymphoma: can have increased IELs, but typically shows atypical lymphoid infiltrate in lamina propria and lymphoepithelial lesions; clonality studies may be needed if suspicious
─ Viral gastritis (e-g-, CMV): may have increased IELs, but look for viral inclusions

Prognosis ─ Natural history is variable; some cases may resolve spontaneously or with treatment of an associated condition (e-g-, gluten-free diet for celiac disease, H- pylori eradication)
─ Often a chronic condition with persistent or relapsing symptoms in idiopathic cases
─ No clear evidence of increased risk for gastric adenocarcinoma or lymphoma in idiopathic lymphocytic gastritis, but associated conditions (celiac disease, H- pylori) may carry their own risks
─ Iron deficiency anemia can occur due to chronic inflammation or erosions

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Collagenous Gastritis

A rare inflammatory condition of the stomach characterized by a thickened subepithelial collagen band, increased intraepithelial lymphocytes, and chronic inflammation in the lamina propria

Clinical ─ Can affect children and adults; more common in middle-aged to older adults, slight female predominance reported in some series
─ Etiology is unknown in many cases (idiopathic); associations include:
─ ─ Celiac disease
─ ─ Collagenous colitis (may coexist in a subset of patients)
─ ─ Other autoimmune conditions (e-g-, lymphocytic colitis, autoimmune thyroiditis)
─ ─ Medications (possible association, but less well-established than in collagenous colitis)
─ Symptoms: epigastric pain, dyspepsia, nausea, vomiting, diarrhea, weight loss, iron deficiency anemia
─ Site: typically involves the entire stomach (pangastritis), but can be antral-predominant or corpus-predominant

Macro ─ Endoscopic findings are often non-specific:
─ ─ Mucosal nodularity (most common finding), erythema, erosions, or a mosaic pattern
─ ─ Gastric body may show atrophic changes in some cases
─ ─ Normal appearance is also possible

Micro ─
─ Diagnostic hallmark: thickened, irregular subepithelial collagen band (>10-20 µm in thickness) beneath the surface foveolar epithelium; the collagen is often hyalinized and may entrap capillaries and inflammatory cells
─ Increased intraepithelial lymphocytes (IELs) in the surface and foveolar epithelium (similar to lymphocytic gastritis)
─ Lamina propria shows a chronic inflammatory infiltrate, typically composed of lymphocytes, plasma cells, and often eosinophils
─ Surface epithelial damage: detachment from the underlying collagen band, degeneration, mucin depletion, reactive atypia
─ Foveolar hyperplasia may be present
─ Neutrophilic activity is usually absent unless there's coexisting H- pylori or erosions
─ Key negative findings: absence of granulomas, viral inclusions, or overt features of lymphoma

Ancillary studies ─
─ Special stains: Masson trichrome stain highlights the subepithelial collagen band (stains blue/green) and can help assess its thickness
─ IHC for CD3 can confirm increased IELs if needed
─ Special stains/IHC for H- pylori to exclude co-infection
─ Serologic testing for celiac disease should be considered

DDx ─
─ Lymphocytic gastritis: increased IELs and surface epithelial damage, but lacks the thickened subepithelial collagen band
─ Reactive gastropathy: foveolar hyperplasia, edema, but lacks significant chronic inflammation, increased IELs, and the collagen band
─ Chronic gastritis (e-g-, H- pylori): chronic inflammation, may have IELs, but no distinct thickened subepithelial collagen band; H- pylori organisms usually present
─ Gastric amyloidosis: amyloid deposits in vessel walls and interstitium, Congo red positive with apple-green birefringence under polarized light; collagen band is absent
─ Ischemic gastropathy (chronic): may show lamina propria fibrosis, but typically deeper, more diffuse, and associated with vascular changes, not a distinct subepithelial band

Prognosis ─ Natural history is variable; often a chronic condition with persistent or relapsing symptoms
─ Response to treatment (e-g-, corticosteroids, budesonide, immunosuppressants, elimination diets if celiac disease is present) is inconsistent
─ Spontaneous remission has been reported
─ Long-term complications are not well-defined due to rarity, but generally not considered a strong premalignant condition in itself, though associated conditions like celiac disease or autoimmune gastritis may have their own risks

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Eosinophilic Gastritis

A chronic inflammatory condition of the stomach characterized by a dense eosinophilic infiltrate in the gastric mucosa, often extending into deeper layers, in the absence of known causes for eosinophilia

Clinical ─ Part of the spectrum of eosinophilic gastrointestinal disorders (EGIDs)
─ Can affect any age group, from infants to adults; some studies suggest a peak in the 3rd-5th decades
─ Etiology is thought to be immune-mediated, often related to food allergies or other atopic conditions (asthma, eczema, allergic rhinitis are common comorbidities)
─ Peripheral eosinophilia is present in a subset of patients (20-80%)
─ Symptoms are variable and depend on the layer of gastric wall involved:
─ ─ Mucosal predominant: nausea, vomiting, abdominal pain, diarrhea, failure to thrive (children)
─ ─ Muscularis predominant: gastric outlet obstruction, postprandial vomiting (due to wall thickening and impaired motility)
─ ─ Serosal predominant: eosinophilic ascites, abdominal distension (rare)
─ Site: antrum is most commonly affected, but can involve any part of the stomach; may be patchy

Macro ─ Endoscopic findings are variable and non-specific:
─ ─ Mucosal erythema, edema, friability, nodularity, erosions, or ulcers
─ ─ Thickened rugal folds
─ ─ Gastric outlet narrowing if muscularis is involved
─ ─ Normal appearance in some cases

Micro ─
─ Diagnostic hallmark: dense eosinophilic infiltrate in the gastric mucosa (lamina propria, epithelium); often extends into submucosa and muscularis propria if these layers are sampled
─ No universally accepted cutoff for eosinophil numbers, but typically >20-30 eosinophils per high-power field (hpf) in multiple areas, often forming sheets or clusters
─ Eosinophils may infiltrate glandular epithelium (cryptitis) and form eosinophilic microabscesses
─ Eosinophil degranulation (extracellular eosinophilic granules) is common
─ Other inflammatory cells (lymphocytes, plasma cells, mast cells) are usually present but outnumbered by eosinophils
─ Neutrophils are generally sparse unless there is ulceration
─ Foveolar hyperplasia, edema, and reactive epithelial changes may be seen
─ Fibrosis can occur in chronic cases, especially with muscularis or serosal involvement
─ Careful exclusion of other causes of gastric eosinophilia is necessary (see DDx)

Ancillary studies ─
─ Generally not required for diagnosis if H&E is characteristic and clinical context fits
─ Special stains/IHC for H- pylori to exclude co-infection (which can sometimes have prominent eosinophils)
─ Stains for parasites (if travel history or clinical suspicion)

DDx ─
─ Helicobacter pylori gastritis: can have increased eosinophils, but usually accompanied by neutrophils, prominent lymphocytes/plasma cells, and organisms
─ Parasitic infections (e-g-, Anisakiasis, Strongyloidiasis): specific organisms may be identified; travel history, peripheral eosinophilia may be clues
─ Drug reactions/hypersensitivity: history of offending medication; eosinophilia may be systemic
─ Allergic gastroenteropathy (food allergy not fitting full EGID criteria): often responds to specific food elimination
─ Inflammatory bowel disease (Crohn's disease): can involve stomach with eosinophils, but usually has granulomas, aphthous ulcers, or other features of Crohn's
─ Hypereosinophilic syndrome: systemic disorder with persistent peripheral eosinophilia and organ involvement; requires exclusion of reactive causes
─ Connective tissue diseases, vasculitis: can have eosinophilic infiltrates but usually with other systemic features
─ Gastric lymphoma (rarely, Hodgkin lymphoma): atypical lymphoid cells, specific immunophenotype

Prognosis ─ Chronic relapsing-remitting course is common
─ Treatment aims to reduce eosinophilic inflammation and manage symptoms
─ Options include dietary therapy (elimination, elemental diets), corticosteroids (systemic or topical swallowed), mast cell stabilizers, leukotriene inhibitors
─ Complications include malnutrition, gastric outlet obstruction, perforation (rare)
─ Not considered a premalignant condition

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Helicobacter pylori Gastritis

Chronic inflammation of the gastric mucosa caused by infection with the bacterium Helicobacter pylori

Clinical ─ One of the most common chronic bacterial infections worldwide; prevalence varies by geography and socioeconomic status
─ Transmission is thought to be person-to-person (oral-oral or fecal-oral)
─ Majority of infected individuals are asymptomatic
─ When symptomatic, can cause dyspepsia, epigastric pain, nausea, bloating
─ Strongly associated with peptic ulcer disease (duodenal and gastric), gastric adenocarcinoma (intestinal type), and MALT lymphoma
─ Site: Typically begins in the antrum (antral-predominant gastritis); can extend to involve the corpus over time (pangastritis), especially if acid secretion decreases
─ Helicobacter heilmannii is a less common, spiral-shaped bacterium, larger than H- pylori, acquired from animals; causes similar but often milder gastritis; typically fewer organisms and less inflammation

Macro ─ Endoscopic findings are variable:
─ ─ Normal appearance (common)
─ ─ Antral erythema, edema, nodularity ("antral nodular gastritis," especially in children)
─ ─ Erosions or ulcers
─ ─ Atrophic changes (pale mucosa, visible vessels) if long-standing with atrophy

Micro ─
─ Chronic superficial gastritis (early phase):
─ ─ Lymphocytes and plasma cells expand the superficial lamina propria of the antrum
─ ─ Lymphoid aggregates or follicles with germinal centers are characteristic
─ ─ H- pylori organisms: small, curved or spiral-shaped bacilli, typically found in the surface mucus layer, within gastric pits, and adherent to surface foveolar cells; rarely intracellular
─ Chronic active gastritis:
─ ─ Neutrophils infiltrate the lamina propria, and characteristically migrate into the surface and pit epithelium (pititis, cryptitis, pit abscesses)
─ ─ Presence of neutrophils indicates active inflammation, strongly associated with H- pylori infection
─ Long-standing infection can lead to:
─ ─ Mucosal atrophy (loss of antral or oxyntic glands)
─ ─ Intestinal metaplasia (goblet cells, Paneth cells, absorptive cells)
─ ─ Pyloric metaplasia in the corpus
─ Surface epithelial changes: mucin depletion, reactive atypia, erosions
─ H- heilmannii: organisms are longer, more tightly coiled (corkscrew-like), and usually less numerous than H- pylori; associated inflammation is often milder, more focal, and may lack prominent neutrophilic activity or lymphoid follicles

Ancillary studies ─
─ Histochemical stains: Giemsa, Diff-Quik (on touch preps), Steiner silver stain, or Warthin-Starry silver stain can highlight H- pylori organisms, which are often pale on H&E
─ IHC: H- pylori-specific antibodies are highly sensitive and specific, useful in cases with few organisms, coccoid forms, or obscuring inflammation/intestinal metaplasia
─ H- heilmannii also stains with these methods, including H- pylori IHC
─ Non-invasive tests: Urea breath test, stool antigen test, serology (for IgG antibodies - indicates exposure, not necessarily active infection)

DDx ─
─ Reactive gastropathy: foveolar hyperplasia, edema, but minimal inflammation and no organisms
─ Other types of chronic gastritis (e-g-, autoimmune, lymphocytic, Crohn's): lack H- pylori; have other specific features (e-g-, corpus atrophy and ECL hyperplasia in AMAG; >25 IELs/100 epithelial cells in lymphocytic gastritis; granulomas in Crohn's)
─ Acute gastritis (other causes): e-g-, NSAID-induced may show erosions but organisms absent

Prognosis ─ Eradication therapy (antibiotics + PPI) is highly effective in curing infection and resolving inflammation
─ Resolution of gastritis can reduce risk of peptic ulcer disease, and may halt or partially reverse atrophy/IM if treated early, potentially reducing long-term cancer risk
─ Risk of gastric adenocarcinoma and MALT lymphoma is significantly increased in individuals with chronic H- pylori infection if untreated
─ H- heilmannii gastritis is also treated with similar antibiotic regimens; its long-term risks are less well-defined but generally considered lower than H- pylori

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Russell Body Gastritis

A rare and unusual form of chronic gastritis characterized by a dense infiltrate of plasma cells in the lamina propria, many of which are distended by intracytoplasmic eosinophilic inclusions (Russell bodies)

Clinical ─ Etiology is largely unknown; some cases have been associated with Helicobacter pylori infection, immunodeficiency (e-g-, HIV), or other chronic inflammatory conditions, but many are idiopathic
─ Can occur at any age, but typically in adults
─ Symptoms are non-specific, including dyspepsia, epigastric pain, or may be an incidental finding
─ Site: most commonly reported in the gastric antrum, but can be diffuse

Macro ─ Endoscopic findings are variable and non-specific:
─ ─ Mucosal erythema, edema, nodularity, or erosions
─ ─ Whitish plaques or thickened folds have been described
─ ─ May appear normal

Micro ─
─ Diagnostic feature: dense, diffuse lymphoplasmacytic infiltrate in the lamina propria, with a striking predominance of plasma cells
─ Many of these plasma cells (often called "Mott cells") contain numerous, large, eosinophilic, globular intracytoplasmic inclusions known as Russell bodies; these are accumulations of immunoglobulin
─ Russell bodies distend the cytoplasm and often push the nucleus to the periphery, giving the cells a signet-ring like appearance
─ The plasma cell infiltrate is typically polyclonal (i-e-, kappa and lambda light chains are expressed in a normal ratio), though monoclonality has been rarely reported, raising concern for plasmacytoma/MALT lymphoma with plasmacytic differentiation
─ Other inflammatory cells (lymphocytes, eosinophils, neutrophils) may be present but are usually sparse
─ Background gastric mucosa may show features of chronic gastritis, foveolar hyperplasia, or intestinal metaplasia
─ Dutcher bodies (intranuclear immunoglobulin inclusions) are generally not a feature

Ancillary studies ─
─ IHC for plasma cell markers (CD138, MUM1) confirms the nature of the infiltrating cells
─ IHC for kappa and lambda light chains is crucial to assess for polyclonality versus monotypic light chain restriction (latter would be concerning for a neoplastic process)
─ Special stains/IHC for H- pylori if an association is suspected
─ PAS stain is positive in Russell bodies (due to glycoprotein nature of immunoglobulins)

DDx ─
─ Chronic gastritis with prominent plasma cells: Russell bodies are few or absent; plasma cells do not dominate the infiltrate to such an extent
─ MALT lymphoma with plasmacytic differentiation: atypical lymphoid cells, lymphoepithelial lesions may be present; plasma cells would show light chain restriction
─ Plasmacytoma (extramedullary): sheets of monoclonal plasma cells; usually forms a discrete mass; systemic workup for multiple myeloma needed
─ Signet ring cell adenocarcinoma: malignant cells with intracytoplasmic mucin (mucin stains positive, e-g-, Alcian blue, mucicarmine), cytokeratin positive; Russell bodies are immunoglobulin, not mucin
─ Xanthoma/Xanthelasma: sheets of foamy macrophages in lamina propria, not plasma cells with Russell bodies

Prognosis ─ Generally considered a benign, reactive inflammatory condition
─ Clinical course is often indolent; may resolve if an underlying cause (like H- pylori) is treated
─ No clear evidence of increased risk for malignancy, but long-term follow-up data is limited due to rarity
─ If associated with H- pylori, eradication is recommended

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Radiation Gastritis

Gastric mucosal injury resulting from therapeutic radiation to the abdomen or adjacent areas

Clinical ─ Occurs in patients undergoing radiotherapy for malignancies such as gastric cancer, lymphoma, pancreatic cancer, or other abdominal/thoracic tumors where the stomach is in the radiation field
─ Acute symptoms (nausea, vomiting, pain, anorexia) can occur during or shortly after radiation
─ Chronic symptoms (dyspepsia, malabsorption, bleeding, stricture formation) can develop months to years later
─ Severity depends on radiation dose, fractionation, volume of stomach irradiated, and concurrent chemotherapy

Macro ─ Acute: mucosal erythema, edema, petechiae, erosions, or ulcerations
─ Chronic: atrophic mucosa, telangiectasias, strictures, or ulceration

Micro ─
─ Acute changes (early, during or shortly after radiation):
─ ─ Epithelial damage: degeneration, apoptosis, and necrosis of glandular and foveolar cells
─ ─ Edema and congestion of the lamina propria
─ ─ Acute inflammation with neutrophils may be present, especially if ulcerated
─ ─ Endothelial swelling and damage to small vessels, with fibrin thrombi
─ Chronic changes (months to years later):
─ ─ Mucosal atrophy: loss of specialized glands (oxyntic or antral)
─ ─ Intestinal metaplasia or pyloric gland metaplasia may develop
─ ─ Atypical reactive epithelial cells: enlarged, hyperchromatic nuclei, prominent nucleoli, often with smudged chromatin; these changes can be bizarre and mimic dysplasia or carcinoma
─ ─ Stromal changes: bizarre radiation fibroblasts (enlarged, hyperchromatic, stellate or spindled cells in lamina propria or submucosa), hyalinization of lamina propria, telangiectatic vessels with thickened, hyalinized walls, submucosal fibrosis
─ ─ Endarteritis obliterans (vascular sclerosis) is a characteristic late finding
─ Key negative findings: absence of H- pylori, granulomas (unless coexisting Crohn's), or specific infectious agents

Ancillary studies ─
─ Generally not required; diagnosis is usually based on history of radiation and characteristic histologic features
─ Special stains for H- pylori if coexisting infection is suspected
─ IHC for p53 may show a wild-type pattern in radiation atypia, helping to distinguish from true dysplasia/carcinoma in difficult cases, but can be variable

DDx ─
─ Reactive gastropathy (other causes): similar foveolar hyperplasia and edema, but lacks the specific radiation-induced atypia in epithelial and stromal cells, and vascular changes
─ Chronic gastritis (e-g-, H- pylori, autoimmune): specific etiologic features and inflammatory patterns differ; AMAG shows corpus-restricted atrophy and ECL hyperplasia
─ Gastric dysplasia/adenocarcinoma: true neoplastic cells show more definitive features of malignancy (loss of polarity, high N/C ratio, architectural complexity like cribriforming) beyond the reactive atypia of radiation; radiation atypia often involves both epithelium and stroma
─ Ischemic gastropathy: may show atrophy and vascular changes, but usually in a setting of systemic hypoperfusion or specific vascular events; radiation fibroblasts are absent

Prognosis ─ Acute radiation gastritis usually resolves after completion of therapy, but symptoms can be significant
─ Chronic radiation gastropathy can lead to persistent symptoms, malabsorption, chronic bleeding, strictures, or perforation (rare)
─ There is an increased long-term risk of developing gastric adenocarcinoma or sarcoma in the irradiated field, typically decades later

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Iron-Pill Gastritis / Medication-Associated Gastric Injury

Gastric mucosal injury caused by direct contact with orally administered iron supplements or other medications

Clinical ─ Caused by direct caustic effect of medications on gastric mucosa, particularly when tablets/capsules adhere or dissolve slowly
─ Iron supplements (ferrous sulfate, ferrous gluconate) are a common cause
─ Other implicated medications: NSAIDs, potassium chloride, bisphosphonates (though more noted for esophagitis)
─ Symptoms: epigastric pain, dyspepsia, nausea, vomiting, gastrointestinal bleeding (melena, hematemesis)
─ Often seen in patients taking iron for iron deficiency anemia

Macro ─ Endoscopy may show focal erythema, erosions, ulcers, or hemorrhagic spots, often with adherent brownish or blackish material (iron deposits)
─ Lesions are often in the antrum or areas of stasis

Micro ─
─ Focal mucosal injury: erosion or ulceration with underlying granulation tissue and acute/chronic inflammation
─ Characteristic feature for iron-pill gastritis: deposition of crystalline or amorphous iron pigment, which is typically golden-brown, refractile, and often encrusted on the surface epithelium, within fibrinopurulent exudate, or in the lamina propria/submucosa
─ Iron pigment stains positive with Prussian blue (Perls) iron stain
─ Reactive epithelial atypia, foveolar hyperplasia, and regenerative changes are common at the margins of erosions/ulcers
─ Underlying mucosa may be otherwise normal or show background gastritis from other causes
─ For other medications, changes are often non-specific erosive/ulcerative gastritis, without the characteristic iron pigment

Ancillary studies ─
─ Prussian blue (Perls) iron stain: confirms the presence of iron pigment (stains blue-green)
─ Special stains for H- pylori if background gastritis is present

DDx ─
─ Peptic ulcer disease (e-g-, H- pylori or NSAID-induced without iron): similar erosions/ulcers but lacks the characteristic iron deposits; NSAID gastropathy often shows foveolar hyperplasia with minimal inflammation if not ulcerated
─ Reactive gastropathy (bile reflux, alcohol): foveolar hyperplasia, edema, but no iron deposits
─ Gastric ulcer with hemosiderin: hemosiderin is typically within macrophages (from old hemorrhage), granular, and less crystalline/encrusted than exogenous iron pill deposits
─ Other causes of erosive/ulcerative gastritis (e-g-, Crohn's, infections): specific features of these conditions would be present (granulomas, viral inclusions, etc-)

Prognosis ─ Generally good if the offending medication is discontinued or formulation is changed (e-g-, liquid iron, enteric-coated if appropriate)
─ Healing of erosions/ulcers usually occurs with acid suppression and removal of the irritant
─ Chronic bleeding can lead to or exacerbate iron deficiency anemia

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Erosive gastritis

A descriptive term for gastric mucosal injury characterized by superficial mucosal defects (erosions) that do not penetrate the muscularis mucosae

Clinical ─ Not a specific disease entity, but a common manifestation of various underlying conditions or exposures
─ Common causes: NSAIDs, alcohol, severe stress (e-g-, critically ill patients - "stress erosions"), H- pylori infection, viral infections, bile reflux, radiation, chemotherapy, ischemia, direct trauma (e-g-, NG tube)
─ Symptoms: often asymptomatic; may cause epigastric pain, dyspepsia, nausea, vomiting, or upper gastrointestinal bleeding (hematemesis, melena), which can be acute and severe

Macro ─ Endoscopy reveals multiple, small, shallow, often hemorrhagic mucosal defects (erosions)
─ Erosions may be punctate, linear, or serpiginous
─ Surrounding mucosa may be erythematous or normal
─ Diffuse hemorrhagic gastritis is a severe form with widespread erosions and submucosal hemorrhage

Micro ─
─ Superficial mucosal defects limited to the epithelium and lamina propria, without breaching the muscularis mucosae
─ Base of erosion often shows necrotic debris, fibrin, acute inflammatory cells (neutrophils), and sometimes hemorrhage
─ Adjacent intact mucosa may show reactive changes: foveolar hyperplasia, mucin depletion, regenerative atypia
─ Lamina propria edema and vascular congestion are common
─ The specific underlying cause may have additional histologic clues (e-g-, H- pylori organisms, viral inclusions, radiation atypia, features of reactive gastropathy)
─ If erosions are healing, granulation tissue and re-epithelialization may be seen

Ancillary studies ─
─ Directed by clinical suspicion for underlying cause:
─ ─ Special stains/IHC for H- pylori
─ ─ IHC for CMV or other viruses if suspected (especially in immunocompromised)

DDx ─
─ Gastric ulcer: deeper lesion, penetrates through the muscularis mucosae into the submucosa or deeper
─ Reactive gastropathy: may have surface epithelial damage but typically lacks overt erosions and significant acute inflammation unless severe
─ Specific types of gastritis (e-g-, H- pylori gastritis, autoimmune gastritis): erosions can occur, but the underlying specific inflammatory pattern and etiology define these conditions
─ Aphthous-like erosions of Crohn's disease: often have associated granulomas or other features of Crohn's

Prognosis ─ Depends on the underlying cause and its management
─ Erosions are typically superficial and heal without scarring if the insult is removed or treated
─ Can be a source of significant acute upper GI bleeding, especially stress-related erosive disease in critically ill patients

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Hypertrophic gastropathy

Menetrier disease

A rare, acquired hypertrophic gastropathy characterized by massive foveolar hyperplasia of the gastric body and fundus, leading to enlarged rugal folds and protein-losing gastropathy

Clinical ─ Etiology is largely unknown; proposed mechanisms involve overproduction of transforming growth factor-alpha (TGF-α), which stimulates epithelial proliferation via the epidermal growth factor receptor (EGFR)
─ Some pediatric cases are associated with CMV infection and may be self-limited
─ Typically affects middle-aged to older adults (peak 40-60 years), with a male predominance
─ Symptoms: epigastric pain, nausea, vomiting, weight loss, peripheral edema (due to hypoalbuminemia from protein loss)
─ Protein-losing gastropathy with hypoalbuminemia and anasarca is a key feature
─ Achlorhydria or hypochlorhydria is common due to loss of parietal cells, which can lead to impaired B12 and iron absorption
─ Increased risk of gastric adenocarcinoma is reported, though the magnitude of risk is debated

Macro ─ Endoscopy reveals massively enlarged, cerebriform (brain-like) gastric rugal folds, predominantly in the fundus and body, often sparing the antrum
─ Mucosa may be edematous, nodular, and secrete copious thick mucus
─ Erosions or ulcers can be present

Micro ─
─ Striking foveolar hyperplasia: gastric pits are massively elongated (often >75% of mucosal thickness), tortuous, and cystically dilated, lined by hyperplastic mucinous foveolar cells
─ Glandular component (oxyntic glands in body/fundus) is often atrophic or reduced due to compression by hyperplastic foveolae and edema
─ Lamina propria is usually edematous and may contain a mild to moderate chronic inflammatory infiltrate (lymphocytes, plasma cells, eosinophils); smooth muscle proliferation may be seen
─ Individual epithelial cells are generally bland without significant atypia, though reactive changes can occur
─ Intestinal metaplasia or dysplasia can develop, particularly in long-standing cases
─ Deep cystic dilation of glands ("gastritis cystica profunda") can occur

Ancillary studies ─
─ IHC for MIB-1 (Ki-67) shows increased proliferation in the foveolar neck region, but not typically at the surface
─ IHC for TGF-α or EGFR may show increased expression but is not routinely used for diagnosis
─ Full-thickness biopsy (rarely done) may be needed to appreciate the extent of foveolar hyperplasia and glandular atrophy if superficial biopsies are non-diagnostic

DDx ─
─ Zollinger-Ellison syndrome: also causes hypertrophic gastropathy, but primarily due to parietal cell hyperplasia in the body/fundus driven by gastrin; foveolar hyperplasia is less prominent, and ECL cell hyperplasia is often seen
─ Hyperplastic polyposis syndrome: multiple discrete hyperplastic polyps, rather than diffuse rugal hypertrophy; background mucosa may show chronic gastritis
─ Gastric lymphoma (especially infiltrative types like MALT or DLBCL): can cause thickened rugal folds, but histology shows atypical lymphoid infiltrate
─ Infiltrating gastric adenocarcinoma (linitis plastica): diffuse wall thickening and rigidity, but histology shows malignant glandular cells
─ Other hypertrophic gastropathies (e-g-, associated with H- pylori, eosinophilic gastritis): specific etiologic or inflammatory features will be present
─ Cronkhite-Canada syndrome: generalized GI polyposis with hamartomatous features, ectodermal changes (alopecia, nail atrophy)

Prognosis ─ Variable clinical course; some patients have mild, stable disease, while others have progressive protein loss and complications
─ Spontaneous remission can occur, especially in pediatric CMV-associated cases
─ Treatment is largely supportive: high-protein diet, PPIs (for symptoms, though acid is usually low), treatment of H- pylori if present
─ EGFR inhibitors (e-g-, cetuximab) have shown promise in some cases by blocking TGF-α signaling
─ Gastrectomy may be required for severe, refractory symptoms, intractable protein loss, or development of dysplasia/cancer
─ Increased risk of gastric adenocarcinoma (reported rates vary widely, ~2-15%) warrants endoscopic surveillance

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Zollinger-Ellison Syndrome

A condition characterized by severe peptic ulcer disease and diarrhea due to gastric acid hypersecretion caused by a gastrin-producing tumor (gastrinoma)

Clinical ─ Caused by a gastrinoma, which is a neuroendocrine tumor typically located in the duodenum (most common), pancreas, or rarely other sites
─ Approximately 20-30% of gastrinomas are associated with Multiple Endocrine Neoplasia type 1 (MEN1) syndrome
─ Symptoms result from hypergastrinemia: severe, recurrent, or atypical peptic ulcers (often multiple, distal duodenum/jejunum), diarrhea, steatorrhea, abdominal pain, GERD symptoms
─ Diagnosis involves documenting elevated fasting serum gastrin levels (>1000 pg/mL or >10x upper limit of normal) and gastric acid hypersecretion; secretin stimulation test is confirmatory
─ Imaging studies (somatostatin receptor scintigraphy, CT, MRI, endoscopic ultrasound) are used to locate the gastrinoma(s)

Macro ─ Endoscopy reveals markedly thickened gastric rugal folds, particularly in the body and fundus, due to parietal cell hyperplasia
─ Peptic ulcers may be seen in the stomach, duodenum (often postbulbar), or jejunum
─ Esophagitis may be present due to severe reflux

Micro ─
─ Gastric Body/Fundus:
─ ─ Striking parietal cell hyperplasia is the most characteristic feature; oxyntic mucosa is thickened due to an increased number and size of parietal cells
─ ─ Chief cells and mucous neck cells may appear compressed or reduced in number
─ ─ Foveolar epithelium is typically short relative to the thickened glandular compartment
─ ─ Enterochromaffin-like (ECL) cell hyperplasia (linear and/or micronodular) is common, driven by chronic hypergastrinemia; this can progress to ECL cell neuroendocrine tumors (Type 2 gastric NETs)
─ ─ Minimal or no significant inflammation unless ulcers are present
─ Antrum: Typically normal or may show mild reactive changes; G-cells are usually not hyperplastic (as the gastrin source is ectopic)
─ Duodenum/Jejunum: May show peptic ulceration, duodenitis with gastric foveolar metaplasia

Ancillary studies ─
─ IHC for gastrin is not performed on gastric biopsies (tumor is elsewhere) but on suspected gastrinoma tissue
─ IHC for chromogranin A or synaptophysin can highlight ECL cell hyperplasia in corpus/fundus biopsies
─ Biopsy of the gastrinoma itself (if found) will show features of a well-differentiated neuroendocrine tumor, positive for neuroendocrine markers and gastrin

DDx ─
─ Menetrier disease: massive foveolar hyperplasia, not parietal cell hyperplasia; protein-losing gastropathy; reduced acid secretion
─ Hypertrophic lymphocytic gastritis: thickened folds with dense intraepithelial lymphocytic infiltrate
─ Infiltrative gastric carcinoma (linitis plastica) or lymphoma: malignant infiltrate causes thickened folds
─ Other causes of peptic ulcer disease (e-g-, H- pylori, NSAIDs): lack the marked parietal cell hyperplasia and hypergastrinemia
─ Reactive gastropathy: foveolar hyperplasia, but not the profound parietal cell hyperplasia

Prognosis ─ Depends on the nature of the gastrinoma (benign vs- malignant, sporadic vs- MEN1-associated) and success in controlling acid hypersecretion and resecting/managing the tumor
─ Gastrinomas can be malignant and metastasize (most commonly to liver and lymph nodes)
─ Control of acid hypersecretion with high-dose PPIs is crucial
─ Surgical resection of solitary gastrinomas can be curative
─ Patients with MEN1 often have multiple gastrinomas and a more complex course

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Gastric Siderosis

A condition characterized by iron deposition within the gastric glandular epithelium, distinct from iron deposition in macrophages (hemosiderosis) or from topical iron pill injury

Clinical ─ Typically seen in patients with systemic iron overload conditions such as:
─ ─ Hereditary hemochromatosis
─ ─ Multiple blood transfusions (e-g-, for thalassemia, sickle cell anemia, myelodysplastic syndrome)
─ ─ Chronic liver disease (e-g-, cirrhosis, alcoholic liver disease)
─ ─ Ineffective erythropoiesis
─ Often asymptomatic from a gastric perspective; symptoms usually relate to the underlying cause of iron overload
─ Gastric iron deposition itself rarely causes significant gastric dysfunction

Macro ─ Endoscopic appearance of the gastric mucosa is often normal or may show non-specific changes like erythema or mild gastritis
─ Mucosa does not typically appear rusty or discolored grossly

Micro ─
─ Key feature: deposition of golden-brown, granular iron pigment (hemosiderin) within the cytoplasm of gastric glandular epithelial cells, particularly in the deeper glands of the body and fundus (oxyntic mucosa)
─ Parietal cells and chief cells can both contain iron pigment
─ Foveolar epithelium is usually spared or shows minimal iron
─ Iron may also be present in lamina propria macrophages (hemosiderin-laden macrophages), but glandular epithelial iron is the defining feature of siderosis
─ Minimal or no associated inflammation or mucosal injury directly attributable to the iron within glands, though background gastritis from other causes may be present
─ Distinction from iron-pill gastritis: In iron-pill gastritis, iron is exogenous, often crystalline or amorphous, encrusted on the surface epithelium or within erosions/ulcers, and associated with acute mucosal injury; in siderosis, iron is endogenous hemosiderin within glandular cells due to systemic overload

Ancillary studies ─
─ Prussian blue (Perls) iron stain: definitively confirms the presence of iron (stains blue-green) within glandular epithelial cells and macrophages

DDx ─
─ Iron-pill gastritis: iron is superficial, crystalline/chunky, associated with erosion/ulcer (see above)
─ Hemosiderosis (macrophage iron): iron confined to lamina propria macrophages, often secondary to local hemorrhage or chronic inflammation, without significant glandular epithelial iron
─ Lipofuscin pigment: finer, browner granules, often in surface epithelium or macrophages, iron stain negative
─ Melanin pigment: rare in stomach, iron stain negative

Prognosis ─ Gastric siderosis itself is generally not clinically significant in terms of gastric symptoms or pathology
─ The prognosis is determined by the underlying cause of systemic iron overload and its complications (e-g-, liver cirrhosis, heart failure, diabetes in hemochromatosis)
─ Management focuses on treating the systemic iron overload (e-g-, phlebotomy, chelation therapy)

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Dieulafoy Lesion

A vascular anomaly characterized by an abnormally large and tortuous submucosal artery that erodes the overlying mucosa, leading to recurrent, often massive, gastrointestinal bleeding

Clinical ─ Accounts for a small percentage (~1-2%) of acute upper GI bleeding cases, but can be life-threatening
─ More common in older men (average age 50-60s)
─ Etiology is thought to be congenital or developmental, not acquired (e-g-, not an aneurysm or result of chronic inflammation)
─ Site: most commonly in the proximal stomach (fundus, high on lesser curvature, within 6 cm of GEJ), but can occur anywhere in the GI tract (esophagus, duodenum, jejunum, colon, rectum)
─ Presents with acute, often severe and recurrent, arterial bleeding (hematemesis, melena); typically painless bleeding as there is no significant ulcer or inflammation apart from the erosion point

Macro ─ Endoscopy is key for diagnosis, but lesion can be difficult to identify if not actively bleeding
─ Appears as a small, isolated mucosal defect or erosion (often <3 mm) with a visible, protruding artery or active arterial spurting
─ No surrounding ulceration, mass, or significant inflammation is typically seen, distinguishing it from peptic ulcer bleeding
─ May be covered by a fresh clot if bleeding has recently stopped

Micro ─
─ Histologic diagnosis is often made on resected specimens (if surgery is required) or rarely on deep endoscopic biopsies if the vessel is sampled
─ Characteristic finding: an abnormally large-caliber, thick-walled, tortuous artery in the submucosa, extending very close to the mucosal surface
─ The artery itself is histologically normal (not an aneurysm, no vasculitis, no atherosclerosis usually) but is simply abnormally large for its location (caliber often >1 mm, up to 3 mm)
─ Medial hypertrophy and reduplication of the internal elastic lamina may be seen in the vessel
─ Overlying mucosa shows a pinpoint erosion or ulceration directly above the vessel, through which bleeding occurs
─ Minimal or no significant inflammation or ulceration in the surrounding mucosa away from the erosion point

Ancillary studies ─
─ Elastic stain (e-g-, Verhoeff-Van Gieson) can highlight the artery and its wall structure, demonstrating its large caliber and proximity to the surface

DDx ─
─ Peptic ulcer with bleeding: shows a true ulcer crater with granulation tissue, inflammation, and fibrinoid necrosis of the vessel wall; Dieulafoy lesion lacks a true chronic ulcer bed
─ Gastric antral vascular ectasia (GAVE): dilated mucosal capillaries with fibrin thrombi in the antrum ("watermelon stomach")
─ Angiodysplasia: malformed, ectatic mucosal/submucosal vessels, usually thin-walled; more common in colon and small intestine
─ Arteriovenous malformation (AVM): direct communication between artery and vein, tangled vessels

Prognosis ─ Risk of rebleeding is high if not adequately treated
─ Endoscopic therapy (e-g-, thermal coagulation, injection sclerotherapy, hemoclipping, band ligation) is the mainstay of treatment and is successful in most cases
─ Angiographic embolization or surgical wedge resection may be required for refractory bleeding or difficult-to-access lesions
─ Mortality rate can be significant if bleeding is massive and uncontrolled, but has decreased with improved endoscopic techniques

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Proton Pump Inhibitor (PPI) Effect

A constellation of morphologic changes in the gastric oxyntic (body/fundus) mucosa resulting from long-term use of proton pump inhibitor drugs.

Clinical ─ An iatrogenic condition. Patients have a history of long-term use of PPIs (e.g., omeprazole, lansoprazole) for conditions like GERD or peptic ulcer disease. Usually an incidental histologic finding. Can be associated with the development of fundic gland polyps.

Macro ─ Endoscopy may be normal or show fundic gland polyps, which appear as small, sessile, often multiple, smooth-surfaced mucosal nodules in the body and fundus. Cobblestone-like mucosa has also been described.

Micro ─

─ Changes are confined to the oxyntic mucosa of the body and fundus.

─ Parietal cell hyperplasia and protrusion: The most characteristic feature. Parietal cells appear enlarged and protrude or bulge prominently into the glandular lumens, creating a "hobnail" appearance. The cytoplasm may be eosinophilic or vacuolated.

─ Glandular cystic dilation: Fundic glands often become cystically dilated, particularly in the deeper portions of the mucosa. This is the histologic basis of fundic gland polyps.

─ Foveolar (surface mucous cell) hyperplasia may be seen.

─ Inflammation is typically absent or minimal.

─ Compensatory G-cell hyperplasia occurs in the antrum (due to drug-induced achlorhydria), but this is not seen on a biopsy limited to the gastric body.

Ancillary studies ─

─ IHC (+) Not required for diagnosis.

─ IHC (-) Not required for diagnosis.

─ Molecular ─ Not applicable.

DDx ─

─ Fundic Gland Polyp (sporadic or FAP-associated): Histologically identical to the changes of PPI effect. Clinical correlation is key. Sporadic polyps are often solitary, while FAP-associated and PPI-associated polyps are often multiple. Dysplasia is rare in PPI-polyps but can be seen in FAP-associated polyps.

─ Menetrier Disease / Hypertrophic Gastropathies: These show much more dramatic foveolar hyperplasia and foveolar gland tortuosity and elongation, often with loss of parietal cells. Clinically present with protein-losing enteropathy.

─ Autoimmune Gastritis: Characterized by oxyntic atrophy (parietal cell loss, not hyperplasia) and a dense lymphoplasmacytic infiltrate.

Gastric Xanthoma (Xanthelasma)

A benign, non-neoplastic lesion characterized by an accumulation of lipid-laden macrophages (foam cells) in the gastric lamina propria.

Clinical ─ Usually an asymptomatic, incidental finding during endoscopy. More common in older adults. Not associated with systemic hyperlipidemia. It is often seen in a background of mucosal injury, such as chronic gastritis, intestinal metaplasia, or atrophic gastritis. Some studies suggest an association with early gastric cancer, likely because both are related to chronic mucosal injury, rather than xanthoma being a direct precursor.

Macro ─ Appears as single or multiple, well-demarcated, yellowish-white plaques or nodules on the mucosal surface, typically <5 mm in diameter. Most often found in the antrum.

Micro ─

─ Well-circumscribed aggregates of foamy macrophages filling and expanding the lamina propria, located just beneath the surface foveolar epithelium.

─ The macrophages have abundant, pale, multivacuolated (foamy) cytoplasm and small, central, benign nuclei.

─ The background mucosa often shows features of chronic gastritis.

Ancillary studies ─

─ IHC (+): CD68 (stains the cytoplasm of the foam cells).

─ IHC (-): Negative for cytokeratins (to rule out signet ring cell carcinoma).

─ Special Stains: PAS and Ziehl-Neelsen (for acid-fast bacilli) are negative, helping to distinguish from Whipple disease and mycobacterial infections.

DDx ─

─ Signet Ring Cell Carcinoma: The main differential. Malignant signet ring cells have hyperchromatic, eccentric nuclei pushed aside by a single large mucin vacuole, whereas xanthoma cells have benign central nuclei and foamy cytoplasm. Signet ring cells are positive for cytokeratins and negative for CD68.

─ Whipple Disease / Mycobacterial Infection: These also feature macrophages in the lamina propria. However, the organisms can be highlighted with PAS (for Whipple) or acid-fast stains (for mycobacteria).

─ Russell Body Gastritis: Lamina propria is filled with plasma cells containing eosinophilic Russell bodies, not foamy macrophages.

Polyps, Adenomas, and Dysplasia

Fundic Gland Polyp (FGP) / Oxyntic Gland Hyperplasia

Benign polyps composed of hyperplastic oxyntic glands, commonly found in the gastric body and fundus

Clinical ─ One of the most common types of gastric polyps, especially in patients on long-term proton pump inhibitor (PPI) therapy
─ Can be sporadic or syndromic (associated with Familial Adenomatous Polyposis - FAP, or Gardner syndrome)
─ Sporadic FGPs: more common in middle-aged to older women; strongly associated with PPI use; inversely associated with H- pylori infection (rare in H- pylori gastritis)
─ FAP-associated FGPs: occur in younger patients, M=F; often numerous (gastric polyposis); carry a risk of dysplasia
─ Zollinger-Ellison syndrome: can also be associated with FGPs due to gastrin-induced parietal cell hyperplasia
─ Usually asymptomatic and found incidentally during endoscopy

Macro ─ Small (<1 cm, usually <5 mm), sessile, smooth-surfaced, dome-shaped polyps
─ Often multiple, especially with PPI use or FAP
─ Mucosa appears similar to surrounding fundic/oxyntic mucosa, or may be slightly translucent
─ Located in the gastric body and fundus (oxyntic mucosa)

Micro ─
─ Composed of cystically dilated and irregularly branched oxyntic glands lined by parietal cells (large, eosinophilic, with central nuclei) and chief cells (basophilic, granular, basal nuclei)
─ Superficial foveolar epithelium is often flattened or attenuated over the polyp surface, but may show some hyperplasia
─ Minimal or no lamina propria inflammation
─ No significant cytologic atypia in sporadic FGPs
─ Parietal cell hypertrophy/hyperplasia with apical "snouts" or tufting into gland lumens can be prominent, especially with PPI use
─ Dysplasia is rare in sporadic FGPs (<1%), but more common in FAP-associated FGPs (up to 25-40% may show low-grade dysplasia, rarely high-grade); dysplasia in FGPs is typically of foveolar or gastric type, with enlarged, hyperchromatic nuclei and pseudostratification, often at the surface of the polyp
─ Background oxyntic mucosa is typically normal or shows changes of PPI effect (parietal cell hypertrophy)

Ancillary studies ─
─ Generally not required for diagnosis of typical FGPs
─ IHC for MIB-1 (Ki-67) shows low proliferation, confined to neck region (unless dysplastic)
─ Molecular: Sporadic FGPs often have somatic activating mutations in CTNNB1 (β-catenin gene); FAP-associated FGPs have germline APC mutations and may acquire somatic CTNNB1 mutations or show loss of the second APC allele in dysplastic areas

DDx ─
─ Hyperplastic polyp: occurs in inflamed mucosa (e-g-, H- pylori gastritis, reactive gastropathy), characterized by elongated, tortuous foveolae with edematous, inflamed stroma; usually in antrum
─ Gastric adenoma (intestinal or foveolar type): composed of dysplastic epithelium from the outset; different architecture and cytology
─ Oxyntic gland adenoma (chief cell adenoma): very rare, true neoplasm of chief cells, more solid architecture, may show atypia
─ Pyloric gland adenoma: composed of pyloric-type glands, MUC6 positive; usually in antrum or transitional zones
─ Menetrier disease: diffuse massive foveolar hyperplasia, not discrete polyps of oxyntic glands

Prognosis ─ Sporadic FGPs are benign with virtually no malignant potential; dysplasia is exceptionally rare
─ No specific surveillance is generally needed for sporadic FGPs unless very numerous or large
─ FAP-associated FGPs require surveillance due to the risk of dysplasia, though progression to carcinoma is still uncommon
─ Discontinuation of PPIs may lead to regression of PPI-induced FGPs

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Hyperplastic Polyp (Gastric)

The second most common type of gastric polyp, characterized by elongated, tortuous, and dilated foveolar glands with an edematous and inflamed lamina propria

Clinical ─ Often associated with chronic gastritis, particularly Helicobacter pylori infection or autoimmune gastritis; also seen with reactive gastropathy or adjacent to ulcers/erosions
─ Most are asymptomatic and found incidentally; larger polyps can cause bleeding or outlet obstruction
─ Usually solitary but can be multiple; if numerous, consider syndromes like gastric hyperplastic polyposis, Menetrier disease, Cronkhite-Canada syndrome, or Peutz-Jeghers syndrome
─ Site: most commonly in the antrum, but can occur anywhere in the stomach
─ Size ranges from small (<0-5 cm) to large (>2 cm)

Macro ─ Sessile or pedunculated, often with a smooth or slightly mamillated surface; may be erythematous or show surface erosions

Micro ─
─ Markedly elongated, dilated, and architecturally distorted gastric foveolae (pits), often with a corkscrew or serrated appearance superficially
─ Lined by hyperplastic foveolar cells, which may show mucin depletion or increased mucin
─ Lamina propria is typically edematous and contains a mixed inflammatory infiltrate (lymphocytes, plasma cells, eosinophils, neutrophils if active inflammation/erosion is present)
─ Smooth muscle fibers from the muscularis mucosae may extend into the lamina propria between glands
─ Surface erosion is common
─ Background gastric mucosa often shows features of chronic gastritis, atrophy, or intestinal metaplasia
─ Dysplasia can occur in a small percentage of hyperplastic polyps (0-6-2%), more commonly in larger polyps (>1-2 cm) or those in patients with atrophic gastritis/intestinal metaplasia; dysplasia is usually intestinal type

Ancillary studies ─
─ Special stains/IHC for H- pylori to assess background gastritis
─ Mucin stains (e-g-, PAS-Alcian blue) can highlight foveolar mucin and any intestinal metaplasia

DDx ─
─ Fundic gland polyp: located in body/fundus, composed of dilated oxyntic glands, minimal inflammation
─ Gastric adenoma: composed of dysplastic epithelium from the outset, lacks the prominent foveolar hyperplasia and stromal inflammation of hyperplastic polyps
─ Juvenile polyp (if in stomach): similar cystic dilation and inflammation, but typically has more abundant, less inflamed stroma and occurs in syndromic settings or children
─ Menetrier disease: diffuse massive foveolar hyperplasia of body/fundus, not discrete polyps
─ Prolapse gastropathy polyp / Inflammatory cloacogenic polyp (if near GEJ or pylorus): prominent fibromuscular proliferation from muscularis mucosae, vascular congestion, often diamond-shaped crypts
─ Hamartomatous polyps (e-g-, Peutz-Jeghers): arborizing smooth muscle core, normal glandular elements

Prognosis ─ Benign, but carry a small risk of dysplasia and carcinoma, especially if large or in a background of atrophy/IM
─ May regress if underlying cause (e-g-, H- pylori) is treated
─ Large polyps (>1 cm) or those with dysplasia are usually removed endoscopically
─ Surveillance may be recommended depending on size, number, presence of dysplasia, and background mucosal status

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Gastric Adenoma (Intestinal-type)

A neoplastic polypoid lesion of the stomach composed of dysplastic columnar cells resembling colonic adenomas, often arising in a background of chronic gastritis with atrophy and intestinal metaplasia

Clinical ─ Accounts for ~10-20% of gastric polyps
─ More common in older individuals (peak 60s-70s)
─ Associated with chronic atrophic gastritis, intestinal metaplasia, pernicious anemia, and previous gastric surgery
─ Increased incidence in populations with high rates of H- pylori infection and gastric cancer
─ Can be solitary or multiple; often asymptomatic, but may cause bleeding or symptoms of obstruction if large
─ Site: most commonly in the antrum, but can occur in the body/fundus, especially if intestinal metaplasia is present there

Macro ─ Sessile, lobulated, or pedunculated polyps, often with a velvety or villous surface texture
─ Size varies, from small (<1 cm) to large (>2 cm)
─ Color may be similar to surrounding mucosa or more erythematous

Micro ─
─ Composed of dysplastic columnar epithelial cells with intestinal differentiation, forming tubular, villous, or tubulovillous architecture, similar to colorectal adenomas
─ Dysplasia is characterized by nuclear enlargement, hyperchromasia, elongation (pencillate nuclei), pseudostratification, and loss of mucin (goblet cells may be present or reduced)
─ Graded as low-grade or high-grade dysplasia:
─ ─ Low-grade dysplasia: nuclei maintain polarity, pseudostratification usually confined to basal half of cell, mild to moderate atypia, preserved glandular architecture
─ ─ High-grade dysplasia: nuclei lose polarity, more severe pleomorphism, prominent nucleoli, increased and atypical mitoses, complex glandular architecture (e-g-, cribriforming, back-to-back glands, intraglandular bridging)
─ Background gastric mucosa frequently shows chronic gastritis, atrophy, and intestinal metaplasia
─ Paneth cells and endocrine cells may be present within the adenoma

Ancillary studies ─
─ IHC (+): CDX2, CK20 (often diffuse), MUC2 (goblet cells) supporting intestinal differentiation
─ IHC (-/+): CK7 (can be patchy), MUC5AC (usually negative or focal in foveolar areas if present)
─ p53 IHC: may show overexpression or null pattern in high-grade dysplasia or carcinoma
─ Ki-67: increased proliferation index, extending towards surface, especially in HGD

DDx ─
─ Hyperplastic polyp with dysplasia: background of typical hyperplastic polyp features (elongated, tortuous foveolae, inflamed stroma) with a focal area of intestinal-type dysplasia
─ Foveolar-type gastric adenoma: lined by dysplastic cells with foveolar (gastric mucin) differentiation, MUC5AC positive, usually CK20 negative or focal
─ Pyloric gland adenoma: composed of closely packed pyloric-type glands, MUC6 positive
─ Reactive atypia in gastritis/erosions: atypia usually more basal, surface maturation present, prominent inflammation/granulation tissue; lacks the clonal, full-thickness atypia of adenoma
─ Invasive adenocarcinoma: evidence of invasion into lamina propria (intramucosal carcinoma) or submucosa, often with desmoplastic response

Prognosis ─ Premalignant lesions with a significant risk of progression to adenocarcinoma, especially if large (>2 cm), villous, or contain high-grade dysplasia
─ Risk of carcinoma in an adenoma is ~10% for LGD and up to 40-60% for HGD
─ Complete endoscopic removal is recommended for all gastric adenomas
─ Surveillance endoscopy is necessary due to risk of synchronous/metachronous adenomas or carcinoma in the background atrophic/metaplastic mucosa

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Gastric Adenoma (Foveolar-type)

A neoplastic polypoid lesion of the stomach composed of dysplastic cells with gastric foveolar-type differentiation, typically arising in a background without significant atrophy or intestinal metaplasia

Clinical ─ Less common than intestinal-type adenomas
─ May be associated with Familial Adenomatous Polyposis (FAP) syndrome
─ Can occur in patients without chronic gastritis or H- pylori infection
─ Site: often found in the gastric body or fundus, but can occur in antrum
─ Usually solitary, but can be multiple, especially in FAP

Macro ─ Sessile or slightly raised polyps, often with a smooth or finely granular surface
─ Typically smaller than intestinal-type adenomas

Micro ─
─ Composed of dysplastic cells resembling gastric foveolar epithelium, with cuboidal to low columnar shape and pale, eosinophilic, or clear mucinous cytoplasm (apical mucin cap often present)
─ Nuclei are typically round to oval, often basally located in low-grade dysplasia, but can become enlarged, hyperchromatic, and lose polarity in high-grade dysplasia
─ Architectural patterns include tubular, tubulovillous, or villous structures; glands may be crowded or show branching
─ Graded as low-grade or high-grade dysplasia based on cytologic and architectural atypia, similar to intestinal-type adenomas, but nuclear features may be more rounded and less pencillate
─ Background gastric mucosa is often normal or shows reactive gastropathy, typically without significant atrophy or intestinal metaplasia (unlike intestinal-type adenomas)

Ancillary studies ─
─ IHC (+): MUC5AC (diffuse cytoplasmic staining, characteristic), cytokeratins (CAM5-2, AE1/AE3)
─ IHC (-/+): CK7 (can be positive), MUC6 (may be positive in deeper glands)
─ IHC (-): CK20, CDX2, MUC2 (usually negative or very focal, helping distinguish from intestinal-type adenoma)
─ p53 and Ki-67 can be used similarly to intestinal-type adenomas to assess dysplasia grade
─ Molecular: APC gene mutations are common in FAP-associated foveolar adenomas; sporadic cases may have KRAS or GNAS mutations

DDx ─
─ Hyperplastic polyp: prominent foveolar hyperplasia but lacks true dysplasia; has edematous, inflamed stroma
─ Intestinal-type gastric adenoma: shows intestinal differentiation (goblet cells, CDX2/CK20+), arises in atrophic/metaplastic mucosa
─ Pyloric gland adenoma: composed of pyloric-type glands (MUC6+), different cytology
─ Fundic gland polyp with dysplasia: dysplasia arises in a typical FGP (oxyntic glands); dysplasia in FGPs is often foveolar type, but the underlying polyp architecture is key
─ Reactive foveolar atypia: lacks the clonal expansion and full-thickness atypia of adenoma; often associated with erosions or inflammation

Prognosis ─ Premalignant lesion with risk of progression to adenocarcinoma, though some studies suggest a lower risk compared to intestinal-type adenomas of similar size/grade, particularly for low-grade lesions
─ High-grade dysplasia carries a significant risk of malignant transformation
─ Complete endoscopic removal is recommended
─ Surveillance is indicated, especially if associated with FAP or if multiple

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Pyloric Gland Adenoma

A rare type of gastric adenoma composed of closely packed tubules resembling pyloric glands or Brunner's glands, often arising in a background of autoimmune gastritis or chronic gastritis

Clinical ─ Uncommon, accounts for a small percentage of gastric polyps
─ More frequent in older individuals (mean age 60s-70s), with a female predominance reported in some series
─ Associated with autoimmune gastritis (pernicious anemia), chronic H- pylori gastritis with atrophy, and less commonly, FAP
─ Can occur in other GI locations (duodenum, gallbladder, bile ducts, pancreas)
─ Site: in the stomach, typically found in the corpus or fundus (on a background of atrophic oxyntic mucosa with pyloric metaplasia), but can also occur in the antrum
─ Usually solitary, but can be multiple
─ Often asymptomatic; may cause bleeding if large or ulcerated

Macro ─ Sessile or pedunculated, often lobulated or dome-shaped polyps
─ Surface may be smooth, granular, or slightly villous
─ Size varies, typically 0-5 to 3 cm

Micro ─
─ Composed of closely packed, small, round to oval tubules lined by cuboidal to low columnar cells with pale eosinophilic or amphophilic, often "ground glass" cytoplasm; apical mucin caps are usually absent or inconspicuous
─ Nuclei are typically round to oval, basally located, with smooth contours and inconspicuous nucleoli in low-grade lesions; may show variable atypia
─ Minimal intervening stroma
─ Dysplasia is common (low-grade or high-grade) and is characterized by nuclear stratification, hyperchromasia, pleomorphism, and loss of polarity; architectural complexity (e-g-, budding, cribriforming) in HGD
─ May show areas of intestinal metaplasia or foveolar-type epithelium focally
─ Background gastric mucosa often shows autoimmune gastritis (oxyntic atrophy, ECL hyperplasia, pyloric metaplasia) or chronic atrophic gastritis of other causes

Ancillary studies ─
─ IHC (+): MUC6 (strong and diffuse cytoplasmic staining, characteristic), MUC5AC (often positive), cytokeratins (CAM5-2, AE1/AE3)
─ IHC (-/+): CK7 (can be positive)
─ IHC (-): CK20, CDX2, MUC2 (usually negative, helping distinguish from intestinal-type adenoma)
─ Synaptophysin/Chromogranin may highlight entrapped or hyperplastic endocrine cells, but tumor cells are negative
─ Molecular: GNAS mutations are common; KRAS mutations also reported; APC mutations in FAP-associated cases

DDx ─
─ Intestinal-type gastric adenoma: intestinal differentiation (CDX2/CK20+), arises in intestinal metaplasia
─ Foveolar-type gastric adenoma: foveolar differentiation (MUC5AC+ but MUC6 usually negative or focal), different cytology
─ Well-differentiated neuroendocrine tumor (NET): organoid pattern, "salt & pepper" chromatin, synaptophysin/chromogranin positive; PGA cells are NET marker negative
─ Hyperplastic polyp: foveolar hyperplasia with inflamed, edematous stroma; lacks the packed pyloric-type glands and MUC6 positivity of PGA
─ Fundic gland polyp: composed of oxyntic glands (parietal/chief cells), typically in non-atrophic fundic mucosa
─ Brunner gland adenoma/hamartoma (if in duodenum): similar histology but defined by duodenal location and origin from Brunner's glands

Prognosis ─ Considered a premalignant lesion with a significant risk of progression to adenocarcinoma (reported up to 30-40%, especially with HGD)
─ Carcinomas arising from PGAs are often well-differentiated and may retain MUC6 expression
─ Complete endoscopic or surgical resection is recommended
─ Surveillance is necessary due to malignant potential and association with atrophic gastritis, which itself is a risk factor for cancer

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Oxyntic Gland Adenoma

A very rare benign epithelial neoplasm of the stomach composed predominantly of chief cells, with variable numbers of parietal cells, arising in the oxyntic mucosa

Clinical ─ Also known as chief cell adenoma or gastric adenocarcinoma of fundic gland type (if showing invasive features, though behavior is often indolent)
─ Extremely rare; few cases reported
─ Typically occurs in adults, no clear sex predilection
─ Usually asymptomatic and found incidentally during endoscopy
─ Site: exclusively in the gastric body or fundus (oxyntic mucosa)
─ Not clearly associated with H- pylori infection or autoimmune gastritis; background mucosa is often non-atrophic

Macro ─ Small, sessile or slightly elevated, well-demarcated polyps or plaques
─ Often <1 cm in size
─ May appear yellowish or tan due to lipid content in chief cells

Micro ─
─ Well-circumscribed, unencapsulated proliferation of glands resembling normal or hyperplastic oxyntic glands, but with architectural differences
─ Predominantly composed of chief cells (basophilic granular cytoplasm, basal nuclei) with variable numbers of parietal cells (eosinophilic cytoplasm, central nuclei) and mucous neck cells
─ Glands are often closely packed, forming solid nests, cords, trabeculae, or irregular anastomosing channels; may show some cystic dilation
─ Cells may show mild to moderate cytologic atypia: nuclear enlargement, hyperchromasia, and prominent nucleoli can be seen, but mitotic activity is typically low
─ "Adenocarcinoma of fundic gland type" is a term used for lesions showing more significant atypia and/or infiltrative growth into the lamina propria or submucosa, but these often behave indolently with low metastatic potential
─ Superficial foveolar epithelium may be normal or hyperplastic
─ No significant desmoplastic stromal reaction

Ancillary studies ─
─ IHC (+): Pepsinogen-I (chief cells), H+/K+ ATPase (parietal cells), MUC6 (mucous neck cells and some chief cells)
─ IHC (-): MUC5AC (foveolar cells, usually only at surface), MUC2, CDX2, CK20 (all negative, ruling out intestinal differentiation)
─ IHC (-): Neuroendocrine markers (synaptophysin, chromogranin)
─ Ki-67: typically shows a low proliferation index

DDx ─
─ Fundic gland polyp (FGP): more cystic dilation, less cellular, composed of both parietal and chief cells without the predominance of chief cells or the architectural complexity/atypia that can be seen in OGA; lacks infiltrative pattern if considering fundic gland type adenocarcinoma
─ Hyperplastic polyp: foveolar hyperplasia, inflamed stroma, typically antral or in inflamed corpus
─ Pyloric gland adenoma: MUC6 positive, but composed of pyloric-type glands, lacks chief/parietal cells
─ Well-differentiated neuroendocrine tumor (NET): organoid pattern, "salt & pepper" chromatin, positive for neuroendocrine markers
─ Conventional gastric adenocarcinoma: typically intestinal or diffuse type, different cytology and immunoprofile (e-g-, CDX2+, CK20+)

Prognosis ─ Generally considered benign or of very low malignant potential, even for "adenocarcinoma of fundic gland type"
─ Metastases are exceedingly rare for the fundic gland type adenocarcinoma variant
─ Complete endoscopic resection is usually curative for polypoid lesions
─ Long-term follow-up data is limited due to rarity

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Gastric Dysplasia (flat, non-polypoid)

Neoplastic transformation of the gastric epithelium that is not forming a discrete polypoid mass, often arising in a background of chronic gastritis, atrophy, and intestinal metaplasia

Clinical ─ Represents a precursor lesion to gastric adenocarcinoma
─ Risk factors are similar to those for intestinal-type gastric adenocarcinoma: chronic H- pylori infection, autoimmune gastritis, pernicious anemia, partial gastrectomy, smoking, high salt intake, low intake of fruits/vegetables
─ Often asymptomatic and detected during surveillance endoscopy for chronic gastritis/atrophy/IM, or incidentally
─ Site: can occur anywhere in the stomach, location often mirrors that of the underlying chronic gastritis (e-g-, antrum in H- pylori, corpus in AMAG)

Macro ─ Endoscopically, flat dysplasia can be very subtle and difficult to detect with standard white light endoscopy
─ May appear as flat or slightly depressed areas, altered mucosal color (erythema or pallor), or subtle changes in mucosal texture/pattern
─ Chromoendoscopy (e-g-, indigo carmine, acetic acid) and narrow-band imaging can improve detection rates

Micro ─
─ Defined by cytologic and architectural features of neoplastic epithelium, confined by the basement membrane, without forming an exophytic polyp
─ Can be intestinal-type (more common) or gastric/foveolar-type
─ Intestinal-type flat dysplasia:
─ ─ Resembles dysplasia in intestinal-type adenomas; cells have enlarged, hyperchromatic, often pencillate and pseudostratified nuclei; cytoplasm may be eosinophilic or contain goblet cells
─ ─ Arises in areas of intestinal metaplasia
─ Gastric/Foveolar-type flat dysplasia:
─ ─ Cells resemble foveolar epithelium with cuboidal/columnar shape, apical mucin (may be reduced), and round to oval atypical nuclei
─ ─ May arise in native gastric mucosa or areas of foveolar hyperplasia
─ Graded as low-grade or high-grade based on severity of cytologic and architectural atypia (see Gastric Adenoma sections for detailed criteria for LGD and HGD)
─ Low-grade: mild to moderate atypia, preserved polarity, minimal architectural complexity
─ High-grade: severe atypia, loss of polarity, marked architectural complexity (e-g-, cribriforming, budding)
─ Must be distinguished from reactive/regenerative atypia, which is common in inflamed or eroded mucosa; reactive atypia typically shows surface maturation, less severe nuclear changes, and is associated with active inflammation or repair

Ancillary studies ─
─ IHC for p53 (overexpression or null pattern) and Ki-67 (increased proliferation extending to surface) can help support diagnosis of dysplasia and distinguish from reactive atypia, especially in borderline cases
─ Mucin stains and IHC for cytokeratins (CK7, CK20), CDX2, MUC2, MUC5AC, MUC6 can help classify the type of dysplasia (intestinal vs- gastric/foveolar vs- pyloric gland type)

DDx ─
─ Reactive/regenerative atypia: see above; key is presence of significant inflammation/erosion and surface maturation in reactive changes
─ Gastric adenoma (if lesion becomes slightly raised or plaque-like): distinction is somewhat arbitrary, based on endoscopic appearance; histologic features of dysplasia are the same
─ Intramucosal adenocarcinoma: evidence of invasion into lamina propria (e-g-, single cells, disorganized small glands, desmoplasia if present)

Prognosis ─ Carries a significant risk of progression to invasive gastric adenocarcinoma
─ Risk is higher for high-grade dysplasia compared to low-grade dysplasia
─ Risk is also influenced by extent of dysplasia, type (incomplete IM with dysplasia may be higher risk), and background mucosal status
─ Management depends on grade and extent:
─ ─ Low-grade dysplasia: often managed with close endoscopic surveillance and biopsies; eradication of H- pylori if present; some advocate for endoscopic ablation/resection, especially if extensive or persistent
─ ─ High-grade dysplasia: high risk of synchronous or metachronous carcinoma; typically managed with endoscopic resection (EMR/ESD) if localized, or gastrectomy if extensive or associated with invasive cancer

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Stomach Adenocarcinomas

Gastric Adenocarcinoma, intestinal type

A common type of gastric cancer characterized by the formation of glandular structures, often arising in a background of chronic gastritis, atrophy, and intestinal metaplasia

Clinical ─ Represents one of the main histological types in the Lauren classification
─ More common in older individuals and in high-incidence geographic areas for gastric cancer
─ Associated with chronic H- pylori infection, dietary factors (e-g-, high salt, nitrates), smoking, and precursor lesions like atrophic gastritis and intestinal metaplasia
─ Tends to form exophytic or ulcerated masses, more common in the antrum
─ Spreads primarily hematogenously (e-g-, to liver) rather than by diffuse peritoneal infiltration
─ Molecularly, often associated with chromosomal instability (CIN) pathway, TP53 mutations, and sometimes KRAS mutations or microsatellite instability (MSI) in a subset

Macro ─ Typically forms a discrete, polypoid, fungating, or ulcerated mass
─ More common in the antrum and lesser curvature

Micro ─
─ Characterized by neoplastic glands that resemble intestinal glands or colonic adenocarcinoma
─ Glandular structures can be tubular, papillary, or tubulopapillary
─ Cells are columnar or cuboidal with varying degrees of nuclear atypia, pleomorphism, hyperchromasia, and prominent nucleoli
─ Mucin production can be variable, from minimal to abundant (if >50% extracellular mucin, classified as mucinous adenocarcinoma variant)
─ Dirty necrosis (luminal necrotic debris with karyorrhexis) within glands is common
─ Stroma is often desmoplastic
─ Grading is typically based on the percentage of gland formation (well-differentiated >95% glands, moderately differentiated 50-95% glands, poorly differentiated <50% glands)
─ May arise from dysplastic intestinal metaplasia or an intestinal-type adenoma
─ Papillary adenocarcinoma variant: predominantly papillary architecture; often exophytic; may have better prognosis stage for stage in some studies, but generally aggressive
─ Tubular adenocarcinoma variant: predominantly tubular architecture; most common pattern
─ Mucinous adenocarcinoma variant: >50% of the tumor volume is composed of extracellular mucin pools containing floating tumor cells or glands; often associated with MSI

Ancillary studies ─
─ IHC (+): Cytokeratins (AE1/AE3, CAM5-2), CK20 (often), CDX2 (often), Villin
─ IHC (-/+): CK7 (can be positive, especially in proximal/GEJ tumors or papillary type), MUC2 (intestinal mucin), MUC5AC (gastric mucin, can be focal)
─ HER2 (ERBB2) testing is crucial for advanced/metastatic cases to guide therapy
─ MMR/MSI testing may be considered, as MSI-H tumors (~10-20%) may have different prognosis and therapeutic responses (e-g-, immunotherapy)

DDx ─
─ Gastric adenoma (intestinal type) with high-grade dysplasia: lacks invasion into lamina propria
─ Diffuse-type gastric adenocarcinoma: infiltrative pattern of poorly cohesive cells, signet-ring cells; lacks well-formed glands
─ Metastatic adenocarcinoma (e-g-, colorectal, pancreaticobiliary): clinical history, morphology, and IHC panel (e-g-, SATB2 for colorectal, SMAD4 loss for pancreatic) are important; gastric intestinal type can mimic colorectal primary closely
─ Well-differentiated neuroendocrine tumor with glandular features: neuroendocrine markers positive

Prognosis ─ Stage (TNM) is the most important prognostic factor
─ Generally better prognosis than diffuse-type gastric cancer stage for stage, but still often poor due to late presentation
─ MSI-H tumors may have a better prognosis

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Gastric Adenocarcinoma, diffuse type

An aggressive type of gastric cancer characterized by infiltrative growth of poorly cohesive cells, often including signet-ring cells, with minimal or no gland formation

Clinical ─ Represents one of the main histological types in the Lauren classification
─ More common in younger patients (relative to intestinal type) and has a more equal sex distribution or slight female predominance in some studies
─ Incidence is more uniform across different geographic regions compared to intestinal type
─ Less strongly associated with H- pylori and chronic gastritis/intestinal metaplasia than intestinal type, though these can be present
─ Strong association with hereditary diffuse gastric cancer (HDGC) syndrome due to germline CDH1 (E-cadherin) mutations
─ Tends to infiltrate diffusely through the gastric wall, leading to mural thickening and rigidity (linitis plastica or "leather bottle stomach") rather than a discrete mass
─ Spreads primarily by peritoneal dissemination and lymphatic invasion; hematogenous spread also occurs
─ Molecularly, often associated with CDH1 mutations (somatic or germline), RHOA mutations, and genomic stability (less CIN or MSI)

Macro ─ Often results in diffuse thickening and induration of the gastric wall (linitis plastica) with effacement of rugal folds
─ Mucosa may appear relatively intact, ulcerated, or show superficial erosions
─ No discrete exophytic mass is typically formed

Micro ─
─ Characterized by infiltrative growth of individual cells or small clusters of poorly cohesive cells within a desmoplastic stroma
─ Signet-ring cell carcinoma is a major subtype, defined by >50% of tumor cells being signet-ring cells (intracytoplasmic mucin vacuole displacing the nucleus to the periphery)
─ Other poorly cohesive cells may have scant cytoplasm, hyperchromatic nuclei, and irregular contours, without obvious mucin
─ Minimal or no gland formation
─ Tumor cells often infiltrate widely through all layers of the gastric wall and along lymphatic channels
─ May show pagetoid spread within intact overlying foveolar epithelium
─ Inflammation can be variable, from minimal to prominent
─ Grading: By definition, diffuse-type adenocarcinomas (including signet-ring cell carcinoma) are considered poorly differentiated (high-grade)

Ancillary studies ─
─ Mucin stains (PAS-diastase, Alcian blue, mucicarmine) highlight intracytoplasmic mucin in signet-ring cells
─ IHC (+): Cytokeratins (AE1/AE3, CAM5-2); CK7 is often positive
─ IHC (-/+): CK20 (often negative or patchy), CDX2 (usually negative)
─ E-cadherin (CDH1) IHC: Often shows loss of membranous expression or aberrant cytoplasmic staining, reflecting CDH1 dysfunction (especially in HDGC-associated cases and many sporadic diffuse cancers)
─ HER2 testing is important for advanced/metastatic cases, though overexpression is less common than in intestinal type (~5-10%)
─ MMR/MSI testing: MSI-H is uncommon in pure diffuse type

DDx ─
─ Intestinal-type gastric adenocarcinoma, poorly differentiated: may have areas of poorly cohesive cells, but usually some gland formation is evident elsewhere; immunoprofile may differ (e-g-, CDX2+)
─ Lymphoma (especially diffuse large B-cell or other high-grade lymphomas): atypical lymphoid cells, CD45 positive, cytokeratin negative
─ Metastatic lobular breast carcinoma: can closely mimic diffuse gastric cancer with signet-ring cells; history of breast cancer, IHC for GATA3, ER, GCDFP-15 are key; E-cadherin is typically lost in lobular breast cancer as well
─ Reactive signet-ring cell change (e-g-, in ulcer repair, gastritis): cells are bland, confined to glands or surface, lack infiltrative growth and desmoplasia; E-cadherin usually preserved
─ Histiocytic infiltrates (e-g-, xanthoma, muciphages): cells are CD68 positive, cytokeratin negative

Prognosis ─ Generally has a worse prognosis than intestinal-type gastric cancer stage for stage
─ Often presents at an advanced stage due to insidious infiltrative growth
─ High propensity for peritoneal carcinomatosis and distant metastasis (e-g-, Krukenberg tumor of ovary)

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Gastric Carcinoma with Lymphoid Stroma

A rare subtype of gastric cancer characterized by poorly differentiated carcinoma cells admixed with a prominent, dense lymphoid infiltrate

Clinical ─ Also known as medullary carcinoma of the stomach or lymphoepithelioma-like carcinoma (LELC)
─ Accounts for about 1-4% of all gastric cancers
─ Strong association with Epstein-Barr virus (EBV) infection (found in >80-90% of cases)
─ More common in males and in younger patients compared to conventional gastric adenocarcinoma
─ Often occurs in the proximal stomach (cardia, fundus, body)
─ May have a better prognosis compared to conventional gastric adenocarcinoma of similar stage, possibly due to the host immune response (lymphoid stroma)

Macro ─ Typically forms a well-circumscribed, fleshy, polypoid or ulcerated mass
─ Cut surface is often homogenous, grey-white or tan

Micro ─
─ Composed of nests, sheets, or syncytial clusters of large, poorly differentiated epithelial cells with indistinct cell borders
─ Tumor cells have large, vesicular nuclei, prominent eosinophilic nucleoli, and moderate amounts of eosinophilic or amphophilic cytoplasm
─ Hallmark feature: a dense, diffuse lymphoid infiltrate (stroma) composed primarily of mature T-lymphocytes (CD3+, often CD8+), with admixed B-cells, plasma cells, and histiocytes; lymphoid follicles may be present
─ Tumor cells are intimately admixed with the lymphoid stroma, sometimes appearing "starry sky" like due to scattered apoptotic bodies or tingible body macrophages
─ Minimal or no gland formation or mucin production
─ Pushing borders are common, rather than an infiltrative pattern
─ Mitotic figures are usually frequent

Ancillary studies ─
─ IHC (+): Cytokeratins (AE1/AE3, CAM5-2) confirm epithelial nature of tumor cells; often CK7 positive
─ IHC (-): Typically negative for markers of intestinal differentiation (CDX2, CK20) and gastric foveolar/glandular mucins (MUC5AC, MUC6)
─ EBV detection: In situ hybridization for EBV-encoded RNA (EBER) is positive in the tumor cell nuclei in most cases and is a key diagnostic feature
─ Lymphoid markers (CD3, CD20, CD8) highlight the nature of the stromal infiltrate
─ PD-L1 expression is frequently high in these tumors, suggesting potential for immunotherapy
─ MMR/MSI status: A subset of EBV-negative LELCs may be MSI-High

DDx ─
─ Diffuse-type gastric adenocarcinoma: lacks the prominent lymphoid stroma and syncytial growth; often E-cadherin negative
─ Poorly differentiated intestinal-type adenocarcinoma: may have some lymphoid infiltrate, but not as dense or intimately admixed; usually shows some gland formation and is EBV negative
─ Lymphoma (especially high-grade B-cell or T-cell lymphomas): atypical lymphoid cells are the primary neoplastic population (CD45+, cytokeratin-); LELC tumor cells are cytokeratin positive
─ Undifferentiated carcinoma: lacks the dense lymphoid stroma; diagnosis by exclusion
─ Metastatic nasopharyngeal carcinoma (lymphoepithelioma): can be histologically identical and is also EBV-associated; clinical history is crucial for distinction

Prognosis ─ Generally considered to have a better prognosis than conventional gastric adenocarcinomas of similar stage, particularly EBV-positive cases
─ Lower rates of lymph node metastasis have been reported in some series
─ The host immune response (lymphoid stroma) is thought to contribute to the more favorable outcome

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Hepatoid Adenocarcinoma

A rare and aggressive variant of gastric adenocarcinoma characterized by morphologic and immunophenotypic features resembling hepatocellular carcinoma (HCC)

Clinical ─ Accounts for <1% of gastric cancers
─ Predominantly affects older males (mean age 60s)
─ Often presents with advanced disease, including liver metastases at diagnosis
─ Serum alpha-fetoprotein (AFP) levels are frequently elevated (in ~70-80% of cases), but can be normal
─ Site: most commonly in the antrum

Macro ─ Typically large, bulky tumors, often with ulceration and necrosis
─ May have a yellowish or greenish cut surface if bile production is present (rare)

Micro ─
─ Two main components are often present, though proportions vary:
─ ─ Hepatoid component: sheets, nests, or trabeculae of large polygonal cells with abundant eosinophilic to clear granular cytoplasm, distinct cell borders, large vesicular nuclei, and prominent central nucleoli, closely mimicking HCC
─ ─ Adenocarcinomatous component: usually a conventional tubular or papillary adenocarcinoma, which may be intermingled or distinct from the hepatoid areas
─ Some tumors may be purely hepatoid
─ Intracytoplasmic hyaline globules (PAS-D positive, AFP positive) may be seen in hepatoid cells
─ Canalicular-like structures or bile production are rare but highly suggestive features
─ Sinusoidal vascular pattern may be present in hepatoid areas
─ Background gastric mucosa may show chronic gastritis or intestinal metaplasia

Ancillary studies ─
─ IHC (+):
─ ─ AFP: Often positive in tumor cells (cytoplasmic), especially in hepatoid areas; serum AFP is also often elevated
─ ─ HepPar-1 (Hepatocyte Paraffin 1): Cytoplasmic granular staining in hepatoid areas (marker of hepatocyte differentiation)
─ ─ Glypican-3: Can be positive in hepatoid areas (membranous/cytoplasmic)
─ ─ SALL4: Nuclear positivity, also seen in yolk sac tumors and other germ cell tumors, but can be positive in hepatoid adenocarcinoma
─ ─ Cytokeratins: Usually positive for AE1/AE3, CAM5-2; CK7 and CK20 expression is variable
─ ─ Polyclonal CEA (pCEA): May show a canalicular staining pattern in hepatoid areas, similar to HCC
─ IHC (-): Typically negative for specific markers of other tumor types (e-g-, neuroendocrine markers)

DDx ─
─ Metastatic hepatocellular carcinoma (HCC) to the stomach: extremely rare; clinical history of primary HCC is key; morphology and IHC can be identical; presence of a conventional adenocarcinoma component in the stomach favors primary gastric hepatoid adenocarcinoma
─ Conventional gastric adenocarcinoma with clear cell features or oncocytic features: lacks AFP production and specific hepatocyte markers (HepPar-1, Glypican-3)
─ Yolk sac tumor (metastatic or rarely primary gastric): SALL4 positive, AFP positive, but typically has other characteristic patterns (e-g-, Schiller-Duval bodies, reticular pattern) and occurs in a different clinical context
─ Gastric adenocarcinoma with neuroendocrine differentiation: neuroendocrine markers positive

Prognosis ─ Very aggressive tumor with a poor prognosis
─ High rates of vascular invasion, lymph node metastasis, and early liver metastasis
─ Median survival is often short, even after surgical resection
─ Elevated serum AFP is a poor prognostic indicator

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Micropapillary Adenocarcinoma (Gastric)

A rare variant of gastric adenocarcinoma characterized by small papillary tufts of tumor cells lacking fibrovascular cores, floating in clear spaces, and associated with aggressive behavior

Clinical ─ Rare, accounts for a small percentage of gastric adenocarcinomas
─ Tends to occur in older individuals, similar to conventional gastric cancer
─ Often presents at an advanced stage with frequent lymph node metastasis and lymphovascular invasion
─ Symptoms are non-specific, similar to other gastric cancers (e-g-, abdominal pain, weight loss, anemia)

Macro ─ May present as an ulcerated mass or diffusely infiltrative lesion
─ Gross appearance is often not distinct from other types of gastric adenocarcinoma

Micro ─
─ Defining feature: presence of small, cohesive clusters or tufts of tumor cells forming micropapillae that lack a central fibrovascular core
─ These micropapillary clusters are typically found floating within stromal retraction clefts or clear spaces, which may be artifactual or represent lymphatic spaces
─ Tumor cells are usually cuboidal to columnar, with eosinophilic cytoplasm and high-grade nuclear features (pleomorphism, hyperchromasia, prominent nucleoli)
─ The micropapillary component often coexists with conventional tubular or papillary adenocarcinoma; the proportion of micropapillary pattern required for diagnosis can vary (e-g-, some use >5% or >10%)
─ Extensive lymphovascular invasion is a very common finding, even with small amounts of micropapillary component
─ Background gastric mucosa may show chronic gastritis, intestinal metaplasia, or atrophy

Ancillary studies ─
─ IHC: Tumor cells are positive for cytokeratins (AE1/AE3, CAM5-2, CK7 often positive)
─ Markers of intestinal differentiation (CDX2, CK20) may be positive if associated with an intestinal-type adenocarcinoma component
─ MUC1 (EMA) often shows a characteristic "inside-out" staining pattern on the stromal-facing surface of the micropapillae (reverse polarity)
─ HER2 overexpression/amplification can occur, similar to other gastric adenocarcinomas; testing recommended for advanced disease

DDx ─
─ Conventional papillary adenocarcinoma: has true fibrovascular cores supporting the papillae
─ Gastric adenocarcinoma with retraction artifact: may mimic micropapillary pattern, but tumor cells typically lack the distinct tufting and reverse polarity of MUC1 staining; true micropapillary pattern is a specific growth pattern, not just artifact
─ Metastatic micropapillary carcinoma (e-g-, from lung, breast, ovary, bladder): clinical history and IHC panel for site-specific markers are crucial; gastric primary is favored if a conventional gastric adenocarcinoma component is present and no other primary is known

Prognosis ─ Generally considered a very aggressive variant with a poor prognosis
─ Strongly associated with frequent lymph node metastasis, extensive lymphovascular invasion, and peritoneal dissemination, even when the micropapillary component is minor
─ Worse survival outcomes compared to conventional gastric adenocarcinoma of similar stage

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Fundic Gland-type Adenocarcinoma (Gastric)

A rare, typically well-differentiated variant of gastric adenocarcinoma with morphologic features resembling chief cells and/or parietal cells of the oxyntic glands

Clinical ─ Also known as oxyntic gland adenoma/adenocarcinoma or chief cell predominant adenocarcinoma
─ Extremely rare, usually found in older adults; some reports suggest a slight male predominance
─ Often asymptomatic and discovered incidentally during endoscopy for other reasons
─ Typically arises in the gastric fundus or body, in a background of non-atrophic oxyntic mucosa, often without H- pylori infection or autoimmune gastritis
─ Most reported cases behave indolently, with very low risk of metastasis, even if showing some infiltrative features

Macro ─ Usually small (<1-2 cm), solitary, sessile or slightly elevated, well-demarcated polypoid lesions or plaques
─ May have a yellowish hue on cut section

Micro ─
─ Composed of closely packed glands or anastomosing cords of cells that resemble normal or hyperplastic oxyntic gland epithelium, particularly chief cells and parietal cells
─ Chief cell predominant type: Majority of cells are cuboidal to columnar with basophilic granular cytoplasm and basal nuclei (resembling chief cells); may form solid nests or acinar structures
─ Parietal cell predominant type: Cells are larger, polygonal, with abundant eosinophilic granular cytoplasm and central nuclei (resembling parietal cells)
─ Mixed patterns also occur
─ Glands are often irregular, may show some branching or budding, but typically lack the complex architecture of conventional adenocarcinoma
─ Cytologic atypia is generally mild to moderate; nuclei may be enlarged and hyperchromatic with visible nucleoli, but mitotic activity is usually low
─ Some lesions may show deeper infiltration into the lamina propria or submucosa, but usually with a "pushing" border rather than destructive invasion, and minimal desmoplastic stromal response
─ Overlying foveolar epithelium is usually unremarkable

Ancillary studies ─
─ IHC (+):
─ ─ Pepsinogen-I (PG-I): Strong diffuse positivity in chief cell areas (highly characteristic)
─ ─ H+/K+ ATPase: Positive in parietal cell areas
─ ─ MUC6: Often positive in mucous neck cell areas and can be in chief cells
─ ─ Somatostatin: May highlight entrapped endocrine cells but tumor cells are negative
─ IHC (-):
─ ─ Intestinal markers (CDX2, CK20, MUC2) are typically negative
─ ─ Foveolar mucin (MUC5AC) is usually negative in tumor cells or confined to surface epithelium
─ ─ Neuroendocrine markers (synaptophysin, chromogranin) are negative in tumor cells
─ Ki-67 proliferation index is usually very low (<5%)

DDx ─
─ Oxyntic gland adenoma (chief cell adenoma): Terminology overlap; lesions confined to mucosa with minimal atypia are often considered adenomas, while those with more atypia or invasion are termed fundic gland-type adenocarcinoma; the distinction is not always clear-cut, but behavior is generally indolent for both
─ Fundic gland polyp (FGP): More cystic, less cellular, composed of both parietal and chief cells without the architectural complexity or atypia that can be seen in fundic gland-type adenocarcinoma/oxyntic gland adenoma
─ Well-differentiated neuroendocrine tumor (NET): Organoid pattern, "salt & pepper" chromatin, positive for neuroendocrine markers
─ Conventional gastric adenocarcinoma (intestinal or diffuse type): Different cytology, architecture, and immunoprofile (e-g-, often CDX2/CK20 positive)
─ Pyloric gland adenoma: MUC6 positive, but composed of pyloric-type glands, lacks pepsinogen-I expression

Prognosis ─ Generally considered to have a very good prognosis with an indolent clinical course
─ Metastases are exceptionally rare, even for lesions designated as "adenocarcinoma of fundic gland type" with some invasion
─ Complete endoscopic or surgical resection is usually curative
─ Long-term surveillance recommendations are not well established due to rarity, but recurrence is uncommon

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Gastric Choriocarcinoma

An extremely rare and highly aggressive form of gastric cancer containing trophoblastic differentiation, specifically syncytiotrophoblasts and/or cytotrophoblasts, and often associated with beta-human chorionic gonadotropin (β-hCG) production

Clinical ─ Very rare, usually occurs in older adults (median age 60s), with a strong male predominance
─ Patients often present with symptoms of advanced gastric cancer (pain, weight loss, bleeding) and may have symptoms related to ectopic β-hCG production (e-g-, gynecomastia in males)
─ Serum β-hCG levels are usually markedly elevated
─ Highly aggressive with early and widespread metastases, particularly to liver, lungs, and lymph nodes

Macro ─ Typically large, bulky, hemorrhagic, and necrotic tumors
─ May be polypoid or ulcerative and deeply infiltrative

Micro ─
─ Defining feature is the presence of malignant trophoblastic cells:
─ ─ Syncytiotrophoblasts: Large, multinucleated giant cells with abundant eosinophilic or amphophilic cytoplasm and pleomorphic, hyperchromatic nuclei
─ ─ Cytotrophoblasts: Smaller, mononucleated cells with clear or pale cytoplasm and distinct cell borders, often arranged in clusters or sheets
─ These trophoblastic elements are often admixed with a more conventional gastric adenocarcinoma component (e-g-, tubular, papillary, or poorly differentiated) – termed "mixed choriocarcinoma-adenocarcinoma"
─ Pure gastric choriocarcinoma (composed only of trophoblastic elements) is exceptionally rare
─ Extensive hemorrhage, necrosis, and vascular invasion are characteristic features
─ The trophoblastic cells are typically found at the invasive front or within vascular spaces

Ancillary studies ─
─ IHC (+):
─ ─ β-hCG: Strong cytoplasmic positivity in syncytiotrophoblasts is diagnostic; cytotrophoblasts are usually negative or weakly positive
─ ─ Cytokeratins (AE1/AE3, CAM5-2): Positive in both trophoblastic and any adenocarcinoma components
─ ─ Other trophoblastic markers like GATA3, SALL4, inhibin, or PLAP may be positive but are less specific in this context
─ IHC (-): Typically negative for markers of other specific tumor types if it's a primary gastric choriocarcinoma (e-g-, HepPar-1, CDX2 in pure choriocarcinoma areas, though an associated adenocarcinoma component might be CDX2+)

DDx ─
─ Metastatic choriocarcinoma (from gonadal or gestational primary): Clinical history is paramount; primary gastric choriocarcinoma is a diagnosis of exclusion. Testicular examination/imaging in males and gynecologic history in females is essential.
─ Poorly differentiated gastric adenocarcinoma with pleomorphic giant cells: May mimic syncytiotrophoblasts, but will be negative for β-hCG
─ Gastric adenocarcinoma with neuroendocrine differentiation (some large cell NECs can have giant cells): Neuroendocrine markers positive, β-hCG negative
─ Melanoma: Can have pleomorphic giant cells; S100/SOX10 positive, β-hCG negative

Prognosis ─ Extremely poor, one of the most aggressive gastric cancer variants
─ Rapidly progressive disease with early and widespread metastases
─ Median survival is typically very short (months), even with multimodality treatment
─ Resistance to conventional chemotherapy for gastric adenocarcinoma is common

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Malignant Rhabdoid tumor of the stomach

An exceptionally rare and highly aggressive gastric malignancy characterized by cells with "rhabdoid" features: large, eccentric nuclei, prominent nucleoli, and eosinophilic cytoplasmic inclusions

Clinical ─ Extremely rare in the stomach, more commonly seen in pediatric kidney (malignant rhabdoid tumor of kidney)
─ In adults, rhabdoid phenotype can occur in various carcinomas or sarcomas ("composite rhabdoid tumor" or "carcinoma with rhabdoid features") or rarely as a pure rhabdoid tumor
─ Usually affects older adults when primary in the stomach
─ Presents with symptoms of advanced cancer (pain, weight loss, bleeding, mass)
─ Highly aggressive with rapid progression and early metastasis

Macro ─ Typically large, infiltrative, and often necrotic and hemorrhagic masses

Micro ─
─ Diffuse sheets or poorly cohesive infiltrates of large, polygonal to round cells with characteristic rhabdoid cytology:
─ ─ Eccentrically placed, vesicular nuclei
─ ─ Prominent, often eosinophilic, central nucleoli
─ ─ Abundant eosinophilic cytoplasm containing a paranuclear, dense, hyaline-like inclusion (composed of aggregated intermediate filaments, mainly vimentin and keratin) that displaces the nucleus
─ Cells may be discohesive or form vague nests
─ High mitotic rate and extensive necrosis are common
─ May be associated with a conventional adenocarcinoma component (carcinoma with rhabdoid features) or exist as a pure rhabdoid tumor
─ Inactivation of SMARCB1 (INI1/hSNF5/BAF47), a tumor suppressor gene and core subunit of the SWI/SNF chromatin remodeling complex, is a hallmark of classic rhabdoid tumors (pediatric) and a subset of adult tumors with rhabdoid features

Ancillary studies ─
─ IHC (+):
─ ─ Vimentin: Strong positivity in cytoplasmic inclusions and cytoplasm
─ ─ Cytokeratins (AE1/AE3, CAM5-2, EMA): Often positive, confirming epithelial origin if present, especially in carcinomas with rhabdoid features; can be lost in pure rhabdoid tumors
─ ─ SMARCB1 (INI1): Loss of nuclear expression is characteristic of true rhabdoid tumors and is a key diagnostic marker; retained expression may be seen in some carcinomas with focal rhabdoid features that are not driven by INI1 loss
─ IHC (-/+): SMA, desmin, myogenin (usually negative, helping to exclude rhabdomyosarcoma); S100 (usually negative)
─ PAS stain: Cytoplasmic inclusions are typically PAS-negative or weakly positive

DDx ─
─ Poorly differentiated adenocarcinoma with oncocytic or pleomorphic features: May have large eosinophilic cells, but lacks the classic paranuclear inclusions and INI1 loss of true rhabdoid tumor
─ Signet ring cell carcinoma: Intracytoplasmic mucin, not filamentous inclusions; INI1 retained
─ Malignant melanoma: Can have rhabdoid cells; S100/SOX10 positive; INI1 retained
─ Epithelioid sarcoma: Can have rhabdoid features and INI1 loss, but typically arises in soft tissues; may express keratins. Distinction from primary gastric rhabdoid tumor can be challenging and rely on clinicopathologic context.
─ Rhabdomyosarcoma (especially pleomorphic or embryonal): Expresses muscle markers (desmin, myogenin, MyoD1); INI1 retained
─ Plasmacytoma/Plasma cell myeloma with anaplastic features: CD138 positive, light chain restriction; INI1 retained

Prognosis ─ Extremely poor, regardless of whether it's a pure rhabdoid tumor or a carcinoma with rhabdoid features
─ Highly aggressive with early and widespread metastases (lung, liver, lymph nodes, peritoneum)
─ Poor response to conventional chemotherapy and radiation
─ Median survival is very short

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Stomach Lymphomas

Diffuse Large B-Cell Lymphoma (DLBCL), gastric

An aggressive lymphoma composed of a diffuse proliferation of large neoplastic B-lymphocytes, representing the most common type of lymphoma involving the stomach either as a primary site or secondary involvement

Clinical ─ Can occur de novo or as a transformation from a lower-grade lymphoma (e-g-, MALT lymphoma)
─ Symptoms are often non-specific: epigastric pain, weight loss, nausea, vomiting, bleeding, or palpable mass
─ May be associated with Helicobacter pylori infection, particularly if arising from MALT lymphoma
─ Median age typically in 6th-7th decades, slight male predominance
─ Staging involves assessment of GI tract involvement and systemic spread (e-g-, Ann Arbor staging, Lugano classification for GI lymphomas)

Macro ─ Can present as a bulky ulcerative mass, an infiltrative lesion causing thickened gastric wall (linitis plastica-like), or multiple nodules/polyps
─ Often involves antrum or body, but can occur anywhere in the stomach

Micro ─
─ Diffuse infiltrate of large, atypical lymphoid cells that efface normal gastric architecture
─ Neoplastic cells are typically centroblastic (large cells with vesicular nuclei, distinct nucleoli, and moderate cytoplasm) or immunoblastic (large cells with prominent central nucleolus and more abundant basophilic cytoplasm)
─ Other morphologic variants exist (e-g-, anaplastic)
─ High mitotic rate and apoptotic bodies are common
─ Necrosis may be present
─ Lymphoepithelial lesions (infiltration of gastric glands by lymphoma cells) may be seen, especially if associated with a MALT lymphoma component, but are not as characteristic as in pure MALT lymphoma
─ Tumor cells may infiltrate between gastric glands, sometimes dissecting the muscularis mucosae
─ Background of chronic gastritis or MALT lymphoma may be present

Ancillary studies ─
─ IHC (+): Pan-B cell markers (CD20, CD79a, PAX5) are strongly and diffusely positive
─ IHC (+/-): CD10, BCL6, MUM1 (used for subtyping into Germinal Center B-cell like (GCB) vs Non-GCB/Activated B-cell like (ABC) types, which has prognostic implications; Hans algorithm commonly used)
─ IHC (+/-): BCL2 (often positive), MYC (overexpression in a subset, especially with MYC translocations)
─ IHC (-): CD3 (T-cell marker), Cyclin D1 (negative, helps exclude blastoid mantle cell lymphoma)
─ Ki-67: High proliferation index (typically >40%, often much higher)
─ EBER ISH: May be positive in a subset of cases, particularly in immunodeficiency settings or EBV+ DLBCL of the elderly
─ Molecular: Clonally rearranged immunoglobulin heavy and light chain genes
─ ─ Translocations involving MYC, BCL2, and/or BCL6 ("double-hit" or "triple-hit" lymphomas) are associated with very aggressive behavior and poor prognosis; FISH can detect these

DDx ─
─ MALT lymphoma with increased large cells: Distinction can be difficult; sheets of large cells favor DLBCL over MALT lymphoma with scattered transformed blasts
─ Poorly differentiated adenocarcinoma: Cytokeratin positive, CD45 negative; cells may form vague nests or glands
─ Melanoma: S100/SOX10/Melan-A positive; can be composed of large atypical cells
─ Other high-grade lymphomas (e-g-, Burkitt lymphoma, Mantle cell lymphoma blastoid variant): Specific immunophenotype and molecular features (e-g-, Cyclin D1 in MCL, MYC translocation without BCL2/BCL6 in Burkitt)
─ Reactive lymphoid hyperplasia with large transformed cells: Polyclonal, lacks diffuse sheets of atypical large cells, often preserves architecture better

Prognosis ─ Aggressive lymphoma, but potentially curable with immunochemotherapy (e-g-, R-CHOP: Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, Prednisone)
─ Prognosis depends on stage, International Prognostic Index (IPI) score, molecular subtype (GCB vs Non-GCB), and presence of high-risk genetic alterations (e-g-, MYC translocations, double/triple-hit status)
─ Gastric DLBCL may have a better prognosis than nodal DLBCL in some studies, possibly due to localized presentation
─ Some H- pylori-positive gastric DLBCLs, especially those with MALT lymphoma components, may respond to H- pylori eradication therapy alone if disease is limited and low-grade appearing, but this is controversial and requires careful selection/monitoring

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MALT Lymphoma (Extranodal Marginal Zone Lymphoma of MALT), gastric

A low-grade B-cell lymphoma arising from mucosa-associated lymphoid tissue (MALT), strongly associated with chronic Helicobacter pylori infection in the stomach

Clinical ─ Most common type of primary gastric lymphoma
─ Median age ~60 years, slight female predominance
─ Strong etiologic link to chronic H- pylori gastritis; eradication of H- pylori leads to lymphoma regression in a majority (70-80%) of early-stage cases
─ Other associations (rare): Hepatitis C virus, autoimmune diseases
─ Symptoms are often vague: dyspepsia, epigastric pain, nausea; may be asymptomatic or present with bleeding/anemia
─ Usually localized to the stomach at diagnosis, but can disseminate

Macro ─ Endoscopic appearance is variable:
─ ─ Mucosal erythema, erosions, or shallow ulcerations
─ ─ Thickened rugal folds, nodules, or mass-like lesions
─ ─ May mimic gastritis or peptic ulcer disease
─ Most commonly involves the antrum, but can be multifocal or diffuse

Micro ─
─ Dense lymphoid infiltrate in the lamina propria, often extending into the submucosa
─ Neoplastic cells are small to medium-sized B-cells with irregular (centrocyte-like) nuclei, condensed chromatin, and moderate amounts of pale cytoplasm ("monocytoid B-cells")
─ Scattered larger transformed cells (centroblast- or immunoblast-like) are usually present but should not form sheets (if sheets present, consider transformation to DLBCL)
─ Characteristic lymphoepithelial lesions (LELs): infiltration and destruction of gastric glands by clusters of neoplastic lymphoid cells; epithelium may appear reactive or damaged
─ Reactive-appearing lymphoid follicles are often present, which may be colonized by the neoplastic marginal zone cells, resulting in expanded and irregular mantle/marginal zones around the follicles
─ Plasmacytic differentiation (plasma cells within the infiltrate) is common; these plasma cells are part of the neoplastic clone and will show light chain restriction
─ Dutcher bodies (intranuclear immunoglobulin inclusions) can be seen in plasma cells
─ Background chronic gastritis, often with H- pylori organisms, is usually present

Ancillary studies ─
─ IHC (+): Pan-B cell markers (CD20, CD79a, PAX5)
─ IHC (-/+): CD43 (aberrantly co-expressed in ~30-50% of cases), BCL2 (often positive in neoplastic cells, helping distinguish from reactive follicular hyperplasia where germinal centers are BCL2 negative)
─ IHC (-): CD5, CD10, CD23, Cyclin D1 (helps exclude CLL/SLL, follicular lymphoma, mantle cell lymphoma)
─ Kappa and Lambda light chain IHC/ISH: to demonstrate monotypic light chain restriction in cases with prominent plasmacytic differentiation
─ Cytokeratin IHC (e-g-, AE1/AE3, CAM5-2): highlights lymphoepithelial lesions by staining the entrapped epithelial cells
─ Special stains/IHC for H- pylori to confirm infection status
─ Molecular: Clonally rearranged immunoglobulin heavy and light chain genes
─ ─ Common translocations: t(11;18)(q21;q21) creating API2-MALT1 fusion gene (~25-50% of gastric MALT lymphomas, associated with resistance to H- pylori eradication); t(1;14)(p22;q32) involving BCL10 and IGH; t(14;18)(q32;q21) involving IGH and MALT1; trisomy 3 and 18 also common

DDx ─
─ Reactive lymphoid hyperplasia / H- pylori gastritis: prominent lymphoid follicles and plasma cells, but lacks diffuse infiltrate of monocytoid B-cells, definite LELs, and monoclonality; distinction can be very difficult in early/borderline cases
─ Diffuse Large B-Cell Lymphoma (DLBCL): sheets of large transformed cells; MALT lymphoma can transform to DLBCL
─ Mantle Cell Lymphoma: CD5+, Cyclin D1+
─ Follicular Lymphoma: CD10+, BCL6+; typically forms distinct neoplastic follicles
─ Lymphocytic gastritis: marked intraepithelial T-lymphocytosis (CD3+, CD8+), surface epithelial damage, lacks atypical B-cell infiltrate and LELs

Prognosis ─ Generally an indolent lymphoma with a good prognosis, especially if localized and H- pylori-positive (responsive to eradication)
─ 5-year survival rates are high (>75-90% for early stage)
─ Cases with t(11;18) are less likely to respond to H- pylori eradication and may require other therapies (e-g-, radiation, chemotherapy, rituximab)
─ Risk of transformation to DLBCL is ~5-10%, associated with worse prognosis
─ Regular follow-up is necessary to monitor for recurrence or transformation

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Small Intestine

Small Intestine Anatomy

Feature	Description
Structure	Longest part of GI tract (~6-7m), from pylorus to ileocecal valve. Main site of digestion/absorption.
Segments	Duodenum: ~25 cm, C-shaped, mostly retroperitoneal. Jejunum: Middle 2/5, upper left quadrant. Ileum: Final 3/5, lower right quadrant.
Surface Area Features	Plicae Circulares: Permanent mucosal/submucosal folds (most prominent in jejunum). Villi: Finger-like mucosal projections (longest in jejunum). Microvilli: Apical "brush border" on enterocytes.
Blood Supply	Superior mesenteric artery (SMA). Proximal duodenum also from celiac trunk.
Venous Drainage	Superior mesenteric vein -> Portal vein.
Lymphatics	Rich network including central lacteals in villi, draining to mesenteric nodes.

Small Intestine Histology

Feature / Cell Type	Description
Mucosal Structure	Villi and Crypts of Lieberkühn. Crypt-to-villous ratio is normally 1:3 to 1:5.
Enterocytes	Tall columnar absorptive cells with an apical brush border (microvilli).
Goblet Cells	Secrete mucin; increase in number from duodenum to ileum.
Paneth Cells	At crypt base; contain large, eosinophilic apical granules with antimicrobial substances (lysozyme, defensins).
Neuroendocrine Cells	Scattered hormone-secreting cells (e.g., secretin, cholecystokinin [CCK]).
Intraepithelial Lymphocytes	Normal count is one per five epithelial cells, or <25 per 100 enterocytes.
Regional Features	Duodenum: Long, broad, leaf-shaped villi. Brunner's glands in submucosa (alkaline mucus). Jejunum: Longest, most finger-like villi. Most prominent plicae circulares. Ileum: Shorter, more club-shaped villi. Peyer's patches (large lymphoid aggregates) are characteristic. Most numerous goblet cells.

Congenital malformations

Meckel Diverticulum

A common congenital anomaly of the small intestine, resulting from incomplete obliteration of the vitelline (omphalomesenteric) duct

Clinical ─ Rule of 2s: occurs in ~2% of the population, typically symptomatic by age 2, twice as common in males, located within 2 feet (about 60 cm) of the ileocecal valve, often ~2 inches (5 cm) in length, and may contain 2 types of ectopic mucosa (gastric and/or pancreatic)
─ Most are asymptomatic and found incidentally
─ Symptomatic presentation can include: painless rectal bleeding (due to peptic ulceration from ectopic gastric mucosa), intestinal obstruction (due to volvulus, intussusception, or Littre's hernia - diverticulum in an inguinal or femoral hernia), diverticulitis (mimicking appendicitis), or rarely perforation
─ Site: antimesenteric border of the ileum

Macro ─ A true diverticulum, containing all layers of the bowel wall
─ Appears as an out-pouching from the antimesenteric side of the ileum
─ Mucosa within the diverticulum may appear normal ileal, or thickened/ulcerated if ectopic gastric mucosa is present and causing peptic injury

Micro ─
─ Wall contains all layers: mucosa, submucosa, muscularis propria, and serosa
─ Lining mucosa is typically ileal type, but ectopic tissue is common:
─ ─ Ectopic gastric mucosa (most common, ~50-60% of symptomatic cases): usually fundic type (parietal and chief cells), can cause peptic ulceration of adjacent ileal mucosa or within the diverticulum itself
─ ─ Ectopic pancreatic tissue (acini, ducts, rarely islets): ~5-16% of cases
─ ─ Less commonly, ectopic duodenal, colonic, or Brunner's glands may be found
─ Peptic ulceration, if present, is histologically similar to peptic ulcers elsewhere (necrosis, granulation tissue, inflammation)
─ Inflammation (neutrophils, chronic inflammatory cells) if diverticulitis occurs
─ Neoplasms can rarely arise within a Meckel diverticulum, most commonly neuroendocrine tumors (carcinoids), followed by GISTs, adenocarcinomas, and lymphomas

Ancillary studies ─
─ Technetium-99m pertechnetate scan ("Meckel scan"): can identify ectopic gastric mucosa due to uptake by parietal cells; used in cases of unexplained GI bleeding, especially in children
─ IHC for gastrin, pepsinogen, H+/K+ ATPase can confirm gastric mucosa; amylase/lipase for pancreatic tissue if morphology is unclear

DDx ─
─ Acquired diverticula (pseudodiverticula): lack a full muscularis propria layer; more common in colon and duodenum, rare in ileum unless due to chronic inflammation/stricture (e-g-, Crohn's)
─ Duplication cyst: usually on mesenteric side, shares a common muscular wall, does not always communicate with lumen (Meckel's always communicates proximally)
─ Appendicitis (if Meckel's diverticulitis presents as RLQ pain): clinical and imaging distinction; histology of appendix vs diverticulum

Prognosis ─ Asymptomatic diverticula generally have an excellent prognosis and require no treatment if found incidentally during surgery for another reason (though prophylactic removal is debated, especially in children or if ectopic tissue is suspected)
─ Symptomatic diverticula require surgical resection, which is usually curative
─ Complications like bleeding, obstruction, or perforation can be serious if not managed promptly

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Patterns of Injury

Peptic duodenitis / Peptic Ulcer Disease (Duodenal)

Inflammation and mucosal injury in the duodenum, typically the bulb, caused by exposure to gastric acid and pepsin

Clinical ─ Strongly associated with Helicobacter pylori infection (major cause of increased acid exposure to duodenum) and/or NSAID use
─ Zollinger-Ellison syndrome (gastrinoma) is a rare cause of severe peptic duodenitis and multiple/refractory ulcers
─ Symptoms: epigastric pain (often gnawing or burning, may be relieved by food or antacids), nausea, bloating; complications include bleeding, perforation, and obstruction
─ Site: most commonly affects the duodenal bulb (first part of duodenum)

Macro ─ Endoscopy may show:
─ ─ Mucosal erythema, edema, friability, erosions, or frank ulceration in the duodenal bulb
─ ─ "Cobblestone" or nodular appearance may be seen due to Brunner gland hyperplasia and/or mucosal edema
─ ─ Ulcers are typically round to oval, sharply demarcated, with a clean base or overlying exudate

Micro ─
─ Peptic duodenitis (without frank ulceration):
─ ─ Acute inflammation: neutrophils in the lamina propria and infiltrating surface/crypt epithelium (intraepithelial neutrophils, cryptitis)
─ ─ Chronic inflammation: increased lymphocytes and plasma cells in the lamina propria
─ ─ Surface epithelial injury: degeneration, mucin depletion, erosions
─ ─ Gastric (foveolar) surface metaplasia: patches of gastric-type surface mucous cells replacing normal duodenal absorptive cells; a common response to acid injury
─ ─ Brunner gland hyperplasia: increased number and size of submucosal Brunner's glands, which may extend into the mucosa; glands are composed of cuboidal cells with pale eosinophilic cytoplasm and basal nuclei, secreting alkaline mucus
─ ─ Villous blunting or atrophy may be present
─ Peptic Ulcer (Duodenal):
─ ─ Defect extending through the muscularis mucosae into the submucosa or deeper
─ ─ Classic four zones (from lumen outwards): necrotic debris and fibrin, acute inflammation (neutrophils), granulation tissue, fibrous scar tissue (in chronic ulcers)
─ ─ Underlying Brunner gland hyperplasia is common
─ ─ Search for H- pylori in associated gastric metaplasia if present, or on concomitant gastric biopsies

Ancillary studies ─
─ Special stains/IHC for H- pylori on gastric biopsies (duodenal biopsies are less sensitive for H- pylori itself, but gastric metaplasia in duodenum can be colonized)

DDx ─
─ Crohn's disease involving duodenum: aphthous ulcers, granulomas (non-caseating), transmural inflammation, skip lesions; often associated with ileal/colonic Crohn's
─ Celiac disease: villous atrophy, crypt hyperplasia, increased intraepithelial lymphocytes, but typically lacks the acute inflammation and gastric metaplasia of peptic duodenitis (unless coexisting)
─ Giardiasis: may cause mild duodenitis; pear-shaped trophozoites visible on surface or in mucus
─ Other infections (e-g-, CMV, Cryptosporidium in immunocompromised): specific organisms or viral inclusions
─ NSAID-induced duodenopathy: can cause erosions/ulcers similar to peptic ulcers; history is key

Prognosis ─ Good with treatment of underlying cause (e-g-, H- pylori eradication, NSAID cessation, PPI therapy)
─ Ulcers typically heal with acid suppression
─ Complications (bleeding, perforation, obstruction) can be serious but are less common with effective modern therapies
─ Recurrence is common if underlying cause is not addressed

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Acute duodenitis (non-peptic)

Acute inflammation of the duodenal mucosa not primarily driven by gastric acid/pepsin hypersecretion or H- pylori/NSAID-related peptic injury

Clinical ─ Causes are diverse and can include:
─ ─ Infections: Viral (e-g-, rotavirus, norovirus, CMV in immunocompromised), bacterial (e-g-, Salmonella, Shigella, Campylobacter), parasitic (e-g-, Giardia, Cryptosporidium)
─ ─ Medications other than NSAIDs (e-g-, some antibiotics, chemotherapy)
─ ─ Ischemia (in critically ill patients)
─ ─ Radiation therapy to the abdomen
─ ─ Allergic reactions (e-g-, food allergies, eosinophilic duodenitis)
─ Symptoms: acute onset nausea, vomiting, diarrhea, abdominal pain, fever (if infectious)

Macro ─ Endoscopic findings are often non-specific: mucosal erythema, edema, friability, scattered erosions, or petechiae
─ Mucosa may appear normal in some mild cases

Micro ─
─ Presence of acute inflammatory cells (neutrophils) in the lamina propria and/or epithelium (cryptitis, intraepithelial neutrophils)
─ Villous architecture may be blunted or normal
─ Surface epithelial damage, increased apoptosis, or erosions may be present
─ Lamina propria edema and vascular congestion
─ Specific etiologic clues should be sought:
─ ─ Viral infections: may show increased intraepithelial lymphocytes, epithelial cell degeneration, or specific viral inclusions (e-g-, CMV in endothelial/stromal cells)
─ ─ Bacterial infections: often marked neutrophilic infiltrate, crypt abscesses, erosions; organisms usually not seen without culture/special tests
─ ─ Giardiasis: pear-shaped trophozoites on surface or in mucus
─ ─ Eosinophilic duodenitis: prominent eosinophilic infiltrate (>20-30/hpf)
─ ─ Ischemic changes: mucosal necrosis, hyalinization of lamina propria, withered crypts (more chronic finding)
─ Gastric foveolar metaplasia is typically absent or minimal, distinguishing from peptic duodenitis

Ancillary studies ─
─ Stool cultures, ova and parasite examination, viral PCR on stool/biopsy if infection suspected
─ IHC for CMV if patient is immunocompromised and inclusions are suspected
─ Special stains for other organisms if clinically indicated

DDx ─
─ Peptic duodenitis: prominent gastric foveolar metaplasia, often Brunner gland hyperplasia, related to acid/pepsin; H- pylori often in stomach
─ Celiac disease: chronic changes (villous atrophy, crypt hyperplasia, increased IELs), not primarily acute neutrophilic inflammation
─ Crohn's disease: can have acute inflammation, but look for aphthous ulcers, granulomas, transmural inflammation
─ Graft-versus-Host Disease (GVHD): history of transplant, prominent epithelial apoptosis, lymphocytic infiltrate

Prognosis ─ Usually self-limited if infectious and in immunocompetent individuals
─ Depends on the underlying cause and its specific treatment
─ Severe cases (e-g-, ischemic duodenitis in critically ill) can have high morbidity/mortality

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Acute ileitis

Acute inflammation of the ileal mucosa, often presenting with right lower quadrant pain and diarrhea

Clinical ─ Common causes include:
─ ─ Infections: Bacterial (e-g-, Yersinia enterocolitica, Salmonella, Campylobacter, Shigella), viral (e-g-, CMV in immunocompromised)
─ ─ NSAID use (NSAID enteropathy can affect ileum)
─ ─ Ischemia (less common in ileum than colon but can occur)
─ ─ Early manifestation of Crohn's disease
─ Symptoms: right lower quadrant abdominal pain (mimicking appendicitis), diarrhea (may be bloody), fever, nausea, vomiting
─ "Terminal ileitis" refers to inflammation specifically of the distal ileum

Macro ─ Endoscopy or imaging may show mucosal erythema, edema, aphthous ulcers, larger ulcers, or nodularity
─ Wall thickening may be present

Micro ─
─ Neutrophilic infiltrate in the lamina propria and epithelium (cryptitis, crypt abscesses, intraepithelial neutrophils)
─ Erosions or ulcerations of the mucosa
─ Villous blunting or distortion may be present
─ Lamina propria edema and vascular congestion
─ Lymphoid hyperplasia is common in the ileum and may be prominent
─ Specific etiologic clues:
─ ─ Yersinia infection: may show prominent lymphoid hyperplasia with necrotizing granulomas or microabscesses in Peyer's patches or lymph nodes (granulomas often stellate with central neutrophils)
─ ─ CMV infection: viral inclusions in endothelial/stromal cells at ulcer base (in immunocompromised)
─ ─ NSAID enteropathy: may show diaphragm-like strictures (chronic use), erosions, or ulcers; eosinophils can be prominent
─ ─ Early Crohn's disease: aphthous ulcers, focal cryptitis, architectural distortion, or small, poorly formed granulomas (may not be present in early biopsies)

Ancillary studies ─
─ Stool cultures for bacterial pathogens
─ Biopsy cultures for specific organisms if suspected (e-g-, Yersinia)
─ IHC for CMV in immunocompromised patients
─ Serologic tests for Yersinia (less useful in acute setting)

DDx ─
─ Crohn's disease: key differential; look for chronicity features (crypt distortion, granulomas, transmural inflammation, fistulas, strictures) on follow-up or more extensive sampling if acute ileitis is recurrent or persistent
─ Other infectious enterocolitis (e-g-, viral, other bacteria): often more diffuse colonic involvement as well
─ Ischemic enteritis: typically segmental, often in watershed areas; mucosal necrosis, hyalinization
─ Behçet's disease: can cause ileal ulcers, but usually associated with oral/genital ulcers and other systemic features
─ Diversion ileitis (in patients with ileostomy): inflammation in the diverted segment

Prognosis ─ Depends on the underlying cause
─ Most infectious ileitis is self-limited or responds to antibiotics if bacterial
─ NSAID-induced ileitis usually improves with drug withdrawal
─ If it's an early manifestation of Crohn's disease, it will likely become a chronic condition

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Chronic Injury Patterns (Small Intestine)

Persistent or recurrent injury to the small intestinal mucosa leading to characteristic architectural and inflammatory changes

Clinical ─ Etiologies are diverse, including inflammatory bowel disease (Crohn's), chronic infections, celiac disease (though often has specific immune-mediated features), long-term medication use (e-g-, NSAIDs leading to diaphragm disease), chronic ischemia, and radiation enteritis
─ Symptoms are often chronic and relapsing, such as abdominal pain, diarrhea, malabsorption, weight loss, and anemia

Macro ─ Endoscopic findings vary with etiology and severity
─ May include mucosal erythema, edema, ulcerations (aphthous or linear), strictures, cobblestoning (Crohn's), scalloping of folds (celiac disease), or a relatively normal appearance

Micro ─
─ Architectural changes:
─ ─ Villous blunting or atrophy: villi are shorter and broader than normal; may be partial or total
─ ─ Crypt hyperplasia: crypts become elongated and more numerous, often with increased mitotic activity, as a regenerative response
─ ─ Crypt distortion: irregular crypt shapes (branching, budding, dilated, angulated), loss of parallel orientation
─ ─ Crypt dropout: loss of crypts, leading to a scarred or atrophic mucosa
─ Metaplastic changes:
─ ─ Pyloric (gastric) gland metaplasia: presence of glands resembling gastric pyloric glands (cuboidal cells with pale eosinophilic cytoplasm, basal nuclei) in the small intestinal mucosa, especially duodenum; common in chronic duodenitis and Crohn's disease
─ ─ Gastric surface (foveolar) metaplasia: patches of gastric-type surface mucous cells, especially in duodenum due to acid injury
─ ─ Paneth cell metaplasia: Paneth cells (with characteristic eosinophilic apical granules) appearing more proximally than usual or in increased numbers
─ Inflammatory changes:
─ ─ Increased chronic inflammatory cells (lymphocytes, plasma cells) in the lamina propria; basal plasmacytosis (plasma cells concentrated at the base of crypts) is a common feature of chronicity, especially in IBD
─ ─ Neutrophilic activity (cryptitis, crypt abscesses) indicates active chronic inflammation if superimposed on chronic changes
─ ─ Granulomas (non-caseating) are a hallmark of Crohn's disease but not always present
─ ─ Increased intraepithelial lymphocytes (IELs) can be seen in various conditions (e-g-, celiac disease, viral enteritis, GVHD)
─ Fibrosis: Lamina propria or submucosal fibrosis can occur in long-standing injury, potentially leading to strictures (e-g-, Crohn's, radiation, NSAID-induced diaphragm disease)
─ Diaphragm Disease (NSAID-induced): Circumferential, thin, web-like strictures in the small intestine due to chronic NSAID use; histologically show submucosal fibrosis, ulceration, and hyalinization, with less chronic inflammation than Crohn's disease

Ancillary studies ─
─ Dependent on suspected etiology (e-g-, serology/biopsy for celiac disease, imaging/biopsy for Crohn's)

DDx ─
─ Specific entities causing chronic injury need to be distinguished based on the constellation of findings and clinical context (e-g-, Crohn's disease, celiac disease, infectious enteritis, radiation enteritis, medication-induced enteropathy)

Prognosis ─ Dependent on the underlying cause and severity of chronic injury
─ Can lead to malabsorption, malnutrition, strictures, fistulae (Crohn's), and increased risk of neoplasia in some conditions (e-g-, adenocarcinoma in Crohn's or celiac disease)

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Ischemic Enteropathy (Small Intestine)

Mucosal injury and inflammation of the small intestine due to inadequate blood supply

Clinical ─ Causes include arterial occlusion (e-g-, atherosclerosis, thrombosis, embolism, vasculitis), venous occlusion (e-g-, thrombosis), non-occlusive ischemia (low flow states, e-g-, shock, sepsis, heart failure, vasoconstrictive drugs), strangulation (e-g-, hernia, volvulus, intussusception), or small vessel disease (e-g-, diabetes, radiation)
─ Can be acute (sudden onset, often severe) or chronic (insidious onset, "intestinal angina")
─ Symptoms: abdominal pain (often severe and out of proportion to physical findings in acute mesenteric ischemia), nausea, vomiting, diarrhea (may be bloody), abdominal distension; chronic ischemia may cause postprandial pain and weight loss
─ Site: can affect any part of the small intestine; watershed areas (e-g-, splenic flexure in colon, but analogous areas in SI) are more vulnerable to non-occlusive ischemia

Macro ─ Acute ischemia: bowel wall may be edematous, congested, hemorrhagic, or frankly necrotic and gangrenous; mucosal ulceration and pseudomembranes may be seen
─ Chronic ischemia: mucosal atrophy, fibrosis, strictures

Micro ─
─ Spectrum of changes depending on severity and duration of ischemia:
─ ─ Early/mild ischemia: villous tip necrosis and edema, lamina propria hemorrhage, epithelial sloughing, crypt epithelial atypia/degeneration ("withering crypts")
─ ─ More severe/established acute ischemia: transmucosal necrosis, ulceration, pseudomembrane formation (fibrin, neutrophils, necrotic debris); neutrophils may be sparse initially due to poor perfusion, but can be prominent with reperfusion injury
─ ─ Submucosal edema and hemorrhage are common
─ ─ Transmural infarction: full-thickness necrosis of the bowel wall, leading to perforation if untreated
─ ─ Chronic ischemia: mucosal atrophy (villous blunting), crypt loss, lamina propria hyalinization and fibrosis, submucosal fibrosis, vascular sclerosis; hemosiderin-laden macrophages may be present
─ Reperfusion injury: can exacerbate damage, with increased neutrophilic infiltrate and hemorrhage
─ Key negative findings: absence of granulomas (unlike Crohn's), specific infectious agents, or features of other distinct enteropathies

Ancillary studies ─
─ Generally diagnosed based on clinical presentation, imaging (e-g-, CT angiography), and endoscopic findings, supported by histology
─ Histology is often non-specific for the cause of ischemia but confirms ischemic pattern of injury

DDx ─
─ Infectious enteritis: can cause mucosal necrosis and inflammation, but specific pathogens may be identifiable; ischemic changes often lack a robust initial inflammatory response
─ Inflammatory bowel disease (Crohn's): chronic inflammation, granulomas, architectural distortion, fistulas; can have superimposed ischemia in strictured segments
─ Radiation enteritis: history of radiation; atypical fibroblasts and vascular changes are characteristic in chronic phase
─ Drug-induced injury (e-g-, NSAIDs, cocaine): history of exposure; NSAIDs can cause ulcers/diaphragms
─ Vasculitis: evidence of vessel wall inflammation (if sampled)

Prognosis ─ Highly variable, depends on cause, extent, and severity of ischemia, and promptness of diagnosis and treatment
─ Acute mesenteric ischemia has a high mortality rate if not treated rapidly (e-g-, revascularization, resection of necrotic bowel)
─ Chronic ischemia can lead to malabsorption, strictures, and recurrent pain

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Drug-induced injury (Small Intestine)

Mucosal damage and inflammation in the small intestine caused by various medications

Clinical ─ Numerous drugs can injure the small intestine; common examples include:
─ ─ NSAIDs: very common cause; can cause erosions, ulcers, diaphragm-like strictures ("diaphragm disease"), and chronic enteropathy with blood/protein loss
─ ─ Mycophenolate mofetil (MMF): immunosuppressant used in transplant patients; can cause an IBD-like picture, GVHD-like features, or apoptosis-predominant injury
─ ─ Olmesartan (angiotensin II receptor blocker): associated with a sprue-like enteropathy, characterized by severe diarrhea, weight loss, and villous atrophy, often with increased IELs and apoptosis, mimicking celiac disease but seronegatives
─ ─ Chemotherapeutic agents: cause mucositis due to direct toxicity to rapidly dividing epithelial cells (e-g-, methotrexate, 5-FU)
─ ─ Other drugs: colchicine, some antibiotics, checkpoint inhibitors (can cause an autoimmune-like enterocolitis)
─ Symptoms vary widely: nausea, vomiting, diarrhea, abdominal pain, malabsorption, bleeding, protein-losing enteropathy

Macro ─ Endoscopic findings depend on the drug and severity:
─ ─ NSAIDs: erosions, ulcers (often multiple, small, superficial), diaphragm-like strictures (thin, web-like)
─ ─ Mycophenolate: may show erosions, ulcerations, edema, or normal mucosa; can mimic IBD or GVHD
─ ─ Olmesartan: may show scalloping, mucosal fissures, or normal appearance despite severe villous atrophy histologically
─ ─ Chemotherapy: mucositis with erythema, edema, erosions, ulcerations

Micro ─
─ NSAID enteropathy:
─ ─ Erosions, ulcers, often with an eosinophil-rich inflammatory infiltrate
─ ─ Diaphragm disease: submucosal fibrosis and hyalinization forming a circumferential stricture, overlying mucosal ulceration or atrophy
─ Mycophenolate mofetil (MMF) injury:
─ ─ Can mimic IBD: cryptitis, crypt abscesses, crypt distortion, chronic inflammation
─ ─ Can mimic GVHD: increased epithelial apoptosis (especially in crypts), crypt damage/loss, lymphocytic infiltrate
─ ─ May show features of apoptosis-predominant injury without significant inflammation
─ Olmesartan-associated enteropathy:
─ ─ Villous atrophy (partial to total), crypt hyperplasia (less prominent than celiac), increased intraepithelial lymphocytes (IELs, often CD3+ and CD8+)
─ ─ Increased epithelial apoptosis
─ ─ Lamina propria chronic inflammation, may include eosinophils
─ ─ Subepithelial collagen band thickening has been reported in some cases, mimicking collagenous sprue
─ Chemotherapy-induced mucositis:
─ ─ Epithelial atypia (enlarged nuclei, hyperchromasia), apoptosis, mitotic arrest, crypt loss, villous blunting, erosions/ulcerations
─ ─ Paucity of inflammation in neutropenic patients

Ancillary studies ─
─ Generally diagnosis relies on clinical history of drug exposure and exclusion of other causes
─ Celiac serology and HLA testing to exclude celiac disease, especially in cases of villous atrophy (e-g-, olmesartan enteropathy)
─ IHC for CMV if MMF injury resembles GVHD in an immunocompromised patient

DDx ─
─ Celiac disease: villous atrophy, crypt hyperplasia, increased IELs; positive celiac serology, HLA-DQ2/DQ8, response to gluten-free diet (Olmesartan enteropathy is a key mimic)
─ Inflammatory bowel disease (Crohn's): granulomas, transmural inflammation, fistulas, skip lesions (MMF injury can mimic)
─ Graft-versus-Host Disease (GVHD): history of allogeneic transplant, prominent apoptosis, lymphocytic infiltrate (MMF injury can mimic)
─ Infectious enteritis: specific pathogens, different inflammatory patterns
─ Autoimmune enteropathy: villous atrophy, apoptosis, loss of goblet/Paneth cells, anti-enterocyte antibodies

Prognosis ─ Usually improves or resolves upon withdrawal of the offending drug
─ Recovery time varies; olmesartan enteropathy may take months to resolve after drug cessation
─ Chronic NSAID use can lead to persistent complications like strictures or anemia
─ Severe mucositis from chemotherapy can be dose-limiting and increase infection risk

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Graft-versus-Host Disease (GVHD) (Small Intestine)

A common and serious complication of allogeneic hematopoietic stem cell transplantation (HSCT), where donor immune cells (graft) recognize host tissues (including small intestine) as foreign and mount an immune attack

Clinical ─ Acute GVHD: typically occurs within the first 100 days post-transplant (can be later)
─ Chronic GVHD: typically occurs >100 days post-transplant, or can evolve from acute GVHD
─ GI tract is commonly involved in both acute and chronic GVHD, along with skin and liver
─ Symptoms of GI GVHD: watery diarrhea (often profuse and secretory), abdominal pain/cramping, nausea, vomiting, anorexia, GI bleeding (less common)
─ Severity is graded based on clinical symptoms (e-g-, stool volume) and endoscopic/histologic findings

Macro ─ Endoscopic findings in acute GI GVHD:
─ ─ Can be normal in mild cases
─ ─ Mucosal erythema, edema, friability, erosions, aphthous ulcers, or diffuse sloughing ("snakeskin" appearance) in more severe cases
─ Duodenum and ileum are frequently biopsied sites
─ Chronic GI GVHD may show fibrotic strictures or esophageal webs

Micro ─
─ Acute GI GVHD:
─ ─ Hallmark feature: epithelial cell apoptosis (single cell necrosis), particularly prominent in the crypt bases; apoptotic bodies (acidophil bodies) are small, eosinophilic, shrunken cells with pyknotic nuclei
─ ─ Crypt damage and destruction: cryptitis (lymphocytes and neutrophils infiltrating crypt epithelium), crypt abscesses (neutrophils in crypt lumen), crypt branching, dilatation, or complete dropout (denuded mucosa in severe cases)
─ ─ Increased intraepithelial lymphocytes (IELs), often T-cells
─ ─ Lamina propria inflammation is often surprisingly mild relative to epithelial damage, but can show lymphocytes, plasma cells, eosinophils
─ ─ Endothelialitis (lymphocytic infiltration of venular endothelium) may be seen
─ ─ Grading systems (e-g-, Lerner, Sale) exist based on severity of apoptosis and crypt destruction
─ ─ ─ Grade 1: Increased apoptosis without significant crypt destruction
─ ─ ─ Grade 2: Crypt loss/destruction involving single crypts
─ ─ ─ Grade 3: Crypt loss/destruction involving contiguous crypts
─ ─ ─ Grade 4: Total denudation of mucosa or extensive ulceration
─ Chronic GI GVHD: (less commonly biopsied for this indication)
─ ─ Fibrosis in lamina propria and submucosa
─ ─ Chronic inflammation, often with features resembling autoimmune conditions (e-g-, lymphocytic infiltration, epithelial damage)
─ ─ Esophageal involvement may show features similar to lichen planus or scleroderma

Ancillary studies ─
─ IHC for CMV is crucial to exclude concurrent CMV infection, which can cause similar symptoms and histologic changes (apoptosis, ulceration) in transplant patients
─ IHC for CD3/CD8 can highlight IELs but is not specific for GVHD

DDx ─
─ Acute GI GVHD vs-:
─ ─ CMV enteritis: viral inclusions in endothelial/stromal cells (often at ulcer base); apoptosis can be present but CMV inclusions are key
─ ─ Drug-induced injury (e-g-, Mycophenolate Mofetil - MMF): MMF is an immunosuppressant used to prevent GVHD but can itself cause GVHD-like histologic changes including apoptosis and crypt damage; clinical correlation is essential, may be indistinguishable histologically in some cases
─ ─ Chemotherapy/Radiation effect: can cause apoptosis and mucositis, timing relative to transplant is important
─ ─ Other infections (e-g-, adenovirus, bacterial enteritis): specific pathogens, different inflammatory patterns, apoptosis usually less prominent as the primary feature
─ ─ Conditioning regimen toxicity: occurs very early post-transplant, often diffuse epithelial damage and apoptosis

Prognosis ─ Morbidity and mortality from GI GVHD can be significant
─ Treatment involves immunosuppression (e-g-, corticosteroids, calcineurin inhibitors, MMF, sirolimus)
─ Response to treatment varies; severe, steroid-refractory GVHD has a poor prognosis
─ Increased risk of opportunistic infections due to immunosuppression

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Immune-Mediated Enteropathies

Celiac Disease

An immune-mediated enteropathy triggered by dietary gluten in genetically predisposed individuals, characterized by small intestinal mucosal inflammation, villous atrophy, and crypt hyperplasia

Clinical ─ Genetic predisposition (HLA-DQ2 and/or HLA-DQ8 haplotypes are present in >95% of patients)
─ Symptoms are highly variable: classic malabsorptive diarrhea, weight loss, steatorrhea; atypical symptoms include anemia, fatigue, osteoporosis, dermatitis herpetiformis, neurological issues, or can be asymptomatic
─ Diagnosis relies on a combination of clinical suspicion, positive celiac-specific serology (anti-tissue transglutaminase [tTG] IgA, anti-endomysial [EMA] IgA, anti-deamidated gliadin peptide [DGP] IgG/IgA), characteristic duodenal/jejunal biopsies, and clinical/histologic response to a gluten-free diet (GFD)
─ Site: typically most severe in the proximal small intestine (duodenum, proximal jejunum) where gluten exposure is highest, but can be patchy or involve more distal segments
─ Increased risk of T-cell lymphoma (EATL), small bowel adenocarcinoma, and other autoimmune diseases
─ Refractory Celiac Disease (RCD): persistence or recurrence of malabsorptive symptoms and villous atrophy despite strict GFD for >12 months;
─ ─ RCD Type 1: normal intraepithelial lymphocyte (IEL) phenotype (CD3+, CD8+); may respond to immunosuppressants
─ ─ RCD Type 2: aberrant IEL phenotype (often loss of CD8, clonal TCR rearrangement, sometimes CD30+); higher risk of progression to Enteropathy-Associated T-cell Lymphoma (EATL)

Macro ─ Endoscopic findings can be subtle or normal
─ May show scalloping or mosaic pattern of duodenal folds, mucosal fissures, nodularity, or reduced number of folds

Micro ─
─ Spectrum of histologic changes (Marsh-Oberhuber classification):
─ ─ Type 0: Normal mucosa (pre-infiltrative)
─ ─ Type 1 (Infiltrative): Increased intraepithelial lymphocytes (IELs; typically >25-30 IELs per 100 enterocytes), normal villous architecture
─ ─ Type 2 (Hyperplastic): Increased IELs, crypt hyperplasia, normal villous architecture (rarely diagnosed, often considered part of Type 1 or 3a)
─ ─ Type 3 (Destructive): Increased IELs, crypt hyperplasia, and villous atrophy
─ ─ ─ 3a: Mild villous atrophy (villi still present but blunted, villus:crypt ratio ~1:1)
─ ─ ─ 3b: Marked villous atrophy (villi severely blunted or rudimentary)
─ ─ ─ 3c: Total villous atrophy (flat mucosa)
─ IELs are typically CD3+ and often CD8+ T-cells, concentrated at villous tips and along lateral borders of enterocytes
─ Crypt hyperplasia: elongated, hypercellular crypts with increased mitotic activity
─ Lamina propria inflammation: increased lymphocytes, plasma cells, and often eosinophils
─ Surface enterocyte damage: vacuolization, loss of brush border, cuboidal appearance
─ Paneth cell metaplasia may be seen more proximally
─ Key negative findings: absence of granulomas (unless coexisting Crohn's), viral inclusions
─ In RCD Type 2, IELs may show aberrant immunophenotype (e-g-, loss of CD8, clonal TCR by molecular studies)

Ancillary studies ─
─ IHC for CD3 and CD8 can help confirm increased IELs and assess phenotype, especially if subtle or in RCD workup
─ TCR gene rearrangement studies (on biopsy or flow cytometry) if RCD Type 2 or lymphoma is suspected
─ HLA-DQ2/DQ8 genotyping: high negative predictive value (absence makes celiac disease very unlikely)

DDx ─
─ Other causes of villous atrophy and increased IELs:
─ ─ Tropical sprue: history of travel to endemic areas, often involves entire small bowel, responds to antibiotics/folate
─ ─ Autoimmune enteropathy: often more severe villous atrophy, may have anti-enterocyte antibodies, can involve colon
─ ─ Common Variable Immunodeficiency (CVID): villous atrophy, increased IELs, but characteristically absent or markedly reduced plasma cells in lamina propria
─ ─ Drug-induced enteropathy (e-g-, olmesartan): can mimic celiac histologically and clinically, but serology negative, no response to GFD, improves on drug withdrawal
─ ─ Infectious enteritis (e-g-, Giardia, viral): acute onset, specific organisms may be seen, IELs can be increased but often with more acute inflammation
─ ─ Bacterial overgrowth: patchy villous atrophy, often in setting of stasis (e-g-, stricture, diverticula)
─ ─ Eosinophilic gastroenteritis: prominent eosinophilic infiltrate in lamina propria and often deeper layers, may have peripheral eosinophilia
─ ─ Crohn's disease: can cause villous blunting, but usually patchy, with aphthous ulcers, granulomas, transmural inflammation

Prognosis ─ Excellent with strict lifelong adherence to a gluten-free diet for most patients; symptoms and histology usually improve/normalize
─ Non-compliance or undiagnosed disease can lead to complications: malnutrition, osteoporosis, infertility, increased risk of malignancy (EATL, adenocarcinoma)
─ RCD Type 2 has a poor prognosis due to high risk of EATL development

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Common Variable Immunodeficiency (CVID)-associated enteropathy

Gastrointestinal manifestations in patients with Common Variable Immunodeficiency, a primary immunodeficiency characterized by defective B-cell differentiation and impaired immunoglobulin production

Clinical ─ CVID is the most common symptomatic primary immunodeficiency
─ Patients have recurrent sinopulmonary infections, autoimmune phenomena, and an increased risk of lymphoma and gastric cancer
─ GI symptoms are common (~20-50% of CVID patients): chronic diarrhea, malabsorption, weight loss, abdominal pain
─ Enteropathy can mimic celiac disease, inflammatory bowel disease, or infectious enteritis

Macro ─ Endoscopic findings can be variable:
─ ─ Normal appearance
─ ─ Duodenal/jejunal mucosa may show villous atrophy, scalloping, or nodularity (lymphoid hyperplasia)
─ ─ Colonic mucosa may show features resembling IBD (erythema, erosions, ulcers) or microscopic colitis

Micro ─
─ Small Intestine:
─ ─ Villous atrophy (partial to total) and crypt hyperplasia are common, mimicking celiac disease
─ ─ Increased intraepithelial lymphocytes (IELs) may be present
─ ─ Key diagnostic feature (though not universally present): marked reduction or complete absence of plasma cells in the lamina propria; remaining plasma cells may be predominantly IgM-producing if IgA/IgG are deficient
─ ─ Nodular lymphoid hyperplasia (prominent lymphoid follicles in lamina propria/submucosa) can be seen
─ ─ Increased epithelial apoptosis may be present
─ ─ Giardia lamblia infection is common in CVID and should be specifically excluded
─ Colon:
─ ─ May show features resembling IBD (chronic active colitis, crypt distortion, granulomas - though granulomas are less common than in Crohn's)
─ ─ Can also show features of lymphocytic or collagenous colitis
─ ─ Paucity of plasma cells in lamina propria is also a helpful clue in colonic biopsies

Ancillary studies ─
─ IHC for CD138 (plasma cell marker) or immunoglobulin light/heavy chains can confirm the paucity or absence of plasma cells
─ Special stains for Giardia if suspected
─ Serum immunoglobulin levels (low IgG, IgA, and/or IgM) and impaired vaccine responses are needed for CVID diagnosis (clinical diagnosis)

DDx ─
─ Celiac disease: villous atrophy, increased IELs, but lamina propria plasma cells are typically increased; positive celiac serology, response to GFD
─ Autoimmune enteropathy: villous atrophy, but usually has plasma cells; may have anti-enterocyte antibodies
─ Infectious enteritis: specific pathogens; plasma cells usually present/increased
─ Inflammatory bowel disease (Crohn's, UC): characteristic features of IBD; plasma cells are usually abundant (basal plasmacytosis in UC)
─ Drug-induced enteropathy (e-g-, olmesartan): can mimic celiac/CVID histologically, but history of drug, negative CVID workup

Prognosis ─ GI symptoms can be chronic and difficult to manage
─ Treatment involves immunoglobulin replacement therapy for CVID, management of infections, and symptomatic treatment for GI issues
─ Increased risk of lymphoma (especially non-Hodgkin B-cell lymphoma) and gastric cancer requires surveillance in some patients

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Autoimmune enteropathy

A rare disorder characterized by severe persistent diarrhea, malabsorption, and villous atrophy due to an autoimmune attack on intestinal epithelial cells

Clinical ─ Can occur in infants/young children (often X-linked, associated with IPEX syndrome - Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked - due to FOXP3 gene mutations) or adults (often idiopathic or associated with other autoimmune conditions like CVID, thyroiditis, type 1 diabetes)
─ Presents with intractable watery diarrhea, malabsorption, weight loss, dehydration, and electrolyte abnormalities
─ Diagnosis often involves demonstrating circulating anti-enterocyte antibodies or anti-goblet cell antibodies, though these are not always present or specific
─ Exclusion of other causes of villous atrophy and malabsorption is crucial

Macro ─ Endoscopy may show normal mucosa, or features of villous atrophy such as scalloping, reduced folds, or mucosal thinning, primarily in the small intestine but can involve the colon

Micro ─
─ Small Intestine:
─ ─ Variable degrees of villous atrophy (partial to total) and crypt hyperplasia
─ ─ Increased intraepithelial lymphocytes (IELs), often CD8+ T-cells
─ ─ Increased lamina propria inflammation (lymphocytes, plasma cells, eosinophils may be prominent)
─ ─ Increased epithelial cell apoptosis, particularly in crypts
─ ─ Goblet cell depletion or Paneth cell depletion/hyperplasia can occur, depending on the specific antibodies (if present)
─ ─ Necrotic crypts or crypt abscesses may be seen
─ Colon: May show chronic inflammation, crypt apoptosis, lymphocytic colitis-like features, or IBD-like changes if involved
─ IPEX syndrome: Histology is similar, often very severe; may have associated autoimmune manifestations in other organs

Ancillary studies ─
─ Serology for anti-enterocyte or anti-goblet cell antibodies (availability and specificity vary)
─ Genetic testing for FOXP3 mutations if IPEX syndrome is suspected in male infants
─ IHC for CD3/CD8 to assess IELs; IHC for plasma cells (CD138) to exclude CVID (plasma cells are present/increased in AIE, unlike CVID)
─ IHC for FOXP3 (reduced/absent in IPEX) on biopsy tissue or blood

DDx ─
─ Celiac disease: positive celiac serology, HLA-DQ2/DQ8, response to GFD
─ Common Variable Immunodeficiency (CVID): paucity/absence of plasma cells in lamina propria
─ Infectious enteritis: specific pathogens, often acute onset
─ Drug-induced enteropathy: history of offending drug, improvement on withdrawal
─ Microvillous inclusion disease: congenital disorder, PAS-positive inclusions in enterocytes, electron microscopy diagnostic
─ Tufting enteropathy: congenital disorder, epithelial tufts, specific gene mutations (e-g-, EPCAM)
─ Graft-versus-Host Disease (GVHD): history of HSCT, prominent crypt apoptosis

Prognosis ─ Often a severe and chronic condition, particularly in infants
─ Treatment involves immunosuppression (e-g-, corticosteroids, cyclosporine, tacrolimus, infliximab), nutritional support (often parenteral nutrition)
─ HSCT may be an option for severe IPEX syndrome
─ Morbidity and mortality can be high due to malabsorption, malnutrition, and complications of immunosuppression

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Infectious enteritis

Whipple disease

A rare, chronic, multisystemic infectious disease caused by the bacterium Tropheryma whipplei

Clinical ─ Primarily affects middle-aged Caucasian men (M:F ratio ~8:1)
─ Classic presentation involves a tetrad of arthralgias (often migratory polyarthritis), abdominal pain, diarrhea (with steatorrhea), and weight loss
─ Other systemic manifestations can include fever, lymphadenopathy, neurological symptoms (cognitive changes, ophthalmoplegia, myoclonus), cardiac involvement (endocarditis), and skin hyperpigmentation
─ GI symptoms are present in most patients, but systemic symptoms may precede GI manifestations by years
─ Diagnosis is confirmed by identifying characteristic macrophages in affected tissues (typically small intestinal biopsy) or by PCR for T- whipplei DNA

Macro ─ Endoscopy of the small intestine (duodenum, jejunum) may show pale, thickened, or shaggy mucosal folds, sometimes with yellowish-white specks or plaques
─ Lymphadenopathy (mesenteric, peripheral) may be present

Micro ─
─ Diagnostic hallmark: infiltration of the small intestinal lamina propria by numerous large, foamy macrophages with granular, eosinophilic cytoplasm
─ These macrophages contain abundant small, rod-shaped bacilli (T- whipplei), which are PAS-positive and diastase-resistant (appearing as magenta granules)
─ Villi are often distended, broadened, and blunted due to the massive macrophage infiltrate
─ Dilated lymphatics (lymphangiectasia) in the lamina propria may be seen due to lymphatic obstruction by the macrophages
─ Fat droplets may be visible within the lamina propria or macrophages
─ Epithelial cells themselves are not infected; minimal to mild chronic inflammation (lymphocytes, plasma cells) apart from the macrophage infiltrate
─ Similar macrophages can be found in other affected organs (lymph nodes, synovium, brain, heart valves)
─ Key negative findings: Acid-fast bacilli are negative (unlike MAI infection)

Ancillary studies ─
─ Special stains: Periodic acid-Schiff (PAS) stain with diastase digestion is crucial; macrophages are filled with PAS-positive, diastase-resistant granules (bacillary bodies)
─ IHC: Antibodies against T- whipplei can confirm the diagnosis, staining the bacilli within macrophages
─ Molecular: PCR for T- whipplei DNA on biopsy tissue or other affected fluids/tissues is highly sensitive and specific; can also be used to monitor treatment response
─ Acid-fast stain (e-g-, Ziehl-Neelsen) should be performed to exclude Mycobacterium avium-intracellulare (MAI) infection, which can also cause PAS-positive macrophages

DDx ─
─ Mycobacterium avium-intracellulare (MAI) infection: occurs in severely immunocompromised (e-g-, AIDS); macrophages are also PAS-positive but bacilli are acid-fast positive; granulomas may be present
─ Histoplasmosis: foamy macrophages containing yeast forms (PAS and GMS positive), especially in immunocompromised
─ Malakoplakia: sheets of histiocytes (von Hansemann cells) with Michaelis-Gutmann bodies (calcified spherules), often associated with E- coli infection
─ Xanthoma: clusters of foamy lipid-laden macrophages, usually focal, PAS-negative for bacilli
─ Storage diseases (e-g-, Gaucher, Niemann-Pick): specific enzyme deficiencies, characteristic storage material in macrophages

Prognosis ─ Untreated Whipple disease is progressive and usually fatal
─ Prolonged antibiotic therapy (typically starting with IV ceftriaxone or penicillin, followed by oral trimethoprim-sulfamethoxazole for at least 1 year) is usually curative
─ Relapses can occur, especially with neurological involvement, and may require longer or different antibiotic regimens
─ Immune reconstitution inflammatory syndrome (IRIS) can occur during treatment

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Appendix

Appendix Anatomy

Feature	Description
Structure	A narrow, blind-ended tube connected to the cecum. Part of the gut-associated lymphoid tissue (GALT).
Location	Arises from the posteromedial wall of the cecum, inferior to the ileocecal valve. Position is variable (most commonly retrocecal). The base is at the convergence of the three taeniae coli.
Mesoappendix	A short triangular mesentery suspending the appendix. Contains the appendiceal artery and vein.
Blood Supply	Appendiceal artery (usually a branch of the ileocolic artery from SMA).
Lymphatics	Drains to ileocolic lymph nodes.

Appendix Histology

Layer	Components & Features
Mucosa	Simple columnar epithelium with goblet cells, similar to colon. Characteristic: Abundant lymphoid tissue with large lymphoid follicles, often with prominent germinal centers. Follicles frequently disrupt and efface the muscularis mucosae.
Submucosa	Thin and often heavily infiltrated by lymphoid follicles.
Muscularis Propria	Inner circular and outer continuous longitudinal layer (no taeniae coli).
Serosa	Completely covered by peritoneum.

Appendicitis

Acute Appendicitis

Acute appendicitis is one of the most common surgical emergencies. It is classically caused by luminal obstruction, often by a fecalith, leading to increased intraluminal pressure, ischemia, and subsequent bacterial overgrowth.

Histologic Features:

The key diagnostic feature is neutrophilic infiltration of the muscularis propria.
Early findings may include mucosal ulceration and luminal neutrophilic exudate (pus).
As it progresses, inflammation extends through the appendiceal wall, leading to serositis (inflammation of the serosal surface), which corresponds to the clinical finding of localized peritonitis (pain shifting to the right lower quadrant).
Complications include perforation (leading to abscess or generalized peritonitis) and suppurative (pus-forming) inflammation.

Granulomatous Appendicitis

This is a rare form of appendicitis characterized by the presence of granulomas. It can be idiopathic but is often associated with other conditions.

Etiologies and Features:

Crohn's Disease: The appendix can be the first and only site of involvement by Crohn's disease. The presence of non-necrotizing, well-formed granulomas, especially if away from areas of ulceration, should raise suspicion.
Infections: Certain infections can cause a granulomatous reaction, most notably Yersinia enterocolitica and tuberculosis. Special stains (AFB for mycobacteria, GMS for fungi) and clinical correlation are crucial.
Foreign Body Reaction: Retained foreign material (e.g., vegetable matter, suture material from prior surgery) can elicit a foreign body giant cell reaction and granulomas.
Idiopathic: Some cases have no identifiable cause.

Mucocele of the Appendix

A mucocele is a descriptive term for a dilated, mucus-filled appendix. It results from luminal obstruction and continued mucus secretion. The underlying cause can range from benign to malignant.

Classification and Histologic Features:

Simple Mucocele/Retention Cyst: Caused by benign obstruction (e.g., fecalith, fibrous obliteration). The appendix is dilated and filled with mucin, but the lining epithelium is flattened and attenuated, without atypia.
Mucinous Cystadenoma: This is a benign neoplasm characterized by a proliferation of mucinous epithelium, similar to that seen in the ovary. The architecture may be flat or villous, and the epithelium shows low-grade cytologic atypia. This is the most common cause of a mucocele.
Mucinous Cystadenocarcinoma: A malignant neoplasm. Histologic features include complex architecture (cribriforming, papillary tufts), high-grade cytologic atypia, and invasion through the basement membrane into the appendiceal wall. If it perforates, it can lead to pseudomyxoma peritonei, a condition where the peritoneum becomes filled with mucin and neoplastic cells.

Fibrous Obliteration / Neuroma (Appendix)

A common, age-related, non-neoplastic process characterized by partial or complete replacement of the appendiceal lumen by fibrous tissue and/or a neuroma-like proliferation of nerve fibers

Clinical ─ Often an incidental finding in appendectomy specimens removed for other reasons or at autopsy
─ More common with increasing age; considered a normal involutional change by some
─ Not associated with specific symptoms, though some have questioned if it predisposes to acute appendicitis by obstructing the lumen (controversial)
─ "Appendiceal neuroma" is often used when neural proliferation is prominent

Macro ─ Appendix may appear normal externally or show distal narrowing or a firm tip
─ Cut section may show a white, firm, solid obliteration of the lumen, typically distally, progressing proximally with age

Micro ─
─ Partial or complete replacement of the appendiceal lumen and mucosa by loose or dense collagenous fibrous tissue
─ Adipose tissue infiltration within the fibrous tissue is common ("fibrolipomatous obliteration")
─ Proliferation of small nerve fibers and Schwann cells, often forming neuroma-like tangles or nodules, especially in the submucosa and muscularis propria; these nerves are often S100 positive
─ Entrapped, atrophic, or cystically dilated crypts may be present within the fibrous tissue
─ Chronic inflammatory cells (lymphocytes, plasma cells) and eosinophils are often scattered within the fibrous tissue
─ Muscularis mucosae and muscularis propria are usually intact but may be splayed or atrophic
─ No evidence of dysplasia or malignancy
─ Remnants of lymphoid tissue may be seen

Ancillary studies ─
─ IHC for S100 can highlight the neural proliferation if prominent (neuroma component)
─ Trichrome stain can highlight fibrous tissue
─ Generally not required for diagnosis

DDx ─
─ Healed (resolved) acute appendicitis: may show fibrosis and chronic inflammation, but typically has more architectural distortion, granulation tissue remnants, or evidence of prior acute inflammation (e-g-, hemosiderin) without the prominent organized neural proliferation of a neuroma
─ Carcinoid tumor (Well-differentiated neuroendocrine tumor): neoplastic cells forming nests, trabeculae, or glands; positive for neuroendocrine markers (synaptophysin, chromogranin); fibrous obliteration lacks these neoplastic cells
─ Low-grade appendiceal mucinous neoplasm (LAMN) with mural fibrosis: LAMN will have atypical mucinous epithelium and dissecting mucin, which are absent in fibrous obliteration
─ Schwannoma: rare in appendix; a discrete, encapsulated tumor of Schwann cells, S100 positive, but forms a distinct mass rather than luminal obliteration
─ Granulation tissue polyp (post-inflammatory polyp): more cellular, vascular, and inflamed than the paucicellular fibrosis of obliteration

Prognosis ─ Benign, non-neoplastic condition with no malignant potential
─ No specific treatment or follow-up required if an incidental finding

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Appendiceal serrated lesions and polyps

Hyperplastic Polyp (Appendiceal)

A benign, non-neoplastic serrated polyp of the appendix, morphologically similar to colonic hyperplastic polyps

Clinical ─ Usually an incidental finding in appendectomy specimens
─ Generally small and asymptomatic
─ No clear association with increased risk of appendiceal or colorectal neoplasia

Macro ─ Small, sessile, or slightly raised mucosal lesions, often <5 mm
─ May not be grossly visible

Micro ─
─ Characterized by serrated (sawtooth) appearance of the luminal aspect of the crypts, typically confined to the upper half or two-thirds of the crypts
─ Crypts are often straight, not dilated or branched at the base (unlike sessile serrated lesions)
─ Lined by columnar cells with abundant apical mucin (goblet cells) and/or eosinophilic cytoplasm with microvesicular mucin (similar to microvesicular hyperplastic polyps of colon)
─ Nuclei are small, round to oval, basally located, without significant atypia or pseudostratification
─ Proliferative zone (Ki-67 positive cells) is confined to the crypt bases
─ Lamina propria may show mild edema or chronic inflammation but is not a prominent feature
─ No features of dysplasia

Ancillary studies ─
─ Generally not required for diagnosis
─ Ki-67 IHC can confirm basal proliferation if needed to distinguish from sessile serrated lesion (which shows expanded proliferation)

DDx ─
─ Sessile Serrated Lesion/Polyp (SSL/P) of the appendix: shows serration extending to the crypt base, basal crypt dilation/branching (T- or L-shapes, boot shapes), and often expanded proliferation zone; cytologic dysplasia may be present
─ Traditional Serrated Adenoma (TSA) of the appendix: rare; characterized by villous architecture, ectopic crypt formation, and cells with eosinophilic cytoplasm and pencillate, dysplastic nuclei
─ Mucinous adenoma/LAMN: composed of atypical mucinous epithelium, often with villous architecture or flat growth, and may produce abundant mucin; lacks the characteristic serrated architecture of hyperplastic polyps
─ Reactive epithelial changes: may show some foveolar hyperplasia or surface irregularity due to inflammation, but lacks the well-formed serrations and typical polypoid structure

Prognosis ─ Benign, with no known malignant potential
─ No specific follow-up is typically required

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Sessile Serrated Lesion/Polyp (SSL/P), with or without dysplasia (Appendiceal)

A neoplastic serrated polyp of the appendix characterized by architectural features similar to colonic SSL/Ps, including basal crypt dilation and branching, which may or may not be associated with cytologic dysplasia

Clinical ─ Less common than hyperplastic polyps in the appendix, but increasingly recognized
─ Often an incidental finding in appendectomy specimens
─ May be a precursor to some appendiceal adenocarcinomas (serrated pathway)
─ Significance and frequency compared to colonic SSL/Ps are still being elucidated

Macro ─ Often flat or sessile, may be covered by a mucus cap (similar to colonic SSL/Ps)
─ Can be subtle or difficult to distinguish from hyperplastic polyps or normal mucosa grossly
─ Size is variable

Micro ─
─ SSL/P without dysplasia:
─ ─ Serration of crypts extending to the base
─ ─ Basal crypt dilation (often forming L-shaped, T-shaped, or "boot-shaped" profiles)
─ ─ Horizontal growth of crypt bases along the muscularis mucosae
─ ─ Crypts lined by goblet cells, columnar cells with eosinophilic cytoplasm, or cells with microvesicular mucin
─ ─ Nuclei are generally bland, round to oval, basally located, without significant atypia (though some minimal atypia/nuclear crowding can be seen)
─ ─ Proliferative zone (Ki-67 positive cells) is often expanded and may involve the mid-crypt or even superficial aspects, not just confined to the base
─ SSL/P with cytologic dysplasia:
─ ─ Background architectural features of SSL/P are present
─ ─ Superimposed cytologic dysplasia, which can be:
─ ─ ─ Conventional (adenomatous) type: similar to dysplasia in colonic adenomas (elongated, hyperchromatic, pseudostratified nuclei)
─ ─ ─ Serrated type: cells with more eosinophilic cytoplasm, vesicular nuclei, prominent nucleoli, maintaining some serrated architecture
─ ─ Dysplasia can be low-grade or high-grade

Ancillary studies ─
─ Ki-67 IHC: shows expanded proliferation zone, not confined to crypt base (helps distinguish from hyperplastic polyp)
─ IHC for MLH1/PMS2: loss of expression may be seen in areas of dysplasia, suggesting progression along the serrated pathway with microsatellite instability (similar to colon)
─ Molecular: BRAF mutations (especially V600E) are common, similar to colonic SSL/Ps; KRAS mutations are less frequent but can occur

DDx ─
─ Hyperplastic polyp (appendiceal): serration limited to upper crypts, no basal dilation/branching, basal proliferation zone
─ Traditional Serrated Adenoma (TSA): villous architecture, ectopic crypts, eosinophilic cytoplasm with pencillate dysplastic nuclei; more common in left colon, rare in appendix
─ Mucinous adenoma/Low-Grade Appendiceal Mucinous Neoplasm (LAMN): primarily villous or flat glandular proliferation of atypical mucinous epithelium, abundant mucin; lacks the characteristic serrated crypt architecture of SSL/P
─ Reactive changes: may show some serration, but lack the specific basal crypt architectural abnormalities and expanded proliferation of SSL/P

Prognosis ─ SSL/P without dysplasia is considered premalignant but with a generally low risk of progression if completely removed
─ SSL/P with dysplasia has a higher risk of progressing to adenocarcinoma
─ Complete excision is recommended
─ The natural history and optimal management/surveillance for appendiceal SSL/Ps are not as well-defined as for their colonic counterparts, but a cautious approach is generally taken, especially if dysplasia is present or if margins are involved

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Appendiceal mucinous neoplasm

Low-Grade Appendiceal Mucinous Neoplasm (LAMN)

A neoplastic proliferation of mucinous epithelium in the appendix, characterized by low-grade cytologic atypia, which may be confined to the appendix or associated with extra-appendiceal mucin or cells, potentially leading to pseudomyxoma peritonei (PMP)

Clinical ─ Often discovered incidentally during appendectomy for suspected acute appendicitis or at imaging/surgery for other reasons
─ Can present with symptoms of acute appendicitis (if lumen is obstructed by mucin or tumor), right lower quadrant pain, or a palpable mass
─ If ruptured or with peritoneal spread, can lead to pseudomyxoma peritonei (PMP), a condition characterized by accumulation of mucinous ascites in the abdomen
─ More common in middle-aged to older adults; slight female predominance in some series

Macro ─ Appendix is often dilated, tense, and filled with copious, thick, gelatinous mucin (mucocele)
─ Wall may be thinned, fibrotic, or calcified
─ External surface may be smooth or show mucinous deposits if there is perforation or transmural extension
─ Careful examination for perforation and extra-appendiceal mucin/implants is crucial

Micro ─
─ Proliferation of mucinous epithelium lining the appendiceal lumen, often forming villous, flat, or undulating architecture
─ Epithelial cells are typically tall columnar with abundant intracytoplasmic mucin and basally located, small, bland to mildly atypical nuclei (low-grade cytologic atypia); mitoses are rare
─ Pushing invasion into the appendiceal wall by neoplastic epithelium or dissecting mucin pools may occur
─ Loss or attenuation of the muscularis mucosae is common
─ Submucosal fibrosis and hyalinization are frequent
─ Calcification of the wall can be seen
─ Key features for risk stratification:
─ ─ LAMN confined to appendix: Neoplastic epithelium and mucin are contained within the appendix wall, without extension to the serosal surface or beyond
─ ─ LAMN with extra-appendiceal acellular mucin: Mucin pools without neoplastic epithelial cells are present on the serosal surface or in the periappendiceal fat/mesoappendix; generally associated with a low risk of PMP if cells are truly absent
─ ─ LAMN with extra-appendiceal mucinous epithelium (leading to PMP, low-grade): Neoplastic epithelial cells are present within mucin deposits outside the appendix (peritoneum, omentum, ovaries); this is diagnostic of low-grade PMP (also termed disseminated peritoneal adenomucinosis - DPAM by some classifications)
─ High-grade cytologic atypia (significant nuclear pleomorphism, loss of polarity, increased mitoses) would classify the lesion as a high-grade appendiceal mucinous neoplasm (HAMN) or mucinous adenocarcinoma

Ancillary studies ─
─ IHC (+): Cytokeratin 20 (often diffuse), CDX2
─ IHC (-/+): Cytokeratin 7 (often negative or patchy, helping distinguish from some ovarian mucinous tumors)
─ Mucin stains (PAS-Alcian blue, mucicarmine) highlight abundant mucin
─ Molecular: KRAS mutations are common (up to 50-80%); GNAS mutations also frequent; BRAF mutations are rare; TP53 mutations are uncommon in LAMN but more frequent in high-grade mucinous adenocarcinoma

DDx ─
─ Mucinous adenoma (simple mucocele): neoplastic mucinous epithelium confined to the mucosa, with an intact muscularis mucosae; some definitions of LAMN encompass these if there is significant dilation/mucin
─ Hyperplastic polyp / Sessile serrated lesion: show serrated architecture, not primarily a mucinous epithelial proliferation with villous/flat growth
─ High-Grade Appendiceal Mucinous Neoplasm (HAMN) / Mucinous Adenocarcinoma: show high-grade cytologic atypia and/or destructive stromal invasion by neoplastic glands or single cells
─ Diverticulosis of appendix with mucinous metaplasia: herniation of mucosa through muscularis propria; epithelium is typically bland or reactive, not neoplastic, though diverticula can be involved by LAMN
─ Endometriosis involving appendix: endometrial glands and stroma; ER/PR/CD10 positive stroma

Prognosis ─ LAMN confined to the appendix (completely excised) has an excellent prognosis with very low risk of recurrence or PMP
─ LAMN with acellular mucin on the serosa has a low risk of PMP, but surveillance is often recommended
─ LAMN with extra-appendiceal neoplastic epithelium (low-grade PMP/DPAM) is an indolent but progressive condition; often requires aggressive cytoreductive surgery and intraperitoneal chemotherapy for long-term control; survival is measured in years, but recurrence is common
─ Presence of high-grade cytologic features (HAMN/mucinous adenocarcinoma) or signet-ring cells is associated with a much worse prognosis

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High-Grade Appendiceal Mucinous Neoplasm (HAMN)

A mucinous neoplasm of the appendix characterized by high-grade cytologic atypia, which may be confined to the appendix or associated with peritoneal dissemination (pseudomyxoma peritonei, high-grade)

Clinical ─ Less common than Low-Grade Appendiceal Mucinous Neoplasms (LAMN)
─ Similar clinical presentation to LAMN if confined to appendix (incidental, appendicitis-like symptoms, mass)
─ If associated with peritoneal spread (high-grade pseudomyxoma peritonei / peritoneal mucinous carcinomatosis), presents with abdominal distension, pain, ascites
─ Considered more aggressive than LAMN, with a higher likelihood of invasive growth and worse prognosis if spread has occurred

Macro ─ Appendix may be dilated and filled with mucin (mucocele), similar to LAMN
─ May show more solid or firm areas compared to the purely gelatinous appearance of some LAMNs
─ Evidence of perforation, mural thickening, or serosal involvement may be more apparent
─ Peritoneal involvement, if present, often appears as more solid tumor implants compared to the gelatinous deposits of low-grade PMP

Micro ─
─ Proliferation of mucinous epithelium lining the appendiceal lumen or within mucin pools, characterized by high-grade cytologic atypia:
─ ─ Significant nuclear pleomorphism, enlarged and irregular nuclei, coarse chromatin, prominent nucleoli
─ ─ Loss of nuclear polarity, increased nuclear-to-cytoplasmic ratio
─ ─ Increased mitotic activity, including atypical mitoses
─ Complex architectural patterns are common: cribriforming, papillary tufts with scant stroma, solid sheets, or back-to-back glands
─ May show destructive stromal invasion by individual cells or small irregular glands, qualifying as invasive mucinous adenocarcinoma
─ If confined to the appendix without destructive invasion, but showing high-grade cytologic atypia, it's termed HAMN (some pathologists may use "mucinous adenoma with high-grade dysplasia" if strictly confined to mucosa with intact muscularis mucosae, though this is rare for lesions with HGD)
─ Peritoneal spread associated with HAMN is typically classified as peritoneal mucinous carcinomatosis (PMCA) or high-grade pseudomyxoma peritonei, characterized by more cellular mucinous implants with high-grade atypia and often destructive invasion of underlying tissues
─ Signet-ring cells may be present and, if predominant, indicate a signet-ring cell adenocarcinoma, which is inherently high-grade

Ancillary studies ─
─ IHC (+): Cytokeratin 20 (often diffuse), CDX2
─ IHC (-/+): Cytokeratin 7 (often negative or patchy)
─ p53 IHC: Overexpression or null pattern is common, reflecting TP53 mutations associated with high-grade transformation
─ Ki-67: Typically shows a higher proliferation index compared to LAMN
─ Molecular: TP53 mutations are common; KRAS and GNAS mutations can also occur, similar to LAMN, but additional alterations driving high-grade behavior are likely present

DDx ─
─ Low-Grade Appendiceal Mucinous Neoplasm (LAMN): lacks high-grade cytologic atypia; epithelium is bland or shows only low-grade atypia
─ Appendiceal adenocarcinoma, intestinal type (non-mucinous): forms glands but lacks the abundant extracellular mucin characteristic of mucinous neoplasms
─ Goblet cell adenocarcinoma: characteristic nests of goblet-like cells with amphicrine differentiation; different morphology and immunoprofile
─ Metastatic mucinous carcinoma to the appendix (e-g-, from colon, ovary, pancreas): clinical history and IHC panel (e-g-, CK7, PAX8 for ovarian) are crucial; primary appendiceal origin favored if precursor lesion (LAMN or adenoma) is identified in appendix

Prognosis ─ Significantly worse than LAMN, especially if peritoneal dissemination (PMCA) has occurred
─ PMCA (high-grade PMP) has a much poorer response to cytoreductive surgery and intraperitoneal chemotherapy compared to low-grade PMP (DPAM)
─ Median survival for PMCA is considerably shorter
─ Factors influencing prognosis include completeness of cytoreduction, histologic grade, presence of signet-ring cells, and extent of disease

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Appendiceal adenocarcinoma

Appendiceal adenocarcinoma, intestinal type (non-mucinous)

A malignant glandular neoplasm of the appendix resembling conventional colorectal adenocarcinoma, without abundant mucin production

Clinical ─ Rare, less common than mucinous neoplasms or neuroendocrine tumors of the appendix
─ Often presents with symptoms of acute appendicitis due to luminal obstruction by the tumor
─ May also present as a palpable mass, with pain, or be found incidentally
─ Can occur in a background of a pre-existing adenoma (tubular, tubulovillous, or villous) or serrated lesion
─ Tends to affect older adults

Macro ─ May appear as a discrete, firm, infiltrative mass, often in the proximal appendix or base, but can occur anywhere
─ May cause luminal narrowing or obstruction
─ Ulceration can be present
─ If arising from a polyp, the precursor lesion may be visible

Micro ─
─ Histologically similar to colorectal adenocarcinoma: invasive glands, tubules, or cribriform structures lined by atypical columnar cells with enlarged, hyperchromatic, pleomorphic nuclei and increased mitotic activity
─ Glandular differentiation varies from well to poorly differentiated
─ Desmoplastic stromal reaction is typically present
─ Extracellular mucin, if present, constitutes <50% of the tumor volume (otherwise classified as mucinous adenocarcinoma)
─ Signet-ring cells, if present and constituting >50% of tumor, would be classified as signet-ring cell adenocarcinoma
─ Lymphovascular and perineural invasion are common
─ May show origin from a pre-existing adenomatous polyp or serrated lesion with dysplasia

Ancillary studies ─
─ IHC (+): Cytokeratin 20 (usually diffuse), CDX2 (usually diffuse)
─ IHC (-/+): Cytokeratin 7 (usually negative, but can be positive, especially if near the base or involving cecum)
─ MMR/MSI testing: Can be performed, as a subset may be MSI-High, similar to colorectal cancer, which can have prognostic and therapeutic implications
─ KRAS, BRAF, NRAS mutation testing may be relevant for therapy if metastatic, similar to colorectal cancer

DDx ─
─ Mucinous adenocarcinoma of appendix: >50% extracellular mucin
─ Goblet cell adenocarcinoma: characteristic goblet-like cells in nests and cords, often with neuroendocrine differentiation
─ Well-differentiated neuroendocrine tumor (carcinoid): organoid pattern, "salt & pepper" chromatin, positive for neuroendocrine markers
─ Metastatic adenocarcinoma (e-g-, from colon, ovary, stomach): clinical history and IHC panel are key; distinction from cecal adenocarcinoma involving appendix base can be challenging and may depend on tumor epicenter
─ Endometriosis: endometrial glands and stroma

Prognosis ─ Similar to colorectal adenocarcinoma of the same stage
─ Stage (TNM) at diagnosis is the most important prognostic factor
─ Often diagnosed at a later stage due to non-specific symptoms or presentation as appendicitis
─ Treatment typically involves appendectomy for very early, localized tumors, or right hemicolectomy for more advanced lesions to ensure adequate lymph node staging
─ Adjuvant chemotherapy may be considered based on stage, similar to colorectal cancer guidelines

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Appendiceal adenocarcinoma, mucinous

A malignant glandular neoplasm of the appendix characterized by >50% of the tumor volume being composed of extracellular mucin

Clinical ─ A subtype of appendiceal adenocarcinoma, distinct from LAMN/HAMN which typically have "pushing" invasion or spread as mucinous ascites without the overtly destructive stromal invasion of typical adenocarcinoma
─ Can arise de novo or from a pre-existing adenoma or serrated lesion
─ Symptoms are similar to non-mucinous appendiceal adenocarcinoma: appendicitis-like pain, mass, or incidental finding
─ May be associated with peritoneal spread (peritoneal mucinous carcinomatosis), which is often more cellular and aggressive than low-grade PMP from LAMN

Macro ─ Often large, gelatinous tumors, may cause appendiceal dilation (mucocele)
─ May show infiltrative growth into the appendiceal wall and surrounding tissues
─ Peritoneal surfaces may be studded with mucinous and/or solid tumor implants if spread has occurred

Micro ─
─ Defined by >50% of the tumor consisting of pools of extracellular mucin
─ Within the mucin, there are neoplastic epithelial cells arranged as glands, strips, clusters, or individual cells
─ Cytologic atypia of the neoplastic cells can range from low-grade to high-grade
─ Destructive stromal invasion by neoplastic glands or cells is usually evident, distinguishing it from LAMN where epithelium might be "floating" in mucin or showing only pushing borders
─ Signet-ring cells may be present; if they constitute >50% of the cellular component, it's classified as signet-ring cell carcinoma (a high-grade pattern)
─ Lymphovascular and perineural invasion can occur

Ancillary studies ─
─ IHC (+): Cytokeratin 20, CDX2
─ IHC (-/+): Cytokeratin 7 (usually negative or patchy)
─ Mucin stains (PAS-Alcian blue, mucicarmine) highlight abundant extracellular mucin
─ Molecular: KRAS mutations are common; GNAS mutations may also be present; TP53 mutations more common in higher-grade lesions

DDx ─
─ Low-Grade Appendiceal Mucinous Neoplasm (LAMN) / High-Grade Appendiceal Mucinous Neoplasm (HAMN): These terms are often used for neoplasms with pushing invasion or those associated with classic pseudomyxoma peritonei (low or high grade cellularity in mucin pools without the typical destructive stromal invasion of conventional adenocarcinoma); mucinous adenocarcinoma implies more aggressive infiltrative growth patterns
─ Appendiceal adenocarcinoma, intestinal type (non-mucinous): <50% extracellular mucin
─ Goblet cell adenocarcinoma: distinct morphology and immunoprofile
─ Metastatic mucinous adenocarcinoma (e-g-, from colon, ovary, pancreas): clinical history and IHC are crucial

Prognosis ─ Generally carries a worse prognosis than non-mucinous intestinal-type adenocarcinoma of the appendix, particularly if associated with peritoneal spread
─ Prognosis is heavily dependent on stage and completeness of surgical resection
─ Peritoneal mucinous carcinomatosis from appendiceal mucinous adenocarcinoma is often aggressive
─ Treatment involves surgical resection (appendectomy or right hemicolectomy); cytoreductive surgery and HIPEC may be considered for peritoneal disease, but outcomes are often less favorable than for low-grade PMP from LAMN

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Appendiceal goblet cell adenocarcinoma

A rare and unique amphicrine malignant neoplasm of the appendix, showing dual differentiation with features of both goblet cells (mucin production) and neuroendocrine cells

Clinical ─ Formerly known as goblet cell carcinoid, adenocarcinoid, or crypt cell carcinoma; current WHO terminology is Goblet Cell Adenocarcinoma (GCA)
─ Typically affects adults, with a peak incidence in the 5th-6th decades; slight male predominance
─ Most common presentation is acute appendicitis due to luminal obstruction by the tumor
─ Can also present as a palpable mass, chronic abdominal pain, or be an incidental finding
─ Site: often involves the appendiceal tip but can be diffuse, causing circumferential wall thickening
─ Behaves more aggressively than typical appendiceal well-differentiated NETs (carcinoids) but often less aggressively than conventional appendiceal adenocarcinomas, though this is variable and depends on grade/subtype
─ Frequent metastasis to peritoneum (carcinomatosis, often with a desmoplastic response) and ovaries (Krukenberg-like tumors)

Macro ─ Appendix often appears diffusely thickened, indurated, and fibrotic, rather than forming a discrete mass or mucocele
─ Lumen may be narrowed or obliterated
─ Cut surface is typically firm and white-tan

Micro ─
─ Characteristic infiltrative growth pattern of nests, cords, tubules, or single cells within a desmoplastic stroma
─ Tumor cells are typically small to medium-sized, with eosinophilic cytoplasm and eccentrically placed nuclei, resembling goblet cells; intracytoplasmic mucin vacuoles are present
─ Neuroendocrine features: cells may have finely granular ("salt-and-pepper") chromatin; Paneth-like eosinophilic granules may be seen
─ Grading system (Tang et al-) is often used:
─ ─ Grade 1 (Typical goblet cell carcinoid/GCA): cohesive nests/acini of classic goblet-like cells, minimal atypia, low mitotic rate, pushing invasion or minimal infiltration
─ ─ Grade 2 (Adenocarcinoma ex-GCA, signet-ring cell type): discordant atypia, more single cells/signet-ring cells, or more infiltrative growth
─ ─ Grade 3 (Adenocarcinoma ex-GCA, poorly differentiated type): sheets of poorly differentiated cells, high-grade atypia, high mitotic rate, necrosis; may resemble conventional adenocarcinoma or signet-ring cell carcinoma with only focal goblet cell features
─ Perineural and lymphovascular invasion are common

Ancillary studies ─
─ IHC (+): Cytokeratin 20 (often strong and diffuse), CDX2, CEA
─ IHC (+/-): Neuroendocrine markers (Synaptophysin, Chromogranin A) show variable positivity, often focal or patchy, and may be more prominent in classic (Grade 1) areas; Chromogranin A is often negative even when synaptophysin is positive
─ IHC (+/-): Cytokeratin 7 (can be positive in a subset, especially higher-grade areas or metastases)
─ Mucin stains (PAS-D, Alcian blue) highlight intracytoplasmic mucin
─ Ki-67: proliferation index is variable, generally higher in higher-grade tumors
─ Molecular: Less well characterized than conventional adenocarcinomas; KRAS, BRAF, SMAD4, TP53 mutations are generally infrequent in classic GCA, but may occur in higher-grade components; MSI is rare

DDx ─
─ Well-differentiated neuroendocrine tumor (carcinoid) of appendix: distinct organoid pattern, strong diffuse neuroendocrine marker expression, lacks significant mucin production or goblet cell morphology
─ Appendiceal adenocarcinoma (intestinal or mucinous type): forms true glands, lacks the characteristic goblet cell nests and significant neuroendocrine differentiation of GCA
─ Signet-ring cell adenocarcinoma: composed purely of signet-ring cells without the nested goblet cell pattern or neuroendocrine features of GCA (though high-grade GCA can have prominent signet-ring cells)
─ Metastatic adenocarcinoma (especially from stomach or colon with signet-ring cells): clinical history, distribution of disease, and detailed immunoprofile comparison are important

Prognosis ─ Variable, depends on grade and stage; overall 5-year survival is ~70-80% for localized disease, but significantly lower for metastatic disease
─ Grade 1 tumors have a better prognosis than Grade 2 or 3
─ Peritoneal spread and ovarian metastases are common and associated with worse outcomes
─ Treatment typically involves at least a right hemicolectomy due to risk of nodal metastasis and infiltrative nature
─ Cytoreductive surgery and HIPEC may be used for peritoneal disease, but efficacy is debated and may be less than for PMP from LAMN
─ Systemic chemotherapy regimens are similar to those for colorectal cancer

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Appendiceal neuroendocrine neoplasms

Well-differentiated neuroendocrine tumor (Carcinoid) of appendix

The most common primary neoplasm of the appendix, typically composed of serotonin-producing enterochromaffin (EC) cells, and generally follows an indolent clinical course

Clinical ─ Most are found incidentally during appendectomy for acute appendicitis or other reasons
─ Peak incidence in 4th-5th decades, slightly more common in females
─ Usually asymptomatic; carcinoid syndrome is extremely rare with appendiceal primaries, even with liver metastases, because they are often small and serotonin is metabolized by the liver
─ Site: vast majority (60-75%) arise in the distal tip of the appendix
─ Metastatic risk is low, primarily related to size (>2 cm), mesoappendiceal invasion, and higher proliferative activity (G2)

Macro ─ Typically a firm, solid, yellow-tan to greyish nodule, often well-circumscribed
─ Most are small (<1 cm); tumors >2 cm are uncommon
─ May cause luminal obliteration if large or at the tip

Micro ─
─ Composed of uniform, polygonal cells with round to oval nuclei, "salt-and-pepper" (stippled) chromatin, and inconspicuous nucleoli
─ Cytoplasm is typically eosinophilic and granular
─ Architectural patterns:
─ ─ Insular (nested) pattern (Type A) is most common: discrete nests of tumor cells separated by fibrovascular stroma
─ ─ Trabecular pattern (Type B) can also occur
─ ─ Tubular or acinar structures (Type C, "tubular carcinoid") are less common for classic EC-cell NETs but can be seen with L-cell differentiation; these are often very small and incidental
─ Mitotic activity is generally low (G1: <2 mitoses/2 mm² or <2 mitoses/10 HPF)
─ Necrosis is rare
─ Invasion into muscularis propria, mesoappendix, or lymphovascular spaces can occur, especially in larger tumors
─ Perineural invasion may be seen
─ L-cell tumors: composed of cells resembling intestinal L-cells, often forming tubules; may be chromogranin A negative but synaptophysin positive; generally very indolent

Ancillary studies ─
─ IHC (+): Synaptophysin (diffuse), Chromogranin A (often diffuse, but may be focal or negative in L-cell tumors), CD56 (less specific)
─ IHC (+): Serotonin (in classic EC-cell NETs)
─ IHC (+/-): Enteroglucagon, peptide YY (in L-cell tumors)
─ Ki-67 proliferation index: essential for grading; most are G1 (≤2%)
─ IHC (-): Cytokeratin 20 (usually negative or very focal), CDX2 (usually negative)

DDx ─
─ Goblet cell adenocarcinoma (GCA): distinct infiltrative pattern of goblet-like cells, often with dual glandular and neuroendocrine features; more aggressive behavior
─ Adenocarcinoma, intestinal type: forms true glands, lacks neuroendocrine morphology and diffuse marker expression
─ Fibrous obliteration/Neuroma: non-neoplastic, spindle cell proliferation (fibroblasts, nerve fibers), S100+ for neural component, negative for neuroendocrine markers
─ Granular cell tumor: rare; cells with abundant granular cytoplasm, S100 positive
─ Metastatic NET: very rare in appendix; clinical history and comparison with primary needed

Prognosis ─ Excellent for most cases, especially tumors <1 cm confined to the appendix
─ 5-year survival >95% for localized disease
─ Risk factors for metastasis: size >2 cm, mesoappendiceal invasion >3 mm, lymphovascular invasion, G2 grade (higher Ki-67/mitotic rate), positive surgical margins, non-tip location (base/body)
─ Treatment: simple appendectomy is curative for most small (<1-2 cm), incidentally found tumors without adverse features; right hemicolectomy is considered for larger tumors (>2 cm) or those with adverse prognostic factors to ensure adequate lymph node staging and local control

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Poorly differentiated neuroendocrine carcinoma (Small Cell, Large Cell) of appendix

A high-grade, aggressive malignant neoplasm with neuroendocrine differentiation, morphologically similar to its counterparts in the lung and other GI sites, exceedingly rare in the appendix

Clinical ─ Extremely rare in the appendix; most appendiceal NENs are well-differentiated NETs
─ Typically affects older adults
─ Presents with symptoms of acute appendicitis, a palpable mass, or features of metastatic disease
─ Highly aggressive with early and widespread metastases

Macro ─ Often larger tumors with infiltrative growth, necrosis, and hemorrhage
─ May cause diffuse appendiceal thickening or a discrete mass

Micro ─
─ Small cell carcinoma (SmCC):
─ ─ Sheets, nests, or diffuse infiltrates of small, round, oval, or spindle-shaped cells with scant cytoplasm, ill-defined cell borders
─ ─ Nuclei are hyperchromatic with finely granular ("salt-and-pepper") chromatin, nuclear molding, and inconspicuous or absent nucleoli
─ ─ High mitotic rate (typically >20 mitoses/2 mm² or >20 mitoses/10 HPF)
─ ─ Extensive necrosis and apoptosis (karyorrhexis) are characteristic
─ ─ Azzopardi effect (DNA encrustation of blood vessel walls) may be present
─ Large cell neuroendocrine carcinoma (LCNEC):
─ ─ Nests, trabeculae, or sheets of large polygonal cells with more abundant cytoplasm, vesicular nuclei, and often prominent nucleoli
─ ─ Organoid patterns (palisading, rosettes) may be evident
─ ─ High mitotic rate and frequent necrosis
─ Both types are by definition G3 (Ki-67 index >20%)
─ May coexist with a component of adenocarcinoma or squamous cell carcinoma (MiNEN)

Ancillary studies ─
─ IHC (+): Neuroendocrine markers (Synaptophysin, Chromogranin A - may be focal or weak, CD56)
─ IHC (+): Cytokeratins (AE1/AE3, CAM5-2), often with a dot-like perinuclear pattern
─ IHC (+/-): TTF-1 (can be positive in SmCC, similar to lung primaries)
─ Ki-67: High proliferation index (>20%, often >50-70%)
─ EBER ISH to exclude EBV-associated lymphoepithelioma-like carcinoma if morphology is ambiguous and lymphoid stroma prominent

DDx ─
─ Poorly differentiated adenocarcinoma: may have solid growth but usually shows some gland formation or mucin; lacks diffuse strong neuroendocrine marker expression
─ Lymphoma (especially high-grade, e-g-, Burkitt, DLBCL): CD45 positive, cytokeratin negative; specific lymphoid markers
─ Metastatic NEC (especially from lung for SmCC, or colon/pancreas for LCNEC): clinical history crucial; often indistinguishable morphologically and immunophenotypically from primary appendiceal NEC
─ Goblet cell adenocarcinoma, high-grade (Grade 3): can have poorly differentiated areas, but usually some identifiable goblet cell component or classic GCA areas; neuroendocrine markers are often only focal in GCA

Prognosis ─ Extremely poor, regardless of small cell or large cell type
─ Highly aggressive with rapid growth, early lymph node involvement, and distant metastases (liver, lung, bone)
─ Median survival is typically short, often less than 1 year
─ Treatment usually involves systemic chemotherapy, similar to regimens used for NECs at other sites (e-g-, platinum-based chemotherapy for SmCC)
─ Surgical resection (right hemicolectomy) may be performed for localized disease but role of adjuvant therapy is not well defined due to rarity

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Colon

Colon Anatomy

Feature	Description
Structure	Large intestine (~1.5 m), from ileocecal valve to anus. Primary function is water/electrolyte absorption.
Segments	Cecum -> Ascending (retroperitoneal) -> Transverse (intraperitoneal) -> Descending (retroperitoneal) -> Sigmoid (intraperitoneal) -> Rectum.
External Features	Taeniae Coli: Three distinct longitudinal muscle bands. Haustra: Sacculations of the colon wall. Appendices Epiploicae: Fat-filled peritoneal pouches.
Blood Supply	Proximal (to splenic flexure): Superior Mesenteric Artery (SMA). Distal: Inferior Mesenteric Artery (IMA). Marginal Artery of Drummond: Connects SMA and IMA circulation.

Colon Histology

Layer	Components & Features
Mucosa	Surface: Flat, no villi. Crypts of Lieberkühn: Long, straight, parallel, tubular glands that extend to the muscularis mucosae. Epithelium: Simple columnar with abundant goblet cells and absorptive colonocytes. Lamina Propria: Contains prominent plasma cells and lymphocytes, more so than in the stomach. Eosinophils are a normal constituent, especially in the right colon.
Muscularis Mucosae	Thin smooth muscle layer separating mucosa from submucosa.
Muscularis Propria	Inner circular layer. Outer longitudinal layer is condensed into three taeniae coli (becomes continuous again in rectum). Contains Auerbach's plexus.
Serosa / Adventitia	Intraperitoneal parts (transverse, sigmoid) have serosa; retroperitoneal parts (ascending, descending) have adventitia.

Non-IBD Colitis

Microscopic Colitis

Lymphocytic colitis

A type of microscopic colitis characterized by increased intraepithelial lymphocytes (IELs) in the colonic surface and crypt epithelium, associated with chronic watery diarrhea and grossly normal or near-normal endoscopic findings

Clinical ─ One of the two main forms of microscopic colitis (the other being collagenous colitis)
─ More common in middle-aged to older adults, with a slight female predominance in some studies, but can occur at any age
─ Etiology is unknown, but immune-mediated mechanisms are suspected; associations include:
─ ─ Autoimmune diseases (e-g-, celiac disease, thyroiditis, rheumatoid arthritis, Sjögren's syndrome)
─ ─ Medications (e-g-, NSAIDs, PPIs, SSRIs, statins, acarbose, ticlopidine, olmesartan)
─ ─ Bile acid malabsorption (possible link)
─ Cardinal symptom: chronic, non-bloody, watery diarrhea (often secretory type, persisting with fasting)
─ Other symptoms: abdominal pain/cramping, fecal urgency, incontinence, weight loss (less common)
─ Diagnosis requires histologic examination of colonic biopsies, as endoscopy is usually normal or shows only non-specific changes (e-g-, edema, erythema)

Macro ─ Endoscopic appearance of the colon is typically normal or may show subtle, non-specific findings such as mild erythema, edema, or altered vascular pattern
─ Frank ulceration is absent

Micro ─
─ Diagnostic hallmark: increased number of intraepithelial lymphocytes (IELs) in the surface and crypt epithelium, typically defined as ≥20-25 IELs per 100 epithelial cells (normal is <5-10 IELs/100)
─ IELs are predominantly CD3+ and CD8+ T-lymphocytes
─ Surface epithelial damage is common: flattened cells, mucin depletion, vacuolization, focal tufting, or detachment
─ Lamina propria shows increased chronic inflammatory cells (lymphocytes, plasma cells); eosinophils may be mildly increased
─ Crypt architecture is generally preserved; no significant crypt distortion, branching, or atrophy (unlike chronic IBD)
─ Subepithelial collagen band is NOT thickened (unlike collagenous colitis); normal thickness is <7-10 µm
─ Neutrophils in lamina propria or epithelium (active colitis) are usually minimal or absent; if prominent, consider other diagnoses or superimposed infection/IBD flare
─ Key negative findings: absence of granulomas, significant crypt distortion, thickened subepithelial collagen band

Ancillary studies ─
─ IHC for CD3 can help highlight and quantify IELs if uncertain on H&E, but not routinely necessary
─ Special stains (e-g-, Masson trichrome) are not needed if collagen band appears normal on H&E, but can be used to definitively measure it if collagenous colitis is in the differential and H&E is equivocal

DDx ─
─ Collagenous colitis: key distinguishing feature is a thickened subepithelial collagen band (>10-20 µm); IELs may also be increased but collagen band is diagnostic
─ Inflammatory bowel disease (Crohn's, UC): shows crypt distortion, basal plasmacytosis, often active inflammation (neutrophils), granulomas (Crohn's), or diffuse mucosal ulceration (UC)
─ Infectious colitis (especially viral or resolving bacterial): may have increased IELs, but often more acute inflammation, edema, and clinical history of acute onset
─ Celiac disease-associated colitis: lymphocytic colitis can be a manifestation of celiac disease; duodenal biopsies and celiac serology are important
─ Drug-induced colitis (other than those causing lymphocytic colitis pattern): various histologic patterns depending on drug
─ Normal colon with prominent IELs: ensure true increase above normal range and appropriate clinical context

Prognosis ─ Generally a benign condition with a good prognosis, though symptoms can be chronic and impact quality of life
─ Many patients respond to treatment (e-g-, budesonide, loperamide, bismuth subsalicylate); discontinuation of offending drugs if identified
─ Spontaneous remission occurs in some patients
─ Does not increase risk of colorectal cancer
─ May coexist or overlap with collagenous colitis or celiac disease

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Collagenous colitis

A type of microscopic colitis characterized by a thickened subepithelial collagen band in the colonic mucosa, associated with chronic watery diarrhea and grossly normal or near-normal endoscopic findings

Clinical ─ One of the two main forms of microscopic colitis (the other being lymphocytic colitis)
─ More common in middle-aged to older adults, with a strong female predominance (F:M ratio up to ~9:1)
─ Etiology is unknown, but immune-mediated mechanisms are suspected; associations include:
─ ─ Autoimmune diseases (e-g-, celiac disease, thyroiditis, rheumatoid arthritis, Sjögren's syndrome, type 1 diabetes)
─ ─ Medications (e-g-, NSAIDs, PPIs, SSRIs, statins, acarbose, lansoprazole, ranitidine, ticlopidine, olmesartan)
─ ─ Smoking has been identified as a risk factor
─ Cardinal symptom: chronic, non-bloody, watery diarrhea (often secretory, persisting with fasting), often with nocturnal episodes
─ Other symptoms: abdominal pain/cramping, fecal urgency, incontinence, weight loss (less common)
─ Diagnosis requires histologic examination of colonic biopsies, as endoscopy is usually normal or shows only non-specific changes

Macro ─ Endoscopic appearance of the colon is typically normal or may show subtle, non-specific findings such as mild erythema, edema, altered vascular pattern, or mucosal tears (from scope passage due to friability)
─ Frank ulceration is absent

Micro ─
─ Diagnostic hallmark: thickened, irregular, band-like deposit of collagen in the subepithelial layer of the surface mucosa, typically >10-20 µm in thickness (normal is <7-10 µm); the collagen band often entraps capillaries, red blood cells, and inflammatory cells
─ Increased chronic inflammatory cells (lymphocytes, plasma cells, eosinophils) in the lamina propria
─ Intraepithelial lymphocytes (IELs) are often increased in the surface epithelium (similar to lymphocytic colitis, but usually less prominent)
─ Surface epithelial damage is common: flattened cells, mucin depletion, vacuolization, detachment from the underlying thickened collagen band, focal erosions
─ Crypt architecture is generally preserved; no significant crypt distortion, branching, or atrophy (unlike chronic IBD)
─ Neutrophils in lamina propria or epithelium (active colitis) are usually minimal or absent
─ Key negative findings: absence of granulomas, significant crypt distortion

Ancillary studies ─
─ Special stains: Masson trichrome stain is very helpful to highlight the subepithelial collagen band (stains blue/green) and to assess its thickness, especially in borderline cases or when H&E is not definitive
─ IHC for Tenascin may show increased expression in the subepithelial region, but not routinely used
─ IHC for CD3 can help quantify IELs if needed

DDx ─
─ Lymphocytic colitis: lacks the thickened subepithelial collagen band; IELs are typically more numerous
─ Chronic ischemic colitis: can cause lamina propria fibrosis and hyalinization, but this is usually deeper, more diffuse, and associated with mucosal atrophy, hemosiderin deposition, and vascular changes; lacks the distinct, continuous subepithelial band
─ Inflammatory bowel disease (Crohn's, UC): shows crypt distortion, basal plasmacytosis, often active inflammation; collagen band is absent
─ Amyloidosis: amyloid deposits in vessel walls and interstitium, Congo red positive; collagen band absent
─ Normal colon with tangential sectioning: can artifactually make the basement membrane appear thickened; multiple biopsies and proper orientation are important; trichrome stain helps clarify true band thickness
─ Fibrosis due to prior ulcer healing or prolapse: fibrosis is usually more focal, less band-like, and associated with architectural distortion or features of prolapse

Prognosis ─ Generally a benign condition with a good prognosis in terms of mortality, but symptoms can be chronic, relapsing, and significantly affect quality of life
─ Many patients respond well to treatment (e-g-, budesonide is highly effective; loperamide, bismuth subsalicylate, cholestyramine); discontinuation of offending drugs if identified
─ Spontaneous remission occurs in a subset of patients
─ Does not increase risk of colorectal cancer
─ May coexist or overlap with lymphocytic colitis or celiac disease

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Checkpoint Inhibitor-related colitis

Colitis occurring as an immune-related adverse event in patients treated with immune checkpoint inhibitors (ICIs) such as anti-CTLA-4, anti-PD-1, or anti-PD-L1 antibodies

Clinical ─ Increasingly recognized due to widespread use of ICIs for various malignancies (e-g-, melanoma, lung cancer, renal cell carcinoma)
─ Can occur weeks to months after initiation of ICI therapy, or even after cessation
─ Symptoms: diarrhea (often watery, can be bloody if severe), abdominal pain, cramping, fecal urgency; may mimic inflammatory bowel disease (IBD) flare
─ Incidence and severity vary depending on the specific ICI agent (anti-CTLA-4 > anti-PD-1/PD-L1), combination therapy, and patient factors
─ Endoscopic findings range from normal to patchy erythema, erosions, aphthous ulcers, or diffuse colitis resembling IBD or infectious colitis
─ Management involves withholding ICI and administering corticosteroids; infliximab or vedolizumab may be used in refractory cases

Macro ─ Endoscopic appearance can be variable:
─ ─ Normal mucosa in some mild cases
─ ─ Patchy or diffuse erythema, edema, loss of vascular pattern
─ ─ Aphthous ulcers, erosions, or larger, deeper ulcerations
─ ─ Findings can mimic IBD (Crohn's or UC-like patterns) or infectious colitis

Micro ─
─ Histologic patterns are diverse and can overlap with other colitides; no single pathognomonic feature
─ Common patterns include:
─ ─ Acute colitis pattern: Neutrophilic inflammation in lamina propria, cryptitis, crypt abscesses, epithelial injury, erosions/ulcers (can mimic infectious colitis or acute IBD flare)
─ ─ Chronic active colitis pattern (IBD-like): Features resembling Crohn's disease (aphthoid ulcerations, patchy chronic inflammation, occasional granulomas) or ulcerative colitis (diffuse chronic inflammation, basal plasmacytosis, crypt distortion, Paneth cell metaplasia)
─ ─ Apoptosis-predominant pattern (GVHD-like): Increased epithelial apoptosis, especially in crypt bases, crypt damage/loss, often with lymphocytic infiltrate (can mimic graft-versus-host disease or mycophenolate injury)
─ ─ Lymphocytic/Collagenous colitis-like pattern: Increased intraepithelial lymphocytes or subepithelial collagen band thickening (less common)
─ Increased eosinophils in lamina propria may be seen
─ Expansion of lamina propria by lymphocytes and plasma cells is common
─ Ulceration with granulation tissue and fibrinopurulent exudate can occur in severe cases
─ It's important to exclude infection (especially CMV in immunocompromised patients on ICIs and steroids)

Ancillary studies ─
─ Stool studies (cultures, C- difficile toxin assay, ova and parasites) to exclude infectious causes of diarrhea
─ IHC for CMV if ulceration or severe inflammation is present, or if patient is on significant immunosuppression

DDx ─
─ Inflammatory bowel disease (Crohn's, UC): de novo IBD or flare; ICI colitis can be histologically indistinguishable; clinical history (pre-existing IBD vs new onset after ICI) is crucial
─ Infectious colitis (e-g-, bacterial, viral, C- difficile): specific pathogens may be identified; stool studies are key
─ Graft-versus-Host Disease (GVHD): history of allogeneic HSCT; apoptosis-predominant pattern is similar
─ Drug-induced colitis (other medications): history of other culprit drugs; some drugs (e-g-, mycophenolate) can cause GVHD-like changes
─ Ischemic colitis: segmental distribution, hyalinized lamina propria, withered crypts

Prognosis ─ Most cases respond to ICI discontinuation and corticosteroids
─ Severe or refractory cases may require biologic agents (e-g-, infliximab)
─ Complications can include perforation (rare), severe dehydration, electrolyte imbalance
─ Long-term sequelae are not fully understood, but some patients may develop persistent IBD-like symptoms

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Ischemic colitis

Colonic mucosal injury and inflammation due to reduced blood flow, most commonly affecting elderly patients with atherosclerotic disease or in settings of systemic hypoperfusion

Clinical ─ Most common form of intestinal ischemia
─ Risk factors: advanced age, atherosclerosis, hypertension, diabetes, heart failure, shock, sepsis, major surgery (e-g-, aortic aneurysm repair), vasculitis, certain medications (e-g-, vasoconstrictors, cocaine), long-distance running
─ Symptoms: sudden onset of crampy abdominal pain (often left-sided), hematochezia (rectal bleeding), diarrhea, fecal urgency
─ Site: "Watershed" areas with limited collateral circulation are most vulnerable:
─ ─ Splenic flexure (Griffiths' point - junction of SMA and IMA supply) - most common site
─ ─ Sigmoid colon (Sudeck's point - junction of IMA and hypogastric artery supply)
─ ─ Right colon can also be affected, especially in systemic hypoperfusion
─ Can range from transient, reversible mucosal ischemia to transmural infarction with gangrene and perforation

Macro ─ Endoscopic findings vary with severity and timing:
─ ─ Early/mild: pale, edematous mucosa, petechial hemorrhages, bluish discoloration
─ ─ More severe: segmental erythema, friability, erosions, hemorrhagic ulcerations (often linear or longitudinal - "thumbprinting" on imaging due to submucosal edema/hemorrhage), pseudomembranes
─ ─ Chronic: strictures, mucosal atrophy
─ Transmural infarction: dusky, necrotic bowel wall

Micro ─
─ Spectrum of changes depending on severity and chronicity:
─ Acute ischemic colitis:
─ ─ Surface epithelial sloughing and necrosis, especially at villous tips (if right colon) or superficial crypts
─ ─ Crypts may appear "withered" or show regenerative atypia
─ ─ Lamina propria hemorrhage, edema, and hyalinization (glassy, eosinophilic appearance) are characteristic
─ ─ Neutrophilic infiltrate is often initially sparse due to poor perfusion, but can become prominent with reperfusion or ulceration
─ ─ Pseudomembrane formation (fibrin, neutrophils, necrotic debris) over ulcerated areas
─ ─ Submucosal edema and hemorrhage
─ ─ Transmural necrosis in severe cases
─ Chronic ischemic colitis:
─ ─ Mucosal atrophy, crypt loss, and architectural distortion
─ ─ Lamina propria fibrosis and hyalinization
─ ─ Hemosiderin-laden macrophages in lamina propria and submucosa
─ ─ Submucosal fibrosis leading to stricture formation
─ ─ Vascular changes (e-g-, intimal fibrosis, thrombosis) may be seen but are often non-specific
─ Key negative findings: absence of granulomas, significant chronic inflammation typical of IBD (unless IBD is complicated by ischemia)

Ancillary studies ─
─ Generally diagnosed based on clinical presentation, imaging (CT scan may show bowel wall thickening, thumbprinting, pneumatosis), and endoscopic findings, supported by histology
─ Histology confirms ischemic pattern but may not identify the specific cause of ischemia

DDx ─
─ Infectious colitis (especially C- difficile, enterohemorrhagic E- coli): can cause pseudomembranes and hemorrhage; stool studies and cultures are key
─ Inflammatory bowel disease (Crohn's, UC): chronic inflammation, crypt distortion, basal plasmacytosis, granulomas (Crohn's); IBD can sometimes have superimposed ischemic changes, especially in older patients or with strictures
─ Radiation colitis: history of radiation; atypical fibroblasts and vascular changes in chronic phase
─ Drug-induced colitis (e-g-, NSAIDs): can cause ulcers, but pattern of injury differs
─ Diverticular disease-associated colitis (SCAD): segmental colitis adjacent to diverticula

Prognosis ─ Variable, depends on severity and extent of ischemia, underlying cause, and patient's overall condition
─ Most cases are transient and resolve with supportive care (bowel rest, IV fluids, antibiotics if severe)
─ Transmural infarction requires surgical resection and has high morbidity/mortality
─ Chronic ischemic colitis can lead to strictures requiring intervention
─ Recurrence is possible if underlying vascular disease persists

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Pseudomembranous Colitis

An acute colitis characterized by the formation of inflammatory pseudomembranes on the colonic mucosa, almost always caused by toxins produced by the bacterium Clostridioides difficile (formerly Clostridium difficile)

Clinical ─ C- difficile infection (CDI) typically occurs after disruption of normal gut flora by antibiotic therapy; other risk factors include advanced age, hospitalization, immunosuppression, GI surgery, and PPI use
─ Symptoms: watery diarrhea (often profuse, can be bloody), abdominal pain/cramping, fever, leukocytosis
─ Severe cases can lead to toxic megacolon, perforation, sepsis, and death
─ Diagnosis is confirmed by detecting C- difficile toxin (A and/or B) or toxigenic C- difficile by PCR in stool

Macro ─ Endoscopy reveals characteristic yellowish, adherent plaques or pseudomembranes on the colonic mucosa, ranging from small, discrete lesions to confluent sheets covering large areas
─ Underlying mucosa is often erythematous, edematous, and friable
─ Most commonly involves the left colon and rectum, but can be pancolonic

Micro ─
─ Hallmark feature: Pseudomembranes composed of an exudate of fibrin, mucin, neutrophils, and sloughed epithelial cells, typically erupting from the superficial crypts like a "volcano" or "mushroom cloud"
─ Superficial colonic crypts are often dilated and disrupted, filled with neutrophils and necrotic debris
─ Surface epithelium between pseudomembranes may be eroded or show reactive changes
─ Lamina propria is edematous and contains a mixed inflammatory infiltrate with prominent neutrophils
─ Capillary thrombi may be seen in the superficial lamina propria
─ Deeper crypts are often relatively preserved, especially in early or mild cases
─ In severe cases, inflammation can extend into submucosa, and mucosal necrosis can be extensive
─ Key negative findings: absence of granulomas, viral inclusions, or features of chronic IBD (though CDI can complicate IBD)

Ancillary studies ─
─ Histology is characteristic but not always specific without clinical correlation or toxin detection
─ Stool testing for C- difficile toxin or toxigenic C- difficile PCR is the gold standard for diagnosis

DDx ─
─ Ischemic colitis: can also form pseudomembranes, but typically shows more prominent lamina propria hyalinization, hemorrhage, and withered crypts; clinical context differs
─ Other infectious colitides (e-g-, enterohemorrhagic E- coli, Shigella): can cause hemorrhagic colitis and exudates, but specific "volcano" pseudomembranes are less typical; stool cultures help differentiate
─ Inflammatory bowel disease (UC flare): can have severe inflammation and ulceration, but pseudomembranes are not typical unless superimposed CDI occurs; IBD shows chronic architectural changes
─ Drug-induced colitis (other than antibiotic-associated CDI): various patterns, but usually lacks the specific pseudomembranes of CDI

Prognosis ─ Most cases respond to discontinuation of the offending antibiotic (if possible) and treatment with specific anti-C- difficile antibiotics (e-g-, oral vancomycin, fidaxomicin, metronidazole)
─ Recurrence of CDI after treatment is common (10-30%)
─ Severe or fulminant colitis has a high morbidity and mortality rate, may require colectomy
─ Fecal microbiota transplantation (FMT) is highly effective for recurrent CDI

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Diversion colitis

Inflammation occurring in a surgically diverted segment of the colon or rectum (e-g-, after colostomy or ileostomy with a retained distal segment like a Hartmann's pouch or mucous fistula)

Clinical ─ Develops in the defunctioned segment of bowel due to lack of exposure to the normal fecal stream and its constituents, particularly short-chain fatty acids (SCFAs) like butyrate, which are the primary energy source for colonocytes
─ Can occur weeks to years after surgical diversion
─ Often asymptomatic, especially if diversion is permanent
─ Symptoms, if present (more common if segment is later re-anastomosed or if patient has mucous fistula discharge): rectal discharge (mucus, blood), tenesmus, abdominal pain, pelvic discomfort
─ Symptoms usually resolve after re-anastomosis and restoration of fecal flow

Macro ─ Endoscopic findings in the diverted segment:
─ ─ Mucosal erythema, edema, friability, granularity, erosions, or aphthous ulcers
─ ─ Nodularity due to lymphoid hyperplasia can be prominent
─ ─ Findings can mimic inflammatory bowel disease (especially UC) or infectious colitis

Micro ─
─ Spectrum of changes, often patchy:
─ ─ Chronic inflammation in the lamina propria (lymphocytes, plasma cells); eosinophils may be present
─ ─ Lymphoid hyperplasia with prominent lymphoid follicles and germinal centers is very characteristic
─ ─ Cryptitis and crypt abscesses (neutrophilic inflammation) can occur, indicating active colitis
─ ─ Crypt architectural distortion (branching, shortening) may be present, but usually mild compared to chronic IBD
─ ─ Paneth cell metaplasia can be seen
─ ─ Surface epithelial injury, mucin depletion, and erosions may occur
─ ─ Granulomas are typically absent (their presence would suggest underlying Crohn's disease in the diverted segment)
─ ─ Villous atrophy or blunting if a segment of small bowel is diverted (diversion ileitis)
─ Key negative findings: absence of granulomas, viral inclusions, significant dysplasia (unless pre-existing condition)

Ancillary studies ─
─ Generally diagnosed based on clinical history of surgical diversion and characteristic histologic/endoscopic findings in the defunctioned segment
─ Stool studies/biopsies from the segment to exclude superimposed infection if symptoms are severe or atypical

DDx ─
─ Inflammatory bowel disease (Crohn's or UC): can be difficult to distinguish, especially if patient had IBD leading to diversion; features favoring IBD over pure diversion colitis include granulomas, transmural inflammation, fistulas, more severe architectural distortion, or typical IBD features in the in-stream bowel
─ Infectious colitis: specific pathogens; diversion colitis lacks a specific infectious agent
─ Ischemic colitis: ischemic features (hyalinization, withered crypts) not typical of diversion colitis
─ Radiation proctocolitis: history of radiation; radiation fibroblasts, vascular changes

Prognosis ─ Benign condition, inflammation typically resolves after re-establishment of bowel continuity (re-anastomosis)
─ If diversion is permanent, inflammation may persist but is often asymptomatic or manageable
─ Treatment (if symptomatic and diversion is maintained) can include topical SCFA enemas (e-g-, butyrate), topical steroids, or 5-ASA preparations, though efficacy is variable
─ No clear evidence of increased risk of malignancy due to diversion colitis itself, but underlying conditions (e-g-, IBD) may still carry risk

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Melanosis coli

A benign condition characterized by dark pigmentation of the colonic mucosa due to the accumulation of lipofuscin-laden macrophages in the lamina propria, commonly associated with chronic use of anthraquinone laxatives

Clinical ─ Strongly associated with long-term use of anthraquinone-containing laxatives (e-g-, senna, cascara, aloe, rhubarb)
─ The pigment is not melanin, but lipofuscin, a wear-and-tear pigment derived from lysosomal breakdown of cellular components, particularly from apoptotic colonocytes induced by laxatives
─ Usually asymptomatic and discovered incidentally during colonoscopy
─ Reversible upon discontinuation of the causative laxatives, though pigmentation may take months to years to fade
─ Not considered premalignant and does not increase risk of colorectal cancer
─ Site: typically affects the cecum and right colon most intensely, but can involve the entire colon and rectum; spares the small intestine (unless there's stasis) and appendix; polyps and carcinomas are characteristically spared by the pigmentation, appearing pale against the dark background

Macro ─ Endoscopically, the colonic mucosa appears brown to black, often with a reticular or snake-skin pattern due to sparing of lymphoid follicles which appear as pale nodules
─ Intensity of pigmentation varies with duration and dose of laxative use
─ Adenomas, carcinomas, and lymphoid follicles typically lack pigmentation and stand out as paler areas

Micro ─
─ Diagnostic feature: presence of pigment-laden macrophages in the colonic lamina propria
─ Macrophages contain coarse, granular, brown-black pigment (lipofuscin)
─ Pigment is typically most prominent in the superficial lamina propria, just beneath the surface epithelium
─ Colonic epithelium itself is not pigmented
─ Crypt architecture is usually normal; no significant inflammation or epithelial atypia is directly caused by melanosis coli (though underlying conditions or laxative effects might cause other changes)
─ Lymphoid follicles are characteristically spared by pigment deposition

Ancillary studies ─
─ Special stains:
─ ─ PAS (Periodic acid-Schiff) stain: Lipofuscin granules are PAS-positive and diastase-resistant
─ ─ Fontana-Masson stain (for melanin): Negative, confirming the pigment is not melanin
─ ─ Iron stain (Prussian blue): Negative, distinguishing from hemosiderin deposition (hemosiderosis)
─ Generally, diagnosis is made on H&E alone with appropriate clinical history

DDx ─
─ Hemosiderosis: iron deposition (blue with Prussian blue stain), usually in settings of iron overload or chronic bleeding
─ True melanocytic lesions (e-g-, metastatic melanoma, primary mucosal melanoma - extremely rare in colon): cells are atypical melanocytes, S100/Melan-A/HMB45 positive; pigment is melanin (Fontana-Masson positive)
─ Pseudomelanosis duodeni: similar pigmentation in duodenal macrophages, often associated with iron therapy, GI bleeding, or certain medications; pigment is often a mixture of hemosiderin, lipofuscin, and other substances
─ Anthracosis: black carbon pigment, usually in macrophages associated with lymphatics, rare in colon unless from fistulas or severe pneumatosis with rupture

Prognosis ─ Benign condition with no direct clinical consequences other than the mucosal discoloration
─ Serves as an indicator of chronic anthraquinone laxative use
─ Reversible upon cessation of laxative use

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IBD Colitis

Crohn's Disease

A chronic, relapsing inflammatory bowel disease (IBD) characterized by segmental, transmural, and often granulomatous inflammation that can affect any part of the gastrointestinal tract from mouth to anus, most commonly the terminal ileum and colon

Clinical ─ Etiology is multifactorial: genetic predisposition (e-g-, NOD2/CARD15 gene mutations), dysregulated immune response to gut microbiota, and environmental factors (e-g-, smoking is a risk factor)
─ Bimodal age of onset (peaks at 15-30 years and 50-70 years)
─ Symptoms vary widely: chronic diarrhea (often non-bloody), abdominal pain (often RLQ), weight loss, fatigue, fever; perianal disease (fissures, fistulas, abscesses) is common
─ Extraintestinal manifestations are common (e-g-, arthritis, uveitis, erythema nodosum, pyoderma gangrenosum, primary sclerosing cholangitis - though less common than in UC)
─ Complications: strictures, fistulas (enteroenteric, enterovesical, enterocutaneous), abscesses, malabsorption, increased risk of colorectal and small bowel adenocarcinoma (though lower than UC for CRC)

Macro ─ Endoscopic/gross findings are characteristic:
─ ─ Segmental involvement ("skip lesions"): areas of inflamed bowel interspersed with normal bowel
─ ─ Aphthous ulcers (early lesion): small, superficial ulcers with erythematous halo
─ ─ Linear, serpiginous, or deep "bear claw" ulcers
─ ─ Cobblestone appearance: intersecting longitudinal and transverse ulcers with intervening edematous mucosa
─ ─ Strictures (fibrotic narrowing of lumen)
─ ─ Fistula openings
─ ─ Transmural inflammation leads to thickened, rigid bowel wall; mesenteric fat often "creeps" onto the serosal surface ("creeping fat")
─ ─ Terminal ileum is the most common site of involvement, followed by colon (often right-sided or ileocolonic)

Micro ─
─ Hallmarks (though not all are always present):
─ ─ Transmural inflammation: Lymphoid aggregates and inflammation extending through all layers of the bowel wall (mucosa, submucosa, muscularis propria, serosa); lymphoid aggregates often prominent in submucosa and serosa
─ ─ Non-caseating granulomas: Well-formed collections of epithelioid histiocytes, with or without multinucleated giant cells; found in ~30-60% of cases, can be in any layer of bowel wall or regional lymph nodes; their presence is highly specific for Crohn's in the right clinical context, but absence does not exclude diagnosis
─ ─ Fissuring ulcers: Deep, knife-like ulcers that can penetrate into submucosa or muscularis propria, potentially leading to fistulas
─ Mucosal changes:
─ ─ Patchy (segmental) chronic inflammation: increased lymphocytes and plasma cells in lamina propria, often with basal plasmacytosis
─ ─ Crypt architectural distortion: irregular, branched, or shortened crypts, crypt dropout (evidence of chronic injury)
─ ─ Paneth cell metaplasia (especially in left colon)
─ ─ Pyloric gland metaplasia (especially in terminal ileum)
─ ─ Active inflammation (neutrophils in lamina propria, cryptitis, crypt abscesses) during flares
─ ─ Aphthous ulcers: focal erosion/ulceration overlying a lymphoid aggregate
─ IELs may be increased, but not as diffusely as in lymphocytic colitis
─ Submucosal fibrosis and muscularis propria hypertrophy in chronic disease leading to strictures

Ancillary studies ─
─ Generally diagnosis is clinicopathologic; histology supports clinical/endoscopic findings
─ Serologic markers (e-g-, ASCA - anti-Saccharomyces cerevisiae antibodies) may be positive but are not diagnostic alone
─ Special stains (AFB, GMS) to exclude infectious granulomatous diseases if granulomas are prominent or atypical

DDx ─
─ Ulcerative colitis: inflammation is typically continuous, circumferential, and limited to mucosa/superficial submucosa (except in fulminant cases); rectum almost always involved; granulomas absent; no significant small bowel disease (except "backwash ileitis")
─ Infectious colitis/ileitis (e-g-, Yersinia, tuberculosis, fungal): specific pathogens; TB causes caseating granulomas; Yersinia can cause necrotizing granulomas in ileum/lymph nodes
─ Ischemic colitis: segmental, but histology shows hyalinization, withered crypts, hemosiderin; granulomas absent
─ Diversion colitis: occurs in defunctioned bowel; lymphoid hyperplasia prominent, but granulomas typically absent
─ NSAID enteropathy/colopathy: can cause ulcers, strictures (diaphragm disease); history of NSAID use; granulomas absent
─ Segmental colitis associated with diverticulosis (SCAD): inflammation localized to segment with diverticula, typically sigmoid; granulomas usually absent
─ Behçet's disease: can cause GI ulcers similar to Crohn's, but associated with oral/genital ulcers, skin lesions, uveitis; vasculitis may be prominent

Prognosis ─ Chronic, lifelong condition with relapsing and remitting course
─ No cure, but treatments (5-ASA, corticosteroids, immunomodulators, biologics like anti-TNF) aim to induce and maintain remission, and prevent complications
─ Many patients require surgery during their lifetime for complications (strictures, fistulas, abscesses)
─ Increased risk of small bowel adenocarcinoma and colorectal cancer (risk depends on extent and duration of colonic involvement); surveillance colonoscopy recommended for patients with significant colonic Crohn's

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Ulcerative Colitis

A chronic inflammatory bowel disease (IBD) characterized by diffuse, continuous, relapsing and remitting inflammation limited to the colonic mucosa and superficial submucosa, almost always involving the rectum

Clinical ─ Etiology is multifactorial: genetic predisposition, dysregulated immune response, environmental factors (smoking is paradoxically protective or ameliorating in UC, unlike Crohn's)
─ Bimodal age of onset (peaks at 15-30 years and 50-70 years)
─ Symptoms: bloody diarrhea (cardinal symptom), rectal urgency, tenesmus, abdominal pain (often LLQ), fecal incontinence; systemic symptoms like fever, weight loss in severe flares
─ Extent of disease: proctitis (rectum only), proctosigmoiditis (rectum and sigmoid), left-sided colitis (up to splenic flexure), extensive colitis (beyond splenic flexure), pancolitis (entire colon)
─ Extraintestinal manifestations are common (e-g-, arthritis, uveitis, erythema nodosum, pyoderma gangrenosum, primary sclerosing cholangitis - PSC is more common in UC than Crohn's)
─ Complications: toxic megacolon, perforation, severe hemorrhage, increased risk of colorectal cancer (risk increases with duration and extent of colitis)

Macro ─ Endoscopic/gross findings:
─ ─ Continuous, circumferential inflammation starting in the rectum and extending proximally for a variable distance; sharp demarcation may be seen between involved and uninvolved bowel
─ ─ Mucosa appears erythematous, edematous, friable, granular, with loss of normal vascular pattern
─ ─ Erosions, superficial ulcerations, and spontaneous bleeding are common
─ ─ Pseudopolyps (islands of regenerating mucosa surrounded by ulceration) are common in chronic disease
─ ─ In severe/fulminant colitis: deep ulcerations, mucosal sloughing, toxic megacolon (dilated, thin-walled colon)
─ ─ Chronic disease: colon may be shortened, narrowed, and "lead-pipe" like due to fibrosis and loss of haustra; mucosal atrophy
─ ─ Terminal ileum is typically normal, but "backwash ileitis" (mild inflammation in distal ileum) can occur in severe pancolitis with an incompetent ileocecal valve

Micro ─
─ Mucosal inflammation: Diffuse, continuous chronic inflammatory infiltrate (lymphocytes, plasma cells) expanding the lamina propria, often with prominent basal plasmacytosis (plasma cells concentrated between crypt bases and muscularis mucosae)
─ Active inflammation (during flares): Neutrophils in lamina propria, infiltrating crypt epithelium (cryptitis), and accumulating in crypt lumens (crypt abscesses)
─ Epithelial changes: Goblet cell depletion (reduced mucin in crypts) is a hallmark of active UC; surface epithelial damage, erosions, ulcerations
─ Crypt architectural distortion: Irregular, branched, shortened crypts, crypt dropout (evidence of chronic injury and regeneration)
─ Paneth cell metaplasia is common, especially in distal colon/rectum
─ Inflammation is typically limited to the mucosa and superficial submucosa; muscularis propria and serosa are usually not significantly involved (except in fulminant colitis where transmural inflammation and necrosis can occur)
─ Granulomas are absent (their presence suggests Crohn's disease)
─ Dysplasia can develop in long-standing UC and is a precursor to colorectal cancer; requires careful surveillance and histologic assessment
─ "Backwash ileitis": mild acute and chronic inflammation, villous blunting in terminal ileum in patients with severe pancolitis; usually lacks granulomas or deep ulceration of Crohn's ileitis

Ancillary studies ─
─ Generally diagnosis is clinicopathologic
─ Serologic markers (e-g-, pANCA - perinuclear anti-neutrophil cytoplasmic antibodies) may be positive in a majority of UC patients, but are not diagnostic alone
─ Stool studies to exclude infectious colitis, especially C- difficile during flares

DDx ─
─ Crohn's disease: segmental/skip lesions, transmural inflammation, granulomas, fistulas, strictures, frequent small bowel or perianal involvement; rectum may be spared
─ Infectious colitis (e-g-, bacterial, amoebic): acute onset, specific pathogens; lacks features of chronicity like crypt distortion (unless recurrent or in specific infections like amoebiasis)
─ Ischemic colitis: segmental, often watershed areas; hyalinization, withered crypts; acute onset in older patients usually
─ Diversion colitis: occurs in defunctioned segment; prominent lymphoid hyperplasia; usually resolves with reanastomosis
─ Drug-induced colitis (e-g-, NSAIDs, checkpoint inhibitors): history of drug; specific patterns may differ
─ Radiation proctocolitis: history of pelvic radiation; atypical fibroblasts, vascular changes

Prognosis ─ Chronic, lifelong condition with relapsing and remitting course
─ Severity and extent of disease vary greatly
─ Treatments (5-ASA, corticosteroids, immunomodulators, biologics) aim to induce and maintain remission
─ Colectomy is curative for colonic disease and removes cancer risk; indications include medically refractory disease, fulminant colitis, toxic megacolon, perforation, uncontrolled bleeding, or dysplasia/cancer
─ Increased risk of colorectal cancer, starting ~8-10 years after diagnosis, especially with pancolitis; regular surveillance colonoscopy with biopsies for dysplasia is crucial
─ Patients with PSC and UC have a very high risk of colorectal cancer and cholangiocarcinoma

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IBD, Unclassified (IBDU) / Indeterminate Colitis

A term used for cases of chronic inflammatory bowel disease where a definitive distinction between Crohn's disease (CD) and ulcerative colitis (UC) cannot be made, even after thorough clinical, endoscopic, radiologic, and pathologic evaluation

Clinical ─ Accounts for ~5-15% of IBD cases, particularly in children or cases primarily involving the colon
─ Used when features overlap between CD and UC, or when classic distinguishing features of either are absent
─ For example, colonic inflammation that is continuous (like UC) but has some deep ulcers or patchy rectal sparing (more like CD), or when granulomas are absent in a case otherwise suggestive of CD
─ The term "indeterminate colitis" was historically used primarily for colectomy specimens where distinguishing CD from UC was difficult, especially in fulminant colitis with extensive ulceration obscuring underlying features
─ "IBD, Unclassified" (IBDU) is a broader term used in clinical practice for unclassifiable cases based on all available data, not just pathology
─ Management often follows general IBD principles, and may be tailored based on the predominant features or response to therapy
─ Over time, some cases of IBDU may evolve to show more definitive features of either CD or UC

Macro ─ Endoscopic and gross findings are variable and show overlapping features of CD and UC, or lack definitive features of either
─ May see continuous colitis (UC-like) but with some atypical features like aphthous ulcers or patchy inflammation elsewhere (CD-like)
─ Rectal sparing with diffuse colitis more proximally would be atypical for UC and lean towards CD or IBDU

Micro ─
─ Histologic features of chronic colitis are present: crypt architectural distortion, basal plasmacytosis, chronic lamina propria inflammation
─ Active inflammation (cryptitis, crypt abscesses) may be present
─ Features that make definitive classification difficult include:
─ ─ Continuous colonic inflammation (UC-like) but with focal deep ulceration, fissures, or prominent submucosal inflammation (CD-like features, but without granulomas or clear transmural extent)
─ ─ Patchy inflammation or rectal sparing (CD-like) but without granulomas or other specific features of CD
─ ─ Severe, fulminant colitis with extensive ulceration and mucosal denudation, where underlying architectural features or depth of inflammation are obscured
─ ─ Absence of granulomas in a case that otherwise has some features suggestive of CD (e-g-, skip lesions, perianal disease clinically)
─ Biopsies from multiple colonic segments and the terminal ileum are important

Ancillary studies ─
─ Serologic markers (ASCA, pANCA) may be performed but are not definitive for classification (ASCA more associated with CD, pANCA with UC, but overlap exists)
─ Genetic markers (e-g-, NOD2) are more associated with CD but not diagnostic

DDx ─
─ Definitive Crohn's disease: presence of granulomas, transmural inflammation, skip lesions, fistulas, significant ileal disease
─ Definitive Ulcerative colitis: continuous mucosal inflammation starting in rectum, absence of granulomas or transmural features (except in fulminant disease)
─ Other colitides (infectious, ischemic, drug-induced): must be excluded; these usually lack the chronic architectural changes of IBD (unless recurrent/chronic forms)

Prognosis ─ Clinical course and prognosis can be variable, similar to IBD in general
─ Some studies suggest IBDU may have a course intermediate between CD and UC, or behave more like severe UC
─ Risk of colorectal cancer is generally considered similar to extensive colitis (either UC or colonic CD) if the colon is extensively involved; surveillance for dysplasia is recommended
─ Pouchitis after ileal pouch-anal anastomosis (IPAA) surgery can occur, and may be more frequent or severe in patients whose underlying disease was truly CD misclassified as UC or IBDU

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IBD-associated Colorectal Carcinoma

A colorectal malignancy arising in the setting of chronic inflammatory bowel disease

Clinical ─ ─ Typically younger age at diagnosis compared to sporadic CRC
─ Risk increases with duration (8-10 years post-IBD diagnosis) and extent of colonic involvement (pancolitis > left-sided > proctitis)
─ Other risk factors include severity of inflammation, family history of CRC, primary sclerosing cholangitis (PSC)
─ Symptoms can be similar to IBD flare or sporadic CRC: change in bowel habits, rectal bleeding, abdominal pain, weight loss
─ Surveillance colonoscopy with biopsies is key for early detection of dysplasia or cancer

Macro ─ ─ Often flat, infiltrative, or plaque-like rather than discrete polypoid masses like sporadic CRC
─ May be multifocal due to "field effect" of chronic inflammation
─ Strictures can harbor malignancy

Micro ─

─ Histologic subtypes can resemble sporadic CRC (tubular, mucinous, signet ring cell) but often higher grade
─ May arise from flat dysplasia (low-grade or high-grade) or dysplasia-associated lesion or mass (DALM)
─ Background features of chronic colitis are usually present
─ Lymphocytic infiltration may be prominent
─ Unique IBD-associated variant: low-grade tubuloglandular adenocarcinoma (CK7+)
─ Serrated pathway lesions can also occur in IBD and progress to carcinoma

Ancillary studies ─

─ IHC (+): CK7 (especially in low-grade tubuloglandular variant); p53 often positive in dysplastic epithelium (earlier than sporadic)
─ IHC (-): Generally CK20 positive, CDX2 positive similar to sporadic CRC; MMR proteins (MLH1, MSH2, MSH6, PMS2) may be lost indicating MSI, though less common than in some sporadic MSI-H CRC unless associated with Lynch syndrome
─ Molecular ─ ─ Inflammation-dysplasia-carcinoma sequence is characteristic
─ TP53 mutations occur earlier in the sequence compared to sporadic CRC
─ APC mutations occur later or are less frequent compared to sporadic CRC
─ Microsatellite instability (MSI) can occur, but pathway may differ from sporadic MSI-H CRC
─ Increased chromosomal instability (CIN) is common
─ KRAS mutations can be present

DDx ─

─ Sporadic colorectal carcinoma
─ Dysplasia (low-grade or high-grade) without invasion
─ Severe active colitis with reactive atypia

Prognosis ─ ─ Historically considered worse than sporadic CRC, but stage-for-stage prognosis may be similar with modern management
─ Multifocality and difficulty in endoscopic detection can contribute to later-stage diagnosis
─ Presence of PSC is a poor prognostic factor

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Colorectal Adenocarcinoma

Conventional Adenocarcinoma

(NOS, tubular, tubulovillous, villous architecture based)

The most common type of colorectal cancer, characterized by glandular differentiation, arising from colonic or rectal mucosa

Clinical ─ ─ Typically affects older adults (>50 years), though incidence in younger individuals is increasing
─ Risk factors include age, personal or family history of colorectal cancer or polyps, inflammatory bowel disease, certain inherited syndromes (e.g., Lynch syndrome, FAP), lifestyle factors (diet low in fiber, high in fat/processed meat, physical inactivity, obesity, smoking, alcohol)
─ Symptoms may be absent in early stages; later symptoms include changes in bowel habits (diarrhea, constipation), rectal bleeding or blood in stool, abdominal discomfort (cramps, gas, pain), feeling of incomplete evacuation, weakness, fatigue, unexplained weight loss
─ Site: Can occur anywhere in colon or rectum; left-sided (descending colon, sigmoid, rectum) more common for some types, right-sided (cecum, ascending colon) for others (especially MSI-H tumors)

Macro ─ ─ Appearance varies:
─ Polypoid or exophytic masses protruding into the lumen
─ Ulcerated lesions with heaped-up edges
─ Annular, constricting ("apple-core") lesions leading to luminal narrowing
─ Flat or infiltrative lesions (less common for conventional type)

Micro ─

─ Glandular (acinar) formation is the hallmark, with varying degrees of differentiation
─ Tumor cells typically columnar with hyperchromatic, pleomorphic, and stratified nuclei
─ Invasion through the muscularis mucosae into the submucosa (or deeper) is diagnostic of adenocarcinoma
─ Desmoplastic stromal reaction is common around invading glands
─ "Dirty necrosis" (luminal necrotic debris) is a characteristic feature, especially in metastatic sites suggesting colorectal primary
─ Architectural patterns define subtypes:
─ Tubular: Predominantly composed of tubules/glands (>50%)
─ Villous: Predominantly (>50%) finger-like projections (rare in pure form)
─ Tubulovillous: Mixture of tubular and villous components (each >25%)
─ Grading is based on the percentage of gland formation:
─ Well-differentiated (Grade 1): >95% gland formation
─ Moderately differentiated (Grade 2): 50-95% gland formation
─ Poorly differentiated (Grade 3): <50% gland formation
─ Tumor budding (single cells or small clusters of <5 cells at invasive front) is an adverse prognostic factor
─ Peritumoral lymphocytic infiltrate (Crohn's-like reaction) may be present and is often associated with MSI-H tumors and better prognosis

Ancillary studies ─

─ IHC (+): CK20 (diffuse, strong), CDX2 (nuclear); CEA (cytoplasmic/luminal, often polyclonal)
─ IHC (-): CK7 (usually negative, helping distinguish from some upper GI or pancreaticobiliary adenocarcinomas)
─ Molecular ─ ─ Two main pathways:
─ Chromosomal Instability (CIN) pathway (most common, ~85%): Characterized by aneuploidy, loss of heterozygosity; mutations in APC (early event), KRAS, TP53 (later event)
─ Microsatellite Instability (MSI) pathway (~15%): Due to deficient DNA mismatch repair (dMMR) system; leads to accumulation of mutations in microsatellites
─ Sporadic MSI-H often due to MLH1 promoter hypermethylation, frequently associated with BRAF V600E mutation, CIMP-high, often right-sided, may have mucinous or medullary features
─ Lynch syndrome-associated MSI-H due to germline mutation in MMR genes (MLH1, MSH2, MSH6, PMS2)
─ RAS (KRAS, NRAS) mutations (in ~40-50%): Predictive biomarker for resistance to anti-EGFR therapy
─ BRAF V600E mutation (in ~5-10%, mostly MSI-H sporadic): Associated with poor prognosis in MSS tumors; therapeutic target
─ HER2 amplification (rare): Potential therapeutic target

DDx ─

─ Metastatic adenocarcinoma from another site (e.g., pancreas, stomach, lung – IHC panel crucial)
─ High-grade dysplasia within an adenoma (adenoma architecture still present, no submucosal invasion)
─ Other primary colorectal tumors (e.g., neuroendocrine tumor, lymphoma)
─ Benign mimics with atypia (e.g., reactive changes, prolapse-related changes)

Prognosis ─ ─ Primarily dependent on anatomical stage (TNM classification): depth of invasion (T), lymph node involvement (N), distant metastasis (M)
─ Histologic grade: poorly differentiated tumors have worse prognosis
─ Lymphovascular invasion and perineural invasion are adverse prognostic factors
─ Tumor budding is an adverse prognostic factor
─ MSI-H tumors generally have a better stage-adjusted prognosis than MSS tumors and may respond differently to chemotherapy; predictive for immunotherapy response
─ BRAF V600E mutation in MSS tumors is associated with poor prognosis
─ Elevated pre-treatment CEA levels indicate worse prognosis

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Mucinous Adenocarcinoma (Colorectal)

A subtype of colorectal adenocarcinoma defined by the presence of >50% extracellular mucin within the tumor volume

Clinical ─ ─ Accounts for 10-15% of colorectal cancers
─ May be more common in the proximal colon (right side)
─ Can present with larger tumor size at diagnosis
─ Often associated with microsatellite instability (MSI-H) and the serrated pathway
─ Symptoms similar to conventional adenocarcinoma but may have increased incidence of peritoneal carcinomatosis

Macro ─ ─ Tumors are typically bulky, gelatinous, or colloid in appearance due to abundant mucin
─ May show cystic changes

Micro ─

─ Extracellular mucin pools constituting >50% of the tumor mass
─ Tumor cells float within the mucin as glands, strips, clusters, or individual cells (including signet-ring cells, though if >50% signet ring cells, it's classified as signet ring cell carcinoma)
─ Can be well, moderately, or poorly differentiated based on the glandular architecture of the cellular component
─ Often associated with a prominent inflammatory infiltrate

Ancillary studies ─

─ IHC (+): CK20, CDX2 (similar to conventional adenocarcinoma); MUC2 is often strongly and diffusely positive (a mucin gene product)
─ IHC (-): CK7 usually negative
─ Molecular ─ ─ Higher frequency of microsatellite instability (MSI-H) compared to conventional adenocarcinoma, often due to MLH1 promoter hypermethylation
─ Frequently associated with BRAF V600E mutations
─ CpG Island Methylator Phenotype (CIMP-high) is common
─ KRAS mutations can occur
─ TP53 mutations are less frequent than in CIN pathway tumors

DDx ─

─ Conventional adenocarcinoma with mucinous features (<50% mucin)
─ Signet-ring cell carcinoma (if signet ring cells are the predominant component)
─ Metastatic mucinous adenocarcinoma from other sites (e.g., ovary, appendix, pancreas, breast – IHC crucial: PAX8, SATB2, CDX2, CK7/CK20 profile)
─ Mucocele or mucinous cystadenoma of the appendix (if appendiceal origin considered)
─ Benign mucinous lesions (e.g., colitis cystica profunda with extensive mucin)

Prognosis ─ ─ Prognosis has been controversial; some studies suggest worse prognosis, particularly for MSS mucinous tumors or those with peritoneal spread
─ MSI-H mucinous adenocarcinomas may have a better prognosis, similar to other MSI-H tumors
─ Stage remains the most important prognostic factor
─ Increased risk of peritoneal metastasis

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Signet-ring cell carcinoma (Colorectal)

An aggressive subtype of colorectal adenocarcinoma defined by the presence of >50% tumor cells with signet-ring morphology

Clinical ─ ─ Rare, accounting for ~1% of colorectal cancers
─ Often affects younger patients compared to conventional adenocarcinoma
─ May present at an advanced stage with peritoneal carcinomatosis
─ Symptoms can be vague and include abdominal pain, distension, weight loss; obstructive symptoms may be less common initially due to infiltrative growth
─ Often associated with linitis plastica appearance on imaging/endoscopy

Macro ─ ─ Characterized by diffuse infiltrative growth (linitis plastica), leading to bowel wall thickening and rigidity
─ Discrete mass may not be apparent
─ Ulceration can be present

Micro ─

─ >50% of tumor cells are signet-ring cells: neoplastic epithelial cells containing large intracytoplasmic mucin vacuoles that push the nucleus to the periphery, creating a crescent or ring shape
─ Cells infiltrate individually or in small clusters/strands through the stroma, often with extensive desmoplasia
─ Glandular formation is minimal or absent in the signet-ring cell component
─ Can be associated with microsatellite instability (MSI-H) in a subset of cases

Ancillary studies ─

─ IHC (+): Cytokeratins (AE1/AE3, CAM5.2); MUC2 and MUC5AC may be positive in mucin; CDX2 usually positive
─ IHC (variable): CK20 may be positive but can be focal or weak; CK7 is usually negative
─ Special Stains: PAS-D or Alcian blue highlight intracytoplasmic mucin
─ Molecular ─ ─ Can be associated with MSI-H, particularly in younger patients or those with Lynch syndrome
─ E-cadherin (CDH1) mutations or loss of expression, though less common as a primary driver than in diffuse gastric cancer, can be seen
─ TP53 mutations may occur

DDx ─

─ Metastatic signet-ring cell carcinoma (especially from stomach, breast, or pancreas – requires careful clinical correlation and IHC panel: GATA3 for breast, other markers for gastric/pancreatic)
─ Mucinous adenocarcinoma with signet-ring cells (<50% signet-ring cells)
─ Poorly differentiated conventional adenocarcinoma with focal signet-ring features
─ Linitis plastica due to other causes (e.g., lymphoma, metastatic carcinoma)
─ Signet-ring cell change in benign conditions (rare, e.g., reactive atypia, signet-ring cell schwannoma – context and IHC vital)

Prognosis ─ ─ Generally associated with a poor prognosis
─ Often diagnosed at an advanced stage
─ High rates of peritoneal metastasis and lymphatic spread
─ Poor response to conventional chemotherapy
─ MSI-H status, if present, might confer slightly better prognosis or predict response to immunotherapy, but overall prognosis remains guarded

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Medullary Carcinoma (Colorectal)

A rare, poorly differentiated subtype of colorectal carcinoma characterized by solid sheets of cells with vesicular nuclei, prominent nucleoli, eosinophilic cytoplasm, and a prominent intraepithelial lymphocytic infiltrate

Clinical ─ ─ Uncommon, representing <1% to ~3% of colorectal carcinomas
─ More common in older females
─ Predominantly occurs in the proximal (right) colon, especially the cecum and ascending colon
─ Often associated with Lynch syndrome or sporadic MSI-H status
─ May present as a bulky mass
─ CEA levels are often not significantly elevated

Macro ─ ─ Typically a well-circumscribed, expansile, soft, fleshy ("medulla-like") mass
─ May have a pushing border rather than an infiltrative one
─ Ulceration can be seen

Micro ─

─ Solid, sheet-like, syncytial, or trabecular growth pattern with minimal or no gland formation
─ Tumor cells are polygonal with abundant eosinophilic cytoplasm, large vesicular nuclei, and prominent nucleoli
─ Cell borders are often indistinct (syncytial appearance)
─ Prominent intratumoral lymphocytic infiltrate (TILs) is a characteristic feature, composed mainly of T-cells
─ Pushing tumor borders are common
─ Comedo-like necrosis may be present
─ Despite high-grade appearance, mitotic activity may not be excessively high

Ancillary studies ─

─ IHC (+): Calretinin (often positive and can be a helpful diagnostic marker); SATB2; BRAF V600E (if sporadic MSI-H)
─ IHC (variable/loss): CK20 and CDX2 expression can be lost or reduced in a significant proportion of cases, which can cause diagnostic difficulty if not considered; MUC1, MUC2, TFF3 may show some intestinal differentiation markers despite loss of CDX2
─ IHC (MMR): Almost invariably shows deficient mismatch repair (dMMR) with loss of MLH1/PMS2 (most common, due to MLH1 promoter hypermethylation in sporadic cases) or MSH2/MSH6 (in Lynch syndrome)
─ IHC (-): Neuroendocrine markers (synaptophysin, chromogranin) are typically negative
─ Molecular ─ ─ Microsatellite instability-high (MSI-H) is a defining feature
─ BRAF V600E mutations are very common in sporadic medullary carcinomas (associated with MLH1 methylation)
─ Associated with CpG Island Methylator Phenotype (CIMP-high)

DDx ─

─ Poorly differentiated conventional adenocarcinoma (lacks prominent TILs and typical medullary cytology; usually MMR proficient or different IHC profile)
─ Lymphoepithelioma-like carcinoma (histologically similar, also EBV-associated in some sites, but in colon, medullary carcinoma is the preferred term for MSI-H tumors with this morphology)
─ Metastatic carcinoma (e.g., melanoma, poorly differentiated carcinoma from other sites – IHC panel for site-specific markers is crucial, especially if CK20/CDX2 are negative)
─ High-grade neuroendocrine carcinoma (especially large cell neuroendocrine carcinoma; will be positive for neuroendocrine markers)
─ Lymphoma (positive for lymphoid markers, negative for cytokeratins)

Prognosis ─ ─ Paradoxically, despite its poorly differentiated appearance, medullary carcinoma generally has a better prognosis than conventional poorly differentiated adenocarcinomas of similar stage
─ This improved prognosis is attributed to its MSI-H status and the robust host immune response (TILs)
─ Less likely to have lymph node metastases at presentation compared to conventional poorly differentiated CRC

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Serrated Adenocarcinoma (Colorectal)

A colorectal carcinoma thought to arise from serrated precursor polyps (e.g., sessile serrated lesion/polyp or traditional serrated adenoma), characterized by specific architectural and cytological features reminiscent of serrated polyps

Clinical ─
─ Often arises in the proximal (right) colon, similar to its precursor lesions
─ May be associated with older age and female sex, similar to sessile serrated lesions
─ Symptoms are similar to conventional colorectal adenocarcinoma, including changes in bowel habits, rectal bleeding, and abdominal pain
─ Endoscopic appearance can be challenging, as precursor lesions may be flat and subtle

Macro ─
─ Can be polypoid, flat, or ulcerated
─ Often located in the right colon
─ May be larger at diagnosis compared to some conventional adenocarcinomas

Micro ─

─ Shows features that overlap with both conventional adenocarcinoma and serrated polyps
─ Key features include:
─ Epithelial serrations (sawtooth or undulating appearance of the luminal border of glands)
─ Eosinophilic or clear cytoplasm in tumor cells
─ Abundant cytoplasm
─ Nuclei that are often vesicular with prominent nucleoli, but can be deceptively bland in some areas
─ Glandular architecture may show irregular branching, budding, or anastomosing patterns
─ Mucin production can be prominent, sometimes with extracellular mucin pools (overlapping with mucinous adenocarcinoma if >50% mucin)
─ May have a filiform, villous, or papillary architecture in some areas
─ Often associated with a background of a serrated polyp (SSL/P or TSA)
─ Tumor infiltrating lymphocytes may be present, but less consistently prominent than in medullary carcinoma

Ancillary studies ─

─ IHC (+): CK20, CDX2 (similar to conventional adenocarcinoma); Annexin A10 may be positive (marker associated with serrated pathway); MUC5AC may be expressed (gastric-type mucin)
─ IHC (-): CK7 usually negative
─ Molecular ─
─ Frequently associated with BRAF V600E mutation (especially those arising from SSL/P)
─ Often exhibits CpG Island Methylator Phenotype (CIMP-high)
─ Can be microsatellite instable (MSI-H) due to MLH1 promoter hypermethylation (common in BRAF-mutated tumors) or microsatellite stable (MSS)
─ KRAS mutations are more common in tumors arising from traditional serrated adenomas (TSAs) and are typically MSS
─ TP53 mutations can occur, particularly in MSS serrated adenocarcinomas or in the progression of MSI-H tumors

DDx ─

─ Conventional adenocarcinoma with focal serrated features (true serrated adenocarcinoma should have more pervasive serrated morphology)
─ Mucinous adenocarcinoma (if extensive extracellular mucin is present; serrated adenocarcinomas can also be mucinous)
─ Medullary carcinoma (also often MSI-H and right-sided, but has a distinct syncytial/solid growth and prominent TILs)
─ Traditional serrated adenoma (TSA) or Sessile Serrated Lesion/Polyp (SSL/P) with dysplasia (distinction relies on identifying unequivocal invasion)
─ Hyperplastic polyp with reactive atypia (lacks true dysplastic features and invasion)

Prognosis ─
─ Prognosis can be variable and may depend on factors like MSI status, BRAF mutation status, and stage
─ Some studies suggest BRAF-mutated MSS serrated adenocarcinomas may have a worse prognosis
─ MSI-H serrated adenocarcinomas may have a better prognosis, similar to other MSI-H CRCs
─ Overall, stage at diagnosis remains a critical prognostic factor

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Micropapillary Carcinoma (Colorectal)

A rare and aggressive histologic variant of colorectal adenocarcinoma characterized by small, cohesive clusters of tumor cells (micropapillae) lying within clear stromal spaces or retraction artifacts, lacking true fibrovascular cores

Clinical ─
─ Represents a small percentage of colorectal cancers
─ Often presents at an advanced stage
─ Associated with a high frequency of lymphovascular invasion and lymph node metastasis, even when the micropapillary component is minor
─ Symptoms are similar to conventional colorectal adenocarcinoma

Macro ─
─ No specific macroscopic features distinguish it from conventional adenocarcinoma
─ Tumor size can vary

Micro ─

─ Diagnostic feature: small, tight, cohesive clusters or tufts of tumor cells (micropapillae) that appear to float within clear, empty stromal spaces or retraction artifacts
─ These micropapillae lack a central fibrovascular core
─ Tumor cells often exhibit "reverse polarity," where the apical surface (if discernible) faces the stroma rather than a central lumen (MUC1/EMA staining highlights this "inside-out" pattern)
─ Cells typically have eosinophilic cytoplasm and high-grade nuclear features (pleomorphism, hyperchromasia)
─ The micropapillary component is often found at the invasive front of the tumor but can be present throughout
─ Even a small proportion (e.g., ≥5% or ≥10%) of micropapillary component is considered significant and should be reported
─ Often coexists with conventional adenocarcinoma components (tubular, villous, etc.)
─ Frequent lymphovascular invasion is a hallmark

Ancillary studies ─

─ IHC (+): CK20, CDX2 (similar to conventional CRC); MUC1 (EMA) shows a characteristic "inside-out" staining pattern on the stromal-facing surface of micropapillae, highlighting the reverse polarity
─ IHC (-): CK7 usually negative
─ Molecular ─
─ Often microsatellite stable (MSS)
─ KRAS mutations are common
─ BRAF mutations can occur but may be less frequent than in serrated pathway tumors
─ TP53 mutations are frequent
─ May show evidence of epithelial-mesenchymal transition (EMT) markers in some studies

DDx ─

─ Conventional adenocarcinoma with retraction artifact (true micropapillary carcinoma has the characteristic cell clusters and reverse polarity)
─ Tumor budding (tumor budding consists of single cells or clusters of <5 cells, whereas micropapillae are typically larger clusters; micropapillae are also usually within the tumor bulk, not just at the invasive front, and have more well-formed structures and reverse polarity)
─ Adenocarcinoma with extensive lymphovascular invasion (micropapillary structures are in stromal spaces that may mimic lymphatics, but true lymphovascular invasion shows endothelial lining of the spaces, which can be highlighted by D2-40 or CD31)
─ Papillary adenocarcinoma (true papillae have fibrovascular cores)

Prognosis ─
─ Associated with a significantly worse prognosis compared to conventional adenocarcinoma of similar stage
─ High rates of lymph node metastasis, distant metastasis, and local recurrence
─ The presence of any micropapillary component, even focal, is an adverse prognostic indicator

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Adenosquamous Carcinoma (Colorectal)

A rare biphasic malignant epithelial neoplasm composed of both a glandular (adenocarcinoma) component and a squamous cell carcinoma component

Clinical ─
─ Extremely rare in the colorectum, with an incidence of <0.1% of all colorectal malignancies
─ Can occur at any age, but often in older individuals
─ Symptoms are similar to conventional colorectal adenocarcinoma (e.g., abdominal pain, change in bowel habits, bleeding) but may present at a later stage or with complications like obstruction or perforation
─ May be more common in the right colon, though can occur anywhere

Macro ─
─ No specific macroscopic features to distinguish it from conventional adenocarcinoma
─ Can be polypoid, ulcerating, or infiltrative

Micro ─

─ Definitive diagnosis requires the presence of two distinct malignant components:
─ Adenocarcinoma component: Glandular differentiation, mucin production may be present
─ Squamous cell carcinoma component: Characterized by intercellular bridges, keratinization (keratin pearls), or sheets of cells with eosinophilic cytoplasm and distinct cell borders
─ Each component must constitute a significant portion of the tumor (e.g., some definitions use a cutoff like >25% or >30% for each, though this can vary; others require clear intermingling)
─ The two components are typically intermingled or in close proximity
─ Both components should exhibit features of malignancy (cytologic atypia, infiltrative growth)
─ The squamous component is usually moderately to poorly differentiated

Ancillary studies ─

─ IHC (Adenocarcinoma component): Positive for CK20, CDX2, CEA (similar to conventional CRC)
─ IHC (Squamous component): Positive for squamous markers like p63, p40, CK5/6, high molecular weight cytokeratins (e.g., 34βE12)
─ IHC (Both components): Pancytokeratin (AE1/AE3) should be positive in both
─ Molecular ─
─ Molecular pathogenesis is not well understood due to rarity
─ Some studies suggest a monoclonal origin with divergent differentiation
─ Mutations common in conventional CRC (e.g., KRAS, TP53) can be found
─ MMR status can be assessed; dMMR/MSI-H has been reported in some cases

DDx ─

─ Conventional adenocarcinoma with squamous metaplasia (squamous component is benign or lacks full criteria for SCC)
─ Squamous cell carcinoma of the anal canal extending into the rectum (distinction based on epicenter and ruling out primary anal SCC)
─ Metastatic adenosquamous carcinoma from another site (e.g., lung, esophagus, gynecologic tract – clinical history and broader IHC panel are essential)
─ Mucoepidermoid carcinoma (rare in colon, has intermediate cells in addition to mucinous and epidermoid cells)
─ Collision tumor (two separate synchronous primary tumors, adenocarcinoma and SCC, that have merged – very rare and components are usually less intermingled)

Prognosis ─
─ Generally considered to have a poorer prognosis than conventional colorectal adenocarcinoma of similar stage
─ Tends to be aggressive with early metastasis
─ The squamous component is often thought to contribute to the aggressive behavior

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Carcinoma with Sarcomatoid Component (Colorectal)

An extremely rare, highly aggressive biphasic malignant neoplasm of the colorectum characterized by the presence of both a carcinomatous (epithelial) component and a sarcomatoid (mesenchymal-like spindle cell or pleomorphic) component

Clinical ─
─ Very rare, with only a small number of cases reported in the literature
─ Can occur over a wide age range, but often in older adults
─ Symptoms are non-specific and similar to other colorectal cancers (abdominal pain, bleeding, change in bowel habits, weight loss)
─ Often presents at an advanced stage with large tumor size and metastases

Macro ─
─ Typically large, often bulky, polypoid, or ulcerated masses
─ May show areas of hemorrhage and necrosis
─ Can occur in any part of the colorectum

Micro ─

─ Biphasic tumor with two intimately mixed components:
─ Carcinomatous component: Usually an adenocarcinoma (gland-forming), which may be well to poorly differentiated. It can sometimes be a squamous cell carcinoma or undifferentiated carcinoma component.
─ Sarcomatoid component: Composed of spindle cells, pleomorphic cells, or giant cells resembling a sarcoma (e.g., fibrosarcoma, malignant fibrous histiocytoma-like, undifferentiated sarcoma). Heterologous elements (e.g., osteosarcomatous, chondrosarcomatous, rhabdomyosarcomatous differentiation) can rarely be present.
─ The sarcomatoid component often predominates and shows high-grade features, including marked atypia, high mitotic activity, and necrosis
─ There should be evidence of transition or intermingling between the carcinomatous and sarcomatoid areas, supporting the concept of a metaplastic or divergent differentiation from a common epithelial origin, rather than a true collision of two separate neoplasms

Ancillary studies ─

─ IHC (Carcinomatous component): Positive for epithelial markers like cytokeratins (AE1/AE3, CAM5.2), EMA, CK20, CDX2 (if adenocarcinoma)
─ IHC (Sarcomatoid component): Often positive for vimentin. May show variable or focal positivity for cytokeratins (key to demonstrate epithelial origin/differentiation of the sarcomatoid component, distinguishing it from a true sarcoma or collision tumor). Can express other mesenchymal markers depending on the line of differentiation (e.g., SMA if myofibroblastic).
─ IHC (-): S100, desmin usually negative unless specific heterologous differentiation is present
─ Molecular ─
─ Pathogenesis is poorly understood due to rarity
─ Believed to be of monoclonal epithelial origin with sarcomatoid dedifferentiation or metaplasia
─ Genetic alterations found in conventional colorectal cancer (e.g., TP53, KRAS, APC mutations) may be present in both components or the carcinomatous component
─ Loss of SMARCA4 (BRG1) has been reported in some cases, similar to some other undifferentiated/sarcomatoid carcinomas
─ MMR status can be assessed

DDx ─

─ True primary colorectal sarcoma (e.g., leiomyosarcoma, GIST – sarcomatoid component would be negative for keratins, and specific mesenchymal markers would be positive)
─ Collision tumor (synchronous adenocarcinoma and sarcoma – components are usually distinct with less intermingling, and sarcomatoid part lacks keratin)
─ Spindle cell melanoma (positive for S100, SOX10, Melan-A/HMB45)
─ Poorly differentiated conventional adenocarcinoma with reactive stromal spindle cells (stromal cells are benign, lack atypia of sarcomatoid component)
─ Inflammatory myofibroblastic tumor (ALK positive in a subset, lacks true carcinomatous component)
─ Metastatic sarcomatoid carcinoma from another site (e.g., lung, kidney, bladder – clinical history and broader IHC panel needed)

Prognosis ─
─ Extremely poor prognosis, among the most aggressive colorectal malignancies
─ High rates of local recurrence, lymph node metastasis, and distant metastasis (often to liver, lungs, peritoneum)
─ Often fatal within a short period despite treatment
─ The sarcomatoid component is thought to drive the aggressive behavior

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Undifferentiated Carcinoma (Colorectal)

A malignant epithelial neoplasm of the colorectum that shows no evidence of specific glandular, squamous, or neuroendocrine differentiation by light microscopy or immunohistochemistry

Clinical ─ ─ Rare and aggressive subtype of colorectal cancer
─ May affect a wide age range, can occur in younger patients
─ Symptoms are often non-specific and similar to other colorectal cancers (e.g., abdominal pain, change in bowel habits, weight loss, bleeding)
─ Often presents at an advanced stage with large tumor size and metastases

Macro ─ ─ Can be a large, bulky, infiltrative mass
─ May show extensive necrosis and hemorrhage
─ Can occur in any part of the colorectum

Micro ─

─ Composed of sheets, nests, or diffuse infiltrates of malignant cells without any discernible glandular structures, keratinization, or features of neuroendocrine differentiation
─ Cells are typically highly pleomorphic, with large, hyperchromatic nuclei, prominent nucleoli, and a high nuclear-to-cytoplasmic ratio
─ Mitotic activity is usually brisk, including atypical mitoses
─ Extensive necrosis is common
─ Stroma can be desmoplastic or scant with an inflammatory infiltrate
─ By definition, lacks features to classify it as adenocarcinoma, squamous cell carcinoma, neuroendocrine carcinoma, or other specific differentiated types

Ancillary studies ─

─ IHC (Epithelial markers): Should be positive for at least one cytokeratin (e.g., AE1/AE3, CAM5.2, CK18) to confirm carcinomatous nature, though expression can sometimes be focal or aberrant
─ IHC (Markers of differentiation): Negative for markers of glandular differentiation (e.g., typically CK20, CDX2, though focal/weak expression doesn't exclude if morphology is undifferentiated), squamous differentiation (e.g., p63, p40, CK5/6), and neuroendocrine differentiation (e.g., synaptophysin, chromogranin A)
─ IHC (Other):
─ Vimentin may be co-expressed in some cases, suggesting epithelial-mesenchymal transition or less differentiation
─ SMARCA4 (BRG1) and SMARCB1 (INI1) loss has been described in some undifferentiated carcinomas, particularly those with rhabdoid features or arising in unusual contexts
─ Molecular ─ ─ Can be associated with microsatellite instability (MSI-H), particularly in the context of Lynch syndrome or sporadic MSI due to MLH1 promoter methylation
─ TP53 mutations are common
─ Other mutations found in conventional colorectal cancer (e.g., KRAS, BRAF) can also occur
─ Extensive molecular profiling may reveal targetable alterations in some cases

DDx ─

─ Poorly differentiated adenocarcinoma (will show at least focal glandular differentiation or mucin production, or express CK20/CDX2 more convincingly)
─ Medullary carcinoma (has a specific morphology with syncytial sheets, vesicular nuclei, prominent TILs, and is MSI-H)
─ Carcinoma with sarcomatoid component (biphasic with identifiable carcinomatous and sarcomatoid areas; sarcomatoid part may be keratin negative or focally positive)
─ High-grade neuroendocrine carcinoma (especially large cell neuroendocrine carcinoma; will be positive for neuroendocrine markers)
─ Lymphoma (positive for lymphoid markers like CD45, CD20, CD3; negative for keratins)
─ Melanoma (positive for S100, SOX10, Melan-A/HMB45; negative for keratins)
─ Metastatic undifferentiated carcinoma from another site (clinical history and broader IHC panel crucial)
─ True sarcoma (negative for keratins, positive for specific mesenchymal markers)

Prognosis ─ ─ Generally has a very poor prognosis due to aggressive behavior and frequent presentation at advanced stage
─ High rates of local recurrence and distant metastasis
─ MSI-H status, if present, might confer a slightly better prognosis or predict response to immunotherapy, but overall outcomes remain poor

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Cribriform Comedo-type Adenocarcinoma (Colorectal)

A rare histologic pattern or variant of colorectal adenocarcinoma characterized by neoplastic glands forming complex, sieve-like (cribriform) structures, often with central necrosis (comedonecrosis) within the glandular lumens

Clinical ─ ─ Considered a rare pattern or variant of colorectal adenocarcinoma
─ Clinical presentation is similar to conventional colorectal adenocarcinoma
─ May be associated with more aggressive behavior and advanced stage at diagnosis in some studies
─ More common in males for some series with predominant cribriform pattern

Macro ─ ─ No specific macroscopic features reliably distinguish it from other types of colorectal adenocarcinoma
─ Can be exophytic, ulcerative, or infiltrative

Micro ─

─ Predominant architectural pattern is cribriform: back-to-back glands or large glandular structures perforated by multiple, rounded, "punched-out" lumens, creating a sieve-like or lace-like appearance
─ The lumens of these cribriform structures often contain necrotic debris (comedonecrosis), similar to comedo-DCIS of the breast
─ Tumor cells are typically high-grade, with pleomorphic nuclei, prominent nucleoli, and increased mitotic activity
─ Solid areas or conventional glandular components may also be present
─ Stromal response can be variable
─ This pattern needs to be distinguished from simple glandular complexity or fusion seen in conventional adenocarcinomas

Ancillary studies ─

─ IHC (+): CK20, CDX2 (similar to conventional colorectal adenocarcinoma)
─ IHC (-): CK7 usually negative
─ Molecular ─ ─ Often microsatellite stable (MSS)
─ KRAS mutations are frequently reported in tumors with a cribriform pattern
─ TP53 mutations are common
─ May be associated with higher frequency of somatic copy number alterations (SCNAs) compared to well-formed gland types in some studies
─ BRAF mutations are less common in this pattern compared to serrated or medullary types

DDx ─

─ Conventional adenocarcinoma with focal cribriform areas (the term "cribriform comedo-type" is usually reserved for tumors where this is a predominant or very striking feature)
─ High-grade dysplasia within an adenoma (especially with complex architecture; invasion into submucosa defines carcinoma)
─ Metastatic adenocarcinoma with cribriform features (e.g., from prostate, breast – IHC panel including PSA, GATA3, ER, etc., is crucial)
─ Other rare variants of colorectal cancer (e.g., micropapillary carcinoma if micropapillae are present within stromal spaces)

Prognosis ─ ─ Often considered an aggressive histologic pattern associated with a poorer prognosis compared to conventional adenocarcinoma NOS of similar stage
─ Associated with increased risk of lymph node metastasis, extramural venous invasion, and distant metastasis
─ The presence of a significant cribriform component, especially with comedonecrosis, should be noted as it may indicate more aggressive behavior

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Polyps

Adenomatous Polyps

Tubular Adenoma (Colorectal)

A benign neoplastic polyp of the colorectal mucosa characterized by a proliferation of dysplastic glandular (tubular) structures, representing a precursor lesion to colorectal adenocarcinoma via the conventional adenoma-carcinoma sequence

Clinical ─ ─ The most common type of adenomatous polyp, accounting for approximately 80%
─ Prevalence increases with age; more common in males
─ Often asymptomatic and detected during screening colonoscopy
─ If symptomatic, may cause rectal bleeding (often occult), changes in bowel habits, or rarely, abdominal pain
─ Risk factors include age, family history of colorectal polyps or cancer, certain genetic syndromes (e.g., FAP, Lynch syndrome), and lifestyle factors (diet, smoking)

Macro ─ ─ Typically <1 cm in diameter, but can be larger
─ Can be pedunculated (with a stalk) or sessile (flat-based)
─ Surface may appear smooth or slightly lobulated
─ Color is similar to or slightly redder than surrounding normal mucosa

Micro ─

─ Composed predominantly (≥75% or ≥80% depending on criteria) of branching and crowded dysplastic tubular glands
─ Glands are lined by columnar epithelial cells showing varying degrees of dysplasia:
─ Nuclear atypia: Enlarged, hyperchromatic, elongated (pencil-like or cigar-shaped), and pseudostratified nuclei
─ Cytoplasmic changes: Reduced intracytoplasmic mucin (loss of goblet cells), increased basophilia
─ Architectural changes: Glandular crowding, branching, some irregularity
─ Dysplasia is graded as low-grade or high-grade:
─ Low-grade dysplasia (LGD): Nuclei are generally confined to the basal half of the cells, though pseudostratification is present; polarity maintained; mild to moderate atypia
─ High-grade dysplasia (HGD): More marked nuclear atypia, pleomorphism, loss of polarity (nuclei extend to the apical surface), increased mitotic activity (often atypical and suprabasal), and more complex glandular architecture (e.g., cribriforming, back-to-back glands, significant crowding). Intramucosal carcinoma is included within HGD if neoplastic cells invade the lamina propria but do not cross the muscularis mucosae.
─ The stroma is composed of lamina propria, which may be edematous or contain a mild chronic inflammatory infiltrate
─ The muscularis mucosae is intact beneath the adenoma (unless there is pseudoinvasion or invasive carcinoma)

Ancillary studies ─

─ IHC:
─ Ki-67 shows increased proliferation, typically in the basal and mid-zones of the crypts, extending higher with increasing dysplasia
─ p53 may show overexpression (strong, diffuse nuclear staining) in areas of high-grade dysplasia or developing carcinoma, but is often wild-type pattern in low-grade dysplasia
─ APC immunohistochemistry is not routinely used for diagnosis but loss can be seen
─ Molecular ─ ─ Central to the chromosomal instability (CIN) pathway
─ APC gene mutations are common early events
─ KRAS mutations can occur, often in larger or more advanced adenomas
─ TP53 mutations are typically later events, associated with progression to high-grade dysplasia and carcinoma
─ Microsatellite instability (MSI) is uncommon in conventional tubular adenomas unless associated with Lynch syndrome

DDx ─

─ Hyperplastic polyp (serrated architecture in upper crypts, no significant dysplasia, bland nuclei, preserved goblet cells)
─ Sessile serrated lesion/polyp (SSL/P) (characteristic basal crypt dilation/branching, L- or T-shaped crypts, horizontal growth along muscularis mucosae; may or may not have cytologic dysplasia)
─ Traditional serrated adenoma (TSA) (complex villiform or filiform architecture, ectopic crypts, eosinophilic cytoplasm, pencillate nuclei)
─ Villous or Tubulovillous adenoma (defined by the proportion of villous architecture: >75% for villous, 25-75% for tubulovillous)
─ Inflammatory polyp (prominent inflammation, regenerative epithelial changes, granulation tissue; lacks true dysplasia)
─ Hamartomatous polyp (e.g., Juvenile polyp, Peutz-Jeghers polyp – characteristic stromal or smooth muscle components)

Prognosis ─ ─ Benign lesion, but is a precursor to adenocarcinoma
─ Risk of progression to cancer depends on size, histologic type (villous component increases risk), and grade of dysplasia (high-grade dysplasia has higher risk)
─ Complete endoscopic removal (polypectomy) is usually curative and prevents progression
─ Surveillance colonoscopy intervals are determined by the number, size, and histology of adenomas removed

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Tubulovillous Adenoma (Colorectal)

A benign neoplastic polyp of the colorectal mucosa characterized by a mixed glandular (tubular) and finger-like (villous) architecture, with each component comprising between 25% and 75% of the lesion; it is a precursor to colorectal adenocarcinoma

Clinical ─ ─ Represents an intermediate category between tubular and villous adenomas in terms of frequency and malignant potential
─ Prevalence and risk factors are similar to other adenomatous polyps (increasing age, family history, lifestyle factors)
─ Often asymptomatic and detected during screening colonoscopy
─ Larger lesions may cause symptoms like rectal bleeding, changes in bowel habits, or mucus discharge

Macro ─ ─ Can be pedunculated or sessile
─ Size is variable, often intermediate between typical tubular and villous adenomas (can range from small to large)
─ Surface may appear more lobulated or frond-like than a pure tubular adenoma, but less uniformly shaggy than a pure villous adenoma

Micro ─

─ Defined by a mixture of tubular glands and villous projections (finger-like or leaf-like extensions of lamina propria covered by dysplastic epithelium)
─ Villous component must constitute 25-75% of the adenoma; if <25% villous, it's a tubular adenoma; if >75% villous, it's a villous adenoma
─ Both tubular and villous components are lined by dysplastic columnar epithelium, similar to that seen in pure tubular or villous adenomas
─ Dysplasia is graded as low-grade or high-grade based on the most atypical area:
─ Low-grade dysplasia (LGD): Crowded, pseudostratified, hyperchromatic, elongated nuclei, generally maintained polarity, reduced goblet cells
─ High-grade dysplasia (HGD): More severe cytologic atypia, loss of polarity, nuclear pleomorphism, prominent nucleoli, increased and atypical mitoses, complex architecture (e.g., cribriforming, back-to-back glands). Intramucosal carcinoma is included in HGD.
─ The stroma of the villous projections consists of lamina propria

Ancillary studies ─

─ IHC:
─ Ki-67 shows increased proliferation in dysplastic epithelium
─ p53 may show overexpression in areas of high-grade dysplasia or carcinoma
─ Molecular ─ ─ Part of the conventional adenoma-carcinoma (CIN) pathway
─ APC mutations are common early events
─ KRAS mutations can occur, frequency may be intermediate between tubular and villous adenomas
─ TP53 mutations are associated with progression to HGD and carcinoma

DDx ─

─ Tubular adenoma (<25% villous component)
─ Villous adenoma (>75% villous component)
─ Traditional serrated adenoma (TSA) (has serrated cytology, eosinophilic cytoplasm, ectopic crypts, characteristic slit-like serrations; can have villous architecture but cytology differs)
─ Hyperplastic polyp (no dysplasia, characteristic serrated pattern in upper crypts)
─ Inflammatory polyp with reactive atypia (background inflammation, regenerative changes rather than true dysplasia)

Prognosis ─ ─ Benign lesion, but carries a higher risk of progression to adenocarcinoma compared to pure tubular adenomas, and a lower risk compared to pure villous adenomas (risk is generally correlated with the amount of villous component and size)
─ Risk of malignancy increases with size and grade of dysplasia
─ Complete endoscopic removal is usually curative
─ Surveillance colonoscopy is required, with intervals based on size, number, and histology of polyps

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Villous Adenoma (Colorectal)

A benign neoplastic polyp of the colorectal mucosa characterized by predominantly (>75%) finger-like or frond-like (villous) projections of dysplastic epithelium; it has the highest malignant potential among conventional adenomas

Clinical ─ ─ Less common than tubular adenomas, but more likely to harbor high-grade dysplasia or invasive carcinoma
─ More frequently found in the rectum and sigmoid colon, but can occur throughout the colorectum
─ Often larger than tubular adenomas at diagnosis
─ More likely to be symptomatic: rectal bleeding, mucus discharge (can be profuse, leading to electrolyte imbalance like hypokalemia in rare cases of very large rectal lesions - McKittrick-Wheelock syndrome), diarrhea, or tenesmus
─ Risk factors are similar to other adenomas

Macro ─ ─ Typically sessile (broad-based) and can be large, sometimes carpeting a significant area of the mucosa
─ Surface has a characteristic velvety, shaggy, or cauliflower-like appearance due to the numerous villous projections
─ Often friable

Micro ─

─ Composed predominantly (>75%) of slender, finger-like or broad, leaf-like villi lined by dysplastic columnar epithelium
─ Each villus has a core of lamina propria containing blood vessels
─ Epithelial cells show dysplastic features similar to those in tubular adenomas, ranging from low-grade to high-grade:
─ Low-grade dysplasia (LGD): Elongated, hyperchromatic, pseudostratified nuclei, reduced mucin
─ High-grade dysplasia (HGD): Marked nuclear atypia, pleomorphism, loss of polarity, complex architecture (cribriforming, intraglandular bridging), increased and atypical mitoses. Intramucosal carcinoma is included in HGD.
─ High-grade dysplasia and invasive carcinoma are more frequently found in villous adenomas compared to tubular adenomas

Ancillary studies ─

─ IHC:
─ Ki-67 shows increased proliferation
─ p53 overexpression is common in areas of HGD and carcinoma
─ Molecular ─ ─ Part of the conventional adenoma-carcinoma (CIN) pathway
─ APC mutations are common
─ KRAS mutations are more frequent than in tubular adenomas
─ TP53 mutations are strongly associated with progression to HGD and carcinoma

DDx ─

─ Tubulovillous adenoma (villous component 25-75%)
─ Tubular adenoma (villous component <25%)
─ Traditional serrated adenoma (TSA) (can have villous architecture but distinct serrated cytology, eosinophilic cells, ectopic crypts)
─ Filiform polyposis / Inflammatory filiform polyps (seen in IBD, non-neoplastic, composed of granulation tissue cores covered by regenerating mucosa, lack true dysplasia)
─ Prolapse-induced mucosal changes (e.g., inflammatory cloacagenic polyp – can have villous hyperplasia but lacks true adenomatous dysplasia, has characteristic fibromuscular proliferation in lamina propria)

Prognosis ─ ─ Benign, but has the highest malignant potential among conventional adenomatous polyps (risk of carcinoma is significantly higher than in tubular adenomas, especially for large lesions)
─ Risk of synchronous or metachronous advanced neoplasia is higher
─ Complete removal is essential; large sessile lesions may require piecemeal endoscopic resection or surgical resection
─ Close surveillance is necessary due to increased risk

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Hyperplastic Polyp (Colorectal)

A common, generally benign, non-neoplastic polyp of the colorectal mucosa characterized by a serrated (sawtooth) glandular architecture, predominantly in the upper half of the crypts, without significant cytologic dysplasia

Clinical ─ ─ Very common, often found incidentally during colonoscopy
─ Typically small (<5 mm) and multiple polyps can be present
─ Most frequently located in the distal colon and rectum (left-sided)
─ Generally considered to have no or very low malignant potential, especially the left-sided, small ones
─ However, some right-sided hyperplastic-appearing polyps, particularly larger ones, may represent sessile serrated lesions/polyps (SSL/Ps), which do have malignant potential

Macro ─ ─ Usually small (often <5 mm), sessile, pale, and flat or slightly raised nodules
─ Surface may appear smooth or slightly mucoid
─ Difficult to distinguish from small adenomas or SSL/Ps by endoscopy alone, though advanced imaging techniques (e.g., NBI) can help

Micro ─

─ Characterized by elongated crypts with a serrated or stellate (star-shaped) luminal outline, primarily in the upper half to two-thirds of the crypts
─ Epithelial cells are typically mature goblet cells and absorptive cells with small, basally located, regular nuclei; no significant cytologic dysplasia
─ Proliferative zone is confined to the crypt bases, and there is normal epithelial maturation towards the surface
─ Crypt architecture is generally straight and parallel, without basal dilation or branching (features that would suggest SSL/P)
─ Lamina propria may be slightly edematous but is otherwise unremarkable
─ Two main subtypes are recognized based on mucin content and cell type (though clinical significance of subtyping is limited for typical small HPs):
─ Microvesicular hyperplastic polyp (MVHP):
─ More common type
─ Epithelium shows cells with eosinophilic cytoplasm containing fine, microvesicular mucin droplets, often with tufting at the luminal surface
─ Goblet cells are interspersed
─ Serrations are often more prominent
─ Some consider MVHP a potential very early precursor in the serrated pathway (especially if BRAF mutated)
─ Goblet cell-rich hyperplastic polyp (GCHRHP):
─ Crypts are lined predominantly by mature goblet cells with minimal intervening absorptive cells
─ Serrations may be less pronounced or appear as simple infoldings
─ Less commonly associated with BRAF mutations; may have KRAS mutations if any molecular alteration

Ancillary studies ─

─ IHC:
─ Ki-67 shows a normal proliferative pattern confined to the crypt bases (helps distinguish from adenomas where proliferation extends upwards, and SSL/Ps where it can be irregular or extend higher)
─ p53 is wild-type (no overexpression)
─ Molecular ─ ─ Most sporadic distal HPs are not associated with significant molecular alterations or have KRAS mutations (especially GCHRHPs)
─ Some HPs, particularly MVHPs and those in the proximal colon, may harbor BRAF V600E mutations, similar to SSL/Ps. This overlap makes the distinction between a BRAF-mutated HP and an early/small SSL/P challenging and an area of ongoing research.
─ Generally lack APC mutations and are microsatellite stable (MSS)

DDx ─

─ Sessile serrated lesion/polyp (SSL/P) (key differentiating features: distorted crypt architecture including basal dilation, horizontal basal crypts [L-shaped, T-shaped], serration extending to crypt base, asymmetric proliferation; often right-sided and larger; BRAF mutated)
─ Traditional serrated adenoma (TSA) (complex villiform architecture, ectopic crypts, tall columnar cells with eosinophilic cytoplasm, pencillate nuclei, slit-like serrations; often KRAS or BRAF mutated)
─ Tubular adenoma (shows cytologic dysplasia, loss of goblet cells, nuclear hyperchromasia and stratification; lacks prominent serration of HP)
─ Inflammatory polyp (shows significant inflammation, granulation tissue, reactive epithelial changes which can mimic serration, but lacks the typical HP architecture and has an obvious inflammatory cause)

Prognosis ─ ─ Excellent; generally considered non-neoplastic with no or extremely low malignant potential for typical small, left-sided HPs
─ Removal is often performed to definitively exclude adenoma or SSL/P, especially for polyps >5mm or those with atypical endoscopic features
─ Hyperplastic polyposis syndrome (multiple, large, and/or proximally located HPs) is a rare condition with an increased risk of colorectal cancer, likely through associated SSL/Ps or other mechanisms

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Sessile Serrated Lesion/Polyp (SSL/P), with or without dysplasia

A premalignant colorectal polyp characterized by abnormal crypt architecture with serration extending to the crypt base, crypt dilation, and horizontal growth along the muscularis mucosae; it is a key precursor in the serrated pathway to colorectal cancer

Clinical ─ ─ More common in the proximal (right) colon
─ Often detected during screening colonoscopy; may be more common in older individuals and females
─ Endoscopically, they can be subtle: flat or slightly elevated, pale, often covered by a mucus cap, with indistinct borders, making them harder to detect than conventional adenomas
─ Most are asymptomatic
─ Serrated polyposis syndrome is a condition characterized by multiple and/or large serrated polyps (including SSL/Ps) and an increased risk of colorectal cancer

Macro ─ ─ Typically sessile (flat or broad-based)
─ Size varies, can be small (<5 mm) to large (>1 cm)
─ Often pale with a glistening surface due to adherent mucus
─ Edges may be poorly defined

Micro ─

─ Diagnostic architectural features (at least one unequivocal abnormal crypt is needed for diagnosis according to WHO 2019):
─ Serration extending to the crypt base (sawtooth appearance involves the entire crypt length, not just the surface)
─ Crypt base dilation (crypts are widened or splayed at the bottom)
─ Horizontal growth of crypt bases along the muscularis mucosae (forming L-shaped, T-shaped, or boot-shaped crypts)
─ Branching crypts
─ Asymmetric proliferation (proliferative zone may be expanded or irregular, not confined to crypt base as in hyperplastic polyps)
─ Mature goblet cells at the crypt base (paradoxical maturation)
─ Cytologic features are often bland in SSL/P without dysplasia, with cells resembling those of hyperplastic polyps (abundant pale eosinophilic or microvesicular cytoplasm, small basal nuclei)
─ SSL/P with dysplasia: ─ Develops within a pre-existing SSL/P
─ Characterized by the presence of conventional adenomatous dysplasia (intestinal-type dysplasia):
─ Nuclear atypia (enlargement, hyperchromasia, stratification, pleomorphism, loss of polarity)
─ Reduced mucin, increased N/C ratio
─ Can be low-grade or high-grade dysplasia
─ Rarely, can show serrated-type dysplasia (more eosinophilic cytoplasm, pencillate nuclei, but with more pronounced atypia than typical TSA cells)

Ancillary studies ─

─ IHC:
─ Ki-67: Shows an expanded and often irregular proliferation zone, not confined to the crypt base (unlike typical hyperplastic polyps); may show asymmetric proliferation
─ MLH1: Loss of MLH1 expression (by IHC) can be seen in SSL/Ps with dysplasia, particularly if progressing towards MSI-H carcinoma (often due to MLH1 promoter hypermethylation)
─ Annexin A10: Can be positive, supporting serrated lineage, but not specific to SSL/P vs. other serrated lesions
─ Molecular ─ ─ BRAF V600E mutation is very common (hallmark lesion of the BRAF-mutated serrated pathway)
─ CpG Island Methylator Phenotype (CIMP-high) is characteristic
─ Often associated with subsequent microsatellite instability (MSI-H) if MLH1 promoter becomes hypermethylated, particularly when dysplasia develops
─ KRAS mutations are uncommon (more typical of traditional serrated adenomas or some hyperplastic polyps)
─ TP53 mutations are generally late events, seen with progression to high-grade dysplasia or carcinoma

DDx ─

─ Hyperplastic polyp (HP) (especially microvesicular HP): Serration typically limited to upper crypts, crypt bases are narrow and straight, proliferative zone confined to base, lacks significant architectural distortion at crypt bases. Small SSL/Ps can be difficult to distinguish from BRAF-mutated HPs.
─ Traditional serrated adenoma (TSA) (villiform architecture, slit-like serrations, tall columnar cells with intensely eosinophilic cytoplasm, pencillate nuclei, ectopic crypt formation)
─ Conventional adenoma (tubular, villous, or tubulovillous) (shows conventional intestinal-type dysplasia throughout, lacks the characteristic architectural distortions of SSL/P at crypt bases)
─ Inflammatory polyp or prolapse-related changes (can show reactive serration and architectural distortion, but usually accompanied by significant inflammation, granulation tissue, or fibromuscular hyperplasia of lamina propria; lacks the specific crypt base changes of SSL/P and BRAF mutation)

Prognosis ─ ─ Premalignant lesion with a recognized risk of progression to colorectal adenocarcinoma, particularly if large, located in the proximal colon, or associated with dysplasia
─ Progression to cancer is thought to occur via the serrated pathway, often leading to MSI-H, BRAF-mutated carcinomas
─ Complete endoscopic removal is recommended
─ Surveillance intervals depend on size, number, and presence/grade of dysplasia, and whether the patient has serrated polyposis syndrome

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Traditional Serrated Adenoma (TSA)

A type of serrated colorectal polyp characterized by a complex villiform or filiform architecture, slit-like serrations, tall columnar cells with eosinophilic cytoplasm, and pencillate (elongated, hyperchromatic) nuclei; it is a precursor to colorectal cancer, often through a KRAS-mutated pathway

Clinical ─ ─ Less common than SSL/Ps or hyperplastic polyps
─ Tend to occur in the distal colon (left side), including the sigmoid colon and rectum, though can be found proximally
─ Often detected in older individuals
─ May be asymptomatic or cause symptoms similar to other polyps (e.g., bleeding)

Macro ─ ─ Typically pedunculated or sessile with a protuberant, exophytic, or "pinecone-like" appearance
─ Can be reddish or tan
─ Size varies, can be small to large

Micro ─

─ Complex, often villous or filiform (papillary) architecture with branching fronds
─ Characteristic "slit-like" serrations, which are narrow and perpendicular to the crypt axis
─ Lined by tall columnar cells with abundant, intensely eosinophilic (oncocytic) cytoplasm
─ Nuclei are typically elongated, hyperchromatic, and pseudostratified ("pencillate" or "cigar-shaped"), often located in the mid-zone of the cell rather than strictly basal
─ Ectopic crypt formation (ECF): Small, disorganized crypts that do not orient towards the muscularis mucosae, often found within the fronds or at the base of the lesion. This is a key diagnostic feature.
─ Cytologic dysplasia is considered inherent to the lesion, but can also develop conventional adenomatous dysplasia (low or high grade) superimposed on the TSA background
─ Increased intraepithelial lymphocytes may be present
─ May arise from a pre-existing goblet cell-rich hyperplastic polyp in some cases

Ancillary studies ─

─ IHC:
─ Ki-67: Proliferation often seen in the ectopic crypts and can be more diffuse than in hyperplastic polyps
─ CK20: Often stains the surface epithelium, while ectopic crypts may be negative or show altered staining
─ MUC5AC (gastric-type mucin) and MUC6 can be expressed
─ Annexin A10 may be positive
─ Molecular ─ ─ Frequently associated with KRAS mutations (more common than BRAF mutations in TSA, contrasting with SSL/Ps)
─ BRAF V600E mutations can also occur, but less commonly than in SSL/Ps. Some TSAs may arise from BRAF-mutated SSL/Ps.
─ Often CIMP-low or CIMP-negative (especially KRAS-mutated TSAs)
─ Typically microsatellite stable (MSS), particularly KRAS-mutated TSAs
─ WNT pathway alterations (e.g., RNF43 mutations, RSPO fusions) can be seen, especially in KRAS-mutated TSAs

DDx ─

─ Villous or Tubulovillous adenoma (conventional intestinal-type dysplasia, lacks eosinophilic cytoplasm, pencillate nuclei, slit-like serrations, and ectopic crypts of TSA; villi have fibrovascular cores lined by typical adenomatous cells)
─ Sessile serrated lesion/polyp (SSL/P) (different architectural features at crypt base – dilation, horizontal growth; typically BRAF mutated; bland cytology unless dysplastic)
─ Hyperplastic polyp (especially goblet cell-rich HP, which can be a precursor): Lacks the complex architecture, prominent eosinophilic cytoplasm, pencillate nuclei, and ectopic crypts of TSA; dysplasia is absent
─ Filiform polyps (seen in IBD; non-neoplastic, slender stalks of lamina propria covered by regenerating epithelium)

Prognosis ─ ─ Premalignant lesion with a risk of progression to colorectal adenocarcinoma
─ The risk is likely related to size and the presence and grade of any superimposed conventional dysplasia
─ Complete endoscopic removal is recommended
─ Surveillance is similar to that for conventional adenomas, based on size, number, and histology

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Anal Canal

Anal Anatomy

Feature	Description
Structure	Terminal part of GI tract (~3-4 cm), from anorectal ring (puborectalis sling) to the anal verge.
Musculature	Internal sphincter: Thickening of inner circular smooth muscle (involuntary). External sphincter: Striated muscle (voluntary).
Landmarks	Dentate (Pectinate) Line: Junction of endodermal hindgut and ectodermal proctodeum. Anal Columns (of Morgagni): Longitudinal mucosal folds superior to the dentate line. Anal Verge: Junction with perianal skin.
Lymphatics	Above dentate line: Drains to perirectal and internal iliac nodes. Below dentate line: Drains to superficial inguinal nodes.

Anal Histology

Zone	Epithelium & Features
Colorectal Zone (Upper)	Simple columnar rectal-type mucosa.
Anal Transitional Zone (ATZ)	0.5-1.0 cm zone proximal to the dentate line. Lined by transitional epithelium (resembles urothelium, 4-9 layers thick). May have squamous or columnar patches. Site of origin for basaloid carcinomas.
Squamous Zone (Lower)	From dentate line to anal verge. Lined by non-keratinized stratified squamous epithelium. Lacks skin appendages. Contains melanocytes.
Perianal Skin	Begins at the anal verge. Keratinized stratified squamous epithelium with hair follicles and glands.
Anal Glands	Submucosal glands draining at the dentate line. Lined by transitional, pseudostratified, or columnar epithelium.

Lower Anogenital Squamous Tract (LAST) Lesions / Squamous Intraepithelial Lesions (SIL)

Low-Grade Squamous Intraepithelial Lesion (LSIL / AIN 1 / Condyloma) (Anal)

A low-grade intraepithelial lesion of the anal squamous mucosa characterized by cytopathic effects of Human Papillomavirus (HPV) infection, with dysplastic changes confined to the lower third of the epithelium

Clinical ─ ─ Caused by HPV infection, most commonly low-risk HPV types (e.g., HPV 6, 11) for classic condyloma acuminatum, but can also be associated with high-risk HPV types
─ Often asymptomatic, but may present with perianal or anal itching, irritation, bleeding, or palpable warts (condylomata)
─ Risk factors include multiple sexual partners, receptive anal intercourse, immunosuppression (e.g., HIV infection), smoking
─ Considered a manifestation of productive HPV infection with a low risk of progression to invasive squamous cell carcinoma if it is truly only LSIL without a concurrent HSIL component
─ Site: Anal canal (squamous mucosa, anal transition zone) and/or perianal skin

Macro ─ ─ Lesions can be exophytic (wart-like, condyloma acuminatum), flat, or papular
─ Condylomata acuminata are typically soft, pink to grey, verrucous or cauliflower-like growths
─ Flat lesions may be subtle and require high-resolution anoscopy for visualization
─ Can be solitary or multiple, and may coalesce

Micro ─

─ Squamous epithelial proliferation with acanthosis (thickening of stratum spinosum), papillomatosis (undulating surface with finger-like projections), and often parakeratosis or hyperkeratosis
─ Koilocytosis is the hallmark cytopathic effect of HPV:
─ Squamous cells (koilocytes) with enlarged, irregular, hyperchromatic (raisinoid) nuclei, often multinucleated
─ Prominent perinuclear cytoplasmic clearing (halo)
─ Dysplastic changes are confined to the lower one-third of the epithelial thickness (AIN 1 equivalent)
─ Mild nuclear atypia (enlargement, hyperchromasia, irregular contours)
─ Increased nuclear-to-cytoplasmic ratio in basal/parabasal layers
─ Orderly maturation towards the surface is generally maintained, though koilocytes are typically in upper layers
─ Mitotic figures, if present, are usually confined to the basal layer and are not atypical
─ Underlying stroma often shows chronic inflammation and dilated capillaries in fibrovascular cores of papillae

Ancillary studies ─

─ IHC (p16INK4a):
─ Typically negative or shows only patchy, weak, non-block positivity. Diffuse, strong block positivity for p16 would be more suggestive of HSIL or a lesion associated with high-risk HPV.
─ Use of p16 in LSIL is generally not recommended by LAST guidelines unless there is diagnostic uncertainty with HSIL
─ IHC (Ki-67): Proliferation generally confined to the basal/parabasal layers, may extend slightly higher but not full thickness like in HSIL
─ Molecular: HPV DNA testing (e.g., in situ hybridization or PCR) can detect HPV; low-risk types (6, 11) are common in condylomata, but high-risk types can also be present in LSIL

DDx ─

─ High-Grade Squamous Intraepithelial Lesion (HSIL/AIN 2-3) (dysplasia extends to middle/upper thirds or full thickness of epithelium, more marked atypia, often strong and diffuse p16 positivity)
─ Reactive squamous atypia (e.g., due to inflammation, trauma – atypia is usually less severe, lacks prominent koilocytosis, p16 negative or patchy)
─ Verrucous carcinoma (a well-differentiated squamous cell carcinoma with bulbous rete ridges and pushing invasion; koilocytosis usually absent or minimal)
─ Squamous cell carcinoma, conventional (invasive nests of atypical squamous cells into stroma)
─ Fibroepithelial polyp (anal skin tag) (fibrovascular core covered by benign squamous epithelium, may be acanthotic but lacks dysplasia and koilocytosis)
─ Psoriasis or lichen planus (specific inflammatory patterns, no true dysplasia or koilocytosis)

Prognosis ─ ─ Generally considered benign with a low risk of progression to invasive cancer for isolated LSIL, especially condylomatous lesions caused by low-risk HPV types
─ Many lesions regress spontaneously, particularly in immunocompetent individuals
─ However, LSIL can persist, recur after treatment, or coexist with or progress to HSIL, especially if associated with high-risk HPV types or in immunosuppressed individuals
─ Management often involves treatment of symptomatic lesions (e.g., topical agents, cryotherapy, excision) and surveillance, especially in high-risk populations

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High-Grade Squamous Intraepithelial Lesion (HSIL / AIN 2-3) (Anal)

A high-grade intraepithelial lesion of the anal squamous mucosa characterized by dysplastic changes involving more than the lower third of the epithelial thickness, representing a direct precursor to invasive anal squamous cell carcinoma

Clinical ─ ─ Caused by persistent infection with high-risk HPV types (especially HPV-16, also HPV-18 and others)
─ Often asymptomatic and detected by screening (e.g., anal cytology, high-resolution anoscopy) in high-risk populations
─ Symptoms, if present, can include anal or perianal itching, pain, bleeding, discharge, or palpable lesions
─ Risk factors are similar to LSIL but with a stronger association with high-risk HPV and immunosuppression (especially HIV infection, organ transplant recipients)
─ Higher risk of progression to invasive squamous cell carcinoma compared to LSIL
─ Site: Anal canal (squamous mucosa, anal transition zone) and/or perianal skin

Macro ─ ─ Lesions can be macular (flat), papular (raised), or slightly thickened plaques
─ May appear white (acetowhite change with acetic acid application during anoscopy), erythematous, or pigmented
─ Often less conspicuous than exophytic condylomata; high-resolution anoscopy is key for detection
─ Can be unifocal or multifocal

Micro ─

─ Dysplastic changes involve the squamous epithelium to a significant degree:
─ AIN 2 (Moderate dysplasia / HSIL component): Dysplastic cells occupy the lower two-thirds of the epithelial thickness. Abnormal maturation in the upper third.
─ AIN 3 (Severe dysplasia / Carcinoma in situ / HSIL component): Dysplastic cells occupy more than two-thirds to the full thickness of the epithelium. Marked loss of maturation.
─ Cytologic features of dysplasia:
─ Increased nuclear-to-cytoplasmic ratio
─ Nuclear hyperchromasia, pleomorphism, irregular nuclear contours
─ Loss of cellular polarity and orderly maturation
─ Mitotic figures are present, may be numerous, and can be found in the mid to upper portions of the epithelium; atypical mitoses may be seen
─ Koilocytotic changes may or may not be prominent, especially in higher-grade lesions (HSIL can "overgrow" koilocytes)
─ The basement membrane is intact (by definition, no stromal invasion)

Ancillary studies ─

─ IHC (p16INK4a):
─ Strong and diffuse "block-positive" staining (nuclear and often cytoplasmic) throughout the dysplastic epithelium is characteristic of HSIL and reflects deregulation of the cell cycle by high-risk HPV E7 oncoprotein. This is a very useful marker to support the diagnosis of HSIL, especially in distinguishing it from mimics or LSIL in equivocal cases.
─ IHC (Ki-67): Increased proliferation extending into the upper two-thirds or full thickness of the epithelium
─ Molecular: High-risk HPV types are typically detectable

DDx ─

─ Low-Grade Squamous Intraepithelial Lesion (LSIL/AIN 1) (dysplasia confined to lower third, p16 typically negative or patchy)
─ Invasive squamous cell carcinoma (nests or single cells of atypical squamous epithelium invading beyond the basement membrane into the underlying stroma)
─ Reactive squamous atypia/inflammation (cellular atypia is usually milder, maturation preserved, inflammation prominent, p16 negative or patchy)
─ Immature squamous metaplasia (can show basaloid cells but lacks significant atypia and high p16 expression of HSIL)
─ Bowenoid papulosis (clinically distinct papules, histologically HSIL, often perianal)
─ Paget's disease (intraepithelial adenocarcinoma cells, typically CK7+, GCDFP-15+, p16 usually negative)

Prognosis ─ ─ HSIL is a direct precursor to invasive anal squamous cell carcinoma
─ Risk of progression is significant if left untreated, particularly in immunosuppressed individuals (e.g., HIV-positive individuals have a higher risk of progression and cancer development)
─ Spontaneous regression can occur but is less common than with LSIL
─ Management typically involves treatment (e.g., topical therapies like imiquimod or 5-FU, ablation with electrocautery, infrared coagulation, laser, or surgical excision) and close surveillance with HRA

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Benign Anal Lesions

Inflammatory Cloacogenic Polyp / Solitary Rectal Ulcer Syndrome (SRUS) (Mucosal Prolapse Spectrum)

A benign, reactive lesion of the anorectal region characterized by fibromuscular obliteration of the lamina propria, glandular distortion, and surface ulceration, thought to result from chronic trauma and ischemia due to mucosal prolapse

Clinical ─ ─ Part of the spectrum of mucosal prolapse syndrome
─ Symptoms include rectal bleeding, mucus discharge, straining during defecation, tenesmus, feeling of incomplete evacuation, perineal or abdominal pain; some patients may be asymptomatic
─ Often associated with constipation, paradoxical puborectalis contraction, or excessive straining
─ Can occur at any age, but often in young to middle-aged adults; slight female predominance in some series
─ Site: Typically anterior or anterolateral wall of the lower to mid rectum, usually within 4-10 cm from the anal verge. Inflammatory cloacogenic polyps specifically arise near the dentate line/anal transition zone.

Macro ─ ─ Endoscopic appearance is variable:
─ Solitary or multiple ulcers (SRUS)
─ Polypoid or sessile mass (inflammatory polyp - cloacogenic or cap polyp)
─ Erythematous, hyperemic mucosa, or nodularity
─ Lesions can range from small (<1 cm) to large (>5 cm)
─ Ulcers are often shallow with a white or yellow base
─ Polyps can be friable and bleed easily

Micro ─

─ Key histologic features (mucosal prolapse changes): ─ Fibromuscular obliteration of the lamina propria: Hypertrophied smooth muscle fibers extending upwards from the muscularis mucosae into the lamina propria, often splaying and surrounding crypts
─ Glandular (crypt) abnormalities:
─ Distortion, elongation, branching, and cystic dilation of crypts
─ Reactive epithelial changes: Hyperplastic, regenerative atypia, mucin depletion, increased mitoses (typically basal)
─ Crypts may appear "diamond-shaped" or angulated
─ Glands may be displaced into the submucosa (pseudoinvasion or colitis cystica profunda), but retain a benign appearance and are surrounded by lamina propria elements
─ Surface ulceration is common, with associated granulation tissue and acute/chronic inflammation
─ Thickened muscularis mucosae
─ Capillary congestion and ectasia in the lamina propria
─ Inflammatory Cloacogenic Polyp specific features: Arises at the anal transition zone, so may show overlying squamous or transitional epithelium in addition to glandular mucosa with prolapse changes
─ Inflammatory Cap Polyp specific features: Characterized by a "cap" of fibrinopurulent exudate and granulation tissue on the surface of an inflamed, elongated polyp

Ancillary studies ─

─ IHC: Generally not required for diagnosis. Can be used to exclude dysplasia or malignancy if reactive atypia is prominent (e.g., p53 wild-type, Ki-67 basal proliferation).
─ Special Stains: Trichrome stain can highlight the fibromuscular proliferation in the lamina propria

DDx ─

─ Adenomatous polyp (tubular, villous, or tubulovillous adenoma) (shows true cytologic dysplasia, lacks prominent fibromuscular obliteration of lamina propria)
─ Adenocarcinoma (invasive malignant glands, desmoplasia, significant cytologic atypia; may arise in SRUS but is rare)
─ Inflammatory bowel disease (Crohn's disease, ulcerative colitis) (shows diffuse chronic inflammation, crypt architectural distortion characteristic of IBD, granulomas in Crohn's; prolapse changes can coexist)
─ Ischemic colitis (can show ulceration and regenerative changes, but typically has hyalinization of lamina propria, withered crypts, hemosiderin deposition)
─ Radiation proctitis (vascular ectasia, stromal hyalinization, atypical fibroblasts, epithelial atypia)
─ Infectious proctitis (specific pathogens may be identified; acute inflammation often prominent)

Prognosis ─ ─ Benign condition, but symptoms can be chronic and recurrent, significantly impacting quality of life
─ Malignant transformation is rare but has been reported, usually in long-standing cases
─ Management focuses on conservative measures: dietary fiber, stool softeners, biofeedback therapy to correct defecatory disorders
─ Topical treatments (e.g., sucralfate, steroids) may provide symptomatic relief
─ Endoscopic or surgical intervention may be needed for persistent, symptomatic, or large lesions, or for complications like severe bleeding or prolapse

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Fibroepithelial Polyp (Anal Skin Tag)

A common, benign, exophytic lesion of the anal or perianal skin, composed of a fibrovascular core covered by squamous epithelium; often referred to as an anal skin tag or hypertrophied anal papilla

Clinical ─ ─ Very common; often asymptomatic and found incidentally
─ Can cause symptoms such as itching (pruritus ani), irritation, discomfort, or difficulty with hygiene
─ May be associated with chronic irritation, previous anal conditions (e.g., hemorrhoids, anal fissures), or trauma during defecation
─ Can occur at any age, equally in males and females
─ Site: Typically arise from the anal verge, perianal skin, or at the dentate line (hypertrophied anal papillae are specifically from the dentate line)

Macro ─ ─ Soft, fleshy, skin-colored or slightly pigmented, pedunculated or sessile polypoid growths
─ Size varies from a few millimeters to several centimeters
─ Surface can be smooth or slightly wrinkled/keratotic
─ Multiple tags can be present

Micro ─

─ Core of loose to dense fibrovascular connective tissue (fibrous stroma with scattered blood vessels)
─ Overlying squamous epithelium, which may be:
─ Acanthotic (thickened stratum spinosum)
─ Hyperkeratotic (thickened stratum corneum)
─ Parakeratotic (retention of nuclei in stratum corneum)
─ No significant cytologic atypia or dysplasia in the squamous epithelium
─ Chronic inflammatory infiltrate (lymphocytes, plasma cells) may be present in the stroma, especially if irritated
─ Dilated lymphatic vessels or small nerves may be seen in the core
─ No glandular elements, unless it's a hypertrophied anal papilla near the dentate line which might incorporate anal glands at its base
─ Remnants of thrombosed hemorrhoidal vessels are usually absent (distinguishing from resolved hemorrhoid)

Ancillary studies ─

─ Generally not required for diagnosis as histology is characteristic
─ IHC: Squamous epithelium positive for cytokeratins (e.g., CK5/6, p63 in basal layers). CD34 may highlight stromal cells and vessels. S100 may highlight nerves.

DDx ─

─ Condyloma acuminatum (anal wart) (shows HPV-related cytopathic effects: koilocytosis, papillomatosis; may show LSIL)
─ Squamous papilloma (benign HPV-related lesion, more prominent papillomatosis and koilocytosis than a simple tag)
─ Anal intraepithelial neoplasia (LSIL or HSIL) (shows dysplastic changes in the squamous epithelium, koilocytosis in LSIL, p16 positivity in HSIL)
─ Invasive squamous cell carcinoma (malignant squamous cells invading stroma)
─ Hemorrhoid (external or thrombosed) (contains dilated, thick-walled veins; thrombus may be present)
─ Melanocytic nevus or melanoma (composed of melanocytes; S100, Melan-A, HMB45 positive)
─ Neurofibroma (spindle cell proliferation, S100 positive)
─ Granulation tissue polyp (if chronically irritated/ulcerated)

Prognosis ─ ─ Entirely benign with no malignant potential
─ May persist or recur if incompletely removed or if underlying irritation continues
─ Treatment (e.g., simple excision) is usually for symptomatic relief or cosmetic reasons

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Anal Condyloma Acuminatum

A benign exophytic lesion of the anogenital region caused by Human Papillomavirus (HPV) infection, primarily low-risk types (HPV 6 and 11), characterized by koilocytic atypia and papillomatosis

Clinical ─ ─ Caused by HPV, most commonly types 6 and 11
─ Presents as single or multiple, soft, fleshy, cauliflower-like, verrucous, or papular growths in the perianal area or anal canal
─ Symptoms can include itching, irritation, bleeding, discharge, or the sensation of a lump
─ Highly contagious and transmitted through sexual contact or skin-to-skin contact
─ Risk factors include multiple sexual partners, anal intercourse, and immunosuppression (e.g., HIV)
─ Site: Perianal skin, anal canal up to the dentate line; can extend into the lower rectum

Macro ─ ─ Variable appearance:
─ Exophytic, papillary, verrucous, or cauliflower-like masses
─ Can be sessile (flat-based) or pedunculated
─ Color can be pink, grey, tan, or skin-colored
─ Size ranges from millimeters to large confluent masses

Micro ─

─ Squamous epithelial proliferation with characteristic features:
─ Papillomatosis: Finger-like projections of squamous epithelium with fibrovascular cores
─ Acanthosis: Thickening of the stratum spinosum
─ Hyperkeratosis and/or parakeratosis are common
─ Koilocytosis is the hallmark of HPV infection:
─ Squamous cells (koilocytes), typically in the upper epithelial layers, with enlarged, irregular, hyperchromatic (raisinoid) nuclei
─ Prominent perinuclear cytoplasmic clearing (halo)
─ Binucleation or multinucleation of koilocytes is common
─ Dysplastic changes, if present, are typically low-grade (LSIL/AIN 1), confined to the lower third of the epithelium, characterized by mild nuclear atypia and increased N/C ratio in basal/parabasal cells
─ Mitotic activity is usually confined to the basal layers
─ Stroma within papillae is fibrovascular and may contain a chronic inflammatory infiltrate

Ancillary studies ─

─ IHC (p16INK4a):
─ Usually negative or shows only patchy, non-block positivity. Strong, diffuse block staining for p16 would raise concern for HSIL or high-risk HPV infection.
─ Molecular: HPV DNA testing can confirm HPV infection and identify types (low-risk types 6 and 11 are classic for condyloma, but co-infection with high-risk types can occur)

DDx ─

─ Low-Grade Squamous Intraepithelial Lesion (LSIL/AIN 1) (Condyloma is a form of LSIL; the terms are often used interchangeably when koilocytosis and low-grade dysplasia are present)
─ High-Grade Squamous Intraepithelial Lesion (HSIL/AIN 2-3) (more severe dysplasia extending higher in the epithelium, often p16 block positive)
─ Verrucous carcinoma (a well-differentiated squamous cell carcinoma with bulbous rete ridges and pushing invasion; koilocytosis is usually minimal or absent)
─ Squamous cell carcinoma, conventional (invasive malignant squamous cells)
─ Fibroepithelial polyp (anal skin tag) (lacks koilocytosis and significant papillomatosis; primarily fibrovascular core with overlying benign squamous epithelium)
─ Seborrheic keratosis (can occur perianally, has horn cysts and pseudo-horn cysts, lacks koilocytosis)
─ Condyloma lata (lesion of secondary syphilis; flatter, broader, often moist, contains numerous plasma cells and spirochetes demonstrable with special stains)

Prognosis ─ ─ Benign lesion with a very low risk of malignant transformation when caused by low-risk HPV types
─ Can be persistent and recurrent, especially in immunosuppressed individuals
─ Treatment is aimed at lesion removal (topical agents, cryotherapy, electrocautery, surgical excision) and symptom relief
─ Important to evaluate for other STIs and to screen for HSIL in high-risk individuals, as condylomata indicate HPV exposure

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Paget’s Disease (Anal, Extramammary)

A rare intraepithelial adenocarcinoma characterized by the presence of malignant glandular cells (Paget cells) within the squamous epithelium of the perianal skin or anal canal; it can be primary (arising from epidermal apocrine glands or pluripotent stem cells) or secondary (due to upward spread from an underlying anorectal adenocarcinoma)

Clinical ─ ─ Typically affects older individuals (usually >50-60 years)
─ Presents as an erythematous, eczematous, scaly, or crusted plaque in the perianal region, often with itching, burning, pain, or bleeding
─ Lesions can be mistaken for benign dermatoses (e.g., eczema, psoriasis, fungal infection), leading to diagnostic delay
─ Site: Perianal skin, may extend into the anal canal
─ Primary Anal Paget's Disease: Arises as an intraepidermal adenocarcinoma, possibly from apocrine gland ducts or epidermal stem cells. May be associated with an underlying invasive Paget's disease (invasive apocrine adenocarcinoma).
─ Secondary Anal Paget's Disease: Represents epidermotropic spread of an underlying internal malignancy, most commonly a colorectal (rectal or anal canal) adenocarcinoma. This is more common than primary invasive Paget's when invasion is present.

Macro ─ ─ Well-demarcated, erythematous, eczematous, or ulcerated plaque-like lesion
─ Surface may be scaly, crusted, weeping, or lichenified
─ May show areas of hypopigmentation or hyperpigmentation
─ Induration or nodularity may suggest underlying invasive disease

Micro ─

─ Characteristic Paget cells are present within the epidermis and sometimes extend into adnexal structures (hair follicles, sweat glands)
─ Paget cells:
─ Large, rounded or polygonal cells with abundant pale, vacuolated, or eosinophilic cytoplasm
─ Large, pleomorphic, vesicular nuclei, often with prominent nucleoli; nuclei are typically eccentric
─ May occur singly, in small clusters, or form glandular (acinar) structures within the epidermis
─ Often show a "buckshot" scatter or pagetoid spread (infiltration of malignant cells throughout the epidermis)
─ The underlying dermis usually shows a chronic inflammatory infiltrate
─ In invasive Paget's disease, Paget cells infiltrate into the dermis
─ In secondary Paget's disease, an underlying adenocarcinoma (typically colorectal type) in the submucosa or deeper tissues will be present, with Paget cells in the overlying epidermis representing intraepithelial spread

Ancillary studies ─

─ IHC (Paget cells):
─ Primary Anal Paget's Disease (apocrine phenotype): Typically CK7 (+), GCDFP-15 (+), GATA3 (+), Androgen Receptor (AR) (+/-). CK20 (-), CDX2 (-).
─ Secondary Anal Paget's Disease (from colorectal adenocarcinoma): Typically CK20 (+), CDX2 (+). CK7 (- or focal +), GCDFP-15 (-).
─ MUC stains can be helpful: MUC1 often positive in both; MUC2 more specific for colorectal origin (secondary); MUC5AC can be seen in primary
─ HER2 overexpression/amplification can be seen in a subset of primary Paget's disease
─ Special Stains: PAS-D and Alcian blue can highlight intracytoplasmic mucin in Paget cells

DDx ─

─ Melanoma in situ or invasive melanoma (Paget cells are S100, SOX10, Melan-A, HMB45 negative; melanoma cells are positive for these)
─ Bowen's disease (Squamous cell carcinoma in situ / HSIL of skin) (cells are squamous, p16 positive if HPV-related, lack mucin, CK7/GCDFP-15 negative)
─ Eczematous dermatitis (inflammatory infiltrate, spongiosis, acanthosis, but no Paget cells)
─ Psoriasis (parakeratosis, Munro's microabscesses, acanthosis with elongated rete ridges, no Paget cells)
─ Fungal infection (fungal elements visible with PAS or GMS stain)

Prognosis ─ ─ Primary Intraepidermal Paget's Disease: Generally good prognosis if confined to the epidermis, but local recurrences are common after excision due to often widespread subclinical involvement
─ Primary Invasive Paget's Disease: Carries a risk of lymph node and distant metastasis; prognosis depends on depth of invasion and stage
─ Secondary Anal Paget's Disease: Prognosis is dictated by the underlying internal malignancy (usually colorectal adenocarcinoma) and its stage. The presence of Pagetoid spread often implies an advanced underlying tumor.
─ Thorough investigation for an underlying anorectal or other visceral malignancy is crucial in all cases of anal Paget's disease

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Squamous Cell Carcinoma (Anal)

Squamous Cell Carcinoma (Anal) (Conventional Keratinizing/Non-keratinizing SCC)

An invasive malignant epithelial neoplasm arising from the squamous mucosa of the anal canal or perianal skin, characterized by squamous differentiation

Clinical ─ ─ Most common malignancy of the anal canal and perianal region
─ Associated with high-risk Human Papillomavirus (HPV) infection (especially HPV-16) in the majority of cases (70-90%)
─ Risk factors include HPV infection, history of anal HSIL, immunosuppression (e.g., HIV infection, organ transplant), smoking, chronic anal inflammation, receptive anal intercourse, increasing age, female sex (though incidence is rising in men who have sex with men)
─ Symptoms: Rectal bleeding (most common), anal pain or discomfort, sensation of a mass, anal discharge, pruritus, change in bowel habits, tenesmus, fecal incontinence (if sphincter involved). Some may be asymptomatic initially.
─ Site: Can arise in the anal canal (above, at, or below the dentate line) or perianal skin (anal margin, within 5 cm of anal verge). Tumors of the anal margin may behave more like skin cancers.

Macro ─ ─ Variable appearance:
─ Ulcerated, indurated lesions
─ Exophytic, fungating, or polypoid masses
─ Infiltrative plaques or strictures
─ Size can range from small, localized lesions to large, deeply invasive tumors

Micro ─

─ Invasive nests, cords, or sheets of malignant squamous cells infiltrating the underlying stroma (submucosa, muscularis propria, or deeper tissues)
─ Squamous differentiation is evident by:
─ Presence of intercellular bridges (desmosomes)
─ Keratinization (formation of keratin pearls or individual cell keratinization with dense eosinophilic cytoplasm)
─ Tumor cells exhibit features of malignancy:
─ Nuclear atypia (enlargement, hyperchromasia, pleomorphism, irregular contours)
─ Increased and often atypical mitotic figures
─ Variable nuclear-to-cytoplasmic ratios
─ Subtypes based on differentiation:
─ Keratinizing SCC: Prominent keratin pearl formation and individual cell keratinization. Typically well to moderately differentiated.
─ Non-keratinizing SCC (Large cell non-keratinizing): Minimal or no obvious keratinization by light microscopy. Composed of larger cells with vesicular nuclei and prominent nucleoli, often growing in solid sheets or nests. May resemble transitional cell carcinoma or poorly differentiated carcinoma. (This is the most common type in the anal canal).
─ Stromal response is often desmoplastic, with variable chronic inflammatory infiltrate
─ Lymphovascular and perineural invasion may be present
─ Grading (well, moderately, poorly differentiated) is based on the degree of squamous differentiation, nuclear pleomorphism, and mitotic activity

Ancillary studies ─

─ IHC:
─ Positive for squamous markers: p63, p40, CK5/6, high molecular weight cytokeratins (e.g., 34βE12)
─ p16INK4a: Strong, diffuse block positivity is seen in the majority of anal SCCs, reflecting oncogenic HPV infection. It is a useful surrogate marker for HPV involvement.
─ Ki-67: High proliferation index
─ Molecular:
─ High-risk HPV DNA (especially HPV-16) is detectable in most cases
─ TP53 mutations can occur, particularly in HPV-negative tumors (which are rare)

DDx ─

─ High-Grade Squamous Intraepithelial Lesion (HSIL/AIN 3) (dysplasia confined to epithelium, basement membrane intact, no stromal invasion)
─ Verrucous carcinoma (subtype of well-differentiated SCC with bulbous rete ridges, pushing invasion, minimal atypia)
─ Basaloid squamous cell carcinoma (distinct basaloid morphology, peripheral palisading; also HPV-related and p16 positive)
─ Adenocarcinoma of the anal canal or rectum (glandular differentiation, positive for CK20, CDX2; negative for squamous markers)
─ Melanoma (positive for S100, SOX10, Melan-A/HMB45; negative for p63/p40)
─ Metastatic squamous cell carcinoma (e.g., from cervix, lung – clinical history and imaging important)
─ Inflammatory conditions with pseudoepitheliomatous hyperplasia (reactive epithelial proliferation without true cytologic malignancy or invasion; p16 typically negative or patchy)

Prognosis ─ ─ Prognosis depends on several factors, primarily tumor stage (TNM classification: size/depth of invasion, nodal status, distant metastasis)
─ Other factors: histologic grade, HPV status (HPV-positive tumors may have a better response to chemoradiation and better prognosis), immune status of the patient
─ Treatment for most localized anal canal SCC is chemoradiation (Nigro protocol or similar regimens), with surgery reserved for salvage or very early/small anal margin tumors
─ Overall 5-year survival rates vary significantly by stage, from >80% for early-stage disease to <30% for metastatic disease

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Basaloid Squamous Cell Carcinoma (Anal) (Cloacogenic Carcinoma)

A subtype of anal squamous cell carcinoma characterized by nests and cords of small to medium-sized basaloid cells with peripheral palisading, often arising in the anal transition zone and associated with HPV infection

Clinical ─ ─ Represents a distinct histologic variant of anal SCC, historically termed "cloacogenic carcinoma" due to its presumed origin from cloacogenic remnants
─ Symptoms are similar to conventional anal SCC: rectal bleeding, anal pain, mass sensation, or changes in bowel habits
─ Risk factors are similar to conventional anal SCC, including HPV infection (especially HPV-16), immunosuppression, and smoking
─ Tends to arise in the anal canal, particularly in the anal transition zone

Macro ─ ─ May present as an ulcerated, infiltrative, or exophytic mass in the anal canal
─ Appearance is often indistinguishable from conventional SCC on gross examination

Micro ─

─ Characterized by nests, ribbons, or trabeculae of relatively uniform, small to medium-sized basaloid cells with scant cytoplasm and hyperchromatic nuclei
─ Peripheral palisading of nuclei at the edge of tumor nests is a classic feature
─ Central comedo-like necrosis within tumor nests can be seen
─ May show areas of abrupt keratinization or squamous differentiation (squamous pearls, individual cell keratinization), often focal, helping to confirm its squamous nature
─ Stroma is often desmoplastic
─ Small cystic spaces or glandular differentiation (adenoid basaloid pattern) can occasionally be present
─ High mitotic rate is common
─ Often associated with overlying or adjacent high-grade squamous intraepithelial lesion (HSIL/AIN)

Ancillary studies ─

─ IHC:
─ Positive for squamous markers: p63, p40, CK5/6 (often strong and diffuse)
─ p16INK4a: Strong and diffuse block positivity is characteristic, indicating HPV involvement
─ CEA may be positive
─ BerEP4: Typically negative (helps distinguish from basal cell carcinoma of the skin)
─ Neuroendocrine markers (synaptophysin, chromogranin): Negative (helps distinguish from neuroendocrine carcinoma)
─ Molecular:
─ High-risk HPV DNA (especially HPV-16) is detectable in most cases

DDx ─

─ Conventional squamous cell carcinoma (keratinizing or non-keratinizing) (may lack the prominent basaloid pattern and peripheral palisading, though overlap exists and basaloid SCC is a subtype of SCC)
─ Basal cell carcinoma (perianal skin) (typically BerEP4 positive, p16 negative or patchy, arises from skin, shows characteristic stromal retraction and more typical basal cell morphology)
─ Adenoid cystic carcinoma (rare in anus; biphasic pattern with ductal and myoepithelial cells, cribriform growth, often MYB positive; basaloid SCC can have cribriform areas but lacks true myoepithelial component)
─ Small cell neuroendocrine carcinoma (positive for neuroendocrine markers, characteristic nuclear molding and "salt-and-pepper" chromatin)
─ Metastatic basaloid carcinoma (e.g., from lung, head/neck – clinical history and broader IHC panel needed)

Prognosis ─ ─ Prognosis is generally considered similar to conventional anal SCC of the same stage
─ Treatment is also similar, typically chemoradiation for localized disease
─ HPV status and stage at diagnosis are important prognostic factors

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Verrucous Carcinoma (Anal)

A rare, highly well-differentiated (low-grade) subtype of squamous cell carcinoma characterized by an exophytic, warty growth pattern, minimal cytologic atypia, and a locally infiltrative "pushing" border rather than destructive invasion

Clinical ─ ─ Uncommon variant of SCC in the anogenital region
─ Presents as a large, slow-growing, exophytic, warty, or cauliflower-like mass
─ May be associated with chronic inflammation, irritation, or HPV infection (though HPV association is less consistent than for conventional anal SCC)
─ Symptoms include a palpable mass, bleeding, pain, or discharge
─ Site: Typically involves the perianal skin or anal canal

Macro ─ ─ Large, exophytic, fungating, warty, or cauliflower-like mass with a papillary surface
─ Often has deep clefts filled with keratin debris
─ Base of the lesion is typically broad and may appear to push into underlying tissues

Micro ─

─ Marked acanthosis, papillomatosis, and hyperkeratosis forming complex exophytic fronds
─ Squamous epithelium is very well-differentiated with minimal cytologic atypia; cells are large with abundant eosinophilic cytoplasm and small, relatively uniform nuclei
─ Mitotic figures are infrequent and confined to the basal layer
─ Koilocytic changes are usually absent or inconspicuous
─ Characteristic "pushing" invasion at the base of the lesion, with broad, bulbous rete ridges extending into the underlying stroma, rather than infiltrative cords or single cells
─ Significant stromal inflammation is often present
─ Diagnosis can be challenging on superficial biopsies due to the bland cytology; deep biopsy showing the pushing border is crucial

Ancillary studies ─

─ IHC:
─ Positive for squamous markers (p63, p40, CK5/6)
─ p16INK4a: Often negative or patchy, reflecting a lower association with high-risk HPV compared to conventional SCC, though some cases can be HPV positive
─ Ki-67: Proliferation typically restricted to basal layers, low overall index
─ Molecular:
─ HPV DNA may be detected in a subset of cases, but not universally

DDx ─

─ Giant condyloma acuminatum (Buschke-Löwenstein tumor) (can be very large and exophytic, shows prominent HPV cytopathic effects/koilocytosis, and typically lacks the true pushing invasion of verrucous carcinoma, though distinction can be difficult and some consider them related entities or a spectrum)
─ Conventional squamous cell carcinoma (shows more significant cytologic atypia, infiltrative invasion, and often higher p16 expression)
─ Pseudoepitheliomatous hyperplasia (reactive epithelial proliferation secondary to chronic inflammation or ulceration; lacks the degree of architectural complexity and the characteristic broad, pushing rete ridges of verrucous carcinoma; no true invasion)
─ Fibroepithelial polyp or extensive skin tags (benign, lack atypia and the specific architecture of verrucous carcinoma)

Prognosis ─ ─ Locally aggressive and can recur if incompletely excised, but has a very low metastatic potential
─ Treatment is primarily wide surgical excision
─ Radiation therapy has been controversial, with some historical reports suggesting it might induce anaplastic transformation or be ineffective, though modern radiotherapy may be used in select cases
─ Prognosis is generally good if completely excised, due to the low metastatic rate

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Anal Adenocarcinoma

A malignant glandular neoplasm arising in the anal canal or perianal region; it can originate from anal glands, anal canal surface epithelium (colorectal type), or within chronic fistulae

Clinical ─ ─ Rare compared to anal squamous cell carcinoma, accounting for 5-19% of anal cancers
─ Symptoms can include rectal bleeding, pain, mass sensation, discharge, or changes in bowel habits; may mimic benign conditions like hemorrhoids or fistulae
─ Risk factors are less clearly defined than for anal SCC but may include chronic inflammation (e.g., Crohn's disease, chronic fistulae), prior radiation, and possibly HPV in some subtypes
─ Three main subtypes/origins are considered:
─ Adenocarcinoma of anal glands/ducts: Arises from the submucosal anal glands or their ducts. These are apocrine-like glands.
─ Colorectal-type adenocarcinoma: Arises from the columnar epithelium of the upper anal canal (anal transition zone or rectal mucosa extending into the anal canal). Histologically and immunophenotypically similar to rectal adenocarcinoma. This is the most common type.
─ Fistula-associated adenocarcinoma: Develops in the setting of a chronic anorectal fistula (often long-standing, e.g., >10 years), typically mucinous type

Macro ─ ─ Appearance is variable:
─ May be an ulcerated, infiltrative, or exophytic mass
─ Fistula-associated tumors may present as induration or a mass along a fistula tract, sometimes with external drainage
─ Anal gland origin tumors can be deep-seated or submucosal initially

Micro ─

─ Adenocarcinoma of anal glands/ducts: ─ Glandular, cribriform, or papillary architecture
─ Cells may have eosinophilic cytoplasm, apocrine-like snouts, or clear cytoplasm
─ Mucin production can be variable
─ May show pagetoid spread into overlying squamous epithelium (see Anal Paget's Disease, primary type)
─ Colorectal-type adenocarcinoma: ─ Histologically indistinguishable from rectal adenocarcinoma (tubular, villous, or mucinous patterns)
─ Composed of columnar cells with nuclear atypia, stratification, and gland formation
─ Fistula-associated adenocarcinoma: ─ Often well-differentiated to moderately differentiated mucinous adenocarcinoma, with pools of extracellular mucin containing floating tumor cells or glands
─ May also be non-mucinous glandular patterns
─ Chronic inflammation and fistula tract changes are present in the background
─ All types show invasive growth into surrounding tissues

Ancillary studies ─

─ IHC profile helps distinguish subtypes and from other tumors:
─ Adenocarcinoma of anal glands/ducts: ─ CK7 (+), GCDFP-15 (+/-), Androgen Receptor (AR) (+/-), GATA3 (+/-)
─ CK20 (- or focal +), CDX2 (- or focal +)
─ PSA (-)
─ Colorectal-type adenocarcinoma: ─ CK20 (+), CDX2 (+)
─ CK7 (-), GCDFP-15 (-)
─ Fistula-associated adenocarcinoma: ─ Usually CK20 (+), CDX2 (+) (intestinal phenotype)
─ CK7 (- or focal +)
─ MUC2 often positive in mucinous types
─ HPV status: Generally HPV-negative, especially for anal gland and colorectal types, though some studies suggest HPV might play a role in a small subset of anal canal adenocarcinomas of other types

DDx ─

─ Metastatic adenocarcinoma (e.g., from prostate, bladder, ovary, upper GI – clinical history and IHC panel crucial; PSA for prostate, PAX8/WT1 for ovarian, etc.)
─ Anal squamous cell carcinoma with glandular differentiation (rare; will show predominant squamous component and express squamous markers)
─ Endometriosis (benign endometrial glands and stroma)
─ Villous adenoma with invasive adenocarcinoma (if arising from a pre-existing adenoma)
─ Prolapse-related changes with glandular displacement (e.g., colitis cystica profunda in SRUS – benign glands, lack atypia, characteristic fibromuscular stroma)
─ Paget's disease (intraepithelial spread; if secondary, look for underlying adenocarcinoma)

Prognosis ─ ─ Generally, anal adenocarcinoma has a poorer prognosis than anal squamous cell carcinoma
─ Prognosis depends on stage at diagnosis, histologic subtype, and grade
─ Colorectal-type adenocarcinomas are often treated similarly to rectal adenocarcinomas (e.g., neoadjuvant chemoradiation followed by surgery for locally advanced cases)
─ Anal gland adenocarcinomas and fistula-associated adenocarcinomas are often aggressive and may require radical surgery; response to chemoradiation is less well-established
─ Fistula-associated adenocarcinomas often present at an advanced stage due to diagnostic delay

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Anal Neuroendocrine Neoplasms

A heterogeneous group of neoplasms arising from neuroendocrine cells within the anal canal, ranging from well-differentiated neuroendocrine tumors (NETs, formerly carcinoids) to poorly differentiated neuroendocrine carcinomas (NECs)

Clinical ─ ─ Rare in the anal canal
─ Symptoms can be non-specific: rectal bleeding, pain, mass, or asymptomatic and found incidentally on endoscopy or imaging
─ Carcinoid syndrome (flushing, diarrhea due to hormone production) is very rare with anal NETs as they seldom produce serotonin or other vasoactive substances in significant amounts
─ Risk factors are not well-defined; some association with HPV or HIV has been suggested for NECs, but not consistently for NETs
─ Classified based on WHO criteria (differentiation, morphology, Ki-67 index, mitotic count) into:
─ Well-differentiated Neuroendocrine Tumor (NET), Grade 1, 2, or 3: Organoid, trabecular, or nested growth; uniform nuclei; "salt-and-pepper" chromatin. Grade is based on proliferation (Ki-67/mitoses).
─ Poorly differentiated Neuroendocrine Carcinoma (NEC), Small Cell or Large Cell type: Diffuse sheets, high-grade cytology, extensive necrosis, high proliferation. Always Grade 3.
─ Mixed Neuroendocrine-Non-Neuroendocrine Neoplasm (MiNEN): Contains both neuroendocrine and non-neuroendocrine (e.g., adenocarcinoma, SCC) components, each >30%.

Macro ─ ─ NETs: Often small (<1-2 cm), yellowish or tan, firm, submucosal nodules or polyps. May ulcerate if larger.
─ NECs: Typically larger, infiltrative, often ulcerated masses with necrosis and hemorrhage; may be indistinguishable from other high-grade carcinomas

Micro ─

─ Well-differentiated Neuroendocrine Tumor (NET): ─ Architectural patterns: Nests (insular), trabeculae (ribbons), gyriform, or solid sheets
─ 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
─ Mitotic activity is generally low (for G1/G2) but can be higher in G3 NETs. Necrosis is usually absent or minimal in G1/G2.
─ Grading:
─ G1: Mitotic count <2/2 mm² (10 HPF) AND Ki-67 index <3%
─ G2: Mitotic count 2-20/2 mm² OR Ki-67 index 3-20%
─ G3 NET: Mitotic count >20/2 mm² OR Ki-67 index >20% (but still well-differentiated morphology)
─ Poorly differentiated Neuroendocrine Carcinoma (NEC): ─ Small Cell Carcinoma: Sheets of small, round, blue cells with scant cytoplasm, nuclear molding, finely granular chromatin, inconspicuous nucleoli, high mitotic rate, extensive necrosis, Azzopardi effect (DNA encrustation of blood vessels)
─ Large Cell Neuroendocrine Carcinoma: Sheets or nests of larger cells with more abundant cytoplasm, vesicular nuclei with prominent nucleoli, high mitotic rate, frequent necrosis. May have organoid or trabecular patterns focally.
─ Both are always Grade 3 (Ki-67 usually >20%, often much higher, e.g., >55%)

Ancillary studies ─

─ IHC (Neuroendocrine markers):
─ Synaptophysin: Diffusely positive in most NETs and NECs (cytoplasmic)
─ Chromogranin A: Often positive in well-differentiated NETs (granular cytoplasmic); may be focal or negative in NECs, especially small cell type
─ CD56 (NCAM): Often positive, but less specific than synaptophysin/chromogranin
─ INSM1: A newer, sensitive, and specific nuclear marker for neuroendocrine differentiation
─ IHC (Proliferation markers):
─ Ki-67 (MIB-1): Essential for grading NETs and confirming high proliferation in NECs
─ IHC (Other markers for NECs):
─ TTF-1: Can be positive in a subset of small cell carcinomas (though more typical of pulmonary origin)
─ CK20: Usually negative in NECs; CDX2 may be positive in some rectal/anal NETs/NECs
─ p63/p40: Negative (to exclude SCC)
─ HPV ISH/p16 IHC:
─ Anal NECs (especially small cell type) can be associated with high-risk HPV and show p16 positivity, similar to some anal SCCs. This is less common in well-differentiated NETs.

DDx ─

─ For NETs: ─ Metastatic NET from another site (e.g., small intestine, pancreas, lung – clinical history, imaging, and IHC for site-specific markers like CDX2, ISL1, TTF-1 can help)
─ Paraganglioma (S100 positive sustentacular cells around nests; GATA3 positive)
─ Melanoma (S100, SOX10, Melan-A/HMB45 positive)
─ Solid pattern adenocarcinoma (negative for NE markers, positive for glandular markers)
─ For NECs: ─ Poorly differentiated squamous cell carcinoma (especially basaloid or lymphoepithelioma-like) (positive for p63/p40, CK5/6; p16 often positive; NE markers negative)
─ Poorly differentiated adenocarcinoma (positive for glandular markers; NE markers negative)
─ Lymphoma (positive for lymphoid markers like CD45; negative for keratins and NE markers)
─ Metastatic small cell carcinoma (e.g., from lung – TTF-1 often positive)

Prognosis ─ ─ NETs: ─ Prognosis is generally favorable for small (<1-2 cm), low-grade (G1), localized anal NETs, often cured by local excision
─ Risk of metastasis increases with size (>2 cm), higher grade (G2, G3 NET), muscularis propria invasion, and lymphovascular invasion
─ G3 NETs have a more aggressive behavior than G1/G2 NETs but may be less aggressive than NECs
─ NECs (Small Cell and Large Cell): ─ Highly aggressive malignancies with a poor prognosis, regardless of site
─ Tend to present at an advanced stage with early and widespread metastases
─ Treatment typically involves platinum-based chemotherapy, similar to pulmonary small cell carcinoma
─ MiNENs: Prognosis is generally driven by the more aggressive component, often the NEC part

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Melanoma (Anal)

A malignant neoplasm arising from melanocytes located in the anal canal or perianal skin, characterized by its aggressive behavior and potential for early metastasis

Clinical ─ ─ Rare, accounting for <1% of all melanomas and <1-2% of all anorectal malignancies
─ More common in older individuals (typically 6th-8th decades), with a slight female predominance in some series
─ Symptoms are often non-specific and can mimic benign conditions, leading to delayed diagnosis:
─ Rectal bleeding (most common)
─ Anal pain or discomfort
─ Palpable mass or lump
─ Pruritus, tenesmus, or change in bowel habits
─ Site: Can arise in the anal canal (mucosal melanoma, often near the dentate line) or perianal skin. Mucosal melanomas are generally more aggressive than cutaneous melanomas.
─ Risk factors are not as clearly defined as for cutaneous melanoma (UV exposure is not relevant here); no definitive link to HPV
─ Approximately 20-40% of anal melanomas are amelanotic (lacking pigment), which can make clinical and pathologic diagnosis more challenging

Macro ─ ─ Variable appearance:
─ Polypoid, nodular, or ulcerated mass
─ May be pigmented (brown/black) or amelanotic (pink/flesh-colored)
─ Can be friable and bleed easily
─ Size can range from small lesions to large, bulky tumors
─ Often located within 6 cm of the anal verge

Micro ─

─ Composed of atypical melanocytes, which can exhibit various morphologies:
─ Epithelioid cells: Large, polygonal cells with abundant eosinophilic cytoplasm, large vesicular nuclei, and prominent nucleoli
─ Spindle cells: Elongated cells with fusiform nuclei, arranged in fascicles
─ Lymphoma-like (small cell): Small, round cells with scant cytoplasm and hyperchromatic nuclei, mimicking lymphoma
─ Pleomorphic cells: Marked variation in cell size and shape, bizarre nuclei
─ Melanin pigment may be present within tumor cells or melanophages in the stroma, but can be sparse or absent (amelanotic melanoma)
─ Invasion into the submucosa, muscularis propria, or deeper structures is characteristic
─ Junctional activity (atypical melanocytes along the basal layer of the overlying squamous or transitional epithelium) may be present, especially in primary lesions, and is an important clue for primary origin
─ Mitotic figures, including atypical forms, are usually present and often numerous
─ Necrosis and ulceration are common
─ Lymphovascular and perineural invasion can occur

Ancillary studies ─

─ IHC (Melanocytic markers):
─ S100 protein: Diffusely positive (nuclear and cytoplasmic); sensitive but not specific
─ SOX10: Diffusely positive (nuclear); highly sensitive and relatively specific for melanocytic differentiation (also stains Schwann cells/nerves)
─ Melan-A (MART-1): Positive (cytoplasmic); specific but may be less sensitive in desmoplastic or spindle cell melanomas
─ HMB-45: Positive (cytoplasmic); specific, often highlights junctional component or more immature cells, can be patchy in invasive tumor
─ Tyrosinase: Positive (cytoplasmic); specific
─ IHC (To exclude other tumors):
─ Cytokeratins (AE1/AE3, CAM5.2): Negative (to rule out carcinoma)
─ p63/p40: Negative (to rule out SCC)
─ CD45 (LCA): Negative (to rule out lymphoma)
─ Synaptophysin/Chromogranin: Negative (to rule out neuroendocrine tumors)
─ Molecular:
─ Mucosal melanomas (including anal) have different molecular profiles than most cutaneous melanomas. BRAF mutations (e.g., V600E) are less common.
─ KIT mutations are more frequent in mucosal melanomas (around 10-20%) and can be a therapeutic target
─ NRAS mutations can also occur
─ GNAQ/GNA11 mutations are rare in this location (more common in uveal melanoma)

DDx ─

─ Poorly differentiated squamous cell carcinoma (especially non-keratinizing or basaloid types if melanoma is amelanotic; SCC is p63/p40 positive, melanocytic markers negative)
─ Poorly differentiated adenocarcinoma (melanocytic markers negative; glandular markers like CK20/CDX2 may be positive if colorectal type)
─ High-grade neuroendocrine carcinoma (especially if melanoma has small cell features; NEC is positive for synaptophysin/chromogranin, melanocytic markers negative)
─ Lymphoma (positive for CD45 and other lymphoid markers; melanocytic markers negative)
─ Gastrointestinal stromal tumor (GIST) (if spindle cell melanoma; GIST is CD117/DOG1 positive, melanocytic markers negative)
─ Angiosarcoma (if epithelioid and hemorrhagic; angiosarcoma is positive for vascular markers like CD31/ERG)
─ Benign melanocytic nevus (junctional, compound, or intramucosal; lacks significant atypia, deep invasion, high mitotic rate)
─ Pigmented Paget's disease (Paget cells can contain melanin; Paget cells are CK7/GCDFP-15 positive)

Prognosis ─ ─ Generally poor, worse than cutaneous melanoma of similar thickness and stage
─ Often diagnosed at a late stage due to non-specific symptoms and anatomical location
─ Prognostic factors include tumor thickness (Breslow depth), ulceration, mitotic rate, lymph node involvement, and distant metastasis
─ Amelanotic melanomas may have a worse prognosis due to diagnostic delays
─ Treatment typically involves surgical resection (abdominoperineal resection or wide local excision for smaller lesions), often with adjuvant therapy considerations (immunotherapy, targeted therapy if specific mutations like KIT are present)
─ High rates of local recurrence and distant metastasis

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Perianal Skin Tumors

Basal Cell Carcinoma (Perianal)

A rare type of skin cancer arising from basal cells of the epidermis in the perianal skin; it is the most common form of skin cancer overall but very uncommon in the perianal region

Clinical ─ ─ Extremely rare in the perianal area, as BCCs are typically associated with sun-exposed skin
─ When it occurs perianally, risk factors may include chronic irritation, inflammation, prior radiation therapy, immunosuppression (e.g., HIV, organ transplant), arsenic exposure, or genetic syndromes like Gorlin syndrome (Nevoid Basal Cell Carcinoma Syndrome)
─ More common in older individuals, with a male predominance in some reports of perianal BCC
─ Presents as a slow-growing papule, nodule, or plaque; may be pearly, ulcerated (rodent ulcer), crusted, or pigmented
─ Symptoms can include itching, pain, bleeding, or a non-healing sore
─ Site: Perianal skin (within 5 cm of the anal verge)

Macro ─ ─ Variable appearance:
─ Nodular: Pearly papule or nodule with telangiectasias, may have a rolled border and central ulceration
─ Superficial: Erythematous, scaly patch, often with a thread-like border
─ Ulcerating: Crusted ulcer with indurated edges
─ Pigmented: Contains melanin, appearing brown or black, mimicking melanoma
─ Morpheaform (sclerosing): Indurated, scar-like plaque with ill-defined borders

Micro ─

─ Nests and cords of basaloid tumor cells infiltrating the dermis, often originating from the epidermis or adnexal structures
─ Basaloid cells:
─ Scant cytoplasm, large hyperchromatic oval to elongated nuclei
─ Peripheral palisading of nuclei at the edges of tumor nests is characteristic
─ Stromal retraction artifact (clefting) around tumor nests is common
─ Various histologic patterns:
─ Nodular (most common): Solid nests of basaloid cells of varying sizes
─ Superficial: Buds and nests of basaloid cells extending from the epidermis into the papillary dermis
─ Infiltrative/Morpheaform: Narrow strands and cords of tumor cells infiltrating deeply within a dense, fibrotic stroma
─ Micronodular: Multiple small tumor nests
─ Pigmented: Contains melanin pigment within tumor cells or melanocytes/melanophages
─ Mitotic figures can be present but are not usually as numerous or atypical as in SCC or melanoma
─ Stroma is often fibromyxoid

Ancillary studies ─

─ IHC:
─ Positive for BerEP4 (highly sensitive and relatively specific for BCC vs. SCC)
─ Positive for BCL2
─ May be positive for Androgen Receptor (AR)
─ Squamous markers (p63, p40, CK5/6) can be positive, especially in BCCs with squamous differentiation (basosquamous carcinoma), but BerEP4 helps distinguish
─ CK20 and CDX2 are negative (ruling out colorectal adenocarcinoma spread)
─ S100, Melan-A, HMB-45 are negative (ruling out melanoma)
─ p16 is typically negative or patchy (unlike HPV-related anal SCC)
─ Molecular:
─ Mutations in the Hedgehog signaling pathway (e.g., PTCH1, SMO) are common in BCCs, including those in sun-protected areas

DDx ─

─ Squamous cell carcinoma (anal or perianal) (shows more squamous differentiation, keratinization, intercellular bridges; p16 often positive if HPV-related; BerEP4 negative)
─ Basaloid SCC of the anus can resemble BCC, but typically arises in the anal canal, is HPV/p16 positive, and BerEP4 negative
─ Seborrheic keratosis (benign, horn cysts, pseudo-horn cysts, papillomatosis, no true invasion)
─ Melanocytic nevus or Melanoma (composed of melanocytes; S100/SOX10/Melan-A/HMB-45 positive)
─ Trichoepithelioma/Trichoblastoma (benign follicular tumors, can have basaloid cells but more organized, papillary mesenchymal bodies, less stromal retraction)
─ Adenoid cystic carcinoma (rare, biphasic, cribriform pattern)
─ Metastatic carcinoma to skin (clinical history, different IHC profile)

Prognosis ─ ─ Generally excellent prognosis for perianal BCC, similar to BCCs elsewhere on the skin, as it is typically a locally invasive tumor with very low metastatic potential
─ Treatment is primarily surgical excision with clear margins (e.g., Mohs micrographic surgery or wide local excision)
─ Recurrence can occur if incompletely excised, especially for infiltrative/morpheaform subtypes
─ Metastasis is extremely rare

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Liver

Liver Anatomy

Feature	Description
Structure	Largest solid organ in the RUQ of abdomen. Covered by Glisson's capsule.
Lobes	Right, Left, Caudate, and Quadrate lobes.
Blood Supply (Dual)	Hepatic Artery (~25%): Supplies oxygenated blood from the celiac trunk. Portal Vein (~75%): Supplies nutrient-rich blood from the GI tract.
Venous Drainage	Central veins -> Hepatic veins -> Inferior Vena Cava.
Biliary Drainage	Bile canaliculi -> Ducts -> Common hepatic duct -> Common bile duct.

Liver Histology

Structure / Unit	Components & Features
Hepatocytes	Polygonal cells with eosinophilic cytoplasm arranged in one-cell-thick plates radiating from a central vein.
Lobular Architecture	Classic Lobule: Hexagonal, centered on a central vein. Portal Lobule: Triangular, centered on a portal triad. Hepatic Acinus (of Rappaport): Diamond-shaped functional unit defining 3 metabolic zones.
Acinar Zones	Zone 1 (Periportal): Highest oxygen. Site of oxidative metabolism. Zone 2 (Mid-zonal): Intermediate. Zone 3 (Pericentral): Lowest oxygen. Site of detoxification (P-450). Most susceptible to ischemia.
Portal Triad	Located at corners of classic lobules. Contains branches of the portal vein, hepatic artery, and a bile duct.
Sinusoids	Vascular channels between hepatocyte plates. Lined by fenestrated endothelium and Kupffer cells (macrophages).
Space of Disse	Perisinusoidal space containing Hepatic stellate cells (Ito cells), which store vitamin A and are involved in fibrosis.
Bile Canaliculi	Apical channels between adjacent hepatocytes that drain bile.

Liver, Non-Neoplastic

Patterns of Liver Injury (General concepts: Lobular, Portal, Biliary, Steatotic, Fibrotic)

Broad categories describing the primary location and nature of liver damage, which can provide clues to the underlying etiology when evaluating liver biopsies

Clinical ─ ─ Liver injury can be acute or chronic, leading to a spectrum of clinical presentations from asymptomatic liver test abnormalities to fulminant hepatic failure or cirrhosis
─ Different etiologies (viral, alcohol, drugs, autoimmune, metabolic, vascular, biliary obstruction) tend to produce characteristic, though often overlapping, patterns of injury
─ Understanding these patterns helps pathologists guide clinicians towards a differential diagnosis

Macro ─ ─ Gross appearance varies with the type and severity of injury. Acute severe injury may show a swollen, congested liver. Chronic injury can lead to fibrosis and cirrhosis (shrunken, nodular liver). Steatosis causes an enlarged, pale, greasy liver.

Micro ─

1) Hepatocellular (Lobular) Pattern: ─ Injury predominantly affects hepatocytes within the hepatic lobules (acini)
─ Features:
─ Hepatocyte degeneration/necrosis: Ballooning degeneration (swollen cells with rarefied cytoplasm), apoptosis (acidophil/Councilman bodies), lytic necrosis (cell dropout)
─ Lobular inflammation: Inflammatory cells (lymphocytes, macrophages, neutrophils, eosinophils) scattered within the lobules, often around injured hepatocytes. Spotty necrosis refers to focal areas of hepatocyte necrosis with inflammation.
─ Kupffer cell hyperplasia and hypertrophy, often containing pigment (lipofuscin, hemosiderin, ceroid) or cellular debris
─ Confluent necrosis: Bridging necrosis (linking central veins to portal tracts, or portal tracts to portal tracts) or panacinar/multiacinar necrosis in severe injury
─ Common etiologies: Acute viral hepatitis, drug-induced liver injury (DILI), autoimmune hepatitis (can also have portal features), ischemic injury, some metabolic disorders
─ Zonal distribution of injury can be a clue (e.g., zone 3/centrilobular necrosis in ischemia or acetaminophen toxicity; zone 1/periportal necrosis in phosphorus poisoning or eclampsia)
2) Cholestatic Pattern (Biliary an d Canalicular): ─ Impairment of bile flow, leading to accumulation of bile within hepatocytes, canaliculi, and sometimes Kupffer cells or portal tracts
─ Features:
─ Canalicular cholestasis: Bile plugs (inspissated bile) within dilated bile canaliculi (often prominent in zone 3)
─ Hepatocellular cholestasis: Bile pigment (golden-brown) accumulation within hepatocyte cytoplasm; may lead to feathery degeneration (pale, swollen hepatocytes with wispy cytoplasm)
─ Ductular reaction/cholangiolar proliferation: Proliferation of small bile duct-like structures at the portal tract periphery, often with associated neutrophils
─ Bile duct injury/loss (if chronic or severe, e.g., PBC, PSC): Lymphocytic cholangitis, ductular degeneration, ductopenia
─ Portal edema and inflammation (often neutrophilic in acute obstruction, lymphocytic/plasmacytic in chronic biliary diseases)
─ Copper accumulation in periportal hepatocytes (long-standing cholestasis)
─ Common etiologies: Biliary obstruction (intrahepatic or extrahepatic), primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), drug-induced cholestasis, sepsis, certain genetic disorders (e.g., Alagille syndrome, progressive familial intrahepatic cholestasis - PFIC)
3) Portal-Based Pattern: ─ Injury and/or inflammation primarily centered on portal tracts
─ Features:
─ Portal inflammation: Increased inflammatory cells (lymphocytes, plasma cells, eosinophils, neutrophils) within portal tracts
─ Interface hepatitis (piecemeal necrosis): Inflammation spilling out of the portal tract into the adjacent periportal parenchyma with erosion of the limiting plate and damage to periportal hepatocytes
─ Bile duct damage/loss (as in cholestatic pattern, if biliary component)
─ Portal fibrosis and scarring (in chronic conditions)
─ Common etiologies: Chronic viral hepatitis (B, C), autoimmune hepatitis, PBC, PSC, drug-induced injury
4) Steatotic Pattern: ─ Accumulation of fat (triglycerides) within hepatocytes
─ Features:
─ Macrovesicular steatosis: Hepatocytes contain one or few large fat droplets that displace the nucleus to the periphery (most common type in NAFLD, ALD)
─ Microvesicular steatosis: Hepatocytes contain numerous tiny lipid droplets, with a centrally located nucleus (e.g., Reye's syndrome, acute fatty liver of pregnancy, some drug toxicities like valproate)
─ Steatohepatitis (e.g., NASH, ASH): Steatosis combined with evidence of hepatocyte injury (ballooning degeneration, Mallory-Denk bodies - rope-like eosinophilic intracytoplasmic inclusions) and lobular inflammation (often with neutrophils around ballooned cells - satellitosis)
─ Common etiologies: Non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), certain medications, viral hepatitis C (genotype 3), Wilson disease, malnutrition
5) Fibrotic Pattern: ─ Excessive deposition of collagen and other extracellular matrix components, leading to scarring
─ Fibrosis can result from any chronic liver injury pattern
─ Pattern of fibrosis can offer clues to etiology:
─ Perisinusoidal/pericellular fibrosis ("chicken-wire" fibrosis): Characteristic of steatohepatitis (NASH, ASH), often starting in zone 3
─ Portal fibrosis: Expansion of portal tracts by fibrous tissue
─ Periportal fibrosis: Fibrosis extending from portal tracts into adjacent parenchyma
─ Bridging fibrosis: Fibrous septa connecting portal tracts to central veins, or portal tracts to portal tracts
─ Cirrhosis: End-stage liver disease characterized by diffuse fibrosis, formation of regenerative parenchymal nodules, and disruption of normal hepatic architecture
─ Special stains (e.g., Masson's trichrome, Sirius red) highlight collagen

Ancillary studies ─

─ Special stains:
─ Trichrome, Sirius Red: Highlight collagen/fibrosis
─ PAS-D (Periodic Acid-Schiff with diastase): Highlights glycogen, basement membranes, alpha-1 antitrypsin globules
─ Iron (Prussian blue): Detects hemosiderin deposition (hemochromatosis, secondary iron overload)
─ Copper (Rhodanine, Orcein): Detects copper accumulation (Wilson disease, chronic cholestasis)
─ Reticulin: Highlights the hepatic plate architecture; loss or condensation suggests necrosis or collapse
─ IHC: Can be used to identify viral antigens (e.g., HBsAg, HBcAg, HCV), characterize inflammatory infiltrates, or detect specific proteins (e.g., alpha-1 antitrypsin)

DDx ─

─ Specific etiologies are differentiated based on the predominant pattern(s) of injury, clinical history, serologies, and sometimes specific histologic clues or IHC/molecular findings

Prognosis ─ ─ Depends on the underlying cause, severity, and chronicity of the liver injury
─ Chronic injury leading to significant fibrosis and cirrhosis carries risks of liver failure, portal hypertension, and hepatocellular carcinoma

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Steatosis and Steatohepatitis

Non-alcoholic Fatty Liver Disease (NAFLD) / Non-alcoholic Steatohepatitis (NASH)

A spectrum of liver conditions characterized by excessive fat accumulation in the liver (steatosis) in individuals without significant alcohol consumption. NAFLD ranges from simple steatosis (NAFL) to non-alcoholic steatohepatitis (NASH), which involves inflammation and hepatocyte injury and can progress to cirrhosis and hepatocellular carcinoma. Recently proposed terminology: Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD) and Metabolic dysfunction-Associated Steatohepatitis (MASH).

Clinical ─ ─ Most common chronic liver disease worldwide, strongly associated with metabolic syndrome components: obesity (especially central/visceral), type 2 diabetes mellitus, insulin resistance, dyslipidemia (high triglycerides, low HDL cholesterol), hypertension
─ Most patients are asymptomatic, especially in early stages. May be discovered incidentally due to elevated liver enzymes or fatty liver on imaging.
─ Symptoms, if present, can be non-specific: fatigue, malaise, vague right upper quadrant discomfort
─ NASH (MASH) is the progressive form that can lead to fibrosis, cirrhosis, liver failure, and hepatocellular carcinoma (HCC). HCC can also arise in non-cirrhotic NASH.
─ Diagnosis is often one of exclusion (ruling out significant alcohol use, viral hepatitis, other known causes of liver disease) combined with evidence of steatosis and features of metabolic syndrome

Macro ─ ─ Liver may be enlarged, pale yellow, and greasy in appearance, especially with significant steatosis
─ In cirrhotic stages, the liver becomes shrunken, firm, and nodular

Micro ─

─ Non-alcoholic fatty liver (NAFL) / Simple Steatosis: ─ Presence of hepatic steatosis (typically macrovesicular) in ≥5% of hepatocytes
─ Usually most prominent in zone 3 (pericentral/centrilobular)
─ Minimal or no evidence of significant lobular inflammation or hepatocyte injury (ballooning)
─ Non-alcoholic steatohepatitis (NASH) / Metabolic dysfunction-Associated Steatohepatitis (MASH): Requires the presence of:
─ 1. Steatosis: Usually macrovesicular, often zone 3 predominant
─ 2. Lobular inflammation: Mild to moderate, mixed infiltrate (lymphocytes, Kupffer cells, sometimes neutrophils), often as scattered foci or aggregates. Neutrophils may cluster around ballooned hepatocytes (satellitosis).
─ 3. Hepatocyte ballooning: Swollen hepatocytes with rarefied, wispy cytoplasm, often containing Mallory-Denk bodies (intracytoplasmic eosinophilic rope-like inclusions of damaged cytokeratins). Ballooning is a key indicator of hepatocyte injury and is considered essential for NASH diagnosis.
─ Other common but not required features in NASH: ─ Fibrosis: Characteristic pattern is perisinusoidal/pericellular fibrosis ("chicken-wire" fibrosis) in zone 3, which can progress to portal/periportal fibrosis, bridging fibrosis, and eventually cirrhosis. Portal fibrosis can also occur independently.
─ Mallory-Denk bodies (MDBs): More common in NASH than NAFL, but not specific (also seen in alcoholic liver disease, Wilson disease, etc.)
─ Glycogenated nuclei in hepatocytes (clear, empty-appearing nuclei)
─ Lipogranulomas (small clusters of foamy macrophages around lipid droplets)
─ Acidophil bodies (apoptotic hepatocytes)
─ Mild portal chronic inflammation may be present
─ Grading and Staging (e.g., NASH CRN system): ─ Activity Score (NAS): Sum of scores for steatosis (0-3), lobular inflammation (0-3), and ballooning (0-2). A NAS score ≥5 is often correlated with "definite NASH", 3-4 with "borderline NASH", <3 with "not NASH".
─ Fibrosis Stage (F0-F4):
─ F0: No fibrosis
─ F1: Perisinusoidal or portal/periportal fibrosis (F1a: mild, zone 3, perisinusoidal; F1b: moderate, zone 3, perisinusoidal; F1c: portal/periportal only)
─ F2: Perisinusoidal AND portal/periportal fibrosis
─ F3: Bridging fibrosis
─ F4: Cirrhosis

Ancillary studies ─

─ Special Stains:
─ Masson's trichrome or Sirius red: To highlight and stage fibrosis
─ Iron stain: Usually negative or shows mild focal iron, helps exclude significant hemochromatosis (though secondary iron overload can occur in NASH)
─ PAS-D: Can highlight MDBs (though often subtle) and glycogenated nuclei
─ IHC: Not routinely used for diagnosis of NAFLD/NASH itself, but may be used to exclude other conditions or in research (e.g., cytokeratin 8/18 for MDBs)
─ Molecular: Research ongoing for biomarkers; PNPLA3 gene variants are strongly associated with increased steatosis and risk of NASH/fibrosis. TM6SF2 variants also implicated.

DDx ─

─ Alcoholic liver disease (ALD) / Alcoholic steatohepatitis (ASH): Histologically can be very similar or identical to NAFLD/NASH. Clinical history of significant alcohol consumption is key for differentiation. ASH may more commonly show prominent MDBs, neutrophilic satellitosis, and sclerosing hyaline necrosis.
─ Drug-induced steatohepatitis (e.g., amiodarone, methotrexate, tamoxifen, corticosteroids)
─ Viral hepatitis (especially HCV genotype 3, which can cause significant steatosis)
─ Wilson disease (can have steatosis, ballooning, MDBs; look for copper accumulation)
─ Alpha-1 antitrypsin deficiency (PAS-D positive globules in periportal hepatocytes)
─ Autoimmune hepatitis (can have overlapping features if steatosis is present due to metabolic factors; look for prominent plasma cells, interface hepatitis, specific autoantibodies)
─ Celiac disease (can be associated with abnormal liver tests and steatosis)

Prognosis ─ ─ NAFL (Simple steatosis): Generally considered benign with a low risk of progression to advanced liver disease if it remains simple steatosis
─ NASH (MASH): Is a progressive disease in a subset of patients. Risk of progression to advanced fibrosis, cirrhosis, and end-stage liver disease is significant (estimated 10-20% or more over 10-20 years for progression to cirrhosis from NASH).
─ Development of cirrhosis increases risk of hepatocellular carcinoma (HCC) and liver-related mortality
─ NAFLD/NASH is also associated with increased risk of cardiovascular disease and type 2 diabetes, which are major causes of morbidity/mortality in these patients
─ Lifestyle modifications (weight loss, diet, exercise), management of metabolic comorbidities are the cornerstones of treatment. No FDA-approved pharmacotherapies specifically for NASH fibrosis yet, but many are in development.

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Alcoholic Liver Disease (ALD) / Alcoholic Steatohepatitis (ASH)

A spectrum of liver injury caused by chronic excessive alcohol consumption, ranging from simple steatosis (fatty liver) to alcoholic steatohepatitis (ASH), progressive fibrosis, cirrhosis, and hepatocellular carcinoma

Clinical ─ ─ Develops in individuals with a history of chronic and excessive alcohol intake (amount and duration vary, but generally >40-80g/day for men, >20-40g/day for women for years)
─ Genetic predisposition, sex (females more susceptible), nutritional status (malnutrition worsens), coexisting liver diseases (e.g., viral hepatitis, iron overload) influence susceptibility and severity
─ Alcoholic Steatosis: Often asymptomatic; may have hepatomegaly; usually reversible with abstinence
─ Alcoholic Steatohepatitis (ASH) / Alcoholic Hepatitis (AH - clinical term): ─ Can present acutely on chronic ALD, often after a period of heavy drinking
─ Symptoms: Malaise, anorexia, fever, right upper quadrant pain/tenderness, jaundice, tender hepatomegaly
─ Severe AH: Ascites, variceal bleeding, hepatic encephalopathy, coagulopathy; high short-term mortality
─ Lab findings: Elevated AST and ALT (AST > ALT, typically AST:ALT ratio >1.5 or >2, with AST usually <300-400 U/L), elevated GGT, elevated bilirubin, leukocytosis (neutrophilia), elevated INR, low albumin
─ Alcoholic Cirrhosis: Develops in a subset of patients with chronic ALD/ASH; signs of portal hypertension and liver failure

Macro ─ ─ Steatosis: Enlarged, yellow, greasy liver
─ ASH: Liver may be enlarged, congested, and firm; can be mottled
─ Cirrhosis: Shrunken, firm, nodular liver (can be micronodular or mixed)

Micro ─

─ 1. Alcoholic Steatosis (Fatty Liver): ─ Predominantly macrovesicular steatosis (large fat droplets displacing hepatocyte nuclei), typically most prominent in zone 3 (centrilobular)
─ May be accompanied by mild lobular inflammation or portal changes
─ Reversible with abstinence
─ 2. Alcoholic Steatohepatitis (ASH): Key features include:
─ Steatosis: Usually macrovesicular, often mixed with microvesicular droplets
─ Hepatocyte ballooning: Swollen, rounded hepatocytes with rarefied cytoplasm, indicative of cell injury; often prominent in zone 3
─ Mallory-Denk bodies (MDBs): Eosinophilic, rope-like, irregular intracytoplasmic inclusions within ballooned hepatocytes (composed of damaged cytokeratin filaments). Highly characteristic but not specific (also seen in NASH, Wilson disease, etc.).
─ Lobular inflammation with neutrophils: Neutrophils often cluster around ballooned hepatocytes containing MDBs (satellitosis)
─ Perisinusoidal/pericellular fibrosis: "Chicken-wire" pattern of fibrosis in zone 3, surrounding individual or groups of hepatocytes. This is an early and characteristic fibrotic pattern.
─ Cholestasis: Canalicular bile plugs and hepatocellular bile accumulation can be prominent in severe ASH/AH, often associated with a poorer prognosis
─ Megamitochondria: Enlarged, often spherical, eosinophilic mitochondria, can be seen in some hepatocytes
─ Sclerosing hyaline necrosis: Perivenular fibrosis with obliteration of central veins and necrosis of adjacent hepatocytes (severe form of injury)
─ 3. Alcoholic Fibrosis and Cirrhosis: ─ Progressive fibrosis starting with perisinusoidal pattern, leading to portal-central bridging, and eventually cirrhosis
─ Cirrhosis is often initially micronodular but can become mixed or macronodular over time
─ Active ASH features may or may not be present in the cirrhotic liver, depending on ongoing alcohol consumption

Ancillary studies ─

─ Special Stains:
─ Masson's trichrome or Sirius red: To highlight fibrosis pattern and stage
─ Iron (Prussian blue): May show increased hepatic iron stores (in hepatocytes and/or Kupffer cells) in a subset of patients with ALD, which can exacerbate liver injury
─ PAS-D: Can highlight MDBs (though often subtle)
─ IHC: Not typically required for diagnosis but can be used in research or to exclude other conditions. CK8/18 can highlight MDBs.

DDx ─

─ Non-alcoholic fatty liver disease (NAFLD) / Non-alcoholic steatohepatitis (NASH): Histologically can be indistinguishable from ALD/ASH. Clinical history of alcohol consumption is the primary differentiating factor. AST:ALT ratio <1 is more typical for NASH.
─ Drug-induced liver injury (DILI) (some drugs can cause steatohepatitis-like changes)
─ Wilson disease (can show steatosis, ballooning, MDBs, chronic hepatitis features; check copper studies)
─ Alpha-1 antitrypsin deficiency (PAS-D positive globules)
─ Viral hepatitis (especially HCV genotype 3 can cause steatosis; chronic viral hepatitis has predominantly portal-based inflammation)

Prognosis ─ ─ Steatosis: Generally reversible with abstinence
─ ASH: Spectrum of severity. Mild ASH may improve with abstinence. Severe alcoholic hepatitis has high short-term mortality (20-50% at 1 month in some series). Prognostic scores (e.g., Maddrey's Discriminant Function, MELD score, Glasgow Alcoholic Hepatitis Score) are used to assess severity and guide therapy (e.g., corticosteroids for severe AH).
─ Cirrhosis: Irreversible; abstinence improves survival and reduces risk of decompensation and HCC. Continued drinking leads to poor prognosis.
─ Risk of hepatocellular carcinoma is increased, especially in cirrhotic stage

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Chronic Inflammation / Hepatitis

Primary Biliary Cholangitis (PBC)

A chronic, progressive autoimmune liver disease characterized by immune-mediated destruction of small to medium-sized intrahepatic bile ducts, leading to cholestasis, fibrosis, and eventually cirrhosis and liver failure

Clinical ─ ─ Predominantly affects middle-aged women (female:male ratio ~9:1)
─ Often asymptomatic at diagnosis, detected by routine liver function tests (elevated alkaline phosphatase - ALP)
─ Symptomatic patients may present with:
─ Fatigue (common, can be debilitating)
─ Pruritus (itching, can be severe)
─ Jaundice (later sign, indicates more advanced disease)
─ Right upper quadrant discomfort
─ Associated with other autoimmune conditions (e.g., Sjögren's syndrome, autoimmune thyroiditis, rheumatoid arthritis, scleroderma/CREST)
─ Diagnostic hallmarks:
─ Cholestatic liver enzyme pattern (elevated ALP and GGT, often with normal or mildly elevated aminotransferases)
─ Presence of anti-mitochondrial antibodies (AMA), particularly M2 subtype (highly specific, found in ~90-95% of patients)
─ Characteristic liver histology (if biopsy is performed)
─ PBC-specific ANAs (e.g., anti-sp100, anti-gp210) may be present in AMA-negative PBC or coexist with AMA

Macro ─ ─ Early stages: Liver may appear normal or slightly enlarged
─ Advanced stages (cirrhosis): Liver becomes firm, nodular, often bile-stained (greenish)

Micro ─

─ Key histologic lesion (though not always seen, especially in early or treated disease): Florid duct lesion / Chronic non-suppurative destructive cholangitis:
─ Damage and destruction of interlobular and septal bile ducts (small to medium-sized)
─ Bile ducts are infiltrated by a dense aggregate of lymphocytes, plasma cells, eosinophils, and often epithelioid histiocytes forming granulomas (non-caseating, often periductal or within portal tracts)
─ Ductular epithelial cells may appear swollen, vacuolated, irregular, or show evidence of apoptosis/necrosis
─ Other common features: ─ Portal inflammation: Lymphoplasmacytic infiltrate, often with lymphoid aggregates or follicles
─ Ductular reaction/proliferation at the portal tract periphery
─ Ductopenia (loss of bile ducts): A feature of later stages; defined as loss of bile ducts in >50% of portal tracts (relative to accompanying arteries)
─ Cholestasis: Hepatocellular and canalicular bile accumulation, especially in later stages
─ Periportal copper deposition (stains with Rhodanine or Orcein) in hepatocytes due to chronic cholestasis
─ Interface hepatitis may be present but is usually mild
─ Progressive portal fibrosis, bridging fibrosis, and eventually biliary cirrhosis (often with a "jigsaw puzzle" nodular pattern)
─ Histologic Staging (e.g., Ludwig or Scheuer systems): ─ Stage 1: Portal inflammation, florid duct lesions, +/- granulomas (ductal stage)
─ Stage 2: Periportal inflammation/fibrosis, ductular proliferation (periportal stage)
─ Stage 3: Bridging fibrosis/septal fibrosis (septal stage)
─ Stage 4: Cirrhosis (cirrhotic stage)

Ancillary studies ─

─ Special Stains:
─ CK7 or CK19: Highlight bile duct epithelium, useful for assessing ductopenia and ductular reaction
─ Copper stain (Rhodanine, Orcein): Demonstrates copper accumulation in periportal hepatocytes (indicates chronic cholestasis)
─ Trichrome: Highlights fibrosis
─ IHC: Not typically used for primary diagnosis but can characterize inflammatory cells

DDx ─

─ Primary Sclerosing Cholangitis (PSC) (affects larger intra- and extrahepatic ducts, "onion-skin" periductal fibrosis, more common in males, often associated with IBD; AMA negative)
─ Autoimmune Hepatitis (AIH) (prominent interface hepatitis, lobular inflammation, many plasma cells; typically different autoantibody profile - ANA, ASMA, anti-LKM1; can overlap with PBC - "PBC-AIH overlap syndrome")
─ Drug-induced cholestasis or ductopenia (history of offending drug; histology can mimic PBC)
─ Chronic biliary obstruction (extrahepatic or large intrahepatic duct obstruction; often shows portal edema, neutrophilic cholangitis, prominent ductular reaction)
─ Sarcoidosis (can have hepatic granulomas, but typically not centered on bile ducts and AMA negative)
─ Graft-versus-host disease (GVHD) (in transplant setting; can cause bile duct injury and ductopenia)

Prognosis ─ ─ Chronic and progressive, but course is variable
─ Ursodeoxycholic acid (UDCA) is first-line therapy; improves liver biochemistry, slows histologic progression, and improves transplant-free survival in responders
─ Obeticholic acid or fibrates may be used as second-line therapy for UDCA non-responders or intolerant patients
─ Prognosis is worse in patients with high bilirubin, advanced histologic stage at diagnosis, or poor response to UDCA
─ Complications include fatigue, pruritus, osteoporosis, fat-soluble vitamin deficiencies, portal hypertension, cirrhosis, and hepatocellular carcinoma (risk increased in cirrhotic stage)
─ Liver transplantation is an option for end-stage liver disease

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Autoimmune Hepatitis (AIH)

A chronic, and sometimes acute, inflammatory liver disease of unknown etiology, characterized by circulating autoantibodies, hypergammaglobulinemia (especially elevated IgG), and a liver biopsy showing interface hepatitis; it responds to immunosuppressive therapy

Clinical ─ ─ Can occur at any age, with bimodal peaks in young adulthood and peri/post-menopause; more common in females
─ Clinical presentation is highly variable:
─ Asymptomatic, detected by incidental liver enzyme elevation
─ Non-specific symptoms: fatigue (common), malaise, anorexia, arthralgias, myalgias
─ Acute hepatitis presentation: jaundice, right upper quadrant pain, nausea (can mimic viral hepatitis)
─ Fulminant hepatic failure (rare)
─ Signs of chronic liver disease/cirrhosis at presentation in some cases
─ Associated with other autoimmune diseases (e.g., autoimmune thyroiditis, rheumatoid arthritis, celiac disease, type 1 diabetes, IBD)
─ Diagnostic features:
─ Elevated aminotransferases (AST, ALT), often markedly (hepatocellular pattern of injury)
─ Hypergammaglobulinemia, particularly elevated serum IgG levels
─ Presence of characteristic autoantibodies:
─ Type 1 AIH (most common): ANA (anti-nuclear antibody) and/or ASMA (anti-smooth muscle antibody). Anti-SLA/LP (anti-soluble liver antigen/liver pancreas antigen) antibodies are highly specific but less common.
─ Type 2 AIH (less common, often pediatric or more severe): Anti-LKM1 (anti-liver kidney microsomal type 1 antibody) and/or Anti-LC1 (anti-liver cytosol type 1 antibody)
─ Characteristic liver histology (interface hepatitis, plasma cell-rich infiltrate)
─ Exclusion of other causes of chronic liver disease (e.g., viral hepatitis, drug-induced, Wilson disease, NAFLD)
─ Response to corticosteroids and other immunosuppressants is a key feature

Macro ─ ─ Early stages: Liver may appear normal or slightly enlarged and congested
─ Chronic disease: Can lead to a shrunken, nodular, cirrhotic liver

Micro ─

─ Interface hepatitis (piecemeal necrosis) is the histologic hallmark: ─ Lymphoplasmacytic infiltrate (often rich in plasma cells) in portal tracts that breaches the limiting plate and extends into the adjacent periportal parenchyma, causing damage and apoptosis of periportal hepatocytes
─ Lobular inflammation and injury: ─ Scattered lymphocytes and plasma cells within the hepatic lobules
─ Hepatocyte apoptosis (acidophil bodies) and focal necrosis ("spotty necrosis")
─ Hepatocyte rosette formation (gland-like arrangement of hepatocytes around a central space, often seen in areas of regeneration and severe inflammation)
─ Portal inflammation: Expanded portal tracts with a dense mononuclear inflammatory infiltrate, predominantly lymphocytes and numerous plasma cells. Eosinophils may be present.
─ Emperipolesis: Presence of intact inflammatory cells (lymphocytes) within the cytoplasm of hepatocytes (not specific but can be seen)
─ Fibrosis: Can range from portal fibrosis to bridging fibrosis and cirrhosis in untreated or advanced disease. Fibrosis pattern can be portal-based or sometimes centrilobular in cases with severe lobular activity.
─ Absence of significant bile duct injury or steatosis (unless an overlap syndrome or coexisting condition is present)
─ Severe AIH can show confluent or bridging necrosis

Ancillary studies ─

─ Special Stains:
─ Trichrome or Sirius red: To assess fibrosis stage
─ Reticulin: Can show collapse of reticulin framework in areas of necrosis
─ Iron/Copper: Usually negative, to help exclude hemochromatosis/Wilson disease
─ IHC:
─ Not specific for diagnosis, but can help characterize the inflammatory infiltrate (e.g., CD3 for T-cells, CD20 for B-cells, CD138 for plasma cells)
─ IgG4 staining may be done if IgG4-related disease/autoimmune pancreatitis is in the differential, but AIH itself is not typically an IgG4-rich process

DDx ─

─ Chronic viral hepatitis (B or C) (serologies positive; portal inflammation is predominantly lymphocytic, plasma cells less prominent than in AIH; ground glass cells in HBV, lymphoid aggregates/steatosis in HCV)
─ Drug-induced liver injury (DILI) (history of offending drug; can mimic AIH histologically and serologically - "drug-induced autoimmune-like hepatitis")
─ Primary Biliary Cholangitis (PBC) / Primary Sclerosing Cholangitis (PSC) (cholestatic features, bile duct injury/loss, different autoantibodies - AMA for PBC; PSC often associated with IBD, characteristic cholangiography)
─ Overlap syndromes (AIH-PBC, AIH-PSC): Patients may show features of both AIH and a cholestatic autoimmune liver disease.
─ Wilson disease (especially in younger patients; check ceruloplasmin, urinary copper)
─ Alpha-1 antitrypsin deficiency (PAS-D positive globules)
─ Non-alcoholic steatohepatitis (NASH) (steatosis, ballooning, perisinusoidal fibrosis; usually lacks prominent interface hepatitis and hypergammaglobulinemia of AIH, though overlap can occur if patient has both metabolic risk factors and AIH)

Prognosis ─ ─ Untreated AIH can progress to cirrhosis, liver failure, and death
─ With immunosuppressive treatment (corticosteroids +/- azathioprine or mycophenolate mofetil), remission can be achieved in most patients, and long-term prognosis is generally good, especially if diagnosed and treated before cirrhosis develops
─ Relapses are common after treatment withdrawal, and many patients require long-term maintenance therapy
─ Factors associated with poorer prognosis include severe histologic activity or cirrhosis at diagnosis, acute severe presentation, and failure to achieve remission with standard therapy
─ Liver transplantation is an option for end-stage liver disease or fulminant failure unresponsive to medical therapy

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Chronic Viral Hepatitis (HBV, HCV - patterns of injury)

Persistent inflammation and injury to the liver caused by chronic infection with hepatitis B virus (HBV) or hepatitis C virus (HCV), which can lead to fibrosis, cirrhosis, and hepatocellular carcinoma (HCC)

Clinical ─ ─ HBV: ─ Transmission: Parenteral (blood), sexual, perinatal
─ Chronic infection develops in ~5% of immunocompetent adults, but much higher (~90%) in perinatally infected infants
─ Clinical course is variable: inactive carrier state, chronic hepatitis (HBeAg-positive or HBeAg-negative), cirrhosis, HCC. Flares of activity can occur.
─ Serologic markers are key for diagnosis and staging (HBsAg, HBeAg, anti-HBe, HBV DNA levels)
─ HCV: ─ Transmission: Primarily parenteral (blood); sexual/perinatal less common but possible
─ Chronic infection develops in ~50-85% of acutely infected individuals
─ Often asymptomatic for decades until advanced liver disease develops
─ Can lead to progressive fibrosis, cirrhosis, and HCC. Extrahepatic manifestations are common (e.g., cryoglobulinemia, porphyria cutanea tarda).
─ Diagnosis by anti-HCV antibodies and HCV RNA testing
─ Symptoms of chronic viral hepatitis, if present, are often non-specific: fatigue, malaise, mild right upper quadrant discomfort. Jaundice is uncommon unless advanced disease or acute flare.

Macro ─ ─ Early/mild chronic hepatitis: Liver may appear normal or slightly enlarged
─ Advanced fibrosis/cirrhosis: Liver becomes shrunken, firm, and nodular

Micro ─

─ General features common to both chronic HBV and HCV hepatitis (though intensity and specific features can vary): ─ Portal inflammation: Predominantly lymphocytic infiltrate in portal tracts, can be mild to dense. Lymphoid aggregates or follicles are common, especially in HCV.
─ Interface hepatitis (piecemeal necrosis): Inflammation extending from portal tracts into the periportal parenchyma, with damage to hepatocytes at the limiting plate. Severity varies.
─ Lobular inflammation and injury: Scattered lymphocytes within lobules ("spotty necrosis"), hepatocyte apoptosis (acidophil bodies), focal hepatocyte necrosis. Kupffer cell hyperplasia.
─ Fibrosis: Begins as portal fibrosis, progresses to periportal fibrosis, bridging fibrosis (portal-portal or portal-central), and eventually cirrhosis. Staging systems (e.g., Metavir, Ishak) are used to grade activity and stage fibrosis.
─ Specific features more characteristic of HBV: ─ "Ground glass" hepatocytes: Cells with pale, eosinophilic, finely granular cytoplasm due to abundant HBsAg in the endoplasmic reticulum (more common in chronic carriers or HBeAg-positive disease). Can be highlighted by Victoria blue or orcein stains, or HBsAg IHC.
─ "Sanded" nuclei: Hepatocyte nuclei filled with HBcAg (less common, indicates active viral replication). Can be highlighted by HBcAg IHC.
─ Fibrosing cholestatic hepatitis: A severe, rapidly progressive form seen in immunosuppressed patients (e.g., post-transplant) with high HBV replication, characterized by marked cholestasis and perisinusoidal fibrosis
─ Specific features more characteristic of HCV: ─ Lymphoid aggregates/follicles in portal tracts: Often prominent
─ Bile duct damage: Mild, non-destructive lymphocytic cholangitis can be seen in some portal tracts
─ Macrovesicular steatosis: Common, especially with HCV genotype 3. Can sometimes be extensive.
─ Sinusoidal lymphocytic infiltrates
─ Grading of Activity (Necroinflammatory Score): Based on the severity of interface hepatitis, confluent necrosis, focal lobular necrosis, and portal inflammation. (e.g., Metavir activity grade A0-A3, Ishak HAI score).
─ Staging of Fibrosis: Based on the extent and pattern of fibrosis (e.g., Metavir fibrosis stage F0-F4, Ishak fibrosis stage 0-6).

Ancillary studies ─

─ Special Stains:
─ Trichrome or Sirius red: To assess fibrosis stage
─ Reticulin: Highlights lobular architecture and areas of collapse
─ Orcein or Victoria blue: Can highlight HBsAg-containing ground glass hepatocytes in HBV
─ Iron: To exclude significant coexisting iron overload
─ IHC:
─ HBsAg and HBcAg: To detect HBV antigens in hepatocytes. HBsAg is cytoplasmic; HBcAg is nuclear (and sometimes cytoplasmic).
─ HCV antigens: IHC for HCV is not routinely used for diagnosis in clinical practice (RNA testing is standard)

DDx ─

─ Autoimmune hepatitis (AIH) (prominent plasma cells, more severe interface hepatitis, hypergammaglobulinemia, specific autoantibodies)
─ Drug-induced liver injury (DILI) (history of offending drug; can mimic various patterns)
─ Primary Biliary Cholangitis (PBC) / Primary Sclerosing Cholangitis (PSC) (if cholestatic features or bile duct injury are prominent; PBC has AMA, PSC has characteristic cholangiography and often IBD)
─ Non-alcoholic fatty liver disease (NAFLD/NASH) (if steatosis is prominent; look for metabolic risk factors, ballooning, perisinusoidal fibrosis)
─ Wilson disease, Alpha-1 antitrypsin deficiency (specific clinical and lab findings, special stains/IHC)

Prognosis ─ ─ Variable, depends on viral factors (e.g., HBV genotype, viral load, HBeAg status for HBV; HCV genotype for HCV), host factors (age at infection, immune status, comorbidities, alcohol use), and stage of liver disease at diagnosis
─ Both chronic HBV and HCV can lead to progressive fibrosis, cirrhosis, and an increased risk of hepatocellular carcinoma (HCC). HBV can cause HCC even in the absence of cirrhosis.
─ Antiviral therapies are available for both HBV (can suppress viral replication, reduce inflammation/fibrosis, lower HCC risk) and HCV (direct-acting antivirals - DAAs - can achieve sustained virologic response/cure in most, reducing fibrosis and HCC risk)
─ Regular monitoring for disease progression and HCC screening is important in patients with chronic viral hepatitis, especially those with advanced fibrosis or cirrhosis

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Primary Sclerosing Cholangitis (PSC)

A chronic, progressive cholestatic liver disease characterized by inflammation, fibrosis, and stricturing of intrahepatic and/or extrahepatic bile ducts, leading to biliary cirrhosis and an increased risk of cholangiocarcinoma

Clinical ─ ─ More common in males (male:female ratio ~2:1), often diagnosed in young to middle-aged adults (mean age 30-40 years)
─ Strongly associated with inflammatory bowel disease (IBD), particularly ulcerative colitis (UC), which is present in ~70-80% of PSC patients. PSC may precede or follow IBD diagnosis.
─ Clinical presentation is variable:
─ Asymptomatic, detected by persistently elevated alkaline phosphatase (ALP)
─ Symptoms: Fatigue, pruritus, intermittent jaundice, right upper quadrant pain, recurrent bacterial cholangitis (fever, chills, jaundice)
─ Diagnosis is primarily based on characteristic cholangiographic findings (MRCP or ERCP) showing multifocal strictures and dilatations of intra- and/or extrahepatic bile ducts ("beaded" appearance)
─ No specific autoantibodies are diagnostic; pANCA may be positive in a subset but is not specific
─ Increased risk of cholangiocarcinoma (10-20% lifetime risk), gallbladder cancer, and hepatocellular carcinoma (in cirrhotic stage)
─ Small duct PSC: Affects only small intrahepatic bile ducts, normal cholangiogram; diagnosis requires liver biopsy showing characteristic features. May have a better prognosis than large duct PSC.

Macro ─ ─ Liver may appear normal initially or show features of chronic cholestasis (greenish discoloration)
─ Bile ducts may be visibly thickened and fibrotic; strictures and dilatations can be seen on gross examination of explanted livers or large resections
─ Advanced disease leads to biliary cirrhosis with a firm, nodular liver

Micro ─

─ Large duct involvement (classic PSC): Biopsy findings can be patchy and non-specific, especially in early stages. Characteristic features are often best seen in larger ducts not typically sampled by needle biopsy.
─ Periductal "onion-skin" fibrosis: Concentric, lamellar fibrosis around interlobular or septal bile ducts is highly characteristic but not always present, especially in needle biopsies.
─ Chronic portal inflammation, often lymphocytic, with variable interface activity
─ Bile ductular reaction/proliferation
─ Bile duct injury: Epithelial vacuolization, atrophy, irregularity; may lead to ductopenia in later stages
─ Cholestasis (hepatocellular and canalicular) may be present, especially with significant obstruction
─ Progressive portal fibrosis, bridging fibrosis, and biliary cirrhosis
─ Small duct PSC: ─ Histologic features similar to large duct PSC but confined to smaller interlobular bile ducts; cholangiogram is normal
─ Fibro-obliterative duct lesions: Bile ducts may be replaced by fibrous scars
─ May show prominent ductular reaction and cholestasis
─ Absence of florid duct lesions with granulomas (as seen in PBC)
─ Dysplastic changes in biliary epithelium should be carefully sought, especially in surveillance biopsies, due to cholangiocarcinoma risk

Ancillary studies ─

─ Special Stains:
─ Trichrome or Sirius red: Highlight periductal and portal fibrosis
─ Copper stain (Rhodanine, Orcein): May show periportal copper deposition in chronic cholestasis
─ CK7 or CK19: Highlight bile duct epithelium, useful for assessing ductular reaction and ductopenia
─ IHC: Not specific for diagnosis. IgG4 staining may be performed to exclude IgG4-related sclerosing cholangitis (typically shows >10-50 IgG4+ plasma cells/HPF and elevated IgG4:IgG ratio in IgG4-RSC).

DDx ─

─ IgG4-related sclerosing cholangitis (IgG4-RSC) (elevated serum IgG4, other organ involvement like autoimmune pancreatitis, dense lymphoplasmacytic infiltrate rich in IgG4+ plasma cells, storiform fibrosis, obliterative phlebitis; responds to steroids)
─ Secondary sclerosing cholangitis (due to known causes like choledocholithiasis, ischemic injury, infections, prior biliary surgery, intra-arterial chemotherapy)
─ Primary Biliary Cholangitis (PBC) (AMA positive, florid duct lesions with granulomas, predominantly affects small ducts, female predominance)
─ Cholangiocarcinoma (PSC is a major risk factor; biopsy may show dysplastic or malignant biliary epithelium)
─ Autoimmune hepatitis (AIH) (hepatocellular pattern of injury, different autoantibodies, interface hepatitis often more prominent; overlap with PSC can occur - "PSC-AIH overlap syndrome")
─ Ischemic cholangiopathy (history of vascular insult)

Prognosis ─ ─ Progressive disease with variable course; median survival from diagnosis without transplant was historically ~10-12 years, but is improving
─ No medical therapy has been definitively proven to halt disease progression, though UDCA may improve liver enzymes and is often used
─ Major causes of morbidity/mortality: complications of cirrhosis and portal hypertension, recurrent bacterial cholangitis, cholangiocarcinoma development
─ Liver transplantation is the only curative option for end-stage PSC; recurrence in the graft can occur
─ Regular surveillance for cholangiocarcinoma (e.g., imaging, ERCP with brushings/biopsies) and colorectal cancer (if IBD is present) is essential

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Alpha-1 Antitrypsin Deficiency (Liver Manifestations)

An autosomal co-dominant genetic disorder caused by mutations in the SERPINA1 gene, leading to deficient levels of circulating alpha-1 antitrypsin (AAT) protein and accumulation of abnormal AAT protein in hepatocytes, which can cause liver disease (neonatal hepatitis, chronic hepatitis, cirrhosis, hepatocellular carcinoma) and lung disease (emphysema)

Clinical ─ ─ Liver disease occurs primarily in individuals homozygous for the Z allele (PiZZ genotype), and less commonly in other genotypes (e.g., PiSZ, PiMZ in combination with other risk factors)
─ Clinical presentation of liver disease is variable:
─ Neonatal cholestatic jaundice/hepatitis syndrome (in ~10-15% of PiZZ infants)
─ Asymptomatic liver enzyme elevation in childhood or adulthood
─ Chronic hepatitis, fibrosis, and cirrhosis developing in adulthood (in ~10-40% of Pi*ZZ individuals over their lifetime)
─ Hepatocellular carcinoma (HCC) risk is significantly increased, especially in the setting of cirrhosis
─ Lung disease (emphysema, typically panacinar and basilar predominant) is the most common manifestation in adults, especially in smokers
─ Diagnosis: Low serum AAT levels, AAT protein phenotyping (by isoelectric focusing) or genotyping (SERPINA1 gene sequencing) to identify specific alleles (M=normal, S and Z=deficient alleles)

Macro ─ ─ Liver may appear normal, pale (if steatosis is present), or cirrhotic (firm, nodular)
─ Explanted cirrhotic livers may not have specific gross features distinguishing AATD from other causes of cirrhosis

Micro ─

─ Characteristic histologic hallmark: Presence of eosinophilic, round to oval, intracytoplasmic globules within hepatocytes, particularly in periportal (zone 1) hepatocytes
─ These globules represent accumulated, misfolded AAT protein within the endoplasmic reticulum
─ Globules are PAS-positive and diastase-resistant (PAS-D positive)
─ Other liver histologic findings can be variable and non-specific: ─ Neonatal hepatitis pattern: Lobular disarray, giant cell transformation, cholestasis, portal inflammation (in affected infants)
─ Chronic hepatitis: Portal and/or lobular inflammation (lymphocytic), interface hepatitis (can be mild to moderate)
─ Steatosis (macrovesicular) can be present
─ Hepatocyte injury (ballooning, apoptosis)
─ Fibrosis: Portal fibrosis, periportal fibrosis, bridging fibrosis, and cirrhosis can develop over time. The pattern of fibrosis is not specific.
─ Bile ductular reaction may be seen with advancing fibrosis
─ In cirrhosis, the globules may become less conspicuous or be absent in some nodules

Ancillary studies ─

─ Special Stains:
─ PAS-D (Periodic Acid-Schiff with diastase): Highlights the characteristic magenta-colored, diastase-resistant intracytoplasmic globules in hepatocytes. This is a key diagnostic stain.
─ Trichrome: To assess fibrosis
─ Iron: Usually negative, to exclude hemochromatosis (though iron can accumulate in any end-stage liver disease)
─ IHC:
─ Alpha-1 antitrypsin IHC: Stains the intracytoplasmic globules, confirming they are composed of AAT protein

DDx ─

─ Other causes of neonatal cholestasis (e.g., biliary atresia, other metabolic disorders)
─ Other causes of chronic hepatitis/cirrhosis in adults (e.g., viral hepatitis, autoimmune hepatitis, NAFLD/NASH, alcoholic liver disease, Wilson disease, hemochromatosis). The PAS-D positive globules are key to suggesting AATD.
─ Other conditions with eosinophilic hepatocellular globules (these are typically PAS-D negative or have different morphology/distribution):
─ Mallory-Denk bodies (larger, rope-like, irregular, often in ballooned cells; seen in ASH/NASH)
─ Megamitochondria (can be eosinophilic, round; PAS-D negative)
─ Fibrinogen globules (rare, in hereditary hypofibrinogenemia; PAS-D negative)
─ Lafora bodies (rare, in Lafora disease; PAS-D positive but also stain with Best's carmine)

Prognosis ─ ─ Highly variable, depends on genotype (PiZZ most severe), presence and severity of liver and/or lung disease, and environmental factors (e.g., smoking greatly accelerates emphysema)
─ Not all PiZZ individuals develop clinically significant liver disease
─ Development of cirrhosis significantly worsens prognosis and increases HCC risk
─ Management includes avoidance of smoking, alcohol, and hepatotoxic drugs; supportive care for liver disease complications; AAT augmentation therapy (for lung disease, not proven effective for liver disease); liver transplantation for end-stage liver disease or HCC

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IgG4-related Sclerosing Cholangitis (IgG4-RSC)

A fibroinflammatory biliary disease characterized by dense lymphoplasmacytic infiltration rich in IgG4-positive plasma cells, storiform fibrosis, and often obliterative phlebitis, affecting intrahepatic and/or extrahepatic bile ducts; it is a manifestation of systemic IgG4-related disease (IgG4-RD) and typically responds to corticosteroids

Clinical ─ ─ Part of the spectrum of IgG4-RD, which can affect multiple organs (e.g., pancreas - autoimmune pancreatitis type 1, salivary glands, kidneys, retroperitoneum, lymph nodes)
─ More common in older males (typically >60 years)
─ Clinical presentation:
─ Obstructive jaundice (most common)
─ Abdominal pain, weight loss, pruritus
─ May be asymptomatic with abnormal liver tests or incidental imaging findings
─ Often associated with autoimmune pancreatitis (AIP type 1) in a significant proportion of cases (up to 70-90%)
─ Laboratory findings:
─ Elevated serum IgG4 levels (>135 mg/dL or >1.35 g/L) are characteristic but not universally present (normal in ~10-30% of cases) and not entirely specific
─ Elevated ALP, GGT, and bilirubin (cholestatic pattern)
─ Mildly elevated aminotransferases may occur
─ Other autoantibodies (ANA, RF) may be present at low titers
─ Imaging (MRCP/ERCP/CT/MRI): Shows biliary strictures (often long, continuous, or multifocal), diffuse or focal bile duct wall thickening, and may show involvement of other organs (e.g., "sausage-shaped" pancreas in AIP)

Macro ─ ─ Bile duct walls are often thickened and fibrotic
─ Strictures can be seen in intrahepatic and/or extrahepatic ducts, particularly the distal common bile duct if associated with AIP
─ Liver may appear normal or show signs of cholestasis or secondary biliary cirrhosis in advanced cases

Micro ─

─ Key histologic features in bile duct biopsies or resections: ─ Dense lymphoplasmacytic infiltrate in the bile duct wall and periductal tissue, often transmural
─ Numerous IgG4-positive plasma cells: Typically >10-50 IgG4+ plasma cells per high-power field (HPF), and an IgG4+/IgG+ plasma cell ratio >40% are supportive diagnostic criteria (thresholds may vary slightly by consensus group and sample type)
─ Storiform fibrosis: Characteristic "cartwheel" or irregularly whorled pattern of fibrosis
─ Obliterative phlebitis: Inflammation and obliteration of small veins within the affected tissue
─ Eosinophils may be present in the inflammatory infiltrate
─ Bile duct epithelium is often relatively preserved or may show reactive changes, but typically not the florid destructive cholangitis of PBC or the "onion-skin" fibrosis of PSC
─ Liver biopsy findings (if primarily intrahepatic involvement or secondary changes): ─ Portal inflammation with lymphoplasmacytic infiltrate, often rich in IgG4+ plasma cells
─ Bile ductular reaction, cholestasis
─ Interface hepatitis can be present
─ Lobular inflammation may be seen
─ Fibrosis, progressing to biliary cirrhosis in untreated or advanced cases
─ Granulomas are typically absent

Ancillary studies ─

─ IHC:
─ IgG4 immunostain: Essential for diagnosis; demonstrates increased numbers of IgG4-positive plasma cells in the tissue (>10-50/HPF, depending on criteria and site)
─ IgG immunostain: Used to calculate the IgG4/IgG ratio (>40% supports diagnosis)
─ CK7/CK19: Highlight bile duct epithelium
─ Serology: Elevated serum IgG4 levels support the diagnosis but are not diagnostic alone and can be normal

DDx ─

─ Primary Sclerosing Cholangitis (PSC) (often associated with IBD, typically normal serum IgG4, "onion-skin" fibrosis, lacks prominent IgG4+ plasma cells and storiform fibrosis; usually poor response to steroids)
─ Cholangiocarcinoma (malignant epithelial cells, desmoplasia; can cause obstructive jaundice and mimic IgG4-RSC on imaging, making biopsy crucial. IgG4-RSC can sometimes form a mass-like lesion. Important to exclude malignancy)
─ Primary Biliary Cholangitis (PBC) (AMA positive, florid duct lesions with granulomas, affects small ducts)
─ Secondary sclerosing cholangitis (due to stones, surgery, ischemia – history and imaging are key)
─ Autoimmune hepatitis (if interface hepatitis is prominent; different autoantibody profile, typically hepatocellular injury pattern, usually responds to steroids but IgG4 features are absent)

Prognosis ─ ─ Generally good response to corticosteroid therapy, leading to resolution of jaundice and improvement in biliary strictures and liver tests in most patients
─ Relapses can occur after steroid withdrawal or tapering, and long-term low-dose maintenance therapy may be needed
─ If untreated, can progress to secondary biliary cirrhosis and liver failure
─ Risk of cholangiocarcinoma is thought to be lower than in PSC, but careful exclusion of malignancy at diagnosis is critical
─ Long-term outcomes are still being defined, but appear more favorable than PSC if diagnosed and treated appropriately

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Cirrhosis (and its complications/histologic features)

An advanced stage of chronic liver disease characterized by the irreversible replacement of normal liver parenchyma with extensive fibrosis (scar tissue) and the formation of structurally abnormal regenerative nodules, leading to disruption of liver architecture and function

Clinical ─ ─ Results from various chronic liver injuries (e.g., chronic viral hepatitis HBV/HCV, alcoholic liver disease, NAFLD/NASH, autoimmune hepatitis, PBC, PSC, hemochromatosis, Wilson disease)
─ Can be asymptomatic for long periods (compensated cirrhosis)
─ Decompensated cirrhosis presents with complications:
─ Portal hypertension: Increased pressure in the portal venous system due to disrupted blood flow through the fibrotic liver. Leads to:
─ Ascites (fluid accumulation in the abdomen)
─ Esophageal and gastric varices (dilated veins at risk of life-threatening bleeding)
─ Splenomegaly (enlarged spleen, can cause thrombocytopenia/leukopenia)
─ Caput medusae (dilated periumbilical veins)
─ Hepatic insufficiency (liver failure): Impaired liver synthetic and metabolic functions. Leads to:
─ Jaundice (yellowing of skin/eyes due to bilirubin accumulation)
─ Coagulopathy (impaired synthesis of clotting factors, leading to easy bruising/bleeding)
─ Hypoalbuminemia (low serum albumin, contributing to edema/ascites)
─ Hepatic encephalopathy (neuropsychiatric dysfunction due to accumulation of toxins like ammonia)
─ Hepatocellular carcinoma (HCC): Increased risk of developing primary liver cancer
─ Other symptoms: Fatigue, weakness, weight loss, muscle wasting, pruritus, spider angiomata, palmar erythema, gynecomastia, testicular atrophy, amenorrhea
─ Diagnosis is based on clinical signs, imaging (ultrasound, CT, MRI showing nodular liver, signs of portal hypertension), laboratory tests (liver function tests, markers of synthetic function), and often liver biopsy (though less frequently needed if non-invasive markers and imaging are conclusive)

Macro ─ ─ Liver is typically shrunken (though can be enlarged in early stages or with steatotic cirrhosis), firm to hard, and has a diffusely nodular surface
─ Nodules vary in size:
─ Micronodular cirrhosis: Nodules are small, generally <3 mm in diameter, and relatively uniform in size (often seen in alcoholic cirrhosis, hemochromatosis, chronic biliary obstruction)
─ Macronodular cirrhosis: Nodules are larger, >3 mm, and more variable in size and shape (often seen in chronic viral hepatitis, Wilson disease, A1AT deficiency)
─ Mixed cirrhosis: Features of both micronodular and macronodular patterns
─ Fibrous septa separate the nodules
─ Color can vary depending on etiology (e.g., yellow in steatotic cirrhosis, green in biliary cirrhosis, brown/rust-colored in hemochromatosis)

Micro ─

─ Defining features of cirrhosis: ─ Fibrosis: Diffuse, extensive fibrous septa that surround and subdivide the liver parenchyma
─ Regenerative nodules: Nodules of hepatocytes attempting to regenerate, but within a distorted architectural framework. These nodules lack normal portal tracts and central veins in their centers and are surrounded by fibrous septa.
─ Disruption of normal hepatic architecture: Loss of the normal lobular arrangement of portal tracts, hepatocytes, and central veins
─ Other features that may be present depending on etiology and activity: ─ Evidence of ongoing liver injury (e.g., inflammation, steatosis, hepatocyte ballooning, cholestasis, Mallory-Denk bodies) may be seen within the nodules or septa, reflecting the underlying cause or activity of the disease
─ Ductular reaction is typically prominent within the fibrous septa
─ Vascular changes: Thickened arteries, obliterated portal or central vein branches within septa
─ Dysplastic nodules (low-grade or high-grade) can arise within cirrhotic livers and are precursors to HCC

Ancillary studies ─

─ Special Stains:
─ Masson's trichrome or Sirius red: Essential to highlight the extent and pattern of fibrosis and the nodular architecture
─ Reticulin: Shows collapsed framework in areas of previous necrosis and dense reticulin around nodules
─ Stains for iron (Prussian blue), copper (Rhodanine), PAS-D (for A1AT globules) may help identify specific etiologies if not already known
─ IHC: Generally not used for the diagnosis of cirrhosis itself, but can be used to investigate underlying etiology or to evaluate for dysplasia/HCC in cirrhotic nodules (e.g., glypican-3, HSP70, glutamine synthetase for HCC)

DDx ─

─ Severe bridging fibrosis without definite nodule formation (Stage 3 fibrosis / incomplete cirrhosis)
─ Nodular regenerative hyperplasia (diffuse micronodularity without significant fibrosis; reticulin stain shows preserved framework around nodules with compressed and atrophic areas between them)
─ Congenital hepatic fibrosis (developmental disorder with broad fibrous septa and abnormal bile duct structures, but usually lacks true regenerative nodules and architectural distortion of cirrhosis)
─ Focal nodular hyperplasia (typically a solitary, well-circumscribed lesion with a central scar, not a diffuse process)
─ Partial nodular transformation (large regenerative nodules near the hilum, usually without diffuse fibrosis)

Prognosis ─ ─ Cirrhosis is generally considered irreversible, although some degree of fibrosis regression may occur if the underlying cause is effectively treated (e.g., viral eradication in HCV, alcohol abstinence)
─ Prognosis depends on the etiology, severity (Child-Pugh score, MELD score), presence of complications (decompensation), and development of HCC
─ Decompensated cirrhosis has a significantly worse prognosis than compensated cirrhosis
─ Management focuses on treating the underlying cause, preventing and managing complications, nutritional support, and screening for HCC
─ Liver transplantation is the definitive treatment for end-stage cirrhosis and selected cases of HCC within cirrhosis

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Congenital and Developmental Conditions

Congenital Hepatic Fibrosis (CHF)

An autosomal recessive developmental disorder of the portobiliary system characterized by abnormal remodeling of the ductal plate, leading to excessive embryonic bile duct structures, portal tract fibrosis, and portal hypertension, typically without significant hepatocellular dysfunction in early stages

Clinical ─ ─ Often presents in late childhood or adolescence, but can be diagnosed in infancy or adulthood
─ Clinical manifestations are primarily due to portal hypertension:
─ Hepatosplenomegaly (firm, enlarged liver is common)
─ Variceal bleeding (esophageal, gastric) is a common presenting symptom
─ Ascites (less common initially)
─ Hypersplenism (thrombocytopenia, leukopenia)
─ Liver synthetic function (e.g., albumin, coagulation factors) is usually preserved until late stages or if complications arise
─ Associated with other fibropolycystic diseases/ciliopathies:
─ Autosomal Recessive Polycystic Kidney Disease (ARPKD) is invariably associated with CHF (due to PKHD1 gene mutations)
─ Caroli syndrome (CHF + Caroli disease - saccular dilatation of larger intrahepatic bile ducts)
─ Joubert syndrome, Meckel-Gruber syndrome, Bardet-Biedl syndrome
─ Recurrent bacterial cholangitis can occur, especially if associated with Caroli disease or other biliary abnormalities
─ Diagnosis often made via liver biopsy in the context of portal hypertension and/or associated renal cystic disease

Macro ─ ─ Liver is typically enlarged, firm to hard, with a smooth or finely granular surface. Gross nodules of cirrhosis are absent.
─ Cut surface shows diffuse fibrosis, particularly around portal areas
─ Spleen is usually enlarged due to portal hypertension

Micro ─

─ Key diagnostic features: ─ Broad bands of dense fibrous tissue expanding and linking portal tracts, subdividing the parenchyma into irregular islands. This fibrosis is typically portal-centered.
─ Abnormal bile duct profiles (ductal plate malformation): Numerous, often irregularly shaped, branching, or ectatic bile duct-like structures embedded within the fibrous septa. These ducts are remnants of the embryonic ductal plate.
─ Intact lobular architecture: Hepatocytes within the parenchymal islands generally appear normal, with preserved lobular organization (central veins present, though may be compressed). True regenerative nodules of cirrhosis are absent.
─ Hypoplastic or absent portal vein branches within the expanded portal tracts are common
─ Hepatic artery branches are usually present and may appear prominent
─ Minimal to mild portal inflammation (lymphocytes) unless complicated by cholangitis
─ No significant hepatocellular necrosis or inflammation in uncomplicated CHF
─ Cholestasis is usually absent unless there are complications like cholangitis or associated Caroli disease

Ancillary studies ─

─ Special Stains:
─ Masson's trichrome or Sirius red: Highlights the extensive portal and periportal fibrosis, outlining the "jigsaw puzzle" like pattern of parenchymal islands
─ CK7 or CK19: Stains the epithelium of the abnormal bile duct structures within the fibrous septa, emphasizing the ductal plate malformation
─ Reticulin: Shows preserved reticulin framework within the parenchymal islands, distinguishing from cirrhosis where reticulin is collapsed around regenerative nodules
─ IHC: Not typically required for diagnosis if classic features are present. Can confirm biliary origin of ductal structures (CK7/19).
─ Molecular:
─ PKHD1 gene mutations are found in patients with CHF associated with ARPKD
─ Mutations in other ciliopathy-related genes may be found in syndromic cases

DDx ─

─ Cirrhosis (especially biliary cirrhosis or macronodular cirrhosis): Cirrhosis shows true regenerative nodules surrounded by fibrous septa, with loss of normal lobular architecture (absent portal tracts/central veins within nodules). CHF has preserved lobular architecture within parenchymal islands separated by fibrous bands containing ductal plate malformations.
─ Caroli disease (often coexists as Caroli syndrome = CHF + Caroli disease): Caroli disease involves saccular dilatation of larger intrahepatic bile ducts, which may not be evident on needle biopsy but is seen on imaging. Biopsy may show features of CHF and/or changes related to biliary stasis/inflammation in larger ducts if sampled.
─ Primary Sclerosing Cholangitis (PSC) (especially small duct PSC): PSC shows periductal "onion-skin" fibrosis, inflammation, and damage/loss of mature bile ducts. Ductal plate malformation is not a feature of PSC. Often associated with IBD.
─ Nodular regenerative hyperplasia (NRH): Diffuse micronodularity without significant fibrosis; reticulin stain shows preserved framework around hyperplastic nodules with intervening atrophy. Lacks the broad fibrous bands and ductal plate malformation of CHF.
─ Partial nodular transformation (large regenerative nodules, usually hilar, without diffuse fibrosis or ductal plate malformation)

Prognosis ─ ─ Variable, depends on the severity of portal hypertension and associated renal disease (if present)
─ Liver synthetic function often remains preserved for a long time
─ Major morbidity and mortality are related to complications of portal hypertension (variceal bleeding) and recurrent cholangitis (especially if Caroli disease is present)
─ Increased long-term risk of cholangiocarcinoma, particularly in Caroli syndrome
─ Management focuses on controlling portal hypertension (e.g., endoscopic therapy for varices, shunt surgery in some cases) and treating cholangitis. Liver transplantation may be considered for end-stage complications or cholangiocarcinoma.

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Macroregenerative Nodule (in cirrhosis)

A distinct, usually solitary or few, regenerative hepatocellular nodule significantly larger than the surrounding cirrhotic nodules (typically >1 cm, often up to several cm), occurring in a cirrhotic liver; it represents an exaggerated regenerative response and is part of the spectrum of nodular lesions in cirrhosis that includes dysplastic nodules and hepatocellular carcinoma

Clinical ─ ─ Occurs in the setting of established cirrhosis of any etiology
─ Often asymptomatic and detected incidentally on imaging (ultrasound, CT, MRI) performed for cirrhosis surveillance or other reasons
─ May be difficult to distinguish from dysplastic nodules or well-differentiated hepatocellular carcinoma (HCC) on imaging alone, often requiring biopsy or close follow-up
─ Not considered overtly premalignant in itself like a high-grade dysplastic nodule, but indicates a liver at high risk for HCC development elsewhere or within the nodule over time

Macro ─ ─ Appears as a relatively well-circumscribed nodule that is noticeably larger than the background cirrhotic nodules
─ Typically ≥1 cm in diameter, can be several centimeters
─ Color and texture may be similar to or slightly different from the surrounding cirrhotic liver (e.g., paler, more yellow if steatotic, or browner)
─ Does not usually show the distinct encapsulation or mosaic pattern often seen in HCC
─ Cut surface is usually relatively uniform

Micro ─

─ Composed of regenerative hepatocytes arranged in thickened hepatic plates (often 1-2 cells thick, occasionally up to 3 cells thick), similar to or slightly more cellular than the adjacent cirrhotic nodules
─ Hepatocytes generally lack significant cytologic atypia; nuclei are usually small and regular, though some variation in size and mild atypia can be seen, reflecting the regenerative process and background cirrhosis
─ Presence of portal tracts (often small, fibrotic, and sometimes inconspicuous) within the nodule is a key feature distinguishing it from high-grade dysplastic nodules and HCC, which typically lack portal tracts or only have unpaired arteries ─ Architecture is broadly similar to the background cirrhosis but on a larger scale; the nodule is surrounded by fibrous septa
─ Sinusoids are present
─ Features of the underlying chronic liver disease (e.g., steatosis, inflammation, Mallory-Denk bodies, cholestasis, iron deposition) may be present within the macroregenerative nodule, similar to the surrounding liver
─ Bile ductular reaction may be seen at the interface with fibrous septa
─ No evidence of frankly malignant features such as marked nuclear atypia, increased N/C ratio, prominent nucleoli, infiltrative growth, thick trabeculae (>3 cells), or vascular invasion

Ancillary studies ─

─ Special Stains:
─ Reticulin stain: Shows preserved or only slightly expanded/disorganized reticulin framework supporting the thickened hepatic plates. Significant loss or marked disarray of reticulin, as seen in HCC, is absent.
─ Trichrome: Highlights the surrounding fibrous septa and any internal fibrosis
─ Iron/Copper/PAS-D: May show positivity reflecting the underlying liver disease
─ IHC:
─ CD34: Sinusoidal capillarization (diffuse CD34 staining of sinusoids) is typically absent or only very focal/patchy, unlike in HCC where it's often extensive. Normal liver and regenerative nodules show CD34 only in portal tract vessels.
─ Glypican-3 (GPC3): Typically negative (positive in a significant proportion of HCC)
─ Heat Shock Protein 70 (HSP70): Typically negative (positive in a subset of HGDN and HCC)
─ Glutamine Synthetase (GS): Usually shows a normal heterogeneous or perivenular staining pattern, or may be negative. Diffuse/strong positivity or map-like positivity is more suggestive of FNH or some HCCs/HGDNs.
─ Ki-67: Low proliferation index, similar to surrounding cirrhotic liver

DDx ─

─ Low-grade dysplastic nodule (LGDN): Can be very difficult to distinguish from MRN on morphology alone. LGDNs may show slightly increased cellularity, mild atypia, and focal architectural irregularities but still often contain portal tracts. The distinction is subtle and has limited clinical impact as both are managed similarly (surveillance).
─ High-grade dysplastic nodule (HGDN): Shows more significant cytologic and architectural atypia (e.g., increased N/C ratio, nuclear irregularities, focal pseudogland formation, small cell change), often lacks portal tracts, and may show focal reticulin loss or early sinusoidal capillarization. Higher risk of progression to HCC.
─ Well-differentiated Hepatocellular Carcinoma (HCC): Shows unequivocal features of malignancy, such as thickened trabeculae (>3 cells), definite loss of reticulin framework, diffuse sinusoidal capillarization (CD34+), increased N/C ratio, prominent nucleoli, unpaired arteries, and potentially stromal or vascular invasion. Usually negative for GPC3/HSP70 in very well-differentiated forms but positive in less differentiated forms.
─ Large regenerative nodule in non-cirrhotic liver (e.g., partial nodular transformation, focal nodular hyperplasia-like nodule) - context of cirrhosis is key for MRN definition

Prognosis ─ ─ MRNs are benign regenerative lesions but occur in a liver that is at high risk for developing HCC
─ While not considered directly premalignant in the same way as HGDN, they can harbor foci of dysplasia or HCC, or HCC can develop within them over time
─ Patients with MRNs require continued surveillance for HCC, typically with imaging and AFP, similar to other cirrhotic patients

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Focal Nodular Hyperplasia (FNH)

A benign, non-neoplastic, regenerative hepatocellular lesion thought to be a hyperplastic response of hepatocytes to a pre-existing localized vascular anomaly (arterial malformation), characterized by a central stellate scar with radiating fibrous septa and abnormal thick-walled arteries

Clinical ─ ─ Second most common benign liver tumor after hemangioma (prevalence ~0.3-3%)
─ More common in women, often diagnosed in young to middle-aged adults (20-50 years)
─ Usually asymptomatic and discovered incidentally on imaging or at autopsy
─ Rarely, large lesions may cause symptoms like abdominal pain or a palpable mass
─ Not associated with oral contraceptive use (unlike hepatocellular adenoma), though hormones might promote growth of pre-existing lesions
─ Typically occurs in an otherwise normal (non-cirrhotic) liver
─ Multiple FNH lesions can occur in ~20% of cases; association with hepatic hemangiomas or vascular malformations elsewhere (FNH syndrome)

Macro ─ ─ Usually a solitary, well-circumscribed but non-encapsulated lesion, often subcapsular
─ Size varies, typically <5 cm, but can be much larger
─ Characteristic feature: A central stellate fibrous scar from which fibrous septa radiate, dividing the lesion into nodules. The scar may not be apparent in all lesions, especially small ones.
─ Parenchyma is usually lighter in color (tan or yellow-brown) than surrounding normal liver, and has a firm consistency
─ Hemorrhage and necrosis are rare

Micro ─

─ Key architectural features: ─ Central stellate scar: Composed of dense fibrous tissue containing:
─ Numerous thick-walled, often malformed arteries ─ Prominent bile ductular proliferation (reactive ductules at the interface of fibrous septa and hepatocytes)
─ Chronic inflammatory cells (lymphocytes, plasma cells)
─ Radiating fibrous septa: Extend from the central scar, dividing the hepatocellular parenchyma into nodules
─ Hepatocellular nodules: Composed of relatively normal-appearing hepatocytes, often arranged in slightly thickened plates (1-2 cells thick). Hepatocytes may contain glycogen or mild steatosis. No significant cytologic atypia.
─ Absence of normal portal tracts within the lesion: The fibrous septa mimic portal tracts but lack normal portal vein branches and true interlobular bile ducts. Only arteries and ductular reaction are typically seen in the septa.
─ Sinusoids within the nodules may be dilated or show capillarization (CD34 positivity) in some areas, but not as diffusely as in HCC
─ Cholestasis is usually absent
─ The interface between the FNH and surrounding normal liver is usually well-demarcated but not encapsulated
─ Variants exist, e.g., telangiectatic FNH (now largely reclassified as inflammatory hepatocellular adenoma), FNH with steatosis, FNH with large cell change

Ancillary studies ─

─ Special Stains:
─ Masson's trichrome or Sirius red: Highlights the central scar and radiating fibrous septa
─ Reticulin: Shows preserved or only slightly thickened hepatic plates within the nodules; outlines the nodular architecture
─ PAS: May show glycogen in hepatocytes
─ IHC:
─ Glutamine Synthetase (GS): Shows a characteristic "map-like" or geographic pattern of staining. This is due to heterogeneous activation of the Wnt/β-catenin pathway in FNH, leading to strong GS expression in irregular, often periseptal, zones of hepatocytes, while other areas are negative. This pattern is highly specific for FNH when classic.
─ CK7 or CK19: Highlights the prominent bile ductular proliferation within the central scar and fibrous septa
─ CD34: May show some sinusoidal capillarization, particularly near septa, but usually not as diffuse as in HCC. Highlights the abnormal arteries.
─ Smooth Muscle Actin (SMA): Stains the thick walls of arteries in the scar/septa

DDx ─

─ Hepatocellular Adenoma (HCA): ─ Lacks the central scar and radiating septa with ductular proliferation (though some subtypes like inflammatory HCA can have sinusoidal dilatation and inflammation that might mimic FNH features without a scar)
─ Lacks the map-like GS staining pattern (HCAs have different GS patterns depending on subtype: β-catenin mutated HCA is diffusely GS positive; HNF1α-inactivated HCA is GS negative in the lesion; inflammatory HCA can be patchy GS positive but not typically map-like)
─ Composed of monotonous sheets of hepatocytes, often with unpaired arteries but no ductular reaction in septa
─ Carries risks of hemorrhage and malignant transformation (unlike FNH)
─ Well-differentiated Hepatocellular Carcinoma (HCC): ─ Shows cytologic atypia, thickened trabeculae (>3 cells), loss of reticulin, diffuse sinusoidal capillarization (CD34+), often GPC3 or HSP70 positive. Lacks central scar with ductular proliferation and map-like GS staining.
─ Fibrolamellar Carcinoma (FLC): ─ Malignant tumor, often in young adults without cirrhosis. Characterized by large eosinophilic tumor cells with prominent nucleoli, arranged in nests or trabeculae separated by lamellar fibrous bands. Lacks the specific ductular reaction and arterial pattern of FNH scar. Positive for CK7 and CD68 (in fibrous bands).
─ Macroregenerative Nodule / Dysplastic Nodule (in cirrhosis): ─ Occur in a cirrhotic background (FNH occurs in normal liver). MRN/DN lack the characteristic central scar and arterial malformation of FNH. GS staining is different.
─ Nodular Regenerative Hyperplasia (NRH): ─ Diffuse micronodularity without a dominant mass or central scar; lacks fibrous septa with ductular proliferation.

Prognosis ─ ─ Benign lesion with no malignant potential
─ Complications like hemorrhage or rupture are extremely rare
─ Generally does not require treatment if asymptomatic and diagnosis is confident
─ Observation with imaging may be done for large lesions or if diagnosis is uncertain initially
─ Discontinuation of oral contraceptives is sometimes suggested if growth is observed, but a direct causal link is not firmly established for FNH itself

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Polycystic Liver Disease (ADPLD)

An autosomal dominant genetic disorder characterized by the progressive development of multiple (>10-20) fluid-filled cysts throughout the liver parenchyma, often in the absence of significant kidney cysts (distinguishing it from the liver involvement in Autosomal Dominant Polycystic Kidney Disease - ADPKD)

Clinical ─ ─ Caused by mutations in several genes, most commonly PRKCSH (encoding hepatocystin) or SEC63; other genes like LRP5, ALG8, GANAB, SEC61B are less common causes
─ Prevalence is estimated around 1 in 10,000 to 1 in 100,000; may be underdiagnosed
─ Often asymptomatic for many years; symptoms typically develop in adulthood (3rd to 5th decades) as cysts enlarge and increase in number
─ Symptom severity correlates with liver volume/cyst burden:
─ Abdominal distension, chronic pain, early satiety, nausea, dyspnea (due to mass effect from hepatomegaly)
─ Back pain
─ Complications are relatively uncommon but can include:
─ Cyst hemorrhage (causing acute pain)
─ Cyst infection (fever, pain, leukocytosis)
─ Cyst rupture (rare, can cause peritonitis)
─ Compression of biliary tree (leading to jaundice) or portal/hepatic veins (leading to portal hypertension or Budd-Chiari like syndrome) is rare but possible with massive cystic involvement
─ Liver function tests (transaminases, bilirubin, synthetic function) are usually normal or only mildly elevated (e.g., ALP, GGT) unless complications arise
─ Diagnosis is typically made by imaging (ultrasound, CT, MRI) showing multiple liver cysts, in the context of a family history or after excluding ADPKD (by renal imaging)
─ Diagnostic criteria often involve >10 or >20 cysts
─ Female sex and exposure to estrogens (e.g., oral contraceptives, multiple pregnancies) are risk factors for more severe cystic disease and faster growth

Macro ─ ─ Liver is often massively enlarged, sometimes weighing several kilograms
─ Surface and cut section show numerous cysts of varying sizes, from millimeters to many centimeters
─ Cysts are typically thin-walled and filled with clear, serous, or (if hemorrhage occurred) brownish fluid
─ Remaining liver parenchyma between cysts may appear compressed but is generally non-cirrhotic

Micro ─

─ Cysts are lined by a single layer of flattened to cuboidal biliary-type epithelial cells, similar to those lining normal bile ducts or von Meyenburg complexes
─ Cyst wall is composed of a thin layer of fibrous connective tissue
─ The surrounding liver parenchyma is usually normal or compressed, without significant inflammation or fibrosis in uncomplicated ADPLD. Cirrhosis is not a typical feature of isolated ADPLD.
─ Von Meyenburg complexes (bile duct hamartomas) – small clusters of dilated, irregular bile ducts in a fibrous stroma – are often present in the surrounding liver parenchyma and are thought to be precursor lesions for some cysts
─ If cyst complications occur (hemorrhage, infection), evidence of bleeding (hemosiderin) or inflammation (neutrophils, lymphocytes) may be seen in or around the cyst wall

Ancillary studies ─

─ IHC (Cyst lining): Epithelial cells are positive for biliary cytokeratins (CK7, CK19)
─ Molecular (Germline - blood test): Genetic testing can identify mutations in PRKCSH, SEC63, or other associated genes, confirming the diagnosis, especially in familial cases or for genetic counseling. However, not all patients with a clinical diagnosis of ADPLD will have an identifiable mutation in known genes.

DDx ─

─ Autosomal Dominant Polycystic Kidney Disease (ADPKD) with liver cysts: This is the most important differential. ADPKD is characterized by numerous bilateral kidney cysts leading to renal insufficiency, and liver cysts are very common (up to 90%). In ADPKD, kidney involvement is primary and usually more severe. Mutations are in PKD1 or PKD2 genes.
─ Caroli disease / Caroli syndrome: Characterized by saccular, segmental dilatations of larger intrahepatic bile ducts communicating with the biliary tree. Often associated with congenital hepatic fibrosis (Caroli syndrome). Cysts in ADPLD are typically parenchymal and do not necessarily communicate with large bile ducts.
─ Simple liver cysts (biliary cysts): Usually solitary or few, common incidental finding, not genetically determined, no family history. ADPLD involves numerous cysts.
─ Von Meyenburg complexes (bile duct hamartomas): Microscopic lesions, usually small and numerous, but typically do not form large symptomatic cysts on their own, though they are part of the spectrum of ductal plate malformations seen in ADPLD
─ Hydatid cysts (Echinococcal cysts): Parasitic cysts, often have daughter cysts, laminated membrane, and characteristic imaging features; serology for Echinococcus is positive
─ Cystic neoplasms of the liver (e.g., mucinous cystic neoplasm, intraductal papillary neoplasm of bile duct with cystic change, cystic cholangiocarcinoma, cystic metastases): Usually solitary or fewer in number, have specific neoplastic epithelial linings (mucinous, papillary) and/or stromal features (e.g., ovarian-type stroma in MCN), and may show atypia or invasion.
─ Liver abscess with cystic change (clinical signs of infection, imaging features of abscess)

Prognosis ─ ─ Generally a benign condition in terms of liver function, which usually remains preserved
─ Morbidity is primarily related to the mass effect of enlarging cysts and potential complications (hemorrhage, infection, rupture)
─ Does not typically progress to cirrhosis or liver failure in isolated ADPLD (unlike ADPKD where renal failure is common, or Caroli syndrome where biliary complications and cholangiocarcinoma are risks)
─ Risk of malignancy (cholangiocarcinoma) arising from cysts in pure ADPLD is considered very low, much lower than in Caroli disease or PSC
─ Management is usually conservative and focused on symptomatic relief. Options for severe symptoms include cyst aspiration/sclerotherapy, fenestration, segmental liver resection, or rarely, liver transplantation for intractable symptoms and massive hepatomegaly.
─ Avoidance of exogenous estrogens is often recommended for women

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Liver Allograft - Chronic Rejection (Ductopenic, Vascular)

A late, often irreversible form of allograft injury characterized by progressive loss of small bile ducts (ductopenic rejection) and/or obliterative arteriopathy (vascular rejection), leading to graft dysfunction and failure

Clinical ─ ─ Typically occurs months to years after liver transplantation, but can develop earlier
─ May evolve from unresolved or recurrent acute cellular rejection, inadequate immunosuppression, or occur de novo
─ Clinical presentation is often insidious with gradually worsening cholestasis:
─ Progressive jaundice, pruritus
─ Elevated alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT)
─ Bilirubin levels rise with disease progression
─ Aminotransferases (AST, ALT) may be mildly elevated or normal
─ Synthetic liver dysfunction (low albumin, prolonged PT/INR) occurs in advanced stages
─ Risk factors include: previous episodes of severe or recurrent acute rejection, HLA mismatch, non-compliance with immunosuppression, certain underlying liver diseases (e.g., PSC, AIH may have higher risk)

Macro ─ ─ Liver may appear enlarged and cholestatic (greenish) in earlier phases
─ With progression, the liver can become firm, shrunken, and cirrhotic (secondary biliary cirrhosis if ductopenic rejection is predominant)
─ Cut surface may show dilated bile ducts proximal to obliterated segments or a generally fibrotic appearance

Micro ─

─ Ductopenic Chronic Rejection (Vanishing Bile Duct Syndrome): ─ Bile duct loss (ductopenia): The hallmark feature. Defined as absence of interlobular bile ducts in >50% of portal tracts that contain an artery.
─ Early changes include bile duct epithelial injury: atrophy, vacuolization, irregular nuclear contours, eosinophilic cytoplasm, lymphocytic infiltration (ductitis)
─ Progressive destruction and disappearance of small bile ducts
─ Portal tracts may show minimal inflammation or become fibrotic and devoid of ducts
─ Cholestasis (hepatocellular and canalicular) is often prominent due to impaired bile drainage
─ Copper deposition in periportal hepatocytes (due to chronic cholestasis)
─ Foamy macrophages may be present in areas of cholestasis or duct loss
─ Can lead to secondary biliary cirrhosis
─ Vascular Chronic Rejection (Obliterative Arteriopathy): ─ Primarily affects small to medium-sized arteries within the allograft
─ Characterized by intimal fibrosis and proliferation of myofibroblasts and foam cells (lipid-laden macrophages) within the intima, leading to luminal narrowing or occlusion (endarteritis obliterans)
─ Medial hypertrophy or atrophy, and adventitial fibrosis may also be seen
─ This vascular lesion is less commonly seen on needle biopsies (as it affects larger arteries not always sampled) but is a key feature in explanted grafts with chronic rejection
─ Ischemic changes in the parenchyma may result, including centrilobular necrosis, atrophy, or infarction, and can contribute to bile duct injury/loss (ischemic cholangiopathy)
─ Both ductopenic and vascular changes can coexist
─ Centrilobular changes: Sinusoidal congestion, hemorrhage, and hepatocyte dropout/necrosis can occur, particularly if there's a vascular component or severe cholestasis

Ancillary studies ─

─ Special Stains:
─ CK7 or CK19: Essential to highlight biliary epithelium and accurately assess for ductopenia. Helps distinguish true duct loss from atrophic ducts.
─ Trichrome or Sirius red: To assess the degree and pattern of fibrosis and to highlight obliterative vascular lesions
─ Copper stain (Rhodanine, Orcein): Demonstrates copper accumulation
─ Elastic stains (e.g., Verhoeff-Van Gieson): Can highlight arterial intimal thickening and disruption of elastic lamina in vascular rejection
─ IHC:
─ C4d staining: May be positive in portal capillaries or arterioles in some cases, suggesting an antibody-mediated component contributing to chronic rejection, but not consistently present in all chronic rejection

DDx ─

─ Recurrent primary disease (e.g., recurrent PSC, PBC, AIH – requires careful correlation with pre-transplant diagnosis and specific histologic features of recurrence)
─ Biliary obstruction (e.g., anastomotic stricture, choledocholithiasis – imaging is key; biopsy may show portal edema, neutrophilic cholangitis, prominent ductular reaction without the characteristic duct loss or obliterative arteriopathy of chronic rejection)
─ Ischemic cholangiopathy (e.g., due to hepatic artery thrombosis/stenosis unrelated to rejection – can cause bile duct injury and loss, but usually lacks the specific immune-mediated features of chronic rejection)
─ Drug-induced liver injury (DILI) (some drugs can cause cholestasis or ductopenia)
─ Chronic acute cellular rejection (persistent or recurrent acute rejection that hasn't fully evolved to classic chronic rejection features, but may be a precursor)
─ GVHD (in bone marrow transplant recipients who subsequently receive liver transplant, or rarely in liver transplant itself; can cause bile duct injury)

Prognosis ─ ─ Generally poor once established, as the changes are often irreversible
─ Leads to progressive graft dysfunction, cholestasis, fibrosis, and eventual graft failure requiring re-transplantation
─ Management involves optimizing immunosuppression, but response is often limited for established chronic rejection
─ Early detection and aggressive treatment of acute rejection episodes may prevent progression to chronic rejection

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Liver Allograft - Antibody-Mediated Rejection (AMR)

A form of allograft rejection primarily driven by donor-specific antibodies (DSAs) targeting donor HLA or other endothelial antigens, leading to microvascular injury, complement activation, and graft dysfunction

Clinical ─ ─ Less common in liver transplantation compared to kidney or heart, due to the liver's relative "immune privilege"
─ Can occur at any time post-transplant:
─ Hyperacute AMR: Rare, within minutes to hours, due to pre-existing high-titer DSAs (e.g., ABO incompatibility)
─ Acute AMR: Days to weeks post-transplant, often associated with de novo DSA production or anamnestic response
─ Chronic AMR: Months to years, insidious onset, contributes to chronic graft dysfunction and fibrosis
─ Clinical presentation: Graft dysfunction (elevated liver enzymes, bilirubin), fever, thrombocytopenia (in severe cases). Often overlaps with or mimics acute cellular rejection (ACR).
─ Diagnosis requires a combination of:
─ Clinical graft dysfunction
─ Detection of circulating DSAs (anti-HLA or other endothelial antigens)
─ Histologic evidence of microvascular injury and inflammation
─ Evidence of antibody interaction with tissue (e.g., C4d deposition)

Macro ─ ─ Acutely, the liver may appear swollen, congested, and mottled
─ Chronically, may lead to fibrosis and features of chronic cholestasis or graft failure

Micro ─

─ Acute AMR: Histologic features can be variable and sometimes subtle or overlap with other injuries. Key features suggestive of AMR include:
─ Portal microvascular inflammation: Neutrophils and/or mononuclear cells within portal vein branches, capillaries, or arterioles; endothelial swelling/damage (endotheliitis)
─ Sinusoidal injury: Sinusoidal endothelial cell swelling, inflammation (neutrophils, mononuclear cells), congestion, hemorrhage, and necrosis of centrilobular hepatocytes
─ Cholestasis: Canalicular and hepatocellular
─ Portal inflammation (mixed, may include eosinophils) and bile duct injury can be present but are less specific for AMR alone and often overlap with ACR
─ Fibrin thrombi in small vessels (rare, in severe cases)
─ Periportal or centrilobular edema and hemorrhage
─ Chronic AMR: Features are less well-defined but may include:
─ Persistent portal and/or sinusoidal inflammation
─ Fibrous portal venopathy (obliteration or sclerosis of portal vein branches)
─ Sinusoidal fibrosis, perivenular fibrosis
─ Nodular regenerative hyperplasia-like changes
─ Biliary strictures or ductopenia (possibly due to chronic ischemia from vascular injury)

Ancillary studies ─

─ IHC:
─ C4d deposition: Linear staining along portal vein endothelium, sinusoidal endothelium, and/or central vein endothelium is a key marker of complement activation due to antibody binding. Diffuse C4d staining (>50% of portal tracts or sinusoids) is considered significant.
─ Can be detected by IHC or immunofluorescence
─ However, C4d can be positive in other conditions (e.g., preservation injury, ABO incompatibility without overt rejection) and may not always be present in DSA-positive AMR, so interpretation requires correlation with histology and DSA status
─ CD68 can highlight sinusoidal Kupffer cell hypertrophy/hyperplasia and inflammatory cells
─ Serology: Detection of donor-specific anti-HLA antibodies (DSAs) in recipient serum is crucial. Titers and C1q-binding capacity of DSAs may correlate with injury.

DDx ─

─ Acute Cellular Rejection (ACR) (predominantly T-cell mediated; classic triad of portal inflammation, bile duct injury/ductitis, and venous endotheliitis. AMR and ACR can coexist.)
─ Preservation-reperfusion injury (occurs early post-transplant; sinusoidal dilatation, endothelial damage, hepatocyte necrosis, often centrilobular; C4d can be positive but usually more focal/granular and transient)
─ Hepatic artery or portal vein thrombosis/stenosis (ischemic injury pattern)
─ Biliary obstruction or leak (cholestatic features, ductular reaction, neutrophils)
─ Drug-induced liver injury (DILI)
─ Recurrent or de novo viral hepatitis
─ Sepsis-related cholestasis/injury

Prognosis ─ ─ AMR can lead to significant graft injury and dysfunction
─ Acute AMR, if recognized and treated promptly (e.g., with plasmapheresis, IVIG, rituximab, bortezomib, increased immunosuppression), may be reversible
─ Chronic AMR is often associated with progressive fibrosis, graft failure, and a poorer long-term prognosis
─ The impact of DSAs and C4d positivity on long-term graft survival is an area of active research; not all DSA presence leads to AMR

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Liver Allograft - Recurrent disease in allograft

The reappearance of the original liver disease for which the patient received a transplant, occurring in the new liver graft; this is a significant cause of late allograft dysfunction and failure

Clinical ─ ─ Can occur months to many years post-transplantation
─ Clinical presentation depends on the original disease:
─ Recurrent Hepatitis C (HCV): Historically almost universal and often aggressive, leading to chronic hepatitis, rapid fibrosis/cirrhosis. Incidence dramatically reduced with DAAs. Symptoms: fatigue, jaundice, elevated LFTs.
─ Recurrent Hepatitis B (HBV): Risk significantly reduced with HBIG and nucleos(t)ide analogue prophylaxis. If occurs, can range from acute hepatitis to chronic hepatitis/cirrhosis.
─ Recurrent Autoimmune Hepatitis (AIH): Can occur in 10-40% of patients; presents with elevated LFTs, autoantibodies, interface hepatitis on biopsy. May require increased immunosuppression.
─ Recurrent Primary Biliary Cholangitis (PBC): Occurs in ~20-30% by 10 years; elevated ALP, AMA may reappear, histologic features of PBC (florid duct lesions, granulomas) can be seen. Usually slowly progressive.
─ Recurrent Primary Sclerosing Cholangitis (PSC): Occurs in ~20-30%; presents with cholestasis, biliary strictures on imaging (similar to original PSC). Histology may show periductal fibrosis, ductopenia.
─ Recurrent Non-alcoholic Fatty Liver Disease (NAFLD)/Steatohepatitis (NASH): Common, especially if metabolic risk factors (obesity, diabetes, dyslipidemia) persist or develop post-transplant. Can progress to NASH, fibrosis, and cirrhosis in the graft.
─ Recurrent Alcoholic Liver Disease (ALD): Occurs if patient resumes significant alcohol consumption. Histology similar to ALD in native liver.
─ Recurrent Hepatocellular Carcinoma (HCC): Risk depends on pre-transplant tumor characteristics (size, number, vascular invasion, differentiation) and adherence to Milan criteria or similar guidelines. Recurrence can be intrahepatic or extrahepatic.
─ Diagnosis often involves a combination of clinical suspicion, biochemical tests, imaging, serology, and liver biopsy

Macro ─ ─ Gross appearance of the allograft will reflect the nature of the recurrent disease (e.g., steatosis in recurrent NAFLD, cirrhosis in advanced recurrent hepatitis, biliary strictures in recurrent PSC, tumor nodules in recurrent HCC)

Micro ─

─ Histologic features generally recapitulate those of the original disease in the native liver, although the morphology can sometimes be modified by the transplant setting or immunosuppression
─ Recurrent HCV: Portal and lobular inflammation, interface hepatitis, lymphoid aggregates, bile duct damage, steatosis; fibrosis progression can be accelerated
─ Recurrent HBV: Similar to chronic HBV in native liver (portal/lobular inflammation, ground glass cells if HBsAg high, interface activity)
─ Recurrent AIH: Prominent interface hepatitis with lymphoplasmacytic infiltrate, hepatocyte rosettes, lobular inflammation
─ Recurrent PBC: Portal inflammation, lymphocytic cholangitis, florid duct lesions (granulomatous destruction of bile ducts), ductopenia, cholestasis, copper deposition
─ Recurrent PSC: Periductal fibrosis ("onion-skinning" less common in graft), ductular reaction, bile duct injury/loss, cholestasis; may resemble chronic rejection or biliary obstruction
─ Recurrent NAFLD/NASH: Steatosis, hepatocyte ballooning, lobular inflammation (neutrophils, lymphocytes), perisinusoidal fibrosis
─ Recurrent ALD: Steatosis, Mallory-Denk bodies, neutrophilic inflammation, perisinusoidal fibrosis
─ Recurrent HCC: Histology of the recurrent tumor is usually similar to the original HCC, but can sometimes be less differentiated

Ancillary studies ─

─ Dependent on the suspected recurrent disease:
─ Viral serologies and RNA/DNA levels (for HCV, HBV)
─ Autoantibodies (ANA, ASMA, anti-LKM1 for AIH; AMA for PBC)
─ Serum IgG levels (for AIH)
─ Special stains on biopsy (e.g., PAS-D for A1AT if that was the original disease, Orcein for HBsAg, copper for PBC/PSC)
─ IHC for viral antigens (HBsAg, HBcAg)
─ Imaging (cholangiography for PSC recurrence, tumor markers/imaging for HCC recurrence)

DDx ─

─ Allograft rejection (acute cellular rejection, chronic rejection, antibody-mediated rejection) – key differential for any graft dysfunction
─ Drug-induced liver injury (from immunosuppressants or other medications)
─ De novo autoimmune hepatitis (can occur post-transplant in patients transplanted for other reasons)
─ Biliary complications (strictures, leaks, obstruction unrelated to PSC recurrence)
─ Vascular complications (hepatic artery or portal vein thrombosis/stenosis)
─ Infections (CMV, EBV, fungal)
─ Post-transplant lymphoproliferative disorder (PTLD)

Prognosis ─ ─ Varies greatly depending on the specific recurrent disease, its severity, rate of progression, and response to treatment
─ Recurrent HCV (before DAAs) was a major cause of graft loss; DAAs have markedly improved outcomes
─ Recurrent HBV can be managed with antiviral prophylaxis
─ Recurrent AIH often responds to increased immunosuppression, but can lead to graft loss if severe or refractory
─ Recurrent PBC and PSC can lead to progressive cholestasis and graft failure, potentially requiring re-transplantation
─ Recurrent NASH can lead to cirrhosis in the graft
─ Recurrent HCC has a poor prognosis, especially if early or multifocal
─ Management involves treating the specific recurrent disease, optimizing immunosuppression, and addressing complications

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Liver, Neoplastic

Hepatocellular tumors

Hepatocellular Adenoma (HCA) - General Overview

Benign monoclonal neoplasms of hepatocytes, typically occurring in an otherwise normal liver, most commonly in women of childbearing age using oral contraceptives; HCAs are heterogeneous with distinct molecular subtypes that have different clinical associations, histologic features, and risks of complications (hemorrhage, malignant transformation)

Clinical ─ ─ Relatively uncommon, incidence ~3-4 per 100,000 in women using oral contraceptives (OCPs); much rarer in men
─ Risk factors: ─ Oral contraceptive use (strongest association, particularly long-duration and high-estrogen content pills)
─ Anabolic androgenic steroid use (especially in men)
─ Glycogen storage diseases (GSD types I and III)
─ Metabolic syndrome (obesity, diabetes) - associated with inflammatory HCA subtype
─ Familial adenomatous polyposis (FAP) - associated with β-catenin activated HCA
─ Maturity Onset Diabetes of the Young, type 3 (MODY3) - associated with HNF1A-inactivated HCA
─ Often asymptomatic and discovered incidentally on imaging
─ Symptomatic presentation: Abdominal pain or discomfort (due to mass effect or hemorrhage), palpable mass
─ Complications: ─ Hemorrhage: Can be intratumoral or intraperitoneal (rupture), potentially life-threatening. Risk increases with size (>5 cm) and certain subtypes (e.g., inflammatory, SHH-activated).
─ Malignant transformation to Hepatocellular Carcinoma (HCC): Rare overall (<5%), but risk is significantly higher in specific subtypes (β-catenin activated HCA) and in males.
─ Multiple HCAs (>10) is termed hepatic adenomatosis; can occur sporadically or in association with germline HNF1A mutations or GSD

Macro ─ ─ Usually solitary (70-80%), but can be multiple
─ Typically well-demarcated, often subcapsular, but usually non-encapsulated or having a thin pseudocapsule
─ Size varies from <1 cm to >30 cm (average ~5-10 cm)
─ Appearance of cut surface depends on subtype:
─ Often pale tan-yellow to light brown, may be soft
─ Steatotic areas appear distinctly yellow (common in HNF1A-inactivated HCA)
─ Hemorrhagic areas appear dark red/brown (common in inflammatory HCA)
─ Peliosis (blood-filled cysts) can be seen
─ Fibrosis or scarring is generally absent (unlike FNH), except for focal scars post-hemorrhage

Micro ─

─ Composed of sheets, plates, or cords of benign-appearing hepatocytes, usually 1-2 cells thick, separated by sinusoids
─ Hepatocytes often contain glycogen (pale cytoplasm) or fat (steatosis, especially in HNF1A-inactivated HCA)
─ Cytologic atypia is generally absent or mild; nuclei are typically small, round, and uniform with inconspicuous nucleoli (except in β-catenin activated HCA which can show more atypia)
─ Absence of normal portal tracts (no portal veins or true interlobular bile ducts) within the lesion is a key feature ─ Unpaired, thin-walled arteries are present scattered throughout the lesion
─ Reticulin framework is generally preserved, outlining the thin hepatic plates (may be focally lost or condensed in areas of hemorrhage or atypia)
─ Specific histologic features vary by molecular subtype (see individual subtypes)

Ancillary studies ─

─ IHC panel is crucial for subtyping, which has prognostic and management implications: ─ Liver Fatty Acid-Binding Protein (L-FABP): Loss of staining in HNF1A-inactivated HCA
─ Serum Amyloid A (SAA) & C-Reactive Protein (CRP): Diffuse strong positivity in Inflammatory HCA
─ β-catenin: Nuclear staining in β-catenin activated HCA
─ Glutamine Synthetase (GS): Diffuse strong positivity in β-catenin activated HCA; map-like in FNH; normal perivenular or negative in other HCAs
─ CK7/CK19: Negative in hepatocytes (highlights entrapped normal ductules at periphery if any, or ductular reaction in Inflammatory HCA)
─ CD34: Sinusoidal staining is usually absent or very focal (unlike diffuse capillarization in HCC)
─ Molecular analysis (gene sequencing) can confirm specific mutations (HNF1A, CTNNB1, IL6ST, STAT3, GNAS, JAK1, INHBE-GLI1 fusion) but IHC is often used as a surrogate

DDx ─

─ Focal Nodular Hyperplasia (FNH): Contains a central scar with abnormal arteries and ductular proliferation; characteristic map-like GS staining; no risk of hemorrhage or malignancy
─ Well-differentiated Hepatocellular Carcinoma (HCC): Shows cytologic atypia, thickened trabeculae (>3 cells), reticulin loss, diffuse sinusoidal capillarization (CD34+), expression of HCC markers (GPC3, HSP70, GS in certain patterns); malignant potential
─ Macroregenerative nodule / Dysplastic nodule (in cirrhosis): Occur in cirrhotic liver (HCAs usually in normal liver); MRN/DN have different architectural and IHC features
─ Focal fatty change / Focal fatty sparing: Non-neoplastic, geographic areas of fat accumulation or sparing, no discrete mass on histology
─ Metastatic carcinoma: Usually shows glandular or other non-hepatocellular morphology and IHC profile of primary tumor

Prognosis ─ ─ Generally benign, but carries risks of hemorrhage and malignant transformation depending on subtype, size, and sex of patient
─ HNF1A-inactivated HCA: Very low risk of malignancy; moderate risk of bleeding if large
─ Inflammatory HCA: Low risk of malignancy (unless co-mutated with β-catenin); higher risk of bleeding, especially if large
─ β-catenin activated HCA: Highest risk of malignant transformation to HCC; also risk of bleeding
─ Sonic Hedgehog (SHH) activated HCA: Increased risk of bleeding; malignant potential unclear but thought to be low
─ Unclassified HCA: Risk profile less certain, generally considered low if β-catenin activation excluded
─ Management depends on subtype, size, symptoms, and patient factors:
─ Discontinuation of OCPs/anabolic steroids
─ Observation for small, asymptomatic, low-risk subtype lesions
─ Resection for large (>5 cm) lesions, symptomatic lesions, male patients, β-catenin activated HCA, or diagnostic uncertainty

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Hepatocellular Adenoma - Inflammatory type (I-HCA)

The most common subtype of hepatocellular adenoma, characterized by activating mutations in the IL-6/JAK/STAT pathway, leading to an inflammatory phenotype with sinusoidal dilatation, inflammatory infiltrates, and expression of acute phase reactants

Clinical ─ ─ Accounts for ~40-55% of all HCAs
─ Strongly associated with oral contraceptive use in women and obesity/metabolic syndrome in both sexes; also linked to alcohol consumption
─ Patients may present with abdominal pain or discomfort, or the lesion may be found incidentally
─ Can be associated with systemic inflammatory symptoms (fever, elevated C-reactive protein - CRP) in some cases
─ Risk of hemorrhage is present, particularly in larger lesions (>5 cm)
─ Risk of malignant transformation to HCC is generally low in pure I-HCA, but is increased if there is coexisting β-catenin activation (β-I-HCA subtype)

Macro ─ ─ Often large, well-demarcated, but usually non-encapsulated
─ Cut surface is typically variegated, with areas of hemorrhage, necrosis, and peliosis (blood-filled cystic spaces) reflecting the sinusoidal dilatation and inflammation
─ May appear more heterogeneous than other HCA subtypes

Micro ─

─ Key histologic features: ─ Sheets and cords of benign-appearing hepatocytes, often with mild atypia but no overt malignancy
─ Sinusoidal dilatation and peliosis: Prominent feature, with ectatic, blood-filled sinusoidal spaces
─ Inflammatory infiltrates: Patchy or diffuse infiltrates of lymphocytes, plasma cells, neutrophils, and histiocytes within the sinusoids and stroma
─ Dystrophic arteries (thick-walled, tortuous arteries): Often seen scattered throughout the lesion, sometimes within "pseudo-portal tracts" (fibrous areas lacking normal portal veins and true bile ducts but containing arteries and ductular reaction)
─ Ductular reaction: Proliferation of small bile duct-like structures, often at the interface of hepatocytes and fibrous areas
─ Steatosis can be present but is usually focal or less prominent than in HNF1A-inactivated HCA
─ No normal portal tracts within the lesion
─ Reticulin framework is generally preserved or only focally lost/condensed

Ancillary studies ─

─ IHC:
─ Serum Amyloid A (SAA): Strong and diffuse cytoplasmic positivity in hepatocytes is characteristic and a key diagnostic marker
─ C-Reactive Protein (CRP): Strong and diffuse cytoplasmic positivity in hepatocytes is also characteristic
─ Liver Fatty Acid-Binding Protein (L-FABP): Retained expression (unlike HNF1A-inactivated HCA which shows loss of L-FABP)
─ Glutamine Synthetase (GS): Usually negative or shows a normal/heterogeneous perivenular pattern. Diffuse strong staining would suggest β-catenin activation.
─ β-catenin: Membranous staining only (nuclear staining indicates β-catenin activation, classifying it as β-I-HCA or β-HCA)
─ Molecular ─ ─ Activating mutations in genes of the IL-6/JAK/STAT3 signaling pathway (e.g., IL6ST (gp130), STAT3, GNAS, JAK1)
─ No HNF1A mutations

DDx ─

─ Focal Nodular Hyperplasia (FNH): Can have some overlapping features (central scar-like areas, ductular reaction, abnormal vessels). However, classic FNH has a well-formed central scar with radiating septa, lacks diffuse SAA/CRP positivity, and shows a characteristic "map-like" GS staining pattern. I-HCA lacks true portal tracts and a typical FNH scar.
─ Hepatocellular Carcinoma (HCC), well-differentiated: HCC shows more significant cytologic atypia, thickened trabeculae, loss of reticulin, diffuse CD34 sinusoidal capillarization, and may express HCC markers (GPC3, HSP70). SAA/CRP are usually negative in HCC.
─ HNF1A-inactivated HCA: Characterized by diffuse steatosis and loss of L-FABP staining; SAA/CRP negative
─ β-catenin activated HCA: Shows nuclear β-catenin and diffuse/strong GS staining; typically lacks prominent inflammation and SAA/CRP positivity unless it's a mixed β-I-HCA
─ Angiomyolipoma or other mesenchymal tumors with epithelioid cells: IHC for melanocytic markers (HMB45, Melan-A for AML) and other mesenchymal markers would be positive; SAA/CRP negative
─ Peliosis hepatis (non-neoplastic): Diffuse blood-filled cystic spaces without a discrete tumor mass or the specific inflammatory/cellular features of I-HCA

Prognosis ─ ─ Benign, with a low risk of malignant transformation in pure I-HCA (<1%)
─ Risk of hemorrhage is a significant concern, especially for lesions >5 cm
─ Management often involves cessation of oral contraceptives, observation for smaller lesions, and consideration of resection for larger lesions (>5 cm), symptomatic lesions, or if β-catenin activation is suspected/confirmed

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Hepatocellular Adenoma - β-catenin activated type (β-HCA)

A subtype of hepatocellular adenoma characterized by activating mutations in the CTNNB1 gene (encoding β-catenin), leading to nuclear translocation of β-catenin and activation of Wnt signaling pathway targets; this subtype has the highest risk of malignant transformation to hepatocellular carcinoma (HCC)

Clinical ─ ─ Accounts for ~10-15% of all HCAs
─ More common in males compared to other HCA subtypes, and often associated with anabolic androgen steroid use, glycogen storage diseases (especially type I), and familial adenomatous polyposis (FAP)
─ Can also occur in women, sometimes related to oral contraceptive use
─ Often asymptomatic or may present with abdominal pain
─ Highest risk of malignant transformation to HCC (estimated 5-13% or higher) among all HCA subtypes ─ May also have a risk of hemorrhage, particularly if large

Macro ─ ─ Can be solitary or multiple
─ Appearance is variable, may not have specific gross features to distinguish it from other HCAs or well-differentiated HCC without histologic/molecular confirmation
─ May appear more solid and less steatotic than H-HCA, and less hemorrhagic/peliosis-rich than I-HCA, but overlap exists

Micro ─

─ Composed of sheets or slightly thickened trabeculae (often 1-3 cells thick) of hepatocytes
─ Hepatocytes may show mild to moderate cytologic atypia, including slightly increased N/C ratio, nuclear irregularities, and more prominent nucleoli compared to normal liver or other HCA subtypes. These features can sometimes overlap with well-differentiated HCC.
─ Architectural atypia such as pseudoglandular (acinar) formations or rosettes can be present
─ Steatosis is typically absent or minimal (a key feature helping to distinguish from H-HCA)
─ Inflammatory infiltrates are usually not prominent (unlike I-HCA)
─ Sinusoidal dilatation and peliosis are generally not features (unlike I-HCA)
─ No normal portal tracts within the lesion
─ Reticulin framework is usually preserved but may show focal abnormalities or slight expansion, especially in areas with atypia
─ β-catenin activated Inflammatory HCA (β-I-HCA): A mixed subtype showing features of both I-HCA (inflammation, SAA/CRP+) and β-HCA (nuclear β-catenin, GS+). Also carries an increased risk of HCC.

Ancillary studies ─

─ IHC:
─ β-catenin: Aberrant nuclear staining in tumor hepatocytes is the hallmark (cytoplasmic staining alone is not sufficient for this classification). Nuclear staining can be diffuse or focal.
─ Glutamine Synthetase (GS): Strong and diffuse cytoplasmic positivity in tumor hepatocytes is a surrogate marker for β-catenin activation and is highly characteristic. This contrasts with the normal liver's perivenular GS staining or the map-like pattern in FNH.
─ Liver Fatty Acid-Binding Protein (L-FABP): Retained expression (helps distinguish from H-HCA)
─ Serum Amyloid A (SAA) / C-Reactive Protein (CRP): Typically negative (helps distinguish from I-HCA, unless it's a mixed β-I-HCA which would be SAA/CRP positive)
─ Molecular ─ ─ Activating mutations in the CTNNB1 gene, most commonly in exon 3 (especially S45, T41 mutations) or less commonly exon 7/8. Mutations in exon 3 (other than S45) are often associated with stronger β-catenin activation and higher HCC risk.

DDx ─

─ Well-differentiated Hepatocellular Carcinoma (HCC): This is the most critical differential due to the malignant potential of β-HCA. HCC will show more definitive malignant features (e.g., thickened trabeculae >3 cells, marked atypia, reticulin loss, diffuse CD34 sinusoidal capillarization, expression of HCC markers like GPC3, HSP70). However, distinguishing β-HCA with high-grade atypia from early/well-differentiated HCC can be very challenging on biopsy.
─ Focal Nodular Hyperplasia (FNH): FNH has a central scar, ductular proliferation, and a characteristic "map-like" GS staining pattern. β-catenin nuclear staining is absent.
─ HNF1A-inactivated HCA (H-HCA): Shows diffuse steatosis, L-FABP loss; negative for nuclear β-catenin and diffuse GS
─ Inflammatory HCA (I-HCA): Shows inflammation, sinusoidal dilatation, SAA/CRP positivity; negative for nuclear β-catenin and diffuse GS (unless mixed β-I-HCA)
─ Macroregenerative nodule / Dysplastic nodule (in cirrhosis): Occur in cirrhotic liver; MRN/LGDN typically lack diffuse GS and nuclear β-catenin staining. HGDN can be difficult to distinguish from well-differentiated HCC and some β-HCAs if atypia is marked.

Prognosis ─ ─ Highest risk of malignant transformation to HCC among HCA subtypes
─ Risk of hemorrhage also exists
─ Management typically involves surgical resection, regardless of size, especially in males or if β-catenin activation is confirmed, due to the high malignant potential
─ Close surveillance is warranted if not resected or if multiple lesions are present

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Hepatocellular Adenoma - Sonic Hedgehog (SHH) activated type (sh-HCA)

A more recently described molecular subtype of hepatocellular adenoma characterized by activation of the Sonic Hedgehog pathway, often due to INHBE-GLI1 gene fusion; associated with an increased risk of bleeding

Clinical ─ ─ Accounts for a small percentage of HCAs (~4-10%)
─ May be associated with obesity
─ Clinically, these patients may present with symptoms related to hemorrhage more frequently than other subtypes, even in smaller lesions
─ Risk of malignant transformation is currently considered low, but data is still emerging

Macro ─ ─ May show intralesional hemorrhage or necrotic-hemorrhagic changes more frequently than other subtypes
─ Fluid-filled cavities within the tumor have been described as a potential imaging feature

Micro ─

─ Histologic features are not yet as sharply defined or specific as other subtypes and can be variable
─ Often lack the prominent steatosis of H-HCA or the marked inflammation of I-HCA
─ May show areas of hemorrhage, peliosis, or sinusoidal dilatation
─ Cytologic atypia is generally mild
─ No consistent defining morphological features have been established to reliably distinguish sh-HCA on H&E alone without molecular or specific IHC confirmation

Ancillary studies ─

─ IHC:
─ Argininosuccinate Synthase 1 (ASS1): Often shows positive staining; may be a potential surrogate marker
─ Prostaglandin D2 Synthase (PTGDS): May show positive staining
─ L-FABP: Expression is typically retained
─ SAA/CRP: Usually negative
─ Glutamine Synthetase (GS): Not diffusely positive (unlike β-HCA)
─ β-catenin: No nuclear accumulation
─ Molecular ─ ─ Characterized by activation of the Sonic Hedgehog signaling pathway
─ Most commonly due to a focal deletion leading to an INHBE-GLI1 gene fusion (juxtaposition of the INHBE promoter to the GLI1 gene, leading to GLI1 overexpression)
─ Other mechanisms of SHH pathway activation might exist

DDx ─

─ Unclassified HCA: If specific molecular testing or IHC markers for SHH activation are not performed, these may fall into the unclassified category based on morphology and standard IHC (L-FABP+, SAA/CRP-, GS normal, β-catenin membranous)
─ Other HCA subtypes: Distinction relies on the specific molecular alterations or IHC profiles (e.g., H-HCA has L-FABP loss; I-HCA is SAA/CRP+; β-HCA has nuclear β-catenin/diffuse GS)
─ Hepatocellular Carcinoma (HCC): If there is significant atypia or worrisome features; HCC markers would be needed
─ Focal Nodular Hyperplasia (FNH): FNH has a central scar and map-like GS staining

Prognosis ─ ─ Considered benign, but associated with an increased risk of hemorrhage, even in smaller lesions
─ Malignant transformation risk is thought to be low, but long-term data is still accumulating
─ Management may lean towards resection or intervention if hemorrhage occurs or if the lesion is large, given the bleeding risk. Otherwise, management strategies are still evolving for this subtype.

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Hepatocellular Adenoma - Unclassified type (U-HCA)

A category of hepatocellular adenomas that do not fit into the well-defined molecular/immunohistochemical subtypes (HNF1A-inactivated, Inflammatory, β-catenin activated, or Sonic Hedgehog activated)

Clinical ─ ─ Represents a minority of HCAs (~5-10%) after other subtypes are excluded
─ Clinical features are variable and less well-characterized as a group compared to the defined subtypes
─ May occur in women using oral contraceptives or in individuals without clear risk factors
─ Risk of complications (hemorrhage, malignant transformation) is generally considered low for most U-HCAs, but this is a heterogeneous category, and risk assessment may depend on individual lesion characteristics (size, growth, atypia) and exclusion of β-catenin activation

Macro ─ ─ No specific gross features define this category
─ Appearance can be variable, similar to other HCAs (well-demarcated, tan-yellow to red-brown)

Micro ─

─ Composed of benign-appearing hepatocytes arranged in sheets or thin trabeculae (1-2 cells thick)
─ Lacks the specific defining features of the other subtypes:
─ No diffuse steatosis (unlike typical H-HCA)
─ No significant inflammation, sinusoidal dilatation, or peliosis (unlike typical I-HCA)
─ No cytologic atypia or architectural features strongly suggestive of β-catenin activation (though thorough IHC is needed to exclude it)
─ No features specifically pointing to SHH activation (though this is primarily a molecular diagnosis)
─ Portal tracts are absent
─ Reticulin framework is generally preserved
─ Cytologic atypia is usually minimal

Ancillary studies ─

─ IHC (by definition for U-HCA):
─ Liver Fatty Acid-Binding Protein (L-FABP): Retained expression (rules out H-HCA)
─ Serum Amyloid A (SAA) and C-Reactive Protein (CRP): Negative or only very focal/weak (rules out I-HCA)
─ Glutamine Synthetase (GS): Shows a normal heterogeneous or perivenular staining pattern (not diffuse strong staining, helping to rule out typical β-HCA)
─ β-catenin: Shows normal membranous staining only (no nuclear accumulation, helping to rule out β-HCA)
─ ASS1/PTGDS: Negative or not fitting the pattern for sh-HCA (if tested)
─ Molecular ─ ─ By definition, lacks the characteristic mutations of HNF1A, IL-6/JAK/STAT pathway, CTNNB1, or INHBE-GLI1 fusion found in the other major subtypes
─ This category may still be molecularly heterogeneous, and new subtypes may emerge from this group with further research

DDx ─

─ Other HCA subtypes: Diagnosis of U-HCA is one of exclusion after appropriate IHC (and molecular, if performed) rule out the defined subtypes
─ Focal Nodular Hyperplasia (FNH): FNH has a central scar, ductular proliferation, and map-like GS staining. U-HCA lacks these.
─ Well-differentiated Hepatocellular Carcinoma (HCC): HCC shows malignant features (significant atypia, thickened trabeculae, reticulin loss, etc.). Careful evaluation is needed, especially for larger U-HCAs or those with any atypia.
─ Nodular regenerative hyperplasia (NRH): NRH is typically diffuse, not a discrete adenoma-like mass, and shows characteristic reticulin changes (hyperplastic nodules with compressed intervening parenchyma) without true neoplasia
─ Focal fatty change or focal fatty sparing: These are non-neoplastic alterations in fat distribution, not true neoplasms

Prognosis ─ ─ Generally considered to have a low risk of hemorrhage and malignant transformation, provided that β-catenin activated HCA has been confidently excluded by IHC (and molecular testing if necessary)
─ Management often involves observation for smaller (<5 cm) asymptomatic lesions, with consideration for stopping oral contraceptives
─ Resection may be considered for larger lesions (>5 cm), symptomatic lesions, or if there is diagnostic uncertainty, especially regarding exclusion of β-HCA or HCC

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Hepatocellular Carcinoma (HCC) - Conventional (various architectural patterns)

The most common primary malignant tumor of the liver, composed of cells with hepatocellular differentiation; it typically arises in the setting of chronic liver disease and cirrhosis

Clinical ─ ─ Fifth most common cancer worldwide and a leading cause of cancer-related death
─ Incidence is higher in regions with high rates of chronic hepatitis B (HBV) and C (HCV) infection (e.g., Asia, sub-Saharan Africa)
─ Major risk factors:
─ Cirrhosis of any etiology (HBV, HCV, alcoholic liver disease, NAFLD/NASH, hemochromatosis, alpha-1 antitrypsin deficiency, autoimmune hepatitis, PBC, PSC) - ~80-90% of HCCs develop in cirrhotic livers
─ Chronic HBV infection (can cause HCC even without cirrhosis)
─ Chronic HCV infection
─ Alcoholic liver disease
─ Non-alcoholic fatty liver disease (NAFLD) / Non-alcoholic steatohepatitis (NASH) - increasingly important risk factor
─ Aflatoxin B1 exposure (food contaminant, synergistic with HBV)
─ Certain inherited metabolic diseases (e.g., hemochromatosis, A1AT deficiency, tyrosinemia)
─ More common in males; incidence increases with age (typically >50 years, but can occur earlier with specific risk factors)
─ Symptoms are often absent or vague in early stages. Later symptoms include:
─ Right upper quadrant pain or mass, hepatomegaly
─ Weight loss, anorexia, fatigue
─ Jaundice (if biliary obstruction or extensive liver failure)
─ Ascites, variceal bleeding (signs of decompensated cirrhosis)
─ Paraneoplastic syndromes (rare): hypoglycemia, erythrocytosis, hypercalcemia, watery diarrhea
─ Serum alpha-fetoprotein (AFP) is elevated in ~50-70% of patients, but can be normal, especially in small HCCs. Used for screening (in high-risk populations) and monitoring.
─ Diagnosis often made by characteristic imaging features (arterial phase hyperenhancement and portal/delayed phase washout on CT/MRI - LI-RADS criteria) in cirrhotic patients, or by biopsy

Macro ─ ─ Appearance is variable:
─ Solitary massive type: Large, often well-demarcated mass, may have a fibrous capsule or pseudocapsule. Cut surface can be variegated (tan, yellow, green if bile-stained, hemorrhagic, necrotic).
─ Nodular (multinodular) type: Multiple discrete tumor nodules of varying sizes scattered throughout the liver. Often seen in cirrhotic livers.
─ Diffuse infiltrative type: Ill-defined, widespread infiltration of tumor throughout a large portion of the liver, often without a dominant mass. Can be difficult to distinguish from cirrhosis on imaging.
─ Tumors are often softer than surrounding cirrhotic liver, may bulge on cut section
─ Color: Tan, yellow (if steatotic), green (if bile-producing), brown, or hemorrhagic
─ Satellite nodules and vascular invasion (especially portal vein thrombosis) are common and indicate aggressive behavior
─ Background liver usually shows cirrhosis or chronic hepatitis

Micro ─

─ Composed of malignant cells resembling hepatocytes, but with varying degrees of atypia and architectural disarray
─ Cytologic features: ─ Cells are polygonal with eosinophilic granular cytoplasm (can be clear due to glycogen/fat, or oncocytic)
─ Nuclei are enlarged, hyperchromatic, pleomorphic, with irregular contours and often prominent nucleoli
─ Increased nuclear-to-cytoplasmic (N/C) ratio
─ Intracytoplasmic inclusions can be seen: Mallory-Denk bodies (less common than in steatohepatitis), hyaline globules (A1AT-like), pale bodies, bile
─ Architectural patterns (often mixed within a single tumor): ─ Trabecular pattern (most common): Tumor cells arranged in thickened cords or plates (trabeculae), typically >2-3 cells thick, separated by sinusoidal vascular spaces. This recapitulates, but distorts, normal liver plate architecture.
─ Solid/Compact pattern: Sheets of tumor cells with minimal intervening stroma or sinusoids
─ Pseudoglandular/Acinar pattern: Tumor cells arranged around a central lumen, sometimes containing bile or proteinaceous material. True glands with mucin are absent (distinction from cholangiocarcinoma).
─ Macrotrabecular pattern: Trabeculae >10 cells thick; associated with aggressive behavior and poor prognosis
─ Scirrhous pattern: Abundant dense fibrous stroma separating nests or cords of tumor cells (see separate entry for HCC, scirrhous type)
─ Clear cell pattern: >80% of tumor cells have clear cytoplasm due to glycogen or lipid (see separate entry for HCC, clear cell variant)
─ Steatohepatitic pattern: Tumor shows features resembling steatohepatitis (steatosis, ballooning, inflammation, MDBs) (see separate entry for HCC, steatohepatitic variant)
─ Sinusoidal capillarization: Sinusoids within HCC lose their normal fenestrated endothelium and Kupffer cells, and become lined by continuous endothelium resembling capillaries (highlighted by CD34 IHC)
─ Unpaired arteries: Presence of arteries not accompanied by bile ducts within the tumor (normal portal tracts are absent within HCC)
─ Loss of reticulin framework: Reticulin stain shows loss, fragmentation, or marked disorganization of the reticulin fibers supporting the thickened trabeculae (normal liver and regenerative nodules have intact reticulin around 1-2 cell thick plates)
─ Bile production by tumor cells (intracytoplasmic or canalicular bile plugs) is a specific feature of hepatocellular differentiation
─ Vascular invasion (portal veins, hepatic veins, sinusoids) is common
─ Grading (e.g., Edmondson-Steiner grade I-IV) based on degree of differentiation, nuclear atypia, and resemblance to normal hepatocytes:
─ Grade I (Well-differentiated): Difficult to distinguish from adenoma or dysplastic nodule; minimal atypia, thin trabeculae
─ Grade II (Moderately differentiated): Most common; recognizable trabecular pattern, moderate atypia
─ Grade III (Poorly differentiated): Marked atypia, often solid growth, frequent mitoses
─ Grade IV (Undifferentiated): Anaplastic cells, may lose clear hepatocellular features

Ancillary studies ─

─ IHC:
─ Positive for hepatocellular markers: ─ HepPar-1 (Hepatocyte Paraffin 1): Cytoplasmic granular staining; sensitive but can be lost in poorly differentiated HCC
─ Arginase-1: Nuclear and cytoplasmic staining; considered more sensitive and specific than HepPar-1, especially in poorly differentiated cases
─ Polyclonal CEA (pCEA): Canalicular staining pattern is characteristic of hepatocellular differentiation (membranous staining of bile canaliculi between tumor cells)
─ CD10: Similar canalicular staining pattern to pCEA
─ Albumin mRNA ISH (in situ hybridization): Highly specific for hepatocellular origin
─ Glypican-3 (GPC3): Membranous and/or cytoplasmic staining; often positive in HCC (especially less differentiated ones), but can be negative in well-differentiated HCC. Also positive in yolk sac tumor and some other malignancies.
─ Heat Shock Protein 70 (HSP70): Cytoplasmic staining; often positive in HCC, particularly in progression from dysplastic nodule
─ Glutamine Synthetase (GS): Diffuse, strong cytoplasmic staining can be seen in some HCCs (especially β-catenin activated), contrasting with normal liver's perivenular pattern or FNH's map-like pattern
─ Negative for biliary markers: CK7 and CK19 are typically negative or only focally positive (strong diffuse positivity would suggest cholangiocarcinoma or cHCC-CCA)
─ CD34: Highlights sinusoidal capillarization (diffuse staining of sinusoidal lining cells)
─ Ki-67: Proliferation index is variable, generally higher in poorly differentiated tumors
─ Special Stains:
─ Reticulin: Essential to demonstrate thickened trabeculae and loss/disorganization of reticulin framework
─ PAS-D: May show intracytoplasmic glycogen (clear cell change) or A1AT-like globules
─ Iron: May show iron in background liver or rarely in tumor if arising in hemochromatosis
─ Molecular ─ ─ Common genetic alterations include mutations in TERT promoter, TP53, CTNNB1 (β-catenin), AXIN1, ARID1A, ARID2. Molecular landscape varies with etiology (e.g., TP53 common in aflatoxin/HBV; CTNNB1 in alcohol/NASH).
─ Chromosomal instability is frequent
─ Molecular subclassification (e.g., based on Wnt/β-catenin activation, immune infiltration, proliferation) is an area of active research for prognostic and therapeutic implications

DDx ─

─ High-grade dysplastic nodule (HGDN) (in cirrhosis): Precursor lesion; shows significant atypia but lacks definitive invasion, unequivocal thickened trabeculae (>3 cells), or diffuse sinusoidal capillarization. Distinction from well-differentiated HCC can be very challenging on biopsy. A panel of IHC markers (GPC3, HSP70, GS) can aid.
─ Hepatocellular adenoma (HCA): Benign; usually in non-cirrhotic liver. Lacks significant atypia (except β-catenin activated HCA which can be a challenge), preserved reticulin, no diffuse CD34. Subtyping by IHC is key.
─ Focal nodular hyperplasia (FNH): Benign; central scar, ductular proliferation, map-like GS staining.
─ Intrahepatic cholangiocarcinoma (ICC): Glandular differentiation, mucin production, desmoplastic stroma; positive for CK7/CK19, negative for hepatocellular markers.
─ Combined hepatocellular-cholangiocarcinoma (cHCC-CCA): Shows unequivocal features of both HCC and CCA with intermingling/transition.
─ Metastatic carcinoma: Morphology and IHC profile depend on primary site (e.g., metastatic colorectal adenocarcinoma is CK20+/CDX2+, HepPar-1/Arginase-1-).
─ Neuroendocrine tumor/carcinoma metastatic to liver: Positive for synaptophysin/chromogranin.
─ Melanoma metastatic to liver: Positive for S100/SOX10/Melan-A.

Prognosis ─ ─ Generally poor, but highly dependent on stage at diagnosis, tumor characteristics, underlying liver function (Child-Pugh score), and treatment options
─ Prognostic factors:
─ Tumor size and number (TNM stage, BCLC staging system)
─ Vascular invasion (macrovascular or microvascular)
─ Histologic grade (poorly differentiated = worse)
─ Presence of satellite nodules
─ Serum AFP levels
─ Molecular subtypes are emerging as prognostic indicators
─ Treatment options include surgical resection, liver transplantation, locoregional therapies (TACE, TARE, ablation), and systemic therapies (sorafenib, lenvatinib, immunotherapy combinations like atezolizumab-bevacizumab)
─ Surveillance of high-risk populations (e.g., cirrhotics) aims for early detection when curative therapies are more feasible

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Fibrolamellar HCC (FL-HCC)

A rare and distinct histologic variant of hepatocellular carcinoma, typically occurring in young adults (adolescents and young adults, <40 years) without underlying cirrhosis or chronic liver disease, characterized by large, eosinophilic tumor cells arranged in nests or cords separated by dense, lamellar fibrous bands

Clinical ─ ─ Rare, accounts for <1-2% of all HCCs
─ Affects adolescents and young adults (median age ~25 years), with no significant sex predilection
─ Typically arises in a non-cirrhotic, otherwise normal liver (key distinguishing feature from conventional HCC)
─ No association with HBV, HCV, alcohol, or other common HCC risk factors
─ Symptoms are often non-specific: abdominal pain or fullness, palpable mass, weight loss, fatigue, nausea. Jaundice is uncommon.
─ Serum AFP is usually normal or only mildly elevated (unlike many conventional HCCs)
─ Elevated serum Vitamin B12 binding capacity and neurotensin have been reported in some cases but are not routinely used for diagnosis
─ Imaging often shows a large, solitary, well-demarcated mass, frequently with a central fibrous scar that may contain calcifications (can mimic FNH on imaging, but FNH scar usually enhances on delayed phase, FL-HCC scar usually does not)

Macro ─ ─ Typically a large, solitary, well-circumscribed, firm mass
─ Cut surface is often lobulated, tan-yellow or pale brown, with characteristic radiating fibrous bands or a central stellate scar
─ Calcification within the scar or tumor is common
─ Vascular invasion can occur; lymph node metastases are relatively common at presentation (50-70%)

Micro ─

─ Defining histologic features: ─ Tumor cells: Large, polygonal cells with abundant, deeply eosinophilic, granular cytoplasm (oncocytic appearance due to numerous mitochondria). Nuclei are large and vesicular with prominent, centrally located, eosinophilic nucleoli. Cytologic atypia is usually mild to moderate.
─ Lamellar fibrosis: Thick bands of dense, hyalinized collagen arranged in parallel layers (lamellae) that surround nests or cords of tumor cells. This is the most characteristic feature.
─ Arrangement: Tumor cells are arranged in sheets, nests, cords, or trabeculae separated by the lamellar fibrous stroma
─ Pale bodies: Intracytoplasmic, faintly eosinophilic, glassy inclusions (fibrinogen) may be present in tumor cells
─ Bile production by tumor cells can sometimes be seen
─ Background liver is typically non-cirrhotic and unremarkable

Ancillary studies ─

─ IHC:
─ Positive for some hepatocellular markers: HepPar-1, Arginase-1 (may be weaker or patchier than conventional HCC)
─ CK7: Often diffusely positive (cytoplasmic), which is unusual for conventional HCC (usually negative or focal). This is a helpful diagnostic feature.
─ Epithelial Membrane Antigen (EMA): Often positive (membranous/canalicular)
─ CD68: Can highlight macrophages within the fibrous stroma, but not specific
─ Glypican-3: May be positive, but often weaker or patchier than in conventional HCC
─ AFP: Usually negative or only focally positive in tumor cells
─ Neuroendocrine markers (synaptophysin, chromogranin): Generally negative, despite some reports of neurotensin elevation
─ Molecular ─ ─ Characteristic genetic alteration: A recurrent ~400kb somatic deletion on chromosome 19 resulting in a DNAJB1-PRKACA fusion gene is found in virtually all (80-100%) cases of FL-HCC. This fusion is specific for FL-HCC and not found in conventional HCC or other liver tumors.
─ Detection of this fusion (e.g., by RT-PCR, FISH, or RNA sequencing) can confirm the diagnosis, especially in challenging cases
─ Unlike conventional HCC, TP53 and CTNNB1 mutations are rare

DDx ─

─ Conventional HCC with sclerosis or oncocytic features: Conventional HCC usually occurs in older patients with cirrhosis, lacks the distinct lamellar fibrosis and DNAJB1-PRKACA fusion, and typically has a different IHC profile (e.g., CK7 usually negative).
─ Focal Nodular Hyperplasia (FNH): Benign lesion, also can have a central scar and occur in young adults/women. FNH scar contains abnormal thick-walled arteries and prominent ductular reaction (CK7/19 positive ductules). Hepatocytes in FNH are bland and arranged in thin plates. GS shows map-like staining. FNH lacks the oncocytic cytology and lamellar fibrosis of FL-HCC and the DNAJB1-PRKACA fusion.
─ Hepatocellular adenoma (especially inflammatory or β-catenin activated types if large or with atypia): HCAs lack lamellar fibrosis and the specific cytology of FL-HCC. IHC and molecular subtyping of HCA is distinct.
─ Cholangiocarcinoma (especially scirrhous type): CCA is a glandular malignancy with desmoplastic stroma, positive for biliary markers (CK7, CK19) but negative for hepatocellular markers. FL-HCC has hepatocellular differentiation.
─ Metastatic carcinoma with oncocytic features or desmoplasia (e.g., from kidney, thyroid, adrenal) - Clinical history and IHC panel for site-specific markers needed.

Prognosis ─ ─ Historically considered to have a better prognosis than conventional HCC, particularly when compared to HCC arising in cirrhosis, due to younger patient age and absence of underlying liver disease allowing for more aggressive surgical resection
─ However, FL-HCC often presents at an advanced stage with large tumor size and frequent lymph node or distant metastases
─ Surgical resection is the mainstay of treatment and offers the best chance for long-term survival
─ Recurrence rates after resection are high
─ Response to systemic chemotherapy used for conventional HCC is generally poor
─ The impact of the DNAJB1-PRKACA fusion on targeted therapy is an area of active research
─ Overall 5-year survival rates vary widely (e.g., 30-70%), highly dependent on stage at diagnosis and resectability

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HCC, scirrhous type

A rare histologic variant of hepatocellular carcinoma characterized by abundant, dense fibrous (desmoplastic) stroma separating nests, cords, or tubules of tumor cells; it can mimic cholangiocarcinoma or metastatic adenocarcinoma both radiologically and pathologically

Clinical ─ ─ Rare, accounts for a small percentage (<5%) of all HCCs
─ May occur in patients with or without cirrhosis; association with chronic viral hepatitis (HBV, HCV) is common, similar to conventional HCC
─ Clinical presentation is often similar to conventional HCC (abdominal pain, mass, weight loss)
─ Serum AFP levels may be elevated, but can also be normal or only mildly increased, potentially less frequently or markedly elevated than in some conventional HCCs
─ Imaging features can be atypical for HCC due to the desmoplastic stroma:
─ Often shows delayed contrast enhancement rather than typical arterial hyperenhancement and washout, mimicking cholangiocarcinoma or metastasis
─ Capsular retraction may be seen

Macro ─ ─ Typically a firm, grey-white, unencapsulated, infiltrative mass
─ Cut surface is often gritty or hard due to the dense fibrous stroma
─ May have ill-defined borders
─ Less likely to show the soft, fleshy, variegated appearance of conventional HCC

Micro ─

─ Defining feature: Abundant, dense collagenous (desmoplastic or scirrhous) stroma constituting a significant portion of the tumor volume (often >50%)
─ Tumor cells are arranged in small nests, thin cords, tubules, or as individual cells embedded within and separated by the dense fibrous stroma
─ Tumor cells show hepatocellular differentiation, though this can sometimes be subtle or focal:
─ Polygonal cells with eosinophilic cytoplasm
─ Nuclear atypia varies from mild to marked
─ Bile production may be present but can be difficult to identify amidst the stroma
─ The trabecular pattern typical of conventional HCC is usually attenuated or lost in scirrhous areas
─ Lymphocytic infiltration within the stroma can be present
─ Vascular invasion may occur
─ Can coexist with areas of conventional HCC morphology

Ancillary studies ─

─ IHC:
─ Positive for hepatocellular markers: HepPar-1, Arginase-1, polyclonal CEA (canalicular pattern), CD10 (canalicular pattern), Glypican-3. Staining may be focal or less intense in some cases due to cell morphology or fixation in dense stroma. Albumin ISH is also useful.
─ Negative for definitive biliary markers: CK7 and CK19 are usually negative or only very focally positive in neoplastic cells (entrapped reactive ductules within stroma will be CK7/19 positive and can be a pitfall). Strong, diffuse CK7/19 would favor cholangiocarcinoma or cHCC-CCA.
─ Markers of stem/progenitor cells (e.g., CK19, EpCAM) may be expressed in a subset of scirrhous HCCs, suggesting a possible link to progenitor cell origin or epithelial-mesenchymal transition
─ Special Stains:
─ Trichrome or Sirius red: Highlights the abundant fibrous stroma
─ Reticulin: Often shows attenuated or lost reticulin framework around tumor cell nests/cords, but can be difficult to interpret in densely fibrotic areas

DDx ─

─ Intrahepatic Cholangiocarcinoma (ICC), desmoplastic type: This is the most important differential. ICC is composed of malignant glands positive for biliary markers (CK7, CK19, MUC1, S100P) and negative for hepatocellular markers. Scirrhous HCC shows hepatocellular differentiation.
─ Combined Hepatocellular-Cholangiocarcinoma (cHCC-CCA): Contains unequivocal components of both HCC and CCA. Scirrhous HCC is purely hepatocellular despite the stroma.
─ Metastatic adenocarcinoma with desmoplastic stroma (e.g., from pancreas, stomach, breast, colon) - IHC panel for site-specific markers is crucial.
─ Fibrolamellar HCC: Has characteristic lamellar fibrosis and large oncocytic cells with prominent nucleoli; DNAJB1-PRKACA fusion positive. Scirrhous HCC stroma is usually more irregular and dense, cells are different.
─ Sclerosed hemangioma: Benign vascular lesion that has undergone extensive fibrosis; lacks atypical hepatocytes. Vascular markers would be positive in residual endothelial cells.
─ Inflammatory pseudotumor (Inflammatory myofibroblastic tumor): Spindle cell proliferation with prominent inflammatory infiltrate; ALK positive in a subset; lacks atypical hepatocytes.
─ Confluent fibrosis / Central scar in cirrhosis: Non-neoplastic scarring; may contain entrapped, reactive hepatocytes but no malignant cells.

Prognosis ─ ─ Prognosis of scirrhous HCC has been debated; some studies suggest it may be similar to or slightly worse than conventional HCC of comparable stage, while others suggest it might be more aggressive due to infiltrative growth and challenges in radiological diagnosis leading to later detection
─ The abundant stroma may contribute to chemoresistance
─ Complete surgical resection is the primary treatment if feasible
─ Tendency for local recurrence and metastasis is similar to conventional HCC

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HCC, clear cell variant

A histologic variant of hepatocellular carcinoma where a predominant component (>80-90%) of the tumor cells exhibit clear cytoplasm due to accumulation of glycogen and/or lipid

Clinical ─ ─ Accounts for a small percentage (~2-7%) of all HCCs
─ Clinical presentation and risk factors are generally similar to conventional HCC (e.g., association with cirrhosis, viral hepatitis, alcohol)
─ Serum AFP levels may be elevated or normal, similar to conventional HCC
─ No specific clinical features uniquely distinguish it from other HCC types preoperatively

Macro ─ ─ Tumor appearance can be variable, often yellowish or paler than conventional HCC due to lipid/glycogen content
─ May be solitary or multiple, well-circumscribed or infiltrative, similar to conventional HCC

Micro ─

─ Defining feature: Majority (>80% or >90% by some definitions) of tumor cells have abundant clear or vacuolated cytoplasm
─ The clear appearance is due to accumulation of:
─ Glycogen: Results in optically clear cytoplasm that is PAS-positive and diastase-sensitive
─ Lipid (fat): Results in sharply demarcated cytoplasmic vacuoles (macrovesicular or microvesicular steatosis within tumor cells). Oil Red O stain on frozen tissue would be positive.
─ Often, both glycogen and lipid are present
─ Tumor cells are arranged in typical HCC architectural patterns: trabecular, solid, or pseudoglandular
─ Nuclei are often centrally or eccentrically placed, and may show features of malignancy (hyperchromasia, pleomorphism, prominent nucleoli), though atypia can sometimes be less pronounced than in some conventional HCCs, especially in well-differentiated clear cell HCC
─ Sinusoidal capillarization (CD34+) and loss of reticulin framework are present, as in conventional HCC
─ Bile production may be seen
─ Background liver often shows cirrhosis or chronic hepatitis

Ancillary studies ─

─ Special Stains:
─ PAS with and without diastase (PAS-D): Confirms presence of glycogen (PAS positive, diastase sensitive)
─ Oil Red O (on frozen tissue): Confirms presence of lipid
─ Reticulin: Shows loss or disorganization of reticulin framework
─ IHC:
─ Positive for hepatocellular markers: HepPar-1, Arginase-1, pCEA (canalicular), CD10 (canalicular), Glypican-3 (may be less consistently positive in very well-differentiated clear cell HCC)
─ Negative for biliary markers (CK7, CK19)
─ CD34: Highlights sinusoidal capillarization

DDx ─

─ Metastatic clear cell carcinoma: This is the most important differential. Common primaries include:
─ Renal cell carcinoma, clear cell type: Positive for PAX8, CAIX, CD10 (cytoplasmic/membranous, different from HCC's canalicular CD10); negative for hepatocellular markers.
─ Adrenocortical carcinoma: Positive for inhibin, Melan-A, SF-1; negative for hepatocellular markers.
─ Clear cell carcinoma of gynecologic origin (ovary, endometrium): Positive for PAX8, WT1 (ovarian serous), ER/PR; negative for hepatocellular markers.
─ Clear cell carcinoma of lung, thyroid, salivary gland: IHC for site-specific markers (e.g., TTF-1/Napsin A for lung; TTF-1/Thyroglobulin for thyroid) needed.
─ Hepatocellular adenoma with steatosis (HNF1A-inactivated HCA) or clear cell change: HCAs are benign, lack significant atypia, have preserved reticulin, and specific IHC profiles (e.g., L-FABP loss in H-HCA). HCC shows malignant features.
─ Steatohepatitic HCC: Shows steatosis but also ballooning, inflammation, and Mallory-Denk bodies, mimicking steatohepatitis. Clear cell HCC is predominantly clear cytoplasm without necessarily these inflammatory features.
─ Balloon cell melanoma metastatic to liver: Positive for S100/SOX10/Melan-A; negative for hepatocellular markers.
─ Lipid-rich angiomyolipoma (rare): Positive for HMB45, SMA; negative for hepatocellular markers.

Prognosis ─ ─ The prognostic significance of pure clear cell HCC has been debated
─ Some older studies suggested a potentially better prognosis compared to conventional HCC of similar stage, possibly due to often being well-differentiated
─ However, other studies have found no significant difference in prognosis when matched for stage and grade
─ Prognosis is largely determined by the same factors as conventional HCC: stage, grade, vascular invasion, and underlying liver function
─ Treatment is similar to conventional HCC

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Hepatoblastoma

The most common primary malignant liver tumor of childhood, thought to arise from hepatic precursor cells, exhibiting various patterns of differentiation (embryonal, fetal, macrotrabecular, small cell undifferentiated, and mesenchymal)

Clinical ─ ─ Typically presents in infants and young children (most cases <3 years old; median age ~18 months)
─ Male predominance (approx. 1.5-2:1)
─ Clinical presentation:
─ Abdominal distension or palpable abdominal mass (most common)
─ Weight loss, anorexia, nausea, vomiting, lethargy
─ Jaundice is uncommon at presentation (unless large tumor causes biliary obstruction)
─ Precocious puberty (due to ectopic β-hCG production by some tumors) is a rare but characteristic sign, more common in mixed epithelial and mesenchymal subtype with teratoid features
─ Elevated serum alpha-fetoprotein (AFP) is a key tumor marker, found in >90% of cases and useful for diagnosis and monitoring response to therapy
─ Associated with certain genetic syndromes/conditions:
─ Beckwith-Wiedemann syndrome (BWS)
─ Familial adenomatous polyposis (FAP) – germline APC mutations
─ Trisomy 18 (Edwards syndrome)
─ Low birth weight/prematurity
─ Other associations: hemihypertrophy, renal malformations

Macro ─ ─ Usually a solitary, large, well-circumscribed mass, but can be multifocal
─ Cut surface is variable depending on histologic subtype:
─ Often tan-yellow, fleshy, or variegated
─ May show areas of hemorrhage, necrosis, or cystic change
─ Calcification can be present
─ Well-differentiated fetal areas may appear more homogeneous and bile-stained
─ Mesenchymal areas can be myxoid or firm
─ Typically arises in an otherwise normal (non-cirrhotic) liver

Micro ─

─ Histologically diverse, often with mixed patterns. Classified into several subtypes:
─ Epithelial Type: ─ Fetal pattern: Composed of cells resembling fetal hepatocytes, arranged in thin trabeculae (1-2 cells thick) separated by sinusoids. Cells have moderate eosinophilic or clear cytoplasm (due to glycogen/fat), round central nuclei, inconspicuous nucleoli. Mitoses are infrequent. May show extramedullary hematopoiesis.
─ Embryonal pattern: More primitive appearance, with sheets, ribbons, or rosette-like structures of small, crowded cells with scant cytoplasm, high N/C ratio, hyperchromatic nuclei, and more frequent mitoses.
─ Macrotrabecular pattern (≥10 cells thick): Broad trabeculae of hepatocyte-like cells; associated with a more aggressive course. This pattern needs to be distinguished from fetal areas with thickened plates.
─ Small cell undifferentiated (anaplastic) pattern: Sheets of highly malignant small round blue cells with scant cytoplasm, hyperchromatic nuclei, high mitotic rate, and apoptosis. Often associated with poor prognosis. Requires IHC to differentiate from other small round blue cell tumors.
─ Cholangioblastic pattern: Rare, features tubules and duct-like structures resembling developing bile ducts
─ Mixed Epithelial and Mesenchymal Type: ─ Contains both epithelial elements (as above) and mesenchymal components.
─ Mesenchymal component can be undifferentiated (primitive mesenchyme) or show differentiation towards osteoid, chondroid, rhabdomyoblastic, or fibrous tissue.
─ Teratoid features (e.g., squamous epithelium, melanin, neural tissue, intestinal glands) can be present in some mixed tumors; these are often associated with β-hCG production and precocious puberty.
─ Post-chemotherapy changes: Increased fibrosis, necrosis, calcification, maturation of epithelial components (e.g., fetal differentiation), and reduction in tumor cellularity

Ancillary studies ─

─ IHC:
─ Epithelial components: ─ HepPar-1, Arginase-1: Usually positive in fetal and embryonal components (hepatocellular differentiation)
─ AFP: Often positive in tumor cells
─ Glypican-3 (GPC3): Diffusely positive in most hepatoblastomas (both epithelial and some mesenchymal components)
─ β-catenin: Nuclear accumulation is very common, indicating Wnt pathway activation
─ Cytokeratins (e.g., AE1/AE3, CAM5.2, CK8/18): Positive in epithelial cells. CK7 and CK19 may highlight cholangioblastic areas or ductal plates if present.
─ Small cell undifferentiated component: May be negative or weak for hepatocellular markers; may express FLI1, CD99, or synaptophysin focally, requiring careful distinction from other small round blue cell tumors. Often INI1 (SMARCB1) retained (unlike rhabdoid tumor).
─ Mesenchymal components: Markers depend on differentiation (e.g., desmin/myogenin for rhabdomyoblastic, S100 for chondroid)
─ Molecular ─ ─ Activation of the Wnt/β-catenin pathway (CTNNB1 mutations or other alterations) is the most common genetic event, found in >80% of cases
─ Other recurrently mutated genes include NFE2L2, TERT promoter mutations (more common in older children/adolescents or tumors with macrotrabecular pattern)
─ Associated with specific chromosomal gains and losses

DDx ─

─ Hepatocellular carcinoma (HCC): Usually occurs in older children/adolescents or adults, often in the setting of chronic liver disease (hepatoblastoma in normal liver). Histology of conventional HCC differs (thicker trabeculae, sinusoidal capillarization, specific cytologic features). Fibrolamellar HCC is a key differential in adolescents.
─ Metastatic neuroblastoma: Especially for small cell undifferentiated hepatoblastoma. Neuroblastoma is positive for neuroendocrine markers (synaptophysin, chromogranin), PHOX2B, and typically shows Homer-Wright rosettes or neuropil.
─ Other pediatric small round blue cell tumors metastatic to liver (e.g., Ewing sarcoma, rhabdomyosarcoma, lymphoma, Wilms tumor) – IHC panel is crucial
─ Infantile hemangioendothelioma / Hepatic angiosarcoma: Vascular tumors, positive for vascular markers (CD31, CD34, ERG)
─ Mesenchymal hamartoma of the liver: Benign lesion, typically cystic and myxoid, lacks the malignant epithelial components of hepatoblastoma, though can have primitive mesenchyme
─ Germ cell tumor (yolk sac tumor metastatic to liver): Can produce AFP; histology shows characteristic Schiller-Duval bodies and hyaline globules; positive for SALL4, AFP, Glypican-3, but negative for HepPar-1

Prognosis ─ ─ Prognosis has significantly improved with multimodal therapy (chemotherapy followed by surgical resection, and liver transplantation for unresectable cases)
─ Key prognostic factors:
─ PRETEXT staging (PRETreatment EXTent of tumor): Based on imaging, number of liver sections involved
─ Histologic subtype: Pure fetal histology generally has the best prognosis. Small cell undifferentiated and macrotrabecular patterns are associated with worse prognosis.
─ Presence of metastasis at diagnosis (most commonly to lungs)
─ Completeness of surgical resection
─ Serum AFP levels (post-operative decline and normalization)
─ Specific molecular alterations (e.g., TERT mutations may indicate poorer outcome)
─ Overall survival for standard-risk hepatoblastoma is >80-90%; high-risk disease has a poorer outcome

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Biliary tumors

Bile Duct Hamartoma (Von Meyenburg Complex - VMC)

Benign, typically multiple, small, malformative lesions of the liver composed of dilated, irregular bile duct structures embedded in a fibrous stroma; considered a type of ductal plate malformation

Clinical ─ ─ Common incidental finding at autopsy (0.6-2.8%), surgery, or on imaging
─ Usually asymptomatic and of no clinical significance when found incidentally in small numbers
─ Can occur at any age, no sex predilection
─ Typically multiple and scattered throughout the liver, often subcapsular or periportal
─ Rarely, numerous VMCs ("biliary hamartomatosis") can cause hepatomegaly or mildly abnormal liver function tests
─ Associated with other fibropolycystic liver diseases (e.g., Autosomal Dominant Polycystic Liver Disease - ADPLD, Caroli disease, Congenital Hepatic Fibrosis) and autosomal recessive polycystic kidney disease (ARPKD)
─ Generally considered benign with a very low risk of malignant transformation to cholangiocarcinoma, though rare cases have been reported, especially in the setting of diffuse hamartomatosis or underlying chronic liver disease

Macro ─ ─ Appear as small (usually <0.5 cm, rarely up to 1-1.5 cm), firm, grey-white or whitish-yellow nodules on the liver surface or within the parenchyma
─ Often subcapsular
─ May have a slightly cystic or "spongy" appearance on cut section if ducts are very dilated

Micro ─

─ Composed of clusters of irregularly shaped, often dilated, branching bile duct-like structures lined by a single layer of bland cuboidal to flattened biliary epithelial cells
─ These ductal structures are embedded in a dense, often hyalinized, fibrous stroma
─ Lumina of the ducts may be empty or contain inspissated bile, proteinaceous material, or rarely, small calculi
─ The ductal epithelium lacks cytologic atypia and mitotic activity
─ No normal portal vein branches or hepatic artery branches are typically seen within the hamartoma itself (distinguishing from portal tracts)
─ The lesion is usually well-demarcated from the surrounding normal liver parenchyma but not truly encapsulated
─ Inflammation is typically absent or minimal unless complicated by stasis or infection (rare)

Ancillary studies ─

─ Special Stains:
─ Trichrome: Highlights the fibrous stroma
─ PAS: May show some mucin in ductal cells or lumens
─ IHC:
─ CK7 and CK19: Strong and diffuse positivity in the epithelial lining of the ductal structures, confirming their biliary origin
─ Ki-67: Very low proliferation index

DDx ─

─ Metastatic adenocarcinoma (especially from pancreas, stomach, or colon): This is the most important clinical differential, particularly when VMCs are numerous and seen on imaging. Metastases typically show cytologic atypia, infiltrative growth, desmoplastic stromal reaction different from VMC stroma, and IHC profile consistent with primary site (e.g., CDX2/CK20 for colorectal, CA19-9/CEA for pancreatobiliary). VMCs have bland cytology and characteristic ductal plate malformation appearance.
─ Small intrahepatic cholangiocarcinoma: Shows malignant cytology, infiltrative growth, often more cellular stroma, and higher Ki-67. VMCs are benign.
─ Bile duct adenoma: Typically solitary, well-circumscribed lesion composed of small, closely packed, uniform tubules with minimal stroma; VMCs are usually multiple and have more dilated/irregular ducts in more abundant fibrous stroma
─ Peribiliary gland hamartoma: Similar to bile duct adenoma but arises from peribiliary glands of larger bile ducts
─ Polycystic liver disease (ADPLD): Characterized by much larger, macroscopic cysts, though VMCs can be an associated finding
─ Caroli disease: Involves segmental saccular dilatation of larger intrahepatic bile ducts communicating with the biliary tree; VMCs affect smaller, more peripheral ductules and usually don't communicate directly with major ducts
─ Congenital hepatic fibrosis: Broad fibrous bands with abnormal ductal structures, but also associated with portal hypertension features; VMCs are more discrete nodules

Prognosis ─ ─ Excellent; VMCs are benign lesions and typically do not progress or cause symptoms
─ The main clinical significance is their potential to be mistaken for metastatic disease on imaging or at surgery, leading to unnecessary investigations or anxiety
─ Malignant transformation into cholangiocarcinoma is exceptionally rare but has been reported, so very large or changing lesions might warrant closer follow-up or biopsy, especially if there's a background of chronic liver disease

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Bile Duct Adenoma (Intrahepatic Biliary Neoplasm of Adenoma Type)

A rare, benign epithelial tumor of the liver composed of a proliferation of small, uniform bile duct-like tubules embedded in a variable fibrous stroma; also known as peribiliary gland hamartoma by some, especially when associated with larger bile ducts

Clinical ─ ─ Uncommon, usually found incidentally during surgery, imaging for other reasons, or at autopsy
─ Typically asymptomatic
─ Can occur at any age, but more common in middle-aged to older adults; no clear sex predilection
─ Usually solitary, but can rarely be multiple
─ No known strong association with chronic liver disease or specific risk factors
─ Generally considered to have no or very low malignant potential

Macro ─ ─ Small (typically <1 cm, rarely up to 2 cm), firm, well-circumscribed, non-encapsulated nodule
─ Usually located subcapsularly
─ Appears as a grey-white or whitish-tan, solid lesion on cut section

Micro ─

─ Composed of numerous small, closely packed, generally uniform, round to oval or slightly irregular tubules resembling normal interlobular bile ducts or peribiliary glands
─ Tubules are lined by a single layer of bland cuboidal to low columnar biliary epithelial cells with round to oval nuclei, inconspicuous nucleoli, and scant to moderate eosinophilic cytoplasm
─ Cytologic atypia and mitotic activity are absent or minimal
─ Lumina of the tubules are usually small and may be empty or contain inspissated eosinophilic material or rarely, bile
─ The tubules are embedded in a variable amount of fibrous stroma, which can range from scant and loose to dense and hyalinized. The stroma may contain a sparse chronic inflammatory infiltrate (lymphocytes, plasma cells).
─ The lesion is well-demarcated from the surrounding liver parenchyma, but not truly encapsulated. It may show an irregular interface with adjacent hepatocytes.
─ No features of invasion are present

Ancillary studies ─

─ Special Stains:
─ Trichrome: Highlights the fibrous stroma
─ PAS: May show mucin in some ductal cells
─ IHC:
─ CK7 and CK19: Strong and diffuse positivity in the epithelial cells of the tubules, confirming biliary differentiation
─ CEA (monoclonal): Usually negative or only apical/luminal staining (unlike the cytoplasmic staining often seen in cholangiocarcinoma)
─ Ki-67: Very low proliferation index (<1-2%)
─ p53: Wild-type expression (no overexpression)
─ CD56: May be focally positive in some cases (has been suggested to help differentiate from well-differentiated cholangiocarcinoma which is often CD56 negative, but utility is debated)

DDx ─

─ Well-differentiated intrahepatic cholangiocarcinoma: This is the most important differential. Cholangiocarcinoma shows infiltrative growth, cytologic atypia (nuclear pleomorphism, hyperchromasia, prominent nucleoli), desmoplastic stromal reaction (often more cellular and reactive than BDA stroma), and may show perineural or lymphovascular invasion. IHC for p53 (overexpression or null pattern) and a higher Ki-67 index would favor malignancy.
─ Bile duct hamartoma (Von Meyenburg Complex - VMC): VMCs are usually multiple, have more irregularly shaped and dilated ducts, and often more abundant fibrous stroma compared to the typically solitary BDA with more uniform, packed tubules. However, there can be morphologic overlap, and some consider them related entities on a spectrum of ductal plate malformations or benign biliary proliferations.
─ Metastatic adenocarcinoma: Especially from pancreas or upper GI. Metastases usually show greater cytologic atypia, infiltrative growth, and an IHC profile consistent with their origin (e.g., CA19-9, CK17 for pancreatic). BDAs are CK7+/CK20- typically.
─ Reactive ductular proliferation: Occurs in response to various liver injuries (e.g., cholestasis, inflammation, necrosis). Ductules are usually at the periphery of portal tracts or along fibrous septa, accompanied by other signs of liver injury, and lack the discrete nodular growth of a BDA.
─ Sclerosed hemangioma: May appear as a firm, whitish nodule, but histologically composed of obliterated vascular channels and fibrous tissue, not biliary tubules.

Prognosis ─ ─ Excellent; bile duct adenomas are benign lesions with virtually no risk of malignant transformation reported for typical cases
─ Usually require no treatment if diagnosis is confident (e.g., on biopsy or if classic imaging features for a small lesion, though imaging diagnosis can be challenging)
─ Surgical excision may be performed if there is diagnostic uncertainty (especially to rule out cholangiocarcinoma), if the lesion is symptomatic (rare), or if it shows growth on follow-up

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Biliary Adenofibroma

A rare, benign, complex tubulocystic epithelial tumor of the liver characterized by glands and cysts lined by biliary-type epithelium, embedded in an abundant, dense fibrous (desmoplastic-like) stroma

Clinical ─ ─ Extremely rare; fewer than 30-40 cases reported in English literature
─ Affects adults, wide age range (20s to 70s), no clear sex predilection
─ Often asymptomatic and discovered incidentally on imaging or at surgery for unrelated reasons
─ May present with non-specific symptoms like abdominal pain or discomfort if large
─ Serum tumor markers (AFP, CEA, CA19-9) are typically normal
─ Considered benign, but there are reports of associated dysplasia or progression to intrahepatic cholangiocarcinoma in a small subset of cases, leading to its classification as a potential precursor lesion by WHO (2019)

Macro ─ ─ Usually a solitary, well-circumscribed, firm, solid and cystic mass
─ Size can vary significantly, from a few centimeters to very large (>15-20 cm)
─ Cut surface is typically grey-white or tan, firm, and may show small cystic spaces or a honeycomb appearance due to dilated tubules and cysts embedded in dense stroma
─ May be unencapsulated or have a pseudocapsule

Micro ─

─ Biphasic appearance: ─ Epithelial component: Composed of numerous, variably sized, branching and anastomosing tubules, glands, and microcysts lined by a single layer of bland cuboidal to low columnar biliary-type epithelial cells.
─ Epithelial cells have round to oval nuclei, inconspicuous nucleoli, and scant to moderate eosinophilic cytoplasm. Cytologic atypia is usually absent or minimal in typical cases.
─ Lumina may contain eosinophilic secretions or bile
─ Mitotic activity is very low
─ Stromal component: Abundant, dense, paucicellular fibrous or collagenous stroma surrounding the epithelial structures. This stroma is often hyalinized and desmoplastic-like.
─ Spindle cells within the stroma are bland and fibroblastic/myofibroblastic in appearance
─ Chronic inflammatory cells (lymphocytes, plasma cells) may be scattered within the stroma
─ The overall architecture is often complex and labyrinthine
─ No evidence of infiltrative growth into surrounding liver parenchyma in typical benign cases
─ Atypical features / Dysplasia: In some reported cases, foci of biliary intraepithelial neoplasia (BilIN)-like changes or frank carcinomatous transformation (intrahepatic cholangiocarcinoma) have been described arising in association with biliary adenofibroma. These areas would show increased cytologic atypia, architectural complexity, and potentially invasion.

Ancillary studies ─

─ Special Stains:
─ Trichrome: Highlights the abundant fibrous stroma
─ Mucicarmine or PAS: May show focal mucin production by epithelial cells
─ IHC:
─ Epithelial cells: Positive for biliary cytokeratins (CK7, CK19, CAM5.2, AE1/AE3). EMA may also be positive.
─ CEA (monoclonal): Usually negative or only apical/luminal (non-specific)
─ Ki-67: Very low proliferation index in both epithelial and stromal components in benign lesions. Increased in areas of dysplasia or carcinoma.
─ p53: Wild-type expression in benign lesions. Overexpression or null pattern may be seen in dysplastic/malignant areas.
─ Stromal cells: May be positive for vimentin, SMA (focally, if myofibroblastic)

DDx ─

─ Intrahepatic Cholangiocarcinoma (especially desmoplastic/sclerosing types): This is the most critical differential. Cholangiocarcinoma shows clear malignant cytologic features, infiltrative growth, perineural/lymphovascular invasion, and often a higher Ki-67 index. The stroma in cholangiocarcinoma is typically more cellular and reactive (desmoplastic response to invasion). Biliary adenofibroma has bland epithelium and a more "organized" though dense stroma. However, distinction can be very difficult on small biopsies, and sampling error is a concern given potential for focal malignancy.
─ Bile Duct Adenoma: Typically smaller, less stromal component, and composed of more uniform, closely packed small tubules. Biliary adenofibroma has more complex tubulocystic structures and much more abundant, dense stroma.
─ Von Meyenburg Complex (Bile Duct Hamartoma): Usually multiple, smaller lesions (<0.5 cm), with more irregular and dilated ducts in a less dense fibrous stroma compared to the prominent desmoplastic-like stroma of adenofibroma.
─ Sclerosed Hemangioma: Composed of obliterated vascular channels within sclerotic stroma; negative for biliary cytokeratins
─ Metastatic Adenocarcinoma with desmoplasia: Cytologic atypia and IHC profile of the primary tumor would be key.
─ Fibrolamellar HCC (if stroma is very prominent): FLC has large, oncocytic hepatocytes, lamellar fibrosis, and is positive for hepatocellular markers and often CK7; lacks the biliary tubulocystic structures of adenofibroma.

Prognosis ─ ─ Generally considered benign, but because of the reported (though rare) association with dysplasia and cholangiocarcinoma, complete surgical excision is often recommended, especially for larger lesions or if there is any diagnostic uncertainty
─ Long-term prognosis after complete excision of benign lesions is excellent
─ If malignant transformation occurs, the prognosis is dictated by the stage and grade of the cholangiocarcinoma component
─ Due to its rarity, the natural history and true malignant potential are still not fully understood; more case studies with long-term follow-up are needed

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Biliary Intraepithelial Neoplasia (BilIN)

A preinvasive neoplastic lesion of the biliary tract epithelium, characterized by cellular atypia and architectural changes, considered a precursor to cholangiocarcinoma; graded from BilIN-1 (low-grade) to BilIN-3 (high-grade/carcinoma in situ)

Clinical ─ ─ Microscopic lesion, not usually visible on gross examination or routine imaging, unless it causes subtle mucosal irregularities or is associated with an invasive carcinoma
─ Often found incidentally in livers resected for chronic biliary diseases or cholangiocarcinoma
─ Risk factors are similar to those for cholangiocarcinoma:
─ Primary sclerosing cholangitis (PSC)
─ Hepatolithiasis (intrahepatic stones)
─ Choledochal cysts
─ Liver fluke infestation (Opisthorchis viverrini, Clonorchis sinensis)
─ Chronic viral hepatitis (HBV, HCV)
─ Biliary tract malformations
─ May be multifocal and can occur in intrahepatic or extrahepatic bile ducts
─ Asymptomatic in itself; symptoms, if any, are usually due to the underlying condition or associated invasive carcinoma

Macro ─ ─ Usually not macroscopically visible as a distinct lesion
─ May appear as subtle mucosal granularity, opacity, or slight thickening if extensive
─ Often found in the vicinity of or overlying an invasive cholangiocarcinoma

Micro ─

─ Characterized by atypical epithelial cells lining the bile ducts, without invasion through the basement membrane
─ Epithelial cells are typically columnar or cuboidal, with varying degrees of nuclear atypia, stratification, and architectural complexity
─ Graded into three tiers based on the degree of atypia:
─ BilIN-1 (Low-grade intraepithelial neoplasia): ─ Mild cytologic atypia: Nuclei are mildly enlarged, hyperchromatic, and pseudostratified, but generally maintain polarity (basally oriented)
─ Architectural changes are minimal, may show slight papillary tufting or flat atypia
─ Mitotic figures are rare and basal
─ BilIN-2 (Intermediate-grade/Moderate intraepithelial neoplasia): ─ Moderate cytologic atypia: Increased nuclear size and hyperchromasia, more pronounced pseudostratification, some loss of polarity
─ Architectural changes more evident: Micropapillary projections, tufting, or cribriform-like structures may be present but are not complex or extensive
─ Mitotic figures may be present, occasionally suprabasal
─ BilIN-3 (High-grade intraepithelial neoplasia / Carcinoma in situ): ─ Severe cytologic atypia: Marked nuclear pleomorphism, hyperchromasia, irregular nuclear contours, significant loss of polarity (nuclei extend to apical surface)
─ Architectural complexity is often prominent: Complex micropapillary or cribriform patterns, "Roman bridge" formations, or nearly solid growth filling the duct lumen
─ Mitotic figures are usually frequent and can be atypical or suprabasal
─ Distinction from intraductal spread of an established invasive carcinoma can be difficult without seeing the invasive component
─ The basement membrane remains intact in all grades of BilIN

Ancillary studies ─

─ IHC:
─ p53: Overexpression (strong, diffuse nuclear staining) or null pattern (complete absence of staining with positive internal controls) is common in BilIN-2 and BilIN-3, suggesting TP53 mutation. BilIN-1 is usually wild-type.
─ Ki-67 (MIB-1): Proliferation index increases with the grade of BilIN (low in BilIN-1, moderate in BilIN-2, high in BilIN-3)
─ S100P: May be overexpressed in higher grades of BilIN and cholangiocarcinoma
─ IMP3 (IGF2BP3): Expression increases with grade of dysplasia
─ MUC1: Aberrant expression can be seen in higher grades
─ CK7, CK19: Positive (confirm biliary lineage), but not useful for grading
─ Molecular ─ ─ Accumulation of genetic alterations similar to those in invasive cholangiocarcinoma:
─ KRAS mutations are common, often early events (can be seen in BilIN-1)
─ TP53 mutations are more frequent in higher grades (BilIN-2, BilIN-3)
─ SMAD4 inactivation can occur
─ CDKN2A (p16) alterations (e.g., homozygous deletion or promoter hypermethylation) are also seen in higher grades

DDx ─

─ Reactive biliary atypia: Seen in response to inflammation, stones, or stasis. Shows nuclear enlargement and some hyperchromasia, but atypia is usually less severe, polarity is maintained, N/C ratio is not markedly increased, and inflammation is often prominent. Lacks the progressive architectural complexity and consistent p53/Ki-67 alterations of high-grade BilIN.
─ Intraductal Papillary Neoplasm of the Bile Duct (IPNB): IPNBs are grossly visible, typically larger, exophytic papillary or villous lesions within dilated bile ducts, composed of neoplastic biliary epithelium covering fibrovascular stalks. BilIN is typically flat or micropapillary and microscopic. However, BilIN-like changes can be seen on the surface of IPNBs or adjacent to them.
─ Invasive cholangiocarcinoma with intraductal spread: Malignant glands invading stroma will be present elsewhere. The intraductal component can mimic BilIN-3.
─ Normal bile duct epithelium (no atypia or architectural abnormalities)

Prognosis ─ ─ BilIN is a precursor to invasive cholangiocarcinoma, particularly intrahepatic and perihilar types
─ The risk of progression increases with the grade of BilIN (BilIN-3 has the highest risk)
─ Detection of BilIN, especially high-grade, warrants close follow-up and surveillance for development of invasive carcinoma, or may prompt resection if found at a margin or associated with other high-risk features
─ Natural history and precise progression rates are still being fully elucidated due to the difficulty in detecting these microscopic lesions prospectively

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Intraductal Papillary Neoplasm of the Bile Duct (IPNB)

A grossly visible, preinvasive or early invasive neoplastic lesion of the biliary tract characterized by intraductal papillary or villous proliferation of neoplastic biliary-type epithelium, often associated with mucin production and bile duct dilatation; considered a precursor to invasive cholangiocarcinoma

Clinical ─ ─ More common in Asian countries, particularly where hepatolithiasis and liver fluke infections (Clonorchis sinensis, Opisthorchis viverrini) are endemic; increasing recognition in Western countries
─ Typically affects older adults (median age 60-70 years), slight male predominance in some series
─ Symptoms are often due to biliary obstruction or cholangitis:
─ Abdominal pain (right upper quadrant or epigastric)
─ Jaundice (intermittent or persistent)
─ Fever, chills (if cholangitis develops)
─ Elevated liver enzymes (ALP, GGT, bilirubin)
─ Can occur in intrahepatic or extrahepatic bile ducts; intrahepatic IPNBs are more common in the left lobe
─ Associated with risk factors for cholangiocarcinoma: hepatolithiasis, PSC, choledochal cysts, liver fluke infection
─ Imaging (US, CT, MRI/MRCP) shows dilated bile ducts often containing intraductal masses or mural nodules; mucin production can lead to marked ductal ectasia

Macro ─ ─ Grossly visible, exophytic (papillary, villous, or granular) tumor growing within the lumen of a dilated bile duct
─ Can be solitary or multiple (biliary papillomatosis if diffuse)
─ Tumor size varies from small nodules to large, bulky masses filling and expanding the duct
─ May be associated with abundant mucin production, which can fill the dilated ducts ("mucin-producing IPNB")
─ Underlying bile duct wall may be thickened

Micro ─

─ Characterized by intraductal growth of neoplastic biliary epithelium forming papillary, villous, tubulopapillary, or flat structures supported by fine fibrovascular stalks
─ Epithelial lining can be of several types, similar to pancreatic IPMN:
─ Pancreatobiliary type (most common in some series): Cuboidal to columnar cells with eosinophilic cytoplasm, high-grade atypia, complex architecture (most common type to have associated invasion)
─ Intestinal type: Tall columnar cells with elongated, pseudostratified nuclei, resembling colonic villous adenoma; often mucin-producing
─ Gastric type (foveolar or pyloric gland type): Tall columnar cells with abundant apical mucin (foveolar) or cuboidal cells with clear cytoplasm (pyloric gland); typically low-grade atypia
─ Oncocytic type: Large polygonal cells with abundant granular eosinophilic cytoplasm (oncocytes) and prominent nucleoli, forming complex papillae
─ Dysplasia is graded as low-grade or high-grade intraepithelial neoplasia based on cytologic and architectural atypia. High-grade dysplasia is common.
─ An associated invasive carcinoma (tubular adenocarcinoma, mucinous adenocarcinoma, or colloid carcinoma) is present in a significant proportion of cases (40-80%). The invasive component should be documented and graded.
─ Mucin production can be prominent, with extracellular mucin filling duct lumens

Ancillary studies ─

─ IHC (Epithelial cells):
─ MUC expression varies by subtype: ─ MUC1: Often positive in pancreatobiliary type and invasive components
─ MUC2: Often positive in intestinal type (goblet cells)
─ MUC5AC: Often positive in gastric (foveolar) and pancreatobiliary types
─ MUC6: Often positive in gastric (pyloric gland) type
─ CK7, CK19: Positive (biliary lineage)
─ CDX2: Can be positive in intestinal type
─ p53: Overexpression or null pattern common in high-grade dysplasia and invasive carcinoma
─ Ki-67: Proliferation index increases with grade of dysplasia and invasion
─ Molecular ─ ─ Genetic alterations can vary by subtype and geographic region:
─ KRAS mutations: Common, especially in intestinal and gastric types, and in Western patients
─ GNAS mutations: Can occur, particularly in intestinal type (similar to pancreatic IPMN)
─ RNF43 mutations: Can occur
─ TP53 mutations: Associated with progression to high-grade dysplasia and invasion
─ SMAD4 inactivation
─ Loss of heterozygosity (LOH) at various loci
─ Different molecular pathways may be involved compared to conventional (non-papillary) cholangiocarcinoma

DDx ─

─ Biliary Intraepithelial Neoplasia (BilIN): BilIN is a flat or micropapillary microscopic lesion. IPNB is a grossly visible papillary mass. High-grade BilIN can be on the surface of an IPNB.
─ Conventional Cholangiocarcinoma (mass-forming or periductal-infiltrating types): These lack the predominant intraductal papillary growth pattern of IPNB. However, IPNB can have an associated invasive component that resembles conventional cholangiocarcinoma.
─ Mucinous Cystic Neoplasm of the Liver (MCN-L): MCN-L is a cyst-forming neoplasm with ovarian-type stroma, typically not communicating with the bile duct system. IPNB grows within pre-existing bile ducts.
─ Bile duct adenoma/hamartoma: Benign lesions, lack the complex papillary architecture and significant cytologic atypia of IPNB.
─ Inflammatory polyps or reactive papillary hyperplasia: Due to chronic inflammation/stones; lack true neoplastic atypia of IPNB.
─ Metastatic papillary carcinoma to bile ducts (rare): History of primary elsewhere; IHC profile of primary

Prognosis ─ ─ Prognosis is generally better than for conventional cholangiocarcinoma of similar stage, especially if non-invasive or only minimally invasive
─ Presence and extent of an associated invasive carcinoma are the most important prognostic factors
─ Histologic subtype may also influence prognosis (e.g., pancreatobiliary type may be more aggressive)
─ Complete surgical resection is the mainstay of treatment and offers the best chance for cure
─ High recurrence rate, even after resection, due to multifocality or field defect ("biliary papillomatosis" if diffuse)
─ Long-term surveillance is necessary

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Mucinous Cystic Neoplasm of the Liver (MCN-L)

A rare, solitary, multilocular or unilocular cystic epithelial neoplasm of the liver, characterized by a mucin-producing epithelial lining and a distinctive underlying ovarian-type stroma; occurs almost exclusively in women and does not communicate with the biliary tree

Clinical ─ ─ Rare, accounts for <5% of all cystic liver lesions
─ Predominantly affects women (often >90-95% of cases), typically in middle age (4th-5th decades)
─ Usually asymptomatic and discovered incidentally on imaging
─ Symptomatic patients may present with abdominal pain or discomfort, a palpable mass, or rarely, jaundice (if large and compressing bile ducts)
─ Serum tumor markers (CEA, CA19-9) may be elevated in some cases, especially if associated with invasive carcinoma, but are often normal
─ No clear association with oral contraceptive use or other specific risk factors, though hormonal influences are suspected due to female predominance and ovarian-type stroma
─ Site: Almost always intrahepatic, can occur in any lobe, usually solitary

Macro ─ ─ Typically a large, well-circumscribed, multilocular (most common) or unilocular cystic mass
─ Size varies, can be several centimeters to >20-30 cm
─ Cysts are filled with clear, mucoid, gelatinous, or hemorrhagic fluid
─ Cyst wall is often thick and fibrous; septations are common in multilocular lesions
─ Mural nodules or papillary projections may be present on the inner surface, raising suspicion for malignancy
─ Crucially, MCN-L does not communicate with the native bile duct system (a key distinguishing feature from IPNB)

Micro ─

─ Epithelial lining: ─ Composed of a single layer of columnar to cuboidal, mucin-producing epithelial cells, resembling biliary or gastric foveolar/intestinal-type epithelium
─ Epithelium can show varying degrees of dysplasia:
─ Low-grade dysplasia: Mild atypia, basal nuclei, preserved polarity
─ Intermediate-grade/Moderate dysplasia
─ High-grade dysplasia (carcinoma in situ): Marked atypia, loss of polarity, complex architecture (papillary, cribriform)
─ An associated invasive carcinoma (mucinous adenocarcinoma or undifferentiated carcinoma) can arise from the dysplastic epithelium in a subset of cases (~10-20%)
─ Ovarian-type stroma (OTS): ─ The defining histologic feature of MCN-L ─ A subepithelial layer of densely cellular, spindle-shaped stromal cells resembling ovarian stroma
─ Stromal cells are often plump with scant cytoplasm and ovoid nuclei
─ May show luteinization (eosinophilic cytoplasm) or decidua-like change
─ This stroma is typically immunoreactive for estrogen receptors (ER), progesterone receptors (PR), and inhibin
─ Outer fibrous capsule or wall may be present
─ Hemorrhage, cholesterol clefts, foamy macrophages, and calcification can be seen in the cyst contents or wall

Ancillary studies ─

─ IHC:
─ Epithelial lining: Positive for cytokeratins (CK7, CK19, CAM5.2, AE1/AE3). Mucin stains (PAS-D, Alcian blue) highlight intracellular and intraluminal mucin. CEA may be positive, especially with dysplasia/carcinoma.
─ Ovarian-type stroma: ─ Estrogen Receptor (ER) & Progesterone Receptor (PR): Nuclear positivity in stromal cells is characteristic
─ Inhibin-alpha: Cytoplasmic positivity in stromal cells is characteristic
─ Smooth Muscle Actin (SMA): May be positive in some stromal cells
─ CD10: Can be positive in stromal cells
─ Molecular ─ ─ KRAS mutations are common, especially in lesions with high-grade dysplasia or invasive carcinoma
─ TP53 mutations and SMAD4 loss can occur in invasive components
─ RNF43 mutations have also been reported

DDx ─

─ Simple biliary cyst / Polycystic liver disease (ADPLD): Lined by bland, flattened biliary epithelium, lack ovarian-type stroma and mucinous lining. ADPLD has numerous cysts and genetic basis.
─ Intraductal Papillary Neoplasm of the Bile Duct (IPNB) with cystic dilatation: IPNB arises within and communicates with the native bile duct system; lacks ovarian-type stroma. Histologic subtypes differ.
─ Echinococcal (Hydatid) cyst: Parasitic cyst with characteristic laminated membrane and scolices; serology positive. Lacks mucinous epithelium and ovarian-type stroma.
─ Hemorrhagic cyst or post-traumatic cyst: History of trauma or bleeding; lacks neoplastic epithelial lining and ovarian-type stroma.
─ Cystic cholangiocarcinoma or metastatic adenocarcinoma with cystic change: Shows frank malignant cytology and infiltrative growth; lacks ovarian-type stroma (though desmoplastic stroma can be present in malignancy).
─ Bile duct hamartoma (Von Meyenburg Complex): Small, multiple, solid or microcystic lesions with irregular ducts in fibrous stroma; lacks ovarian-type stroma and large cyst formation.
─ Endometriotic cyst (rare in liver): Contains endometrial glands and stroma (CD10+ stroma, ER/PR+ glands and stroma)

Prognosis ─ ─ MCN-L without invasive carcinoma (biliary cystadenoma): Benign with excellent prognosis after complete surgical resection. Recurrence is rare if completely excised.
─ MCN-L with an associated invasive carcinoma (biliary cystadenocarcinoma): Prognosis depends on the stage, grade, and extent of the invasive component, similar to conventional cholangiocarcinoma. Ovarian-type stroma itself does not dictate prognosis of the invasive part.
─ Complete surgical resection is the treatment of choice for all MCN-Ls due to the risk of harboring or developing invasive carcinoma and the difficulty in definitively excluding malignancy preoperatively in all cases

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Intrahepatic Cholangiocarcinoma (ICC)

A primary malignant epithelial neoplasm of the liver arising from the epithelium of intrahepatic bile ducts (ranging from interlobular bile ducts to second-order bile ducts); it is the second most common primary liver cancer after hepatocellular carcinoma

Clinical ─ ─ Incidence is rising globally
─ Typically affects older adults (6th-7th decades), slight male predominance in some regions
─ Risk factors:
─ Primary sclerosing cholangitis (PSC) - strong association
─ Hepatolithiasis (intrahepatic stones)
─ Liver fluke infestation (Opisthorchis viverrini, Clonorchis sinensis - endemic in Southeast Asia)
─ Choledochal cysts and other biliary malformations (e.g., Caroli disease)
─ Chronic viral hepatitis (HBV, HCV) and cirrhosis (any cause, though less strongly linked than for HCC)
─ Non-alcoholic fatty liver disease (NAFLD)/NASH
─ Thorotrast exposure (historical)
─ Certain toxins and industrial exposures
─ Often asymptomatic in early stages. Symptoms of advanced disease include:
─ Abdominal pain (dull, right upper quadrant or epigastric)
─ Weight loss, anorexia, malaise
─ Jaundice (if large tumor obstructs major bile ducts or with extensive disease)
─ Pruritus, dark urine, pale stools (cholestatic symptoms)
─ Serum tumor markers: CA19-9 is often elevated (but not specific); CEA may also be elevated. AFP is typically normal (unless combined HCC-CCA).

Macro ─ ─ Classified into three main gross types:
─ Mass-forming type (most common, ~60-80%): Forms a distinct, firm, grey-white or yellowish-white, often irregular mass within the liver parenchyma. May have satellite nodules. Central necrosis or fibrosis/scarring can be present.
─ Periductal-infiltrating type: Tumor grows infiltratively along the bile ducts, causing thickening and stenosis of the duct wall and often proximal biliary dilatation. May not form a discrete mass.
─ Intraductal-growing type (rare, ~5-10%): Polypoid or papillary mass growing within the lumen of a dilated intrahepatic bile duct. Often associated with IPNB.
─ Tumor size is variable. Can be solitary or multifocal.
─ Background liver may be normal, cirrhotic, or show features of underlying biliary disease (e.g., PSC changes)

Micro ─

─ Predominantly adenocarcinoma with glandular, tubular, or cribriform structures lined by atypical cuboidal to columnar biliary-type epithelial cells
─ Tumor cells typically have eosinophilic to amphophilic cytoplasm, pleomorphic nuclei with irregular contours, hyperchromasia, and prominent nucleoli
─ Desmoplastic stromal reaction (abundant fibrous stroma) is a characteristic feature of most ICCs, especially mass-forming and periductal-infiltrating types ─ Mitotic activity is variable
─ Mucin production (intracytoplasmic or extracellular) is common, especially in well to moderately differentiated tumors
─ Lymphovascular and perineural invasion are frequent findings and indicate aggressive behavior
─ Histologic grading (well, moderately, poorly differentiated) is based on degree of gland formation, nuclear atypia, and mitotic activity
─ Subtypes based on cell of origin/duct size (WHO 2019): ─ Small duct type ICC: Arises from interlobular bile ducts or canals of Hering; often composed of small, uniform tubules or anastomosing cords in a less desmoplastic stroma; may resemble reactive ductular proliferation or bile duct adenoma in well-differentiated forms. Often CK19+, HepPar-1-, S100P-, MUC1-, MUC5AC variable. Associated with chronic liver disease/cirrhosis more often. Better prognosis than large duct type.
─ Large duct type ICC: Arises from larger intrahepatic bile ducts; forms larger, more irregular glands, often with papillary or cribriform architecture and significant mucin production; prominent desmoplastic stroma. Often CK19+, CK7+, S100P+, MUC1+, MUC5AC+. More commonly associated with fluke infection or hepatolithiasis. Worse prognosis.
─ Rare histologic variants: adenosquamous carcinoma, squamous cell carcinoma, sarcomatoid cholangiocarcinoma, clear cell cholangiocarcinoma, lymphoepithelioma-like cholangiocarcinoma, mucinous carcinoma

Ancillary studies ─

─ IHC:
─ Positive for biliary cytokeratins: CK7, CK19, CAM5.2, AE1/AE3 are usually diffusely positive
─ Mucin markers: MUC1, MUC5AC often positive, especially in large duct type
─ CEA (monoclonal): Often positive (cytoplasmic/luminal)
─ CA19-9: Can be positive in tumor cells
─ S100P: Often positive, particularly in large duct type
─ Albumin (by ISH or IHC): Typically negative (unlike HCC)
─ HepPar-1, Arginase-1, Glypican-3: Negative (to distinguish from HCC, though GPC3 can be rarely positive in some CCAs)
─ CDX2: Can be positive in a subset (up to 40%), creating a pitfall with metastatic colorectal adenocarcinoma
─ p53: Overexpression or null pattern is common, indicating TP53 mutation
─ Ki-67: Variable, generally higher in poorly differentiated tumors
─ Molecular ─ ─ Heterogeneous molecular landscape:
─ IDH1/IDH2 mutations: Common in small duct type ICC (~10-25%), associated with better prognosis
─ FGFR2 fusions/rearrangements: Occur in ~10-15% of ICCs, more common in younger patients without cirrhosis, often small duct type; targetable alteration
─ KRAS mutations: More common in extrahepatic CCA, but can occur in ICC (~10-20%)
─ TP53 mutations: Common, associated with aggressive behavior
─ SMAD4, ARID1A, BAP1, PBRM1 mutations also reported
─ ERBB2 (HER2) amplifications/mutations (rare, targetable)
─ Microsatellite instability (MSI-H) is rare in ICC (<5%)

DDx ─

─ Hepatocellular Carcinoma (HCC): Especially poorly differentiated HCC or HCC with pseudoglandular pattern. HCC is positive for HepPar-1, Arginase-1, Glypican-3, albumin ISH; negative for CK7/CK19 (or only focal). ICC is typically negative for these HCC markers and positive for CK7/CK19.
─ Combined Hepatocellular-Cholangiocarcinoma (cHCC-CCA): Tumors with unequivocal features of both HCC and CCA. Requires careful sampling and IHC.
─ Metastatic Adenocarcinoma: Most common differential, especially from pancreas, colorectum, stomach, lung, breast. IHC panel is crucial (e.g., CDX2/CK20 for colorectal; PAX8/WT1 for gynecologic; TTF-1/Napsin A for lung; GATA3/mammaglobin for breast; CA19-9, SMAD4 loss for pancreatic).
─ Bile duct adenoma / Biliary adenofibroma: Benign; lack significant atypia and infiltrative growth.
─ Biliary Intraepithelial Neoplasia (BilIN) / Intraductal Papillary Neoplasm of the Bile Duct (IPNB): Precursor lesions; lack stromal invasion (unless IPNB with associated invasive carcinoma)
─ Sclerosing hemangioma or epithelioid hemangioendothelioma: If stroma is prominent or tumor has epithelioid features; vascular markers positive.

Prognosis ─ ─ Generally poor, as most patients present with advanced, unresectable disease
─ Surgical resection offers the only chance for cure but is only possible in a minority of patients
─ Prognostic factors: tumor stage (size, number, vascular invasion, lymph node status, distant metastasis), histologic grade, resection margin status, presence of underlying liver disease (e.g., PSC)
─ Small duct type ICC generally has a better prognosis than large duct type
─ Specific molecular alterations (e.g., IDH1/2 mutations associated with better prognosis; FGFR2 fusions are targetable) are increasingly important for prognosis and therapy selection
─ Adjuvant chemotherapy may be offered post-resection. Systemic chemotherapy, targeted therapy (e.g., FGFR inhibitors, IDH1 inhibitors), and immunotherapy are options for advanced/metastatic disease.

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Perihilar Cholangiocarcinoma (Klatskin tumor)

An adenocarcinoma arising from the biliary epithelium at the confluence of the right and left hepatic ducts, or involving the common hepatic duct proximal to the cystic duct insertion; it is a subtype of extrahepatic cholangiocarcinoma

Clinical ─ ─ Represents the most common type of cholangiocarcinoma (~50-60% of cases)
─ Typically affects older adults (6th-7th decades), with a slight male predominance
─ Risk factors are similar to intrahepatic cholangiocarcinoma (ICC), including:
─ Primary sclerosing cholangitis (PSC) - very strong association
─ Choledochal cysts
─ Liver fluke infestation (Clonorchis, Opisthorchis)
─ Hepatolithiasis
─ Chronic biliary inflammation
─ Presents most commonly with obstructive jaundice (painless or associated with vague upper abdominal pain, pruritus, pale stools, dark urine)
─ Weight loss, malaise, and anorexia are common
─ Serum CA19-9 is often elevated; CEA may also be elevated
─ Diagnosis involves imaging (ultrasound, CT, MRI/MRCP) to define the extent of biliary obstruction and tumor mass, and often ERCP with brushing/biopsy or cholangioscopy for tissue diagnosis
─ Staging (e.g., Bismuth-Corlette classification) is based on the level of biliary involvement at the hilum, which guides surgical resectability

Macro ─ ─ Typically appears as a firm, grey-white, infiltrative mass constricting the bile ducts at the hepatic hilum
─ May be predominantly intraductal, periductal-infiltrating, or mass-forming, though the periductal-infiltrating pattern is common, leading to wall thickening and luminal narrowing
─ Proximal intrahepatic bile ducts are usually dilated
─ Tumor may invade adjacent liver parenchyma, portal vein, and hepatic artery
─ Lymph node metastasis to regional (hilar) nodes is common at presentation

Micro ─

─ Histologically similar to large duct type intrahepatic cholangiocarcinoma and distal extrahepatic cholangiocarcinoma
─ Adenocarcinoma, usually well to moderately differentiated, forming glands, tubules, or papillary structures
─ Tumor cells are cuboidal to columnar, with variable mucin production
─ Prominent desmoplastic stromal reaction is characteristic, with abundant fibrous tissue surrounding infiltrating glands
─ Perineural invasion is very common and a hallmark feature, contributing to local spread and recurrence
─ Lymphovascular invasion is also frequent
─ May show areas of biliary intraepithelial neoplasia (BilIN) in adjacent non-invasive ducts
─ Grading is based on glandular differentiation, nuclear atypia, and mitotic activity

Ancillary studies ─

─ IHC:
─ Positive for biliary cytokeratins: CK7, CK19, CAM5.2
─ Positive for MUC1, MUC5AC (often)
─ CEA (monoclonal): Often positive
─ CA19-9: Can be expressed by tumor cells
─ S100P: Often positive
─ Negative for hepatocellular markers (HepPar-1, Arginase-1, Glypican-3)
─ p53 overexpression or null pattern is common
─ Molecular ─ ─ KRAS mutations are relatively common (~20-40%)
─ TP53 mutations are frequent
─ SMAD4 inactivation
─ IDH1/2 mutations and FGFR2 fusions are less common in perihilar/extrahepatic CCA compared to intrahepatic CCA (small duct type)
─ ERBB2 (HER2) alterations can occur in a subset and may be targetable

DDx ─

─ Benign biliary stricture (e.g., due to PSC, IgG4-related sclerosing cholangitis, post-surgical/traumatic) - Biopsy is crucial. IgG4-RSC shows characteristic IgG4+ plasma cells and storiform fibrosis. PSC shows "onion-skin" fibrosis.
─ Metastatic adenocarcinoma to hilar lymph nodes causing biliary obstruction (e.g., from pancreas, gallbladder, stomach, colon) - IHC panel for site-specific markers is key (CDX2/CK20 for colorectal, etc.)
─ Gallbladder carcinoma extending to the hilum ─ Hepatocellular carcinoma with biliary obstruction (rare; HCC will be positive for hepatocellular markers)
─ Intraductal Papillary Neoplasm of the Bile Duct (IPNB) (predominantly intraductal papillary growth; may have associated invasive carcinoma that can mimic Klatskin tumor if at hilum)
─ Mirizzi syndrome (extrinsic compression of common hepatic duct by an impacted stone in cystic duct or gallbladder neck, causing inflammation and fibrosis)

Prognosis ─ ─ Generally poor, as tumors are often diagnosed at an advanced stage and complete surgical resection (which may involve major hepatectomy and bile duct reconstruction) is challenging and achieved in a minority of patients
─ Prognostic factors: Resectability, margin status, lymph node involvement, perineural invasion, tumor differentiation, and underlying PSC
─ Even with resection, recurrence rates are high
─ Palliative options for unresectable disease include biliary stenting, chemotherapy, and radiation therapy
─ Median survival for unresected tumors is typically 6-12 months; for resected tumors, 5-year survival can be 20-40% in selected series

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Combined Hepatocellular-Cholangiocarcinoma (cHCC-CCA)

A rare primary liver cancer containing unequivocal, intimately intermixed components of both hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA)

Clinical ─ ─ Accounts for ~0.4-14% of primary liver cancers; incidence may be underestimated
─ More common in males, typically in older adults (5th-7th decades)
─ Risk factors overlap with both HCC and CCA, including chronic viral hepatitis (HBV, HCV), cirrhosis (any cause), alcohol, and possibly NAFLD
─ Clinical presentation is often similar to HCC or ICC: abdominal pain, weight loss, palpable mass, jaundice (less common than pure CCA unless biliary obstruction is present)
─ Serum tumor markers can be variable:
─ AFP may be elevated (suggesting HCC component)
─ CA19-9 may be elevated (suggesting CCA component)
─ Some cases have elevation of both, or neither
─ Imaging features can be heterogeneous and challenging, sometimes mimicking pure HCC or pure ICC, or showing mixed features

Macro ─ ─ Typically a solitary mass, but can be multifocal
─ Gross appearance is variable, depending on the proportion and distribution of HCC and CCA components:
─ May resemble HCC (e.g., soft, tan/brown, possibly bile-stained, with areas of necrosis/hemorrhage)
─ May resemble ICC (e.g., firm, grey-white, scirrhous)
─ Often appears as a heterogeneous tumor with mixed characteristics
─ Vascular invasion can be present

Micro ─

─ Defining feature: Presence of both unequivocal hepatocellular differentiation and unequivocal cholangiocarcinoma (glandular/ductal differentiation with mucin production and/or desmoplastic stroma) within the same tumor, with areas of transition or intimate admixture between the two components
─ Hepatocellular component (HCC): Shows features of HCC, such as trabecular, solid, or pseudoglandular patterns; polygonal cells with eosinophilic cytoplasm; bile production; expression of HCC markers (see IHC)
─ Cholangiocarcinoma component (CCA): Shows features of CCA, such as glandular or tubular structures, mucin production, desmoplastic stroma; expression of biliary markers (see IHC)
─ Transition zones: Areas where HCC and CCA components merge or intermingle, sometimes with cells showing intermediate or ambiguous morphology. These zones are important for diagnosis and support a common clonal origin rather than a collision tumor.
─ WHO 2019 Classification: ─ Classical type cHCC-CCA: Composed of typical HCC and typical CCA components that are intermingled
─ cHCC-CCA with stem/progenitor cell features: Shows a component resembling hepatic stem or progenitor cells, often characterized by small cells with scant cytoplasm, high N/C ratio, arranged in nests, ductules, or trabeculae. This category includes several subtypes:
─ Stem cell feature, typical subtype
─ Stem cell feature, intermediate cell subtype (cells with features intermediate between hepatocytes and cholangiocytes)
─ Stem cell feature, cholangiolocellular subtype (tumor composed of small ductules resembling canals of Hering, often with hyalinized stroma; formerly cholangiolocarcinoma)
─ The proportion of each component can vary widely

Ancillary studies ─

─ IHC is crucial for confirming biphenotypic differentiation:
─ HCC component markers: ─ HepPar-1 (+)
─ Arginase-1 (+)
─ Glypican-3 (+) (especially in less differentiated HCC areas)
─ Polyclonal CEA (pCEA) showing canalicular pattern (+)
─ CD10 (canalicular pattern) (+)
─ Albumin mRNA ISH (+)
─ CCA component markers: ─ CK7 (+)
─ CK19 (+)
─ EpCAM (MOC31) (+)
─ MUC1 (+)
─ CA19-9 (+)
─ Stem/progenitor cell markers (may be positive in stem cell feature subtypes or transition zones): ─ CK19, EpCAM, CD56 (NCAM), KIT (CD117), SALL4
─ Special Stains:
─ Reticulin: Shows thickened trabeculae or loss in HCC areas; highlights glandular structures in CCA areas
─ Mucin stains (PAS-D, Alcian blue): Positive in CCA component
─ Bile stain: May be positive in HCC component

DDx ─

─ Pure Hepatocellular Carcinoma (HCC): Lacks definitive CCA component and biliary IHC markers (though HCC can sometimes show pseudoglandular patterns or focal CK7/CK19 expression, especially in poorly differentiated areas or progenitor cell-rich HCC, but true glandular differentiation with mucin and desmoplasia is absent)
─ Pure Intrahepatic Cholangiocarcinoma (ICC): Lacks definitive HCC component and hepatocellular IHC markers (though some ICCs can have clear cells or oncocytic features that might vaguely resemble hepatocytes, but true bile production or specific HCC markers are absent)
─ Collision tumor: Two separate, distinct masses of HCC and CCA that abut or intermingle at the periphery but lack a true transition zone or intimate admixture. Each component behaves as a separate primary.
─ Metastatic carcinoma to the liver with a desmoplastic response mimicking CCA, adjacent to a separate HCC (rare scenario)
─ Hepatocellular adenoma with malignant transformation to HCC and entrapped reactive ductules (ductules are benign, lack atypia of CCA)

Prognosis ─ ─ Generally considered to have a poorer prognosis than pure HCC and possibly similar to or worse than pure ICC of comparable stage
─ Behavior is often aggressive, with high rates of vascular invasion, lymph node metastasis, and intrahepatic/distant metastasis
─ Prognostic factors include tumor size, number of tumors, vascular invasion, lymph node status, proportion of CCA component (some studies suggest higher CCA proportion is worse), and presence of stem cell features
─ Optimal treatment strategies are still evolving due to rarity; surgical resection is the primary curative option. Response to systemic therapies developed for HCC or CCA can be variable.

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Other Primary Liver Tumors

Cavernous Hemangioma (Liver)

The most common benign tumor of the liver, composed of dilated, blood-filled vascular channels lined by flat endothelial cells, separated by fibrous septa

Clinical ─ ─ Very common, found in up to 5-20% of the population at autopsy or on imaging
─ More frequent in women; can occur at any age but often diagnosed in adults (30-50 years)
─ Usually asymptomatic and discovered incidentally
─ Large hemangiomas (>4-5 cm, sometimes called "giant hemangiomas") may rarely cause symptoms:
─ Abdominal pain or discomfort (due to mass effect, stretching of Glisson's capsule, or thrombosis)
─ Nausea, early satiety
─ Spontaneous rupture or hemorrhage is extremely rare, even for giant hemangiomas
─ Kasabach-Merritt syndrome (thrombocytopenia, consumptive coagulopathy) is exceptionally rare with hepatic hemangiomas (more typical of kaposiform hemangioendothelioma in infants)
─ Usually solitary, but can be multiple (hepatic hemangiomatosis if numerous and diffuse, though this term is also used for other conditions)
─ No known malignant potential
─ Diagnosis is typically made by characteristic imaging features (e.g., peripheral nodular enhancement with centripetal fill-in on contrast-enhanced CT/MRI). Biopsy is usually avoided due to bleeding risk if diagnosis is clear on imaging.

Macro ─ ─ Well-demarcated, unencapsulated, soft, spongy, dark red-purple or bluish mass
─ Size varies from millimeters to very large (>20-30 cm)
─ Cut surface shows a honeycomb or sponge-like appearance due to multiple blood-filled vascular spaces separated by fine fibrous septa
─ Areas of thrombosis, fibrosis/sclerosis (hyalinization), or calcification can be seen, especially in larger or older lesions
─ Usually located subcapsularly but can be deep within the parenchyma

Micro ─

─ Composed of large, dilated, anastomosing vascular channels (cavernous spaces) of varying sizes
─ Vascular channels are lined by a single layer of bland, flattened endothelial cells without atypia or significant mitotic activity
─ Channels are filled with blood and may show evidence of thrombosis (recent or organized)
─ The vascular spaces are separated by thin to moderately thick fibrous septa, which may contain small arteries, veins, and sometimes bile ductules (if entrapped portal structures are incorporated)
─ Areas of sclerosis/hyalinization, calcification, or ossification can be present in long-standing lesions
─ Inflammation is usually minimal unless there is thrombosis or secondary changes
─ No evidence of infiltrative growth into surrounding liver parenchyma

Ancillary studies ─

─ IHC:
─ Endothelial cells lining the vascular channels are positive for vascular markers: CD31, CD34, ERG, Factor VIII-related antigen ─ Smooth Muscle Actin (SMA) may highlight pericytes or smooth muscle in walls of larger vessels within septa
─ Ki-67: Very low proliferation index
─ Special Stains:
─ Trichrome: Highlights the fibrous septa

DDx ─

─ Peliosis hepatis: Characterized by blood-filled cystic spaces within the liver parenchyma, but these spaces often lack a true endothelial lining or are lined by sinusoidal endothelium, and lack the organized fibrous septa of a cavernous hemangioma. Associated with various conditions (e.g., anabolic steroids, OCPs, Bartonella infection).
─ Angiosarcoma: Malignant vascular tumor; shows infiltrative growth, cellular atypia, multilayering of endothelial cells, high mitotic activity, necrosis. Can have cavernous areas, but malignancy is evident.
─ Epithelioid Hemangioendothelioma (EHE): Malignant vascular tumor with epithelioid or histiocytoid endothelial cells in a characteristic myxohyaline or fibrous stroma. Different morphology and IHC (often CAMTA1 positive).
─ Anastomosing Hemangioma / Hepatic Small Vessel Neoplasm (HSVN): Benign vascular neoplasms with anastomosing sinusoidal-like channels, but typically smaller vessels than classic cavernous hemangioma, and may show hobnail endothelial cells or an infiltrative pattern (HSVN).
─ Hepatocellular adenoma with peliosis (Inflammatory HCA): HCA is a hepatocellular neoplasm; peliosis is secondary. SAA/CRP positive.
─ Metastatic carcinoma with cystic/hemorrhagic change: Malignant epithelial cells would be present; IHC for keratins and site-specific markers would be positive.
─ Focal Nodular Hyperplasia (FNH) - Telangiectatic type (now often considered Inflammatory HCA): Has dilated sinusoids but also hepatocellular hyperplasia and a different overall architecture.

Prognosis ─ ─ Excellent; cavernous hemangiomas are benign and generally do not grow significantly or cause complications
─ Malignant transformation does not occur
─ Management is usually conservative (observation) for asymptomatic lesions
─ Intervention (e.g., embolization, surgical resection, rarely transplantation) is reserved for rare cases with severe, persistent symptoms, diagnostic uncertainty, or very rare complications like rupture or Kasabach-Merritt syndrome (though the latter is exceptionally rare for typical cavernous hemangiomas)

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Anastomosing Hemangioma & Hepatic Small Vessel Neoplasm (HSVN)

Anastomosing hemangioma (AH) and Hepatic Small Vessel Neoplasm (HSVN) are related, rare, benign vascular neoplasms. AH is typically well-circumscribed with anastomosing sinusoidal-like capillaries. HSVN often shows a more infiltrative pattern of similar small vessels. Some consider them part of a spectrum.

Clinical ─ ─ Anastomosing Hemangioma (AH): ─ Rare, initially described in genitourinary tract, but can occur in liver and other sites
─ Often an incidental finding on imaging or at surgery
─ Usually asymptomatic; if large, may cause non-specific abdominal pain
─ Can occur in patients with end-stage renal disease or cirrhosis, but also in normal livers
─ Hepatic Small Vessel Neoplasm (HSVN): ─ Also rare, described more recently
─ Often an incidental finding in patients undergoing imaging or liver resection for other reasons (e.g., HCC, cirrhosis)
─ Typically small lesions
─ Both affect adults, wide age range, slight male predominance for some series of AH

Macro ─ ─ Anastomosing Hemangioma (AH): ─ Usually well-demarcated, solitary or multiple nodules
─ Spongy, red-brown or mahogany appearance on cut section
─ Size varies, from small to several centimeters
─ Hepatic Small Vessel Neoplasm (HSVN): ─ Often ill-defined, infiltrative, or vaguely nodular pale or reddish areas
─ Typically small (<1-2 cm)

Micro ─

─ Anastomosing Hemangioma (AH): ─ Characterized by a distinctive pattern of anastomosing sinusoidal-like capillary channels
─ Vessels are lined by a single layer of bland endothelial cells, which may show focal hobnail morphology (nuclei bulge into the lumen)
─ Mild cytologic atypia may be present, but significant pleomorphism and mitoses are absent
─ Stroma is often scant and hyalinized, or may be edematous
─ Fibrin thrombi within vascular lumens can be seen
─ Extramedullary hematopoiesis is a common associated finding
─ Eosinophilic hyaline globules may be present within endothelial cells or stroma
─ Usually well-circumscribed, but may have slightly irregular interface with surrounding liver
─ Hepatic Small Vessel Neoplasm (HSVN): ─ Composed of an infiltrative proliferation of small, thin-walled, often inconspicuous vascular channels lined by bland endothelial cells
─ Vessels often permeate between hepatocytes and portal tracts, sometimes with a "dissecting" pattern through sinusoids, without significant destruction of underlying liver architecture
─ Endothelial cells are flat to slightly plump, without significant atypia or mitoses
─ Hobnail features are less common than in AH
─ Stroma is usually minimal
─ Often associated with background liver disease (e.g., cirrhosis, steatohepatitis)

Ancillary studies ─

─ IHC (Both AH and HSVN):
─ Endothelial cells are positive for vascular markers: CD31, CD34, ERG, FLI1 ─ Ki-67: Low proliferation index (<5%, usually <1-2%)
─ Smooth Muscle Actin (SMA): May highlight pericytes around vessels
─ Cytokeratins (AE1/AE3, CAM5.2): Negative in vascular cells (highlights entrapped hepatocytes or bile ducts)
─ Molecular:
─ Activating mutations in G protein alpha subunits (GNAQ, GNA14, GNA11) have been identified in a significant proportion of anastomosing hemangiomas (and some related vascular lesions), but not typically in angiosarcomas. Data for HSVN is still emerging but similar mutations are expected.

DDx ─

─ Well-differentiated Angiosarcoma: This is the most important differential, especially for HSVN due to its infiltrative pattern, or for AH if any atypia is present. Angiosarcoma shows more significant cytologic atypia, multilayering of endothelial cells, increased mitoses, necrosis, and destructive infiltrative growth. While some AHs can have mild atypia, the overall blandness, lack of mitoses, and specific GNAQ/11/14 mutations (if tested) favor AH. Angiosarcoma often has TP53 or KDR mutations.
─ Cavernous Hemangioma: Composed of much larger, dilated cavernous vascular spaces separated by thicker fibrous septa. AH/HSVN have smaller, capillary/sinusoidal-sized vessels.
─ Peliosis hepatis: Blood-filled cystic spaces often lacking a true endothelial lining or lined by sinusoidal endothelium; lacks the organized anastomosing pattern of AH and the infiltrative small vessel proliferation of HSVN.
─ Sinusoidal Dilatation: Non-neoplastic expansion of sinusoids, often secondary to congestion, inflammation, or drug effect; lacks a neoplastic endothelial proliferation.
─ Bacillary Angiomatosis/Peliosis (in immunocompromised): Caused by Bartonella infection; shows lobular proliferation of capillaries with plump endothelial cells and characteristic purplish granular material (bacteria); Warthin-Starry stain positive.
─ Kaposi Sarcoma: Spindle cell vascular proliferation, often with slit-like spaces and extravasated red blood cells; HHV-8 positive.

Prognosis ─ ─ Anastomosing Hemangioma (AH): Considered benign. Most reported cases have shown no recurrence or metastasis after excision or on follow-up.
─ Hepatic Small Vessel Neoplasm (HSVN): Also considered to have a benign or very low-grade malignant potential. Most reported cases have an indolent clinical course with no recurrence or metastasis after resection or even on follow-up of unresected lesions. However, due to its infiltrative nature and some morphologic overlap with well-differentiated angiosarcoma, complete excision and careful follow-up are often recommended if diagnosed on biopsy.
─ Long-term behavior, especially of HSVN, is still being fully elucidated due to the rarity of these entities

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Gallbladder

Gallbladder Anatomy

Feature	Description
Structure	Pear-shaped organ on the inferior surface of the liver; stores and concentrates bile.
Parts	Fundus: Rounded distal part. Body: Main portion. Neck: Tapering portion connecting to the cystic duct.
Cystic Duct	Connects gallbladder to the common hepatic duct. May contain a spiral valve of Heister.
Blood Supply	Cystic artery (usually from right hepatic artery).
Lymphatics	Drains to cystic nodes, then hepatic and celiac nodes.

Gallbladder Histology

Layer	Components & Features
Mucosa	Epithelium: Simple columnar with absorptive cells (brush border) to concentrate bile. Thrown into numerous deep folds (no true villi).
Wall Structure	Key Feature: Lacks a muscularis mucosae and a submucosa. Lamina propria lies directly on the muscularis propria.
Muscularis Propria	Interlacing bundles of smooth muscle (not in distinct layers).
Serosa / Adventitia	Adventitia: Attaches to liver. Serosa: Covers unattached surfaces.
Rokitansky-Aschoff Sinuses	Deep mucosal invaginations into the muscularis propria. A common finding.

Adenomyoma / Adenomyomatous Hyperplasia

A benign condition of the gallbladder characterized by mucosal herniation into a thickened muscularis propria, forming Rokitansky-Aschoff sinuses, which may be focal (adenomyoma) or diffuse (adenomyomatous hyperplasia)

Clinical ─
─ Often asymptomatic and found incidentally; may cause chronic right upper quadrant pain
─ More common in adult females
─ Associated with cholelithiasis

Macro ─
─ Focal (adenomyoma): typically a nodule or localized thickening, often in the fundus
─ Diffuse (adenomyomatous hyperplasia): generalized gallbladder wall thickening
─ Cut surface may show small cystic spaces (dilated Rokitansky-Aschoff sinuses)

Micro ─

─ Epithelial invaginations (Rokitansky-Aschoff sinuses) extending into a thickened, hyperplastic muscularis propria
─ Sinuses are lined by bland, cuboidal to columnar biliary epithelium, similar to the surface mucosa
─ Surrounding smooth muscle is often hypertrophied and hyperplastic
─ Lumina of sinuses may contain bile, debris, or small calculi
─ No significant cytologic atypia or desmoplasia

Ancillary studies ─

─ IHC (+): Epithelial cells positive for biliary cytokeratins (e.g., CK7, CK19)
─ IHC (-): Smooth muscle component is desmin and SMA positive

DDx ─

─ Gallbladder adenocarcinoma (distinguished by infiltrative growth, desmoplastic stromal reaction, significant cytologic atypia, and mitotic activity)
─ Xanthogranulomatous cholecystitis (characterized by foamy histiocytes, inflammation, and fibrosis; Rokitansky-Aschoff sinuses may be present but are part of the inflammatory process)

Prognosis ─
─ Benign condition with no inherent malignant potential

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Choledochal Cyst

Congenital cystic dilatations of any portion of the biliary tree, which can be intrahepatic, extrahepatic, or both

Clinical ─
─ Presentation varies with age; infants may present with jaundice and acholic stools, older children/adults with abdominal pain, jaundice, or a palpable mass (classic triad is uncommon)
─ More common in females (F:M ratio of 3:1 to 4:1)
─ Often associated with an anomalous pancreaticobiliary junction (APBJ)
─ Complications include cholangitis, pancreatitis, stone formation, and an increased risk of malignancy

Macro ─
─ Classified by location and morphology (Todani classification Types I-V)
─ Type I (most common): fusiform or saccular dilatation of the extrahepatic common bile duct
─ Cyst wall may be thickened and fibrotic

Micro ─

─ Cyst wall typically lined by columnar, cuboidal, or flattened biliary epithelium; ulceration and metaplasia (gastric, intestinal) can occur
─ Wall composed of dense fibrous connective tissue, often with variable degrees of acute and chronic inflammation
─ Smooth muscle fibers may be sparse or absent in the cyst wall
─ Mucous glands may be present
─ Dysplasia or carcinoma (cholangiocarcinoma) can arise within the cyst lining, particularly in adults and in long-standing cysts

Ancillary studies ─

─ Imaging (ultrasound, CT, MRCP, ERCP) is crucial for diagnosis, classification, and surgical planning

DDx ─

─ Acquired biliary dilatation (due to obstruction by stones, strictures, or tumors; lacks the typical congenital features and often has an identifiable obstructing cause)
─ Caroli disease (Type V choledochal cyst; characterized by multiple saccular dilatations of the intrahepatic bile ducts)
─ Simple biliary cysts (usually thin-walled, unilocular, and not associated with APBJ)
─ Mucinous cystic neoplasm of the liver/bile ducts (characterized by mucinous epithelium and ovarian-type stroma)

Prognosis ─
─ Surgical excision is the treatment of choice to prevent complications, especially malignancy
─ Risk of cholangiocarcinoma is significantly elevated (5-15% lifetime risk, higher in older patients and with intrahepatic involvement) even after excision if remnants remain

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Cholesterol Polyp (of the Gallbladder)

The most common type of non-neoplastic gallbladder polyp, representing a focal form of cholesterolosis where excess cholesterol accumulates within lamina propria macrophages.

Clinical ─ Usually asymptomatic and discovered incidentally on imaging (ultrasound) or in a cholecystectomy specimen removed for gallstones. They are not considered premalignant.

Macro ─ Typically small (<10 mm), often multiple, yellow, pedunculated or sessile polyps attached to the gallbladder mucosa by a delicate stalk. They give the mucosa a stippled, yellow appearance known as "strawberry gallbladder" when cholesterolosis is diffuse.

Micro ─

─ A polypoid structure with a core of lamina propria expanded by large aggregates of foamy macrophages (histiocytes) with abundant, pale, vacuolated cytoplasm.

─ The polyp is covered by a single layer of benign, normal-appearing gallbladder epithelium.

─ The fibrovascular stalk is typically delicate and edematous. Significant inflammation is usually absent.

Ancillary studies ─

─ IHC (+): CD68 (highlights the foam cells, but not necessary for diagnosis).

─ IHC (-): Not required for diagnosis.

─ Molecular ─ Not applicable.

DDx ─

─ Inflammatory Polyp: Shows granulation tissue, mixed inflammatory cells, and reactive epithelial changes. Associated with chronic cholecystitis.

─ Adenomyomatous Hyperplasia (Adenomyoma): A focal thickening of the gallbladder wall with smooth muscle hyperplasia and infoldings of epithelium forming Rokitansky-Aschoff sinuses. Usually located in the fundus.

─ Pyloric Gland Adenoma / Intracholecystic Papillary Neoplasm (ICPN): These are true neoplastic polyps. They are characterized by proliferative glands (pyloric-type glands in PGA) or papillary architecture lined by dysplastic epithelium. They lack the prominent foamy macrophage collections.

Xanthogranulomatous Cholecystitis

An uncommon, destructive, chronic inflammatory process of the gallbladder characterized by a mixed inflammatory infiltrate rich in foamy macrophages and fibrosis. It is important because it can grossly and radiologically mimic gallbladder carcinoma.

Clinical ─ Presents similarly to severe acute or chronic cholecystitis, with right upper quadrant pain, fever, and leukocytosis. A palpable mass may be present. Almost always associated with cholelithiasis and obstruction. The inflammation can extend into adjacent structures like the liver, duodenum, or colon, creating dense adhesions and fistulae.

Macro ─ The gallbladder wall is markedly thickened, firm, and fibrotic, often with poor demarcation from the adjacent liver. The cut surface shows ill-defined, yellow-brown nodules or streaks within the wall. The lumen often contains stones and purulent material. Perforation and abscess formation can occur.

Micro ─

─ A transmural, destructive inflammatory process.

─ Key feature is the presence of large numbers of foamy histiocytes (lipid-laden macrophages) and multinucleated giant cells.

─ Abundant admixed inflammatory cells, including lymphocytes, plasma cells, and neutrophils (often forming abscesses).

─ Fibrosis is prominent.

─ Spillage of bile can be seen, often with cholesterol clefts and bile pigment.

─ Ruptured Rokitansky-Aschoff sinuses are thought to be the initiating event.

Ancillary studies ─

─ IHC (+): CD68 (highlights the histiocytes, but not needed for diagnosis).

─ IHC (-): Cytokeratins (AE1/AE3) are negative in the inflammatory infiltrate but will highlight entrapped native gallbladder epithelium. This helps distinguish it from carcinoma.

─ Molecular ─ Not applicable.

DDx ─

─ Gallbladder Carcinoma: The most important differential. Carcinoma consists of infiltrating, malignant glands or single cells with desmoplasia. A cytokeratin stain will be positive in the malignant epithelial cells, which will show cytologic atypia (irregular nuclei, prominent nucleoli, increased N/C ratio). It's crucial to extensively sample any xanthogranulomatous-appearing gallbladder to rule out a coexisting carcinoma.

─ Conventional Chronic Cholecystitis: Shows fibrosis and a lymphoplasmacytic infiltrate but lacks the prominent sheets of foamy histiocytes and destructive, mass-forming quality of xanthogranulomatous cholecystitis.

Factors favoring reactive atypia in biliary epithelium

Benign cellular changes in the biliary epithelium resulting from injury, inflammation, or regeneration, which can mimic dysplasia

Clinical ─
─ Occurs in settings of cholelithiasis, cholecystitis (acute or chronic), cholangitis, biliary stenting, instrumentation, or other irritants

Macro ─
─ No specific macroscopic appearance; findings reflect the underlying inflammatory or injurious process

Micro ─

─ Nuclear enlargement, hyperchromasia, and prominent nucleoli may be present
─ Cytoplasm can be vacuolated, eosinophilic, or squamoid
─ Glandular architecture is generally preserved, though some crowding or irregularity may occur
─ Atypia often shows a gradient, being more pronounced in areas of active inflammation or repair, and may show surface maturation (less atypia towards the lumen)
─ Nuclei typically maintain relatively smooth contours and evenly distributed chromatin despite enlargement
─ Mitotic figures can be seen but are usually typical and confined to the regenerative zones
─ Background inflammation (neutrophilic or lymphoplasmacytic) is usually evident
─ Key negative findings: Absence of significant architectural complexity (e.g., true cribriforming, complex papillae), diffuse loss of nuclear polarity, markedly atypical mitoses, or invasive growth

Ancillary studies ─

─ IHC (p53): Typically shows a wild-type pattern (scattered, weak to moderate staining); aberrant patterns (strong diffuse staining or complete absence/null pattern) favor dysplasia or carcinoma
─ IHC (Ki-67): Proliferation index is usually low to moderately increased, with staining predominantly in the basal/regenerative zones; a high index with surface staining is more concerning for dysplasia

DDx ─

─ Biliary intraepithelial neoplasia (BilIN) (dysplasia shows more pronounced and diffuse cytologic atypia, loss of nuclear polarity, architectural disorganization, and often aberrant p53/Ki-67 expression)
─ Invasive adenocarcinoma (characterized by infiltrative growth, desmoplastic stromal reaction, and unequivocal malignant cytology)
─ Viral cytopathic effect (e.g., CMV) (look for characteristic viral inclusions)

Prognosis ─
─ Benign and reversible if the underlying cause is removed or resolved; does not independently increase the risk of malignancy

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Pyloric Gland Adenoma of the Gallbladder/Bile Ducts

A benign glandular neoplasm composed of closely packed tubules resembling gastric pyloric glands, occurring in the gallbladder or extrahepatic bile ducts

Clinical ─
─ Uncommon; typically occurs in older adults, with a female predominance for gallbladder lesions
─ Often an incidental finding, but may be associated with abdominal pain or cholelithiasis
─ In the stomach, associated with autoimmune gastritis and pernicious anemia

Macro ─
─ Usually solitary polypoid or sessile lesion, can be flat or slightly raised
─ Variable in size, from a few millimeters to several centimeters
─ Cut surface is typically tan-white and solid, may have a slightly lobulated appearance

Micro ─

─ Composed of closely packed, small, uniform, round to oval glands or tubules
─ Glands are lined by cuboidal to low columnar cells with pale eosinophilic or clear "ground glass" cytoplasm and indistinct cell borders
─ Apical mucin caps are usually absent or minimal
─ Nuclei are typically round, basally located, with fine chromatin and inconspicuous nucleoli; minimal atypia in low-grade lesions
─ Minimal intervening stroma, which may be hyalinized
─ Dysplasia (low-grade or high-grade) is common and can be extensive; this is the most important feature to evaluate
─ May show areas of cystic change or surface erosion

Ancillary studies ─

─ IHC (+): MUC6 (consistent and strong positivity, characteristic), MUC5AC (often positive), CK7
─ IHC (-): MUC2 (usually negative), CDX2 (usually negative), Chromogranin A, Synaptophysin
─ Molecular ─ GNAS mutations are common in gastric pyloric gland adenomas; data in biliary tract lesions is more limited

DDx ─

─ Conventional biliary adenoma (intestinal type) (typically MUC2 and/or CDX2 positive, resembles colonic adenoma)
─ Hyperplastic polyp (gastric type, in gallbladder) (shows foveolar hyperplasia, edematous inflamed stroma, less densely packed glands)
─ Adenomyoma / Adenomyomatous hyperplasia (contains prominent smooth muscle stroma and Rokitansky-Aschoff sinuses)
─ Well-differentiated adenocarcinoma (shows invasive growth, desmoplasia, significant cytologic atypia beyond that of high-grade dysplasia)
─ Neuroendocrine tumor (would be positive for neuroendocrine markers)

Prognosis ─
─ Benign, but has a recognized potential for malignant transformation to adenocarcinoma, particularly if large or with high-grade dysplasia
─ Complete excision is recommended

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Biliary Intraepithelial Neoplasia (BilIN)

A preinvasive, flat or micropapillary neoplastic proliferation of biliary epithelial cells, typically occurring in the extrahepatic bile ducts and gallbladder, analogous to pancreatic intraepithelial neoplasia (PanIN)

Clinical ─
─ Often an incidental finding in specimens resected for invasive carcinoma, cholelithiasis, or primary sclerosing cholangitis (PSC)
─ Risk factors include PSC, choledochal cysts, hepatolithiasis, and chronic biliary inflammation
─ Most common in older adults

Macro ─
─ Usually not visible grossly; may sometimes appear as subtle mucosal granularity or thickening

Micro ─

─ Ranges from low-grade (BilIN-1, BilIN-2) to high-grade (BilIN-3/carcinoma in situ)
─ BilIN-1 (Low-grade): ─ Mildly atypical cells with slightly enlarged, hyperchromatic, and pseudostratified nuclei
─ Nuclear polarity is generally maintained
─ Minimal architectural complexity; may show some papillary tufting
─ Mitotic figures are rare
─ BilIN-2 (Low-grade): ─ More pronounced nuclear atypia, including increased nuclear size, hyperchromasia, and loss of polarity in some cells
─ Increased mitotic activity may be present
─ More complex architecture with papillary or micropapillary structures may be seen
─ BilIN-3 (High-grade/Carcinoma in situ): ─ Marked cytologic atypia with significant nuclear pleomorphism, hyperchromasia, irregular nuclear contours, and loss of polarity
─ Architectural complexity is often prominent, including cribriform patterns or complex papillary structures
─ Mitotic figures, including atypical forms, are often readily identifiable
─ Neoplastic cells replace the normal biliary epithelium, typically confined by the basement membrane
─ Peribiliary gland involvement is common, especially in high-grade lesions

Ancillary studies ─

─ IHC (p53): Aberrant expression (strong diffuse positivity or null pattern) is common in high-grade BilIN (BilIN-3) and less frequent in lower grades
─ IHC (Ki-67): Proliferation index increases with grade; BilIN-3 shows significantly higher proliferation
─ IHC (S100P): Often positive, especially in higher grades, but not specific
─ IHC (IMP3): May be positive in higher grades

DDx ─

─ Reactive atypia (shows less cytologic atypia, maintained nuclear polarity, inflammation, and lacks diffuse p53 alteration or high Ki-67)
─ Invasive cholangiocarcinoma (distinguished by stromal invasion, desmoplasia)
─ Intraductal papillary neoplasm of the bile duct (IPNB) (typically forms a larger, grossly visible mass with more complex papillary architecture)

Prognosis ─
─ Considered a precursor to invasive cholangiocarcinoma; the risk of progression increases with grade
─ BilIN-3 is considered carcinoma in situ and has a high risk of associated or subsequent invasive carcinoma

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Intracholecystic Papillary Neoplasm (ICPN) of the Gallbladder

A grossly visible, noninvasive neoplastic proliferation of the gallbladder epithelium forming papillary or tubulopapillary structures within the gallbladder lumen, analogous to intraductal papillary mucinous neoplasm (IPMN) of the pancreas

Clinical ─
─ More common in older adults; slight female predominance
─ Symptoms may include abdominal pain, jaundice (if obstructing the cystic or common bile duct), or may be an incidental finding
─ Associated with cholelithiasis in some cases

Macro ─
─ Exophytic, papillary, or polypoid mass within the gallbladder lumen, typically >1 cm
─ May be sessile or pedunculated
─ Can be associated with mucin secretion, sometimes distending the gallbladder

Micro ─

─ Characterized by papillary and/or tubulopapillary fronds lined by neoplastic columnar epithelium
─ Four main histologic subtypes are recognized, similar to IPMN:
─ Pancreaticobiliary type: Lined by cuboidal to columnar cells with eosinophilic cytoplasm, high-grade atypia, and complex architecture (most common type)
─ Intestinal type: Resembles colonic villous adenoma, with tall columnar cells, elongated hyperchromatic nuclei, and goblet cells
─ Gastric type: Lined by foveolar-type cells with abundant apical mucin and basally located nuclei; typically low-grade atypia
─ Oncocytic type: Composed of cells with abundant granular eosinophilic cytoplasm and prominent nucleoli
─ Dysplasia is graded as low-grade or high-grade; high-grade dysplasia is common, especially in pancreaticobiliary and intestinal types
─ An associated invasive carcinoma is present in a significant proportion of cases (up to 50% or more in some series)

Ancillary studies ─

─ IHC (Mucin core proteins):
─ Pancreaticobiliary: MUC1 (+), MUC5AC (+/-)
─ Intestinal: MUC2 (+), CDX2 (+)
─ Gastric: MUC5AC (+), MUC6 (+/-)
─ IHC (p53): Aberrant expression common in high-grade dysplasia and associated invasive carcinoma

DDx ─

─ Adenomyomatous hyperplasia (shows Rokitansky-Aschoff sinuses and smooth muscle proliferation, lacks true papillary architecture and high-grade dysplasia)
─ Cholesterol polyp (composed of foamy histiocytes within lamina propria cores, covered by bland epithelium)
─ Conventional gallbladder adenoma (tubular or villous, lacks the complex papillary architecture of ICPN or is <1cm)
─ Invasive papillary adenocarcinoma (distinguished by stromal invasion)

Prognosis ─
─ Risk of malignancy is high if an invasive component is present
─ Noninvasive ICPNs generally have a good prognosis after cholecystectomy
─ Prognosis depends on the grade of dysplasia and the presence/extent of associated invasive carcinoma

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Intraductal Papillary Neoplasm of the Bile Ducts (IPNB) - extrahepatic

A grossly visible, preinvasive neoplastic proliferation within the extrahepatic bile duct lumens, characterized by papillary or tubulopapillary structures lined by mucin-producing or biliary-type epithelium

Clinical ─
─ Typically affects older adults (6th-7th decades); slight male predominance
─ Symptoms often relate to biliary obstruction: jaundice, abdominal pain, cholangitis
─ Risk factors include hepatolithiasis, choledochal cysts, primary sclerosing cholangitis, and liver fluke infestation (in endemic areas)

Macro ─
─ Intraductal polypoid or papillary mass, often associated with ductal dilatation
─ May be solitary or multiple, and can involve any part of the extrahepatic biliary tree
─ Mucin secretion may be prominent

Micro ─

─ Papillary or tubulopapillary structures lined by neoplastic columnar cells, confined within the bile duct lumen
─ Fibrovascular cores support the papillary fronds
─ Histologic subtypes similar to pancreatic IPMN and gallbladder ICPN:
─ Pancreaticobiliary type: Most common; cuboidal to columnar cells with eosinophilic cytoplasm, often high-grade atypia
─ Intestinal type: Tall columnar cells with goblet cells, resembling colonic villous adenoma
─ Gastric type: Foveolar-type cells with apical mucin, usually low-grade atypia
─ Oncocytic type: Cells with abundant granular eosinophilic cytoplasm
─ Dysplasia is graded as low-grade or high-grade; high-grade dysplasia is frequent
─ An associated invasive carcinoma (tubular, mucinous, or colloid type) is found in a substantial percentage of cases (40-80%)

Ancillary studies ─

─ IHC (Mucin core proteins): Similar to ICPN, depending on the histologic subtype (MUC1, MUC2, MUC5AC, MUC6)
─ IHC (CDX2): Positive in intestinal type
─ IHC (p53): Aberrant expression in high-grade dysplasia and invasive carcinoma

DDx ─

─ Biliary Intraepithelial Neoplasia (BilIN) (BilIN is typically flat or micropapillary and not grossly visible as a distinct mass)
─ Invasive papillary cholangiocarcinoma (distinguished by stromal invasion beyond the duct wall)
─ Reactive papillary hyperplasia (less cytologic atypia, associated with inflammation/injury)

Prognosis ─
─ Good prognosis if entirely noninvasive and completely resected
─ Overall prognosis is largely determined by the presence, grade, and stage of an associated invasive carcinoma

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Mucinous Cystic Neoplasm (MCN) - if occurring extrahepatically

A cyst-forming epithelial neoplasm composed of mucin-producing columnar epithelium and a characteristic ovarian-type stroma, occurring in the liver or, rarely, extrahepatic sites like the pancreas or retroperitoneum

Clinical ─
─ Predominantly occurs in middle-aged women (F:M ratio > 9:1)
─ Often asymptomatic or presents with vague abdominal pain or a palpable mass
─ Extrahepatic MCNs are rare

Macro ─
─ Typically a large, solitary, multiloculated cyst filled with mucin
─ Cyst wall may be thick and fibrotic; septations are common
─ May show mural nodules if high-grade dysplasia or invasive carcinoma is present

Micro ─

─ Cyst lined by columnar, mucin-producing epithelium, which can range from bland to dysplastic (low-grade or high-grade)
─ Characteristic feature: subepithelial ovarian-type stroma, which is densely cellular and composed of spindle cells
─ This stroma is typically positive for estrogen receptor (ER), progesterone receptor (PR), and inhibin
─ Dysplasia is graded similarly to IPMN/ICPN:
─ Low-grade dysplasia: Mild atypia, basally located nuclei, preserved polarity
─ High-grade dysplasia: Significant atypia, nuclear stratification, loss of polarity, mitoses
─ An associated invasive adenocarcinoma (tubular or mucinous type) is present in a subset of cases (around 10-20% for hepatic MCNs)
─ No communication with the native bile duct system (a key feature distinguishing it from IPMN when in the pancreas, or IPNB when in the bile ducts)

Ancillary studies ─

─ IHC (stroma): ER (+), PR (+), Inhibin (+), Calretinin (+/-)
─ IHC (epithelium): CK7 (+), CK19 (+); MUC5AC often positive
─ IHC (p53): Aberrant expression in high-grade dysplasia and invasive carcinoma

DDx ─

─ Simple biliary cyst/Choledochal cyst (lack ovarian-type stroma and significant epithelial atypia)
─ Intraductal Papillary Neoplasm of the Bile Duct (IPNB) (communicates with bile ducts, lacks ovarian-type stroma, forms intraductal papillary growth)
─ Echinococcal cyst (shows characteristic laminated cyst wall and scolices, parasitic etiology)
─ Cystic metastasis (e.g., from ovary or colon; lacks ovarian-type stroma unless it's a metastasis from a mucinous ovarian tumor with similar stroma)

Prognosis ─
─ Benign if no high-grade dysplasia or invasive carcinoma
─ Risk of recurrence if incompletely excised
─ Prognosis worsens significantly if associated with invasive adenocarcinoma; depends on stage of invasion

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Carcinoma of the Gallbladder (Adenocarcinoma, various subtypes)

A malignant epithelial neoplasm arising from the gallbladder mucosa, most commonly adenocarcinoma

Clinical ─
─ More common in older adults (peak incidence 7th decade); F > M (approx 2-3:1)
─ Major risk factor: Cholelithiasis (gallstones) and chronic cholecystitis
─ Other risk factors: Porcelain gallbladder, choledochal cysts, anomalous pancreaticobiliary junction, primary sclerosing cholangitis, obesity, smoking, certain ethnic groups (e.g., Native Americans, Hispanics)
─ Often asymptomatic in early stages; may present with right upper quadrant pain, jaundice, weight loss, or a palpable mass in advanced stages
─ Frequently discovered incidentally during cholecystectomy for presumed benign disease

Macro ─
─ Can be infiltrative (most common), exophytic/papillary, or a combination
─ Infiltrative type: Diffuse or localized wall thickening, often with a firm, scirrhous appearance
─ Exophytic type: Polypoid or papillary mass protruding into the gallbladder lumen
─ Most commonly arises in the fundus or body of the gallbladder

Micro ─

─ Adenocarcinoma, NOS (Biliary type): Most common; resembles pancreatic ductal adenocarcinoma or cholangiocarcinoma, with irregular glands and tubules infiltrating a desmoplastic stroma; cells are cuboidal to columnar with variable mucin
─ Papillary adenocarcinoma: Predominantly papillary architecture; often less invasive initially but can have deep invasion
─ Mucinous adenocarcinoma: >50% of the tumor is composed of extracellular mucin pools containing clusters or strips of malignant epithelial cells
─ Signet-ring cell carcinoma: >50% of tumor cells are signet-ring cells with intracytoplasmic mucin displacing the nucleus; aggressive behavior
─ Adenosquamous carcinoma: Contains both glandular and squamous malignant components
─ Undifferentiated carcinoma: Lacks clear glandular or squamous differentiation; may have sarcomatoid features
─ Grading is typically two-tiered (low-grade/well-moderately differentiated vs high-grade/poorly differentiated) based on glandular formation and cytologic atypia
─ Lymphovascular and perineural invasion are common and prognostically important
─ Precursor lesions like BilIN or ICPN may be seen in adjacent mucosa

Ancillary studies ─

─ IHC (+): CK7 (strong/diffuse), CK19, CA19-9, CEA
─ IHC (-/+): CK20 (often focal or negative), CDX2 (often negative or focal)
─ IHC (p53): Aberrant expression is common
─ Molecular ─ Mutations in TP53, KRAS, CDKN2A, SMAD4, ERBB2 (HER2) amplification (in a subset, ~10-15%) can occur

DDx ─

─ Xanthogranulomatous cholecystitis (can mimic infiltrative carcinoma grossly and microscopically due to wall thickening and inflammation; lacks true malignant cytology)
─ Adenomyomatous hyperplasia (benign proliferation of glands and smooth muscle)
─ Metastatic adenocarcinoma (e.g., from stomach, pancreas, colon; clinical history and IHC profile can help distinguish)
─ High-grade biliary intraepithelial neoplasia (BilIN-3) (lacks stromal invasion)

Prognosis ─
─ Generally poor prognosis due to late presentation and aggressive behavior
─ Stage is the most important prognostic factor:
─ pTis (carcinoma in situ/BilIN-3) and pT1a (invades lamina propria) have excellent prognosis after cholecystectomy
─ pT1b (invades muscular layer) has a higher risk of nodal metastasis
─ pT2 (invades perimuscular connective tissue) and beyond have significantly worse outcomes
─ Other adverse factors: high grade, lymphovascular/perineural invasion, positive resection margins, lymph node metastasis

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Carcinoma of the Extrahepatic Bile Ducts (Cholangiocarcinoma)

A malignant glandular neoplasm arising from the epithelial lining of the extrahepatic bile ducts, including hilar (Klatskin tumor), distal extrahepatic, and ampullary cholangiocarcinomas (if not primarily duodenal or pancreatic)

Clinical ─
─ Incidence increases with age; typically 6th-7th decades
─ Slight male predominance for hilar tumors
─ Risk factors: Primary sclerosing cholangitis (PSC), choledochal cysts, hepatolithiasis, liver fluke infestation (Opisthorchis viverrini, Clonorchis sinensis - endemic in Southeast Asia), chronic biliary inflammation, toxins (e.g., Thorotrast)
─ Symptoms: Progressive jaundice (often painless initially), pruritus, dark urine, pale stools, abdominal pain, weight loss, fever (cholangitis)
─ Elevated CA 19-9 and CEA may be present

Macro ─
─ Hilar (Klatskin tumor): Typically infiltrative, causing strictures at the confluence of the right and left hepatic ducts; may be nodular or exophytic
─ Distal extrahepatic: Often infiltrative, causing strictures in the common bile duct; may be polypoid or mass-forming
─ Tumors are often firm, gray-white, and scirrhous due to desmoplasia

Micro ─

─ Most are adenocarcinomas of pancreatobiliary type, resembling pancreatic ductal adenocarcinoma
─ Characterized by irregular, angulated, or branching glands and tubules infiltrating a dense desmoplastic stroma
─ Tumor cells are cuboidal to columnar, with variable amounts of eosinophilic cytoplasm and atypical nuclei (enlarged, hyperchromatic, irregular contours, prominent nucleoli)
─ Mucin production is variable; some tumors may have signet-ring cells or be predominantly mucinous
─ Perineural and lymphovascular invasion are common
─ Precursor lesions: Biliary intraepithelial neoplasia (BilIN) is often found in adjacent ducts; intraductal papillary neoplasm of the bile duct (IPNB) can also give rise to invasive cholangiocarcinoma
─ Histologic variants are less common but include adenosquamous carcinoma, squamous cell carcinoma, undifferentiated carcinoma, and neuroendocrine carcinoma

Ancillary studies ─

─ IHC (+): CK7 (strong/diffuse), CK19, CEA (monoclonal), CA19-9, MUC1, MUC5AC
─ IHC (-/+): CK20 (often negative or focal), CDX2 (often negative or focal)
─ IHC (-): HepPar1, Arginase-1 (to exclude hepatocellular carcinoma with glandular features)
─ Molecular ─ KRAS, TP53, SMAD4/DPC4 mutations are common, similar to pancreatic cancer
─ IDH1/2 mutations and FGFR2 fusions are more frequent in intrahepatic cholangiocarcinoma but can occur in extrahepatic tumors

DDx ─

─ Metastatic adenocarcinoma (e.g., from pancreas, stomach, colon, breast; clinical history and IHC panel including site-specific markers are crucial)
─ Pancreatic adenocarcinoma involving the bile duct (often indistinguishable histologically; location of the main tumor mass is key)
─ Benign biliary strictures/Reactive atypia (lack infiltrative growth, significant cytologic atypia, and desmoplasia; p53 typically wild-type)
─ Biliary intraepithelial neoplasia (BilIN) (lacks stromal invasion)
─ Intraductal papillary neoplasm of the bile duct (IPNB) (predominantly intraductal growth pattern, though invasive carcinoma can arise from IPNB)

Prognosis ─
─ Generally poor due to late presentation and aggressive behavior
─ Surgical resection offers the only chance for cure, but many tumors are unresectable at diagnosis
─ Prognostic factors: Tumor stage (depth of invasion, lymph node status, distant metastasis), resection margin status, histologic grade, lymphovascular/perineural invasion
─ Hilar cholangiocarcinomas (Klatskin tumors) often have a worse prognosis due to their critical location and difficulty of complete resection

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Neuroendocrine Neoplasms of the Gallbladder and Extrahepatic Bile Ducts

A heterogeneous group of neoplasms arising from neuroendocrine cells within the gallbladder or extrahepatic bile ducts, ranging from well-differentiated neuroendocrine tumors (NETs) to poorly differentiated neuroendocrine carcinomas (NECs)

Clinical ─
─ Rare; account for <1% of all gallbladder and biliary tract malignancies
─ Occur predominantly in older adults (median age 60s-70s)
─ May be asymptomatic and found incidentally, or present with symptoms similar to adenocarcinoma (jaundice, abdominal pain, weight loss)
─ Functional syndromes (e.g., carcinoid syndrome) are very rare with gallbladder/biliary NETs
─ Risk factors are not well-defined but may overlap with those for adenocarcinoma (e.g., chronic inflammation, gallstones for gallbladder NETs)

Macro ─
─ Gallbladder NETs/NECs: Often present as polypoid masses, nodules, or diffuse wall thickening; may be indistinguishable from adenocarcinoma
─ Extrahepatic bile duct NETs/NECs: Can cause strictures or intraluminal masses
─ Well-differentiated NETs are typically firm and yellow-tan on cut section
─ Poorly differentiated NECs are often larger, infiltrative, and may show necrosis/hemorrhage

Micro ─

─ Well-differentiated Neuroendocrine Tumor (NET), G1 or G2: ─ Composed of relatively uniform cells with round to oval nuclei, "salt-and-pepper" chromatin, and eosinophilic granular cytoplasm
─ Architectural patterns: nests, trabeculae, ribbons, glands, or solid sheets (organoid patterns)
─ Mitotic activity and Ki-67 index determine grade (G1: <2 mitoses/10 HPF and/or Ki-67 <3%; G2: 2-20 mitoses/10 HPF and/or Ki-67 3-20%)
─ Necrosis is usually absent or minimal in G1/G2 NETs
─ Poorly Differentiated Neuroendocrine Carcinoma (NEC), G3: ─ Small cell carcinoma: Sheets of small, round, blue cells with scant cytoplasm, nuclear molding, high N:C ratio, finely granular chromatin, and brisk mitotic activity; extensive necrosis and Azzopardi effect are common
─ Large cell neuroendocrine carcinoma: Large cells with vesicular nuclei, prominent nucleoli, moderate cytoplasm, and organoid, nested, or diffuse growth; high mitotic rate and necrosis are characteristic
─ Ki-67 index is >20% by definition for NECs
─ Mixed Neuroendocrine-Non-Neuroendocrine Neoplasm (MiNEN): ─ Contains both neuroendocrine (NET or NEC) and non-neuroendocrine (e.g., adenocarcinoma) components, with each comprising at least 30% of the tumor

Ancillary studies ─

─ IHC (+, Neuroendocrine markers): Synaptophysin (usually diffuse), Chromogranin A (can be focal), CD56 (less specific)
─ IHC (+, Cytokeratins): Often positive for CK7, CK19, CAM5.2; CK20 is usually negative
─ IHC (Ki-67): Essential for grading
─ Specific hormone stains (e.g., somatostatin, serotonin) are usually not performed unless a functional syndrome is suspected (rare)

DDx ─

─ Adenocarcinoma with neuroendocrine differentiation (scattered neuroendocrine cells <30% of tumor; managed as adenocarcinoma)
─ Metastatic neuroendocrine neoplasm (clinical history, imaging, and IHC for site-specific markers like TTF-1 for lung or CDX2 for GI primary can be helpful)
─ Poorly differentiated adenocarcinoma (may mimic LCNEC; neuroendocrine markers are key)
─ Lymphoma (especially small cell NEC vs lymphoma; lymphoid markers like CD45, CD20, CD3 are key)
─ Cholangiocarcinoma (for NETs with glandular patterns; neuroendocrine markers are diagnostic)

Prognosis ─
─ Highly dependent on tumor type (NET vs NEC), grade, and stage
─ Well-differentiated NETs (G1/G2) generally have a more indolent course than NECs, but metastatic potential exists, especially for G2 tumors and larger lesions
─ Poorly differentiated NECs are highly aggressive with poor prognosis, similar to small cell lung cancer
─ Gallbladder NECs often have a worse prognosis than gallbladder adenocarcinomas
─ Presence of lymph node or distant metastases significantly worsens prognosis

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Pancreas

Pancreas Anatomy

Feature	Description
Structure	Elongated, retroperitoneal gland with both exocrine and endocrine functions.
Parts	Head: Nestled in duodenum's C-curve. Neck, Body, Tail: Extends to the left towards the spleen hilum.
Ductal System	Main Duct (Wirsung): Joins common bile duct at ampulla of Vater. Accessory Duct (Santorini): Drains separately in some individuals.
Blood Supply	Branches from celiac trunk (splenic and gastroduodenal arteries) and SMA.
Venous Drainage	Drains into the portal venous system (splenic vein, SMV).

Pancreas Histology

Component

Cells & Features

Exocrine Pancreas (80-85%)

Composed of densely packed serous acini.

Acinar Cells: Pyramidal cells with apical eosinophilic zymogen granules (digestive proenzymes).

Ductal System: Begins with centroacinar cells (unique to pancreas) within acini.

Endocrine Pancreas (1-2%)

Islets of Langerhans: Clusters of endocrine cells (most numerous in tail).

- Beta (β) cells (~70%): Insulin (central).

- Alpha (α) cells (~20%): Glucagon (peripheral).

- Delta (δ) cells (~5-10%): Somatostatin.

- PP cells: Pancreatic polypeptide.

Acute Pancreatitis

An acute inflammatory condition of the pancreas characterized by parenchymal injury and enzymatic autodigestion, leading to variable local and systemic manifestations

Clinical ─
─ Common causes: Gallstones (choledocholithiasis causing ampullary obstruction, ~40%), alcohol abuse (~30%)
─ Other causes: Hypertriglyceridemia, hypercalcemia, medications (e.g., azathioprine, diuretics, valproic acid), trauma (including iatrogenic, e.g., ERCP), infections (e.g., mumps, Coxsackie virus), ischemia, autoimmune pancreatitis, pancreatic divisum, tumors obstructing the pancreatic duct, scorpion stings, idiopathic (~10-15%)
─ Cardinal symptom: Acute onset of severe, persistent epigastric abdominal pain, often radiating to the back
─ Nausea, vomiting, fever, tachycardia, and abdominal distension are common
─ Elevated serum amylase and lipase (lipase is more specific and remains elevated longer) are key diagnostic laboratory findings

Macro ─
─ Pancreas may appear edematous, hemorrhagic, or necrotic
─ Chalky white areas of fat necrosis (saponification) in the peripancreatic fat and mesentery are characteristic
─ Pseudocysts: Collections of fluid, necrotic debris, and pancreatic enzymes encapsulated by fibrous tissue, lacking a true epithelial lining; typically develop 4+ weeks after acute pancreatitis onset

Micro ─

─ Interstitial edematous pancreatitis (mild form): ─ Interstitial edema separating acini and ducts
─ Mild acute inflammation (neutrophils, lymphocytes, macrophages) in the interstitium and around ducts/acini
─ Focal acinar cell injury/necrosis may be present but is not widespread
─ Fat necrosis: Enzymatic destruction of adipocytes, appearing as shadowy outlines of fat cells with basophilic calcium deposits and surrounding inflammation
─ Necrotizing pancreatitis (severe form): ─ Extensive parenchymal necrosis affecting acinar cells, ductal epithelium, and islets of Langerhans
─ Hemorrhage is often prominent
─ Intense acute inflammatory infiltrate, often with abscess formation
─ Vascular injury, thrombosis, and destruction can occur
─ Fat necrosis: Ghost-like outlines of adipocytes with loss of nuclei, surrounded by an inflammatory reaction and often associated with saponification (calcium deposition, appearing basophilic)
─ Pseudocyst wall: Composed of granulation tissue, fibrous tissue, and chronic inflammation; lacks an epithelial lining (distinguishing it from true cysts)

Ancillary studies ─

─ Imaging (CT, MRI, ultrasound) is crucial for diagnosis, assessing severity (e.g., Balthazar score), and detecting complications (necrosis, pseudocysts, abscesses)
─ ERCP may be used for diagnosis and treatment of gallstone pancreatitis

DDx ─

─ Chronic pancreatitis (shows fibrosis, chronic inflammation, ductal distortion, and acinar atrophy, but typically lacks extensive acute necrosis and hemorrhage unless there is an acute exacerbation)
─ Pancreatic adenocarcinoma (can cause obstructive pancreatitis; tumor cells would be present)
─ Autoimmune pancreatitis (lymphoplasmacytic infiltrate, storiform fibrosis, obliterative phlebitis; often presents as a mass)
─ Perforated peptic ulcer with peripancreatic inflammation/fat necrosis (clinical history and endoscopic findings are key)

Prognosis ─
─ Variable; mild interstitial pancreatitis often resolves with supportive care
─ Severe necrotizing pancreatitis has significant morbidity and mortality (10-30%), especially if complicated by infection, organ failure, or systemic inflammatory response syndrome (SIRS)
─ Complications: Pancreatic necrosis (sterile or infected), pseudocysts, abscess, pancreatic fistula, hemorrhage, multi-organ failure

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Chronic Pancreatitis

A progressive inflammatory disease of the pancreas characterized by irreversible destruction of exocrine and eventually endocrine parenchyma, replaced by fibrosis, leading to chronic pain and pancreatic insufficiency

Clinical ─
─ Most common cause in adults: Chronic alcohol abuse (70-80%)
─ Other causes: Idiopathic (most common in some non-Western populations), recurrent acute pancreatitis, genetic mutations (e.g., PRSS1, SPINK1, CFTR), autoimmune pancreatitis, ductal obstruction (tumors, strictures, stones, pancreatic divisum), hypercalcemia, hypertriglyceridemia, tropical pancreatitis
─ Symptoms: Recurrent or persistent epigastric pain (often severe, radiating to the back, worsened by eating), maldigestion (steatorrhea, weight loss due to exocrine insufficiency), diabetes mellitus (due to endocrine insufficiency)
─ Serum amylase/lipase may be normal or mildly elevated, especially in late-stage disease

Macro ─
─ Pancreas may be enlarged, firm, or atrophic and fibrotic
─ Ducts are often dilated, irregular, and may contain protein plugs or calcified stones (pancreaticolithiasis)
─ Pseudocysts can occur
─ Fibrosis can be diffuse or focal

Micro ─

─ Key features: ─ Parenchymal fibrosis: Irregular deposition of collagen throughout the gland, initially periductal, then interlobular, and finally intralobular, leading to acinar atrophy
─ Acinar cell loss/atrophy: Progressive destruction and replacement of acinar tissue by fibrosis
─ Chronic inflammatory infiltrate: Predominantly lymphocytes and plasma cells, often around ducts and in areas of fibrosis; neutrophils may be present during acute exacerbations
─ Ductal changes: Dilatation, irregular contours, squamous metaplasia of ductal epithelium, intraductal protein plugs (inspissated secretions), and calcifications (stones)
─ Relative sparing of Islets of Langerhans initially, but they can become entrapped in fibrotic tissue, appear clustered (pseudo-islet hyperplasia), and eventually be destroyed in advanced disease
─ Perineural inflammation and fibrosis may contribute to chronic pain
─ Fat necrosis and pseudocysts may be present, especially after acute exacerbations

Ancillary studies ─

─ Imaging (CT, MRI/MRCP, EUS) shows ductal dilatation, calcifications, parenchymal atrophy, and fibrosis
─ ERCP can visualize ductal abnormalities but carries a risk of pancreatitis
─ Pancreatic function tests (e.g., fecal elastase, secretin stimulation test) assess exocrine insufficiency

DDx ─

─ Pancreatic ductal adenocarcinoma (can cause obstructive pancreatitis and fibrosis; malignant glands with desmoplasia and atypia are diagnostic)
─ Distinguishing reactive ductal atypia in chronic pancreatitis from well-differentiated adenocarcinoma can be challenging on small biopsies; features favoring malignancy include incomplete gland lumens, >4:1 nuclear size variation, prominent nucleoli, mitoses, perineural/lymphovascular invasion
─ Autoimmune pancreatitis (Type 1 shows storiform fibrosis, obliterative phlebitis, dense lymphoplasmacytic infiltrate rich in IgG4+ plasma cells; Type 2 shows granulocytic epithelial lesions/duct destruction by neutrophils)
─ Pancreatic neuroendocrine tumor (can be associated with fibrosis; neuroendocrine markers are positive)
─ Groove pancreatitis (fibrosis and inflammation in the groove between the pancreas head, duodenum, and common bile duct)

Prognosis ─
─ Progressive and irreversible condition
─ Complications: Chronic pain, malabsorption, diabetes mellitus, pseudocysts, biliary obstruction, splenic vein thrombosis, increased risk of pancreatic cancer (especially in hereditary and alcoholic pancreatitis)

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Autoimmune Pancreatitis (AIP)

A distinct form of chronic pancreatitis characterized by an immune-mediated inflammatory process, often associated with elevated serum IgG4 levels and responsiveness to steroid therapy; two main subtypes are recognized

Clinical ─
─ Type 1 AIP (Lymphoplasmacytic Sclerosing Pancreatitis - LPSP): ─ More common; typically affects older males (6th-7th decade)
─ Often part of a systemic IgG4-related disease, with involvement of other organs (e.g., bile ducts, salivary glands, retroperitoneum, kidneys)
─ Presents with obstructive jaundice (due to biliary strictures), abdominal pain, or a pancreatic mass mimicking cancer
─ Elevated serum IgG4 levels are common but not universal; autoantibodies (ANA, RF) may be present
─ Type 2 AIP (Idiopathic Duct-Centric Pancreatitis - IDCP; AIP with Granulocytic Epithelial Lesions - GELs): ─ Affects younger patients, no sex predominance
─ Usually pancreas-specific; rarely associated with IgG4-related disease elsewhere, though inflammatory bowel disease (especially ulcerative colitis) is associated in up to 30% of cases
─ Presents similarly to Type 1 AIP (jaundice, pain, mass)
─ Serum IgG4 levels are typically normal
─ Both types usually respond well to corticosteroid therapy

Macro ─
─ Diffuse or focal pancreatic enlargement ("sausage-shaped" pancreas)
─ Pancreas is often firm and fibrotic
─ Main pancreatic duct may be narrowed or irregular
─ A discrete mass can mimic pancreatic cancer

Micro ─

─ Type 1 AIP (LPSP): ─ Dense lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells (>10-50/HPF depending on criteria, and IgG4/IgG ratio >40%)
─ Storiform fibrosis: Characteristic swirling or "cartwheel" pattern of fibrosis
─ Obliterative phlebitis: Venules obliterated by a lymphoplasmacytic infiltrate and fibrosis
─ Periductal and interlobular inflammation and fibrosis
─ Eosinophils may be present
─ Acinar atrophy is common
─ Type 2 AIP (IDCP with GELs): ─ Duct-centric inflammation with granulocytic epithelial lesions (GELs): Neutrophils infiltrating and destroying pancreatic ductal epithelium, sometimes forming microabscesses
─ Periductal lymphoplasmacytic inflammation (typically not as dense or IgG4-rich as Type 1)
─ Interlobular fibrosis may be present, but storiform fibrosis and obliterative phlebitis are usually absent or inconspicuous
─ Serum IgG4 levels are usually normal, and tissue IgG4+ plasma cells are not significantly increased

Ancillary studies ─

─ IHC (IgG4, IgG): Essential for Type 1 AIP diagnosis (increased IgG4+ plasma cells and IgG4/IgG ratio)
─ Serum IgG4 levels: Elevated in many Type 1 AIP cases
─ Imaging (CT, MRI, EUS): Shows diffuse or focal pancreatic enlargement, ductal narrowing; can help differentiate from cancer

DDx ─

─ Pancreatic ductal adenocarcinoma (malignant glands, desmoplasia, significant atypia; can be very difficult to distinguish from AIP on biopsy, especially Type 1 due to fibrosis and mass effect)
─ Chronic pancreatitis (alcoholic/obstructive) (less dense or specific inflammation, lacks storiform fibrosis, obliterative phlebitis, or prominent GELs; IgG4+ cells not significantly increased)
─ Primary sclerosing cholangitis (PSC) (can involve pancreas, but biliary changes are predominant; often IgG4-negative)
─ Lymphoma (monoclonal lymphoid infiltrate; specific lymphoid markers positive)

Prognosis ─
─ Generally good response to corticosteroids for both types
─ Relapses can occur, especially in Type 1 AIP, sometimes requiring long-term immunosuppression
─ Long-term risk of pancreatic insufficiency or malignancy is still being defined, but may be lower than in other forms of chronic pancreatitis

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Congenital Cysts (Pancreas)

Rare, true cysts of the pancreas lined by epithelium, resulting from anomalous development of pancreatic ducts

Clinical ─
─ Often asymptomatic and discovered incidentally
─ May present with abdominal pain or pancreatitis if large or complicated
─ Can be associated with syndromes like Von Hippel-Lindau disease (VHL), autosomal dominant polycystic kidney disease (ADPKD), and cystic fibrosis
─ No sex or age predilection typically, but syndromic cases may present earlier

Macro ─
─ Usually unilocular, but can be multilocular
─ Variable size, can be small or large
─ Thin-walled, filled with clear, serous fluid
─ Can occur in any part of the pancreas

Micro ─

─ Lined by a single layer of bland, cuboidal to flattened ductal-type epithelium
─ Cyst wall is typically thin and composed of fibrous tissue
─ Minimal to no inflammation unless complicated (e.g., secondary infection, hemorrhage)
─ Surrounding pancreatic parenchyma is usually unremarkable, unless there's an associated syndrome or complication
─ Key negative findings: Absence of ovarian-type stroma, significant epithelial atypia/dysplasia, papillary projections, or communication with the main pancreatic duct (helps distinguish from neoplastic cysts)

Ancillary studies ─

─ IHC (epithelium): Positive for cytokeratins (CK7, CK19, CAM5.2)
─ IHC (stroma): Negative for ER, PR, inhibin (helps exclude MCN)
─ Cyst fluid analysis: Low CEA, low amylase (helps distinguish from pseudocysts and some neoplastic cysts)

DDx ─

─ Pancreatic pseudocyst (lacks an epithelial lining; history of pancreatitis is common)
─ Serous cystadenoma (typically microcystic or oligocystic, composed of glycogen-rich clear cells)
─ Mucinous cystic neoplasm (MCN) (characterized by mucinous epithelium and ovarian-type stroma)
─ Intraductal papillary mucinous neoplasm (IPMN) (communicates with the pancreatic duct system, shows papillary architecture)
─ Lymphoepithelial cyst (lined by squamous epithelium with surrounding lymphoid tissue)
─ Acinar cystic transformation (lined by cells with acinar differentiation)

Prognosis ─
─ Benign; generally no malignant potential unless associated with a syndrome that predisposes to pancreatic neoplasia
─ Complications are rare but can include pancreatitis, infection, or hemorrhage if large

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Pseudocysts (Pancreas)

Localized collections of pancreatic fluid, necrotic debris, and inflammatory cells that lack a true epithelial lining, typically developing as a complication of acute or chronic pancreatitis, or pancreatic trauma

Clinical ─
─ Most common cystic lesion of the pancreas (75-80% of all pancreatic cysts)
─ Develops in 5-15% of patients after acute pancreatitis and 20-40% with chronic pancreatitis
─ Symptoms (if present): abdominal pain, nausea, vomiting, early satiety, palpable mass; may be asymptomatic
─ Elevated serum amylase/lipase may be present
─ Typically develop 4 or more weeks after an episode of acute pancreatitis or trauma

Macro ─
─ Usually unilocular, variable in size (can be very large)
─ Located within or adjacent to the pancreas
─ Cyst wall is thick and fibrous, may contain areas of hemorrhage or calcification
─ Contents are typically turbid, brown, or hemorrhagic fluid, rich in pancreatic enzymes

Micro ─

─ Cyst wall composed of granulation tissue, fibrous connective tissue, and chronic inflammatory cells (macrophages, lymphocytes, plasma cells)
─ Hemosiderin-laden macrophages are common
─ Lacks a true epithelial lining (key diagnostic feature)
─ Inner surface may have necrotic debris and acute inflammatory cells
─ Surrounding pancreatic tissue often shows features of chronic pancreatitis (fibrosis, acinar atrophy, ductal changes) or acute pancreatitis (fat necrosis, inflammation)

Ancillary studies ─

─ Imaging (CT, MRI, EUS): Shows a well-defined fluid collection with a thick, enhancing wall; EUS with FNA can be used for diagnosis
─ Cyst fluid analysis: High amylase levels (typically >1000 U/L, often much higher), low CEA levels (helps distinguish from mucinous neoplasms)
─ Cytology of cyst fluid: Shows inflammatory cells, macrophages, necrotic debris; absence of epithelial cells (unless contaminated from GI tract during FNA)

DDx ─

─ True pancreatic cysts (e.g., congenital cysts, serous cystadenoma, MCN, IPMN) (all have an epithelial lining)
─ Cystic pancreatic neoplasms (especially MCN or IPMN if CEA is elevated in fluid, or if imaging shows complex features)
─ Walled-off necrosis (WON) (a mature, encapsulated collection of pancreatic and/or peripancreatic necrosis that has developed a well-defined inflammatory wall; a sequela of necrotizing pancreatitis)

Prognosis ─
─ Many resolve spontaneously, especially if <6 cm and related to acute pancreatitis
─ Complications: Infection, hemorrhage into the cyst, rupture, fistula formation, compression of adjacent organs (e.g., biliary obstruction, gastric outlet obstruction)
─ Treatment (if symptomatic or complicated): Endoscopic drainage, surgical drainage, or percutaneous drainage

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Lymphoepithelial Cyst (Pancreas)

A rare, benign cyst of the pancreas lined by squamous epithelium and surrounded by lymphoid tissue with germinal centers

Clinical ─
─ Typically affects middle-aged to elderly men (M:F ratio ~4:1)
─ Usually asymptomatic and discovered incidentally on imaging
─ May cause abdominal pain or pancreatitis if large
─ Serum tumor markers (CEA, CA 19-9) are usually normal

Macro ─
─ Well-circumscribed, unilocular or multilocular cyst
─ Can occur in any part of the pancreas, but more common in the body or tail
─ Size varies, average around 5 cm, can be up to 15-20 cm
─ Cyst contents are typically keratinaceous, cheesy, or turbid material; may be clear fluid

Micro ─

─ Cyst lined by mature, stratified squamous epithelium, often with keratinization (keratin debris in lumen)
─ The squamous lining may be attenuated or focally replaced by columnar or cuboidal epithelium
─ Characteristic feature: A dense band of lymphoid tissue with well-formed germinal centers is present in the cyst wall, immediately beneath the epithelial lining
─ The lymphoid tissue consists of mature lymphocytes, plasma cells, and histiocytes
─ Cholesterol granulomas or foreign body giant cell reaction to keratin may be present
─ Surrounding pancreatic parenchyma is usually unremarkable
─ Key negative findings: Absence of ovarian-type stroma, mucinous epithelium, or significant cytologic atypia

Ancillary studies ─

─ IHC (epithelium): Squamous cells positive for high molecular weight cytokeratins (e.g., CK5/6)
─ IHC (lymphoid tissue): Shows a reactive polyclonal B and T cell population
─ Cyst fluid analysis: High squamous cells, keratin debris; low amylase, low CEA

DDx ─

─ Epidermoid cyst in intrapancreatic accessory spleen (may have squamous lining but associated with splenic tissue, not prominent lymphoid tissue with germinal centers directly apposed to the cyst lining)
─ Pancreatic pseudocyst (lacks epithelial lining; wall is granulation/fibrous tissue)
─ Congenital/Simple cyst (lined by cuboidal/flattened ductal epithelium; lacks prominent lymphoid tissue)
─ Mucinous cystic neoplasm (MCN) (lined by mucinous epithelium with ovarian-type stroma)
─ Squamous-lined cyst of other types (e.g., dermoid cyst/mature cystic teratoma - very rare in pancreas, would have other germ cell elements)
─ Squamous metaplasia in other cyst types (e.g., in an IPMN or chronic pancreatitis-associated cyst; lacks the characteristic dense lymphoid wall with germinal centers)

Prognosis ─
─ Benign with no malignant potential
─ Surgical resection is curative; recurrence is rare if completely excised

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Serous Cystadenoma (Pancreas)

A benign cystic neoplasm of the pancreas composed of numerous small cysts lined by glycogen-rich, cuboidal to flattened epithelial cells

Clinical ─
─ Represents ~30% of all pancreatic cystic neoplasms; more common in females (F:M ~3:1)
─ Typically occurs in older adults (mean age 60s-70s)
─ Often asymptomatic and found incidentally; may cause abdominal pain, mass effect, or jaundice if large
─ Associated with Von Hippel-Lindau (VHL) syndrome in a subset of cases (up to 30% of VHL patients develop pancreatic serous cystadenomas)
─ Serum tumor markers (CEA, CA 19-9) are usually normal

Macro ─
─ Typically well-circumscribed, often lobulated mass
─ Microcystic type (most common, ~70%): Composed of numerous small cysts (<1 cm to 2 cm), giving a "honeycomb" or "sponge-like" appearance on cut section; a central stellate scar with calcification is characteristic but not always present
─ Macrocystic (oligocystic) type (~30%): Fewer, larger cysts (>2 cm), which can mimic MCN or IPMN; lacks a central scar
─ Can occur in any part of the pancreas, but slightly more common in the body or tail

Micro ─

─ Cysts are lined by a single layer of bland, cuboidal to flattened epithelial cells with clear cytoplasm (due to abundant glycogen) and small, round, centrally or basally located nuclei with inconspicuous nucleoli
─ Minimal to no cytologic atypia; mitotic figures are rare
─ Cysts are separated by thin fibrous septa containing a rich capillary network
─ The central scar (if present in microcystic type) is composed of dense hyalinized fibrous tissue, sometimes with dystrophic calcification
─ Ovarian-type stroma is absent
─ No communication with the main pancreatic duct system
─ Key negative findings: Absence of mucinous differentiation, significant atypia, papillary structures, or ovarian-type stroma

Ancillary studies ─

─ IHC (epithelium): Positive for cytokeratins (CK7, CK19, CAM5.2), EMA, Inhibin (often positive, especially in VHL-associated cases), GLUT-1 (membranous staining)
─ IHC (-): Negative for CEA, MUC1, MUC2, MUC5AC, Chromogranin A, Synaptophysin, ER, PR
─ Histochemistry: PAS stain highlights intracytoplasmic glycogen (diastase sensitive)
─ Molecular ─ VHL gene inactivation (mutations or LOH) is common, especially in syndromic cases and many sporadic microcystic lesions
─ Cyst fluid analysis: Thin, watery fluid; low CEA, low amylase; cytology shows bland cuboidal cells, often with stripped nuclei

DDx ─

─ Mucinous cystic neoplasm (MCN) (especially oligocystic SCA vs MCN; MCN has mucinous lining and ovarian-type stroma, high CEA in fluid)
─ Intraductal papillary mucinous neoplasm (IPMN) (communicates with ducts, papillary architecture, mucinous cells, high CEA/amylase in fluid)
─ Pancreatic pseudocyst (lacks epithelial lining, history of pancreatitis, high amylase in fluid)
─ Congenital/Simple cyst (usually unilocular, lined by flattened ductal epithelium, lacks glycogen-rich cells)
─ Solid pseudopapillary neoplasm (SPN) with cystic degeneration (SPNs have characteristic solid and pseudopapillary areas, distinctive cytology, and nuclear beta-catenin positivity)
─ Lymphoepithelial cyst (squamous lining, lymphoid stroma)

Prognosis ─
─ Benign; malignant transformation (serous cystadenocarcinoma) is exceptionally rare
─ Observation may be appropriate for small, asymptomatic, incidentally discovered lesions, especially in elderly or high-risk surgical patients
─ Surgical resection is curative and indicated for symptomatic lesions, large lesions (>4 cm), uncertain diagnosis, or rapid growth

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Acinar Cystic Transformation (Acinar Cell Cystadenoma)

A rare benign cystic lesion of the pancreas characterized by multiloculated cysts lined by cells with acinar or ductal differentiation, previously often called acinar cell cystadenoma

Clinical ─
─ Very rare, with a wide age range (pediatric to elderly), slight female predominance
─ Often asymptomatic and discovered incidentally; may present with abdominal pain or a palpable mass
─ No clear association with specific syndromes

Macro ─
─ Typically a well-circumscribed, multiloculated cystic mass
─ Can occur in any part of the pancreas
─ Cysts are variable in size and may contain clear or hemorrhagic fluid

Micro ─

─ Multiloculated cysts lined by a single layer of cuboidal to columnar cells
─ Lining cells often show features of acinar differentiation: granular eosinophilic apical cytoplasm (zymogen-like granules) and basally located nuclei
─ Some areas may show ductal-type lining cells (cuboidal, non-granular) or a mixture
─ Minimal cytologic atypia and rare mitotic figures
─ Fibrous septa separate the cysts, may contain scant chronic inflammation
─ No ovarian-type stroma
─ Key negative findings: Absence of significant atypia, invasive growth, or features of other specific cystic neoplasms (e.g., glycogen-rich cells of serous cystadenoma, extensive mucin of MCN/IPMN)

Ancillary studies ─

─ IHC (acinar cells): Positive for acinar markers like trypsin, chymotrypsin, BCL10, and lipase
─ IHC (ductal cells): Positive for CK7, CK19
─ IHC (-): Typically negative for neuroendocrine markers, ER, PR
─ Cyst fluid analysis: Variable amylase and lipase (can be high if acinar component is prominent); CEA usually low

DDx ─

─ Serous cystadenoma (especially oligocystic variant; serous adenomas have clear, glycogen-rich cells, GLUT1+)
─ Mucinous cystic neoplasm (MCN) (mucinous lining, ovarian-type stroma)
─ Intraductal papillary mucinous neoplasm (IPMN) (papillary architecture, communication with ducts)
─ Congenital cysts (usually unilocular, simple cuboidal/flattened lining)
─ Pancreatic pseudocyst (no epithelial lining)
─ Solid pseudopapillary neoplasm with cystic change (distinctive solid areas and pseudopapillae, beta-catenin nuclear +)

Prognosis ─
─ Benign; malignant transformation has not been convincingly documented
─ Surgical resection is curative

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Mucinous Cystic Neoplasm (MCN) of the pancreas

A cyst-forming epithelial neoplasm composed of mucin-producing columnar epithelium and a characteristic underlying ovarian-type stroma, typically occurring in the body or tail of the pancreas and not communicating with the pancreatic duct system

Clinical ─
─ Predominantly occurs in women (F:M ratio >20:1), typically in middle age (mean age 40s-50s)
─ Often asymptomatic and discovered incidentally; may present with abdominal pain, a palpable mass, or symptoms related to compression of adjacent organs
─ Serum tumor markers (CEA, CA 19-9) may be elevated, especially if associated with invasive carcinoma

Macro ─
─ Usually a large, solitary, well-circumscribed, multiloculated cyst (less commonly unilocular)
─ Typically located in the pancreatic body or tail (95%)
─ Cysts are filled with thick, tenacious mucin
─ Cyst wall can be thick and fibrotic; septations are common
─ Mural nodules or areas of wall thickening may indicate high-grade dysplasia or invasive carcinoma
─ No communication with the main pancreatic duct or major branch ducts is a defining feature

Micro ─

─ Cyst lined by columnar, mucin-producing epithelium, which can range from bland to dysplastic
─ Epithelial lining may be gastric foveolar, intestinal, or pancreatobiliary type, or mixed
─ Characteristic feature: A subepithelial layer of densely cellular, spindle cell stroma resembling ovarian stroma
─ This ovarian-type stroma is typically positive for ER, PR, inhibin, and calretinin
─ Dysplasia is graded as:
─ Low-grade dysplasia: Mild atypia, basally located nuclei, preserved polarity, simple architecture
─ High-grade dysplasia: Significant atypia, nuclear stratification, loss of polarity, increased mitoses, complex architecture (papillary, cribriform)
─ An associated invasive adenocarcinoma (usually tubular or mucinous/colloid type) is present in approximately 10-20% of resected MCNs
─ Calcification in the cyst wall can be present

Ancillary studies ─

─ IHC (stroma): ER (+), PR (+), Inhibin (+), Calretinin (+), CD10 (+/-)
─ IHC (epithelium): CK7 (+), CK19 (+), MUC5AC (often + in gastric-type epithelium)
─ IHC (p53): Aberrant expression (strong diffuse or null) common in high-grade dysplasia and invasive carcinoma
─ Molecular ─ KRAS mutations are common (especially in lesions with high-grade dysplasia or invasion)
─ RNF43 mutations can also occur
─ GNAS mutations are typically absent (unlike IPMN)
─ Cyst fluid analysis: High CEA levels are characteristic (often >200 ng/mL, can be >1000 ng/mL); amylase is typically low (as there is no duct communication)

DDx ─

─ Intraductal Papillary Mucinous Neoplasm (IPMN) (communicates with pancreatic ducts, typically lacks ovarian-type stroma [except rare oncocytic types with ovarian-like stroma], more common in males and pancreatic head)
─ Serous Cystadenoma (microcystic or oligocystic, lined by glycogen-rich clear cells, lacks ovarian-type stroma, low CEA in fluid)
─ Pancreatic Pseudocyst (lacks epithelial lining and ovarian-type stroma; history of pancreatitis common; high amylase in fluid)
─ Lymphoepithelial cyst (lined by squamous epithelium with surrounding lymphoid tissue)
─ Solid Pseudopapillary Neoplasm (SPN) with cystic degeneration (SPNs have characteristic solid and pseudopapillary areas, distinctive cytology, and nuclear beta-catenin positivity)
─ Simple epithelial cyst/Congenital cyst (thin wall, bland cuboidal/flattened lining, no ovarian-type stroma)

Prognosis ─
─ Excellent prognosis for MCNs without an associated invasive carcinoma if completely resected
─ Risk of malignancy is associated with size (>4 cm), presence of mural nodules, and grade of dysplasia
─ If invasive carcinoma is present, prognosis depends on the stage of the invasive component

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Intraductal Papillary Mucinous Neoplasm (IPMN)

An intraductal, grossly visible, mucin-producing epithelial neoplasm with papillary proliferation, arising in the main pancreatic duct or its major branches, characterized by varying degrees of dysplasia and risk of progression to invasive carcinoma

Clinical ─
─ Typically affects older adults (60s-70s); slight male predominance for main duct type, more equal for branch duct type
─ Symptoms vary: abdominal pain, pancreatitis (due to duct obstruction by mucin), jaundice (if ampulla involved), weight loss, new-onset diabetes, or asymptomatic (especially branch duct IPMNs found incidentally)
─ Elevated serum amylase/lipase during pancreatitis episodes; CA 19-9 may be elevated, especially with malignancy

Macro ─
─ Main Duct IPMN (MD-IPMN): Diffuse or segmental dilatation of the main pancreatic duct (>5 mm) by thick mucin, often with visible intraductal papillary growths; typically involves the pancreatic head
─ Branch Duct IPMN (BD-IPMN): Cystic dilatation of branch ducts (often >1 cm, can be multicystic "cluster of grapes" appearance), filled with mucin; most common in uncinate process or tail
─ Mixed-Type IPMN: Meets criteria for both MD-IPMN and BD-IPMN
─ Communication with the pancreatic duct system is a defining feature
─ Pancreatic parenchyma may be atrophic due to duct obstruction

Micro ─

─ Intraductal proliferation of mucinous epithelial cells forming papillary structures, villi, or flat arrangements
─ Four main histologic subtypes based on epithelial differentiation and mucin profile:
─ Gastric type: Most common, especially in BD-IPMN; lined by columnar cells with apical mucin caps and basally located nuclei, resembling gastric foveolar epithelium; typically associated with low-grade dysplasia
─ Intestinal type: Resembles colonic villous adenoma, with tall columnar cells, elongated pseudostratified nuclei, and often goblet cells; frequently shows high-grade dysplasia and is more common in MD-IPMN
─ Pancreatobiliary type: Cuboidal to columnar cells with eosinophilic cytoplasm, prominent nucleoli, and complex architecture (e.g., cribriforming, tufting); almost always associated with high-grade dysplasia and invasive carcinoma; aggressive subtype
─ Oncocytic type: (Now often classified separately as Intraductal Oncocytic Papillary Neoplasm - IOPN); large cells with abundant granular eosinophilic cytoplasm and prominent nucleoli, forming complex arborizing papillae; often high-grade dysplasia
─ Dysplasia is graded (International Consensus Guidelines 2012/WHO 2019):
─ Low-grade dysplasia (formerly IPMN with low- to intermediate-grade dysplasia): Mild to moderate cytologic atypia, preserved nuclear polarity (mostly), simple architecture
─ High-grade dysplasia (formerly IPMN with high-grade dysplasia/carcinoma in situ): Significant cytologic atypia, loss of nuclear polarity, nuclear pleomorphism, prominent nucleoli, complex architecture (papillary, cribriform, micropapillary)
─ IPMN with an Associated Invasive Carcinoma: Invasive adenocarcinoma arising in the context of an IPMN; most commonly colloid (mucinous) carcinoma (often from intestinal-type IPMN) or tubular adenocarcinoma (often from gastric or pancreatobiliary-type IPMN)
─ Invasion is defined as neoplastic cells breaching the ductal basement membrane into the pancreatic stroma

Ancillary studies ─

─ IHC (Mucin core proteins):
─ Gastric: MUC5AC (+), MUC6 (+/-)
─ Intestinal: MUC2 (+), MUC5AC (+), CDX2 (+)
─ Pancreatobiliary: MUC1 (+), MUC5AC (+/-), CK7 (+)
─ Oncocytic (IOPN): MUC1 (+), MUC6 (+)
─ IHC (p53): Aberrant expression common in high-grade dysplasia and invasive carcinoma
─ Molecular ─ KRAS mutations are very common (especially in intestinal and gastric types)
─ GNAS mutations are frequent (especially in intestinal and gastric types, less so in pancreatobiliary)
─ TP53, SMAD4/DPC4, RNF43 mutations occur, more often with high-grade dysplasia and invasion
─ Cyst fluid analysis: High CEA levels are common; amylase can be high (due to duct communication); cytology can detect dysplastic/malignant cells; molecular analysis (KRAS, GNAS) can aid diagnosis

DDx ─

─ Mucinous Cystic Neoplasm (MCN) (lacks duct communication, has ovarian-type stroma, almost exclusively in women, body/tail location)
─ Serous Cystadenoma (microcystic, glycogen-rich clear cells, low CEA in fluid)
─ Pancreatic Intraepithelial Neoplasia (PanIN) (microscopic, typically <0.5 cm, precursor to ductal adenocarcinoma, not grossly visible or mucin-producing cysts)
─ Chronic pancreatitis with duct dilatation and mucinous metaplasia (lacks true papillary proliferation and significant dysplasia of IPMN)
─ Retention cyst (simple cuboidal lining, no dysplasia, no papillary structures)

Prognosis ─
─ Risk of malignancy (high-grade dysplasia or invasive carcinoma) is higher in MD-IPMN and mixed-type IPMN compared to BD-IPMN
─ "High-risk stigmata" (obstructive jaundice, enhancing mural nodule >5mm, main duct diameter ≥10mm) and "worrisome features" (cyst ≥3cm, thickened/enhancing cyst walls, non-enhancing mural nodule, main duct diameter 5-9mm, abrupt change in duct caliber with distal atrophy, lymphadenopathy, high serum CA19-9) guide management (Sendai/Fukuoka guidelines)
─ Prognosis for non-invasive IPMN is excellent after complete resection
─ If associated invasive carcinoma is present, prognosis depends on the stage and type of the invasive component (colloid carcinoma generally has a better prognosis than tubular adenocarcinoma)

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Intraductal Oncocytic Papillary Neoplasm (IOPN)

A rare intraductal epithelial neoplasm of the pancreas characterized by complex arborizing papillae lined by oncocytic cells (cells with abundant granular eosinophilic cytoplasm), typically showing high-grade dysplasia and often considered a distinct entity from other IPMN subtypes

Clinical ─
─ Affects adults, wide age range, slight male predominance
─ Symptoms are often nonspecific: abdominal pain, weight loss, jaundice, or pancreatitis; can be an incidental finding
─ Usually involves the main pancreatic duct or major branch ducts, often in the head of the pancreas

Macro ─
─ Intraductal papillary mass, often leading to cystic dilatation of the involved duct(s)
─ May produce abundant mucin
─ Can be large and involve extensive segments of the duct system

Micro ─

─ Complex, arborizing papillary structures with delicate fibrovascular cores, projecting into duct lumens
─ Lined by tall columnar cells with intensely eosinophilic, granular cytoplasm (oncocytic change) due to abundant mitochondria
─ Nuclei are typically large, round to oval, often with prominent, centrally located nucleoli
─ High-grade dysplasia is almost invariably present, characterized by nuclear stratification, pleomorphism, and loss of polarity
─ Intraepithelial lumina or "punched-out" spaces within the epithelium are characteristic
─ Goblet cells are typically absent
─ May have areas resembling conventional pancreatobiliary-type IPMN
─ An associated invasive carcinoma (often oncocytic carcinoma or tubular adenocarcinoma) can occur

Ancillary studies ─

─ IHC (+): MUC1 (apical membranous), MUC6 (cytoplasmic), HepPar-1 (mitochondrial pattern, often), CK7
─ IHC (-): MUC2, MUC5AC (usually), Chromogranin A, Synaptophysin, ER, PR
─ Histochemistry: Abundant mitochondria can be highlighted by PTAH or ultrastructurally
─ Molecular ─ Unlike other IPMN subtypes, KRAS and GNAS mutations are typically absent or rare
─ Recurrent gene fusions involving PRKACA or PRKACB have been reported (similar to fibrolamellar HCC)
─ Alterations in ARHGAP26, ASXL1, EPHA8, ERBB4 have also been described

DDx ─

─ IPMN, pancreatobiliary type (also shows complex architecture and high-grade atypia, but typically lacks diffuse oncocytic cytology and the specific molecular alterations of IOPN)
─ IPMN, other subtypes (gastric and intestinal types have different cytology and mucin profiles)
─ Solid Pseudopapillary Neoplasm (SPN) with oncocytic features (SPNs are solid and cystic, have characteristic pseudopapillae, distinctive nuclear features, and nuclear beta-catenin positivity)
─ Acinar cell carcinoma with oncocytic features (shows acinar differentiation by IHC - trypsin, chymotrypsin)
─ Metastatic oncocytic tumors (e.g., from kidney, thyroid, salivary gland; clinical history and IHC for site-specific markers needed)

Prognosis ─
─ Considered a high-risk precursor lesion due to frequent high-grade dysplasia and association with invasive carcinoma
─ Prognosis for non-invasive IOPN is good after complete resection
─ If invasive carcinoma is present, prognosis depends on the features of the invasive component

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Intraductal Tubulopapillary Neoplasm (ITPN)

A rare intraductal epithelial neoplasm of the pancreas characterized by a predominantly tubular or tubulopapillary growth pattern, lined by cuboidal to columnar non-mucinous or minimally mucinous cells, typically showing high-grade dysplasia

Clinical ─
─ Affects adults, wide age range, no clear sex predominance
─ May present with abdominal pain, jaundice, pancreatitis, or be an incidental finding
─ Tends to involve the main pancreatic duct, often in the head or body of the pancreas

Macro ─
─ Solid or cystic intraductal mass, often causing ductal dilatation
─ Cut surface may appear fleshy or granular, with less obvious mucin production compared to IPMN

Micro ─

─ Predominantly composed of back-to-back, closely packed small tubules and/or tubulopapillary structures, often filling and expanding duct lumens
─ Lined by cuboidal to low columnar cells with relatively scant cytoplasm, which is usually eosinophilic or amphophilic, not overtly mucinous
─ Nuclei are typically round to oval, with high-grade atypia (hyperchromasia, pleomorphism, prominent nucleoli, loss of polarity) being a characteristic feature
─ Mitotic figures are often readily identified
─ Necrosis, often in a comedo-like pattern within the tubules, is common
─ Stroma is usually minimal between the neoplastic tubules
─ No ovarian-type stroma
─ An associated invasive carcinoma (usually tubular adenocarcinoma, poorly differentiated carcinoma, or undifferentiated carcinoma with osteoclast-like giant cells) can occur

Ancillary studies ─

─ IHC (+): CK7, CK19, CAM5.2, MUC1 (often), MUC6 (often)
─ IHC (-): MUC2, MUC5AC (usually negative or very focal, distinguishing from most IPMN subtypes), Trypsin, Chymotrypsin, Chromogranin A, Synaptophysin, ER, PR
─ Molecular ─ KRAS and GNAS mutations are typically absent (unlike most IPMNs)
─ Recurrent alterations include BAP1 mutations, PIK3CA mutations, and FGFR2 fusions
─ Loss of SMAD4/DPC4 expression can occur

DDx ─

─ Pancreatic Ductal Adenocarcinoma (PDAC), conventional type (ITPN is primarily intraductal, though invasion can occur; PDAC is typically infiltrative from onset; some PDACs can have micropapillary areas but usually show overt mucin)
─ IPMN, pancreatobiliary type (also high-grade, but typically shows more overt mucin production and different immunoprofile for mucins)
─ Pancreatic Intraepithelial Neoplasia (PanIN-3) (PanIN is microscopic, involves smaller ducts, and lacks the mass-forming intraductal growth of ITPN)
─ Acinar cell carcinoma (solid and acinar growth, but cells show acinar differentiation by IHC)
─ Solid Pseudopapillary Neoplasm (SPN) (solid and pseudopapillary areas, characteristic nuclear features, beta-catenin nuclear positivity)

Prognosis ─
─ Considered a high-risk intraductal neoplasm with frequent association with invasive carcinoma
─ Even when invasive, some studies suggest a better prognosis than conventional PDAC of similar stage, but data are limited due to rarity
─ Complete surgical resection is the mainstay of treatment

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Pancreatic Intraepithelial Neoplasia (PanIN)

A microscopic, flat or micropapillary, noninvasive neoplastic proliferation of ductal or ductular epithelium within the smaller pancreatic ducts, considered a precursor to pancreatic ductal adenocarcinoma (PDAC)

Clinical ─
─ Asymptomatic and typically an incidental microscopic finding in pancreas specimens resected for other reasons (e.g., PDAC, chronic pancreatitis)
─ More common in older individuals and in patients with a family history of pancreatic cancer, chronic pancreatitis, or smoking history
─ Not detectable by current imaging modalities

Macro ─
─ Not visible grossly

Micro ─

─ Graded into three tiers based on cytologic and architectural atypia:
─ PanIN-1 (Low-grade): Flat to low papillary proliferation of columnar cells with abundant supranuclear mucin and small, basally located, round to oval, uniform nuclei; minimal atypia (formerly PanIN-1A and PanIN-1B)
─ PanIN-1A: Flat or minimally papillary, tall columnar cells, basal nuclei, abundant apical mucin, minimal atypia
─ PanIN-1B: More papillary architecture, still with tall columnar cells, basal nuclei, apical mucin, minimal atypia
─ PanIN-2 (Low-grade): More significant nuclear atypia, including nuclear crowding, stratification, enlargement, hyperchromasia, and some loss of polarity; papillary or micropapillary architecture may be more complex; mitotic figures are rare (formerly PanIN-2)
─ PanIN-3 (High-grade/Carcinoma in situ): Marked cytologic atypia with significant nuclear pleomorphism, irregular nuclear contours, prominent nucleoli, and loss of polarity; architecture is often complex, with cribriforming, budding, or tufting; mitotic figures, including atypical forms, may be present (formerly PanIN-3)
─ Involves small pancreatic ducts and ductules (typically <5 mm in diameter)
─ Neoplastic cells are confined by the ductal basement membrane
─ Often multifocal and can be associated with chronic pancreatitis or adjacent PDAC

Ancillary studies ─

─ IHC (p53): Aberrant expression (strong diffuse or null pattern) is common in PanIN-3 and less frequent in PanIN-1/2
─ IHC (SMAD4/DPC4): Loss of expression can be seen, particularly in higher grades, and is associated with progression to invasive carcinoma
─ IHC (Ki-67): Proliferation index increases with grade of PanIN
─ IHC (MUC1, MUC5AC): Often positive, especially in higher grades
─ Molecular ─ KRAS mutations are early and frequent events, present even in PanIN-1
─ CDKN2A (p16) inactivation is common in PanIN-2 and PanIN-3
─ TP53 and SMAD4/DPC4 mutations/loss are later events, typically seen in PanIN-3 and invasive carcinoma
─ Telomere shortening is an early event

DDx ─

─ Reactive ductal atypia (associated with inflammation/chronic pancreatitis; typically less cytologic atypia, preserved polarity, lacks complex architecture of high-grade PanIN, and lacks molecular alterations of PanIN)
─ Intraductal Papillary Mucinous Neoplasm (IPMN) (IPMNs are grossly visible, typically involve larger ducts, are >1 cm, and have different histologic subtypes and often GNAS mutations)
─ Intraductal Tubulopapillary Neoplasm (ITPN) (grossly visible, distinct tubular/tubulopapillary architecture, often lacks overt mucin, different molecular profile)
─ Invasive pancreatic ductal adenocarcinoma (distinguished by stromal invasion)

Prognosis ─
─ Considered a non-obligate precursor to PDAC; the risk of progression increases with the grade of PanIN
─ PanIN-3 is considered carcinoma in situ and has a high likelihood of association with or progression to invasive PDAC
─ The presence and grade of PanIN in resection margins may have prognostic implications in patients with PDAC

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Pancreatic Ductal Adenocarcinoma (PDAC), conventional

An aggressive malignant epithelial neoplasm arising from the pancreatic ductal system, characterized by infiltrative glands and a prominent desmoplastic stromal reaction

Clinical ─
─ Fourth leading cause of cancer death in the United States; high mortality rate
─ Peak incidence in 6th-8th decades; slightly more common in males and African Americans
─ Risk factors: Smoking (strongest environmental risk factor), chronic pancreatitis, diabetes mellitus (long-standing), obesity, high-fat diet, family history of pancreatic cancer, hereditary cancer syndromes (e.g., BRCA1/2, PALB2, Peutz-Jeghers, Lynch syndrome, FAMMM)
─ Symptoms often vague and nonspecific until late stage: abdominal or back pain, jaundice (if tumor obstructs bile duct, common with head lesions), weight loss, anorexia, nausea, new-onset diabetes, steatorrhea, migratory thrombophlebitis (Trousseau syndrome)
─ Elevated serum CA 19-9 is common but not specific

Macro ─
─ Most commonly arises in the head of the pancreas (~60-70%), followed by body (~15-20%) and tail (~5-10%)
─ Typically a firm, poorly defined, infiltrative, gray-white to yellow-tan mass
─ Often causes obstruction of the common bile duct and/or pancreatic duct
─ May invade adjacent structures (duodenum, stomach, major blood vessels)

Micro ─

─ Infiltrating glands, tubules, and individual cells within a dense desmoplastic (fibrotic) stroma
─ Glands are often irregular, angulated, and haphazardly arranged; may show incomplete lumen formation
─ Tumor cells are typically cuboidal to columnar with variable amounts of mucin
─ Nuclei are enlarged, pleomorphic, hyperchromatic, with irregular contours and prominent nucleoli; loss of polarity is common
─ Mitotic figures, including atypical forms, are usually present
─ Perineural invasion and lymphovascular invasion are very common and characteristic features
─ Often associated with Pancreatic Intraepithelial Neoplasia (PanIN) in adjacent ducts
─ Grading is typically based on the degree of gland formation (WHO/AJCC):
─ Grade 1 (Well differentiated): >95% gland formation
─ Grade 2 (Moderately differentiated): 50-95% gland formation
─ Grade 3 (Poorly differentiated): <50% gland formation (includes solid, single cell, and anaplastic patterns)

Ancillary studies ─

─ IHC (+): CK7, CK19, CA19-9, CEA, MUC1, MUC5AC; SMAD4/DPC4 (positive in ~50-60%, loss in 40-50%)
─ IHC (-/+): CK20 (usually negative or focal)
─ IHC (-): HepPar1, Arginase-1 (to exclude hepatocellular carcinoma), TTF-1 (to exclude lung primary), CDX2 (usually negative, to exclude colorectal primary)
─ Molecular ─ KRAS mutations are nearly ubiquitous (>90%, typically codon 12)
─ TP53 mutations are very common (~75%)
─ CDKN2A (p16) inactivation is common (~90%)
─ SMAD4/DPC4 inactivation/loss is common (~50-55%)
─ BRCA1/2, PALB2 germline mutations in a subset, especially familial cases

DDx ─

─ Chronic pancreatitis with reactive atypia (reactive changes lack the degree of atypia and infiltrative growth of PDAC; inflammation more prominent; lacks extensive desmoplasia and perineural invasion)
─ Adenocarcinoma from other sites (e.g., biliary, gastric, duodenal; clinical history, location, and IHC profile are key for distinction)
─ Well-differentiated neuroendocrine tumor with glandular features (positive for neuroendocrine markers)
─ Acinar cell carcinoma (cells with granular eosinophilic cytoplasm, prominent nucleoli, acinar architecture; positive for acinar markers like trypsin/chymotrypsin)
─ Solid Pseudopapillary Neoplasm (SPN) (characteristic solid and pseudopapillary architecture, distinctive cytology, nuclear beta-catenin positivity)

Prognosis ─
─ Overall very poor; 5-year survival rate is <10%
─ Most patients present with unresectable or metastatic disease
─ Prognostic factors: Stage (TNM), resection margin status (R0 vs R1/R2), lymph node involvement, histologic grade, lymphovascular/perineural invasion
─ Loss of SMAD4/DPC4 expression is associated with worse prognosis and predominantly distant metastatic failure pattern

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Pancreatic Ductal Adenocarcinoma Variants

Distinct histologic subtypes of pancreatic ductal adenocarcinoma with specific morphologic, molecular, and sometimes clinical characteristics; these are generally rare compared to conventional PDAC

─ Adenosquamous Carcinoma: ─ Malignant neoplasm with both glandular (adenocarcinoma) and squamous (squamous cell carcinoma) components, each comprising at least 30% of the tumor
─ Clinical: Similar presentation to conventional PDAC, but often more aggressive; accounts for 1-4% of pancreatic exocrine malignancies
─ Micro: Intermixed areas of adenocarcinoma and squamous cell carcinoma with keratinization, intercellular bridges; desmoplastic stroma
─ IHC: Glandular component CK7+, squamous component p40/p63+, CK5/6+
─ Prognosis: Generally worse than conventional PDAC
─ Colloid Carcinoma (Mucinous Non-cystic Carcinoma): ─ Characterized by large pools of extracellular mucin (>80% of tumor volume) containing floating clusters, glands, or individual cells of neoplastic epithelium
─ Clinical: Rare (<1-3% of PDAC); may arise from intestinal-type IPMN
─ Micro: Abundant extracellular mucin dissecting through stroma; neoplastic cells often bland or show low to moderate atypia; may have signet-ring cells
─ IHC: CK20 (+), CDX2 (+), MUC2 (+) often (intestinal phenotype); CK7 (-/+)
─ Molecular: KRAS and GNAS mutations common if arising from IPMN; SMAD4 loss less frequent than conventional PDAC
─ Prognosis: Better than conventional PDAC, especially when pure and associated with IPMN
─ Hepatoid Carcinoma: ─ Rare variant resembling hepatocellular carcinoma (HCC)
─ Clinical: Aggressive, often with liver metastases and elevated serum AFP
─ Micro: Sheets or trabeculae of large polygonal cells with abundant eosinophilic cytoplasm, prominent nucleoli; may produce bile
─ IHC: AFP (+), HepPar-1 (+/-), Glypican-3 (+/-), CK7 (+/-), CK19 (+/-); Arginase-1 usually negative
─ Prognosis: Poor
─ Medullary Carcinoma: ─ Poorly differentiated carcinoma with a syncytial/solid growth pattern, pushing borders, and prominent tumor-infiltrating lymphocytes (TILs)
─ Clinical: Rare; often associated with Lynch syndrome or sporadic MSI-H status
─ Micro: Sheets of large, pleomorphic cells with vesicular nuclei and prominent nucleoli; minimal gland formation; dense lymphoplasmacytic infiltrate
─ IHC: Often loss of MMR proteins (MLH1, MSH2, MSH6, PMS2); CK7 (+/-), CK20 (-/+)
─ Molecular: Microsatellite instability (MSI-H) is characteristic
─ Prognosis: May have a better prognosis than conventional PDAC of similar stage, potentially due to immunogenicity
─ Signet-Ring Cell Carcinoma: ─ Composed predominantly (>50%) of signet-ring cells (intracytoplasmic mucin displacing the nucleus to the periphery)
─ Clinical: Rare, aggressive; often presents with diffuse infiltration (linitis plastica-like)
─ Micro: Infiltrating individual signet-ring cells or small clusters in a desmoplastic stroma
─ Prognosis: Poor
─ Undifferentiated Carcinoma: ─ Malignant epithelial neoplasm lacking evidence of specific differentiation (glandular, squamous, neuroendocrine, etc) by light microscopy
─ Clinical: Rare, highly aggressive
─ Micro: Sheets, nests, or infiltrative growth of pleomorphic, anaplastic cells; may have spindle cell (sarcomatoid) areas
─ IHC: May be positive for keratins, but often variably or focally; negative for markers of specific differentiation
─ Prognosis: Very poor
─ Undifferentiated Carcinoma with Osteoclast-like Giant Cells (OGCs): ─ Biphasic tumor with a component of undifferentiated/sarcomatoid carcinoma and numerous benign, multinucleated osteoclast-like giant cells
─ Clinical: Rare; can present as a large, hemorrhagic, and necrotic mass
─ Micro: Spindle and/or pleomorphic mononuclear malignant cells admixed with non-neoplastic OGCs within a hemorrhagic and often hemosiderin-rich stroma; a glandular component (PDAC) may be present
─ IHC (mononuclear malignant cells): Keratin (+/-), Vimentin (+), CD68 (+/- in malignant cells, + in OGCs)
─ Molecular: KRAS mutations common in the carcinomatous component
─ Prognosis: Variable, but generally better than conventional PDAC if no associated typical PDAC component, or if the PDAC component is small

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Solid Pseudopapillary Neoplasm (SPN) of the Pancreas

A low-grade malignant epithelial neoplasm with solid and pseudopapillary architecture, composed of poorly cohesive, monomorphic cells.

Clinical ─ Predominantly affects young women (average age ~25-30 years, >85% of cases). Often presents with vague, non-specific symptoms like abdominal pain or discomfort due to mass effect, or may be found incidentally on imaging. Despite being a low-grade malignancy, it can invade locally and has a small but definite potential for distant metastasis (most commonly to liver, peritoneum). Overall prognosis after complete resection is excellent.

Macro ─ Typically large, well-demarcated, encapsulated masses. The cut surface is characteristically heterogeneous, showing a mixture of solid tan-yellow areas, hemorrhage, cystic degeneration, and necrosis. Can occur anywhere in the pancreas but slightly more common in the body/tail.

Micro ─

─ Architecture: A mix of solid sheets and pseudopapillae. The pseudopapillae are formed when the poorly cohesive tumor cells fall away, leaving cells arranged around delicate, often hyalinized fibrovascular stalks.

─ Cytology: Uniform, monotonous cells with round to oval nuclei, fine "salt and pepper" chromatin, and often nuclear grooves or indentations. Cytoplasm is typically eosinophilic or clear/vacuolated. Mitoses are rare.

─ Characteristic features: ─ Eosinophilic, PAS-positive, diastase-resistant hyaline globules are common.

─ Foamy histiocytes, cholesterol clefts, and foreign-body giant cells are frequently seen, especially in areas of hemorrhage and degeneration.

Ancillary studies ─

─ IHC (+): Nuclear beta-catenin (highly characteristic and sensitive), CD10, CD56, Vimentin, Progesterone Receptor (PR), Alpha-1-antitrypsin. Cyclin D1 is also positive.

─ IHC (-): Chromogranin A (in contrast to PanNETs), Trypsin/Chymotrypsin (in contrast to acinar cell carcinoma), CK7. E-cadherin shows aberrant cytoplasmic (non-membranous) staining or loss.

─ Molecular: Activating mutations in the CTNNB1 gene (encoding beta-catenin) are present in >90% of cases, leading to its nuclear accumulation.

DDx ─

─ Pancreatic Neuroendocrine Tumor (PanNET): Can have solid growth and similar "salt and pepper" chromatin. However, PanNETs show strong, diffuse staining for synaptophysin and chromogranin A and are negative for nuclear beta-catenin.

─ Acinar Cell Carcinoma: More aggressive clinically. Cells have more prominent nucleoli and granular, eosinophilic cytoplasm. Positive for acinar markers (Trypsin, Chymotrypsin, BCL10).

─ Pancreatoblastoma: A pediatric tumor. Characterized by acinar differentiation and distinct squamoid nests/corpuscles.

Acinar Cell Carcinoma (ACC)

A malignant epithelial neoplasm demonstrating differentiation towards pancreatic acinar cells, characterized by the production of pancreatic exocrine enzymes

Clinical ─
─ Rare, accounts for ~1-2% of all exocrine pancreatic neoplasms
─ Can occur at any age, but more common in older adults (mean age 60s); slight male predominance
─ Symptoms are often nonspecific: abdominal pain, weight loss, nausea, vomiting; may present with a palpable mass
─ Paraneoplastic syndrome (Schmid's triad): Subcutaneous fat necrosis, polyarthralgia, and eosinophilia, due to systemic release of lipase; occurs in ~10-15% of patients and is highly characteristic
─ Serum lipase and/or amylase may be elevated

Macro ─
─ Typically a relatively well-circumscribed, fleshy, tan-pink to red-brown mass
─ Can occur in any part of the pancreas, but slightly more common in the head or body
─ May show areas of hemorrhage or necrosis
─ Usually larger at diagnosis than PDAC

Micro ─

─ Cells arranged in acinar, glandular, trabecular, or solid patterns
─ Tumor cells are typically polygonal with abundant granular eosinophilic or amphophilic cytoplasm (due to zymogen granules) and round, often basally located nuclei with prominent, centrally located nucleoli
─ Minimal intervening stroma compared to PDAC (lacks significant desmoplasia)
─ Mitotic activity is variable but often readily identified
─ Necrosis can be present
─ Mixed acinar-neuroendocrine carcinoma and mixed acinar-ductal carcinoma can occur

Ancillary studies ─

─ IHC (+, Acinar markers): Trypsin (highly specific), Chymotrypsin (highly specific), BCL10, Pancreatic lipase
─ IHC (+, Cytokeratins): CK7, CK18, CAM5.2 often positive
─ IHC (-/+): Neuroendocrine markers (Synaptophysin, Chromogranin A) may show focal positivity in up to 30-50% of cases, but diffuse staining suggests mixed acinar-neuroendocrine carcinoma
─ IHC (-): MUC1 (usually negative, unlike PDAC), CEA (usually negative)
─ Histochemistry: PAS-diastase stain can highlight zymogen granules
─ Molecular ─ Unlike PDAC, KRAS, TP53, and SMAD4 mutations are rare
─ Alterations in APC/beta-catenin pathway (CTNNB1 mutations) have been reported in a subset
─ Allelic loss on 11p (near the MEN1 locus) is common
─ Recurrent gene fusions involving BRAF or RAF1 have been identified in some cases, particularly in younger patients

DDx ─

─ Pancreatic Ductal Adenocarcinoma (PDAC) (PDAC shows more glandular/tubular architecture, desmoplastic stroma, MUC1 positivity, and lacks acinar markers)
─ Well-differentiated Neuroendocrine Tumor (PanNET) (PanNETs have organoid architecture, "salt-and-pepper" chromatin, and are diffusely positive for neuroendocrine markers; acinar markers negative)
─ Solid Pseudopapillary Neoplasm (SPN) (SPNs have pseudopapillary architecture, characteristic nuclear features, nuclear beta-catenin positivity, and are negative for acinar markers)
─ Pancreatoblastoma (occurs in children, shows squamoid nests, and has beta-catenin nuclear positivity; acinar differentiation is present)

Prognosis ─
─ Better prognosis than conventional PDAC, but still a malignant neoplasm with significant metastatic potential
─ 5-year survival rates are approximately 40-60% for resected tumors
─ Metastases occur most commonly to regional lymph nodes and liver
─ Presence of lipase hypersecretion syndrome is associated with a worse prognosis

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Pancreatoblastoma

A rare malignant epithelial neoplasm of the pancreas, primarily occurring in childhood, characterized by features of acinar differentiation and distinctive squamoid nests (morules)

Clinical ─
─ Very rare; most common pancreatic neoplasm in young children (typically <10 years old, median age ~4-5 years), but can occur in older children and rarely in adults
─ Slight male predominance
─ May present with an abdominal mass, pain, vomiting, or diarrhea; jaundice is uncommon
─ Serum AFP (alpha-fetoprotein) is elevated in a significant proportion of cases
─ Associated with Beckwith-Wiedemann syndrome and familial adenomatous polyposis (FAP) in some cases (APC gene mutations)

Macro ─
─ Typically a large, well-circumscribed, lobulated mass
─ Can occur in any part of the pancreas, but often in the head or body/tail junction
─ Cut surface is often fleshy, tan-white to pink, and may show cystic change, hemorrhage, or necrosis

Micro ─

─ Lobulated architecture with cellular nests separated by fibrous septa
─ Predominant pattern is acinar, with cells forming acini, tubules, or solid sheets, showing granular eosinophilic cytoplasm and prominent nucleoli (similar to acinar cell carcinoma)
─ Characteristic feature: Squamoid nests (morules) – well-demarcated, rounded nests of bland-appearing spindle or ovoid cells with pale eosinophilic or clear cytoplasm, often with biotin-rich, optically clear nuclei; these nests lack keratinization or intercellular bridges
─ Neuroendocrine cells may be scattered or form small clusters
─ Mesenchymal stroma can be cellular or hyalinized
─ Mitotic activity is variable

Ancillary studies ─

─ IHC (Acinar component): Positive for trypsin, chymotrypsin, BCL10, lipase
─ IHC (Squamoid nests): Positive for beta-catenin (nuclear and cytoplasmic), CD10, CDX2 (often), CK5/6 (variable), EMA; negative for acinar and neuroendocrine markers
─ IHC (Neuroendocrine component): Positive for Synaptophysin, Chromogranin A
─ IHC (AFP): May be positive in tumor cells
─ Molecular ─ Alterations in the APC/beta-catenin pathway (CTNNB1 mutations or APC mutations) are characteristic, leading to nuclear beta-catenin accumulation, especially in squamoid nests
─ Allelic loss on chromosome 11p (region of WT1 and Beckwith-Wiedemann syndrome locus) is common

DDx ─

─ Acinar Cell Carcinoma (ACC) (lacks squamoid nests; typically occurs in older adults)
─ Solid Pseudopapillary Neoplasm (SPN) (SPNs have pseudopapillary architecture, characteristic nuclear grooves/folds, lack true acinar differentiation, and squamoid nests are usually not as prominent or typical as in pancreatoblastoma; beta-catenin is nuclear in SPN but often more diffuse)
─ Pancreatic Neuroendocrine Tumor (PanNET) (lacks acinar differentiation and squamoid nests; diffusely positive for neuroendocrine markers)
─ Hepatoblastoma (if AFP is high and tumor is in head of pancreas; hepatoblastoma shows hepatic differentiation, lacks typical squamoid nests of pancreatoblastoma)

Prognosis ─
─ Better prognosis than PDAC, but still a malignant tumor with potential for recurrence and metastasis
─ 5-year survival is around 50-60%, but better for completely resected, localized disease in younger children
─ Metastases most commonly occur to liver, regional lymph nodes, and peritoneum
─ Adult cases tend to have a more aggressive course

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Well-differentiated Pancreatic Neuroendocrine Tumor (PanNET)

A relatively uncommon epithelial neoplasm of the pancreas with neuroendocrine differentiation, generally more indolent behavior than pancreatic ductal adenocarcinoma, and potential for hormone production

Clinical ─
─ Peak incidence in 4th to 6th decades; slight male predominance
─ Can be sporadic or associated with syndromes like Multiple Endocrine Neoplasia type 1 (MEN1), von Hippel-Lindau (VHL) disease, neurofibromatosis type 1 (NF1), and tuberous sclerosis
─ Non-functioning PanNETs (most common, ~60-90%): Often asymptomatic or present late with mass effects (abdominal pain, jaundice, palpable mass) or incidental finding on imaging
─ Functioning PanNETs: Present with symptoms related to specific hormone hypersecretion:
─ Insulinoma (most common functioning type): Hypoglycemia (Whipple's triad - symptoms of hypoglycemia, low plasma glucose, relief of symptoms after glucose administration)
─ Gastrinoma: Zollinger-Ellison syndrome (refractory peptic ulcers, diarrhea, esophageal symptoms)
─ VIPoma: WDHA syndrome (Watery Diarrhea, Hypokalemia, Achlorhydria)
─ Glucagonoma: Necrolytic migratory erythema, diabetes, weight loss, anemia
─ Somatostatinoma: Diabetes, cholelithiasis, steatorrhea, hypochlorhydria
─ ACTH-producing: Cushing's syndrome
─ Serotonin-producing (rare in pancreas): Carcinoid syndrome (if liver metastases)
─ Serum markers: Chromogranin A (general neuroendocrine marker, can be elevated in non-functioning and functioning tumors); specific hormone levels for functioning tumors

Macro ─
─ Typically well-circumscribed, solid, fleshy, tan-yellow to red-brown masses
─ Can occur in any part of the pancreas (head, body, or tail)
─ Size is variable; functioning tumors are often smaller at diagnosis (<2 cm for insulinomas) than non-functioning tumors
─ May show cystic change, hemorrhage, or calcification, especially in larger tumors

Micro ─

─ Composed of relatively uniform cells with round to oval nuclei, "salt-and-pepper" (stippled) chromatin, and eosinophilic granular cytoplasm
─ Architectural patterns:
─ Solid/nested: Compact nests or sheets of cells
─ Trabecular/gyriform: Interconnecting ribbons or cords of cells, often with a delicate fibrovascular stroma
─ Glandular/pseudorosette: Cells forming gland-like structures or rosettes around small lumens or capillaries
─ Stroma is typically highly vascular
─ Amyloid deposition may be seen, especially in insulinomas
─ Psammoma bodies can be seen in somatostatinomas
─ Grading (WHO 2017/2019, based on mitotic count and Ki-67 index):
─ NET G1: Mitotic count <2/10 HPF AND Ki-67 index ≤2%
─ NET G2: Mitotic count 2-20/10 HPF OR Ki-67 index 3-20%
─ NET G3: Mitotic count >20/10 HPF OR Ki-67 index >20% (Note: Morphologically well-differentiated tumors with G3 proliferation are still termed PanNET G3, distinct from PanNEC)
─ Necrosis is uncommon in G1/G2 NETs but can be seen in G3 NETs
─ Lymphovascular invasion may be present

Ancillary studies ─

─ IHC (+, Neuroendocrine markers): Synaptophysin (usually diffuse and strong), Chromogranin A (can be focal or patchy), CD56 (less specific), INSM1 (nuclear, highly sensitive and specific)
─ IHC (+, Cytokeratins): Often positive for CAM5.2, CK8/18; CK19 positivity may be associated with more aggressive behavior in some studies
─ IHC (+, Specific hormones): Insulin, glucagon, somatostatin, gastrin, VIP, etc.,. can confirm functional type but staining intensity does not always correlate with clinical syndrome
─ IHC (Ki-67): Essential for grading; count in "hot spots" (areas of highest proliferation), minimum 500 cells
─ Molecular ─ Sporadic PanNETs: Mutations in MEN1, DAXX/ATRX, and genes in mTOR pathway (e.g., PTEN, TSC2) are common
─ VHL-associated PanNETs: Often non-functioning, multiple; VHL gene inactivation
─ MEN1-associated PanNETs: Often multiple, can be functioning (gastrinomas, insulinomas) or non-functioning; MEN1 gene mutation
─ NF1-associated PanNETs: Typically somatostatin-rich, periampullary; NF1 gene mutation

DDx ─

─ Pancreatic Ductal Adenocarcinoma (PDAC) (PDAC shows infiltrative glands, desmoplasia, more cytologic atypia, MUC1+, and lacks diffuse neuroendocrine marker expression)
─ Acinar Cell Carcinoma (ACC) (ACC has cells with more abundant granular cytoplasm, prominent nucleoli, acinar architecture, and expresses acinar markers like trypsin/chymotrypsin, BCL10)
─ Solid Pseudopapillary Neoplasm (SPN) (SPNs have pseudopapillary structures, characteristic nuclear grooves, nuclear beta-catenin positivity, CD10+, and are usually negative for neuroendocrine markers)
─ Pancreatoblastoma (occurs in children, shows squamoid nests, acinar differentiation, and nuclear beta-catenin)
─ Poorly Differentiated Pancreatic Neuroendocrine Carcinoma (PanNEC) (PanNECs have overt malignant cytology, high mitotic rate, extensive necrosis, and Ki-67 >20%; see separate entry)
─ Metastatic NET from other sites (e.g., GI tract, lung; clinical history and IHC for site-specific markers like CDX2, TTF-1, Islet-1, PAX8 can be helpful; PDX1 is often positive in duodenal and pancreatic NETs)

Prognosis ─
─ Generally more favorable than PDAC, but malignant potential is significant, especially for larger, higher-grade, or non-functioning tumors
─ Prognostic factors: Tumor grade (G1, G2, G3), stage (TNM), size, functionality (some functioning types like insulinomas are often benign if small), lymphovascular invasion, perineural invasion, specific genetic alterations
─ Liver metastases are common and a major determinant of outcome

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Poorly differentiated Pancreatic Neuroendocrine Carcinoma (PanNEC)

A high-grade malignant epithelial neoplasm of the pancreas with neuroendocrine differentiation, characterized by aggressive clinical behavior and poor prognosis

Clinical ─
─ Rare, accounts for a small fraction of pancreatic neoplasms and pancreatic neuroendocrine neoplasms
─ Typically affects older adults (6th-7th decades); often a male predominance
─ Symptoms are usually nonspecific and related to a large, aggressive mass: abdominal pain, weight loss, jaundice (if obstructing bile duct); paraneoplastic syndromes are uncommon
─ Often presents with metastatic disease at diagnosis, commonly to liver and regional lymph nodes
─ Serum tumor markers like CEA or CA 19-9 may be elevated; Chromogranin A may be elevated but less consistently than in well-differentiated PanNETs

Macro ─
─ Usually large, infiltrative masses with ill-defined borders
─ Frequently show areas of necrosis and hemorrhage
─ Can occur in any part of the pancreas

Micro ─

─ Two main histologic subtypes:
─ Small cell carcinoma: Composed of sheets, nests, or diffuse infiltrates of small, round to spindle-shaped cells with scant cytoplasm, finely granular ("salt-and-pepper") or hyperchromatic nuclei, nuclear molding, and inconspicuous nucleoli; mitotic activity is brisk (>20/10 HPF), and extensive necrosis (often comedo-type) and Azzopardi effect (DNA encrustation of blood vessels) are common
─ Large cell neuroendocrine carcinoma (LCNEC): Composed of larger polygonal cells with more abundant cytoplasm, vesicular nuclei, and often prominent nucleoli; growth patterns include nests, trabeculae, or diffuse sheets with organoid features; high mitotic rate (>20/10 HPF) and extensive necrosis are characteristic
─ Both subtypes are by definition Grade 3 (Ki-67 index >20%, often much higher, e.g., >55%)
─ Lymphovascular and perineural invasion are frequent
─ May coexist with a component of adenocarcinoma or a well-differentiated PanNET (classified as MiNEN if each component is ≥30%)

Ancillary studies ─

─ IHC (+, Neuroendocrine markers): Synaptophysin (usually diffuse and strong), Chromogranin A (can be focal, patchy, or negative, especially in small cell type), CD56 (often positive but less specific), INSM1 (nuclear, sensitive)
─ IHC (+, Cytokeratins): Often positive for CAM5.2, CK8/18; dot-like perinuclear staining can be seen
─ IHC (Ki-67): Essential for diagnosis, >20% (typically much higher)
─ IHC (p53): Aberrant expression (strong diffuse or null pattern) is common
─ IHC (RB1): Loss of expression is common, especially in small cell carcinoma
─ IHC (TTF-1): May be positive in a subset of small cell carcinomas, but does not indicate pulmonary primary in this context
─ Molecular ─ Genetic alterations often differ from well-differentiated PanNETs and more closely resemble those of small cell lung cancer or high-grade carcinomas of other sites
─ TP53 and RB1 mutations are common
─ KRAS mutations can occur, especially if associated with a ductal adenocarcinoma component

DDx ─

─ Well-differentiated PanNET, G3 (morphologically well-differentiated but with Ki-67 >20%; PanNECs are poorly differentiated by definition)
─ Pancreatic Ductal Adenocarcinoma (PDAC), poorly differentiated (may have solid growth; neuroendocrine markers are key; PDAC is usually MUC1+)
─ Acinar Cell Carcinoma (ACC) (ACC has acinar differentiation and expresses acinar markers; can have solid pattern but different cytology)
─ Solid Pseudopapillary Neoplasm (SPN) (SPN has pseudopapillary architecture, characteristic nuclear features, nuclear beta-catenin positivity)
─ Pancreatoblastoma (pediatric tumor with squamoid nests)
─ Metastatic NEC from other sites (e.g., lung, GI tract; clinical history and imaging are crucial; IHC for TTF-1 is not definitive for lung primary in NECs)
─ Lymphoma (especially small cell NEC vs lymphoma; lymphoid markers CD45, CD20, CD3 are key)

Prognosis ─
─ Highly aggressive with a very poor prognosis; median survival is often <1 year
─ Most patients have metastatic disease at diagnosis
─ Treatment typically involves platinum-based chemotherapy, similar to small cell lung cancer

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Mixed Neuroendocrine-Non-Neuroendocrine Neoplasm (MiNEN) of the Pancreas

A rare pancreatic neoplasm composed of at least two distinct malignant components: a neuroendocrine component (well-differentiated NET or poorly differentiated NEC) and a non-neuroendocrine component (typically ductal adenocarcinoma or acinar cell carcinoma), with each component representing at least 30% of the tumor volume

Clinical ─
─ Very rare; clinical presentation often depends on the predominant or more aggressive component
─ May present with symptoms similar to PDAC (pain, jaundice, weight loss) or, less commonly, a neuroendocrine syndrome if the NET component is functional and dominant
─ Usually affects older adults

Macro ─
─ Appearance is variable, often a solid, infiltrative mass
─ May show heterogeneity reflecting the different components

Micro ─

─ Two distinct morphologic components intimately admixed or in separate areas:
─ Neuroendocrine component: Can be a well-differentiated PanNET (G1, G2, or G3) or a poorly differentiated PanNEC (small cell or large cell type)
─ Non-neuroendocrine component: Most commonly pancreatic ductal adenocarcinoma (PDAC) or its variants; less commonly acinar cell carcinoma, or other carcinoma types
─ Each component must constitute at least 30% of the tumor by volume (if <30%, it's designated as the primary tumor type with the other as a minor component, e.g., "PDAC with neuroendocrine differentiation")
─ The components are usually histologically distinct and can be confirmed by IHC
─ Grading and staging are complex:
─ The neuroendocrine component is graded according to WHO criteria for PanNET/PanNEC
─ The non-neuroendocrine component is graded according to its specific type (e.g., PDAC grading)
─ Overall behavior is often driven by the more aggressive component (usually NEC or high-grade adenocarcinoma)

Ancillary studies ─

─ IHC is crucial to confirm the dual differentiation and delineate the extent of each component:
─ Neuroendocrine markers (Synaptophysin, Chromogranin A, INSM1) for the NE component
─ Markers for adenocarcinoma (e.g., CK7, CK19, MUC1, CEA) or acinar cell carcinoma (Trypsin, Chymotrypsin, BCL10) for the non-NE component
─ Ki-67 staining should be assessed in both components if possible, as proliferation rates can differ significantly
─ Molecular ─ Genetic profiles can be heterogeneous, sometimes reflecting the predominant component or a common clonal origin with divergent differentiation

DDx ─

─ PDAC with scattered neuroendocrine cells (neuroendocrine cells <30%; classified as PDAC)
─ PanNET with entrapped benign ducts/acini (benign non-neoplastic component)
─ Collision tumor (two separate primary tumors growing into each other; rare, may lack true intermingling)
─ PanNEC (if the non-NE component is <30%)
─ PDAC (if the NE component is <30%)
─ Acinar cell carcinoma with neuroendocrine differentiation (neuroendocrine cells <30%)

Prognosis ─
─ Generally poor, often dictated by the more aggressive component (e.g., NEC or high-grade adenocarcinoma)
─ Prognosis is worse than for pure well-differentiated PanNETs
─ Treatment strategies are challenging and may need to target both components; often based on the more aggressive histology

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Mesenchymal Tumors

General IHC Panel

An overview of common immunohistochemical markers used in the differential diagnosis of mesenchymal tumors throughout the gastrointestinal tract

Clinical ─
─ IHC is an essential ancillary tool for classifying mesenchymal tumors, which can have overlapping morphologies
─ Selection of an appropriate IHC panel is guided by the tumor's location, histologic pattern (spindle cell, epithelioid, round cell, pleomorphic), and the clinical context

─ Core Markers for Spindle Cell Lesions: ─ CD117 (c-KIT): Primarily for Gastrointestinal Stromal Tumor (GIST); strong and diffuse cytoplasmic/membranous staining is characteristic of most GISTs
─ DOG1 (Anoctamin-1): Highly sensitive and specific for GIST, including many CD117-negative GISTs
─ Smooth Muscle Actin (SMA): Marks smooth muscle differentiation (leiomyoma, leiomyosarcoma) and myofibroblastic differentiation (e.g., desmoid-type fibromatosis, inflammatory myofibroblastic tumor); GISTs can be focally SMA+
─ Desmin: More specific for smooth muscle differentiation than SMA; strongly positive in leiomyomas, variably in leiomyosarcomas; GISTs are usually desmin-negative
─ S100 protein: Marks neural differentiation (schwannoma, neurofibroma, granular cell tumor, ganglioneuroma) and melanocytic differentiation (melanoma); GISTs are usually S100-negative, but a subset of GI schwannomas can be S100-negative or only focally positive in the GI tract, and some GISTs can show focal S100 positivity
─ SOX10: More specific for neural crest origin (schwannoma, melanoma) than S100
─ CD34: Positive in GIST (especially esophageal and gastric), solitary fibrous tumor, Kaposi sarcoma, some vascular tumors, and inflammatory fibroid polyp; less specific than CD117/DOG1 for GIST
─ Cytokeratins (e.g., AE1/AE3, CAM5.2): To exclude spindle cell carcinoma, sarcomatoid carcinoma, and synovial sarcoma (which is often keratin-positive)
─ Markers for Epithelioid Mesenchymal Lesions: ─ CD117, DOG1 (for epithelioid GIST)
─ S100, SOX10, HMB-45, Melan-A (to exclude melanoma, or confirm PEComa if co-expressed with muscle markers)
─ Cytokeratins (to exclude carcinoma)
─ SMA, Desmin (for epithelioid smooth muscle tumors, PEComa)
─ Additional/Second-Line Markers (based on morphology and initial panel): ─ Beta-catenin (nuclear): For desmoid-type fibromatosis (most sporadic cases and FAP-associated) and solitary fibrous tumor (some)
─ ALK: For inflammatory myofibroblastic tumor (positive in ~50%, often with a characteristic cytoplasmic granular or perinuclear pattern)
─ STAT6 (nuclear): Highly sensitive and specific for solitary fibrous tumor (reflects NAB2-STAT6 fusion)
─ MDM2/CDK4: For well-differentiated/dedifferentiated liposarcoma (amplification leads to nuclear staining)
─ ERG, CD31: Vascular markers (for angiosarcoma, Kaposi sarcoma, hemangioma)
─ Caldesmon: Another marker for smooth muscle differentiation
─ GFAP: Can be positive in schwannomas
─ EMA: Positive in perineuriomas (often weak/focal), synovial sarcoma, and some carcinomas
─ TLE1: For synovial sarcoma (nuclear staining)
─ SDHB: Loss of expression by IHC is characteristic of SDH-deficient GISTs and some paragangliomas
─ Important Considerations: ─ No single marker is 100% specific; panels are crucial
─ Staining patterns (diffuse vs focal, intensity, cellular localization) are important
─ Beware of non-specific staining or staining of entrapped normal cells (e.g., KIT+ mast cells in a non-GIST tumor)
─ Correlation with morphology, clinical information, and sometimes molecular genetics is essential for accurate diagnosis

Gastrointestinal Stromal Tumor (GIST)

The most common mesenchymal neoplasm of the gastrointestinal tract, believed to originate from or differentiate towards interstitial cells of Cajal (ICCs) or their precursors, characterized by activating mutations in KIT or PDGFRA receptor tyrosine kinase genes in most cases

Clinical ─
─ Peak incidence in 5th to 7th decades; rare in children/adolescents (except SDH-deficient GISTs)
─ Equal sex distribution
─ Most common in stomach (~60%), then small intestine (~30%), colorectum (~5%), and rarely esophagus (<1%) or extra-GI sites (omentum, mesentery - EGISTs)
─ Symptoms: GI bleeding (melena, hematemesis, anemia), abdominal pain or mass, obstruction; many are incidental findings
─ Syndromic associations: Neurofibromatosis type 1 (NF1 - often multiple, small intestinal, KIT/PDGFRA wild-type), Carney triad (gastric GIST, pulmonary chondroma, paraganglioma - SDH-deficient), Carney-Stratakis syndrome (GIST and paraganglioma dyad - germline SDH mutations)

Macro ─
─ Typically well-circumscribed, submucosal or intramural masses arising from the muscularis propria
─ Size varies from <1 cm (micro-GISTs) to >30 cm
─ Cut surface is often tan-white, fleshy, whorled; may show hemorrhage, necrosis, or cystic change, especially in larger/malignant tumors
─ Mucosal ulceration overlying the tumor is common

Micro ─

─ Cellular morphology: ─ Spindle cell type (most common, ~70%): Fascicles of bland to moderately atypical spindle cells with eosinophilic or pale cytoplasm, ovoid to elongated nuclei; paranuclear vacuoles common in gastric GISTs; skeinoid fibers (eosinophilic, acellular collagenous structures) common in small intestinal GISTs
─ Epithelioid type (~20%): Sheets or nests of polygonal cells with eosinophilic or clear cytoplasm, round central nuclei; more common in stomach and omentum; often associated with PDGFRA mutations
─ Mixed spindle and epithelioid type (~10%)
─ Architectural patterns: Fascicular, storiform, palisading, nested, diffuse sheets
─ Stroma: Variable, can be myxoid, hyalinized, or highly vascular (hemangiopericytoma-like pattern)
─ Nuclear atypia is usually mild to moderate; significant pleomorphism is rare except in some epithelioid or dedifferentiated GISTs
─ Risk stratification (e.g., NIH consensus/Fletcher criteria, AFIP/Miettinen criteria, Joensuu criteria): Based on tumor size, mitotic count (per 5 mm² or per 50 HPFs - field size matters!), and anatomic site (gastric GISTs generally have better prognosis than small intestinal or colorectal GISTs of similar size/mitotic rate)
─ Mitotic activity: Crucial for risk assessment; count in most active areas; >5 mitoses/5 mm² (or per 50 HPFs, check microscope field diameter) is a key threshold for higher risk in many schemes
─ Tumor rupture (spontaneous or iatrogenic) is a high-risk feature
─ SDH-deficient GIST: Often gastric, pediatric/young adult females, epithelioid or mixed morphology, multinodular/plexiform growth, frequent lymph node metastasis (unusual for conventional GISTs), often indolent despite metastases; loss of SDHB by IHC

Ancillary studies ─

─ IHC (+): CD117 (c-KIT) (positive in ~95%, diffuse cytoplasmic/membranous/dot-like), DOG1 (Anoctamin-1) (positive in ~95-98%, often stronger/more diffuse than CD117, positive in most CD117-negative GISTs)
─ IHC (+/-): CD34 (~70%, more often in gastric/esophageal GISTs), SMA (~30-40%, often focal), S100 (~5%, often focal), Desmin (rare, ~1-2%), Keratin (rare, focal)
─ IHC (SDHB): Loss of staining in SDH-deficient GISTs (most pediatric GISTs, Carney triad, Carney-Stratakis, subset of adult gastric GISTs)
─ Molecular ─ Activating mutations in KIT (most common, ~70-80%, exon 11 most frequent, then exon 9, rarely exons 13, 17) or PDGFRA (~10-15%, exon 18 D842V most common in epithelioid GISTs, also exons 12, 14)
─ "Wild-type" GISTs (no KIT/PDGFRA mutations, ~10-15%): May have SDH pathway defects (mutations in SDHA, B, C, D or SDHC epimutation), BRAF mutations (rare), NF1 mutations, or other rarer alterations
─ Mutational analysis is important for predicting response to tyrosine kinase inhibitors (TKIs) (e.g., imatinib, sunitinib)

DDx ─

─ Spindle cell GIST: Leiomyoma (desmin+, SMA+, KIT-, DOG1-), Schwannoma (S100+, SOX10+, KIT-, DOG1-; often lymphoid cuff in GI), Desmoid-type fibromatosis (nuclear beta-catenin+, KIT variable/weak), Solitary fibrous tumor (STAT6 nuclear+, CD34+), Inflammatory myofibroblastic tumor (ALK+, SMA+), Spindle cell carcinoma, Sarcomatoid carcinoma, Melanoma (S100+, SOX10+)
─ Epithelioid GIST: Carcinoma (keratin+), Melanoma (S100+, SOX10+, melanocytic markers+), PEComa (HMB-45+, SMA+), Glomus tumor (SMA+, synaptophysin focal+), Epithelioid schwannoma (S100+)

Prognosis ─
─ Variable, from essentially benign to overtly malignant, based on risk stratification (size, mitotic rate, site, rupture)
─ Metastases typically to liver and peritoneum; lung and bone are rare
─ Response to TKIs (imatinib as first-line for metastatic/unresectable GIST) has dramatically improved outcomes; specific mutations predict TKI sensitivity/resistance (e.g., PDGFRA D842V mutation confers imatinib resistance)

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Inflammatory Myofibroblastic Tumor (IMT)

A mesenchymal neoplasm composed of myofibroblastic spindle cells with a prominent inflammatory infiltrate, most commonly occurring in the mesentery, omentum, or retroperitoneum, and rarely involving the GI tract wall directly

Clinical ─
─ Most common in children and young adults, but can occur at any age
─ No clear sex predilection
─ Symptoms are often nonspecific: abdominal pain, mass, fever, weight loss, anemia
─ May be associated with paraneoplastic syndromes (e.g., fever, leukocytosis, thrombocytosis, elevated ESR/CRP)
─ Rare cases occur post-surgery or trauma

Macro ─
─ Typically a well-circumscribed, firm, white-tan, fleshy or whorled mass
─ Size is variable, can be large (average 5-10 cm)
─ May show infiltrative borders into adjacent structures
─ Hemorrhage or necrosis may be present, especially in larger lesions

Micro ─

─ Composed of bland to mildly atypical spindle cells (myofibroblasts) arranged in sweeping fascicles or a storiform pattern, often with a loose, edematous, or myxoid stroma
─ Characteristic prominent inflammatory infiltrate, predominantly plasma cells and lymphocytes, often with eosinophils and neutrophils
─ Lymphoid follicles may be present
─ Blood vessels are often prominent and can have thickened walls or a delicate, arborizing pattern
─ Cellularity is variable; some areas may be hypocellular and fibrotic, while others are more cellular and myxoid
─ Nuclear atypia is usually mild; mitotic figures are generally infrequent but can be present (usually <5/50 HPF)
─ Necrosis is uncommon but can occur
─ Key negative findings: Absence of significant pleomorphism, atypical mitoses, or features of other specific sarcomas

Ancillary studies ─

─ IHC (+): SMA (smooth muscle actin) (often diffuse), Desmin (variable, ~50-70%), ALK (anaplastic lymphoma kinase) (positive in ~50-60% of cases, often with a characteristic cytoplasmic granular or perinuclear dot-like pattern); Vimentin (+)
─ IHC (-): CD117 (KIT), DOG1, S100 protein, STAT6, nuclear beta-catenin (usually)
─ Molecular ─ Rearrangements of the ALK gene (on chromosome 2p23) are found in approximately 50-60% of IMTs, leading to ALK protein overexpression
─ Common fusion partners include TPM3, TPM4, CLTC, RANBP2
─ Rare cases may have ROS1 or RET rearrangements in ALK-negative tumors

DDx ─

─ Gastrointestinal Stromal Tumor (GIST) (GISTs are CD117/DOG1 positive, ALK negative, and typically lack a prominent inflammatory infiltrate)
─ Desmoid-type fibromatosis (Desmoids show nuclear beta-catenin positivity, lack ALK expression, and have a more uniform fibroblastic appearance with less inflammation)
─ Leiomyosarcoma (More cytologic atypia, higher mitotic activity, usually more diffuse desmin positivity, ALK negative)
─ Solitary Fibrous Tumor (SFT) (STAT6 nuclear positive, CD34 positive, lacks ALK expression and prominent inflammation)
─ Sclerosing mesenteritis (More fibrotic, less cellular, often with fat necrosis and foamy macrophages; lacks ALK expression)
─ IgG4-related disease (Can have storiform fibrosis and lymphoplasmacytic infiltrate, but typically shows increased IgG4+ plasma cells and obliterative phlebitis; ALK negative)
─ Lymphoma (especially if plasma cell rich; lymphoid markers are key)

Prognosis ─
─ Intermediate malignant potential; most are cured by complete surgical excision
─ Recurrence rates are ~10-25%, especially if incompletely resected or with adverse features (large size, atypia, necrosis)
─ Metastases are rare (<5%), typically to lungs, liver, or brain; more common in ALK-negative tumors or those with epithelioid/round cell morphology or TP53 mutations
─ ALK positivity may be associated with a more favorable prognosis in some studies, but this is not universally accepted

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Desmoid Fibromatosis (Intra-abdominal)

A clonal, locally aggressive (but non-metastasizing) mesenchymal neoplasm composed of bland-appearing fibroblasts and myofibroblasts, characterized by infiltrative growth and abundant collagenous stroma

Clinical ─
─ Can occur at any age, but most common in young to middle-aged adults (peak 25-40 years)
─ Slight female predominance for extra-abdominal and abdominal wall desmoids; intra-abdominal desmoids have a more equal sex distribution or slight male predominance
─ Intra-abdominal desmoids most commonly involve the small bowel mesentery, pelvis, or retroperitoneum
─ Risk factors: Prior surgery or trauma (scar-associated desmoids), high estrogen states (e.g., pregnancy), Gardner syndrome (a subtype of Familial Adenomatous Polyposis - FAP)
─ Patients with FAP have a significantly increased risk (up to 10-20%) of developing desmoids, which are often multiple and intra-abdominal
─ Symptoms: Abdominal pain, palpable mass, bowel obstruction, or complications related to infiltration of adjacent structures (e.g., ureteral obstruction, vascular compromise)

Macro ─
─ Typically a firm, poorly circumscribed, infiltrative mass with a white-gray, trabeculated, or whorled cut surface resembling scar tissue
─ Size is variable, can be very large
─ Often infiltrates surrounding soft tissues, bowel wall, or retroperitoneal structures

Micro ─

─ Composed of relatively uniform, bland spindle cells (fibroblasts and myofibroblasts) arranged in long, sweeping fascicles or a vaguely storiform pattern
─ Cells have elongated, tapering nuclei with fine chromatin and inconspicuous nucleoli; minimal to no cytologic atypia
─ Cytoplasm is scant and pale eosinophilic
─ Abundant collagenous stroma, ranging from edematous/myxoid to densely hyalinized (keloid-like)
─ Characteristic vasculature: Numerous, elongated, thin-walled, slightly ectatic blood vessels, often arranged parallel to the spindle cell fascicles
─ Infiltrative growth pattern is typical, with tumor cells extending between normal tissue structures (e.g., fat, muscle)
─ Mitotic activity is usually low (typically <1-2/10 HPF); atypical mitoses are absent
─ Degenerative changes like myxoid change, hyalinization, calcification, or ossification can be seen
─ Inflammation is usually sparse

Ancillary studies ─

─ IHC (+): Beta-catenin (nuclear staining in ~80-90% of sporadic cases and FAP-associated cases), SMA (smooth muscle actin) (variable, often patchy), Muscle-specific actin (MSA) (variable)
─ IHC (-/+): Desmin (usually negative, but can be focally positive), Caldesmon (usually negative)
─ IHC (-): CD117 (KIT), DOG1, S100 protein, ALK, STAT6, CD34 (usually, though entrapped vessels are CD34+)
─ Molecular ─ Most sporadic desmoids (~85%) have somatic mutations in the CTNNB1 gene (encoding beta-catenin), leading to nuclear beta-catenin accumulation
─ FAP-associated desmoids have germline APC mutations, which also result in beta-catenin pathway activation and nuclear accumulation
─ A small subset of sporadic desmoids are APC-mutated rather than CTNNB1-mutated

DDx ─

─ Gastrointestinal Stromal Tumor (GIST) (GISTs are CD117/DOG1 positive, usually beta-catenin negative, and have different morphology)
─ Leiomyosarcoma (More cytologic atypia, higher mitotic activity, desmin positive, beta-catenin negative)
─ Solitary Fibrous Tumor (SFT) (STAT6 nuclear positive, CD34 positive, often hemangiopericytoma-like vessels, beta-catenin negative)
─ Inflammatory Myofibroblastic Tumor (IMT) (Prominent inflammatory infiltrate, ALK positive in ~50%, beta-catenin negative)
─ Scar tissue/Reactive fibrosis (Less cellular, more haphazard arrangement of fibroblasts, lacks nuclear beta-catenin staining, lacks infiltrative growth into multiple tissue planes)
─ Low-grade fibromyxoid sarcoma (Rare in mesentery; shows alternating fibrous and myxoid areas, curvilinear vessels, MUC4 positivity, often FUS gene rearrangements)
─ Sclerosing mesenteritis (More prominent inflammation, fat necrosis, foamy macrophages; lacks nuclear beta-catenin)

Prognosis ─
─ Locally aggressive with a high rate of local recurrence (20-70%), especially after incomplete excision
─ Does not metastasize
─ Morbidity and mortality can result from local infiltration and compression of vital structures
─ Management is complex: observation for asymptomatic/stable lesions, surgery (with goal of wide negative margins, though often difficult), radiation therapy, systemic therapies (e.g., NSAIDs, anti-estrogens, TKIs, chemotherapy) for unresectable or recurrent disease

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Sclerosing Mesenteritis / Mesenteric Panniculitis

A rare, idiopathic, chronic inflammatory and fibrosing condition affecting the adipose tissue of the bowel mesentery

Clinical ─
─ Typically affects middle-aged to elderly individuals (peak 6th-7th decade); slight male predominance
─ Etiology is unknown; proposed triggers include prior abdominal surgery/trauma, infection, ischemia, autoimmune processes, or paraneoplastic phenomenon, but often no clear cause is identified
─ Symptoms are variable and often nonspecific: chronic abdominal pain (most common), palpable abdominal mass, nausea, vomiting, diarrhea, constipation, weight loss, fever
─ May be an incidental finding on imaging
─ Associated with other fibroinflammatory conditions (e.g., retroperitoneal fibrosis, Riedel's thyroiditis, orbital pseudotumor) or IgG4-related disease in a subset of cases

Macro ─
─ Ill-defined, firm, indurated, or rubbery mass or diffuse thickening within the mesentery, most commonly the small bowel mesentery near its root
─ Cut surface may be yellow-tan, white, or gray, often with entrapped, opaque, necrotic-appearing fat lobules
─ May encase mesenteric blood vessels or involve the bowel wall by contiguity

Micro ─

─ Spectrum of histologic changes, often with overlapping features:
─ Mesenteric panniculitis (early/inflammatory phase): Predominantly chronic inflammation (lymphocytes, plasma cells, foamy macrophages/lipophages) within mesenteric fat, often with prominent fat necrosis; fibrosis is usually mild
─ Mesenteric lipodystrophy: Predominantly fat necrosis with replacement by foamy macrophages, with minimal inflammation or fibrosis (less common as a pure form)
─ Retractile mesenteritis/Sclerosing mesenteritis (late/fibrotic phase): Dense, hyalinized collagenous fibrosis replacing mesenteric fat, often with a storiform or vaguely nodular pattern; chronic inflammatory infiltrate (lymphocytes, plasma cells) is usually present but may be less conspicuous than in the panniculitis phase; foamy macrophages and fat necrosis may still be seen
─ Lymphoid aggregates, sometimes with germinal centers, are common
─ Small vessels may show thickened walls or perivascular inflammation (lymphocytic phlebitis may be seen, especially if IgG4-related)
─ Calcification or ossification can occur in long-standing lesions
─ Entrapped nerves or ganglion cells may be seen
─ Key negative findings: Absence of significant cytologic atypia, high mitotic activity, or features of specific neoplasms (e.g., GIST, desmoid, lymphoma, liposarcoma)

Ancillary studies ─

─ IHC (IgG4/IgG): Increased IgG4+ plasma cells and an elevated IgG4/IgG ratio (>40%) may be seen in cases associated with IgG4-related disease, but are not specific for sclerosing mesenteritis overall
─ IHC (-): Generally negative for markers that would indicate a specific neoplasm (e.g., CD117, DOG1, ALK, nuclear beta-catenin, STAT6, MDM2)

DDx ─

─ Desmoid-type fibromatosis (More cellular, fascicular growth of bland spindle cells, nuclear beta-catenin positive, less inflammation and fat necrosis)
─ Inflammatory Myofibroblastic Tumor (IMT) (More cellular spindle cell proliferation, ALK positive in ~50%, less fat necrosis)
─ Well-differentiated liposarcoma/Atypical lipomatous tumor (ALT) (Especially sclerosing variant; shows atypical spindle cells and lipoblasts, MDM2/CDK4 amplified/positive)
─ Gastrointestinal Stromal Tumor (GIST) with extraluminal growth (CD117/DOG1 positive)
─ Lymphoma (especially if prominent lymphoid aggregates; lymphoid markers are diagnostic)
─ Carcinoid tumor with mesenteric involvement (Neuroendocrine markers positive; tumor cells have characteristic morphology)
─ Metastatic carcinoma with desmoplastic response (Cytokeratin positive)
─ Infection (e.g., mycobacterial, fungal; special stains and culture needed)
─ Fat necrosis from other causes (e.g., pancreatitis, trauma; clinical context important)

Prognosis ─
─ Generally a benign, self-limiting condition in many cases, but can have a chronic, relapsing course
─ Morbidity can occur due to bowel obstruction, vascular compromise, or other compressive symptoms if extensive
─ Malignant transformation does not occur
─ Treatment is often conservative (observation, NSAIDs, steroids, tamoxifen, colchicine) for mild or asymptomatic cases; surgery may be needed for complications but is often difficult due to infiltrative nature

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Solitary Fibrous Tumor (SFT)

A ubiquitous mesenchymal neoplasm, originally described in the pleura, but now recognized in virtually all anatomic sites, characterized by a patternless proliferation of bland spindle cells in a collagenous stroma with prominent hemangiopericytoma-like (staghorn) vessels; GI involvement is rare

Clinical ─
─ Most common in adults (4th-7th decades); no sex predilection
─ In the GI tract, most reported cases involve the stomach, small intestine, or colorectum; can also arise in the mesentery or retroperitoneum with secondary GI involvement
─ Often asymptomatic and found incidentally; may present with mass effect, pain, or GI bleeding if ulcerated
─ Hypoglycemia (Doege-Potter syndrome) due to IGF2 production is rare, usually with large tumors

Macro ─
─ Typically a well-circumscribed, firm, lobulated, gray-white mass
─ Size is variable, can be very large
─ Cut surface may be fibrous, whorled, or focally myxoid or hemorrhagic

Micro ─

─ "Patternless pattern" of spindle cell proliferation: Bland, ovoid to spindle-shaped cells with indistinct cytoplasm, arranged in short fascicles, storiform arrays, or haphazardly
─ Cellularity varies from paucicellular and densely collagenous ("fibrous" areas) to more cellular ("cellular" areas); myxoid change can be prominent
─ Characteristic vasculature: Numerous thin-walled, branching, "staghorn" or hemangiopericytoma-like vessels are a hallmark, though not always uniformly present
─ Stroma is typically collagenous, ranging from fine and wispy to dense and hyalinized (keloidal collagen)
─ Nuclear atypia is usually minimal; mitotic figures are generally sparse (typically <4/10 HPF in benign/low-risk SFTs)
─ Features associated with increased risk of aggressive behavior ("malignant SFT"): Increased cellularity, nuclear pleomorphism, >4 mitoses/10 HPF, tumor necrosis, infiltrative margins, large size (>10-15 cm)

Ancillary studies ─

─ IHC (+): STAT6 (nuclear staining, highly sensitive and specific, reflects NAB2-STAT6 fusion), CD34 (strong and diffuse in most cases, but can be lost in malignant SFTs), BCL2, CD99 (often)
─ IHC (-/+): SMA (focal), Desmin (negative), S100 protein (negative), Keratins (negative), CD117 (negative), DOG1 (negative)
─ Molecular ─ Most SFTs are characterized by a NAB2-STAT6 gene fusion resulting from an intrachromosomal inversion on 12q13

DDx ─

─ Gastrointestinal Stromal Tumor (GIST) (especially spindle cell type; GISTs are CD117/DOG1 positive, STAT6 negative)
─ Leiomyoma/Leiomyosarcoma (Smooth muscle markers SMA/desmin positive, STAT6 negative)
─ Schwannoma (S100/SOX10 positive, STAT6 negative)
─ Desmoid-type fibromatosis (Nuclear beta-catenin positive, STAT6 negative, lacks prominent staghorn vessels)
─ Hemangiopericytoma (now largely considered part of the SFT spectrum if STAT6 positive; if STAT6 negative, other vascular tumors considered)
─ Low-grade fibromyxoid sarcoma (MUC4 positive, often FUS rearranged, STAT6 negative, different morphology)
─ Spindle cell lipoma (if SFT has fatty areas; spindle cell lipomas are CD34+, S100+ in adipocytes, MDM2-)

Prognosis ─
─ Most SFTs are benign or have low risk of recurrence/metastasis after complete excision
─ Approximately 10-20% behave aggressively (recur locally or metastasize, typically to lungs, liver, bone)
─ Risk factors for aggressive behavior: "Malignant" histologic features (see Micro), large size, incomplete excision
─ GI SFTs seem to have a similar biologic potential to SFTs elsewhere, but experience is limited

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Lipoma (GI tract)

A benign mesenchymal tumor composed of mature adipose tissue, common in soft tissues but relatively uncommon in the GI tract

Clinical ─
─ Can occur at any age, but most common in middle-aged to older adults (5th-7th decades)
─ No clear sex predilection
─ Most common GI site is the colon (especially cecum and ascending colon, ~65-75%), followed by small intestine (~20-25%, often ileum), and rarely stomach or esophagus
─ Usually asymptomatic and found incidentally during endoscopy or imaging for other reasons
─ Larger lipomas (>2 cm) may cause symptoms: abdominal pain, bleeding (if ulcerated), obstruction (especially in small bowel, can act as lead point for intussusception), or change in bowel habits
─ Multiple GI lipomas can occur, sometimes in association with syndromes like Bannayan-Riley-Ruvalcaba syndrome or neurofibromatosis type 1

Macro ─
─ Typically a solitary, well-circumscribed, soft, yellow, submucosal mass that bulges into the lumen
─ May be sessile or pedunculated
─ Overlying mucosa is usually intact but can be stretched, atrophic, or ulcerated, especially in larger lesions
─ Size varies from a few millimeters to several centimeters (rarely >5 cm)
─ "Pillow sign" or "cushion sign": Indentation of the lesion with biopsy forceps during endoscopy is characteristic

Micro ─

─ Composed of lobules of mature adipocytes (fat cells) identical to normal adipose tissue
─ Adipocytes are univacuolated cells with abundant clear cytoplasm and small, eccentric, flattened nuclei; no significant atypia or lipoblasts
─ Thin fibrous septa containing small blood vessels separate the fat lobules
─ The tumor is typically located in the submucosa, but may extend into the muscularis propria or, rarely, be primarily mucosal or subserosal
─ Overlying mucosa may show pressure atrophy, inflammation, or ulceration
─ Key negative findings: Absence of lipoblasts, significant cytologic atypia, increased cellularity, or infiltrative growth (which would suggest liposarcoma)

Ancillary studies ─

─ IHC: S100 protein is positive in adipocytes (nuclear and cytoplasmic)
─ IHC (-): Generally not needed for diagnosis if morphology is typical; negative for markers of other mesenchymal tumors if differential diagnosis is broad
─ Molecular: MDM2 amplification is absent (helps distinguish from well-differentiated liposarcoma/atypical lipomatous tumor if atypia is a concern, though these are very rare in GI tract proper)

DDx ─

─ Lipohyperplasia of the ileocecal valve (non-neoplastic accumulation of fat in the submucosa of the ileocecal valve, often more diffuse and less well-circumscribed than a true lipoma)
─ Well-differentiated liposarcoma/Atypical lipomatous tumor (ALT) (extremely rare as primary GI tumors; show greater variation in adipocyte size, atypical stromal cells, and often lipoblasts; MDM2 amplified/positive)
─ Submucosal fat (normal finding, especially in colon; lipomas are discrete masses)
─ Pneumatosis cystoides intestinalis (gas-filled cysts in bowel wall, lined by histiocytes/giant cells, not adipocytes)
─ Inflammatory fibroid polyp with fatty metaplasia (shows characteristic spindle cells, eosinophils, and perivascular cuffing of IFP)

Prognosis ─
─ Benign, with no malignant potential
─ Endoscopic or surgical removal is curative and usually reserved for symptomatic or large lesions, or if diagnosis is uncertain

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Neurofibroma

A benign peripheral nerve sheath tumor composed of Schwann cells, perineurial-like cells, and fibroblasts, intermixed with axons, within a collagenous or myxoid stroma; GI involvement is often associated with Neurofibromatosis type 1 (NF1)

Clinical ─
─ May occur at any age; often presents in young to middle-aged adults if associated with NF1
─ No clear sex predilection
─ In the GI tract, can occur anywhere but most commonly in the small intestine and stomach
─ Often asymptomatic and found incidentally; may cause pain, bleeding (if ulcerated), or obstruction if large or plexiform
─ Solitary neurofibromas: Usually sporadic and not associated with NF1
─ Diffuse neurofibromas: Infiltrative growth, often involving skin and subcutaneous tissue; can occur in GI tract, especially in NF1
─ Plexiform neurofibromas: Pathognomonic for NF1; involve multiple nerve fascicles, creating a "bag of worms" appearance; can cause significant disfigurement and have a risk of malignant transformation
─ Patients with NF1 have germline mutations in the NF1 gene (a tumor suppressor on chromosome 17q11.2)

Macro ─
─ Solitary: Well-circumscribed but unencapsulated, soft, gray-white to tan, fleshy or rubbery nodule; may be submucosal or intramural
─ Diffuse: Poorly defined, infiltrative thickening of tissue
─ Plexiform: Enlarged, tortuous nerves forming a rope-like or nodular mass; often infiltrative

Micro ─

─ Composed of a relatively hypocellular proliferation of bland spindle cells with wavy, "buckled," or comma-shaped nuclei and scant, pale eosinophilic or amphophilic cytoplasm
─ Cells are typically arranged haphazardly or in loose fascicles within a variably collagenous or myxoid stroma
─ Mast cells are characteristically scattered throughout the lesion
─ Axons (often highlighted by neurofilament protein IHC) are interspersed among the spindle cells
─ Blood vessels are usually inconspicuous
─ Diffuse neurofibroma: Similar cytology but with an infiltrative growth pattern, often entrapping adnexal structures or fat
─ Plexiform neurofibroma: Expands multiple nerve fascicles, with the neoplastic cells replacing the normal endoneurium and perineurium; residual nerve fibers are often visible within the tumor nodules
─ Cytologic atypia is usually minimal; mitotic figures are rare
─ Key negative findings: Absence of Verocay bodies, Antoni A/B patterns (seen in schwannoma), or significant atypia/mitoses (seen in MPNST)

Ancillary studies ─

─ IHC (+): S100 protein (stains Schwann cells, often patchy and less intense than in schwannoma), CD34 (can be positive in a subset of spindle cells and endothelial cells), Neurofilament protein (highlights entrapped axons)
─ IHC (-/+): EMA (may highlight some perineurial-like cells, especially in plexiform neurofibromas)
─ IHC (-): CD117 (KIT), DOG1, SMA, Desmin
─ Molecular ─ NF1-associated neurofibromas have germline NF1 mutation plus somatic inactivation of the second NF1 allele
─ Sporadic neurofibromas often have somatic NF1 mutations

DDx ─

─ Schwannoma (More cellular, often encapsulated, shows Antoni A and B patterns, Verocay bodies, strong diffuse S100 positivity, lacks significant axons within tumor)
─ Gastrointestinal Stromal Tumor (GIST) (CD117/DOG1 positive, S100 negative, different morphology)
─ Leiomyoma (SMA/desmin positive, S100 negative)
─ Mucosal Schwann cell hamartoma (Rectosigmoid, S100 positive, lacks axons, not associated with NF1)
─ Perineurioma/Benign fibroblastic polyp (EMA/claudin-1 positive, S100 negative)
─ Malignant Peripheral Nerve Sheath Tumor (MPNST) (Shows greater cellularity, atypia, mitotic activity, necrosis; may arise from plexiform neurofibroma in NF1 patients)

Prognosis ─
─ Solitary and diffuse neurofibromas are benign with a very low risk of recurrence after complete excision and no metastatic potential
─ Plexiform neurofibromas are benign but can be locally infiltrative, difficult to completely resect, and carry a lifetime risk of malignant transformation to MPNST (estimated at 5-10% in NF1 patients)

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Well-differentiated liposarcoma / Atypical Lipomatous Tumor (ALT)

A locally aggressive malignant mesenchymal neoplasm composed of mature adipocytes with variation in cell size, admixed with atypical spindle cells and often lipoblasts; primarily occurs in deep soft tissues of extremities and retroperitoneum, very rarely involving the GI tract primarily

Clinical ─
─ Most common sarcoma in adults; peak incidence in 5th-7th decades
─ No clear sex predilection
─ Primary GI involvement is exceptionally rare; more commonly involves GI tract by secondary extension from a retroperitoneal primary
─ When primary in GI tract, may present as a submucosal mass, causing obstruction or bleeding
─ Retroperitoneal tumors often present as large, painless abdominal masses

Macro ─
─ Typically a large, lobulated, yellow, fatty mass, often with fibrous septa
─ May appear well-circumscribed but is often infiltrative at the microscopic level
─ Areas of sclerosis, myxoid change, or higher-grade dedifferentiation can be present

Micro ─

─ Composed predominantly of mature adipose tissue with significant variation in adipocyte size and shape
─ Characteristic feature: Atypical spindle cells within fibrous septa or scattered among adipocytes; these cells have enlarged, hyperchromatic, and often pleomorphic nuclei
─ Lipoblasts (cells with one or more sharply demarcated cytoplasmic lipid vacuoles indenting a hyperchromatic, atypical nucleus) are often present but not required for diagnosis if other features are typical, especially MDM2 amplification
─ Fibrous septa are common and may be thick and hyalinized or more cellular and atypical
─ Myxoid change, chronic inflammation, or metaplastic bone/cartilage can be seen
─ Sclerosing variant: Predominantly fibrous/sclerotic stroma with scattered atypical spindle cells and only focal adipocytic component
─ Inflammatory variant: Prominent lymphoplasmacytic infiltrate, can obscure underlying atypical cells
─ Key negative findings: Absence of high-grade sarcoma features (unless dedifferentiated - see below)
─ Dedifferentiated liposarcoma: Arises from ALT/WDL, characterized by a non-lipogenic sarcoma component (often resembling undifferentiated pleomorphic sarcoma or fibrosarcoma) adjacent to or admixed with ALT/WDL; carries a higher risk of metastasis

Ancillary studies ─

─ IHC (+): S100 protein (stains mature adipocytes and lipoblasts), MDM2 (nuclear staining in atypical spindle cells and lipoblasts, reflects gene amplification), CDK4 (nuclear staining, co-amplified with MDM2)
─ IHC (-): Usually negative for other lineage markers (keratins, desmin, SMA, CD117, DOG1)
─ Molecular ─ Hallmark is amplification of the 12q13-15 region, which includes MDM2 and CDK4 genes; detectable by FISH or CGH

DDx ─

─ Lipoma (Lacks atypical spindle cells, lipoblasts, and MDM2/CDK4 amplification/overexpression)
─ Spindle cell lipoma/Pleomorphic lipoma (Occur in subcutis of neck/shoulder, different morphology, CD34+, often RB1 loss, MDM2-)
─ Fat necrosis/Sclerosing mesenteritis (Shows inflammation, foamy macrophages, fat necrosis; lacks atypical cells and MDM2 amplification)
─ Myxoid liposarcoma (Different morphology with prominent myxoid stroma, delicate branching "chicken-wire" vasculature, and characteristic FUS-DDIT3 or EWSR1-DDIT3 fusion)
─ Other sarcomas with fatty differentiation or entrapment of fat (e.g., dedifferentiated GIST invading fat)

Prognosis ─
─ ALT/WDL is a locally aggressive tumor with a high rate of local recurrence if incompletely excised, but virtually no metastatic potential unless it undergoes dedifferentiation
─ Prognosis for primary GI tract ALT/WDL is not well established due to rarity, but likely similar to soft tissue counterparts
─ Dedifferentiated liposarcoma has significant metastatic potential (20-40%) and worse overall survival

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Inflammatory Fibroid Polyp (Vanek's Tumor)

A benign, distinctive mesenchymal polyp of the GI tract, typically submucosal, composed of bland spindle and stellate cells in a fibromyxoid, vascular, and eosinophil-rich stroma

Clinical ─
─ Occurs over a wide age range, peak in 50s-70s
─ Slight female predominance in some series
─ Most common in the stomach (antrum, ~70-80%) and small intestine (ileum, ~15-20%); rarely in colon, esophagus, or duodenum
─ Often asymptomatic and found incidentally; may cause abdominal pain, GI bleeding (if ulcerated), or obstruction/intussusception (especially in small bowel)
─ Usually solitary; rare familial cases ("Devon polyposis syndrome") with multiple polyps have been reported

Macro ─
─ Well-demarcated, firm, gray-white to tan polypoid or nodular submucosal mass, often with overlying mucosal ulceration
─ Size varies from a few millimeters to several centimeters (average 1-3 cm)
─ May be sessile or pedunculated

Micro ─

─ Located primarily in the submucosa, often extending into the overlying mucosa (causing ulceration) or underlying muscularis propria
─ Composed of relatively bland, plump spindle to stellate-shaped cells with ovoid nuclei, fine chromatin, and eosinophilic cytoplasm
─ Cells are arranged loosely or in short fascicles, often haphazardly, within a variably edematous, myxoid, or collagenous stroma
─ Characteristic features:
─ Prominent inflammatory infiltrate, rich in eosinophils; lymphocytes and plasma cells also present
─ Numerous small to medium-sized blood vessels, often with thickened, hyalinized walls or surrounded by concentric ("onion-skin") arrangements of spindle cells
─ Cytologic atypia is usually minimal; mitotic figures are rare to absent
─ Multinucleated stromal giant cells or bizarre reactive stromal cells can be seen, especially beneath ulcers, but do not indicate malignancy
─ Key negative findings: Absence of features of GIST (e.g., paranuclear vacuoles, skeinoid fibers), schwannoma (Verocay bodies), or significant atypia/mitoses

Ancillary studies ─

─ IHC (+): CD34 (strong and diffuse positivity in spindle cells is characteristic), Vimentin
─ IHC (-/+): SMA (smooth muscle actin) (can be focally positive), Calponin (focal)
─ IHC (-): CD117 (KIT), DOG1, S100 protein, Desmin, ALK, Keratins
─ Molecular ─ Activating mutations in the PDGFRA gene (platelet-derived growth factor receptor alpha), particularly in exons 12, 14, or 18 (but not D842V), are found in a majority of cases; these are distinct from the PDGFRA mutations typically seen in GISTs

DDx ─

─ Gastrointestinal Stromal Tumor (GIST) (GISTs are CD117/DOG1 positive, typically CD34 variable, and lack prominent eosinophils and the characteristic perivascular cuffing of IFP)
─ Inflammatory Myofibroblastic Tumor (IMT) (IMTs are often ALK positive, SMA positive, and lack diffuse CD34 positivity and the prominent eosinophilia of IFP; typically larger and more infiltrative)
─ Eosinophilic gastroenteritis (mucosal eosinophilic infiltrate, but lacks the characteristic spindle cell proliferation and vascular changes of IFP)
─ Schwannoma (S100 positive, CD34 usually negative in GI schwannomas, lacks eosinophils)
─ Leiomyoma (SMA/desmin positive, CD34 negative)
─ Granulation tissue polyp (More exuberant endothelial proliferation, less organized spindle cells, often more acute inflammation)

Prognosis ─
─ Benign; complete local excision (endoscopic or surgical) is curative
─ Recurrence is extremely rare, even after incomplete excision
─ No malignant potential

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Calcifying Fibrous Tumor

A rare, benign mesenchymal tumor characterized by a paucicellular proliferation of bland spindle cells in a densely hyalinized collagenous stroma with prominent lymphoplasmacytic infiltrates and psammomatous and/or dystrophic calcifications

Clinical ─
─ Can occur at any age, from infancy to late adulthood; most common in children and young adults for soft tissue lesions, older adults for visceral lesions
─ No clear sex predilection
─ Most commonly arises in the soft tissues of extremities, trunk, neck, or scrotum
─ Visceral involvement is less common but reported in pleura, peritoneum, mediastinum, and rarely in the GI tract (stomach, small intestine, colon, mesentery)
─ Often asymptomatic and found incidentally; may present as a slow-growing, painless mass
─ Rare cases are multiple or associated with IgG4-related disease or inflammatory myofibroblastic tumor

Macro ─
─ Typically a well-circumscribed, unencapsulated, firm, white-gray, gritty mass
─ Size varies, usually a few centimeters (range <1 cm to >15 cm)

Micro ─

─ Hypocellular to moderately cellular proliferation of bland spindle to ovoid cells with indistinct pale eosinophilic cytoplasm
─ Cells are arranged haphazardly or in short fascicles within a dense, hyalinized collagenous stroma
─ Characteristic features:
─ Prominent inflammatory infiltrate composed of lymphocytes and plasma cells, often forming lymphoid aggregates or follicles
─ Abundant calcifications, which can be psammomatous (laminated, concentric) and/or dystrophic (irregular, coarse)
─ Nuclear atypia is minimal; mitotic figures are rare to absent
─ Blood vessels are usually inconspicuous, small caliber
─ Key negative findings: Absence of ALK expression, nuclear beta-catenin, STAT6, or features of malignancy

Ancillary studies ─

─ IHC (+): Vimentin, Factor XIIIa (often positive in lesional spindle cells), CD68 (in scattered histiocytes)
─ IHC (-/+): SMA (smooth muscle actin) (can be focally positive), CD34 (often positive in a patchy distribution, but can be negative)
─ IHC (-): ALK, Desmin, S100 protein, Keratins, CD117 (KIT), DOG1, nuclear beta-catenin, STAT6, MDM2, CDK4
─ Histochemistry: Congo red stain for amyloid is negative

DDx ─

─ Inflammatory Myofibroblastic Tumor (IMT) (IMTs are more cellular, often myxoid, ALK positive in ~50%, and typically lack extensive calcifications)
─ Desmoid-type fibromatosis (More cellular, fascicular growth, nuclear beta-catenin positive, lacks prominent inflammation and calcifications)
─ Solitary Fibrous Tumor (SFT) (STAT6 nuclear positive, often CD34 diffuse, characteristic staghorn vessels, lacks prominent inflammation and psammomatous calcifications)
─ Fibrous histiocytoma/Dermatofibroma (if superficial GI involvement; more storiform, Factor XIIIa+, CD34 often negative in center)
─ Calcified scar tissue (History of trauma/surgery, less organized spindle cells, more haphazard fibrosis)
─ IgG4-related sclerosing lesion (Increased IgG4+ plasma cells, storiform fibrosis, obliterative phlebitis; calcification less typical)
─ Ossifying fibromyxoid tumor (Rare in GI; more lobulated, often with peripheral shell of bone, S100 positive in ~70%)

Prognosis ─
─ Benign; complete surgical excision is usually curative
─ Local recurrence is uncommon (~10-20%), even after incomplete excision
─ No metastatic potential

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Plexiform Fibromyxoma (Gastric)

A rare, benign mesenchymal tumor virtually unique to the gastric antrum/pylorus, characterized by a plexiform or multinodular growth of bland spindle cells in a myxoid stroma with a rich capillary network; also known as Plexiform Angiomyxoid Myofibroblastic Tumor (PAMT)

Clinical ─
─ Affects adults (median age ~50s); slight female predominance in some series
─ Almost exclusively occurs in the gastric antrum or pyloric region; rare cases reported in duodenum or esophagus
─ Often presents with symptoms of gastric outlet obstruction, abdominal pain, or upper GI bleeding; may be an incidental finding

Macro ─
─ Typically a relatively well-circumscribed but unencapsulated, intramural mass, often centered in the muscularis propria
─ Size ranges from 1 to 15 cm (average ~4-5 cm)
─ Cut surface is usually gelatinous, myxoid, gray-white, and may have a multinodular or plexiform appearance

Micro ─

─ Characterized by a distinctive plexiform or multinodular architecture, with lobules of neoplastic cells separated by bands of muscularis propria or fibrous septa
─ Lobules are composed of a paucicellular to moderately cellular proliferation of bland spindle to stellate-shaped cells with ovoid nuclei, fine chromatin, and scant, pale eosinophilic or amphophilic cytoplasm
─ Cells are set in an abundant myxoid or fibromyxoid stroma
─ Prominent, delicate, arborizing capillary network throughout the lobules is a characteristic feature
─ Cytologic atypia is minimal; mitotic figures are rare (usually <1-2/50 HPF)
─ Vascular invasion (tumor cells within small vessels) can be seen but does not appear to confer aggressive behavior
─ Key negative findings: Absence of significant atypia, necrosis, or features of GIST or schwannoma

Ancillary studies ─

─ IHC (+): SMA (smooth muscle actin) (often diffuse), Vimentin
─ IHC (-/+): Desmin (can be focally positive), Calponin (focal)
─ IHC (-): CD117 (KIT), DOG1, S100 protein, CD34, ALK, Keratins, STAT6
─ Molecular ─ Recurrent MALAT1-GLI1 gene fusions or GLI1 gene amplification have been reported in a subset of cases

DDx ─

─ Gastrointestinal Stromal Tumor (GIST), myxoid type (GISTs are CD117/DOG1 positive, usually lack plexiform architecture, and have different vascular pattern)
─ Schwannoma, myxoid or microcystic type (Schwannomas are S100 positive, lack plexiform growth in GI, and have peripheral lymphoid cuffs)
─ Inflammatory Myofibroblastic Tumor (IMT) (IMTs have more prominent inflammation, often ALK positive, lack true plexiform growth)
─ Aggressive angiomyxoma (Rare in stomach; more infiltrative, larger vessels, often PR/ER positive; primarily a tumor of pelvis/perineum in women)
─ Myxoid leiomyoma/leiomyosarcoma (Desmin usually more diffuse, lacks plexiform growth and arborizing capillaries)
─ Nerve sheath myxoma (Cellular Antoni A-like areas, S100 positive, lacks plexiform growth)

Prognosis ─
─ Benign; complete surgical excision is curative
─ Recurrence is very rare, even if margins are close or focally positive
─ No metastatic potential reported to date

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Leiomyoma (Esophageal, Colonic, etc)

A benign mesenchymal tumor composed of mature smooth muscle cells

Clinical ─
─ Most common mesenchymal tumor of the esophagus; also occurs in colon (often muscularis mucosae origin), rectum, and rarely stomach or small intestine
─ Esophageal: Peak incidence 5th decade, M > F; often symptomatic (dysphagia, pain) if large and arising from muscularis propria
─ Colonic/Rectal: Often incidental polyps found in older adults (mean age 60s, M > F), arising from muscularis mucosae
─ Usually solitary, but multiple "seedling" leiomyomas or diffuse leiomyomatosis can occur in the esophagus

Macro ─
─ Well-circumscribed, firm, gray-white, whorled, or rubbery mass or polyp
─ Size varies from millimeters to >20 cm (esophageal)
─ Esophageal: Typically intramural, arising from muscularis propria (inner circular layer common) or muscularis mucosae
─ Colonic/Rectal: Often small (<1 cm) polyps arising from muscularis mucosae

Micro ─

─ Intersecting fascicles of bland spindle cells with eosinophilic, fibrillar cytoplasm and elongated, "cigar-shaped" nuclei with blunt or tapering ends
─ Minimal to no cytologic atypia; mitotic figures are rare or absent (typically <1/50 HPF)
─ Necrosis should be absent
─ Hyalinization or calcification may be present, especially in larger or older lesions
─ Epithelioid leiomyomas are not typically described in the GI tract
─ Degenerative atypia (symplastic change) can rarely occur, similar to uterine leiomyomas, but should not be accompanied by increased mitoses or necrosis

Ancillary studies ─

─ IHC (+): SMA (smooth muscle actin) (diffuse and strong), Desmin (diffuse and strong), Caldesmon (diffuse and strong)
─ IHC (-): CD117 (KIT), DOG1, S100 protein, CD34 (though entrapped vessels may be CD34+)
─ Note: Rare intramural esophageal or gastric leiomyomas may show focal KIT or DOG1 positivity, but diffuse strong staining typical of GIST is absent; mast cells within the tumor will also be KIT+

DDx ─

─ Gastrointestinal Stromal Tumor (GIST) (GISTs are CD117/DOG1 positive; desmin is usually negative or only very focally positive in GISTs)
─ Schwannoma (S100/SOX10 positive; often has peripheral lymphoid cuffs in GI tract)
─ Leiomyosarcoma (Distinguished by significant cytologic atypia, mitotic activity [e.g., ≥5 mitoses/50 HPF or specific criteria for site], and/or tumor necrosis)
─ Inflammatory fibroid polyp (CD34 positive, prominent eosinophils, characteristic perivascular spindle cell arrangement)
─ Perineurioma/Benign fibroblastic polyp (EMA/Claudin-1 positive, SMA variable, desmin negative)

Prognosis ─
─ Benign with no metastatic potential
─ Recurrence is rare, even after incomplete excision of muscularis mucosae lesions; larger muscularis propria lesions may recur if incompletely enucleated

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Leiomyosarcoma (GI tract)

A malignant mesenchymal tumor showing smooth muscle differentiation, rare in the GI tract compared to GIST

Clinical ─
─ Can occur anywhere in the GI tract, but most reported in stomach, small intestine, and colorectum; esophageal primary is exceedingly rare
─ Typically affects older adults (6th-7th decades)
─ Symptoms depend on site and size: abdominal pain, mass, GI bleeding, obstruction
─ Not associated with specific genetic syndromes, unlike some GISTs

Macro ─
─ Often large, fleshy, infiltrative masses, frequently with hemorrhage and necrosis
─ May arise from muscularis propria or, less commonly, from large vessel walls
─ Can be intramural, exophytic, or predominantly extraluminal

Micro ─

─ Intersecting fascicles of atypical spindle cells with eosinophilic cytoplasm and elongated, often blunt-ended nuclei
─ Significant cytologic atypia: Nuclear pleomorphism, hyperchromasia, irregular nuclear contours, prominent nucleoli
─ Mitotic activity is usually readily apparent and often brisk (e.g., ≥5-10 mitoses/50 HPF, but criteria vary by site and some rely more on atypia/necrosis)
─ Tumor cell necrosis is a common and important feature supporting malignancy
─ Epithelioid variants are rare in the GI tract
─ Vascular invasion may be present

Ancillary studies ─

─ IHC (+): SMA (smooth muscle actin) (often diffuse), Desmin (positive in ~50-80%, can be patchy), Caldesmon (often positive)
─ IHC (-): CD117 (KIT), DOG1, S100 protein, CD34, Keratins (though rare focal keratin positivity can occur in some soft tissue leiomyosarcomas)

DDx ─

─ Gastrointestinal Stromal Tumor (GIST) (GISTs are CD117/DOG1 positive; leiomyosarcomas are typically more pleomorphic and desmin is more consistently positive)
─ Schwannoma/Malignant Peripheral Nerve Sheath Tumor (MPNST) (S100/SOX10 positive for schwannoma; MPNSTs are S100 variably positive, SOX10 often lost, and may show heterologous elements)
─ Spindle cell carcinoma/Sarcomatoid carcinoma (Keratin positive, often p63/p40 positive if squamous component)
─ Spindle cell melanoma (S100/SOX10/melanocytic markers positive)
─ Undifferentiated pleomorphic sarcoma (Diagnosis of exclusion; lacks specific line of differentiation by IHC)
─ Desmoid-type fibromatosis (Nuclear beta-catenin positive, bland cytology, low mitoses)
─ Inflammatory Myofibroblastic Tumor (IMT) (ALK positive in ~50%, prominent inflammation)

Prognosis ─
─ Aggressive malignancy with high rates of local recurrence and distant metastasis (commonly to liver, lungs, peritoneum)
─ Prognosis depends on tumor size, grade (mitotic activity, atypia, necrosis), depth of invasion, and completeness of surgical resection
─ Generally has a worse prognosis than GIST of comparable risk category
─ Does not respond to tyrosine kinase inhibitors like imatinib

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Hemangioma (Cavernous, Capillary)

A benign vascular neoplasm composed of blood-filled vascular channels; relatively uncommon in the GI tract

Clinical ─
─ Can occur at any age, including congenital/pediatric cases; may be more common in young adults
─ No clear sex predilection
─ Can arise anywhere in the GI tract, most commonly in the small intestine, followed by colorectum and stomach; esophagus is rare
─ Often asymptomatic and found incidentally; may present with chronic GI bleeding (occult or overt), anemia, or rarely obstruction or intussusception if large and polypoid
─ Multiple GI hemangiomas can occur in syndromes like Blue Rubber Bleb Nevus Syndrome (BRBNS), Maffucci syndrome, or Klippel-Trenaunay syndrome

Macro ─
─ Sessile or polypoid, soft, compressible, red-blue to purple mucosal or submucosal nodules or masses
─ Size varies from millimeters to several centimeters
─ May be solitary or multiple
─ Larger lesions can be associated with mucosal ulceration

Micro ─

─ Cavernous hemangioma (most common type in GI tract): Composed of large, dilated, irregular vascular channels lined by a single layer of bland, flattened endothelial cells; channels are filled with red blood cells and may show thrombosis or phleboliths; stroma is typically scant and fibrous
─ Capillary hemangioma (less common): Composed of closely packed, small, capillary-sized vessels lined by bland endothelial cells, often arranged in lobules; stroma is usually more prominent than in cavernous type
─ Arteriovenous malformation (AVM)/Angiodysplasia: While not true neoplasms, these are localized ectatic mucosal/submucosal vessels that can mimic hemangioma clinically and sometimes histologically; AVMs show abnormal thick-walled arteries and veins, while angiodysplasia features dilated, thin-walled venules and capillaries in the mucosa/submucosa
─ Cytologic atypia and mitotic activity are absent in benign hemangiomas

Ancillary studies ─

─ IHC (+, Endothelial markers): CD31 (strong and diffuse), CD34 (often positive), ERG (nuclear, highly sensitive and specific), Factor VIII-related antigen (von Willebrand factor)
─ IHC (-): Keratins, S100 protein, muscle markers (except for pericytes/smooth muscle in vessel walls)

DDx ─

─ Angiosarcoma (Malignant vascular tumor showing infiltrative growth, anastomosing channels, significant cytologic atypia, mitotic activity, and often necrosis)
─ Kaposi sarcoma (Spindle cell proliferation forming slit-like vascular spaces, extravasated red blood cells, hyaline globules; HHV-8 positive)
─ Lymphangioma (Composed of dilated lymphatic channels lined by D2-40/podoplanin positive endothelial cells, containing proteinaceous lymph fluid, not blood; often with lymphoid aggregates in walls)
─ Telangiectasias (e.g., hereditary hemorrhagic telangiectasia/Osler-Weber-Rendu; dilated capillaries/venules, often subepithelial)
─ Vascular malformations (see Micro above)

Prognosis ─
─ Benign, with no malignant potential
─ May cause significant bleeding if large or ulcerated
─ Treatment (if symptomatic): Endoscopic ablation (e.g., argon plasma coagulation, sclerotherapy), ligation, or surgical resection for larger/problematic lesions

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Lymphangioma / Lymphangiectasia

Benign conditions involving dilated lymphatic channels; lymphangiomas are considered true neoplasms/malformations, while lymphangiectasia is dilatation of pre-existing lymphatics, often secondary to obstruction

Clinical ─
─ Lymphangioma: Usually congenital or presents in childhood/young adulthood; can occur anywhere in GI tract, small intestine and mesentery are common sites; often asymptomatic, may present as a mass, or with protein-losing enteropathy if extensive (lymphangiomatosis)
─ Lymphangiectasia (Primary): Rare disorder (Waldmann's disease), often presents in childhood with protein-losing enteropathy, edema, steatorrhea, lymphocytopenia
─ Lymphangiectasia (Secondary): More common; due to lymphatic obstruction from various causes (e.g., surgery, radiation, inflammation like Crohn's, tumors, cardiac disease like constrictive pericarditis, retroperitoneal fibrosis)
─ Symptoms (for both if extensive or symptomatic): Diarrhea, malabsorption, abdominal pain, ascites

Macro ─
─ Lymphangioma: Often a soft, cystic, polypoid, or diffuse submucosal/mesenteric mass; may appear as whitish/yellowish mucosal vesicles ("lymphangiectatic cysts") on endoscopy; cut surface shows spongy appearance with dilated, lymph-filled spaces
─ Lymphangiectasia: Endoscopically may show prominent, dilated, white-yellow mucosal villi or folds; mucosa may appear edematous

Micro ─

─ Lymphangioma: Composed of variably sized, dilated lymphatic channels lined by a single layer of bland, flattened endothelial cells
─ Channels contain eosinophilic, proteinaceous lymph fluid, often with scattered lymphocytes; red blood cells are typically absent or sparse
─ Lymphoid aggregates are frequently present in the walls of the lymphatic channels or in the intervening stroma
─ Smooth muscle may be present in the walls of larger channels (cystic hygroma type)
─ May be superficial (mucosal/submucosal) or deep (involving muscularis propria, serosa, mesentery)
─ Lymphangiectasia: Dilatation of mucosal and/or submucosal lymphatic channels (lacteals in villi)
─ Villi may be broadened and edematous due to dilated lacteals
─ Underlying cause of obstruction may or may not be apparent in biopsy
─ No significant cytologic atypia or mitotic activity in endothelial cells for either condition

Ancillary studies ─

─ IHC (+, Lymphatic endothelial markers): D2-40 (Podoplanin) (strong and specific), LYVE-1
─ IHC (+, General endothelial markers): CD31, CD34, ERG (will also stain blood vessel endothelium)
─ IHC (-): Markers for other lineages

DDx ─

─ Hemangioma (Vascular channels filled with blood, D2-40 negative endothelial cells)
─ Whipple disease (Can cause lymphatic dilatation due to obstruction by foamy macrophages; macrophages are PAS-D positive and contain Tropheryma whipplei)
─ Mesenteric cyst (Simple cyst lined by mesothelium or fibrous tissue, not endothelium)
─ Cystic mesothelioma (if peritoneal; lined by mesothelial cells, calretinin/WT1 positive)
─ Adenomatoid tumor (if serosal; glandular/tubular structures lined by flattened to cuboidal mesothelial cells)
─ Edema from other causes (may cause apparent widening of spaces, but true endothelial-lined channels are not as prominent or specifically dilated)

Prognosis ─
─ Lymphangioma: Benign; may recur if incompletely excised; extensive lymphangiomatosis can cause significant morbidity due to protein loss or chylous effusions
─ Lymphangiectasia: Prognosis depends on the underlying cause and ability to treat it; primary lymphangiectasia is a chronic condition managed with dietary modifications (low-fat diet with medium-chain triglycerides)

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Kaposi Sarcoma (GI involvement)

A low-grade vascular neoplasm associated with Human Herpesvirus-8 (HHV-8) infection, commonly involving the skin and mucous membranes, but can also affect visceral organs including the GI tract, particularly in immunocompromised individuals

Clinical ─
─ Four main clinical-epidemiologic forms:
─ Classic KS: Older men of Mediterranean or Eastern European descent; typically indolent skin lesions on lower extremities
─ Endemic African KS: Affects children and adults in equatorial Africa; can be aggressive with lymph node involvement
─ Iatrogenic (transplant-associated) KS: Occurs in organ transplant recipients due to immunosuppression; can be aggressive but may regress with reduction of immunosuppression
─ AIDS-associated (epidemic) KS: Most common form in Western countries; occurs in HIV-infected individuals, especially those with low CD4 counts; can be widespread and aggressive
─ GI involvement is common in AIDS-associated KS (up to 40-50%) and can occur in other forms; may be asymptomatic or cause bleeding, pain, obstruction, or diarrhea
─ Any part of the GI tract can be involved, most commonly stomach, duodenum, and colon

Macro ─
─ Endoscopically appears as reddish-purple to violaceous macules, papules, plaques, nodules, or polypoid lesions
─ Lesions may be solitary or multiple, and can be flat or raised
─ Mucosal ulceration and bleeding can occur

Micro ─

─ Characterized by a proliferation of spindle cells forming slit-like vascular spaces, often admixed with extravasated red blood cells and hemosiderin-laden macrophages
─ Patch stage (early): Subtle proliferation of small, irregular vascular channels in the mucosa/submucosa, often around pre-existing larger vessels ("promontory sign"); minimal spindle cell component; mild chronic inflammation
─ Plaque stage: More prominent spindle cell proliferation with more developed slit-like vascular spaces; extravasated red blood cells and hemosiderin are more evident; inflammatory infiltrate includes plasma cells
─ Nodular/Tumor stage (late): Dense proliferation of spindle cells arranged in fascicles or sheets, forming poorly defined vascular slits containing red blood cells; hyaline globules (eosinophilic, PAS-positive globules representing degenerated red blood cells) are often present within spindle cells or stroma; mitoses can be seen but are usually not numerous or atypical
─ The spindle cells are of endothelial origin
─ Chronic inflammatory infiltrate, mainly lymphocytes and plasma cells, is typically present

Ancillary studies ─

─ IHC (+): HHV-8 (LANA-1) (nuclear staining in spindle cells, highly specific and sensitive), CD31, CD34, ERG (endothelial markers)
─ IHC (-/+): D2-40 (Podoplanin) (can be positive, indicating lymphatic differentiation of spindle cells)
─ IHC (-): Cytokeratins, S100 protein, SMA, Desmin

DDx ─

─ Angiosarcoma (More overtly malignant cytology, higher mitotic activity, anastomosing vascular channels, usually HHV-8 negative)
─ Hemangioma (Well-formed vascular channels, lacks significant spindle cell component and HHV-8)
─ Bacillary angiomatosis (Caused by Bartonella species; shows lobular proliferation of capillaries with plump endothelial cells and numerous neutrophils; Warthin-Starry stain highlights bacteria; HHV-8 negative)
─ Spindle cell melanoma (S100/SOX10/melanocytic markers positive, HHV-8 negative)
─ Inflammatory fibroid polyp (Prominent eosinophils, CD34 positive spindle cells, characteristic perivascular arrangement, HHV-8 negative)
─ Granulation tissue (Prominent capillaries, inflammation, edema; lacks atypical spindle cells and HHV-8)

Prognosis ─
─ Variable, depends on the clinical form and extent of disease
─ Classic KS is often indolent
─ AIDS-associated KS can be aggressive if immunity is not restored; GI involvement often indicates widespread disease
─ Iatrogenic KS may regress with reduction of immunosuppression
─ Treatment: Highly active antiretroviral therapy (HAART) for AIDS-KS; local therapies (e.g., cryotherapy, intralesional chemotherapy, radiation) or systemic chemotherapy for more extensive or aggressive disease

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Angiosarcoma (GI tract)

A rare, highly malignant mesenchymal neoplasm composed of atypical endothelial cells forming irregular vascular channels; primary GI angiosarcoma is very uncommon

Clinical ─
─ Can occur at any age, but more common in older adults
─ Slight male predominance
─ Most GI angiosarcomas are metastatic, typically from skin, soft tissue, breast, or liver
─ Primary GI angiosarcoma can arise anywhere in the tract, but small intestine and colon are most reported
─ Risk factors for angiosarcoma in general include chronic lymphedema (Stewart-Treves syndrome), prior radiation, foreign bodies, and certain chemical exposures; specific risk factors for GI primary are unclear
─ Symptoms: GI bleeding (melena, hematemesis, anemia), abdominal pain, mass, perforation, or obstruction

Macro ─
─ Highly variable appearance: erythematous patches, plaques, nodules, ulcers, or large, hemorrhagic, friable masses
─ Often multifocal, reflecting its aggressive, infiltrative nature
─ May appear as ill-defined areas of mucosal discoloration or thickening

Micro ─

─ Ranges from well-differentiated (resembling hemangioma but with atypia) to poorly differentiated (solid sheets of anaplastic cells)
─ Characteristic feature: Infiltrative growth pattern with anastomosing, irregular vascular channels lined by atypical endothelial cells
─ Endothelial cells are often plump, pleomorphic, hyperchromatic, with prominent nucleoli, and may pile up or form papillary tufts into vascular lumens ("hobnailing")
─ Mitotic activity is usually present and can be brisk
─ Extravasated red blood cells, hemorrhage, and necrosis are common
─ Poorly differentiated areas may show solid sheets of epithelioid or spindle cells, making vascular differentiation less obvious
─ "Dissection" of collagen bundles by neoplastic cells can be a helpful clue in poorly differentiated cases

Ancillary studies ─

─ IHC (+, Endothelial markers): CD31 (often strong and diffuse), ERG (nuclear, highly sensitive and specific), CD34 (can be variable, especially in poorly differentiated areas), Factor VIII-related antigen (less sensitive)
─ IHC (-/+): Cytokeratins (can be positive in epithelioid angiosarcomas, leading to misdiagnosis as carcinoma if endothelial markers are not performed)
─ IHC (-): S100 protein, melanocytic markers, muscle markers, HHV-8

DDx ─

─ Hemangioma (Lacks cytologic atypia, infiltrative growth, and high mitotic activity)
─ Kaposi sarcoma (HHV-8 positive; typically less pleomorphic, prominent spindle cells forming slits)
─ Epithelioid hemangioendothelioma (EHE) (Often less overtly malignant cytology, characteristic myxohyaline stroma, specific molecular alterations like WWTR1-CAMTA1 fusion)
─ Poorly differentiated carcinoma with vasoformative features (True endothelial markers are negative in carcinoma)
─ Angioinvasive lymphoma (Lymphoid markers positive)
─ Melanoma (especially epithelioid or spindle cell variants; melanocytic markers positive)

Prognosis ─
─ Very aggressive malignancy with a poor prognosis
─ High rates of local recurrence and distant metastasis (commonly to liver, lungs, lymph nodes, peritoneum)
─ Median survival is often short, even with multimodality treatment (surgery, chemotherapy, radiation)

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Epithelioid Hemangioendothelioma (EHE) - GI involvement

A rare vascular neoplasm of intermediate malignancy, composed of epithelioid to histiocytoid endothelial cells set in a characteristic myxohyaline or sclerotic stroma; primary GI EHE is very uncommon, liver is a more common visceral site

Clinical ─
─ Can occur over a wide age range, but often affects young to middle-aged adults (mean age 30s-40s)
─ Slight female predominance
─ GI involvement is usually metastatic or by direct extension from a primary EHE in liver, lung, or soft tissue
─ Primary GI EHE is exceptionally rare, can occur in stomach, small intestine, colon
─ Symptoms are often nonspecific: abdominal pain, weight loss, GI bleeding, or incidental finding
─ May be multifocal or present with widespread metastases at diagnosis

Macro ─
─ Typically firm, gray-white, nodular, or infiltrative masses
─ May have a sclerotic or fibrotic appearance
─ Can be solitary or multiple nodules
─ Hemorrhage or necrosis is less common than in angiosarcoma

Micro ─

─ Tumor cells are epithelioid (polygonal with eosinophilic cytoplasm) or histiocytoid (resembling histiocytes), often with intracytoplasmic vacuoles or lumina, which may contain red blood cells (a clue to endothelial differentiation)
─ Cells are typically arranged in cords, nests, strands, or short fascicles, embedded in an abundant myxohyaline, chondroid-like, or densely sclerotic stroma
─ Nuclei are usually round to oval, often with vesicular chromatin and small nucleoli; cytologic atypia is generally mild to moderate, but can be more pronounced in some cases
─ Mitotic activity is usually low
─ Infiltrative growth pattern is common
─ Well-formed vascular channels may be inconspicuous
─ Key negative findings: Absence of overt anaplasia or high mitotic rates typical of angiosarcoma

Ancillary studies ─

─ IHC (+, Endothelial markers): CD31, ERG (nuclear), Factor VIII-related antigen; CD34 is often positive but can be variable
─ IHC (+, Cytokeratins): Often positive for cytokeratins (e.g., CAM5.2, AE1/AE3) in a significant subset of cases (up to 30-50%), which can lead to misdiagnosis as carcinoma if endothelial markers are not performed
─ IHC (-): S100 protein, melanocytic markers, muscle markers, HHV-8
─ Molecular ─ Characteristic gene fusions:
─ WWTR1-CAMTA1 fusion (t(1;3)(p36;q25)) is present in the majority of EHEs from various sites
─ YAP1-TFE3 fusion (t(X;11)(p11;q22)) is less common, associated with a different morphology (often more epithelioid, less stroma)

DDx ─

─ Metastatic carcinoma (especially adenocarcinoma or signet-ring cell carcinoma, due to epithelioid cells and potential keratin positivity; endothelial markers are crucial)
─ Angiosarcoma (More cytologic atypia, higher mitotic activity, better-formed anastomosing channels, usually lacks the characteristic stroma and specific fusions of EHE)
─ Epithelioid sarcoma (Keratin positive, CD34 positive in ~50%, INI1 loss is characteristic; lacks specific endothelial markers)
─ Melanoma (Melanocytic markers positive)
─ Histiocytic lesions (CD68/CD163 positive, lack endothelial markers and keratin)

Prognosis ─
─ Behavior is variable and difficult to predict; considered a tumor of intermediate malignancy
─ Many cases are indolent with prolonged survival even with metastases
─ However, a subset (up to 20-30%) can be aggressive, with widespread metastases and fatal outcome
─ Adverse prognostic factors may include large size, high mitotic rate, significant atypia, and presence of YAP1-TFE3 fusion in some studies
─ Primary GI EHE prognosis is not well defined due to rarity

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Glomus Tumor (Gastric)

A benign mesenchymal neoplasm composed of modified smooth muscle cells resembling those of the normal glomus body (a specialized arteriovenous anastomosis involved in thermoregulation); most common in skin and soft tissues of extremities, rare in the GI tract, with stomach being the most frequent GI site

Clinical ─
─ Gastric glomus tumors typically occur in middle-aged to older adults (mean age 50s-60s)
─ Slight female predominance for gastric lesions
─ Usually solitary; multiple glomus tumors (glomangiomas) are rare and usually cutaneous
─ Often asymptomatic and found incidentally; may present with upper GI bleeding (if ulcerated), abdominal pain, or dyspepsia

Macro ─
─ Well-circumscribed, firm, reddish-blue to purple, submucosal or intramural nodule, typically in the gastric antrum
─ Size ranges from <1 cm to several centimeters (average 1-3 cm)
─ Overlying mucosa may be intact or ulcerated

Micro ─

─ Composed of uniform, round to polygonal cells (glomus cells) with sharply demarcated cell borders, scant to moderate amounts of eosinophilic or clear cytoplasm, and round, centrally located nuclei with fine chromatin and inconspicuous nucleoli
─ Cells are arranged in sheets, nests, or cords, often surrounding prominent, branching, thin-walled or thick-walled blood vessels (capillaries or venules)
─ Minimal to no cytologic atypia; mitotic figures are rare or absent
─ Stroma is typically scant, but can be hyalinized or myxoid
─ Mast cells are often scattered throughout the tumor
─ Transition to normal smooth muscle cells may be seen at the periphery
─ Key negative findings: Absence of significant atypia, necrosis, or features of GIST or neuroendocrine tumor
─ Malignant glomus tumor (glomangiosarcoma) is exceedingly rare, defined by large size (>2 cm) and deep location, or moderate to marked atypia and high mitotic activity (≥5/50 HPF), or atypical mitoses

Ancillary studies ─

─ IHC (+): SMA (smooth muscle actin) (strong and diffuse), Vimentin, Calponin, MSA (muscle specific actin)
─ IHC (-/+): Synaptophysin (can show focal positivity in some cases, a potential pitfall for neuroendocrine tumor), CD34 (positive in vasculature, negative in glomus cells)
─ IHC (-): CD117 (KIT), DOG1, S100 protein, Desmin (usually negative or weak/focal, unlike leiomyoma), Keratins, Chromogranin A
─ Histochemistry: PAS stain may highlight basement membrane material around cells and vessels

DDx ─

─ Gastrointestinal Stromal Tumor (GIST), epithelioid type (GISTs are CD117/DOG1 positive, SMA usually negative or focal)
─ Neuroendocrine Tumor (NET) (NETs are Synaptophysin/Chromogranin A positive, SMA negative; glomus tumors can have focal synaptophysin)
─ Leiomyoma, epithelioid type (Rare in stomach; desmin usually positive, lacks prominent vascular pattern of glomus tumor)
─ PEComa (Perivascular Epithelioid Cell Tumor) (Shows coexpression of melanocytic (HMB-45, Melan-A) and muscle (SMA, desmin) markers)
─ Carcinoid tumorlet (if very small; neuroendocrine markers positive)
─ Paraganglioma (S100 positive sustentacular cells, neuroendocrine markers positive in chief cells)

Prognosis ─
─ Benign; complete surgical excision is curative
─ Malignant transformation or metastasis of typical gastric glomus tumors is exceptionally rare

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Schwannoma (Gastric, Colonic)

A benign peripheral nerve sheath tumor composed entirely of Schwann cells; relatively uncommon in the GI tract compared to GIST or leiomyoma

Clinical ─
─ Can occur at any age, but most common in middle-aged to older adults (peak 5th-7th decades)
─ No clear sex predilection for GI schwannomas
─ Most common GI site is the stomach (~70%), followed by colon/rectum (~20%), and rarely small intestine or esophagus
─ Usually asymptomatic and found incidentally during endoscopy or imaging
─ Larger tumors may cause GI bleeding (if ulcerated), pain, or obstruction
─ Most GI schwannomas are sporadic; association with Neurofibromatosis type 2 (NF2) is rare for typical GI schwannomas (NF2 patients get schwannomas of cranial/spinal nerves)

Macro ─
─ Typically a solitary, well-circumscribed, firm, gray-white to yellowish, submucosal or intramural nodule or mass
─ Size varies, can range from <1 cm to >10 cm
─ Cut surface may be solid, whorled, or show cystic change, hemorrhage, or hyalinization, especially in larger lesions
─ Overlying mucosa may be intact or ulcerated

Micro ─

─ Composed of bland spindle cells with wavy, tapering nuclei and indistinct, pale eosinophilic cytoplasm
─ Characteristic features of conventional schwannomas:
─ Antoni A areas: Cellular, compact areas with spindle cells arranged in fascicles, whorls, or showing nuclear palisading (Verocay bodies - two parallel rows of palisading nuclei separated by anuclear eosinophilic zones)
─ Antoni B areas: Hypocellular, loose, myxoid, or edematous areas with haphazardly arranged spindle cells and often microcystic change
─ Blood vessels are often prominent, thick-walled, and hyalinized
─ A peripheral lymphoid cuff or lymphoid aggregates within the tumor are very common and characteristic of GI schwannomas
─ Cytologic atypia is usually minimal ("ancient change" with degenerative atypia can occur in long-standing lesions but lacks mitoses)
─ Mitotic figures are rare or absent
─ Encapsulation may be present but is often incomplete in GI tract
─ GI schwannomas often lack prominent Verocay bodies and may be predominantly Antoni A or show a mixture; some may be more cellular or have unusual patterns (e.g., microcystic/reticular variant)
─ Key negative findings: Absence of significant atypia/mitoses, KIT/DOG1 positivity, or desmin/SMA positivity

Ancillary studies ─

─ IHC (+): S100 protein (strong and diffuse nuclear and cytoplasmic staining is characteristic), SOX10 (nuclear, also strong and diffuse), GFAP (glial fibrillary acidic protein) (often positive, especially in GI schwannomas)
─ IHC (-): CD117 (KIT), DOG1, SMA (smooth muscle actin), Desmin, CD34 (usually negative in tumor cells, but positive in entrapped vessels or focally in some schwannomas), Keratins
─ Molecular ─ Inactivation of the NF2 gene (on chromosome 22q) is common in sporadic schwannomas

DDx ─

─ Gastrointestinal Stromal Tumor (GIST), spindle cell type (GISTs are CD117/DOG1 positive, S100/SOX10 negative)
─ Leiomyoma (SMA/desmin positive, S100/SOX10 negative)
─ Neurofibroma (S100 positive but often weaker/patchier, contains admixed axons (neurofilament+), mast cells, lacks Antoni A/B, associated with NF1)
─ Perineurioma/Benign fibroblastic polyp (EMA/Claudin-1 positive, S100/SOX10 negative)
─ Malignant Peripheral Nerve Sheath Tumor (MPNST) (Shows greater cellularity, atypia, mitotic activity, necrosis; S100/SOX10 positivity can be lost or focal)
─ Spindle cell melanoma (S100/SOX10 positive, but also other melanocytic markers like HMB-45/Melan-A may be positive; more atypia)
─ Mucosal Schwann cell hamartoma (Rectosigmoid, S100 positive, lacks capsule and lymphoid cuff, distinct entity)

Prognosis ─
─ Benign with an excellent prognosis; complete surgical excision is curative
─ Recurrence is very rare, even after incomplete excision
─ Malignant transformation of a typical GI schwannoma is exceptionally rare

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Mucosal Schwann Cell Hamartoma

A benign, polypoid proliferation of Schwann cells within the colonic lamina propria, not associated with systemic neurofibromatosis syndromes

Clinical ─
─ Typically an incidental finding in asymptomatic adults during screening colonoscopy (mean age ~50-60 years)
─ Slight female predominance reported in some series
─ Most commonly found in the rectosigmoid colon
─ Usually solitary and small (<5 mm)

Macro ─
─ Appears as a small, sessile, or dome-shaped polyp, often resembling a hyperplastic polyp or small adenoma endoscopically

Micro ─

─ Well-circumscribed but unencapsulated proliferation of bland spindle cells expanding the lamina propria between colonic crypts
─ Spindle cells have wavy, tapering nuclei, indistinct pale eosinophilic cytoplasm, and are arranged in loose fascicles or haphazardly
─ Stroma is often collagenous or fibrillary
─ Entrapped, and sometimes mildly distorted, colonic crypts are characteristic
─ No significant cytologic atypia, mitotic activity, or necrosis
─ Lacks ganglion cells and true nerve bundles (distinguishing from neurofibroma and ganglioneuroma)
─ Does not involve the submucosa or muscularis propria extensively
─ No peripheral lymphoid cuff (unlike conventional GI schwannomas)
─ Key negative findings: Absence of Verocay bodies, Antoni A/B patterns, or features of other specific neural or mesenchymal tumors

Ancillary studies ─

─ IHC (+): S100 protein (strong and diffuse nuclear and cytoplasmic staining in spindle cells is characteristic), SOX10 (nuclear, often positive)
─ IHC (-): CD117 (KIT), DOG1, SMA, Desmin, CD34 (except in entrapped stromal vessels), EMA, Claudin-1, GFAP (usually negative, unlike some conventional schwannomas)
─ IHC (Neurofilament protein): Typically negative or highlights only rare, entrapped native nerve fibers, not integral to the proliferation (unlike neurofibroma)

DDx ─

─ Neurofibroma (Contains admixed axons, often more myxoid stroma, S100 staining can be patchier; may be associated with NF1)
─ Ganglioneuroma (Contains ganglion cells in addition to Schwann cells and axons)
─ Conventional Schwannoma (Rare in colon mucosa; usually larger, submucosal/mural, often has peripheral lymphoid cuff, may show Antoni A/B areas)
─ Perineurioma (Benign fibroblastic polyp) (EMA and Claudin-1 positive, S100 negative; concentric periglandular spindle cell arrangement)
─ Leiomyoma of muscularis mucosae (SMA/desmin positive, S100 negative)
─ Inflammatory fibroid polyp (CD34 positive, prominent eosinophils, characteristic perivascular spindle cells)

Prognosis ─
─ Benign; complete endoscopic removal is curative
─ No risk of recurrence or malignant transformation reported

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Perineurioma (Mucosal Perineurioma / Benign Fibroblastic Polyp)

A benign, polypoid mesenchymal lesion of the colon, composed of bland spindle cells with perineurial differentiation, typically located in the lamina propria

Clinical ─
─ Usually an incidental finding in asymptomatic adults during screening colonoscopy (mean age ~50-60 years)
─ Slight female predominance
─ Most commonly found in the distal colon (sigmoid and rectum)
─ Typically solitary and small (<5-10 mm)
─ May be associated with overlying serrated epithelial changes (hyperplastic polyp or sessile serrated lesion/polyp) in some cases

Macro ─
─ Appears as a small, sessile, or dome-shaped polyp, often indistinguishable from a hyperplastic polyp or small adenoma endoscopically

Micro ─

─ Well-circumscribed but unencapsulated proliferation of bland spindle cells expanding the lamina propria, often splaying and entrapping colonic crypts
─ Spindle cells have slender, wavy, or tapering nuclei, inconspicuous nucleoli, and scant, pale eosinophilic cytoplasm with indistinct cell borders
─ Cells are often arranged in a lamellar, whorled, or vaguely storiform pattern, characteristically with concentric ("onion-skin") layering around crypts and small blood vessels
─ Stroma is typically delicate and collagenous or slightly myxoid
─ Minimal to no cytologic atypia; mitotic figures are rare or absent
─ Overlying serrated epithelial changes may be present
─ Key negative findings: Absence of S100 positivity, KIT/DOG1 positivity, or significant atypia/mitoses

Ancillary studies ─

─ IHC (+): EMA (epithelial membrane antigen) (often patchy or weak membranous/cytoplasmic staining in spindle cells is characteristic), Claudin-1 (membranous staining), GLUT-1 (membranous staining)
─ IHC (-/+): CD34 (can be focally positive in some cases, but often negative in tumor cells; highlights entrapped vessels), SMA (variable, often negative)
─ IHC (-): S100 protein, SOX10, CD117 (KIT), DOG1, Desmin, Keratins
─ Molecular ─ BRAF V600E mutations have been reported in the perineurial component of lesions associated with overlying serrated polyps, suggesting a possible link or common pathogenesis in these mixed lesions

DDx ─

─ Mucosal Schwann cell hamartoma (S100/SOX10 positive, EMA/Claudin-1 negative)
─ Neurofibroma (S100 positive, contains axons, lacks concentric periglandular growth)
─ Leiomyoma of muscularis mucosae (SMA/desmin positive, more deeply located, forms more solid fascicles)
─ Inflammatory fibroid polyp (CD34 positive, prominent eosinophils, lacks consistent EMA/Claudin-1)
─ Solitary fibrous tumor (STAT6 nuclear positive, CD34 positive)
─ Kaposi sarcoma (if vascular; HHV-8 positive, endothelial markers positive)

Prognosis ─
─ Benign; complete endoscopic removal is curative
─ No risk of recurrence or malignant transformation reported

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Granular Cell Tumor (Esophageal, Colonic)

A benign mesenchymal neoplasm of presumed Schwann cell origin, characterized by cells with abundant eosinophilic granular cytoplasm, occurring in various sites including the GI tract

Clinical ─
─ Can occur at any age, but most common in adults (4th-6th decades)
─ More common in females and individuals of African descent
─ In the GI tract, the esophagus is the most common site, followed by colorectum (especially cecum/right colon and perianal region), and rarely stomach or small intestine
─ Often asymptomatic and found incidentally during endoscopy; may present as a small, firm, yellowish submucosal nodule
─ Larger lesions or those in critical locations (e.g., anal canal) may cause symptoms like dysphagia, pain, or bleeding
─ Usually solitary; multiple lesions can occur, sometimes in the context of a syndrome (e.g., LEOPARD syndrome, Noonan syndrome)

Macro ─
─ Typically a small (<2-3 cm), firm, well-circumscribed but unencapsulated, yellowish-white or tan nodule, often in the submucosa or lamina propria
─ Overlying mucosa may be intact or show pseudoepitheliomatous hyperplasia

Micro ─

─ Composed of nests, sheets, or cords of large polygonal to spindle-shaped cells with abundant, coarsely granular, eosinophilic cytoplasm
─ Nuclei are small, round to oval, centrally or eccentrically located, often with vesicular chromatin and inconspicuous nucleoli; significant atypia is rare in benign lesions
─ Cell borders are usually distinct
─ The granular cytoplasm is PAS-positive and diastase-resistant, reflecting accumulation of lysosomes
─ Infiltrative growth pattern into surrounding tissues (e.g., between muscle fibers) is common but does not necessarily imply malignancy in typical cases
─ Overlying squamous epithelium (especially in esophagus or anus) frequently shows pseudoepitheliomatous hyperplasia, which can be mistaken for squamous cell carcinoma if the underlying granular cell tumor is not appreciated
─ Mitotic figures are rare in benign tumors
─ Malignant granular cell tumor is very rare, characterized by features such as large size (>4 cm), necrosis, spindling, vesicular nuclei with large nucleoli, increased mitotic activity (≥2/10 HPF at 200x), and/or metastatic disease

Ancillary studies ─

─ IHC (+): S100 protein (strong and diffuse nuclear and cytoplasmic staining is characteristic), SOX10 (nuclear), CD68 (lysosomal marker, strong cytoplasmic), Inhibin-alpha (often positive), Calretinin (often positive), TFE3 (can be positive)
─ IHC (-/+): PAS-diastase (highlights cytoplasmic granules)
─ IHC (-): CD117 (KIT), DOG1, SMA, Desmin, Keratins (except in overlying pseudoepitheliomatous hyperplasia), Melanocytic markers (HMB-45, Melan-A)

DDx ─

─ Rhabdomyoma (Shows true skeletal muscle differentiation with cross-striations, desmin/myogenin positive)
─ Histiocytic lesions/Xanthoma (Histiocytes lack S100/SOX10, often have foamy cytoplasm if lipid-laden)
─ Alveolar soft part sarcoma (ASPS) (Rare in GI; shows nested/alveolar pattern, cells with prominent nucleoli, PAS-positive diastolic-resistant crystals, characteristic TFE3 rearrangement, S100 negative)
─ Melanoma (amelanotic) (Melanocytic markers positive, more atypia)
─ Carcinoma with oncocytic or granular cytoplasm (Keratin positive, S100 negative)
─ Leiomyoma with granular cell change (Rare; SMA/desmin positive)

Prognosis ─
─ Vast majority are benign and cured by complete local excision
─ Local recurrence can occur with incomplete excision
─ Malignant granular cell tumors are rare but highly aggressive with frequent metastases and poor outcome

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Ganglioneuroma (Solitary, Polypoid, Diffuse Ganglioneuromatosis)

A benign neural tumor composed of mature ganglion cells, Schwann cells, and nerve fibers; in the GI tract, it can present as solitary polyps, multiple polyps (ganglioneuromatous polyposis), or diffuse transmural involvement (diffuse ganglioneuromatosis)

Clinical ─
─ Solitary/Polypoid Ganglioneuroma: Most common form in GI tract; usually incidental finding in adults undergoing colonoscopy (mean age 40s-60s); typically small (<1-2 cm), sessile polyps, most often in colorectum (especially sigmoid/rectum)
─ Ganglioneuromatous Polyposis: Multiple GI ganglioneuromas; can be sporadic or associated with syndromes like Cowden syndrome (PTEN hamartoma tumor syndrome), Neurofibromatosis type 1 (NF1), Multiple Endocrine Neoplasia type 2B (MEN2B), or Juvenile Polyposis Syndrome
─ Diffuse Ganglioneuromatosis: Extensive, often transmural proliferation of neural elements within the bowel wall, leading to thickening and dysmotility; strongly associated with NF1 and MEN2B (where it can be an early manifestation); can also be idiopathic
─ Symptoms (if present, usually with larger or diffuse lesions): Abdominal pain, constipation, diarrhea, bleeding, obstruction

Macro ─
─ Solitary/Polypoid: Small, sessile, or pedunculated, firm, pale tan or yellowish mucosal polyps
─ Diffuse: Ill-defined thickening of the bowel wall, often with a rubbery consistency; nerve trunks may be visibly enlarged on serosal surface or cut section

Micro ─

─ Composed of a haphazard proliferation of three main neural elements:
─ Mature Ganglion Cells: Large cells with abundant eosinophilic or amphophilic cytoplasm, large vesicular nuclei, and prominent nucleoli; may be uni- or multinucleated; often clustered or scattered individually
─ Schwann Cells: Spindle cells with wavy, tapering nuclei and pale eosinophilic, fibrillary cytoplasm, forming loose fascicles or surrounding ganglion cells
─ Nerve Fibers (Axons): Eosinophilic, fibrillary material, often admixed with Schwann cells
─ Stroma is typically collagenous or myxoid
─ Polypoid Ganglioneuroma: Usually centered in the lamina propria and submucosa, expanding the mucosa and often entrapping and distorting colonic crypts
─ Diffuse Ganglioneuromatosis: Infiltrates all layers of the bowel wall, often with prominent involvement of the myenteric (Auerbach's) and submucosal (Meissner's) plexuses, which appear expanded and hypercellular; can cause muscular hypertrophy
─ No significant cytologic atypia or mitotic activity in any component
─ Inflammation is usually minimal

Ancillary studies ─

─ IHC (Ganglion cells): Positive for neuroendocrine markers (Synaptophysin, Chromogranin A - often cytoplasmic), Neuron-Specific Enolase (NSE), Neurofilament Protein (NFP)
─ IHC (Schwann cells and nerve fibers): S100 protein (strong and diffuse in Schwann cells), SOX10 (Schwann cells), GFAP (variable in Schwann cells)
─ IHC (-): CD117 (KIT), DOG1, SMA, Desmin, Keratins

DDx ─

─ Neurofibroma (Lacks mature ganglion cells, though Schwann cells and axons are present; more prominent mast cells; associated with NF1 if plexiform or multiple)
─ Schwannoma (Composed purely of Schwann cells; often shows Antoni A/B areas, Verocay bodies, peripheral lymphoid cuff in GI; lacks ganglion cells and significant axons within tumor)
─ Mucosal Schwann cell hamartoma (Lacks ganglion cells and prominent axons; S100 positive; rectosigmoid)
─ Gangliocytic Paraganglioma (Duodenal/periampullary; triphasic with epithelioid neuroendocrine cells in addition to ganglion cells and spindle cells; spindle cells are S100+, epithelioid cells are synaptophysin/chromogranin+)
─ Leiomyoma with entrapped ganglion cells (Rare; smooth muscle component is SMA/desmin positive)
─ Inflammatory polyp with reactive ganglion cells (Ganglion cells are reactive, not neoplastic; prominent inflammation)

Prognosis ─
─ Benign; solitary/polypoid ganglioneuromas are cured by local excision
─ Ganglioneuromatous polyposis and diffuse ganglioneuromatosis: Prognosis and management depend on the underlying syndrome (if any) and extent of GI involvement; diffuse disease can cause significant motility problems and may require extensive resection
─ No malignant transformation reported for ganglioneuromas themselves, but associated syndromes (NF1, MEN2B) carry risks for other malignancies

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Gangliocytic Paraganglioma (Duodenal/Periampullary)

A rare, distinctive triphasic tumor typically arising in the periampullary region of the duodenum, composed of epithelioid neuroendocrine cells, ganglion cells, and spindle (Schwann-like) cells

Clinical ─
─ Most common in middle-aged to older adults (mean age 50s-60s); slight male predominance
─ Almost exclusively occurs in the second portion of the duodenum, usually involving the ampulla of Vater or periampullary region
─ Symptoms: Upper GI bleeding (most common, due to mucosal ulceration), abdominal pain, anemia, or obstructive jaundice if ampulla is involved; many are incidental findings
─ Usually sporadic; rare cases associated with Neurofibromatosis type 1 (NF1) or other syndromes
─ Serum hormone levels are typically normal; carcinoid syndrome is exceptionally rare

Macro ─
─ Typically a well-circumscribed, firm, tan-yellow to gray, submucosal nodule or polypoid mass, often with overlying mucosal ulceration
─ Size ranges from <1 cm to >10 cm (average ~2-4 cm)

Micro ─

─ Characterized by a triphasic cellular composition, with variable proportions of each component:
─ Epithelioid neuroendocrine cells: Arranged in nests, ribbons, or trabeculae, resembling cells of a well-differentiated neuroendocrine tumor (carcinoid); cells have moderate amounts of eosinophilic granular cytoplasm, round to oval nuclei with "salt-and-pepper" chromatin
─ Ganglion cells: Large, mature ganglion cells, often with prominent nucleoli and abundant eosinophilic cytoplasm, scattered individually or in small clusters; may be difficult to find in some tumors or small biopsies
─ Spindle cells: Bland Schwann-like cells with wavy, tapering nuclei and fibrillary cytoplasm, often intimately associated with the epithelioid nests (sustentacular-like pattern) or forming fascicles in the stroma
─ Stroma is often fibrous and vascular
─ Tumor typically involves the submucosa and may extend into the muscularis propria or overlying mucosa (causing ulceration)
─ Cytologic atypia is usually minimal in all components; mitotic figures are rare
─ Lymph node involvement is rare (~5-10%) but does not necessarily indicate aggressive behavior if histologically bland (often considered "nodal rests" or benign transport)

Ancillary studies ─

─ IHC (Epithelioid neuroendocrine cells): Positive for Synaptophysin, Chromogranin A, other neuroendocrine markers (e.g., CD56, NSE); may express pancreatic polypeptide, somatostatin, or rarely other hormones
─ IHC (Ganglion cells): Positive for Synaptophysin, NFP, NSE; S100 protein may highlight satellite cells around them
─ IHC (Spindle cells): S100 protein (strong and diffuse), SOX10
─ IHC (-/+): Cytokeratins (AE1/AE3, CAM5.2) can be positive in the epithelioid component in a subset of cases (potential pitfall for adenocarcinoma)
─ IHC (-): CD117 (KIT), DOG1, SMA, Desmin

DDx ─

─ Duodenal well-differentiated neuroendocrine tumor (PanNET/Carcinoid) (Lacks ganglion cells and prominent S100+ spindle cell component; typically composed only of epithelioid neuroendocrine cells)
─ Paraganglioma (extra-adrenal) (True paragangliomas outside the duodenum are rare in GI tract; lack ganglion cells; chief cells are S100 negative, sustentacular cells are S100 positive)
─ Schwannoma (Composed purely of S100+/SOX10+ Schwann cells; lacks epithelioid neuroendocrine and ganglion cell components)
─ Ganglioneuroma (Lacks the epithelioid neuroendocrine cell component; composed of ganglion cells, Schwann cells, and axons)
─ Adenocarcinoma with neuroendocrine differentiation (Adenocarcinoma shows glandular formation, significant atypia, desmoplasia; neuroendocrine component usually <30% or is high-grade NEC)
─ Metastatic neuroendocrine tumor or melanoma (Clinical history; melanoma would be positive for melanocytic markers)

Prognosis ─
─ Vast majority are benign and cured by local excision (endoscopic or surgical)
─ Local recurrence is rare
─ Lymph node involvement, when it occurs, is usually not associated with aggressive behavior or distant metastasis in typical cases
─ True malignant gangliocytic paraganglioma with distant metastasis is exceptionally rare

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Of course. Sclerosing mesenteritis is an excellent and complex entity to include. Here is a detailed entry formatted for your notebook.

Mesentery / Peritoneum

Sclerosing Mesenteritis

A rare, idiopathic disorder characterized by chronic, nonspecific inflammation and fibrosis affecting the adipose tissue of the bowel mesentery.1 It exists on a pathologic spectrum that includes mesenteric panniculitis (inflammation-predominant) and retractile mesenteritis (fibrosis-predominant).2

Clinical ─ Typically affects adults (mean age 60-70 years), with a slight male predominance.3 Presentation is variable, ranging from asymptomatic to symptoms of a mass effect, including abdominal pain, bloating, altered bowel habits, or intestinal obstruction/ischemia from vascular compromise.4 May be associated with an underlying condition in up to 70% of cases, including other autoimmune/inflammatory disorders (e.g., Riedel thyroiditis, retroperitoneal fibrosis), prior abdominal surgery/trauma, or malignancy (e.g., lymphoma, lung cancer, melanoma; the mass may precede, occur with, or follow the cancer diagnosis). Some cases are a manifestation of IgG4-related disease.5

Radiology ─ CT imaging is key for diagnosis. The classic finding is a solitary, well-defined or ill-defined soft tissue mass in the small bowel mesentery root.6 It often demonstrates the "fat ring sign" or "fat halo sign," where there is preservation of fat density around the mesenteric vessels.7 The mass may encase mesenteric vessels and lymph nodes without invading them.8 A "tumoral pseudocapsule," a thin surrounding rim of soft tissue, may also be seen.9

Macro ─ Grossly, the mesentery is thickened, firm, and rubbery, with single or multiple ill-defined, pale-tan, fibrous nodules.10 It may appear as a diffuse, hard, mass-like lesion that can cause retraction and distortion of the adjacent bowel loops.11

Micro ─

─ A spectrum of findings depending on the dominant process:

─ Mesenteric Panniculitis (early/inflammatory phase): A prominent mixed inflammatory infiltrate of lymphocytes and plasma cells, with variable numbers of eosinophils and neutrophils. Foamy macrophages (lipophages) are a key feature, aggregated around areas of fat necrosis.12

─ Sclerosing/Retractile Mesenteritis (late/fibrotic phase): Dominated by dense, paucicellular collagen (fibrosis). Scattered, bland-appearing spindle cells (myofibroblasts) are present, often arranged in short, vague fascicles.13 The inflammatory component is reduced.

─ Both inflammatory and fibrotic components often coexist.

─ Vasculitis or obliterative phlebitis may be seen, particularly in IgG4-related cases.14

─ The process entraps, but does not invade, normal mesenteric structures like fat, vessels, and nerves.15

─ The spindle cells lack significant cytologic atypia, hyperchromasia, or prominent mitotic activity.

Ancillary studies ─

─ IHC (+): Spindle cells are often positive for Smooth Muscle Actin (SMA) and Muscle-Specific Actin (MSA), consistent with a myofibroblastic phenotype.16 Can be positive for Desmin and ALK (focally). CD68 will highlight the foamy macrophages.

─ IHC (-): Spindle cells are negative for nuclear beta-catenin (rules out desmoid), DOG1/CD117 (rules out GIST), S100 (rules out melanoma/nerve sheath tumor), and Cytokeratins (rules out carcinomatosis).

─ Special Stains: An IgG/IgG4 stain can be performed if there is a prominent plasma cell infiltrate and suspicion for IgG4-related disease (a ratio of IgG4+/IgG+ plasma cells > 40% is supportive).

─ Molecular: Typically negative for CTNNB1 gene mutations seen in desmoid fibromatosis.

DDx ─

─ Desmoid-type Fibromatosis: This is a key differential.17 Desmoids are more cellular, composed of long, sweeping fascicles of bland spindle cells and are positive for nuclear beta-catenin by IHC.

─ IgG4-Related Disease: While SM can be a feature of IgG4-RD, a specific diagnosis of IgG4-RD requires other features like storiform fibrosis, obliterative phlebitis, and a high IgG4/IgG ratio.

─ Inflammatory Myofibroblastic Tumor (IMT): Often has a more prominent plasma cell infiltrate and a different architectural pattern (more fascicular). Approximately 50% of IMTs are ALK-positive by IHC.

─ Carcinoid (Neuroendocrine) Tumor with Desmoplasia: The presence of a desmoplastic reaction to a carcinoid tumor can mimic SM.18 A careful search for nests of neuroendocrine cells is crucial; these will be positive for synaptophysin and chromogranin A.19

─ Low-Grade Fibromyxoid Sarcoma: Tends to have alternating fibrous and myxoid areas and is typically negative for actin stains.

─ Well-Differentiated Liposarcoma (Sclerosing type): The defining feature is the presence of atypical adipocytes (lipoblasts) and atypical spindle cells. MDM2 amplification (by FISH) or overexpression (by IHC) is diagnostic.20

─ Peritoneal Carcinomatosis: An infiltrate of malignant epithelial cells or glands, which will be strongly positive for cytokeratins.

GI Tumor Syndromes

Lynch Syndrome (Hereditary Non-Polyposis Colorectal Cancer - HNPCC)

An autosomal dominant genetic disorder caused by germline mutations in DNA mismatch repair (MMR) genes, leading to a significantly increased risk of colorectal cancer and other cancers (e.g., endometrial, ovarian, stomach, small bowel, urinary tract, etc.)

Clinical ─

─ Most common hereditary colorectal cancer syndrome, accounting for 2-5% of all CRCs
─ Characterized by early-onset colorectal cancer (often before age 50)
─ Increased risk of synchronous (multiple primary CRCs at the same time) or metachronous (new primary CRC at a later time) colorectal cancers
─ Tumors often arise in the proximal (right) colon
─ Extracolonic cancers are common, with endometrial cancer being the most frequent in females
─ Diagnosis is suspected based on family history (Amsterdam criteria or revised Bethesda guidelines) and confirmed by germline genetic testing for mutations in MMR genes (MLH1, MSH2, MSH6, PMS2) or EPCAM (which can lead to MSH2 silencing)

Macro ─ ─ Colorectal cancers in Lynch syndrome may not have a specific gross appearance distinguishing them from sporadic CRC, but they are more often right-sided
─ Polyps (adenomas) do occur and are precursors to cancer, but typically not in the hundreds/thousands seen in FAP. The adenoma-carcinoma sequence is accelerated.

Micro ─

─ Colorectal carcinomas arising in Lynch syndrome often exhibit specific histologic features associated with microsatellite instability (MSI-H):
─ Poor differentiation (though paradoxically may have a better prognosis than stage-matched MSS tumors)
─ Medullary carcinoma pattern (solid sheets of cells with vesicular nuclei and prominent nucleoli)
─ Mucinous adenocarcinoma pattern (abundant extracellular mucin)
─ Signet-ring cell features
─ Prominent tumor-infiltrating lymphocytes (TILs) - a Crohn's-like lymphocytic reaction at the tumor periphery or intraepithelial lymphocytes
─ Pushing tumor borders rather than infiltrative
─ Adenomas in Lynch syndrome can be conventional (tubular, villous, tubulovillous) or serrated. They tend to progress to carcinoma more rapidly than sporadic adenomas.

Ancillary studies ─

─ IHC (Tumor tissue):
─ Loss of expression of one or more MMR proteins (MLH1, MSH2, MSH6, PMS2) is characteristic. The pattern of loss can suggest which gene is likely mutated (e.g., loss of MLH1 often leads to concurrent loss of PMS2; loss of MSH2 often leads to concurrent loss of MSH6).
─ If MLH1/PMS2 are lost, BRAF V600E mutation testing and/or MLH1 promoter hypermethylation analysis of the tumor is done to distinguish sporadic MSI-H CRC (often BRAF mutated and MLH1 methylated) from Lynch syndrome (usually BRAF wild-type and no MLH1 promoter methylation).
─ Molecular (Tumor tissue):
─ Microsatellite Instability-High (MSI-H) is the hallmark, detected by PCR-based assays comparing microsatellite loci in tumor vs. normal tissue.
─ Molecular (Germline - blood test):
─ Definitive diagnosis requires detection of a pathogenic germline mutation in one of the MMR genes (MLH1, MSH2, MSH6, PMS2) or EPCAM

DDx ─

─ Sporadic colorectal cancer (especially sporadic MSI-H CRC, which shares histologic and IHC/MSI features but lacks a germline MMR gene mutation; often due to somatic MLH1 promoter hypermethylation)
─ Familial Colorectal Cancer Type X (families meeting Amsterdam criteria but no MMR gene mutation found; MSI-L or MSS tumors)
─ Other polyposis syndromes if multiple polyps are present (e.g., FAP, MAP, Peutz-Jeghers, Juvenile Polyposis)
─ Constitutional Mismatch Repair Deficiency (CMMRD) (biallelic germline MMR mutations, very early onset cancers, café-au-lait macules, hematologic malignancies)

Prognosis ─ ─ Individuals with Lynch syndrome have a significantly increased lifetime risk of developing CRC (up to 80% depending on the gene mutated) and other specific cancers
─ Paradoxically, CRCs that develop in Lynch syndrome (MSI-H tumors) often have a better stage-for-stage prognosis compared to sporadic MSS CRCs
─ May have a different response to certain chemotherapies (e.g., 5-FU based adjuvant chemotherapy may be less effective for MSI-H stage II CRC)
─ MSI-H tumors are often highly responsive to immune checkpoint inhibitor therapy
─ Intensive surveillance (e.g., frequent colonoscopies starting at a young age) and prophylactic surgeries (e.g., colectomy, hysterectomy/oophorectomy) can significantly reduce cancer risk and mortality

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Familial Adenomatous Polyposis (FAP) & Attenuated FAP

An autosomal dominant inherited disorder characterized by the development of hundreds to thousands of adenomatous polyps in the colorectum, caused by germline mutations in the APC gene. If untreated, progression to colorectal cancer is virtually inevitable. Attenuated FAP (AFAP) is a milder form with fewer polyps and later cancer onset.

Clinical ─ ─ Classic FAP: ─ Development of ≥100 (often hundreds to thousands) colorectal adenomatous polyps, typically starting in adolescence or early adulthood (mean age of polyp development ~16 years)
─ If untreated, colorectal cancer develops in nearly 100% of individuals, often by age 40-50 (mean age ~39 years)
─ Extracolonic manifestations are common (Gardner syndrome was an older term for FAP with prominent extracolonic features):
─ Upper GI polyps: Gastric fundic gland polyps (very common, usually benign), duodenal/ampullary adenomas (high risk of malignancy)
─ Desmoid tumors (locally aggressive fibroblastic proliferations, can be intra-abdominal, abdominal wall, or extra-abdominal)
─ Osteomas (benign bone growths, often in skull/mandible)
─ Dental abnormalities (e.g., supernumerary teeth, unerupted teeth, odontomas)
─ Congenital Hypertrophy of the Retinal Pigment Epithelium (CHRPE) (often a diagnostic clue)
─ Epidermoid cysts, fibromas
─ Increased risk of other cancers: Duodenal/ampullary, thyroid (papillary, cribriform-morular variant), pancreatic, hepatoblastoma (in childhood), CNS tumors (medulloblastoma - Turcot syndrome variant)
─ Attenuated FAP (AFAP): ─ Fewer colorectal adenomas (typically 10-99, though some definitions vary)
─ Later onset of polyps and colorectal cancer (average 10-15 years later than classic FAP)
─ Polyps may be more proximally located in the colon
─ Extracolonic manifestations may be less frequent or severe
─ Caused by APC mutations in specific regions (e.g., 5' end, 3' end, exon 9) or sometimes by mutations in other genes mimicking AFAP (e.g., biallelic MUTYH mutations - MAP)

Macro ─ ─ Classic FAP: Carpet of polyps throughout the colon and rectum; polyps are typically small adenomas initially but can vary in size and morphology (tubular, tubulovillous, villous)
─ Attenuated FAP: Fewer, often flat, adenomas, may be more concentrated in the right colon

Micro ─

─ Colorectal polyps are predominantly conventional adenomas (tubular, tubulovillous, or villous) showing varying degrees of dysplasia (low-grade or high-grade)
─ Microadenomas (very small clusters of dysplastic glands) are common
─ Invasive adenocarcinoma develops from these adenomas through the conventional adenoma-carcinoma sequence
─ Fundic gland polyps in the stomach are typically composed of cystically dilated glands lined by parietal and chief cells; dysplasia is rare but can occur, especially in FAP
─ Duodenal adenomas are histologically similar to colorectal adenomas

Ancillary studies ─

─ IHC (on adenomas/carcinomas): Similar to sporadic colorectal neoplasms (e.g., Ki-67, p53 in HGD/carcinoma)
─ Molecular (Germline - blood test):
─ Definitive diagnosis of FAP/AFAP is made by identifying a pathogenic germline mutation in the APC gene (tumor suppressor gene on chromosome 5q21-q22). Most mutations are truncating.
─ Genetic testing should also consider MUTYH if APC is negative and polyposis is present (MUTYH-associated polyposis is autosomal recessive and phenotypically similar to AFAP or FAP with fewer polyps)

DDx ─

─ Lynch Syndrome (fewer polyps, different genetic basis - MMR gene mutations)
─ MUTYH-Associated Polyposis (MAP) (autosomal recessive, often <100 adenomas, can have serrated polyps, increased risk of CRC; biallelic MUTYH mutations)
─ Serrated Polyposis Syndrome (SPS) (multiple serrated polyps, specific diagnostic criteria based on number/size/location of serrated polyps)
─ Other hamartomatous polyposis syndromes (e.g., Peutz-Jeghers, Juvenile Polyposis, Cowden syndrome – polyps have distinct hamartomatous histology)
─ Inflammatory bowel disease with multiple pseudopolyps (polyps are inflammatory, not adenomatous)
─ Lymphomatous polyposis (lymphoid infiltrate, not adenomatous epithelium)

Prognosis ─ ─ Classic FAP: Without prophylactic colectomy, CRC risk is nearly 100%. With colectomy, lifespan is significantly improved, but risk of extracolonic cancers (especially duodenal/ampullary) remains a major concern and cause of mortality. Desmoid tumors can also cause significant morbidity and mortality.
─ Attenuated FAP: Lower CRC risk than classic FAP (around 70% lifetime risk if unmanaged), and later onset, but still significantly elevated. Surveillance and management are tailored to the polyp burden.
─ Regular surveillance of colorectum (starting in early adolescence for classic FAP) and upper GI tract is crucial
─ Prophylactic colectomy (various types, e.g., total proctocolectomy with ileal pouch-anal anastomosis or colectomy with ileorectal anastomosis) is the mainstay of CRC prevention in FAP

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MUTYH-Associated Polyposis (MAP)

An autosomal recessive disorder caused by biallelic (two copies) germline mutations in the MUTYH gene, leading to defective base excision repair and an increased risk of colorectal polyps (adenomas and others) and colorectal cancer (CRC)

Clinical ─ ─ Phenotype can be variable, often resembling attenuated familial adenomatous polyposis (AFAP) or sometimes classic FAP, but can also present with fewer polyps or CRC without significant polyposis
─ Typical presentation involves multiple colorectal adenomas (often 10-100, but can be fewer or more), developing from the 2nd to 6th decades (mean age often in 40s-50s)
─ Increased lifetime risk of CRC (43-100% if unmanaged), often diagnosed at a later age than FAP but earlier than sporadic CRC
─ Extracolonic manifestations can occur, though generally less frequent or well-defined than in FAP:
─ Duodenal adenomas (common, ~17-34%) and gastric polyps (fundic gland polyps, adenomas)
─ Increased risk of duodenal cancer (~4%)
─ Possible increased risk for ovarian, bladder, skin cancers, and thyroid lesions, but data are less consistent than for FAP or Lynch syndrome
─ Individuals with only one MUTYH mutation (heterozygotes/carriers) may have a mildly increased risk of CRC, especially if there is a family history of CRC, but do not have MAP syndrome

Macro ─ ─ Multiple colorectal polyps, typically adenomas (tubular, tubulovillous, villous)
─ Number of polyps is variable, commonly in the range of 10-100, but can be <10 or >100
─ Polyps can be distributed throughout the colon, sometimes with a slight right-sided predominance in some series
─ CRC appearance is similar to sporadic CRC

Micro ─

─ Colorectal polyps are predominantly conventional adenomas (tubular, tubulovillous, villous) with varying degrees of dysplasia
─ Hyperplastic polyps and sessile serrated lesions/polyps (SSL/Ps) can also be seen in some individuals with MAP, though adenomas are the most characteristic
─ Colorectal carcinomas are typically adenocarcinomas, similar to sporadic CRC; they arise through the adenoma-carcinoma sequence
─ Somatic G:C→T:A transversion mutations in genes like APC and KRAS are characteristic in the tumors of MAP patients, reflecting the underlying DNA repair defect

Ancillary studies ─

─ IHC (Tumor tissue):
─ MMR protein expression is typically intact (MAP is not a primary MMR-deficient syndrome like Lynch)
─ IHC for MUTYH protein is not routinely used for diagnosis
─ Molecular (Tumor tissue):
─ Characteristic somatic mutation signature: high frequency of G:C→T:A transversions in tumor DNA (e.g., in APC, KRAS genes)
─ Molecular (Germline - blood test):
─ Definitive diagnosis requires identification of biallelic (homozygous or compound heterozygous) pathogenic germline mutations in the MUTYH gene
─ Two common founder mutations in individuals of European descent are Y179C (formerly Y165C) and G396D (formerly G382D)
─ Full gene sequencing is often needed if common mutations are not found or only one is identified in a patient with a suspicious phenotype

DDx ─

─ Familial Adenomatous Polyposis (FAP) / Attenuated FAP (AFAP) (autosomal dominant, APC gene mutation, typically more polyps in classic FAP, distinct extracolonic features)
─ Lynch Syndrome (autosomal dominant, MMR gene mutations, fewer polyps usually, MSI-H tumors, characteristic spectrum of extracolonic cancers)
─ Serrated Polyposis Syndrome (SPS) (multiple serrated polyps, specific diagnostic criteria, often BRAF mutations in polyps)
─ Polymerase Proofreading-Associated Polyposis (PPAP) (mutations in POLD1 or POLE, multiple adenomas, early-onset CRC)
─ Sporadic multiple adenomas (no identifiable germline mutation)

Prognosis ─ ─ High lifetime risk of CRC if not managed with surveillance and intervention
─ Regular colonoscopic surveillance with polypectomy is crucial, starting in early adulthood (e.g., age 25-30, or earlier based on family history)
─ Colectomy may be considered if polyp burden becomes unmanageable by endoscopy or if CRC develops
─ Surveillance for duodenal polyps/cancer with upper endoscopy is also recommended
─ Prognosis of CRC in MAP, stage for stage, is generally similar to sporadic CRC

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Muir-Torre Syndrome (as a variant of Lynch Syndrome)

An autosomal dominant genodermatosis characterized by the combination of at least one sebaceous gland tumor (e.g., sebaceous adenoma, sebaceous epithelioma, or sebaceous carcinoma) or keratoacanthoma, and at least one internal malignancy; it is most commonly a phenotypic variant of Lynch syndrome

Clinical ─ ─ Skin lesions:
─ Sebaceous adenomas: Most common; yellowish papules/nodules, often on face, scalp, back, chest
─ Sebaceous epitheliomas (sebaceomas): Benign, more basaloid cells than adenomas
─ Sebaceous carcinomas: Malignant, can be locally aggressive, often on eyelids
─ Keratoacanthomas: Rapidly growing, dome-shaped nodules with a central keratin plug; some may show sebaceous differentiation
─ Internal malignancies:
─ Colorectal cancer is the most common (around 50% of MTS patients), often proximal, early onset, and multiple, similar to Lynch syndrome CRCs
─ Genitourinary cancers (endometrial, ovarian, urothelial) are also frequent, consistent with Lynch syndrome spectrum
─ Other Lynch-associated cancers can occur (stomach, small bowel, pancreas, biliary tract, brain)
─ Skin tumors may precede, occur concurrently with, or follow the diagnosis of internal malignancy
─ Average age of onset for first malignancy is around 50-55 years
─ Most cases (~2/3 to 3/4) are due to germline mutations in MMR genes, primarily MSH2, and less commonly MLH1 or MSH6 (Lynch syndrome variant)
─ A smaller subset (~1/4 to 1/3) can be associated with biallelic MUTYH mutations (MAP-associated MTS), which is autosomal recessive and MMR-proficient

Macro ─ ─ Colorectal cancers in MTS (Lynch variant) are similar to other Lynch syndrome CRCs: often right-sided, may be bulky or polypoid
─ Skin lesions: variable appearance as described above

Micro ─

─ Sebaceous tumors:
─ Sebaceous adenoma: Lobules of mature sebocytes mixed with basaloid germinative cells, well-circumscribed
─ Sebaceoma (Sebaceous epithelioma): Predominantly basaloid cells (>50%) with scattered mature sebocytes or small sebaceous ducts
─ Sebaceous carcinoma: Infiltrative growth, cytologic atypia, necrosis, mitoses; evidence of sebaceous differentiation (vacuolated cytoplasm)
─ Keratoacanthoma: Cup-shaped lesion with a central keratin plug, well-differentiated squamous epithelium with glassy eosinophilic cytoplasm, pushing borders; some may show sebaceous differentiation
─ Internal malignancies (e.g., CRC): Histology is often similar to Lynch syndrome-associated cancers (e.g., mucinous, medullary, signet-ring features, prominent TILs if MSI-H)

Ancillary studies ─

─ IHC (Sebaceous tumors and internal malignancies in Lynch-variant MTS):
─ Loss of MMR protein expression (MSH2, MLH1, MSH6, PMS2) in tumor cells is characteristic, mirroring the germline mutation. MSH2 loss is most common in MTS.
─ This helps confirm the link to Lynch syndrome and guides genetic testing
─ IHC (Sebaceous tumors in MUTYH-associated MTS):
─ MMR protein expression is typically intact
─ Molecular (Tumor tissue):
─ Microsatellite instability-high (MSI-H) in tumors from Lynch-variant MTS
─ Microsatellite stable (MSS) in tumors from MUTYH-associated MTS
─ Molecular (Germline - blood test):
─ Identification of pathogenic germline mutation in an MMR gene (MSH2 > MLH1, MSH6) confirms Lynch-variant MTS
─ Identification of biallelic pathogenic MUTYH mutations confirms MUTYH-associated MTS

DDx ─

─ Sporadic sebaceous tumors (usually solitary, in elderly, MMR proficient, no personal/family history of Lynch-related cancers)
─ Other syndromes with multiple skin tumors (e.g., Cowden syndrome, Birt-Hogg-Dubé syndrome – different types of skin lesions and associated internal risks)
─ Lynch syndrome without cutaneous manifestations (MTS is a specific phenotype of Lynch)
─ Basal cell carcinoma with sebaceous differentiation (histologic overlap, but BCC markers like BerEP4 may be helpful)

Prognosis ─ ─ Prognosis is primarily determined by the type, stage, and behavior of the internal malignancies
─ Sebaceous carcinomas can metastasize, but sebaceous adenomas and sebaceomas are benign
─ Cancers in Lynch-variant MTS (MSI-H) may have a better prognosis stage-for-stage than sporadic MSS cancers, similar to general Lynch syndrome
─ Lifelong surveillance for both skin and internal cancers is crucial

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Hereditary Diffuse Gastric Cancer (CDH1-associated)

An autosomal dominant cancer predisposition syndrome caused by germline mutations in the CDH1 gene, characterized by a high lifetime risk of diffuse-type (signet ring cell) gastric cancer and lobular breast cancer in females

Clinical ─ ─ High penetrance for diffuse gastric cancer (DGC): lifetime risk estimated ~70% for males and ~56% for females by age 80
─ Early age of onset for DGC (mean age often in late 30s to 40s, but can range widely)
─ Increased risk of lobular breast cancer in females (lifetime risk ~42-55% by age 80)
─ May be a subtle increased risk for colorectal cancer (specifically signet ring cell type), but this is less well-established and not a primary defining feature for surveillance unless other factors are present
─ Diagnosis is based on clinical criteria (IGCLC criteria) and confirmed by germline CDH1 mutation testing
─ Criteria include: families with ≥2 gastric cancer cases with ≥1 DGC diagnosed <50 years; or ≥3 DGC cases at any age; or personal/family history of DGC and lobular breast cancer with one diagnosed <50 years; or bilateral lobular breast cancer <50; or individual with DGC <40 years, etc.
─ Endoscopic surveillance for DGC is challenging due to the infiltrative nature of the tumor, which often arises submucosally without obvious mucosal lesions in early stages. Multiple random biopsies are needed (Cambridge protocol).

Macro ─ ─ Early DGC in prophylactic gastrectomy specimens is often multifocal and appears as subtle thickening or pallor of the gastric wall, or may be grossly normal
─ Advanced DGC can lead to linitis plastica ("leather bottle stomach") – a diffusely thickened, rigid gastric wall
─ Ulceration or discrete masses are less common than in intestinal-type gastric cancer

Micro ─

─ The hallmark lesion is poorly cohesive carcinoma with signet ring cells (WHO definition of diffuse gastric cancer)
─ Early lesions (foci of intramucosal signet ring cell carcinoma, sometimes called "pagetoid spread of signet ring cells") are found beneath an intact surface epithelium in prophylactic gastrectomy specimens. These are often microscopic and multifocal.
─ Signet ring cells are characterized by intracytoplasmic mucin displacing the nucleus to the periphery
─ Cells infiltrate individually or in small clusters/cords within the lamina propria and gastric wall, often with minimal desmoplastic reaction in very early stages, but can elicit significant desmoplasia as it progresses
─ No gland formation or an in-situ component like intestinal-type adenocarcinoma
─ Lobular breast cancer histology is also characterized by infiltrating cords of cells, often with intracytoplasmic lumina, and loss of E-cadherin expression

Ancillary studies ─

─ IHC (Gastric and Breast tumors):
─ Loss or aberrant expression of E-cadherin (membranous staining) is characteristic, reflecting the CDH1 gene mutation. Complete absence, markedly reduced, or cytoplasmic staining instead of membranous can be seen.
─ Cytokeratin stains (e.g., AE1/AE3, CAM5.2) highlight the infiltrating tumor cells
─ PAS-D or Alcian blue highlights intracytoplasmic mucin in signet ring cells
─ Molecular (Germline - blood test):
─ Definitive diagnosis requires identification of a pathogenic germline mutation in the CDH1 gene
─ Molecular (Tumor tissue):
─ "Second hit" inactivation of the wild-type CDH1 allele in tumor cells (e.g., by promoter hypermethylation, somatic mutation, or LOH)

DDx ─

─ Sporadic diffuse gastric cancer (no germline CDH1 mutation, though somatic CDH1 alterations can occur)
─ Other hereditary gastric cancer syndromes (e.g., Lynch syndrome, FAP, Peutz-Jeghers, GAPPS – typically associated with intestinal-type gastric cancer or different polyp types)
─ Gastritis with signet ring cell change (reactive, non-neoplastic signet ring-like cells, often in response to injury; lack atypia and infiltrative growth of carcinoma; E-cadherin expression usually normal)
─ Metastatic signet ring cell carcinoma to the stomach (rare, primary usually breast or colorectum – clinical history and IHC for site-specific markers needed)

Prognosis ─ ─ Diffuse gastric cancer, when clinically apparent, has a poor prognosis due to its infiltrative nature and tendency for early metastasis (often peritoneal)
─ Prophylactic total gastrectomy (recommended for pathogenic CDH1 mutation carriers, typically between ages 20-30 or based on family history) dramatically reduces gastric cancer risk and is the primary management strategy
─ Surveillance for lobular breast cancer (e.g., annual breast MRI and mammogram) is crucial for female carriers
─ Management of HDGC requires a multidisciplinary team and genetic counseling

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Hamartomatous Polyposis Syndromes

Peutz-Jeghers Syndrome & Polyps

An autosomal dominant disorder characterized by gastrointestinal hamartomatous polyps, mucocutaneous pigmentation, and an increased risk for various cancers

Clinical ─ ─ Caused by germline mutations in the STK11 (LKB1) tumor suppressor gene on chromosome 19p13.3
─ Mucocutaneous pigmentation: Characteristic dark blue to brown macules (lentigines) around the mouth (perioral), lips, buccal mucosa, eyes, nostrils, fingers, toes, and perianal area. These usually appear in infancy or childhood and may fade in adulthood, except for buccal lesions.
─ Gastrointestinal polyps (Peutz-Jeghers polyps): Hamartomatous polyps that can occur anywhere in the GI tract, most commonly in the small intestine (jejunum > ileum > duodenum), but also in the stomach and colon/rectum.
─ Polyps can cause symptoms like abdominal pain (often colicky due to intussusception), bleeding (leading to anemia), obstruction, or prolapse
─ Increased lifetime risk of various cancers (GI and extra-GI):
─ GI cancers: Colorectal, gastric, small bowel, pancreatic
─ Extra-GI cancers: Breast (females), ovarian (sex cord tumors with annular tubules - SCTAT is characteristic, also epithelial ovarian cancer), testicular (Sertoli cell tumors, often bilateral and calcified), lung, cervical (adenoma malignum)
─ Cumulative cancer risk by age 70 is very high (can exceed 80-90%)

Macro ─ ─ Peutz-Jeghers polyps:
─ Typically pedunculated or sessile, ranging in size from millimeters to several centimeters
─ Surface is often lobulated or cerebriform
─ Mucocutaneous lesions: Flat, pigmented macules, 1-5 mm

Micro ─

─ Peutz-Jeghers polyps (Hamartomatous):
─ Diagnostic feature is an arborizing (branching) network of smooth muscle bundles, derived from the muscularis mucosae, extending into the polyp fronds and surrounding glandular elements. This smooth muscle framework is key.
─ Epithelium lining the glands is typically normal-appearing or hyperplastic columnar epithelium of the native GI site (e.g., small intestinal, gastric, or colonic type). Goblet cells are usually abundant.
─ Glands can be cystically dilated or show architectural complexity due to the smooth muscle branching
─ True adenomatous dysplasia is uncommon within the hamartomatous epithelium itself, but adenomas or carcinomas can arise separately or, rarely, within a P-J polyp (often referred to as "P-J polyp with dysplasia" or "adenoma arising in P-J polyp")
─ Epithelial misplacement (pseudoinvasion) into the submucosa or muscularis propria can occur, especially in large small bowel polyps, and should be distinguished from true invasive carcinoma. The misplaced glands are usually bland and surrounded by lamina propria, sometimes with hemosiderin.
─ Mucocutaneous lentigines: Increased melanin in basal keratinocytes without an increase in melanocyte number

Ancillary studies ─

─ IHC (Polyps):
─ Smooth muscle actin (SMA) or desmin highlights the characteristic arborizing smooth muscle bundles within the polyps
─ Cytokeratin stains highlight the epithelium
─ Ki-67 shows low proliferative activity in the hamartomatous epithelium, similar to normal mucosa
─ Molecular (Germline - blood test):
─ Definitive diagnosis requires identification of a pathogenic germline mutation in the STK11 (LKB1) gene

DDx ─

─ For Polyps: ─ Juvenile polyps (typically colonic, solitary or multiple in Juvenile Polyposis Syndrome; characterized by abundant inflamed lamina propria, cystically dilated glands filled with mucin; smooth muscle is usually scant or absent within the polyp head itself)
─ Inflammatory polyps (marked inflammation, granulation tissue, reactive epithelial changes; lack organized smooth muscle arborization)
─ Conventional adenomas (show true cytologic dysplasia throughout; lack the hamartomatous smooth muscle core)
─ Cronkhite-Canada Syndrome polyps (diffuse GI polyposis with protein-losing enteropathy, alopecia, nail changes; polyps are edematous, inflamed, with cystic glands, but different architecture than P-J polyps)
─ For Pigmentation: ─ Simple freckles (ephelides) (darken with sun exposure)
─ Lentigo simplex (no relation to sun, can occur anywhere)
─ Other syndromes with lentigines (e.g., Carney complex, LEOPARD syndrome – associated with different systemic findings)
─ Addison's disease (generalized hyperpigmentation)

Prognosis ─ ─ Morbidity is primarily related to polyp complications (intussusception, bleeding, obstruction) and the high lifetime risk of developing various cancers
─ Regular surveillance for GI polyps (e.g., endoscopy, colonoscopy, video capsule endoscopy) and relevant extra-intestinal cancers is crucial, starting in childhood or adolescence
─ Polypectomy is performed to prevent complications and potentially reduce cancer risk if dysplasia is found
─ Management requires a multidisciplinary approach due to the multisystem involvement

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Juvenile Polyposis Syndrome & Polyps

An autosomal dominant disorder characterized by the presence of multiple juvenile polyps in the gastrointestinal tract, and an increased risk of GI cancers

Clinical ─ ─ Diagnostic criteria:
─ >5 juvenile polyps in the colorectum; OR
─ Multiple juvenile polyps throughout the GI tract; OR
─ Any number of juvenile polyps with a family history of JPS
─ Polyps typically appear in childhood; most patients have polyps by age 20
─ Symptoms include rectal bleeding, anemia, abdominal pain, diarrhea, intussusception, or polyp prolapse
─ Increased lifetime risk of colorectal cancer (up to ~50%), and also gastric, small bowel, and pancreatic cancers
─ Associated with germline mutations in SMAD4 (DPC4) or BMPR1A genes (involved in TGF-β signaling pathway)
─ Patients with SMAD4 mutations may also have features of Hereditary Hemorrhagic Telangiectasia (HHT), such as nosebleeds, telangiectasias, and arteriovenous malformations (AVMs)

Macro ─ ─ Juvenile polyps are typically round, smooth or slightly lobulated, reddish, and often pedunculated
─ Size varies from <0.5 cm to several centimeters
─ Can occur anywhere in the GI tract, but most common in the colorectum; stomach and small bowel can also be involved
─ Number of polyps varies from a few to hundreds

Micro ─

─ Juvenile polyps (Hamartomatous):
─ Characterized by an abundant, edematous, and inflamed lamina propria (often with eosinophils, lymphocytes, plasma cells)
─ Glands are often cystically dilated, filled with mucin, and lined by normal or reactive columnar epithelium (goblet cells and absorptive cells)
─ Surface epithelium is frequently eroded or ulcerated, with associated granulation tissue
─ Smooth muscle is typically scant or absent within the main body of the polyp (unlike Peutz-Jeghers polyps which have arborizing smooth muscle)
─ Dysplasia can occur within juvenile polyps, appearing as conventional adenomatous change (low-grade or high-grade), and is the precursor to carcinoma in JPS. This is more common in larger polyps and in older individuals.

Ancillary studies ─

─ IHC (Polyps):
─ Epithelium is positive for cytokeratins
─ Ki-67 shows proliferation in basal crypts and regenerative areas, but not diffusely increased in the hamartomatous component unless dysplasia is present
─ SMAD4 IHC may show loss of expression in polyps from patients with SMAD4 germline mutations (useful in syndromic context)
─ Molecular (Germline - blood test):
─ Identification of pathogenic germline mutations in SMAD4 or BMPR1A confirms the diagnosis of JPS

DDx ─

─ Sporadic juvenile polyp (solitary, no family history, no other JPS criteria met – histologically identical)
─ Peutz-Jeghers polyp (arborizing smooth muscle core, different genetic basis - STK11)
─ Inflammatory cap polyp (associated with mucosal prolapse, has a cap of granulation tissue and fibrinopurulent exudate)
─ Inflammatory polyps of other causes (e.g., IBD – background features of IBD, different epithelial changes)
─ Cronkhite-Canada Syndrome polyps (diffuse GI polyposis with ectodermal changes; polyps are edematous and inflamed but typically in older adults and non-hereditary)
─ Cowden syndrome polyps (can be hamartomatous, but also inflammatory, lipomatous, ganglioneuromatous; associated with PTEN mutations and characteristic mucocutaneous lesions)

Prognosis ─ ─ Benign polyps, but carry a significant risk of bleeding, intussusception, and malignant transformation (adenocarcinoma)
─ Lifetime cancer risk (mainly GI) is high, necessitating regular endoscopic surveillance of the upper and lower GI tract starting in adolescence, with polypectomy
─ Colectomy or gastrectomy may be required if polyp burden is unmanageable or if high-grade dysplasia/cancer develops
─ Screening for HHT features is important in patients with SMAD4 mutations

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Cronkhite-Canada Syndrome & Polyps

A rare, acquired (non-hereditary) disorder characterized by diffuse gastrointestinal polyposis, protein-losing enteropathy, and characteristic ectodermal abnormalities (alopecia, nail dystrophy, skin hyperpigmentation)

Clinical ─ ─ Typically affects middle-aged to older adults (mean age ~59 years), with a slight male predominance in some series
─ Onset is usually with GI symptoms: watery diarrhea (often severe), abdominal pain, weight loss, anorexia, dysgeusia (altered taste)
─ Protein-losing enteropathy leads to hypoalbuminemia and peripheral edema
─ Ectodermal changes:
─ Alopecia (diffuse hair loss, can be complete)
─ Onychodystrophy (nail thinning, splitting, shedding)
─ Skin hyperpigmentation (brownish macules, often on hands, face, soles)
─ Malabsorption of nutrients (vitamins, minerals) is common
─ Etiology is unknown; an autoimmune or immune-mediated process has been suggested

Macro ─ ─ Diffuse "hamartomatous-like" or inflammatory polyposis throughout the GI tract, typically sparing the esophagus
─ Stomach, small intestine, and colon are usually involved
─ Polyps can be sessile or pedunculated, variable in size, often numerous and carpeting the mucosa
─ Mucosa between polyps may also be edematous and erythematous
─ Gastric folds can be thickened, mimicking Ménétrier's disease

Micro ─

─ Polyps are characterized by:
─ Markedly edematous lamina propria, often with a sparse to moderate lymphoplasmacytic and eosinophilic infiltrate
─ Cystically dilated and distorted glands/foveolae, lined by benign or reactive epithelium; glands may appear to "float" in the edematous stroma
─ Surface epithelium may be attenuated, eroded, or show regenerative changes
─ Smooth muscle proliferation is not a prominent feature (unlike Peutz-Jeghers polyps)
─ The histology can resemble juvenile polyps or inflammatory polyps
─ Mucosa between polyps also often shows edema, inflammation, and glandular changes
─ Dysplasia and carcinoma can develop within these polyps or in the flat mucosa, reported in a subset of patients (risk estimated ~10-15% or higher in some series)

Ancillary studies ─

─ IHC: Not specific for diagnosis; can be used to rule out other conditions or assess for dysplasia/carcinoma if suspected
─ Increased IgG4-positive plasma cells have been reported in some cases, supporting a possible immune basis, but this is not consistent or diagnostic
─ Molecular: No specific germline mutations are associated (it's considered acquired)

DDx ─

─ Juvenile Polyposis Syndrome (hereditary, younger onset, specific gene mutations, polyps are true hamartomas though can look similar)
─ Other hamartomatous polyposis syndromes (Peutz-Jeghers, Cowden – distinct histology, genetic basis, and other clinical features)
─ Inflammatory bowel disease with pseudopolyps (clinical history of IBD, characteristic IBD mucosal changes)
─ Lymphomatous polyposis (lymphoid infiltrate)
─ Diffuse adenomatous polyposis (e.g., FAP – polyps are adenomas with dysplasia)
─ Ménétrier disease (if predominantly gastric with giant folds – foveolar hyperplasia, glandular atrophy, protein loss, but typically lacks the diffuse polyposis and ectodermal changes of CCS)

Prognosis ─ ─ Variable, but can be poor due to severe malnutrition, electrolyte disturbances, infections, and complications like GI bleeding or intussusception
─ Mortality rates have been high in the past, though supportive care and nutritional therapy (including parenteral nutrition), corticosteroids, and other immunosuppressants have improved outcomes in some patients
─ Risk of GI malignancy (gastric, colorectal) is increased, necessitating endoscopic surveillance

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Cowden Syndrome (PTEN Hamartoma Tumor Syndrome) & GI Polyps

An autosomal dominant disorder caused by germline mutations in the PTEN tumor suppressor gene, characterized by multiple hamartomas in various organs, and an increased risk of breast, thyroid, endometrial, and other cancers. GI polyps are common.

Clinical ─ ─ Part of the PTEN Hamartoma Tumor Syndrome (PHTS) spectrum
─ Mucocutaneous lesions are hallmark features, often appearing by the 2nd or 3rd decade:
─ Trichilemmomas (facial, pathognomonic if multiple)
─ Acral keratoses (warty papules on hands/feet)
─ Oral mucosal papillomas (cobblestone appearance)
─ Sclerotic fibromas
─ Macrocephaly (head circumference >97th percentile) is very common
─ Increased lifetime risk of cancers:
─ Breast cancer (females, up to 85% lifetime risk, often early onset)
─ Thyroid cancer (follicular, papillary, up to 35-38% lifetime risk)
─ Endometrial cancer (females, up to 28% lifetime risk)
─ Colorectal cancer (estimated ~9-16% lifetime risk)
─ Kidney cancer (renal cell carcinoma, papillary type, up to 34% lifetime risk)
─ Melanoma (small increased risk)
─ Gastrointestinal polyps are found in up to 90% of individuals, can occur throughout the GI tract (esophagus, stomach, small bowel, colon)
─ Other features: Lhermitte-Duclos disease (dysplastic cerebellar gangliocytoma), thyroid abnormalities (adenomas, goiter), fibrocystic breast disease, uterine fibroids, lipomas, vascular anomalies, developmental delay or autism spectrum disorder in some

Macro ─ ─ GI polyps are variable in appearance and number (can be few to numerous)
─ Can be sessile or pedunculated, small to large
─ Esophageal glycogenic acanthosis (small, whitish plaques) is common

Micro ─

─ GI polyps in Cowden syndrome show a wide spectrum of histologic types, often mixed:
─ Hamartomatous polyps: Most characteristic; can resemble juvenile polyps (edematous lamina propria, cystic glands) or Peutz-Jeghers-like polyps (disorganized smooth muscle, though typically less prominent and less organized arborization than true P-J polyps). The epithelium is usually of the native GI site.
─ Inflammatory polyps
─ Lipomatous polyps (adipose tissue in lamina propria/submucosa)
─ Ganglioneuromatous polyps (neural elements, ganglion cells, spindle cells in lamina propria)
─ Fibromatous/Sclerotic polyps (dense collagenous stroma)
─ Hyperplastic polyps
─ Adenomatous polyps (tubular, villous – less common as the primary "Cowden polyp" type but can occur)
─ Dysplasia can arise within hamartomatous or adenomatous polyps, leading to carcinoma
─ Esophageal glycogenic acanthosis: Squamous epithelium with abundant intracytoplasmic glycogen, appearing pale and vacuolated
─ Trichilemmomas (skin): Benign follicular tumors with lobular proliferation of pale/clear epithelial cells showing peripheral palisading and a thickened basement membrane, connected to epidermis or hair follicle

Ancillary studies ─

─ IHC (Polyps):
─ PTEN IHC may show loss or reduced expression in some lesional tissues, but this is not consistently reliable for diagnostic purposes on GI polyps alone and is more relevant for tumor studies in established PHTS patients. Germline testing is definitive.
─ Molecular (Germline - blood test):
─ Definitive diagnosis requires identification of a pathogenic germline mutation in the PTEN gene
─ Promoter methylation or large deletions/duplications can also occur

DDx ─

─ For GI Polyps: Depending on the predominant histology of the polyp:
─ Juvenile Polyposis Syndrome (if juvenile-like polyps predominate; SMAD4/BMPR1A mutations)
─ Peutz-Jeghers Syndrome (if P-J-like polyps; STK11 mutations, characteristic mucocutaneous pigmentation)
─ Cronkhite-Canada Syndrome (acquired, diffuse inflammatory/hamartomatous polyps with ectodermal changes)
─ Serrated Polyposis Syndrome (multiple serrated polyps)
a─ Conventional adenomas (if adenomatous features predominate)
─ Other syndromes with ganglioneuromas (e.g., NF1, MEN2B – different systemic features)
─ For Mucocutaneous Lesions: Other conditions with facial papules or oral lesions (e.g., Birt-Hogg-Dubé, tuberous sclerosis, Darier disease)

Prognosis ─ ─ Primarily determined by the risk of developing malignant tumors, especially breast, thyroid, and endometrial cancer
─ GI cancer risk is elevated but generally lower than for breast or thyroid cancer in this syndrome
─ Lifelong, intensive surveillance for associated cancers is essential, starting at appropriate ages based on NCCN or other established guidelines
─ Management of GI polyps involves endoscopic surveillance and polypectomy as indicated

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