Structure / Region	Description / Composition
Boundaries	Anterior nares (nostrils) to posterior choanae (opening to nasopharynx)
Nasal Septum	Divides cavity; Composed of Vomer bone, Ethmoid bone (perpendicular plate), Septal cartilage
Lateral Walls	Feature Superior, Middle, and Inferior Turbinates (conchae); Meatuses below turbinates
Roof	Primarily Cribriform plate of the ethmoid bone
Floor	Hard palate (Palatine process of maxilla, Horizontal plate of palatine bone)

Region / Structure	Epithelium	Lamina Propria / Submucosa Features
Nasal Vestibule	Keratinized stratified squamous (like skin)	Hair follicles (vibrissae), sebaceous glands, sweat glands
Respiratory Region	Schneiderian mucosa: Ciliated pseudostratified columnar with goblet cells; (Nonkeratinizing squamous possible)	Loose connective tissue; Abundant seromucinous glands; Rich vascular plexuses (swell bodies); Nerves, lymphatics; Scattered inflammatory cells; Melanocytes possible
Olfactory Region	Specialized olfactory mucosa (thicker): Olfactory neurons, Sustentacular cells, Basal cells; NO goblet cells	Glands of Bowman (serous); Olfactory nerve bundles; Vessels, connective tissue
Paranasal Sinuses	Thinner respiratory mucosa (fewer goblet cells)	Thin layer on bone; Sparse glands (mainly near ostia)
Vomeronasal Organ	(Vestigial - Nonciliated columnar cells often mentioned)	Located in lower anterior septum

Oral Cavity

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Structure / Region	Description / Composition
Boundaries	Anterior: Lip vermilion border; Superior: Hard/soft palates; Lateral: Cheeks (buccal mucosa); Inferior: Anterior tongue/floor of mouth; Posterior: Fauces
Major Regions	Lips (labial mucosa); Buccal mucosa; Gingiva; Palate (hard/soft); Tongue (anterior 2/3rds); Floor of mouth; Retromolar trigone

Region / Structure	Epithelium	Lamina Propria / Submucosa Features
General Lining Mucosa (Lips, Buccal, Floor Mouth, etc.)	Mostly nonkeratinizing stratified squamous; Melanocytes / Merkel cells possible	Lamina Propria: Connective tissue; Submucosa: Variable; Minor salivary glands, fat, muscle
Masticatory Mucosa (Gingiva, Hard Palate)	Keratinized / parakeratinized stratified squamous (friction resistant)	Lamina Propria: Dense connective tissue, attached to bone; Submucosa: Thin / absent; Minor salivary glands on hard palate
Specialized Mucosa (Dorsal Tongue)	Stratified squamous with papillae (Filiform - texture, no taste; Fungiform - taste possible, red; Foliate - taste; Circumvallate - taste, von Ebner's glands); Taste buds (gustatory/supporting/basal cells)	Lamina Propria: Papillae core; Submucosa / Muscle: Blends with tongue muscle; Serous / mucous glands
Specialized Structures	Organ of Chievitz: Squamous nests near mandible angle (benign rest); Fordyce Granules: Ectopic sebaceous glands (yellow spots)	Not Applicable (Structures themselves)
Basal Lamina	Not Applicable (Interface layer)	Separates epithelium / lamina propria; Type IV collagen, laminin

Pharynx (Nasopharynx, Oropharynx, Hypopharynx)

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Structure / Region	Description / Composition
General Structure	Connects nasal/oral cavities to larynx/esophagus; Divided into Nasopharynx, Oropharynx, Hypopharynx
Nasopharynx	Base of skull to soft palate; Features: Nasal choanae (anterior), Eustachian tube openings, Fossa of Rosenmüller, Adenoids
Oropharynx	Soft palate to epiglottis; Features: Fauces (anterior), Palatine tonsils (lateral), Lingual tonsils (base of tongue)
Hypopharynx (Laryngopharynx)	Epiglottis to esophagus; Features: Larynx (anterior), Pyriform sinuses (lateral)

Region / Structure	Epithelium	Lamina Propria / Submucosa Features
Nasopharynx	Mostly ciliated pseudostratified columnar (respiratory); Stratified squamous inferiorly; Tonsillar epithelium (adenoids) is respiratory	Seromucinous glands; Dense lymphoid tissue (adenoids); Scattered lymphoid tissue
Oropharynx	Nonkeratinizing stratified squamous (non-tonsillar); Tonsillar epithelium (palatine/lingual) is stratified squamous in crypts (p16+ normal)	Seromucinous glands (non-tonsillar); Dense lymphoid tissue (tonsils)
Hypopharynx (Laryngopharynx)	Nonkeratinizing stratified squamous	Seromucinous glands; Occasional lymphoid aggregates
Waldeyer's Ring	Not Applicable (Lymphoid collection)	Pharyngeal, Palatine, Lingual tonsils

Larynx & Trachea

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Structure / Region	Description / Composition
General Structure	Larynx: Connects hypopharynx to trachea; Functions: Phonation, airway protection; Trachea: Extends from larynx to bronchi
Laryngeal Cartilages	Thyroid, cricoid, arytenoids (paired) (all hyaline - ossify); Epiglottis, corniculate (paired), cuneiform (paired) (all elastic - no ossification)
Laryngeal Subdivisions	Supraglottis (Epiglottis to superior True Vocal Cord - TVC); Glottis (TVC, anterior/posterior commissures); Subglottis (Inferior TVC to inferior cricoid border)
Laryngeal Spaces	Ventricle (between False Vocal Cord - FVC and TVC); Reinke's Space (TVC submucosa); Paraglottic space; Preepiglottic space
Tracheal Structure	C-shaped hyaline cartilage rings (anteriorly); Trachealis muscle (posteriorly)

Region / Structure	Epithelium	Lamina Propria / Submucosa Features
Supraglottis	Mostly nonkeratinizing stratified squamous; Respiratory patches possible	Loose to dense connective tissue; Abundant seromucinous glands
Glottis (True Vocal Cord)	Nonkeratinizing stratified squamous	Reinke's Space: Loose, fibromyxoid connective tissue; Overlies vocal ligament (elastic) & vocalis muscle (skeletal); NO glands/lymphatics
Ventricle & False Vocal Cord	Respiratory (ciliated pseudostratified columnar with goblet cells)	Loose connective tissue; Abundant seromucinous glands
Subglottis	Respiratory (ciliated pseudostratified columnar with goblet cells)	Loose to dense connective tissue; Abundant seromucinous glands
Trachea	Respiratory (ciliated pseudostratified columnar with goblet cells)	Submucosa with seromucinous glands and cartilage

Ear & Temporal Bone

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Structure / Region	Description / Composition
External Ear	Auricle (Pinna): Elastic cartilage, skin; External Auditory Canal (EAC): Outer 1/3 cartilaginous (hair/glands), Inner 2/3 bony
Middle Ear (Tympanic Cavity)	Air-filled space in temporal bone; Tympanic Membrane (TM) (3 layers); Ossicles (Malleus, Incus, Stapes); Muscles (Tensor tympani, Stapedius); Eustachian Tube; Mastoid Air Cells
Inner Ear (Labyrinth)	Bony Labyrinth (Perilymph): Cochlea, Vestibule, Semicircular canals; Membranous Labyrinth (Endolymph): Cochlear duct, Utricle/Saccule, Semicircular ducts

Region / Structure	Epithelium	Lamina Propria / Submucosa / Other Features
External Ear	Auricle/Outer EAC: Skin (keratinizing stratified squamous); Inner EAC: Thin skin	Auricle: Elastic cartilage, adnexa; Outer EAC: Hair, sebaceous/ceruminous glands, elastic cartilage; Inner EAC: On bone, no adnexa
Middle Ear	Mucosa: Thin simple cuboidal / low columnar; Respiratory type near Eustachian tube; TM: Outer squamous, inner cuboidal	TM: Middle fibrous layer; Ossicles: Bone covered by thin mucosa; Eustachian Tube: Cartilage near pharynx
Inner Ear - Cochlea	Organ of Corti (in Cochlear Duct): Hair cells (inner/outer), Supporting cells; Stria Vascularis	Tectorial membrane overlies hair cells; Stria vascularis produces endolymph
Inner Ear - Vestibule	Maculae (in Utricle/Saccule): Hair cells, Supporting cells	Otolithic membrane (with otoliths) overlies hair cells
Inner Ear - Semicircular Canals	Cristae Ampullares (in Ampulla): Hair cells, Supporting cells	Cupula (gelatinous, no otoliths) overlies hair cells
Inner Ear - Endolymphatic Duct & Sac	Columnar epithelium	Involved in endolymph resorption

Salivary Glands (Major & Minor)

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Structure / Region	Description / Composition
Major Salivary Glands	Parotid (largest, serous, Stensen's duct); Submandibular (mixed serous/mucous, Wharton's duct); Sublingual (smallest, mostly mucous, Bartholin's/Rivinus ducts)
Minor Salivary Glands	Numerous small glands throughout oral cavity (lips, buccal mucosa, palate, tongue base), pharynx, larynx, trachea, sinonasal tract; mostly mucous or seromucous
General Structure	Encapsulated (major) or unencapsulated (minor); Lobulated parenchyma; Ductal system (intralobular: intercalated, striated; interlobular: excretory)

Component	Cell Types / Features
Acinar Cells	Serous cells (proteinaceous secretions, zymogen granules, basophilic cytoplasm, round basal nuclei); Mucous cells (mucin secretions, pale/foamy cytoplasm, flattened basal nuclei); Mixed acini (serous demilunes on mucous acini)
Ductal System	Intercalated ducts (low cuboidal epithelium, connect acini to striated ducts); Striated ducts (columnar cells, eosinophilic cytoplasm, basal striations due to mitochondria, ion transport); Excretory ducts (pseudostratified/stratified columnar to squamous near orifice)
Myoepithelial Cells	Contractile cells surrounding acini and intercalated/striated ducts; spindle/stellate shape; located between epithelial cells and basement membrane
Stroma	Connective tissue septa dividing lobules; contains blood vessels, nerves, lymphatics; adipose tissue (increases with age, esp parotid)

Gnathic Bones (Mandible & Maxilla)

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Structure / Region	Description / Composition
Mandible	Largest/strongest facial bone; Body (horizontal, alveolar process for teeth); Ramus (vertical part with condylar process - TMJ articulation, coronoid process - muscle attachment, mandibular notch, angle, mandibular foramen)
Maxilla (Paired)	Forms upper jaw, part of orbit, nasal cavity, hard palate; Body (contains maxillary sinus); Processes: Frontal, Zygomatic, Palatine, Alveolar (for teeth)
Teeth	(Briefly) Composed of Enamel (outer hardest layer), Dentin (bulk of tooth), Pulp (connective tissue, vessels, nerves), Cementum (covers root)
Temporomandibular Joint (TMJ)	Articulation between condylar process of mandible and mandibular fossa of temporal bone; Articular disc present

Component	Cell Types / Features
Bone Tissue	Cortical (Compact) Bone: Dense outer layer, organized into osteons (Haversian systems) with lamellae, lacunae (osteocytes), canaliculi; Cancellous (Spongy/Trabecular) Bone: Inner porous network of trabeculae, spaces filled with bone marrow
Bone Cells	Osteoblasts (bone formation, on surfaces); Osteocytes (mature bone cells in lacunae, maintain matrix); Osteoclasts (bone resorption, multinucleated, in Howship's lacunae)
Periosteum & Endosteum	Periosteum: Outer fibrous connective tissue covering bone (except articular surfaces); contains osteoprogenitor cells; Endosteum: Inner lining of marrow cavities, Haversian canals; contains osteoprogenitor cells
Bone Marrow	Red Marrow (hematopoietic tissue, in younger individuals and flat bones); Yellow Marrow (adipose tissue, in older individuals' long bone medullary cavities)
Teeth (Histologic Layers)	Enamel (acellular, highly mineralized); Dentin (tubular, less mineralized than enamel, surrounds pulp); Pulp (loose connective tissue, odontoblasts, vessels, nerves); Cementum (bone-like, covers dentin of root)

Thyroid Gland

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Structure / Region	Description / Composition
Location & Shape	Anterior neck, inferior to larynx, anterior and lateral to trachea; Butterfly-shaped
Lobes	Right and Left lobes connected by an Isthmus; Pyramidal lobe (variable superior extension from isthmus, remnant of thyroglossal duct)
Capsule & Vasculature	Thin fibrous capsule; Highly vascular (superior and inferior thyroid arteries)
Relations	Posteriorly: Parathyroid glands, recurrent laryngeal nerves; Medially: Trachea, esophagus; Laterally: Carotid sheath contents

Component	Cell Types / Features
Thyroid Follicles	Functional units; Spherical structures of varying size; Lined by a single layer of follicular epithelial cells (thyrocytes) - cuboidal (euthyroid), columnar (active), flattened (inactive); Lumen filled with colloid (pink, amorphous thyroglobulin)
Follicular Cells (Thyrocytes)	Produce thyroglobulin and thyroid hormones (T4, T3); Apical microvilli; Basal nuclei
Parafollicular Cells (C-cells)	Neuroendocrine cells derived from ultimobranchial body; Located individually or in small clusters in interfollicular stroma or within follicular basement membrane; Larger than follicular cells, pale/clear cytoplasm; Produce calcitonin
Stroma	Delicate connective tissue between follicles; Rich capillary network; Lymphatics

Parathyroid Glands

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Structure / Region	Description / Composition
Number & Location	Typically four glands (two superior, two inferior); Located on posterior surface of thyroid gland, within its capsule or sometimes embedded in thyroid parenchyma; Ectopic locations possible (thymus, mediastinum)
Size & Appearance	Small (3-6 mm length, 2-4 mm width, 0.5-2 mm thick); Oval or bean-shaped; Yellowish-brown color; Combined weight ~120-140 mg (each gland ~30-40 mg)

Component	Cell Types / Features
Chief Cells	Predominant cell type; Small polygonal cells with central, round, dark nuclei; Scant, slightly eosinophilic or clear cytoplasm; Arranged in cords, nests, or follicles; Secrete Parathyroid Hormone (PTH)
Oxyphil Cells	Larger than chief cells; Abundant, granular, intensely eosinophilic cytoplasm (packed with mitochondria); Small, dark, central nuclei; Appear after puberty, increase with age; Function uncertain, may be inactive chief cells
Water-Clear Cells	Rare in normal glands; Large cells with optically clear cytoplasm due to glycogen accumulation; Small, eccentric nuclei
Stromal Fat (Adipocytes)	Interspersed between parenchymal cells; Amount varies with age (increases from ~10-20% in young adults to ~40-60% in older adults); Decreased in hyperplasia/adenoma
Stroma & Vasculature	Delicate fibrovascular stroma; Rich capillary network

Neck (Soft Tissues, Lymph Nodes)

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Structure / Region	Description / Major Components
Triangles of the Neck	Anterior Triangle (subdivided: submental, submandibular, carotid, muscular); Posterior Triangle (subdivided: occipital, supraclavicular/subclavian); Boundaries defined by muscles (e.g., Sternocleidomastoid, Trapezius, Omohyoid)
Major Muscles	Sternocleidomastoid, Trapezius, Strap muscles (infrahyoid), Scalene muscles, Digastric, Mylohyoid
Major Vessels	Carotid arteries (common, internal, external) and branches; Jugular veins (internal, external, anterior) and tributaries
Major Nerves	Cranial nerves (IX, X, XI, XII traversing parts of neck), Brachial plexus roots/trunks, Cervical plexus, Phrenic nerve, Sympathetic trunk
Lymph Node Groups	Superficial and Deep cervical chains; Levels I-VII (e.g., Submental, Submandibular, Jugulodigastric, Supraclavicular) - important for staging/metastasis patterns

Tissue Type	Key Features / Cell Types
Adipose Tissue	Adipocytes (large cells with single large lipid droplet, peripheral nucleus); Delicate connective tissue septa with blood vessels
Fibrous Connective Tissue	Fibroblasts, collagen fibers (Type I most common), elastic fibers; Variable density (loose areolar to dense irregular)
Skeletal Muscle	Multinucleated muscle fibers (syncytia); Peripheral nuclei; Cross-striations (actin/myosin arrangement); Surrounded by endomysium, perimysium, epimysium
Blood Vessels (Arteries & Veins)	Tunica intima (endothelium); Tunica media (smooth muscle, elastic fibers - thicker in arteries); Tunica adventitia (connective tissue, vasa vasorum, nervi vasorum)
Nerves (Peripheral)	Axons (myelinated or unmyelinated) bundled into fascicles; Schwann cells (form myelin sheath, support unmyelinated axons); Connective tissue coverings: Endoneurium, Perineurium, Epineurium
Lymph Nodes	Capsule (dense connective tissue); Cortex (Outer: B-cell rich follicles with/without germinal centers; Paracortex: T-cell rich); Medulla (Medullary cords - plasma cells, macrophages; Medullary sinuses); Sinuses (subcapsular, trabecular, medullary - lined by endothelial cells, contain lymphocytes/macrophages)

Benign Oral Cavity & Oropharynx

Fibroepithelial Polyp / Irritation Fibroma

(Primarily focusing on Irritation Fibroma as the common oral entity)

Benign reactive proliferation of fibrous connective tissue, typically in response to chronic irritation or trauma.

Clinical ─

Age: Any age, peak 4th-6th decades

Sex: Female > male (2:1)

Site: Buccal mucosa (esp along occlusal line), lateral tongue, lips; less common on gingiva

Presentation: Asymptomatic, smooth-surfaced, firm, dome-shaped or polypoid nodule; usually <1.5 cm; normal mucosal color or pale pink

Etiology: Chronic irritation (cheek/lip biting, rubbing from dentures/appliances, calculus)

Treatment: Conservative surgical excision

Prognosis: Excellent; recurrence rare unless irritant persists; no malignant potential

Micro ─

─ Architecture: Unencapsulated, nodular mass of dense, fibrous connective tissue

─ Epithelium: Overlying stratified squamous epithelium, often intact; may show hyperkeratosis, acanthosis, or atrophy due to chronic irritation; ulceration possible if traumatized

─ Stroma: Haphazardly arranged collagen bundles; scattered fibroblasts (stellate or enlarged in Giant Cell Fibroma variant - distinct from Peripheral Giant Cell Granuloma); sparse vascularity

─ Inflammation: Typically minimal unless ulcerated

─ Cytology: Low cellularity; atypia/mitoses absent or minimal

DDx ─

Peripheral Ossifying Fibroma: Gingiva only, mineralization

Pyogenic Granuloma: Red/purple, bleeds easily, vascular

Peripheral Giant Cell Granuloma: Gingiva only, reddish-blue, giant cells

Mucocele: Bluish, fluctuant, mucin extravasation

True Benign Mesenchymal Neoplasms (Lipoma, Neurofibroma): Distinct features

Squamous Papilloma: Papillary surface, HPV-related

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Granular Cell Tumor

Benign mesenchymal neoplasm of Schwann cell origin composed of polygonal, large, granular cells.

Clinical ─

Age: Wide range, most common 3rd-5th decades

Sex: F > M (3:1) for intraoral tumors

Race: Predilection for Black patients

Site: Head and neck favored; Tongue (esp dorsal surface) > 50% of cases; also buccal mucosa, floor of mouth, palate, larynx (posterior vocal fold), trachea

Presentation: Solitary (usually) or multiple (10%-25%), painless, sessile submucosal mass; usually < 2 cm; slight yellow hue sometimes noted

Treatment: Conservative local excision

Prognosis: Excellent; recurrence uncommon (<10%); malignant variant extremely rare

Micro ─

Architecture:

─ Nonencapsulated, poorly circumscribed proliferation

─ Grows as sheets or vague fascicles, often blending with surrounding tissue (esp skeletal muscle)

─ May infiltrate nerves (not prognostically significant)

Cytology:

─ Large polygonal cells with abundant, pale amphophilic to eosinophilic, granular cytoplasm (lysosomes)

─ Ill-defined cell borders (syncytial appearance)

─ Nuclei small, round, centrally located, often pyknotic; minimal atypia

─ Mitoses rare; necrosis absent (if present, consider malignant GCT)

Overlying Epithelium:

─ Pseudoepitheliomatous hyperplasia (PEH) common (30%-50%), can mimic SCC

IHC ─

─ (+) S100 (strong, diffuse nuclear/cytoplasmic), SOX10 (nuclear), Inhibin, CD68 (cytoplasmic granules), Calretinin (variable)

─ (-) Cytokeratins, Desmin, SMA

DDx ─

Adult Rhabdomyoma: Lacks PEH, (+) Desmin, cross-striations/crystals may be seen

Congenital Granular Cell Epulis: Newborns, alveolar ridge exclusive, S100(-), lacks PEH

Alveolar Soft Part Sarcoma: More nuclear atypia, lacks S100/SOX10/Inhibin, TFE3 rearranged

PEComa: (+) HMB45, Melan-A, SMA

Squamous Cell Carcinoma: PEH can be a pitfall; look for underlying granular cells, SCC shows malignant cytology/invasion

Histiocytic lesions: Lack S100/SOX10

Oncocytic lesions: Lack S100/SOX10, epithelial markers (+)

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Oral Hairy Leukoplakia (OHL)

Benign epithelial disease associated with Epstein-Barr virus (EBV), nearly always in HIV-infected or other immunocompromised patients.

Clinical ─

Age: Any age, related to immune status

Sex: More common in males (reflecting HIV demographics)

Site: Lateral border of tongue (classic); may extend to dorsal/ventral surfaces

Etiology: Epstein-Barr Virus (EBV) replication in epithelial cells of immunocompromised host

Presentation: Asymptomatic white patch or plaque, often with vertical streaks or corrugated/shaggy surface; cannot be rubbed off

Association: HIV infection (correlates with viral load/CD4 count), organ transplant recipients, hematologic malignancies, long-term corticosteroid use

Treatment: Usually none required; may regress with improved immune status or antiviral therapy (e.g., for HIV); topical retinoids or podophyllin for cosmetic concerns

Prognosis: Benign; no malignant potential; indicator of immunosuppression

Micro ─

─ Epithelium: Marked acanthosis and hyperparakeratosis; elongation of rete ridges.

─ Cytology: Superficial spinous layer shows "balloon cells" (intracellular edema, clear cytoplasm, nuclear clearing/pyknosis, chromatin margination - viral cytopathic effect).

─ Inflammation: Little to no submucosal inflammation typically.

─ Secondary Infection: Candida coinfection common.

Molecular ─

─ EBV: Demonstrable by ISH (EBER) or IHC for EBV antigens (LMP1, ZEBRA/BZLF1) within epithelial cell nuclei, esp balloon cells.

DDx ─

Frictional Keratosis (tongue biting): Related to trauma, lacks balloon cells/EBV.

Candidiasis (Hyperplastic): Can be white, cannot be rubbed off; PAS/GMS shows hyphae invading superficial epithelium; OHL can have secondary candidiasis.

Idiopathic Leukoplakia/Dysplasia: May be white plaque but histologically shows atypia; EBV(-).

Oral Lichen Planus (Plaque-like): Can be white plaque on tongue; shows characteristic lichenoid interface mucositis.

Geographic Tongue: Migratory red patches with white borders; different clinical appearance.

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Oral Infections (Selected)

Inflammatory conditions caused by microorganisms affecting oral tissues.

Clinical ─

Presentation varies widely depending on organism and host immune status.

Micro ─

(Specific features depend on the infectious agent)

─ Candidiasis (Thrush, Moniliasis)

- Etiology: Candida albicans most common; opportunistic infection. Risk factors: antibiotic use, immunosuppression (HIV, steroids, chemotherapy), diabetes, xerostomia, dentures.

- Presentation: Pseudomembranous (white, curd-like plaques, can be wiped off, leaving erythematous base); Erythematous (red, atrophic patches, often painful/burning, e.g., denture stomatitis, median rhomboid glossitis); Hyperplastic (white plaques, cannot be wiped off, chronic); Angular cheilitis (erythema, fissuring at mouth corners).

- Micro: Superficial parakeratotic epithelium often infiltrated by neutrophils (microabscesses); Candida hyphae and pseudohyphae (2-4 µm wide) with yeast forms (spores) visible in superficial keratin layers, best seen with PAS or GMS stains. Underlying connective tissue shows variable chronic inflammation.

- DDx: Hairy leukoplakia (for hyperplastic), traumatic ulcer, lichen planus, leukoplakia/dysplasia.

─ Herpes Simplex Virus (HSV) Infection (Oral Herpes)

- Etiology: HSV-1 (most oral/perioral), HSV-2 (less common orally). Primary infection often in childhood (primary herpetic gingivostomatitis). Virus remains latent in trigeminal ganglion.

- Presentation:

- Primary: Fever, malaise, lymphadenopathy; multiple painful vesicles on any oral mucosa, which rupture to form shallow ulcers; gingiva often erythematous and edematous.

- Recurrent (Herpes Labialis/"Cold Sore", Intraoral Herpes): Prodrome (tingling, burning); cluster of small vesicles on vermilion border/perioral skin or on keratinized intraoral mucosa (hard palate, attached gingiva); vesicles rupture, crust (extraoral) or ulcerate (intraoral).

- Micro: Intraepithelial vesicles; acantholytic epithelial cells (Tzanck cells) floating in vesicle fluid; multinucleated giant epithelial cells with nuclear molding and "ground glass" chromatin or Cowdry type A intranuclear eosinophilic inclusions (viral cytopathic effect).

- DDx: Aphthous stomatitis (non-keratinized mucosa for recurrent), herpangina (Coxsackie), erythema multiforme, pemphigus vulgaris.

─ Actinomycosis (Lumpy Jaw)

- Etiology: Actinomyces israelii and other Actinomyces species (Gram-positive anaerobic/microaerophilic filamentous bacteria, normal oral flora).

- Presentation: Typically cervicofacial; chronic, slowly progressive, suppurative infection often following trauma (e.g., tooth extraction, jaw fracture) or dental infection. Indurated ("wooden") swelling, multiple abscesses, draining sinus tracts to skin surface; "sulfur granules" (yellowish bacterial colonies) may be expressed in pus.

- Micro: Central area of suppuration (abscess) containing characteristic "sulfur granules" - basophilic, radiating, club-shaped colonies of filamentous bacteria, often with an eosinophilic Splendore-Hoeppli phenomenon at the periphery of granules. Surrounded by neutrophils, granulation tissue, and chronic inflammatory cells (lymphocytes, plasma cells, macrophages); fibrosis in chronic lesions.

- DDx: Other bacterial abscesses (e.g., staphylococcal, streptococcal), tuberculosis, deep fungal infections, nocardiosis (acid-fast).

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Oral Lichen Planus (OLP)

Common chronic inflammatory mucocutaneous disease of unknown etiology, likely T-cell mediated autoimmune process targeting basal keratinocytes.

Clinical ─

Age: Middle-aged adults (peak 30-60 years); rare in children

Sex: Female > male (2:1)

Site: Buccal mucosa (most common, often bilateral), tongue, gingiva, lips; skin, nails, genital mucosa may also be affected

Presentation: Multifocal lesions; several clinical forms:

─ Reticular: Most common; asymptomatic; interlacing white keratotic lines (Wickham striae) or papules

─ Erosive/Ulcerative: Symptomatic (pain, burning); erythematous, atrophic areas with superficial ulceration, often with peripheral Wickham striae

─ Atrophic: Diffuse red patches, often symptomatic

─ Plaque-like: Resembles leukoplakia, white patches/plaques, esp on tongue

─ Bullous: Rare; vesicles/bullae that rupture

Etiology: Idiopathic; associations with stress, certain medications (lichenoid drug reaction), dental materials (lichenoid contact reaction), hepatitis C (controversial)

Treatment: Asymptomatic (reticular): no treatment; Symptomatic (erosive/atrophic): topical corticosteroids (gels, rinses), systemic corticosteroids for severe cases; immunosuppressants (e.g., cyclosporine, tacrolimus) for refractory cases

Prognosis: Chronic, waxing/waning course; small risk (<1%-2%) of malignant transformation to SCC, esp in erosive/atrophic forms (requires long-term follow-up)

Micro ─

─ Epithelium: Variable hyperkeratosis (ortho- or parakeratosis), acanthosis; "saw-tooth" rete ridges (pointed or irregular); liquefaction degeneration of basal cell layer.

─ Cytology: Degenerating keratinocytes (Civatte bodies/colloid bodies/hyaline bodies) at epithelial-connective tissue interface (apoptotic basal cells).

─ Lamina Propria: Dense, band-like lymphoplasmacytic infiltrate immediately subjacent to epithelium, hugging the basal layer.

─ Erosive/Ulcerative lesions: Epithelial separation/ulceration, fibrinopurulent exudate.

IHC ─

(Generally not required for diagnosis; DIF may be used to exclude other vesiculobullous diseases)

─ Direct Immunofluorescence (DIF) of perilesional tissue: Often shows shaggy linear band of fibrinogen at basement membrane zone; less commonly IgM, IgA, C3 (cytoid bodies may stain for immunoglobulins).

DDx ─

Lichenoid Drug/Contact Reaction: Histologically identical; clinical history is key

Lupus Erythematosus: Similar interface mucositis; DIF shows granular band of IgG, IgM, C3 at BMZ ("lupus band")

Chronic Ulcerative Stomatitis: Clinically similar to erosive OLP; DIF shows IgG autoantibodies targeting p63 in basal/parabasal nuclei

Mucous Membrane Pemphigoid: Subepithelial clefting; DIF shows linear IgG/C3 at BMZ

Pemphigus Vulgaris: Intraepithelial clefting; DIF shows intercellular IgG/C3

Dysplasia/SCC: Solitary lesion more common; cytologic atypia present; OLP can coexist or develop into dysplasia/SCC

Candidiasis: Can superinfect OLP; PAS/GMS for hyphae

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Mucous Membrane Pemphigoid (MMP) (Cicatricial Pemphigoid)

Chronic autoimmune subepithelial blistering disease predominantly affecting mucous membranes, characterized by autoantibodies targeting basement membrane zone components.

Clinical ─

Age: Middle-aged to elderly (peak 50-70 years)

Sex: Female > male (~1.5-2:1)

Site: Oral mucosa (most common, ~85-100% of patients, esp gingiva - "desquamative gingivitis"); conjunctiva (ocular involvement can lead to scarring/symblepharon, blindness); also skin, nasopharynx, larynx, esophagus, genitalia

Etiology: Autoantibodies (IgG, IgA, C3) against basement membrane components (e.g., BP180, BP230, laminin-332 (formerly laminin-5), integrin α6β4)

Presentation: Painful blisters that rupture to form erosions/ulcers; positive Nikolsky sign (blister formation with lateral pressure on normal-appearing mucosa); healing with scarring (cicatricial) in some sites (esp ocular)

Treatment: Topical/systemic corticosteroids; dapsone; immunosuppressants (azathioprine, mycophenolate, cyclophosphamide); IVIG for severe/refractory cases; ophthalmology consult crucial for ocular involvement

Prognosis: Chronic disease; morbidity related to scarring (ocular, esophageal, laryngeal stenosis); rarely life-threatening unless severe laryngeal/esophageal involvement

Micro ─

─ Epithelium: Intact stratified squamous epithelium separated from underlying connective tissue (subepithelial cleft/blister).

─ Cleft: Clean separation at basement membrane zone; roof of blister is full-thickness epithelium.

─ Lamina Propria: Variable chronic inflammatory infiltrate (lymphocytes, plasma cells, sometimes eosinophils) in superficial lamina propria; fibrosis in scarred lesions.

IHC ─

(DIF is crucial for diagnosis)

─ Direct Immunofluorescence (DIF) of perilesional tissue: Linear band of IgG and/or C3 (and sometimes IgA or IgM) along the epithelial basement membrane zone. Salt-split skin DIF can help localize antibody binding (epidermal side for bullous pemphigoid, dermal side for epidermolysis bullosa acquisita; MMP can be either or both).

DDx ─

Pemphigus Vulgaris: Intraepithelial clefting; intercellular IgG/C3 on DIF

Erosive Lichen Planus: Interface mucositis, liquefaction degeneration; shaggy fibrinogen at BMZ on DIF

Linear IgA Bullous Dermatosis (LABD): Subepithelial blisters; linear IgA at BMZ on DIF

Epidermolysis Bullosa Acquisita (EBA): Subepithelial blisters, often trauma-induced; linear IgG/C3 on dermal side of salt-split skin DIF

Bullous Pemphigoid: Primarily skin, oral lesions less common; subepidermal blisters; linear IgG/C3 at BMZ (epidermal side of salt-split skin)

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Pemphigus Vulgaris (PV)

Autoimmune intraepithelial blistering disease affecting skin and mucous membranes, characterized by autoantibodies (IgG) against desmosomal proteins (desmoglein-3 and/or desmoglein-1).

Clinical ─

Age: Peak 4th-6th decades; can occur at any age

Sex: Equal predilection

Ethnicity: Higher incidence in Ashkenazi Jews, people of Mediterranean or South Asian descent

Site: Oral mucosa is first site of involvement in ~50-70% of cases; may precede skin lesions by months; any oral site can be affected, esp buccal mucosa, palate, gingiva, lips

Presentation: Painful, flaccid blisters (bullae) that rupture easily, leaving extensive, irregular, slow-healing erosions/ulcers; positive Nikolsky sign; cutaneous lesions often flaccid blisters on normal or erythematous skin, or erosions

Treatment: Systemic corticosteroids are mainstay; adjuvant immunosuppressants (azathioprine, mycophenolate mofetil, cyclophosphamide, rituximab) for steroid-sparing or refractory disease; IVIG

Prognosis: Chronic disease; potentially life-threatening if untreated (due to fluid/electrolyte imbalance, infection); mortality significantly reduced with corticosteroids but side effects of long-term therapy are a concern

Micro ─

─ Epithelium: Intraepithelial clefting/vesicle formation, characteristically suprabasilar (above the basal cell layer).

─ Acantholysis: Loss of intercellular adhesion between keratinocytes results in rounded, detached keratinocytes (Tzanck cells) within the blister cavity.

─ Basal Layer: Basal cells remain attached to basement membrane ("row of tombstones" appearance).

─ Lamina Propria: Usually mild, nonspecific chronic inflammatory infiltrate.

IHC ─

(DIF is crucial for diagnosis)

─ Direct Immunofluorescence (DIF) of perilesional tissue: Deposition of IgG (and often C3) in a net-like or "chicken-wire" pattern around keratinocytes in the intercellular spaces of the epithelium.

─ Indirect Immunofluorescence (IDIF) of serum: Detects circulating anti-desmoglein IgG antibodies in ~80-90% of patients; titer may correlate with disease activity.

DDx ─

Mucous Membrane Pemphigoid: Subepithelial clefting; linear IgG/C3 at BMZ on DIF

Erythema Multiforme: Variable intraepithelial/subepithelial edema/vesiculation, keratinocyte necrosis, lymphocytic infiltrate; DIF usually negative

Hailey-Hailey Disease (Benign Familial Pemphigus): Suprabasilar acantholysis ("dilapidated brick wall"); autosomal dominant; DIF negative

Darier Disease (Keratosis Follicularis): Suprabasilar acantholysis with dyskeratosis (corps ronds, grains); autosomal dominant; DIF negative

Paraneoplastic Pemphigus: Severe mucositis/stomatitis, polymorphous skin lesions; associated with underlying neoplasm (often lymphoma/leukemia); complex autoantibody profile targeting plakin proteins and desmogleins; DIF shows both intercellular and BMZ staining.

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Recurrent Aphthous Stomatitis (RAS) (Canker Sores)

Common oral mucosal condition characterized by recurrent, painful, single or multiple, well-demarcated ulcers on non-keratinized oral mucosa.

Clinical ─

Age: Onset usually in childhood/adolescence, persists into adulthood; frequency/severity may decrease with age

Sex: Slight female predilection

Site: Exclusively on non-keratinized (movable) oral mucosa: buccal mucosa, labial mucosa, ventral tongue, floor of mouth, soft palate; NOT on hard palate or attached gingiva (helps distinguish from recurrent intraoral herpes)

Etiology: Unknown; likely multifactorial with immunologic basis; triggers/associations: stress, local trauma, certain foods (acidic, nuts, chocolate), hormonal changes, nutritional deficiencies (iron, B12, folate), SLS in toothpaste, familial tendency, certain systemic conditions (Behçet disease, celiac disease, Crohn's disease, HIV)

Presentation:

─ Minor Aphthae (most common, ~80%): 1-5 ulcers, <1 cm diameter, shallow, round/oval, yellowish-gray pseudomembrane, erythematous halo; heal in 7-14 days without scarring.

─ Major Aphthae (Sutton disease, periadenitis mucosa necrotica recurrens, ~10%): 1-10 ulcers, >1 cm diameter, deeper, more painful; heal in weeks to months, often with scarring.

─ Herpetiform Aphthae (~10%): Multiple (10-100) small (1-3 mm) pinpoint ulcers that may coalesce; heal in 7-14 days.

Treatment: Symptomatic relief: topical anesthetics, protective pastes, topical corticosteroids (for severe/frequent outbreaks); systemic corticosteroids or other immunomodulators (e.g., colchicine, thalidomide) for severe/refractory major aphthae; address underlying deficiencies/triggers if identified

Prognosis: Benign, self-limiting episodes; chronic recurrence is typical

Micro ─

(Biopsy usually not needed for diagnosis, features are nonspecific)

─ Ulcer Bed: Central area of ulceration covered by a fibrinopurulent membrane (fibrin, neutrophils, necrotic debris).

─ Underlying Connective Tissue: Granulation tissue with increased vascularity; mixed inflammatory infiltrate (lymphocytes, histiocytes, neutrophils; plasma cells in later stages).

─ Adjacent Epithelium: May show spongiosis and inflammatory cell transmigration.

DDx ─

Recurrent Intraoral Herpes Simplex: Keratinized mucosa, vesicular prodrome, viral cytopathic changes on biopsy

Traumatic Ulcer: History of trauma, may be on any mucosa, often solitary

Behçet Disease: Oral aphthae plus genital ulcers, skin lesions, ocular inflammation

Cyclic Neutropenia: Recurrent oral ulcers associated with neutropenic episodes

Erythema Multiforme: Often more extensive, "target" skin lesions may be present

Pemphigus/Pemphigoid: Chronic blistering/erosions, different biopsy/DIF findings

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Traumatic Ulcerative Granuloma with Stromal Eosinophilia (TUGSE)

Reactive, self-limiting, chronic oral ulcerative lesion characterized by a deep, penetrating inflammatory infiltrate that includes eosinophils.

Clinical ─

Age: Any age, but common in adults

Sex: Slight male predilection reported in some series

Site: Tongue (esp lateral/ventral borders) most common; also lips, buccal mucosa; any site prone to trauma

Etiology: Chronic or repetitive trauma (e.g., sharp tooth/restoration, biting, dental appliances); pathogenesis may involve T-cell mediated reaction to muscle damage

Presentation: Solitary, persistent ulcer (days to months); often indurated, rolled borders, may be painful; can clinically mimic SCC

Treatment: Incisional biopsy often performed to rule out malignancy; lesion usually heals rapidly after biopsy or removal of traumatic source; intralesional corticosteroids for persistent lesions

Prognosis: Excellent; self-healing once trauma removed or after biopsy; recurrence rare

Micro ─

─ Ulceration: Surface covered by fibrinopurulent membrane.

─ Inflammation: Deep, diffuse, mixed inflammatory infiltrate extending into submucosa, often into underlying skeletal muscle or salivary gland tissue.

- Eosinophils: Characteristically prominent component of the infiltrate.

- Other cells: Lymphocytes, plasma cells, histiocytes (sometimes large, atypical, CD30+).

─ Atypical Cells: Large, mononuclear cells with vesicular nuclei and prominent nucleoli (histiocytes/myofibroblasts/T-cells) can be present, sometimes alarming; mitoses may be seen but are not atypical.

─ Tissue Damage: Necrosis of muscle fibers, fibrin deposition.

─ Epithelium: Adjacent epithelium may show pseudoepitheliomatous hyperplasia.

IHC ─

(Generally not required for diagnosis, but may be used in atypical cases)

─ Large atypical cells: May be CD30(+), CD68(+); T-cell markers (CD3, CD4, CD8) often positive on infiltrating lymphocytes.

DDx ─

Squamous Cell Carcinoma: Must be excluded, esp clinically; SCC shows malignant cytologic atypia and invasive growth pattern

Aphthous Ulcer (Major): Typically non-keratinized mucosa, lacks deep penetrating eosinophilic infiltrate

Infectious Ulcers (e.g., Deep Fungal, Syphilis): Specific organisms demonstrable with special stains/culture

Lymphoma (esp Angioimmunoblastic T-cell or Hodgkin): Different lymphoid atypia, specific IHC profile

Langerhans Cell Histiocytosis: (+) S100, CD1a, Langerin

Eosinophilic Ulcer of Skin: Similar histology, but different clinical context

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Fordyce Granules

Benign ectopic sebaceous glands (not associated with hair follicles) occurring on oral mucosa; considered a normal anatomic variant.

Clinical ─

Age: More evident after puberty, common in adults (up to 80%)

Sex: Equal predilection

Site: Buccal mucosa (esp bilaterally, posterior), vermilion border of upper lip; less often retromolar pad, tongue, gingiva, frenum

Presentation: Asymptomatic, multiple, small (1-2 mm), discrete, yellowish or yellowish-white, slightly elevated papules; may coalesce into larger plaques

Treatment: None required; reassurance of benign nature

Prognosis: Excellent; normal variant

Micro ─

─ Architecture: Normal-appearing sebaceous gland lobules located superficially in the submucosa, immediately beneath the squamous epithelium.

─ Cytology: Lobules composed of mature sebaceous cells with abundant, foamy cytoplasm and small, central, pyknotic nuclei; peripheral basaloid (germinative) cells may be seen.

─ Ducts: Sebaceous ducts may or may not be seen opening to the surface epithelium.

─ Associated Structures: Hair follicles are absent.

DDx ─

Superficial Mucocele (small): Can be small papules but usually bluish/translucent and fluid-filled

Xanthoma (Verruciform Xanthoma if warty surface): Contains lipid-laden foam cells (macrophages), not sebaceous glands

Lipoid Proteinosis: Rare systemic disease, yellowish infiltrates

Milia: Small keratinous cysts (more common on skin)

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Amalgam Tattoo (Focal Argyrosis)

Common localized iatrogenic exogenous pigmentation of oral mucosa caused by traumatic implantation of dental amalgam particles into soft tissues.

Clinical ─

Age: Any age, common in adults with dental restorations

Sex: Equal predilection

Site: Gingiva, alveolar mucosa, buccal mucosa most common; any site adjacent to amalgam restorations

Presentation: Asymptomatic, flat (macular) or slightly raised, blue, gray, or black discolored area; size varies from small flecks to several centimeters; well-defined or diffuse borders

History: Often history of dental procedure (filling, extraction, apicoectomy) involving amalgam

Radiographs: May show radiopaque amalgam fragments if particles are large enough

Treatment: None required if diagnosis is clear; biopsy if clinical uncertainty (esp to rule out melanocytic lesion) or for cosmetic reasons

Prognosis: Harmless, persistent pigmentation

Micro ─

─ Pigment: Discrete, fine, dark brown to black granules, or larger irregular solid fragments of metallic amalgam.

─ Location: Pigment particles scattered within connective tissue (lamina propria, submucosa), often along collagen fibers, around blood vessels, nerves, or within macrophages.

─ Tissue Reaction: Usually minimal to no inflammatory response; occasionally a foreign body giant cell reaction or chronic inflammation (lymphocytes, plasma cells) around larger particles.

DDx ─

Melanotic Macule (Oral): Flat, brown, increased melanin in basal layer, melanophages; no metallic particles

Nevus (Oral Melanocytic): Usually brown, nested melanocytes; no metallic particles

Malignant Melanoma (Oral): Irregular pigmentation, nodularity, ulceration, atypia; biopsy essential if suspected

Graphite Tattoo (Pencil Lead): Similar dark particles, history of puncture

Heavy Metal Pigmentation (Systemic, e.g., lead, bismuth): More diffuse, often linear along gingival margin, systemic symptoms

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Ectopic Thyroid (Lingual Thyroid)

Thyroid tissue located outside its normal pretracheal position, most commonly at the base of the tongue along the path of embryonic descent of the thyroglossal duct.

Clinical ─

Age: Can present at any age; often detected during puberty, pregnancy, or menopause due to hormonal changes causing enlargement

Sex: Female > male (4-7:1)

Site: Base of tongue, in midline, between foramen cecum and epiglottis (90% of ectopic thyroid cases)

Presentation: Asymptomatic or symptoms due to mass effect: dysphagia, dysphonia, dyspnea, globus sensation; smooth, nodular, vascular submucosal mass

Function: In >70% of lingual thyroid cases, this is the only functioning thyroid tissue; hypothyroidism common (up to 1/3 of patients)

Diagnosis: Thyroid scan (123I or 99mTc pertechnetate) is diagnostic, shows uptake in ectopic location and absence of normal cervical thyroid if it's the only tissue

Treatment: Asymptomatic/euthyroid: observation; Hypothyroid: thyroid hormone replacement (may shrink mass); Symptomatic/obstructive: surgical excision or radioiodine ablation (if other thyroid tissue present or after hormone replacement established)

Prognosis: Generally good; rare (<1%) malignant transformation (usually papillary thyroid carcinoma)

Micro ─

─ Tissue: Unencapsulated collection of thyroid follicles of varying size, containing colloid.

─ Epithelium: Follicles lined by cuboidal to flattened follicular epithelium.

─ Stroma: Interspersed between skeletal muscle fibers of the tongue; variable connective tissue.

─ Associated Changes: May show changes similar to normally located thyroid, e.g., lymphocytic thyroiditis, nodular hyperplasia.

DDx ─

Hypertrophic Lingual Tonsil: Lymphoid tissue, posterior tongue lateral to midline

Granular Cell Tumor: Common on tongue, submucosal, S100(+)

Salivary Gland Tumor (Minor): Different histology (e.g., pleomorphic adenoma)

Vascular Malformation (e.g., Hemangioma, Lymphangioma): Vascular/lymphatic channels

Midline Dermoid/Epidermoid Cyst: Deeper, cystic, keratin/adnexal structures

Metastatic Thyroid Carcinoma to Tongue Base: Rare; typically history of thyroid primary; malignant cytology

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Multifocal Epithelial Hyperplasia (Heck Disease)

Benign, virus-induced (HPV types 13 and 32) proliferation of oral squamous epithelium, presenting as multiple, soft, flat papules or nodules.

Clinical ─

Age: Primarily children and adolescents; can occur in adults

Ethnicity: Higher prevalence in certain populations (Native Americans, Inuit, some Latin American groups), but seen worldwide

Site: Labial mucosa, buccal mucosa, lingual mucosa most common; usually multiple, clustered lesions

Etiology: Human Papillomavirus (HPV) types 13 and 32

Presentation: Asymptomatic, multiple, discrete, soft, sessile, pale pink or mucosa-colored, flat-topped or slightly rounded papules/nodules (few mm to 1 cm); may coalesce into larger plaques

Association: Familial clustering, lower socioeconomic status, HIV infection (may be more extensive)

Treatment: Often none required; spontaneous regression common, esp in children

- If persistent or for cosmetic reasons: conservative surgical excision, cryotherapy, laser ablation

Prognosis: Excellent; benign, no malignant potential; may persist for months to years before regressing

Micro ─

─ Epithelium: Marked acanthosis (thickening of spinous layer) with broad, blunted, and often confluent rete ridges.

─ Cytology: Keratinocytes usually show normal maturation without significant atypia.

- Mitosoid cells: Characteristic feature; altered keratinocytes in upper spinous layer with nuclear fragmentation/condensation resembling atypical mitotic figures, but are a viral cytopathic effect.

- Koilocyte-like cells: May be present; cells with perinuclear halos and pyknotic, crinkled nuclei (less prominent than in typical warts).

─ Surface: Parakeratosis common.

─ Lamina Propria: Minimal inflammation usually.

DDx ─

Condyloma Acuminatum (Oral): More exophytic/papillary, prominent koilocytes, often HPV 6/11

Squamous Papilloma (Oral): Usually solitary, more papillary, often HPV 6/11

Verruca Vulgaris (Oral): More hyperkeratotic, prominent granular layer, often HPV 2/4

Focal Dermal Hypoplasia (Goltz Syndrome): Rare genetic disorder with oral papillomas, skin/skeletal abnormalities

Cowden Syndrome: Multiple oral papillomas/trichilemmomas, other systemic features, PTEN mutation

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Peripheral Ossifying Fibroma (POF)

Reactive, non-neoplastic, exophytic gingival lesion composed of cellular fibrous connective tissue with focal formation of bone or other calcified material.

Clinical ─

Age: Peak incidence in 2nd decade (teenagers, young adults); wide age range

Sex: Female > male (~1.7:1)

Site: Exclusively on gingiva or alveolar ridge, esp interdental papilla region; Maxilla > mandible; Anterior > posterior

Etiology: Reactive proliferation, likely arising from cells of periodontal ligament; local irritants (plaque, calculus, restorations) implicated

Presentation: Well-demarcated, firm, sessile or pedunculated nodule; usually <2 cm; color ranges from pink to red; surface may be intact or ulcerated due to trauma

Treatment: Surgical excision down to periosteum, including removal of any local irritants and scaling of adjacent teeth

Prognosis: Good; recurrence rate ~8-20% (higher if incompletely excised or irritant persists)

Micro ─

─ Epithelium: Overlying stratified squamous epithelium, often ulcerated with associated granulation tissue and inflammation.

─ Stroma: Highly cellular fibroblastic connective tissue.

─ Mineralization: Characteristic feature; randomly distributed, variable amounts of mineralized product:

- Woven or lamellar bone

- Cementum-like material (acellular, basophilic, rounded/globular)

- Dystrophic calcifications

─ Cellularity: Fibroblasts are plump, spindle to stellate; multinucleated giant cells may be present but not numerous.

DDx ─

Pyogenic Granuloma (Lobular Capillary Hemangioma): More vascular, red, bleeds easily, lacks mineralization

Peripheral Giant Cell Granuloma: Reddish-blue, more prominent multinucleated giant cells, vascular stroma, lacks bone/cementum

Irritation Fibroma: Less cellular, more collagenous, lacks mineralization, not exclusive to gingiva

Peripheral Odontogenic Fibroma (WHO type): More organized fibrous stroma, odontogenic epithelial rests prominent, less prominent mineralization (controversial entity, some consider POF a type of this)

Osteoma/Exostosis: Hard, bony mass, mature bone histologically

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Peripheral Giant Cell Granuloma (PGCG) (Giant Cell Epulis)

Reactive, exophytic lesion of the gingiva or edentulous alveolar ridge, characterized by a proliferation of multinucleated giant cells in a vascular, fibroblastic stroma.

Clinical ─

Age: Wide age range, peak 4th-6th decades

Sex: Female > male

Site: Exclusively on gingiva or edentulous alveolar ridge; Mandible > maxilla; often anterior to molars

Etiology: Reactive response to local irritation or trauma (e.g., plaque, calculus, ill-fitting dentures, extractions)

Presentation: Sessile or pedunculated, soft to firm, reddish-blue or purplish nodule; usually <2 cm; surface may be smooth or ulcerated; may cause superficial "cupping" resorption of underlying alveolar bone

Treatment: Surgical excision down to underlying bone; curettage of bone base; removal of local irritants

Prognosis: Good; recurrence rate ~10-18% (higher with incomplete removal or persistent irritation)

Micro ─

─ Epithelium: Overlying stratified squamous epithelium, often ulcerated.

─ Cellular Proliferation: Highly cellular lesion composed of:

- Multinucleated Giant Cells: Numerous, large, osteoclast-like, containing variable numbers of nuclei (few to dozens); haphazardly distributed.

- Mononuclear Stromal Cells: Plump, ovoid to spindle-shaped fibroblasts and histiocyte-like cells forming the background.

─ Stroma: Richly vascular (capillaries prominent); hemorrhage and hemosiderin deposition common (contributes to clinical color).

─ Inflammation: Variable chronic inflammatory infiltrate.

─ Bone: Metaplastic bone formation may be seen at the base, but not within the main lesion.

DDx ─

Pyogenic Granuloma: More distinctly lobular vascular proliferation, lacks prominent giant cells

Peripheral Ossifying Fibroma: Contains bone/cementum-like mineralization, fewer giant cells

Brown Tumor of Hyperparathyroidism: Histologically identical; occurs centrally in bone or peripherally; associated with hyperparathyroidism (check serum calcium/PTH)

Central Giant Cell Granuloma (with perforation): Arises within bone, may perforate cortex to present on gingiva; radiographically an intraosseous lesion

Aneurysmal Bone Cyst (peripheral): Rare on gingiva; blood-filled spaces, fibrous septa with giant cells

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Congenital Granular Cell Epulis (Congenital Epulis of the Newborn, Neumann's Tumor)

Rare benign mesenchymal tumor composed of large cells with coarse granular cytoplasm, classically arising from the anterior alveolar ridge of newborns.

Clinical ─

Age: Present at birth (congenital) or within first few weeks

Sex: Female >>> male (~8-10:1)

Site: Alveolar ridge of maxilla (more common) or mandible, esp anterior/incisor-canine region

Presentation: Solitary (usually), firm, smooth-surfaced, pink or mucosa-colored, pedunculated or sessile polypoid mass; size varies (few mm to several cm, rarely very large causing feeding/breathing issues)

Treatment: Conservative surgical excision; spontaneous regression reported but uncommon/unpredictable

Prognosis: Excellent; does not recur even if incompletely excised; no malignant potential

Micro ─

─ Architecture: Nonencapsulated, submucosal proliferation of cells in sheets, cords, or nests, supported by delicate fibrovascular septa.

─ Cytology: Large, polygonal cells with abundant, eosinophilic, granular cytoplasm (PAS-positive, diastase-resistant granules); nuclei are small, round to oval, often eccentrically placed, bland.

─ Overlying Epithelium: Usually intact, may be atrophic.

─ Odontogenic Epithelium: Strands or rests of odontogenic epithelium may be entrapped within the lesion.

IHC ─

─ (-) S100, SOX10 (unlike adult Granular Cell Tumor)

─ (-) Desmin, Actin, Cytokeratins

─ Variable/focal (+) CD68 (lysosomal marker)

DDx ─

Granular Cell Tumor (Adult type): Histologically similar granular cells but S100(+), SOX10(+); occurs in older individuals, tongue most common site, PEH common

Rhabdomyoma (Fetal/Adult): Shows skeletal muscle differentiation, (+) Desmin, Myogenin

Melanotic Neuroectodermal Tumor of Infancy: Biphasic (small blue cells and larger melanin-containing cells), rapidly growing, often pigmented, involves bone

Hemangioma/Vascular Malformation: Endothelial-lined vascular spaces

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Ectomesenchymal Chondromyxoid Tumor (EMCMT)

Benign mesenchymal neoplasm of uncertain histogenesis (possibly mixed myoepithelial and neural crest features), almost exclusively occurring in the anterior dorsal tongue.

Clinical ─

Age: Wide age range (peak 4th decade)

Sex: Equal predilection

Site: Anterior dorsal tongue (vast majority); rare cases reported in other oral sites (e.g., soft palate)

Presentation: Asymptomatic, slow-growing, well-circumscribed, firm, submucosal nodule; usually 0.5 - 2 cm

Treatment: Conservative local excision

Prognosis: Excellent; recurrence rare, even with incomplete excision; no malignant potential

Micro ─

─ Architecture: Well-circumscribed but unencapsulated; often lobulated; may appear to infiltrate adjacent muscle.

─ Cellularity: Variable; ranges from hypocellular myxoid areas to more cellular chondroid-like areas.

─ Cells: Round, oval, spindle, or stellate cells arranged in cords, strands, nests, or a reticular pattern within an abundant myxoid or chondromyxoid stroma.

─ Cytoplasm: Eosinophilic to amphophilic, sometimes vacuolated or fibrillar.

─ Nuclei: Round to oval, often with indentations or grooves; vesicular chromatin; inconspicuous nucleoli; minimal atypia; mitoses rare.

─ Stroma: Abundant myxoid, chondromyxoid, or hyalinized matrix; Alcian blue positive.

─ Other: Entrapment of skeletal muscle fibers common at periphery.

IHC ─

─ (+) GFAP (often strong and diffuse), S100 (variable, often patchy), Cytokeratins (AE1/AE3, CAM5.2 - often focal/patchy), SMA (variable)

─ (-) Desmin, p63, Calponin (usually), SOX10 (usually)

─ EWSR1 gene fusions reported in a subset, suggesting link to soft tissue myoepithelial neoplasms.

DDx ─

Myxoid Neurofibroma: More wavy/buckled nuclei, less chondromyxoid stroma, S100(+) diffusely, SOX10(+)

Nerve Sheath Myxoma (Neurothekeoma, myxoid variant): More lobulated, epithelioid/spindle cells, S100(+)

Pleomorphic Adenoma (Myxoid predominant): Ductal structures present (even if focal), myoepithelial cells, GFAP(+) in stroma, p63(+)

Myoepithelioma (Myxoid): Lacks ductal structures, more prominent myoepithelial features, S100/SMA/Calponin/p63 often positive

Extraskeletal Myxoid Chondrosarcoma: Rare in oral cavity, more cellular atypia/mitoses, EWSR1::NR4A3 fusion common

Focal Oral Mucinosis: Hypocellular, avascular, myxoid stroma, bland spindle/stellate cells; essentially a myxoma of oral soft tissues

Mucous Retention Phenomenon (Mucocele): Pool of extravasated mucin with inflammatory reaction, lacks true neoplastic cells

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Benign Larynx, Hypopharynx & Trachea

Vocal Cord Polyps and Nodules

Reactive changes of laryngeal mucosa and adjacent stroma resulting in a benign polypoid or nodular growth.

Clinical ─

Age: Polyps any age; Nodules more common young women, children (boys > girls)

Sex: Polyps equal; Nodules F > M (adults), M > F (children)

Site: True vocal cords (nodules usually bilateral, anterior-mid portion; polyps usually unilateral, aryepiglottic fold, ventricular space, vocal fold, or Reinke space)

Etiology: Multifactorial; vocal abuse/overuse (singers, teachers), trauma (accidents, surgery), infection, hypothyroidism, smoking

Presentation: Hoarseness, vocal changes (unstable voice, breathiness, decreased range), discomfort

Treatment: Voice therapy, behavior modification, vocal hygiene; medical management of underlying conditions (e.g., reflux, hypothyroidism); surgery (microlaryngoscopy with excision) for persistent/large lesions

Prognosis: Excellent; resolution with conservative measures common; recurrence possible if underlying cause persists

Micro ─

─ Architecture: Polypoid or nodular submucosal process; surface epithelium usually intact squamous type.

─ Stroma (Spectrum/Arc of Development):

─ Early/Edematous/Telangiectatic: Marked edema, proteinaceous fluid, dilated thin-walled blood vessels, hemorrhage.

─ Myxoid: Pale blue-pink myxoid matrix.

─ Hyaline/Fibrinous: Fibrin deposition, hyalinized collagen, often around vessels.

─ Fibrous: Increased spindle cells (fibroblasts/myofibroblasts) in a dense fibrous stroma (older/organized lesions).

─ Epithelium: Overlying squamous epithelium may show reactive changes (hyperplasia, hyperkeratosis, parakeratosis, acanthosis, atrophy); no significant dysplasia.

─ Inflammation: Usually scant to absent; may be present if ulcerated or traumatized.

─ Basement Membrane: Often thickened and hyalinized, esp in nodules.

DDx ─

Amyloidosis: Acellular eosinophilic deposits, Congo red(+) with apple-green birefringence, perivascular/periglandular

Myxoma: Rare in larynx; avascular, hypocellular, abundant gelatinous/myxoid stroma, stellate cells

Contact Ulcer/Granuloma: Posterior larynx, associated with reflux/intubation/vocal abuse, surface ulceration, granulation tissue

Ligneous Conjunctivitis (Laryngeal involvement): Rare; thick, woody, fibrin-rich pseudomembranous lesions

Granular Cell Tumor: Submucosal, S100(+), characteristic granular cells, often PEH

Spindle Cell Squamous Cell Carcinoma: Malignant cytology, invasive growth, atypical mitoses

Vocal Cord Cysts (Epidermoid/Mucous Retention): True cystic lining

Reinke's Edema: Diffuse gelatinous swelling of Reinke's space, often bilateral, associated with smoking

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Contact Ulcer / Granuloma (Laryngeal)

Benign reactive lesion of the posterior larynx, typically over the vocal processes of the arytenoid cartilages, resulting from mucosal injury.

Clinical ─

Age: Adults, M > F (except post-intubation)

Site: Posterior larynx, medial surface of arytenoid cartilage or vocal process

Etiology: Vocal abuse/misuse (forceful voice, throat clearing, chronic cough); Laryngopharyngeal reflux (LPR); Endotracheal intubation trauma

Presentation: Hoarseness, chronic cough, throat clearing, globus sensation, pain (may radiate to ear); often unilateral but can be bilateral ("kissing ulcers")

Treatment: Voice therapy, anti-reflux medication, behavioral modification; surgical excision for persistent/obstructive lesions (recurrence common if underlying cause not addressed)

Prognosis: Benign; often recurrent if underlying cause persists

Micro ─

─ Ulceration: Surface epithelium denuded, replaced by fibrinopurulent exudate.

─ Granulation Tissue: Underlying stroma shows exuberant granulation tissue: proliferating capillaries (often perpendicular to surface), plump fibroblasts/myofibroblasts, mixed inflammatory infiltrate (neutrophils, lymphocytes, plasma cells, histiocytes).

─ Chronic Phase: May show more fibrosis and re-epithelialization over the granulation tissue; fibrinoid necrosis may persist at the base.

─ Cartilage: Underlying arytenoid cartilage may show perichondritis or reactive changes if ulcer is deep.

DDx ─

Specific Infections (e.g., Fungal, Mycobacterial): Granulomas, organisms on special stains/culture

Granulomatosis with Polyangiitis (GPA): Necrotizing granulomas, vasculitis, c-ANCA(+)

Squamous Cell Carcinoma: Malignant cytology, invasion; PEH adjacent to contact ulcer can be a pitfall

Tuberculosis: Caseating granulomas, AFB(+)

Sarcoidosis: Non-caseating granulomas, systemic involvement

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Laryngeal Amyloidosis

Localized deposition of amyloid protein in the larynx, the most common site for localized amyloidosis in the respiratory tract.

Clinical ─

Age: Adults, wide range (peak 5th-7th decades)

Sex: Male > female

Site: False vocal cords, ventricles, aryepiglottic folds, subglottis > true vocal cords

Presentation: Hoarseness (most common), dysphagia, dyspnea, stridor; smooth, firm, waxy, yellowish or pink submucosal nodules or diffuse swelling

Association: Usually localized (AL type, light chain-derived); rarely associated with systemic amyloidosis or plasma cell dyscrasia (e.g., multiple myeloma)

Treatment: Endoscopic surgical excision/debulking for symptomatic relief; laser ablation; observation for asymptomatic lesions

Prognosis: Generally good for localized disease; slow progression; recurrence common after local excision

Micro ─

─ Deposits: Extracellular, acellular, amorphous, hyaline-like, eosinophilic amyloid material in submucosa.

─ Distribution: Often perivascular, periglandular, or surrounding adipocytes; may compress or replace normal structures.

─ Cellular Reaction: Variable, often sparse lymphoplasmacytic infiltrate; foreign body giant cell reaction to amyloid deposits may be seen.

─ Epithelium: Overlying epithelium usually intact, may be atrophic.

IHC ─

─ Amyloid P Component: (+) in amyloid deposits

─ Light Chains: Often shows lambda (λ) light chain restriction in AL type (immunostaining or mass spectrometry-based proteomic analysis)

─ Calcitonin: (-) (to exclude medullary thyroid carcinoma amyloid)

Special Stains ─

─ Congo Red: Positive (pink/red staining) with characteristic apple-green birefringence under polarized light (diagnostic).

─ Crystal Violet/Thioflavin T: Metachromatic staining.

DDx ─

Vocal Cord Polyp (Hyaline type): Fibrin/collagen, lacks amyloid staining properties

Lipoid Proteinosis (Hyalinosis Cutis et Mucosae): Rare genetic; hyaline deposits in skin/mucosa, PAS(+), Congo Red(-)

Extramedullary Plasmacytoma with Amyloid: Monoclonal plasma cell infiltrate, light chain restriction

Medullary Thyroid Carcinoma (metastatic or direct extension with amyloid): Calcitonin(+) amyloid

Fibrosis/Scar: Collagenous, lacks amyloid staining

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Laryngeal Cysts & Laryngocele

Benign, fluid-filled or air-filled sacs within the larynx.

Clinical ─

Types:

─ Ductal Cysts (Mucous Retention Cysts): Most common (75%); obstruction of submucosal gland ducts; true vocal cords, false vocal cords, epiglottis, aryepiglottic folds.

─ Saccular Cysts: Congenital or acquired; distension of laryngeal saccule (appendix of ventricle); do not communicate with laryngeal lumen; anterior (projects into ventricle) or lateral (projects into false cord/aryepiglottic fold).

─ Laryngocele: Abnormal air-filled dilatation/herniation of laryngeal saccule that communicates with laryngeal lumen; Internal (confined to larynx), External (extends through thyrohyoid membrane into neck), or Mixed. More common in men, glassblowers, wind instrument players.

Age: Cysts - any age, often adults; Laryngoceles - often older adults

Presentation: Hoarseness, dysphonia, globus sensation, cough, stridor, dyspnea (esp large lesions); laryngocele may present as compressible neck mass that enlarges with Valsalva.

Association: Laryngoceles can be associated with laryngeal carcinoma (obstruction of saccule orifice).

Treatment: Marsupialization, endoscopic excision, or external approach for large/external laryngoceles or symptomatic cysts.

Prognosis: Excellent; recurrence possible if not completely excised or predisposing factor persists.

Micro ─

─ Ductal Cyst: Lined by cuboidal, columnar, or squamous epithelium (often metaplastic); wall contains fibrous tissue, may have minor salivary gland remnants and chronic inflammation.

─ Saccular Cyst: Lined by respiratory epithelium (ciliated pseudostratified columnar with goblet cells) or squamous metaplasia; wall may contain seromucous glands and lymphoid aggregates.

─ Laryngocele: Lined by respiratory epithelium or squamous metaplasia; wall is thin, may contain sparse glands/lymphoid tissue; often shows chronic inflammation if obstructed (laryngopyocele if infected).

─ Oncocytic Cysts: Cysts lined by oncocytic epithelium (large cells, granular eosinophilic cytoplasm); can occur as part of oncocytic metaplasia/hyperplasia.

DDx ─

Branchial Cleft Cyst (esp 4th pouch): Usually lateral neck, may connect to pyriform sinus; often squamous lining with lymphoid tissue.

Thyroglossal Duct Cyst: Midline neck, associated with hyoid bone, thyroid follicles in wall.

Dermoid/Epidermoid Cyst: Contain keratin, may have adnexal structures (dermoid).

Lymphangioma/Vascular Malformation: Endothelial-lined spaces.

Laryngeal Carcinoma with Cystic Change: Malignant epithelial lining.

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Reactive Epithelial Changes (Larynx)

Spectrum of non-neoplastic alterations of laryngeal squamous epithelium in response to chronic injury or irritation; distinct from dysplasia but may coexist or predispose.

Clinical ─

Etiology: Chronic laryngitis, vocal abuse, smoking, alcohol, laryngopharyngeal reflux (LPR), radiation, air pollutants

Presentation: Hoarseness, cough, throat clearing; clinically may appear as leukoplakia, erythroplakia, or mucosal thickening

Micro ─

(Often a combination of features)

─ Hyperplasia (Acanthosis): Increased thickness of squamous epithelium due to increased cell layers in spinous layer.

─ Keratosis (Hyperkeratosis/Parakeratosis): Increased surface keratin; Hyperkeratosis (orthokeratosis) - anucleated keratin; Parakeratosis - retained nuclei in keratin layer.

─ Pseudoepitheliomatous Hyperplasia (PEH): Exuberant benign downgrowth of rete ridges, often irregular and elongated, mimicking invasion; lacks significant cytologic atypia; often seen over granular cell tumors or at ulcer edges.

─ Squamous Metaplasia: Replacement of normal respiratory epithelium by stratified squamous epithelium (common in larynx).

─ Inflammation: Variable chronic inflammatory infiltrate (lymphocytes, plasma cells) in lamina propria.

─ Edema: Stromal edema, esp in Reinke's space (Reinke's edema - diffuse polypoid change).

─ Nuclear Atypia (Reactive): Mild nuclear enlargement, hyperchromasia, prominent nucleoli related to regeneration/inflammation; lacks features of true dysplasia (e.g., high N:C ratio, significant pleomorphism, abnormal mitoses extending upwards).

DDx ─

Squamous Dysplasia/CIS: True precancerous changes with progressive architectural and cytologic atypia (see separate entry).

Invasive Squamous Cell Carcinoma: Stromal invasion, malignant cytology.

Verrucous Hyperplasia/Carcinoma: Exophytic, warty, minimal atypia.

Necrotizing Sialometaplasia: Affects minor salivary glands, squamous metaplasia of ducts with acinar necrosis.

Fungal/Specific Laryngitis: Organisms may be identified, specific inflammatory patterns.

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Granular Cell Tumor (Larynx/Trachea)

Benign mesenchymal neoplasm of Schwann cell origin composed of polygonal, large, granular cells.

Clinical ─

Age: Wide range, most common 3rd-5th decades

Sex: No strong predilection for laryngeal/tracheal sites

Site: Larynx (posterior vocal fold most common, also supraglottis, subglottis); Trachea (usually cervical portion)

Presentation: Hoarseness, dysphagia, cough, hemoptysis (larynx); stridor, dyspnea (trachea); small, firm, nontender submucosal nodule

Treatment: Conservative local excision

Prognosis: Excellent; recurrence rare

Micro ─

Architecture:

─ Nonencapsulated, poorly circumscribed proliferation

─ Grows as sheets, nests, or vague fascicles, often infiltrating adjacent stroma or muscle

Cytology:

─ Large polygonal cells with abundant, pale eosinophilic to amphophilic, finely granular cytoplasm (due to lysosomes)

─ Ill-defined cell borders, often syncytial appearance

─ Nuclei small, round to oval, centrally or eccentrically placed, often pyknotic; minimal atypia

─ Mitoses rare; necrosis absent

Overlying Epithelium:

─ Pseudoepitheliomatous hyperplasia (PEH) is very common and can be florid, mimicking SCC

IHC ─

─ (+) S100 (strong, diffuse nuclear/cytoplasmic), SOX10 (nuclear), Inhibin, CD68 (cytoplasmic granules), Calretinin (variable), TFE3 (nuclear)

─ (-) Cytokeratins, Desmin, SMA

DDx ─

Squamous Cell Carcinoma: PEH can be a significant pitfall; must identify underlying granular cells. SCC shows malignant cytology.

Adult Rhabdomyoma: Larger cells, more brightly eosinophilic cytoplasm, cross-striations/crystals may be seen, (+) Desmin, Myogenin.

Oncocytic Lesions (e.g., Oncocytoma, Oncocytic Metaplasia): Epithelial origin, (+) Cytokeratins.

Histiocytic Infiltrates: Lack S100/SOX10, different morphology.

Paraganglioma: Nested (zellballen) architecture, neuroendocrine markers (+), S100(+) in sustentacular cells only.

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Chondroma (Larynx/Trachea)

Benign mesenchymal neoplasm composed of mature hyaline cartilage.

Clinical ─

Age: Adults, wide range (mean ~50-60 years)

Sex: Male > female (~2:1)

Site: Larynx (cricoid cartilage ~70%, then thyroid, arytenoid); Trachea (cartilaginous rings)

Presentation: Slow-growing, firm submucosal mass; Hoarseness, dyspnea, dysphagia (larynx); Airway obstruction (trachea)

Imaging: Well-circumscribed, lobulated mass with characteristic chondroid matrix calcification (rings and arcs, stippled) on CT

Treatment: Conservative surgical excision (e.g., laryngofissure, endoscopic removal); preserve laryngeal function if possible

Prognosis: Excellent; recurrence rare if completely excised

Micro ─

─ Architecture: Well-circumscribed, lobulated nodules of mature hyaline cartilage; may have thin fibrous pseudocapsule.

─ Cellularity: Hypocellular to moderately cellular.

─ Chondrocytes: Small, bland nuclei, regular chromatin, inconspicuous nucleoli; typically one chondrocyte per lacuna; binucleation rare.

─ Matrix: Abundant hyaline cartilaginous matrix, may show focal myxoid change, calcification, or ossification.

─ Atypia/Mitoses: Absent or minimal.

DDx ─

Low-Grade Chondrosarcoma: Key differential; Chondrosarcoma shows increased cellularity, greater nuclear atypia (pleomorphism, hyperchromasia), binucleation/multinucleation, myxoid change, permeation of bone; distinction can be very difficult on small biopsies, often requires correlation with imaging and clinical behavior. Recurrence of a "chondroma" should raise suspicion for low-grade chondrosarcoma.

Chondromatous Metaplasia: Incidental microscopic foci of cartilage, not a true mass.

Pleomorphic Adenoma (with extensive chondroid stroma): Presence of epithelial/ductal elements.

Tracheopathia Osteochondroplastica: Multiple submucosal osseous/cartilaginous nodules along anterior/lateral tracheal wall, usually an incidental finding in older individuals.

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Inflammatory Myofibroblastic Tumor (Larynx/Trachea) (IMT)

Mesenchymal spindle cell neoplasm composed of myofibroblastic cells with a prominent inflammatory infiltrate, of intermediate biologic potential (rarely metastasizes).

Clinical ─

Age: Wide age range, including children; Laryngeal IMT median age ~50-60 years

Sex: Male > female for laryngeal IMT

Site: Larynx (true vocal cord/glottis > supraglottis, subglottis); Trachea; also occurs in other head and neck sites (oral cavity, sinonasal tract) and viscera/soft tissue

Etiology: Unknown; some associated with prior trauma/surgery; subset associated with ALK gene rearrangements

Presentation: Hoarseness, stridor, dysphonia, airway obstruction (larynx/trachea); painless mass +/- ulceration in other sites; systemic symptoms (fever, weight loss) rare in head and neck IMT

Treatment: Conservative but complete surgical excision; ALK inhibitors (e.g., crizotinib) for ALK-rearranged unresectable/metastatic cases

Prognosis: Generally good; local recurrence ~25% (esp if incompletely excised); metastasis rare (<5%)

Micro ─

Architecture:

─ Unencapsulated, submucosal proliferation; often polypoid

─ Varied patterns:

─ Myxoid/Vascular Pattern: Loosely arranged spindle/stellate cells in edematous/myxoid stroma with prominent blood vessels (similar to nodular fasciitis)

─ Compact Spindle Cell Pattern: Denser fascicles of spindle cells with less stroma, more collagen (similar to fibromatosis or fibrous histiocytoma)

─ Hypocellular Fibrous/Sclerotic Pattern: Paucity of cells, dense collagenous stroma (similar to scar)

Cytology:

─ Myofibroblasts: Plump spindle to stellate cells, elongated nuclei, vesicular chromatin, small nucleoli, abundant eosinophilic/amphophilic cytoplasm; minimal atypia

─ "Ganglion-like" cells: Larger cells with more prominent nucleoli and amphophilic cytoplasm may be seen

─ Mitoses: Variable, usually low (<5/10 HPF), not atypical

Inflammation:

─ Prominent mixed inflammatory infiltrate: Lymphocytes, plasma cells (often numerous), eosinophils, neutrophils, histiocytes

Molecular ─

─ ALK gene (chromosome 2p23) rearrangements in ~50-70% of cases (esp in younger patients, non-head and neck sites); various fusion partners (TPM3, TPM4, CLTC)

IHC ─

─ Myofibroblastic Cells: (+) SMA (smooth muscle actin), MSA (muscle-specific actin), Calponin (variable); Desmin variable/focal

─ ALK: (+) Cytoplasmic staining in cases with ALK rearrangement (variable patterns: granular, linear, perinuclear)

─ Cytokeratins (AE1/AE3, CAM5.2): Often focal/patchy positivity

─ CD34: Usually negative

─ S100: Negative

DDx ─

Nodular Fasciitis: More uniformly myxoid/tissue culture-like, rapid growth, lacks ALK rearrangement

Spindle Cell Squamous Cell Carcinoma: Epithelial atypia/CIS at surface or within, keratin(+), p63/p40(+), lacks diffuse SMA, ALK(-)

Fibromatosis (Desmoid): More uniform spindle cells, long sweeping fascicles, denser collagen, nuclear β-catenin(+), ALK(-)

Solitary Fibrous Tumor: Patternless architecture, "staghorn" vessels, ropy collagen, STAT6(+), CD34(+), ALK(-)

Leiomyoma/Leiomyosarcoma: More distinct smooth muscle features, Desmin diffusely (+), ALK(-)

Fibrosarcoma: Herringbone pattern, more atypia/mitoses if high-grade, ALK(-)

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Benign Nasal Cavity

Rhinosinusitis (Acute & Chronic)

Inflammation of the nasal cavity (rhinitis) and/or paranasal sinuses (sinusitis).

Clinical ─

Etiology: Acute: Often viral (rhinovirus, influenza, adenovirus), can have secondary bacterial infection (S. pneumoniae, H. influenzae, M. catarrhalis); Chronic (>12 weeks): Multifactorial (allergy, persistent infection, anatomic issues, mucociliary dysfunction, immune deficiency, irritants, aspirin intolerance)

Presentation: Acute: Nasal congestion, purulent discharge, facial pain/pressure, fever, malaise; Chronic: Nasal obstruction/congestion, facial pain/pressure, discolored nasal discharge/postnasal drip, hyposmia/anosmia

Subtypes of Chronic: CRSsNP (without nasal polyps), CRSwNP (with nasal polyps), Allergic Fungal Rhinosinusitis (AFRS)

Treatment: Acute viral: symptomatic; Acute bacterial: antibiotics if severe/persistent; Chronic: Nasal saline, intranasal corticosteroids, antibiotics for exacerbations, allergy management, surgery (FESS) for refractory cases

Micro ─

Acute Rhinosinusitis:

─ Epithelium: Edema, goblet cell hyperplasia, neutrophilic exocytosis, ulceration possible

─ Stroma: Edema, vascular congestion, prominent neutrophilic infiltrate

Chronic Rhinosinusitis (General Features):

─ Epithelium: Variable; may be normal respiratory, hyperplastic with increased goblet cells, squamous metaplasia, or atrophic; basement membrane often thickened/hyalinized

─ Stroma: Variable edema, fibrosis (esp CRSsNP), and vascular changes

─ Inflammation: Mixed inflammatory infiltrate; lymphocytes and plasma cells common; eosinophils prominent in allergic types and CRSwNP; neutrophils may indicate active/recurrent infection

─ Glands: Submucosal seromucous glands may show hyperplasia, atrophy, or ductal ectasia

DDx ─

Specific Infections (e.g., Invasive Fungal Sinusitis, Tuberculosis): Identify organisms

Granulomatous Diseases (e.g., GPA, Sarcoidosis): Necrosis, vasculitis, well-formed granulomas, systemic features

Sinonasal Polyps: Distinct polypoid structures (often seen with CRS)

Neoplasms (e.g., Papilloma, Carcinoma): Epithelial atypia, invasion

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Inflammatory Sinonasal Polyp

Nonneoplastic inflammatory swelling of sinonasal mucosa.

Clinical ─

Age: All ages, common > 20 years

Site: lateral nasal wall or ethmoid recess; often bilateral and multiple (polyposis)

Etiology: Multifactorial; allergy (atopy), infections, cystic fibrosis, aspirin intolerance (Samter triad: polyps, asthma, aspirin intolerance)

Presentation: Nasal obstruction, rhinorrhea, chronic rhinosinusitis

Micro ─

─ Architecture: Polypoid with markedly edematous stroma; surface epithelium intact

─ Epithelium: Surface ciliated respiratory type, may show squamous metaplasia; basement membrane can be thickened and eosinophilic.

─ Stroma: Markedly edematous/myxoid, lacks seromucous glands (key feature); contains mixed inflammatory cells, bland fibroblasts, and sometimes prominent vascularity

─ Inflammation: eosinophils, plasma cells, lymphocytes

─ Secondary Changes: ulceration, fibrosis, atypical stromal cells (mimics sarcoma), granulation tissue

DDx ─

Inverted Papilloma: Thickened epithelial proliferation with endophytic growth, intraepithelial mucous cysts/neutrophils

REAH: glandular proliferation arising from surface epithelium, thick basement membrane

Allergic Fungal Sinusitis: Allergic mucin, fungal hyphae, Charcot-Leyden crystals, eosinophils

Mycetoma (Fungus Ball): aggregate of fungal elements, minimal inflammation in tissue

Antrochoanal Polyp: Similar histology but arises from maxillary sinus; less eosinophils

Angiofibroma: Nasopharynx, adolescent males, distinct stromal and vascular features

Sarcoma (e.g., Rhabdomyosarcoma): Atypical stromal cells in polyps can be pitfall; true sarcomas show diffuse atypia, high mitotic rate, specific IHC markers

Media ─ pathoutlines WSI WSI WSI (slide 13) & video

Allergic Rhinosinusitis

Inflammation of the sinonasal mucosa driven by an allergic reaction

Clinical ─

Epidemiology: Common cause of chronic rhinosinusitis; all ages

Etiology: Immune reaction to aeroallergens

Presentation: congestion, rhinorrhea, sneezing, pruritus; associated polyps, asthma, atopy

Prognosis: predisposed to secondary infections or polyp formation

Micro ─

─ Epithelium: Surface respiratory epithelium intact; may show goblet cell hyperplasia or squamous metaplasia; basement membrane thickened and hyalinized

─ Stroma: Marked edema characteristic; lacks significant seromucous glands (esp in polyps).

─ Inflammation: eosinophilic infiltrate is hallmark; also lymphocytes, plasma cells, mast cells; neutrophils sparse

─ Allergic Mucin: Distinct from typical inspissated mucus; thick, tenacious, eosinophilic material containing sheets of eosinophils, cellular debris, Charcot-Leyden crystals; fungal hyphae

DDx ─

Non-Allergic Rhinitis with Eosinophilia Syndrome (NARES): Similar but negative allergy testing

Infectious Rhinosinusitis (Viral/Bacterial): Neutrophilic infiltrate more prominent

Chronic Rhinosinusitis without Polyps: Inflammation less eosinophilic, less atopy

Allergic Fungal Rhinosinusitis (AFS): subtype characterized by allergic mucin

Granulomatosis with Polyangiitis (GPA): Necrotizing granulomas, vasculitis, ANCA+; eosinophils not predominant

Media ─ pathoutlines

Allergic Fungal Rhinosinusitis (AFS)

Noninvasive fungal sinusitis characterized by an allergic response within the sinonasal tract mucosa to aerosolized fungal allergens, amplified and perpetuated by eosinophils.

Clinical ─

Epidemiology: Common (~10% of chronic rhinosinusitis or nasal polyposis); increased in warmer climates; usually 3rd-7th decades; equal gender distribution

Etiology: Type 1 hypersensitivity reaction to inhaled fungi (Aspergillus species most common; also dematiaceous fungi like Bipolaris, Curvularia); atopy is common

Presentation: Chronic, unrelenting rhinosinusitis; nasal obstruction; nasal polyps; possibly facial dysmorphia or proptosis; asthma and allergies often present

Laboratory: Peripheral eosinophilia; elevated total and fungal-specific IgE

Treatment: Surgical debridement/evacuation of allergic mucin; postoperative corticosteroids; possibly antifungal therapy or immunotherapy

Prognosis: Good with combined medical/surgical therapy; recurrences common

Micro ─

─ Allergic Mucin: Thick, tenacious, eosinophilic, often laminated material ("tide lines", "tree rings") containing sheets of eosinophils (often degenerated), cellular debris, Charcot-Leyden crystals (eosinophil breakdown products)

─ Fungal Hyphae: Usually sparse, noninvasive (within mucin, not tissue); best seen with GMS or PAS stains; may be absent (termed eosinophilic mucin rhinosinusitis - EMRS)

─ Mucosa: Often shows features of chronic rhinosinusitis or inflammatory polyps (edema, eosinophils, thickened basement membrane); no tissue invasion by fungi

DDx ─

Invasive Fungal Sinusitis: Fungal hyphae invading tissue, vessels; significant tissue necrosis; usually in immunocompromised patients

Mycetoma (Fungus Ball): Dense aggregate/ball of fungal hyphae within sinus lumen; minimal associated inflammation or allergic mucin; no tissue invasion

Chronic Bacterial Rhinosinusitis: Predominantly neutrophilic inflammation; lacks allergic mucin and fungal elements

Sinonasal Inflammatory Polyp: Edematous stroma with eosinophils, plasma cells, lymphocytes; lacks allergic mucin/fungal elements (though may coexist with AFS)

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Paranasal Sinus Mucocele

Expansion of a paranasal sinus due to accumulation of mucoid secretions secondary to obstruction of its ostium or duct; lined by respiratory epithelium.

Clinical ─

Age: Any age, often adults

Site: Frontal sinus (>60%) and ethmoid sinuses most common; less often sphenoid or maxillary

Etiology: Obstruction of sinus ostium due to chronic inflammation (sinusitis), trauma, prior surgery, polyps, or neoplasms

Presentation: Symptoms depend on site and extent of expansion: headache, facial pain/swelling, proptosis, diplopia, visual loss, nasal obstruction; often slow development

Imaging: Opacified, expanded sinus with thinned and remodeled (sometimes eroded) bony walls; CT shows homogeneous low-density contents; MRI signal varies with protein content

Treatment: Surgical drainage and re-establishment of sinus ventilation (often endoscopic)

Prognosis: Excellent with adequate drainage; recurrence possible if obstruction persists or underlying cause not addressed; complications rare (e.g., infection - pyocele, intracranial/orbital extension)

Micro ─

─ Cyst Lining: Typically flattened or attenuated pseudostratified ciliated columnar (respiratory) epithelium; may show squamous metaplasia, goblet cell hyperplasia, or atrophy, esp with chronic inflammation or pressure.

─ Cyst Contents: Amorphous mucoid material, may contain inflammatory cells (neutrophils if pyocele).

─ Cyst Wall: Fibrous connective tissue, often with chronic inflammation; reactive bone formation or resorption may be seen in adjacent bone.

─ Note: Histologic findings are often nonspecific; diagnosis requires clinicoradiologic correlation.

DDx ─

Mucus Retention Cyst (Salivary Gland type): Smaller, within submucosa, distinct from sinus lining, lacks bony expansion

Chronic Rhinosinusitis: Mucosal thickening and inflammation without significant sinus expansion or trapped mucin forming a distinct "cyst"

Neoplasm causing obstruction (e.g., Inverted Papilloma, Carcinoma): Biopsy underlying tissue if suspicious

Encephalocele/Meningoencephalocele: CSF-containing herniation of brain/meninges through skull defect; different imaging and contents

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Hairy Polyp

Developmental abnormality (choristoma), ectodermal and mesodermal tissues, representing accessory auricle from the first or second branchial cleft.

Clinical ─

Age: infants; occasionally

Site: Nasopharynx > oropharynx, middle ear, eustachian tube

Presentation: Symptoms secondary to mass effect

Micro ─

- Keratinizing stratified squamous epithelium (epidermis)

- Dermal appendages (hair follicles, sebaceous glands), adipose and fibrous connective tissue; cartilage or bone may be present

DDx ─

Teratoma: 3 germ layers (endoderm, mesoderm, ectoderm)

Dermoid Cyst: Cyst lined by squamous epithelium with adnexal structures; lacks cartilage/bone/muscle

Nasal Glial Heterotopia: mature glial tissue (GFAP+, S100+)

Media ─ pathoutlines

Respiratory Epithelial Adenomatoid Hamartoma (REAH)

Benign overgrowth of sinonasal glands, arising from surface epithelium.

Clinical ─

Age: Adults, peak 6th decade (Range: 3rd-9th decades)

Site: nasal cavity, esp posterior nasal septum

Micro ─

- Polypoid lesion dominated by glandular proliferation arising in direct continuity with surface epithelium

- Glands invaginate into submucosa, are widely spaced, and contain goblet cells

- Atrophic glandular alterations (flattened/cuboidal epithelium) can be seen

- Characteristic stromal hyalinization with thick, eosinophilic basement membrane around glands

IHC ─

Glandular Proliferation: (+) Cytokeratins (AE1/AE3, CAM5.2, CK7); (-) CK20, CDX2

Basal/Myoepithelial Cells: (+) p63 (TP63) (may be absent); Variable S100
DDx ─
Inverted Papilloma: Endophytic proliferation of thickened epithelium, intraepithelial cysts
Low-Grade Sinonasal Adenocarcinoma (Nonintestina): Complex back-to-back glands, lacks lobular architecture, lacks surface connection, cytologic atypia, infiltrative
Seromucinous Hamartoma: Arises from submucosal glands, lacks complex glands or surface connection (though overlap exists)
Inflammatory Polyp: Edematous stroma, lacks prominent glandular proliferation
Media ─ pathoutlines WSI WSI WSI WSI WSI WSI WSI WSI

Seromucinous Hamartoma

Benign hamartomatous proliferation of seromucinous glands

Clinical ─

Age: middle-aged adults

Site: Nasal cavity, nasopharynx

Micro ─

- Lobular proliferation of submucosal glands with haphazard arrangement

- Bland nuclear features, no significant atypia or mitoses

- Fibrous or edematous stroma, may contain chronic inflammation

- Lacks prominent basement membrane thickening

- Distinction from REAH, key difference is origin (submucosal glands vs. surface epithelium)

IHC ─

- Basal/Myoepithelial Cells: Often (-) or patchy for p63
DDx ─
Respiratory Epithelial Adenomatoid Hamartoma (REAH): Arises from surface, prominent basement membrane
Low-Grade Sinonasal Adenocarcinoma: Infiltrative, atypia, complex architecture
Inflammatory Polyp with Gland Hyperplasia: Background inflammation, less organized
Media ─ WSI WSI WSI

Nasal Chondromesenchymal Hamartoma (NCMH)

Rare tumor-like lesion of the sinonasal tract, mix of chondroid and mesenchymal elements.

Clinical ─

Age: infants and young children

Site: Nasal cavity, ethmoid sinuses; often nasal septum

Micro ─

- Poorly circumscribed, lobulated proliferation of mixed tissues

- Entrapped epithelial elements, giant cells possible:

- Spindle cells are bland

Molecular ─ DICER1 mutations reported

IHC ─

- Spindle Cells: (+) Actin (variable); (-) S100, Desmin (DES), Cytokeratins

DDx ─
Chondrosarcoma: Older, malignant chondrocytes, infiltrative
Fibro-osseous lesions (e.g., Fibrous Dysplasia):lacks prominent chondroid component
Mesenchymal Chondrosarcoma: Biphasic, small blue cells and cartilage
Solitary Fibrous Tumor: More uniform spindle cells, staghorn vessels,lacks cartilage
Media ─ pathoutlines video

Sinonasal Papilloma (Schneiderian Papilloma)

Clinical ─

Age: 40-70 years; Exophytic younger, Oncocytic older

Site:

─ Inverted: Lateral nasal wall (esp middle meatus), maxillary/ethmoid sinuses

─ Oncocytic: Lateral nasal wall, maxillary/ethmoid sinuses (similar to inverted)

─ Exophytic: Nasal septum (most common)

Presentation: Unilateral nasal obstruction

Recurrence: Common, esp inverted type

Prognosis: Inverted associated with SCC, oncocytic with SCC or SNUC

Micro ─

Inverted Papilloma:

─ Endophytic (inverted) growth of thickened ribbons/lobules of epithelium into underlying stroma

─ Epithelium: Squamous, transitional (intermediate), or respiratory type; often mixed

─ Basement membrane intact

─ Variable number of intraepithelial mucous cells or microcysts

─ Stromal inflammation common (lymphocytes, plasma cells, eosinophils)

─ Mitoses usually basal, atypia typically mild (unless dysplasia/carcinoma present)

Oncocytic Papilloma (Cylindrical Cell Papilloma):

─ Papillary exophytic fronds AND/OR inverted endophytic pattern

─ Epithelium: Multilayered (2+ layers) columnar cells with abundant granular eosinophilic cytoplasm (oncocytes)

─ Numerous small intraepithelial mucous cysts/gland-like spaces containing neutrophils ("oncocytic mucinous microcysts") are characteristic

─ Minimal cytologic atypia usually

Exophytic Papilloma (Fungiform Papilloma, Squamous Papilloma):

─ Exophytic papillary fronds with prominent fibrovascular cores

─ Epithelium: Primarily squamous, sometimes transitional or respiratory admixture

─ Resembles squamous papillomas elsewhere (oral, laryngeal) but often thicker epithelium

─ Koilocyte-like changes may be seen (HPV association)

─ Minimal atypia

Molecular ─

─ Low-risk HPV in exophytic > inverted, high-risk HPV possible

─ KRAS in subset of oncocytic, EGFR in subset of inverted

IHC ─

─ p16: if high-risk HPV/dysplasia/SCC

DDx ─

Inflammatory Polyp: Edematous stroma, mixed inflammation, respiratory epithelium attenuated, lacks epithelial proliferation

Respiratory Epithelial Adenomatoid Hamartoma (REAH): Proliferation of small glands below intact surface respiratory epithelium; lacks papillary architecture

Squamous Cell Carcinoma (Conventional, Verrucous, Papillary): Invasive, atypia, desmoplasia

Adenocarcinoma (esp. non-intestinal): Glandular differentiation, invasive

Oncocytic Carcinoma/Mucoepidermoid Carcinoma: Invasive, atypia (for oncocytic carcinoma)

Media ─ pathoutlines

Oncocytic WSI WSI WSI WSI WSI WSI WSI WSI (slide 3) & video

Inverted WSI WSI WSI WSI WSI WSI video

Exophytic WSI WSI

Benign Ear & Temporal Bone

First Branchial Cleft Anomalies (Ear context)

Spectrum of benign congenital fistulas, sinuses, and cysts resulting from incomplete fusion of the first and second branchial arches.

Clinical ─

Age: Type I often adults; Type II usually first year of life

Sex: Female > male (2:1)

Site: Type I: Periauricular, often parallels external auditory canal (EAC); Type II: Angle of mandible, may have tract to EAC or neck skin

Etiology: Persistence of ventral component of first branchial cleft (Type I - ectodermal); includes mesoderm (Type II)

Presentation: Type I: Periauricular cyst, often misdiagnosed as epidermal inclusion cyst; Type II: Draining sinus (otorrhea, neck drainage), often infected

Treatment: Complete surgical excision of cyst and any tract/fistula; antibiotics if infected

Prognosis: Benign; recurrence if incompletely excised

Micro ─

─ Lining Epithelium: Stratified squamous (keratinizing or nonkeratinizing) or ciliated respiratory epithelium, or mixture

─ Cyst Wall: Fibrous connective tissue; often contains lymphoid aggregates with or without germinal centers (esp Type II)

─ Type I (Ectodermal): Primarily epithelial-lined cyst/sinus/fistula

─ Type II (Ectodermal & Mesodermal): Epithelial lining plus cutaneous adnexal structures (sebaceous glands, hair follicles) and/or cartilage in the wall

─ Inflammation: Common if secondarily infected; granulation tissue may replace epithelium

DDx ─

Epidermal Inclusion Cyst: Keratin-filled cyst lined by squamous epithelium; lacks lymphoid tissue or adnexa (unless ruptured)

Cholesteatoma (EAC): Destructive keratinizing squamous proliferation in EAC/middle ear

Lymphoepithelial Cyst (e.g., parotid region): Squamous or respiratory lining with prominent lymphoid wall, but different embryologic origin/location

Accessory Tragus/Chondrocutaneous Branchial Remnant: Solid cartilaginous core with overlying skin/adnexa, no true cyst

Metastatic Cystic Squamous Cell Carcinoma (Neck): Malignant cytology, p16/HPV status relevant if oropharyngeal primary suspected

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Cystic Chondromalacia (Auricular Pseudocyst, Endochondral Pseudocyst)

Uncommon degenerative cystic lesion within the auricular cartilage plate, lacking a true epithelial lining.

Clinical ─

Age: Young to middle-aged adults (mean 35 years)

Sex: Male > female (9:1)

Site: Auricle; helix or antihelix (esp scaphoid fossa)

Etiology: Idiopathic; ?ischemic necrosis from repetitive minor trauma, ?embryologic fusion defect, ?lysosomal enzyme release

Presentation: Unilateral, painless or mildly tender, fluctuant, dome-shaped swelling; overlying skin normal; aspiration yields viscous, clear to yellowish fluid

Treatment: Aspiration with compression; sclerotherapy; surgical unroofing or excision of anterior cartilage wall

Prognosis: Benign; recurrence common with simple aspiration alone

Micro ─

─ Cartilage: Intracartilaginous cleft or cavity within the auricular cartilage plate; no epithelial lining (pseudocyst)

─ Cyst Contents (if present): Amorphous proteinaceous fluid, fibrin, occasional inflammatory cells

─ Cyst Wall (Cartilage Edge): May show degenerative changes (loss of basophilia, chondrocyte dropout); inner aspect of cavity may be lined by granulation tissue or compressed fibrous tissue, esp in older lesions

─ Inflammation: Usually minimal unless secondarily traumatized/infected

DDx ─

Relapsing Polychondritis: Inflammatory destruction of cartilage, pain, erythema, systemic features

Chondrodermatitis Nodularis Helicis: Painful nodule with central ulceration/crusting, epidermal hyperplasia, dermal necrobiosis

Traumatic Perichondritis/Hematoma: History of trauma, acute inflammation, possible hematoma organization

True Cyst (e.g., Epidermal Inclusion Cyst secondarily involving cartilage): Presence of epithelial lining

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Chondrodermatitis Nodularis Helicis (CDNH)

Common, painful, inflammatory, and degenerative condition of the external ear, characterized by a tender nodule typically on the helix or antihelix, with dermal necrobiosis and cartilage changes.

Clinical ─

Age: Middle-aged to elderly adults (peak 6th decade)

Sex: Male > female (helix lesions); Female > male (antihelix lesions)

Site: Helix (esp superior rim) or antihelix of auricle; usually unilateral

Etiology: Chronic pressure/trauma (e.g., sleeping on one side, headphones), actinic damage, compromised vascular supply

Presentation: Exquisitely painful, firm, well-demarcated, round to oval nodule (mm to >1cm); often with central ulceration or adherent crust; may interfere with sleep

Treatment: Conservative (pressure relief, topical/intralesional steroids); surgical excision (shave or wedge) for persistent/painful lesions

Prognosis: Benign; recurrence possible if pressure/trauma continues or incomplete excision

Micro ─

─ Epidermis: Hyperkeratosis, parakeratosis, acanthosis; often forms a collarette around a central crateriform ulcer/erosion

─ Dermal Changes: Central zone of fibrinoid necrosis/necrobiosis of dermal collagen, often extending to perichondrium; this necrotic material may be extruding through the epidermal defect (transepidermal elimination)

─ Inflammation: Surrounding chronic inflammation (lymphocytes, plasma cells, histiocytes) and granulation tissue

─ Vasculature: Vascular proliferation, thickened vessel walls in dermis

─ Cartilage: Underlying cartilage often shows degenerative changes (loss of basophilia, chondrocyte necrosis, fibrosis, inflammation of perichondrium); rarely, cartilage fragments extrude

DDx ─

Squamous Cell Carcinoma/Keratoacanthoma: Must be excluded, esp clinically; SCC shows cytologic atypia and invasion

Actinic Keratosis: Dysplasia confined to epidermis, no deep dermal necrosis or cartilage involvement

Relapsing Polychondritis: Diffuse cartilage inflammation, pain, erythema; lacks central crater/necrobiosis

Cystic Chondromalacia: Intracartilaginous pseudocyst, normal overlying skin

Gouty Tophus: Urate crystal deposits, granulomatous inflammation

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Angiolymphoid Hyperplasia with Eosinophilia (ALHE) (Epithelioid Hemangioma)

Uncommon, benign vascular proliferation typically in skin/subcutis of head and neck, characterized by epithelioid endothelial cells and a prominent eosinophilic and lymphoid infiltrate.

Clinical ─

Age: Young to middle-aged adults (peak 3rd-5th decades)

Sex: No strong sex predilection, some series F > M

Site: Head and neck (esp periauricular, scalp, forehead); less often trunk, extremities, oral mucosa

Presentation: Solitary or multiple, small (<2-3 cm), firm, pink to reddish-brown papules or nodules; often pruritic or tender; may bleed with trauma

Systemic: Peripheral blood eosinophilia in ~10-20%; lymphadenopathy rare

Treatment: Surgical excision, cryotherapy, laser ablation, intralesional steroids; recurrences common

Prognosis: Benign; no malignant potential; recurrences do not imply aggressive behavior

Micro ─

─ Architecture: Well-circumscribed, often lobulated proliferation of blood vessels in dermis/subcutis

─ Vessels: Lined by plump, "epithelioid" or "histiocytoid" endothelial cells with abundant eosinophilic cytoplasm and large, vesicular, sometimes grooved or indented nuclei; endothelial cells often protrude into lumen ("hobnailing"); vessel lumina vary from small capillary-like to larger, sometimes ectatic

─ Stroma: Prominent inflammatory infiltrate composed of lymphocytes (often forming follicles with germinal centers) and numerous eosinophils; plasma cells, mast cells also present

─ Other: Dermal fibrosis may be present; smooth muscle component around vessels is variable

IHC ─

─ Endothelial Cells: (+) CD31, CD34, ERG, FLI1

─ Lymphoid Infiltrate: Mixed T and B cells

DDx ─

Kimura Disease: Deeper lesion, larger, prominent lymphoid follicles, fibrosis, vascular proliferation less prominent, often peripheral eosinophilia/elevated IgE, more common in Asian males

Cutaneous Epithelioid Angiomatous Nodule (CEAN): Solitary, small, well-circumscribed, less prominent lymphoid component, fewer eosinophils

Epithelioid Sarcoma: Infiltrative, atypical epithelioid cells, keratin(+), CD34(+/-), INI1 loss in some

Angiosarcoma (Epithelioid variant): More atypia, mitoses, infiltrative, anastomosing channels, necrosis

Bacillary Angiomatosis: Immunocompromised patients, neutrophilic infiltrate, granular clumps of Bartonella henselae (Warthin-Starry stain)

Insect Bite Reaction: Papillary dermal edema, mixed infiltrate with eosinophils, but lacks characteristic vascular proliferation of ALHE

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Relapsing Polychondritis

Rare, systemic autoimmune disease characterized by recurrent episodes of inflammation and destruction of cartilaginous tissues.

Clinical ─

Age: Peak onset 4th-5th decades; can occur at any age

Sex: Equal predilection

Sites: Auricular cartilage (most common, ~85-90% - "red ear syndrome"), nasal cartilage (saddle nose deformity), laryngotracheobronchial cartilage (hoarseness, stridor, airway collapse), costal cartilages, joints (non-erosive arthritis)

Systemic Features: Ocular inflammation (episcleritis, scleritis, uveitis), audiovestibular dysfunction (hearing loss, vertigo), cardiovascular involvement (aortitis, valvular regurgitation), skin lesions

Etiology: Autoimmune; antibodies to type II collagen and other cartilage components (e.g., matrilin-1) implicated

Diagnosis: Clinical criteria (McAdam's); biopsy supportive but not always necessary if classic clinical picture

Treatment: Corticosteroids (prednisone) for acute flares; NSAIDs; immunosuppressants (methotrexate, azathioprine, cyclophosphamide, biologics) for chronic/severe disease

Prognosis: Variable, chronic relapsing course; mortality related to airway compromise, cardiovascular complications, or associated vasculitis/myelodysplasia

Micro ─

(Biopsy usually from auricular cartilage during acute flare)

─ Cartilage: Loss of normal basophilic staining (chondrolysis); chondrocyte necrosis/dropout; perichondrial inflammation

─ Inflammation: Dense inflammatory infiltrate at cartilage-soft tissue interface (perichondrium) and extending into cartilage; composed of lymphocytes, plasma cells, neutrophils (esp early), and macrophages

─ Late Stage: Cartilage destruction and replacement by granulation tissue and fibrosis; calcification or ossification may occur

DDx ─

Infectious Perichondritis (e.g., Bacterial, Fungal): Organisms may be identifiable; often history of trauma/piercing

Chondrodermatitis Nodularis Helicis (CDNH): Localized painful nodule, epidermal ulceration, dermal necrobiosis

Granulomatosis with Polyangiitis (GPA): Can involve nasal/laryngeal cartilage; necrotizing granulomas, vasculitis, ANCA(+)

Traumatic Chondritis: History of trauma

Cystic Chondromalacia: Intracartilaginous pseudocyst, minimal inflammation

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Cholesteatoma (Keratoma)

Destructive and expansile cystic lesion lined by keratinizing stratified squamous epithelium, typically occurring in the middle ear or mastoid, filled with desquamated keratin debris. Not a true neoplasm.

Clinical ─

Types:

─ Acquired (most common): Secondary to chronic otitis media, Eustachian tube dysfunction, tympanic membrane perforation/retraction

─ Congenital: Develops from embryonic epidermal rests in middle ear behind an intact tympanic membrane; less common

Age: Any age; acquired often children/young adults; congenital usually early childhood

Site: Middle ear (esp epitympanum - Prussak's space), mastoid

Presentation: Foul-smelling otorrhea, conductive hearing loss, otalgia, tinnitus, vertigo; complications: ossicular erosion, facial nerve palsy, labyrinthine fistula, intracranial extension (meningitis, abscess)

Treatment: Surgical excision (tympanomastoidectomy) with goal of eradicating disease and restoring hearing if possible

Prognosis: Good with complete removal; high recurrence rate if epithelium incompletely excised or underlying predisposing factors persist

Micro ─

─ Cyst Lining ("Matrix"): Keratinizing stratified squamous epithelium, often with prominent granular layer; rete ridges may be blunted or hyperplastic

─ Cyst Contents: Abundant anucleated keratin flakes (lamellated appearance)

─ Subepithelial Stroma ("Perimatrix"): Fibrous connective tissue with variable chronic inflammation (lymphocytes, plasma cells, histiocytes); granulation tissue may be present; cholesterol granulomas may coexist

─ Bone Erosion: Osteoclast activity may be seen at interface with bone

DDx ─

Keratosis Obturans: Accumulation of keratin plug in EAC, associated with EAC widening, but no middle ear invasion; different pathogenesis

External Auditory Canal (EAC) Cholesteatoma: Similar histology but confined to EAC, often associated with EAC stenosis or prior surgery

Squamous Cell Carcinoma: Malignant cytologic atypia, invasive growth pattern (cholesteatoma epithelium is bland)

Epidermal Inclusion Cyst (of temporal bone): Rare, true cyst lined by squamous epithelium, keratin filled, but not typically in middle ear cleft with destructive behavior

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Cholesterol Granuloma

Granulomatous foreign body reaction to cholesterol crystals, typically occurring in air-filled spaces of the temporal bone (middle ear, mastoid, petrous apex) secondary to hemorrhage and impaired ventilation/drainage.

Clinical ─

Age: Any age

Site: Middle ear, mastoid air cells, petrous apex

Etiology: Impaired ventilation/drainage of air cell system leading to negative pressure, mucosal edema, hemorrhage; breakdown of blood releases cholesterol, inciting granulomatous reaction

Association: Chronic otitis media, Eustachian tube dysfunction, prior surgery/trauma, cholesteatoma

Presentation: Often asymptomatic; may cause conductive hearing loss, tinnitus, vertigo, otalgia; petrous apex lesions can cause cranial nerve deficits (V, VI, VII, VIII) or "blue eardrum"

Imaging: CT shows expansile lesion with bone erosion; MRI characteristic high signal on both T1 and T2 (due to methemoglobin from old hemorrhage)

Treatment: Surgical drainage and ventilation of affected air cell system; mastoidectomy if extensive

Prognosis: Good with adequate drainage; recurrence if underlying ventilation issue not corrected

Micro ─

─ Cholesterol Clefts: Numerous empty, needle-shaped or rhomboid clefts (cholesterol crystals dissolved during processing)

─ Giant Cells: Multinucleated foreign body giant cells surrounding cholesterol clefts

─ Inflammation: Chronic inflammatory infiltrate (lymphocytes, plasma cells, foamy histiocytes/macrophages laden with hemosiderin)

─ Stroma: Granulation tissue or fibrous connective tissue; evidence of old and recent hemorrhage (hemosiderin pigment)

─ Epithelium: Overlying respiratory mucosa may be present, often inflamed or hyperplastic

DDx ─

Cholesteatoma: Keratinizing squamous epithelium and keratin debris (may coexist with cholesterol granuloma)

Middle Ear Adenoma: Glandular proliferation, neuroendocrine features

Paraganglioma (Glomus Tumor): Nested (zellballen) architecture, neuroendocrine cells

Langerhans Cell Histiocytosis: Characteristic Langerhans cells (S100+, CD1a+), eosinophils

Endolymphatic Sac Tumor: Papillary architecture, destructive growth (petrous apex)

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Ceruminous Adenoma

Benign glandular neoplasm arising from ceruminous glands (modified apocrine sweat glands) of the external auditory canal (EAC).

Clinical ─

Age: Middle-aged adults (mean ~50-55 years)

Sex: Equal predilection

Site: Exclusively in cartilaginous (outer 1/3 to 1/2) portion of EAC, where ceruminous glands reside

Presentation: Slow-growing, painless, firm, polypoid or nodular mass in EAC; may cause obstruction, hearing loss, pain, tinnitus

Treatment: Complete local surgical excision

Prognosis: Excellent; recurrence rare if completely excised

Micro ─

─ Architecture: Well-circumscribed, unencapsulated (or thinly encapsulated) proliferation of glands and cysts in dermis

─ Glandular Pattern: Two cell layers:

─ Inner/Luminal Cells: Cuboidal to columnar cells with abundant eosinophilic, granular cytoplasm; prominent apical "snouts" or decapitation secretion (apocrine feature)

─ Outer/Basal Cells: Flattened myoepithelial cells

─ Ceroid Pigment: Characteristic golden-brown, lipofuscin-like ceroid pigment granules often present in cytoplasm of luminal cells

─ Stroma: Dense, hyalinized, or fibrous stroma separating glandular elements

─ Atypia/Mitoses: Minimal to absent

─ Variants: Ceruminous pleomorphic adenoma (chondroid syringoma - contains chondromyxoid stroma); Ceruminous syringocystadenoma papilliferum (papillary projections, plasma cell-rich stroma, connects to surface epidermis) - these are rarer.

IHC ─

─ Luminal Cells: (+) CK7, GCDFP-15, CD117 (c-kit)

─ Myoepithelial Cells: (+) p63, CK5/6, S100, SMA, Calponin

DDx ─

Ceruminous Adenocarcinoma: Infiltrative growth, cytologic atypia, mitoses, necrosis, loss of dual cell population, absence of prominent ceroid pigment

Middle Ear Adenoma (Neuroendocrine Adenoma): Different location (middle ear), neuroendocrine features/markers, lacks apocrine features/ceroid

Paraganglioma (Glomus Jugulotympanicum): Middle ear/jugular foramen, zellballen pattern, neuroendocrine markers

Metastatic Adenocarcinoma: History of primary, atypical cytology, different IHC profile

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Middle Ear Adenoma (Neuroendocrine Adenoma of the Middle Ear - NAME)

Benign glandular neoplasm of the middle ear, often showing mixed epithelial (mucinous) and neuroendocrine differentiation.

Clinical ─

Age: Adults (mean ~40-50 years)

Sex: Equal predilection

Site: Middle ear cavity; may involve ossicles, mastoid

Presentation: Unilateral conductive hearing loss (most common), tinnitus, ear fullness/pressure, otalgia; intact tympanic membrane with retrotympanic mass

Treatment: Complete surgical excision (tympanomastoidectomy); ossicular chain reconstruction if needed

Prognosis: Excellent; recurrence rare (<15%), usually due to incomplete excision; malignant transformation exceptionally rare (middle ear adenocarcinoma with neuroendocrine features)

Micro ─

─ Architecture: Unencapsulated, infiltrative growth pattern common (infiltrates bone/soft tissue but biologically benign); varied patterns: glandular, trabecular, cord-like, solid sheets, single cells

─ Cytology: Monomorphic population of cuboidal to columnar cells; round to oval nuclei with "salt-and-pepper" (stippled) chromatin; inconspicuous nucleoli; moderate eosinophilic or amphophilic cytoplasm; true mucin production in some cells/lumina

─ Biphasic (sometimes subtle): Inner luminal cells (more eosinophilic/mucinous) and outer/basal cells (more neuroendocrine features)

─ Mitoses: Rare; atypia minimal

─ Stroma: Fibrovascular, may be desmoplastic

IHC ─

─ (+) Pan-Cytokeratin, CK7 (esp luminal cells)

─ (+) Neuroendocrine Markers: Chromogranin, Synaptophysin, CD56 (often patchy or predominantly in basal/outer cells)

─ (+) ISL1 (Islet-1, transcription factor) often strong and diffuse

─ (-) S100 (except entrapped nerves), TTF-1, Calcitonin

DDx ─

Paraganglioma (Glomus Tympanicum): Zellballen pattern, S100(+) sustentacular cells, lacks true glandular formation/mucin, Chromogranin/Synaptophysin strong in chief cells

Ceruminous Adenoma: EAC origin, apocrine features, ceroid pigment, dual apocrine/myoepithelial layers

Meningioma: Whorls, psammoma bodies, EMA(+), S100(+/-)

Metastatic Neuroendocrine Carcinoma (e.g., carcinoid): History of primary, often more atypia/mitoses

Metastatic Adenocarcinoma: Atypia, different IHC profile

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Endolymphatic Sac Tumor (ELST) (Aggressive Papillary Tumor of Temporal Bone)

Low-grade adenocarcinoma of endolymphatic sac origin, locally destructive, with strong association with von Hippel-Lindau (VHL) disease.

Clinical ─

Age: Wide range (peak 3rd-5th decades)

Sex: Equal predilection

Site: Posterior petrous temporal bone, centered on endolymphatic sac/duct region

Association: ~1/3 of cases associated with VHL syndrome (germline VHL mutation); bilateral ELSTs almost pathognomonic for VHL

Presentation: Progressive sensorineural hearing loss, tinnitus, vertigo (Ménière-like symptoms); facial nerve palsy; ataxia; symptoms often present for years

Imaging: CT shows lytic, destructive lesion in petrous bone; MRI T1 hyperintense (hemorrhage), T2 heterogeneous, avid enhancement

Treatment: Complete surgical excision is goal; radiotherapy for residual/recurrent disease

Prognosis: Indolent but locally aggressive; recurrence common if incompletely excised; metastasis extremely rare; mortality usually due to local complications or other VHL manifestations

Micro ─

─ Architecture: Destructive, infiltrative growth into bone; complex papillary, glandular, cystic, and solid patterns

─ Papillae: Broad or delicate fibrovascular cores lined by single layer of cuboidal to low columnar cells

─ Cytology: Relatively bland, uniform cells; round to oval nuclei, inconspicuous nucleoli; moderate eosinophilic cytoplasm; clear cell change may be seen

─ Luminal Contents: Eosinophilic, colloid-like material (PAS-positive, thyroglobulin-negative) often present in glandular/cystic spaces; hemorrhage and hemosiderin common

─ Mitoses: Usually rare; atypia mild

IHC ─

─ (+) Cytokeratins (AE1/AE3, CAM5.2, CK7), EMA

─ (+) S100 (often), PAX8, CAIX (Carbonic Anhydrase IX)

─ (-) Thyroglobulin, TTF-1 (important to exclude metastatic thyroid ca), Chromogranin, Synaptophysin

DDx ─

Metastatic Papillary Thyroid Carcinoma: (+) Thyroglobulin, TTF-1; characteristic nuclear features of PTC

Metastatic Renal Cell Carcinoma (Clear Cell Type): (+) CD10, RCC marker; PAX8 also positive in both; CAIX can be positive in both; ELST lacks extensive clear cells of RCC

Choroid Plexus Papilloma (if intracranial extension): Different location primarily, different IHC (e.g., transthyretin may be +)

Middle Ear Adenoma: Different location primarily, neuroendocrine features, ISL1(+)

Paraganglioma: Zellballen, neuroendocrine markers (+)

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Meningioma (Temporal Bone / Extracranial)

Benign neoplasm of meningothelial (arachnoidal cap) cells, uncommonly presenting as a primary tumor of the ear/temporal bone or extending from an intracranial primary.

Clinical ─

Age: Middle-aged to older adults (peak 5th-6th decades)

Sex: Female > male (~2-3:1)

Site: Temporal bone (petrous ridge, jugular foramen, middle ear, EAC); may be primary extracranial or secondary extension

Presentation: Hearing loss (conductive or sensorineural), tinnitus, vertigo, otalgia, facial nerve dysfunction; symptoms depend on exact location and extent

Imaging: CT shows hyperostosis or bone erosion; MRI shows dural-based enhancing mass (if intracranial component) or well-defined soft tissue mass in temporal bone

Treatment: Surgical excision for symptomatic/growing lesions; observation or stereotactic radiosurgery for selected cases

Prognosis: Generally excellent for WHO Grade I; recurrence depends on extent of resection and grade

Micro ─

(Histologic subtypes are same as intracranial meningiomas; Meningothelial, Fibrous, Transitional most common)

─ Architecture: Whorled, lobular, or sheet-like growth of meningothelial cells

─ Cytology: Uniform cells with oval nuclei, fine chromatin, inconspicuous nucleoli, often with intranuclear cytoplasmic pseudoinclusions; indistinct cell borders, syncytial appearance (meningothelial type); spindle cells in fascicles (fibrous type)

─ Psammoma Bodies: Concentrically laminated calcifications, common esp in transitional/psammomatous types

─ Stroma: Variable, from minimal to collagenous

─ Invasion: May infiltrate bone, soft tissue; WHO grading applies (Grade I, II-atypical, III-anaplastic/malignant)

IHC ─

─ (+) EMA (epithelial membrane antigen - often strong membranous), Vimentin

─ (+) Progesterone Receptor (PR) common

─ (+) S100 (variable, often weaker than schwannoma)

─ (+) Claudin-1

─ (-) Cytokeratins (usually), GFAP, Chromogranin

DDx ─

Schwannoma (Acoustic Neuroma): Antoni A/B patterns, Verocay bodies, strong diffuse S100(+), SOX10(+)

Paraganglioma: Zellballen, neuroendocrine markers(+), S100(+) in sustentacular cells

Middle Ear Adenoma: Glandular/neuroendocrine features, Keratin(+), ISL1(+)

Metastatic Carcinoma: Atypia, different IHC profile

Fibrous Dysplasia (if prominent bone involvement): "Chinese letters" of woven bone in fibrous stroma, lacks meningothelial cells

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Peripheral Nerve Sheath Tumor (Schwannoma / Acoustic Neuroma)

Benign neoplasm of Schwann cells, most commonly affecting the vestibular portion of the vestibulocochlear nerve (CN VIII) in the cerebellopontine angle (CPA) or internal auditory canal (IAC).

Clinical ─

Age: Peak 4th-6th decades

Sex: Slight female predilection

Site: Vestibular nerve (CN VIII) > Cochlear nerve; Facial nerve (CN VII) schwannomas less common but occur in temporal bone

Association: Bilateral acoustic neuromas are hallmark of Neurofibromatosis type 2 (NF2 - NF2 gene mutation)

Presentation: Unilateral sensorineural hearing loss (progressive), tinnitus (high-pitched), vertigo/dysequilibrium; larger tumors can cause facial numbness/weakness (CN V, VII compression), hydrocephalus

Treatment: Observation (for small, asymptomatic/slow-growing tumors), stereotactic radiosurgery (Gamma Knife), or surgical excision (microsurgery via various approaches)

Prognosis: Excellent for sporadic, solitary tumors; hearing preservation is a major goal of treatment; NF2-associated tumors often more challenging due to multiplicity/bilaterality

Micro ─

Architecture: Encapsulated, biphasic pattern:

─ Antoni A areas: Dense, cellular areas composed of spindle cells with elongated, wavy/buckled nuclei arranged in fascicles, palisades, or Verocay bodies (acellular eosinophilic zones formed by two parallel rows of palisading nuclei).

─ Antoni B areas: Loose, hypocellular, myxoid/edematous areas with microcystic change; cells more haphazardly arranged.

─ Vessels: Often prominent, thick-walled, hyalinized vessels, esp in Antoni A areas.

─ Degenerative Changes ("Ancient Schwannoma"): Nuclear atypia/pleomorphism, hemorrhage, hemosiderin, cystic change, fibrosis (can occur but do not imply malignancy if mitoses are absent/rare).

IHC ─

─ (+) S100 (strong, diffuse nuclear and cytoplasmic)

─ (+) SOX10 (nuclear)

─ (+) GFAP (variable, often in Antoni B areas)

─ (+) Collagen IV around individual cells

─ (-) EMA, Cytokeratins

DDx ─

Meningioma: Whorls, psammoma bodies, EMA(+), S100 often weaker/patchier

Neurofibroma: More admixed cell types (Schwann cells, fibroblasts, perineurial cells, mast cells), wavy collagen bundles, less distinct Antoni A/B, S100 often patchier, CD34(+) spindle cells

Malignant Peripheral Nerve Sheath Tumor (MPNST): Increased cellularity, atypia, mitoses, necrosis, infiltrative growth; S100 loss common

Solitary Fibrous Tumor: Patternless, "staghorn" vessels, ropy collagen, STAT6(+), CD34(+)

Fibromatosis: Infiltrative, bland spindle cells, long fascicles, nuclear β-catenin(+)

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Benign Salivary Glands

Developmental Lesions (Salivary Gland Heterotopia, Oncocytosis)

Developmental abnormalities involving salivary gland tissue in unusual locations (heterotopia) or cellular changes like oncocytic transformation.

Clinical ─

Heterotopia:

─ Age: Usually incidental finding at any age; may present due to inflammation or neoplasia arising within it

─ Site: Middle ear, neck (esp lower, anterior to SCM), mandible (intraosseous - Stafne defect), pituitary gland, lymph nodes (esp parotid region); rare sites: vulva, rectum, stomach

─ Presentation: Usually asymptomatic; may present as mass or cyst if associated with inflammation or neoplasm

Oncocytosis/Oncocytic Metaplasia/Hyperplasia:

─ Age: Uncommon <50 years, increases with age (esp >70 years)

─ Site: Major salivary glands (esp parotid) > minor glands

─ Presentation: Usually incidental microscopic finding; Oncocytosis may form diffuse or multifocal nodular enlargement (Nodular Oncocytic Hyperplasia - NOH), sometimes bilateral; may be associated with other salivary lesions/tumors

Treatment: Heterotopia: Excision if symptomatic or neoplastic change suspected; Oncocytosis: Usually no treatment needed, observation; if mass-forming (NOH), may be excised to rule out neoplasm

Prognosis: Excellent for both; heterotopic tissue can develop any lesion seen in normal salivary glands; oncocytosis is benign

Micro ─

Heterotopia:

─ Normal-appearing salivary gland tissue (serous, mucous, or mixed acini and ducts) in an ectopic location

─ May show chronic inflammation or cystic change

Oncocytic Metaplasia/Hyperplasia/Oncocytosis:

─ Oncocytic Cells: Large polygonal epithelial cells (transformed acinar or ductal cells) with abundant, finely granular, eosinophilic cytoplasm (due to numerous mitochondria) and central, round, often pyknotic nuclei; nucleoli can be prominent

─ Metaplasia: Focal replacement of normal ductal or acinar cells by oncocytes

─ Oncocytosis (Diffuse or Nodular/NOH): More extensive replacement or formation of unencapsulated nodules/aggregates of oncocytes; may show acinar, ductal, or solid patterns; NOH can be multifocal and involve intraparotid lymph nodes

IHC ─

Oncocytic Cells:

─ (+) Cytokeratins (e.g., AE1/AE3, CK7)

─ (+) Mitochondrial stains (e.g., PTAH historically, antimitochondrial antibodies)

─ (-) S100 (usually, helps distinguish from granular cell tumor if granular appearance is confusing)

DDx ─

Heterotopia:

─ Metastatic Salivary Gland Carcinoma (in lymph node): Malignant cytology

─ Branchial Cleft Cyst with Salivary Gland Tissue: Cystic structure with lymphoid tissue

Oncocytosis/NOH:

─ Oncocytoma: Benign neoplasm, usually solitary, encapsulated, composed entirely of oncocytes

─ Oncocytic Carcinoma: Malignant features (invasion, atypia, mitoses, necrosis)

─ Acinic Cell Carcinoma (Oncocytic variant): Different architectural patterns, DOG1(+)

─ Mucoepidermoid Carcinoma (Oncocytic variant): Mucous cells present

─ Metastatic Renal Cell Carcinoma (Eosinophilic variant): Clinically exclude, PAX8(+), specific renal markers(+)

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Mucocele & Mucus Retention Cyst, Sialolithiasis

Common lesions characterized by accumulation of mucus due to ductal obstruction or rupture (mucocele) or ductal dilation (mucus retention cyst); Sialolithiasis refers to calculus formation within salivary ducts.

Clinical ─

Mucocele (Extravasation Type):

─ Age: Common, esp children and young adults (peak 1st-3rd decades)

─ Site: Lower lip (most common, ~75%); also buccal mucosa, ventral tongue, floor of mouth (ranula if large, from sublingual or minor glands)

─ Etiology: Trauma to minor salivary gland duct leading to rupture and mucin spillage into connective tissue

─ Presentation: Dome-shaped, fluctuant, translucent or bluish swelling; few mm to cm; may rupture and recur

Mucus Retention Cyst (True Cyst):

─ Age: Less common than extravasation type; older adults (peak >50 years)

─ Site: Major glands (parotid, submandibular), minor glands (palate, floor of mouth, buccal mucosa)

─ Etiology: Ductal obstruction (e.g., sialolith, periductal scar, tumor compression) leading to ductal dilation

─ Presentation: Fluctuant swelling, may be asymptomatic or cause discomfort

Sialolithiasis:

─ Age: Adults (peak 3rd-6th decades)

─ Site: Submandibular gland/Wharton's duct (~80-90%) > parotid gland/Stensen's duct > minor glands

─ Etiology: Formation of calcified concretions (calcium phosphates, carbonates) around a nidus (mucus, desquamated cells, bacteria) within salivary ducts

─ Presentation: Intermittent pain and swelling of affected gland, esp during meals (salivary colic); stone may be palpable or visible at duct orifice; may lead to chronic sialadenitis, infection, ductal ectasia

Treatment: Mucocele/Retention Cyst: Surgical excision, often including associated minor salivary gland to prevent recurrence; Marsupialization for large ranulas. Sialolithiasis: Conservative (hydration, sialogogues, massage) for small stones; surgical removal (intraoral or external), sialoendoscopy, lithotripsy for larger/symptomatic stones

Prognosis: Excellent for all; recurrence of mucocele if gland not removed or continued trauma; sialolithiasis may recur if predisposing factors persist

Micro ─

Mucocele (Extravasation Type):

─ Cavity filled with amorphous, basophilic mucin

─ Lacks a true epithelial lining

─ Wall composed of granulation tissue and compressed fibrous tissue

─ Inflammatory infiltrate rich in foamy macrophages (muciphages), lymphocytes, neutrophils

─ Ruptured duct and associated minor salivary gland acini often seen nearby

Mucus Retention Cyst:

─ Cystic dilated duct lined by cuboidal, columnar, oncocytic, or squamous metaplastic epithelium

─ Lumen contains mucin

─ Wall is fibrous connective tissue, may have chronic inflammation

Sialolithiasis:

─ Sialolith: Lamellated, basophilic, calcified concretion; may show central organic nidus

─ Associated Ductal Changes: Dilation (sialectasis), squamous metaplasia, goblet cell hyperplasia, periductal inflammation and fibrosis

─ Glandular Changes (Chronic Obstructive Sialadenitis): Acinar atrophy, ductal ectasia, interstitial fibrosis, chronic inflammation (lymphocytes, plasma cells)

DDx ─

Mucocele/Retention Cyst:

─ Lymphangioma/Vascular Malformation: Endothelial-lined channels

─ Low-Grade Mucoepidermoid Carcinoma (cystic areas): Infiltrative, neoplastic epithelial proliferation (mucous, intermediate, epidermoid cells)

─ Cystic Salivary Gland Neoplasms (e.g., Cystadenoma, Cystadenocarcinoma): True neoplastic epithelial lining

Sialolithiasis:

─ Calcified lymph node or other soft tissue calcification (phlebolith): Location, lack of ductal association

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Necrotizing Sialometaplasia

Reactive inflammatory condition of salivary glands leading to coagulative necrosis of salivary acini and squamous metaplasia of ductal structures, clinically and histologically mimicking malignancy.

Clinical ─

Age: Wide range (1st-9th decades); mean 5th decade

Sex: Male > female (~2:1)

Site: Minor salivary glands >> major glands; Hard palate/junction of hard-soft palate most common (~75%); less often lips, buccal mucosa, retromolar pad, tongue, larynx, sinonasal tract

Etiology: Ischemic injury secondary to trauma (dental work, surgery, intubation, injections), ill-fitting dentures, infections, adjacent neoplasms/cysts, bulimia, smoking; often idiopathic

Presentation: Non-ulcerated swelling initially, progressing to crater-like ulcer(s) over 2-3 weeks; may have pain or numbness; edges of ulcer may be indurated

Treatment: Biopsy often needed to rule out malignancy; lesion is self-healing over 3-12 weeks (average 5-6 weeks) once irritant removed or ischemia resolves

Prognosis: Excellent; self-healing; recurrence rare unless underlying cause persists

Micro ─

Architecture:

─ Preservation of overall lobular architecture of the involved salivary gland is key feature

─ Acinar coagulative necrosis is prominent in early lesions

─ Ductal squamous metaplasia is hallmark

─ Variable inflammation

Necrosis:

─ Coagulative necrosis affects acinar cells, which often appear as "ghosts" retaining their shape but lacking nuclei

Metaplasia:

─ Salivary ducts undergo extensive squamous metaplasia, forming islands and nests of squamous epithelium

─ Metaplastic squamous cells are generally bland, with eosinophilic cytoplasm, distinct cell borders, and uniform nuclei; lacking significant atypia or pleomorphism

─ Residual ductal lumina may be seen within squamous nests; mucin spillage into stroma possible

Inflammation:

─ Variable acute and chronic inflammatory infiltrate (neutrophils, lymphocytes, plasma cells, histiocytes) surrounds necrotic acini and metaplastic ducts

─ Granulation tissue formation common

Overlying Epithelium:

─ Often ulcerated

─ May show pseudoepitheliomatous hyperplasia (PEH) of adjacent intact surface epithelium, which can mimic invasive carcinoma

IHC ─

─ Metaplastic Squamous Cells: (+) Cytokeratins (e.g., CK5/6, Pan-CK)

─ Residual Myoepithelial Cells: Often present around metaplastic nests; (+) p63 (TP63), SMA (ACTA2), calponin

─ p53 (TP53): Negative or wild-type pattern (unlike SCC)

DDx ─

Squamous Cell Carcinoma (SCC): Lacks preservation of lobular architecture, lacks acinar necrosis, shows frank cytologic malignancy (pleomorphism, hyperchromasia, atypical mitoses) and infiltrative growth; PEH in NSM can be a significant pitfall

Mucoepidermoid Carcinoma (MEC): True epidermoid/intermediate cells and mucous cells, often cystic, lacks lobular necrosis; NSM lacks true intermediate cells and true mucocytes are rare within metaplastic islands

Adenosquamous Carcinoma: Biphasic with true glandular and squamous malignant components

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Lymphoepithelial Sialadenitis (LESA) & Lymphoepithelial Cyst

LESA (Benign Lymphoepithelial Lesion, Myoepithelial Sialadenitis - MESA): Chronic inflammatory and autoimmune condition characterized by lymphocytic infiltration, acinar atrophy, and ductal epithelial proliferation forming epimyoepithelial islands. Lymphoepithelial Cyst: Cystic lesion lined by squamous or respiratory epithelium with a prominent lymphoid wall, often seen in HIV infection or as part of LESA.

Clinical ─

LESA:

─ Age: Adults, peak 4th-6th decades

─ Sex: Female > male (strong predilection, ~9:1)

─ Site: Major salivary glands, esp parotid (often bilateral); can affect minor glands

─ Association: Strongly associated with Sjögren syndrome (primary or secondary); increased risk of MALT lymphoma

─ Presentation: Persistent, firm, diffuse or nodular enlargement of affected gland(s); xerostomia (dry mouth)

Lymphoepithelial Cyst:

─ Age: Any age; HIV-associated often younger adults/children

─ Site: Parotid gland most common; also submandibular, oral minor glands (floor of mouth, lateral tongue)

─ Association: HIV infection (often multiple, bilateral parotid cysts - "HIV-associated salivary gland disease"); Sjögren syndrome; or sporadic

─ Presentation: Painless, fluctuant swelling

Treatment: LESA: Symptomatic (artificial saliva, sialogogues); monitor for lymphoma. Lymphoepithelial Cyst: Aspiration, surgical excision if symptomatic or for diagnosis

Prognosis: LESA: Chronic, risk of lymphoma. Cyst: Benign, recurrence possible if incompletely excised or underlying condition persists

Micro ─

LESA:

─ Lymphocytic Infiltrate: Dense, diffuse infiltrate of lymphocytes (mostly T-cells, some B-cells) and plasma cells, often forming lymphoid follicles with germinal centers

─ Acinar Atrophy: Progressive destruction and loss of salivary acini

─ Epimyoepithelial Islands: Proliferation of ductal epithelial and myoepithelial cells forming solid or slightly lumenized islands, often infiltrated by lymphocytes; islands may show hyalinization

Lymphoepithelial Cyst:

─ Cyst Lining: Stratified squamous epithelium (often nonkeratinizing) or pseudostratified ciliated columnar (respiratory) epithelium, or a mixture

─ Cyst Wall: Dense lymphoid tissue, typically with prominent reactive lymphoid follicles and germinal centers; salivary gland tissue may be present in the wall or adjacent

─ Cyst Contents: Amorphous proteinaceous material, desquamated epithelial cells, lymphocytes

IHC ─

LESA/Cyst:

─ Lymphoid Infiltrate: Polyclonal B and T cells (CD20, CD3); Kappa/Lambda light chains polyclonal (important to exclude MALT lymphoma, which would be monoclonal)

─ Epimyoepithelial Islands/Cyst Lining: (+) Cytokeratins (e.g., CK7, AE1/AE3)

DDx ─

Chronic Sclerosing Sialadenitis (Küttner Tumor): Primarily submandibular; dense fibrosis, periductal lymphocytic infiltrate, acinar atrophy; lacks prominent epimyoepithelial islands

MALT Lymphoma: Monoclonal B-cell infiltrate, destructive lymphoepithelial lesions (more atypical lymphocytes invading ducts), light chain restriction

Warthin Tumor (Cystic areas): Bilayered oncocytic epithelial lining, lymphoid stroma, but distinct papillary architecture

Branchial Cleft Cyst (if in parotid region): Similar lining/lymphoid wall; location and embryologic origin differ; lacks epimyoepithelial islands

Metastatic Cystic Squamous Cell Carcinoma: Malignant cytology in lining, p16/HPV status relevant

HIV-Associated Salivary Gland Disease: Can include LESA-like changes, multiple lymphoepithelial cysts, diffuse infiltrative lymphocytosis syndrome (DILS)

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Sclerosing Polycystic Adenosis (SPA)

Rare, benign, multicystic, and sclerotic lesion of salivary glands, histologically mimicking fibrocystic disease of the breast and other cystic/sclerosing salivary gland neoplasms.

Clinical ─

Age: Wide range (mean ~30-40 years)

Sex: Slight female predilection

Site: Parotid gland most common; rarely submandibular or minor salivary glands

Presentation: Slow-growing, firm, often painless mass; may be multifocal

Treatment: Conservative local excision

Prognosis: Excellent; benign, but local recurrence can occur (~15-30%), esp if incompletely excised; no malignant transformation reported, but can be associated with dysplasia or carcinoma in rare cases (controversial if true SPA or a mimic)

Micro ─

Architecture:

─ Well-circumscribed but unencapsulated, lobulated proliferation

─ Characterized by ductal ectasia, cyst formation, apocrine metaplasia, and stromal sclerosis/hyalinization

─ Sclerosis may be prominent, surrounding and compressing ducts/cysts

Epithelial Components:

─ Ducts and Cysts: Lined by bilayered epithelium: inner cuboidal/columnar luminal cells and outer flattened myoepithelial cells

─ Apocrine Metaplasia: Common; luminal cells become large with abundant eosinophilic granular cytoplasm and apical snouts

─ Foamy Macrophages: Often present within cyst lumina or stroma

─ Epithelial Hyperplasia/Papillary Projections: May be present within cysts/ducts

─ Calcifications/Spherulites: May be seen in lumina or stroma

─ Atypia: Usually minimal; however, focal cytologic atypia or dysplasia has been reported in some cases (raising concern for progression, though rare)

Stroma:

─ Dense, hyalinized collagenous stroma ("sclerosis")

─ Chronic inflammatory infiltrate (lymphocytes, plasma cells) often present

IHC ─

─ Luminal/Apocrine Cells: (+) Cytokeratins (CK7, CAM5.2), GCDFP-15 (apocrine marker)

─ Myoepithelial Cells: (+) p63 (TP63), SMA (ACTA2), S100, Calponin

─ Ki-67: Low proliferation index

DDx ─

Fibrocystic Change of Breast (if metastatic, but SPA is primary salivary): Histologically very similar

Salivary Duct Cyst: Simple cyst, lacks complex adenosis/sclerosis

Mucoepidermoid Carcinoma (Cystic, Sclerosing variants): Infiltrative growth, atypical mucous/intermediate/epidermoid cells, MAML2 rearrangement

Adenoid Cystic Carcinoma (Sclerosing variant): Cribriform/tubular patterns, perineural invasion, characteristic MYB alterations

Polymorphous Adenocarcinoma: More infiltrative, targetoid perineural invasion, lacks prominent apocrine change/sclerosis of SPA

Mammary Analogue Secretory Carcinoma (MASC): Different cytology (vacuolated, eosinophilic), characteristic ETV6 rearrangement, S100(+), Mammaglobin(+)

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Intercalated Duct Hyperplasia (IDH)

Benign, often incidental, proliferation of intercalated duct-like structures in salivary glands.

Clinical ─

Age: Adults, often older individuals

Site: Major salivary glands (parotid, submandibular) > minor glands

Presentation: Usually an incidental microscopic finding; rarely forms a palpable mass

Association: Can be seen adjacent to other salivary gland lesions/neoplasms (e.g., pleomorphic adenoma, Warthin tumor) or in chronically inflamed glands

Treatment: None required if incidental; if forms a mass, excision for diagnosis

Prognosis: Benign; no malignant potential per se, but significance lies in distinguishing from neoplastic proliferations

Micro ─

─ Architecture: Proliferation of small, uniform, duct-like structures resembling normal intercalated ducts

─ Arrangement: Often forms small clusters or aggregates, sometimes with a vaguely lobular configuration; maintains relationship with acini if present

─ Cytology: Ducts lined by a single or double layer of small cuboidal epithelial cells with scant cytoplasm and round, bland nuclei

─ Lumina: Small, inconspicuous

─ Myoepithelial Cells: Present around the proliferating ductules

─ Stroma: Usually minimal, may be slightly hyalinized or contain scant chronic inflammation

DDx ─

Adenoid Cystic Carcinoma (Tubular/Cribriform types): Infiltrative growth, perineural invasion, cytologic atypia (even if subtle), characteristic stroma (hyaline, basement membrane material), MYB alterations

Basal Cell Adenoma (Tubular/Trabecular types): Encapsulated, more organized proliferation, prominent basaloid cells, often palisading

Epithelial-Myoepithelial Carcinoma (Tubular variant): Biphasic proliferation with clear myoepithelial cells, infiltrative

Pleomorphic Adenoma (Cellular areas with ductules): Chondromyxoid stroma usually present elsewhere

Terminal Duct Adenocarcinoma / Intercalated Duct Carcinoma (Low-grade): While IDH is benign, these rare low-grade malignancies arise from intercalated ducts and show infiltrative growth and subtle atypia

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Pleomorphic Adenoma (Benign Mixed Tumor)

Most common benign salivary gland neoplasm, characterized by epithelial and myoepithelial cells arranged in various patterns within a diverse mesenchymal-like (chondromyxoid, hyaline, osseous) stroma.

Clinical ─

Age: Wide range, peak 3rd-6th decades

Sex: Slight female predilection

Site: Parotid gland (~80%, esp tail); Submandibular gland (~10%); Minor salivary glands (~10%, palate most common); rarely sublingual

Presentation: Slow-growing, painless, firm, mobile, well-demarcated mass; size varies

Treatment: Surgical excision (superficial parotidectomy, enucleation with margin, or wider excision depending on site/size)

Prognosis: Excellent with complete excision; recurrence ~1-5% with proper surgery (higher with enucleation alone due to microscopic pseudopods/capsular disruption); risk of malignant transformation (Carcinoma ex Pleomorphic Adenoma) increases with duration and in recurrent tumors (~1.5% overall, up to 9.5% if present >15 yrs)

Micro ─

(Highly variable appearance - "pleomorphic")

─ Architecture: Usually well-circumscribed, encapsulated (capsule may be incomplete or show tumor pseudopods)

─ Epithelial Component: Ductal structures, tubules, cords, sheets, nests, strands of cuboidal, columnar, or polygonal epithelial cells

─ Myoepithelial Component: Spindle, plasmacytoid (hyaline cells), clear, or epithelioid myoepithelial cells; may be intimately admixed with epithelial cells or form sheets/stroma-like areas

─ Stromal Component (Mesenchymal-like): Characteristic feature; chondroid (cartilage-like), myxoid (mucoid, loose), hyalinized (dense eosinophilic), osseous, or adipose tissue; produced by myoepithelial cells

─ Other Features: Squamous metaplasia, oncocytic change, sebaceous differentiation, cystic change, keratin pearls, Tyzzer bodies (intranuclear inclusions) may be seen

IHC ─

─ Epithelial Cells: (+) Cytokeratins (CK7, AE1/AE3, CAM5.2), EMA

─ Myoepithelial Cells: (+) S100, SMA, Calponin, p63 (TP63), GFAP (esp in chondromyxoid stroma), CK14

Molecular ─

─ PLAG1 gene rearrangements (chromosome 8q12) in ~50-70%

─ HMGA2 gene rearrangements (chromosome 12q14-15) in a smaller subset

DDx ─

Carcinoma ex Pleomorphic Adenoma: Evidence of malignancy (e.g., SCC, adenocarcinoma, undifferentiated carcinoma) arising in a PA; look for atypia, invasion, necrosis, high mitoses

Adenoid Cystic Carcinoma: Lacks true chondromyxoid stroma, characteristic cribriform/tubular patterns, perineural invasion, MYB alterations

Basal Cell Adenoma: Lacks chondromyxoid stroma, more monomorphic basaloid cells

Myoepithelioma: Composed almost exclusively (>90%) of myoepithelial cells, minimal/no ductal component

Polymorphous Adenocarcinoma (Minor glands): More infiltrative, targetoid perineural invasion, lacks chondromyxoid stroma

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Basal Cell Adenoma

Benign epithelial neoplasm of salivary glands composed of monomorphic basaloid cells arranged in various patterns, lacking the chondromyxoid stroma of pleomorphic adenoma.

Clinical ─

Age: Peak 6th-7th decades

Sex: Slight female predilection

Site: Parotid gland most common (~75%); upper lip, buccal mucosa for minor glands

Presentation: Slow-growing, painless, firm, mobile, well-demarcated mass; usually <3 cm

Treatment: Surgical excision

Prognosis: Excellent; recurrence rare with complete excision

Micro ─

─ Architecture: Well-encapsulated; composed of uniform basaloid epithelial cells

Patterns (often mixed):

─ Solid: Most common; nests and islands of basaloid cells with peripheral palisading and minimal stroma

─ Trabecular: Interconnecting cords and strands of basaloid cells in a fibrous stroma

─ Tubular: Small duct-like structures lined by basaloid cells

─ Membranous (Dermal Analogue Tumor): Less common; jigsaw puzzle-like nests of basaloid cells surrounded by thick, eosinophilic, PAS-positive basement membrane material; often multiple, associated with skin adnexal tumors (cylindromas, trichoepitheliomas - Brooke-Spiegler syndrome if germline CYLD mutation)

─ Cytology: Monomorphic basaloid cells with scant cytoplasm, oval to elongated hyperchromatic nuclei, inconspicuous nucleoli; peripheral palisading of nuclei common

─ Stroma: Usually scant and fibrous; prominent hyalinized stroma in membranous type

─ Ductal Differentiation: Small lumina may be present within cell nests

IHC ─

─ Basaloid Cells: (+) Cytokeratins (AE1/AE3, CK5/6), p63 (TP63), S100 (variable)

─ Luminal Cells (if present): (+) CK7

─ Membranous Type: (+) Collagen IV, Laminin in basement membrane material

DDx ─

Pleomorphic Adenoma: Presence of chondromyxoid stroma

Adenoid Cystic Carcinoma: Infiltrative, perineural invasion, cribriform pattern with true lumina containing basement membrane material, MYB alterations

Basal Cell Adenocarcinoma: Invasive growth, cytologic atypia, mitoses, necrosis (distinction can be difficult on small biopsy)

Basaloid Squamous Cell Carcinoma: Arises from surface epithelium, more atypia, squamous differentiation

Canalicular Adenoma: Predominantly upper lip, characteristic anastomosing cords of columnar cells, vascular stroma

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Canalicular Adenoma

Benign epithelial neoplasm of salivary glands, almost exclusively in minor glands of upper lip, composed of anastomosing cords and tubules of uniform columnar cells in a delicate vascular stroma.

Clinical ─

Age: Older adults (peak 7th-8th decades)

Sex: Slight female predilection

Site: Upper lip (minor salivary glands, ~80-90%); less often buccal mucosa, palate

Presentation: Slow-growing, painless, firm or fluctuant, well-circumscribed nodule; may be bluish if cystic

Treatment: Conservative surgical excision

Prognosis: Excellent; recurrence rare

Micro ─

─ Architecture: Well-circumscribed, often encapsulated; composed of highly uniform epithelial cells

─ Pattern: Characteristic anastomosing cords (often single cell thick) and tubules forming a "canalicular" or beaded network

─ Cytology: Monomorphic columnar or cuboidal cells with deeply basophilic nuclei (often polarized away from lumen) and moderate amphophilic/eosinophilic cytoplasm

─ Lumina: May contain eosinophilic secretions

─ Stroma: Delicate, loose, highly vascular (capillary-rich) connective tissue separating epithelial structures; cystic degeneration common

IHC ─

─ Epithelial Cells: (+) Cytokeratins (AE1/AE3, CK7), S100 (often strong), SOX10

─ (-) p63 (TP63), SMA (ACTA2) (myoepithelial markers usually negative or very focal, distinguishing from basal cell adenoma)

DDx ─

Basal Cell Adenoma (Tubular/Trabecular): More prominent basaloid cells, peripheral palisading, p63(+), less vascular stroma, not typical upper lip location

Pleomorphic Adenoma: Chondromyxoid stroma, biphasic epithelial/myoepithelial proliferation

Adenoid Cystic Carcinoma (Tubular): Infiltrative, perineural invasion, more atypia, MYB alterations

Polymorphous Adenocarcinoma: Infiltrative, targetoid PNI, more cytologic diversity, different IHC

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Oncocytoma (Oxyphilic Adenoma)

Benign epithelial neoplasm composed exclusively of oncocytes (large epithelial cells with abundant granular eosinophilic cytoplasm due to numerous mitochondria).

Clinical ─

Age: Older adults (peak 6th-8th decades); rare <50 years

Sex: Slight female predilection

Site: Parotid gland most common (~80%); rarely submandibular, sublingual, or minor salivary glands

Presentation: Slow-growing, painless, firm, solitary mass; usually <5 cm

Association: May be associated with oncocytosis in adjacent gland; rarely multiple or bilateral

Imaging: "Hot" spot on Technetium-99m pertechnetate scan (due to mitochondrial activity)

Treatment: Surgical excision

Prognosis: Excellent; recurrence rare

Micro ─

─ Architecture: Well-circumscribed, encapsulated; solid, trabecular, glandular, or acinar arrangement of oncocytes

─ Cytology: Composed entirely of oncocytes: large polygonal cells, abundant granular eosinophilic cytoplasm, central round vesicular or pyknotic nuclei, often prominent nucleoli; minimal atypia; mitoses rare

─ Stroma: Scant fibrovascular stroma

─ Clear Cell Change: Focal clear cell change in oncocytes can occur

─ Oncocytic Cysts: May be present

IHC ─

─ Oncocytes: (+) Cytokeratins (AE1/AE3, CK7, CK8/18), EMA

─ (+) Antimitochondrial antibodies (or PTAH stain historically highlights mitochondria)

─ (-) S100 (usually), p63 (TP63) (except entrapped basal cells), DOG1

DDx ─

Oncocytic Metaplasia/Hyperplasia/Oncocytosis: Diffuse or multifocal nodular change, lacks true capsule/expansile growth of a solitary mass

Warthin Tumor: Papillary cystic architecture, bilayered oncocytic epithelium, lymphoid stroma

Oncocytic Carcinoma: Malignant features (invasion, perineural/vascular invasion, significant atypia, mitoses, necrosis)

Acinic Cell Carcinoma (Oncocytic variant): May have granular cytoplasm but different architecture (microcystic, follicular), DOG1(+)

Mucoepidermoid Carcinoma (Oncocytic variant): Presence of mucous and intermediate cells

Metastatic Renal Cell Carcinoma (Eosinophilic/Oncocytic types): Clinically exclude, PAX8(+), specific renal markers(+)

Granular Cell Tumor: S100(+), SOX10(+), different granularity

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Warthin Tumor (Papillary Cystadenoma Lymphomatosum, Adenolymphoma)

Benign salivary gland neoplasm composed of bilayered oncocytic epithelium forming papillary cystic structures within a prominent lymphoid stroma.

Clinical ─

Age: Older adults (peak 6th-7th decades)

Sex: Male > female (historically, now approaching equal)

Site: Parotid gland almost exclusively (esp tail, inferior pole); often superficial

Association: Strong association with cigarette smoking; rarely bilateral (~5-15%) or multifocal

Presentation: Slow-growing, painless, fluctuant or firm mass; may be cystic on imaging

Imaging: "Warm" or "hot" spot on Technetium-99m scan

Treatment: Surgical excision (superficial parotidectomy or enucleation)

Prognosis: Excellent; recurrence rare (~2-5%); malignant transformation exceedingly rare (carcinoma ex Warthin tumor)

Micro ─

─ Architecture: Well-encapsulated, often multicystic

─ Epithelial Component: Bilayered epithelium lining cystic spaces and forming papillary projections:

─ Inner (Luminal) Layer: Tall columnar oncocytic cells with apically located, often pyknotic nuclei and abundant granular eosinophilic cytoplasm

─ Outer (Basal) Layer: Cuboidal to polygonal oncocytic or basaloid cells

─ Stromal Component: Dense lymphoid stroma with well-formed germinal centers, surrounding the epithelial structures

─ Cyst Contents: Eosinophilic proteinaceous material, cellular debris, cholesterol clefts

─ Squamous metaplasia, mucinous metaplasia, sebaceous differentiation can occur focally

─ Infarction with necrosis and inflammation can occur

IHC ─

─ Oncocytic Epithelium: (+) Cytokeratins (CK7, AE1/AE3), EMA

─ Lymphoid Stroma: Polyclonal B-cells (CD20+) and T-cells (CD3+)

DDx ─

Lymphoepithelial Cyst: Often squamous/respiratory lining, lacks bilayered oncocytic epithelium (though lymphoid stroma similar)

Oncocytoma (with cystic change): Solid areas of oncocytes, lacks bilayered papillary structures and prominent lymphoid stroma

Metastatic Papillary Thyroid Carcinoma to intraparotid lymph node: Thyroid-type nuclear features, Thyroglobulin(+), TTF-1(+)

Mucoepidermoid Carcinoma (cystic, with oncocytic features): Presence of mucous/intermediate cells, infiltrative

Cystic Squamous Cell Carcinoma (metastatic): Malignant cytology, p16 status relevant

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Sebaceous Adenoma & Lymphadenoma

Rare benign salivary gland neoplasms characterized by prominent sebaceous differentiation. Sebaceous Lymphadenoma has an additional prominent lymphoid stromal component.

Clinical ─

Age: Older adults (peak 6th-8th decades)

Sex: Slight male predilection

Site: Parotid gland most common; also submandibular, minor glands

Presentation: Slow-growing, painless, well-circumscribed mass

Treatment: Surgical excision

Prognosis: Excellent; recurrence rare

Micro ─

Sebaceous Adenoma:

─ Architecture: Well-circumscribed, encapsulated; composed of nests and islands of sebaceous cells and small ducts

─ Cytology:

─ Sebaceous Cells: Polygonal cells with abundant, foamy, multivacuolated cytoplasm (lipid) and small, central, often scalloped nuclei; similar to cutaneous sebaceous glands

─ Basaloid/Germinative Cells: Smaller cells with scant cytoplasm and darker nuclei at periphery of nests

─ Ductal Structures: Small ducts lined by cuboidal or squamous epithelium may be present

─ Stroma: Fibrous, may have focal cystic change

Sebaceous Lymphadenoma:

─ Architecture: Similar to sebaceous adenoma but with a prominent, dense lymphoid stroma, often with well-formed germinal centers (similar to Warthin tumor stroma)

─ Epithelial Component: Nests of sebaceous cells and ductal structures scattered within the lymphoid stroma; cysts lined by squamous or ductal epithelium containing sebaceous cells in their walls are common

IHC ─

─ Sebaceous Cells: (+) EMA, Androgen Receptor (AR); Adipophilin or Oil Red O (on frozen tissue) for lipid

─ Ductal/Basaloid Cells: (+) Cytokeratins

─ Lymphoid Stroma (in Lymphadenoma): Polyclonal B and T cells

DDx ─

Sebaceous Carcinoma: Infiltrative growth, cytologic atypia, mitoses, necrosis

Mucoepidermoid Carcinoma with Sebaceous Differentiation: Presence of mucous and intermediate cells, infiltrative

Pleomorphic Adenoma with Sebaceous Differentiation: Chondromyxoid stroma present

Warthin Tumor (with sebaceous metaplasia): Bilayered oncocytic epithelium is dominant feature

Lymphoepithelial Cyst with Sebaceous Metaplasia: Cystic, lymphoid wall, focal sebaceous change in lining

Normal Intraparotid Lymph Node with Sebaceous Glands: Normal lymph node architecture with incidental benign sebaceous elements (developmental)

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Hemangioma (Juvenile Salivary Gland Hemangioma)

Benign vascular neoplasm, most common salivary gland tumor of infancy and childhood.

Clinical ─

Age: Usually present at birth or first few weeks/months of life; rapid growth phase followed by slow involution

Sex: Female > male

Site: Parotid gland most common; also submandibular, minor glands

Presentation: Soft, compressible, bluish or reddish mass; may have overlying skin changes (telangiectasias)

Treatment: Observation for spontaneous involution (majority); Propranolol for problematic/proliferating lesions; surgery for residual or complicated lesions

Prognosis: Excellent; most involute spontaneously by age 5-10 years

Micro ─

(Histology varies with phase - Proliferating vs. Involuting)

Proliferating Phase (Infancy):

─ Highly cellular, unencapsulated but well-demarcated lobular proliferation of capillaries

─ Plump endothelial cells lining small, often indistinct vascular lumina

─ Pericytes may be prominent

─ Mitoses can be frequent (reflects rapid growth, not malignancy)

─ Salivary gland acini and ducts are often entrapped and may appear atrophic

Involuting Phase (Childhood):

─ Decreased cellularity, increased fibrosis and adipose tissue within lobules

─ Vascular lumina become more dilated and apparent

─ Endothelial cells flatten

─ Residual salivary elements more easily seen

IHC ─

─ Endothelial Cells: (+) CD31, CD34, ERG, FLI1

─ Pericytes: (+) SMA, MSA

─ GLUT1: Often positive in juvenile (infantile) hemangiomas (helps distinguish from vascular malformations)

DDx ─

Lymphangioma/Vascular Malformation: Dilated lymphatic/vascular channels, often less cellular, GLUT1(-)

Kaposiform Hemangioendothelioma: More infiltrative, spindle cells, slit-like spaces, associated with Kasabach-Merritt syndrome, GLUT1(-)

Angiosarcoma: Rare in children; marked atypia, mitoses, infiltrative, anastomosing channels

Salivary Gland Carcinoma (infiltrating normal gland): Malignant epithelial cells

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Benign Gnathic Bones (Mandible/Maxilla)

Osteomyelitis

Dentigerous Cyst

Periapical Cyst/Granuloma

Fibrous Dysplasia

Osteonecrosis (ORN & MRON)

Simple Bone Cyst

Nasopalatine Duct Cyst

Tori & Exostoses

Cherubism

Cemento-Osseous Dysplasias

Ossifying Fibroma (Cemento-ossifying Fibroma)

Juvenile Ossifying Fibroma (Trabecular & Psammomatoid)

Central Odontogenic Fibroma

Osteoblastoma & Osteoid Osteoma

Cementoblastoma

Ameloblastoma (Conventional, Unicystic, Peripheral)

Odontogenic Keratocyst (OKC)

Calcifying Epithelial Odontogenic Tumor (CEOT)

Adenomatoid Odontogenic Tumor (AOT)

Central Giant Cell Lesion

Odontoma (Complex & Compound)

Benign Neck (Soft Tissue, Lymph Node)

Cat Scratch Disease

Bacillary Angiomatosis

Cervicofacial Actinomycosis

Nodular Fasciitis

Sinus Histiocytosis with Massive Lymphadenopathy (Rosai-Dorfman Disease)

Langerhans Cell Histiocytosis (Neck involvement)

Lymphangioma (Cystic Hygroma)

Teratoma (Cervical)

Ectopic Hamartomatous Thymoma (EHT)

Spindle Cell Lipoma / Pleomorphic Lipoma

Squamous Cell Carcinoma and Precursors

Squamous Intraepithelial Lesion (Dysplasia/CIS)

Spectrum of potentially premalignant alterations in squamous epithelium characterized by architectural and cytologic atypia, ranging from involvement of the lower epithelial layers (low-grade dysplasia) to full-thickness involvement (high-grade dysplasia/carcinoma in situ).

Clinical ─

Age: Typically adults, esp older individuals (peak 6th-7th decades for keratinizing lesions)

Site: Oral cavity, larynx (esp true vocal cords), pharynx; any squamous mucosa

Etiology: Tobacco and alcohol use (keratinizing); HPV (nonkeratinizing); chronic irritation

Presentation: Leukoplakia, erythroplakia, or erythroleukoplakia; asymptomatic or hoarseness/sore throat

Treatment: Excisional biopsy/removal (stripping, laser, cordectomy) or radiation (extensive CIS); cessation of risk factors; close follow-up

Prognosis: Risk of progression to invasive SCC increases with grade; high-grade lesions (severe dysplasia/CIS) have significant risk if untreated; treatment often curative

Micro ─

Architecture & Cytology (Spectrum):

─ Architectural changes: Irregular stratification, loss of basal polarity, irregular/drop-shaped rete ridges, increased/suprabasal mitoses, abnormal surface maturation (keratinizing type), full-thickness disturbance (high-grade/CIS)

─ Cytologic changes: Nuclear pleomorphism, increased N:C ratio, hyperchromasia, prominent nucleoli, cellular pleomorphism, dyskeratosis, atypical mitoses (esp high-grade/CIS)

Grading (Often simplified to 2 Tiers):

─ Low-Grade Dysplasia (Mild/Moderate): Atypia confined to lower +/- middle 1/3 of epithelium

─ High-Grade Dysplasia (Severe Dysplasia/CIS): Atypia extends to upper 1/3 or full thickness of epithelium; marked cytologic atypia; distinction between severe dysplasia and CIS is often subjective

Types:

─ Keratinizing Type: Shows surface maturation/keratinization despite atypia; more common in larynx/oral cavity; often HPV(-)

─ Nonkeratinizing Type: Lacks surface maturation; resembles cervical intraepithelial neoplasia; often HPV-related (p16+)

Basement Membrane: Intact (no stromal invasion by definition)

Glandular Extension: May extend down ducts (still considered in situ)

IHC ─

─ Ki-67: Increased proliferation index, extends higher in epithelium with increasing grade

─ p53 (TP53): Often overexpressed (mutant pattern) in HPV-negative lesions

─ p16: Often strong/diffuse block positive in HPV-related nonkeratinizing high-grade lesions (esp oropharynx); variable/patchy in keratinizing/HPV-negative lesions

DDx ─

Reactive Epithelial Atypia/Hyperplasia: Lacks significant/high-grade cytologic atypia, mitoses basal, often associated inflammation

Invasive Squamous Cell Carcinoma: Unequivocal invasion through basement membrane into stroma

Pseudoepitheliomatous Hyperplasia: Exuberant reactive downgrowth, lacks significant cytologic atypia

Verrucous Hyperplasia/Carcinoma: Exophytic, warty growth, minimal atypia, uniform base (hyperplasia) or pushing invasion (carcinoma)

Transitional Epithelium (Larynx): Normal finding; lacks atypia/abnormal mitoses

Media ─ Severe WSI Moderate WSI WSI Mild WSI

Conventional Keratinizing Squamous Cell Carcinoma (KSCC)

Clinical ─

Age: older adults (>50 years)

Site: Common in oral cavity (tongue, floor of mouth, gingiva), larynx (glottis), skin; less common in oropharynx, hypopharynx, sinonasal tract compared to non-keratinizing variants

Etiology: tobacco and alcohol use for oral/laryngeal KSCC; UV radiation for cutaneous KSCC; HPV less common compared to non-keratinizing oropharyngeal SCC

Prognosis: Worse than HPV-related SCC of oropharynx

Micro ─

─ Infiltrating nests, islands, cords of malignant squamous cells with desmoplastic response

─ Cells polygonal with eosinophilic cytoplasm, distinct cell borders, intercellular bridges

─ Variable nuclear atypia: enlarged nuclei, irregular contours, hyperchromasia, nucleoli

─ Mitotic activity variable, including atypical forms

─ Keratin pearls (concentric layers of keratinized cells) and single cell keratinization (dyskeratosis)

─ More keratinization in well-differentiated tumors

Molecular ─

─ TP53 mutations common in tobacco/alcohol-related KSCC

─ HPV negative in most typical KSCC outside the oropharynx

IHC ─

─ (+) Pan-Cytokeratin (AE1/AE3), CK5/6, p63, p40

─ p16: non-block in non-HPV related KSCC

DDx ─

Pseudoepitheliomatous Hyperplasia (PEH): Reactive proliferation over granular cell tumor, chronic inflammation, fungal infection; lacks significant atypia, deep invasion absent, inflammation prominent

Verrucous Carcinoma: Well-differentiated, minimal atypia, broad "pushing" invasion, prominent surface hyperkeratosis

Necrotizing Sialometaplasia: Preserved lobular architecture, acinar necrosis, bland squamous metaplasia of ducts

Basaloid SCC: Basaloid features, high grade, comedonecrosis

Adenosquamous Carcinoma: squamous and glandular components

Media ─

Glottic Gross

Salivary WSI Collection

Larynx WSI WSI WSI

HPV-Associated Squamous Cell Carcinoma (Oropharynx)

Squamous cell carcinoma strongly associated with oncogenic human papillomavirus (HPV) infection, most commonly arising in the oropharynx (tonsil, base of tongue) and characterized by distinct clinicopathologic and prognostic features.

Clinical ─

Age: Often younger than HPV-negative SCC patients (peak 50s-60s)

Sex: Male > female (~4-5:1)

Site: Oropharynx (palatine tonsil, base of tongue) >> other head & neck sites

Etiology: High-risk HPV infection (esp type 16 > 18, 31, 33, 35); sexual behavior is major risk factor; smoking is cofactor and worsens prognosis

Presentation: Often presents as neck mass (cystic metastasis from small/occult primary), sore throat, dysphagia; less often as visible primary lesion

Treatment: Highly sensitive to radiation and chemotherapy; de-escalation protocols under investigation

Prognosis: Significantly better stage-for-stage survival compared to HPV-negative OPSCC

Micro ─

─ Architecture: Often nonkeratinizing; infiltrative nests, lobules, trabeculae, or syncytial sheets; pushing borders common; often arises from tonsillar crypt epithelium rather than surface; surface dysplasia often absent.

─ Cytology: Typically basaloid appearance; medium-sized cells with high N:C ratio; scant cytoplasm; indistinct cell borders; hyperchromatic, often pleomorphic nuclei with coarse chromatin; nucleoli may be inconspicuous or prominent; numerous mitoses and prominent apoptosis are characteristic.

─ Keratinization: Minimal or absent by definition in nonkeratinizing type; hybrid variants show focal keratinization (<25%).

─ Stroma: Often associated with prominent, non-desmoplastic lymphoid stroma (tumor-infiltrating lymphocytes).

─ Necrosis: Comedo-type necrosis may be present within tumor nests.

─ Metastases: Often cystic with central necrosis and rim of viable tumor.

Molecular ─

─ HPV: Transcriptionally active high-risk HPV (esp type 16) present

─ TP53: Usually wild-type (not mutated, unlike HPV-negative SCC)

IHC ─

─ p16: Strong, diffuse nuclear and cytoplasmic staining ("block positive") in >70% of tumor cells (reliable surrogate marker)

─ Epithelial Markers: (+) Pan-Cytokeratin, CK5/6, p63, p40

─ p53: Wild-type pattern (patchy, weak to moderate staining) or negative

─ Ki-67: High proliferation index

─ EBV (EBER): Negative (helps distinguish from NPC)

DDx ─

Conventional (Keratinizing) SCC: Overt keratinization, intercellular bridges more obvious, often arises from surface dysplasia, p16(-), TP53 often mutated

Basaloid SCC (HPV-negative): More significant atypia, comedonecrosis more prominent, peripheral palisading, hyalinized stroma, p16(-)

Lymphoepithelial Carcinoma/Metastatic NPC: Histologically similar to undifferentiated nonkeratinizing HPV(+) SCC, but EBER(+), p16 usually (-)

High-Grade Lymphoma: (+) CD45; (-) Cytokeratins, p63

Poorly Differentiated Carcinoma (non-HPV): Lacks characteristic morphology, p16(-)

Media ─ pathoutlines WSI WSI video

Verrucous Carcinoma

Highly differentiated, locally destructive, without metastatic potential, characterized by exophytic &/or warty appearance, absence of epithelial dysplasia, and pushing margins.

Clinical ─

Age: 6th and 7th decades

Sex: Male > female (4:1) (oral cavity: female > male)

Site: Oral cavity > larynx (esp glottic area / anterior true vocal cord)

Etiology: tobacco and alcohol

Presentation: Warty, exophytic, papillary or fungating tumor; hoarseness (larynx)

Treatment: Surgery preferred; not radiotherapy

Prognosis: Excellent following complete surgical removal

Micro ─

─ Exophytic/papillary (warty) appearing squamous epithelial proliferation

─ Multiple filiform, finger-like projections or thickened, club-shaped papillae

─ Abundant keratosis (ortho- and parakeratosis); "church spire" keratosis; parakeratotic crypting

─ Broad pushing border with dense lymphoplasmacytic response at base

─ Very well-differentiated squamous epithelium, maturing to surface, larger cells than conventional SCC, mitoses limited to base

Molecular ─

─ HPV: Low-risk or high-risk types variably detected (represent passengers, not drivers)

IHC ─

─ p53 overexpression common

─ (-) p16

DDx ─

Proliferative Verrucous Leukoplakia/Verrucous Hyperplasia: Lacks deep, pushing invasion below level of adjacent normal epithelium; may show mild/moderate atypia

Exophytic/Papillary Squamous Cell Carcinoma: Significant atypia, lacks prominent surface keratinization

Squamous Papilloma: Thinner papillae, lacks deep bulbous rete/pushing invasion

Pseudoepitheliomatous Hyperplasia: Reactive process, often associated with underlying inflammation/infection or granular cell tumor, lacks pushing invasion

Media ─ pathoutlines larynx WSI WSI tongue WSI oral WSI WSI WSI WSI

Basaloid Squamous Cell Carcinoma (BSCC)

High-grade SCC, basaloid pleomorphic cells

Clinical ─

Age: Older (60-70s); HPV-related in younger patients

Sex: Male > female

Site: base of tongue, hypopharynx, supraglottic larynx

Etiology: Tobacco and alcohol use; high-risk HPV (esp oropharynx)

Presentation: Often presents at high stage with nodal metastases

Treatment: Radical surgery with chemoradiation

Prognosis: Aggressive; better if HPV-positive

Micro ─

─ Varied growth patterns: solid nests, lobules, cords, trabeculae; peripheral palisading

─ Lobules show central comedo-type necrosis, cribriforming, or gland-like spaces

─ Focal and abrupt squamous differentiation

─ Surface high-grade dysplasia / SCC in situ

─ Stroma hyalinized or myxoid

─ Predominantly basaloid cells (small to medium size, high N:C)

─ Numerous mitoses, frequent apoptosis

Molecular ─

─ HPV: High-risk HPV in oropharyngeal cases

─ TP53 mutations in HPV-negative cases

IHC ─

─ Basaloid and Squamous Components: (+) Pan-Cytokeratin, CK5/6, p63, p40

─ Neuroendocrine markers: negative, occasion focal (+)

─ CD117 (KIT): variably (+) (potential overlap with ACC)

─ EBV (EBER): Negative (unlike nasopharyngeal carcinoma)

DDx ─

Adenoid Cystic Carcinoma (ACC): Less pleomorphism, fewer mitoses, true cribriform spaces with basement membrane material, lacks squamous differentiation, MYB fusion

Small Cell Neuroendocrine Carcinoma: Finer chromatin, nuclear molding, crush artifact, strongly (+) neuroendocrine IHC, TTF-1 (+) if lung primary

Basal Cell Adenocarcinoma: Salivary origin, less atypia/mitoses, biphasic ductal-myoepithelial pattern, lacks comedonecrosis, lacks squamous

NUT Carcinoma: younger patients, abrupt squamous differentiation, NUT nuclear positivity

Oropharyngeal Nonkeratinizing SCC (HPV-related): Lacks overt keratinization, prominent lymphoid stroma, strong p16(+)

Media ─ pathoutlines WSI WSI WSI

Spindle Cell SCC (Sarcomatoid SCC)

Squamous cell carcinoma with biphasic appearance yielding spindle cell transformation.

Clinical ─

Age: wide range

Sex: Male >>>> female

Site: Glottic > Supraglottic, transglottic, subglottic

Etiology: smoking and alcohol; radiation reported

Treatment: Wide local excision; postoperative radiation

Prognosis: glottic tumors better than nonglottic tumors

Micro ─:

─ Polypoid, pedunculated, exophytic tumor with surface ulceration and fibrinoid necrosis

─ Storiform, solid, and fascicular architecture with low to intermediate cellularity

─ Imperceptible blending between squamous and spindle cells

─ Areas of classic SCC

─ Mild to moderate pleomorphism, although isolated highly atypical cells are common

─ Tumor giant cells and multinucleated cells common

─ Numerous mitoses including atypical forms

─ Desmoplastic, stromal fibrosis seen in half of cases

─ Heterologous elements: Benign or malignant bone or cartilage;rarely, rhabdomyoblastic

Other Features:

─ Tumor necrosis is limited to absent

─ Eosinophilic cytoplasmic globules rarely present

IHC ─

─ Epithelial immunoreactivity absent in up to third of cases

DDx ─

Contact Ulcer: Bilateral ulcerated polyps, lack atypia, rich vascular and inflammatory infiltrate, mitoses

Synovial Sarcoma: Young age, arising from neck soft tissues

Fibrosarcoma: Herringbone growth; arises from soft tissues of neck rather than lumen of larynx

Nodular Fasciitis: Pseudosarcomatous proliferation of soft tissue adjacent to larynx; myxoid stroma, storiform spindle cell population with extravasated RBCs

Angiosarcoma: High-grade sarcoma with anastomosing vessels, atypical endothelial cells, mitoses

Pleomorphic Sarcoma: Undifferentiated, high-grade sarcoma, from neck soft tissues, not from larynx

Media ─ pathoutlines WSI WSI WSI

Papillary Squamous Cell Carcinoma (PSCC)

Uncommon SCC variant characterized by delicate, stalk-like papillary growth

Clinical ─

Age: 50-60s

Sex: Male >> female (4:1)

Site: Supraglottis >> glottis >> subglottis; also oropharynx, sinonasal tract

Etiology: Tobacco and alcohol; HPV in subset (types 6 or 16, esp oropharynx)

Treatment: Complete excision; radiation for most patients

Prognosis: Better than conventional SCC; recurrs in 1/3 of patients)

Micro ─

Architecture:

─ > 70%) papillary architecture

─ Multiple, thin, delicate, filiform, finger-like papillary projections with delicate fibrovascular cores

─ Tangential sectioning yields "bunch of celery" cut across the stalk appearance

─ Architectural distortion with loss of cellular polarity

─ Nuclear enlargement, increased N:C ratio, prominent nucleoli

─ Frequently immature, basaloid phenotype

─ Numerous mitoses, including atypical forms

─ Koilocytic atypia is frequently noted

─ Keratinization: limited surface keratosis, intracellular keratinization or dyskeratosis may be present

Invasion:

─ Stromal invasion may be found (may require serial sections)

─ Invasion usually superficial, lacking perineural, vascular, or chondroosseous invasion

─ Cohesive nests or single cell infiltration, associated with inflammation

DDx ─

Verrucous SCC: Broad, pushing border, parakeratotic crypting, church spire keratosis; maturation, limited pleomorphism, limited mitoses

Squamous Papilloma: Noncomplex papillae; lack pleomorphism, invasion, necrosis, atypical mitoses; koilocytes may be prominent

Media ─ pathoutlines WSI arising in inverted papilloma WSI

Adenosquamous Carcinoma

Tumor shows mix of true adenocarcinoma and squamous cell carcinoma.

Clinical ─

Age: 50-60s

Sex: Male > female (2:1)

Site: Any region

Etiology: smoking and alcoho

Presentation: Most are metastatic at presentation

Prognosis: Very poor

Micro ─

─ Biphasic appearance of separate or blended tumors, areas of transition

─ SCC can be in situ or invasive (well to poorly differentiated)

─ Adenocarcinoma tends to develop deep in tumor (away from surface), mucin production common but not required

Other Features:

─ Undifferentiated or "intermediate" transitional cells can be seen, with clear cytoplasm

─ Both components may have necrosis, increased mitoses, perineural invasion, angiolymphatic invasion

─ Sparse inflammatory infiltrate; desmoplastic response minimal to absent

─ Concurrent necrotizing sialometaplasia may be seen (pitfall)

─ Metastases may display both components although one usually predominates

IHC ─

─ Squamous: (+) CK5/6, p63, p40

─ Glandular: (+) CK7, CEA; (-) CK20

─ Both: (+) Pan-Cytokeratin; p16 variable (esp oropharynx)

DDx ─

Mucoepidermoid Carcinoma (MEC): Lacks true SCC (has intermediate cells), lacks surface dysplasia/CIS, MAML2 rearrangement

Acantholytic (Adenoid) SCC: Mimics glands due to acantholysis, lacks true glandular diff

Basaloid SCC: Dominant basaloid pattern, comedonecrosis, lacks true glandular diff

Adenocarcinoma With Squamous Metaplasia: Squamous component lacks malignant features

Necrotizing Sialometaplasia (NSM): Preserves lobular architecture, acinar necrosis, bland squamous metaplasia, lacks invasion

Media ─ WSI

Lymphoepithelial Carcinoma of the Larynx

Undifferentiated carcinoma with prominent nonneoplastic lymphoplasmacytic infiltrate, similar to nasopharyngeal carcinoma but arising in larynx.

Clinical ─

Age: Older adults (~60 years)

Etiology: Smoking and alcohol (unlike EBV in nasopharynx)

Prognosis: poor

Micro ─

─ Infiltrating syncytial nests and trabeculae of cells; dense, lymphoplasmacytic infiltrate

─ Desmoplastic stromal minimal or absent

─ Large, undifferentiated polygonal cells with indistinct borders

─ Nuclei large, round to oval, vesicular chromatin, prominent eosinophilic nucleoli

─ Mitoses frequent; necrosis may be present

─ Squamous differentiation (keratinization) is absent by definition

IHC ─

─ Epithelial Cells: (+) Pan-Cytokeratin, EMA, p63, p40

─ Lymphoid Stroma: (+) CD45, mixture of CD3(+) T cells and CD20(+) B cells (polyclonal)

─ EBV (EBER): negative (unlike nasopharyngeal LEC)

─ p16: negative

DDx ─

Nasopharyngeal Carcinoma: excluded clinically/radiographically; EBER(+)

High-Grade NHL (esp DLBCL): (+) CD45, specific lymphoid markers; (-) Cytokeratins, p63

Poorly Differentiated SCC: focal squamous differentiation; lymphoid stroma less prominent

Malignant Melanoma: melanocytic markers; (-) Cytokeratins, p63

Media ─ WSI

Sinonasal and Nasopharyngeal Malignancies

Glandular Malignancies

Low-Grade Nasopharyngeal Papillary Adenocarcinoma

Rare, indolent adenocarcinoma arising in the nasopharynx, characterized by papillary architecture and low-grade cytology, often resembling thyroid papillary carcinoma or villoglandular adenocarcinoma.

Clinical ─

Age: Wide range, often adults

Site: Nasopharynx (surface epithelium)

Presentation: Nasal obstruction, epistaxis, postnasal drip

Treatment: Complete surgical excision

Prognosis: Excellent; very low recurrence rate, metastasis extremely rare

Micro ─

Architecture:

─ Exophytic papillary, tubulopapillary, or villoglandular growth pattern

─ Delicate fibrovascular cores lined by neoplastic epithelium

─ May show complex branching

Cytology:

─ Single layer or pseudostratified columnar to cuboidal cells

─ Minimal cytologic atypia, nuclei often uniform and basal

─ Nuclear features of papillary thyroid carcinoma (grooves, inclusions, clearing) are typically ABSENT

─ Mitoses rare

─ Cilia may be present

─ No significant stromal invasion usually identified

Molecular ─

─ No consistent molecular alterations reported; not associated with EBV or HPV

IHC ─

─ (+) Cytokeratins (CK7, CAM5.2), EMA

─ (-) CK20, TTF-1, Thyroglobulin, CDX2

─ S100 may be (+) in scattered cells

DDx ─

Metastatic Papillary Thyroid Carcinoma: (+) TTF-1, Thyroglobulin; characteristic nuclear features

Villoglandular Adenocarcinoma (of other sites): Histologically similar, but location is key; exclude metastasis

Respiratory Epithelial Adenomatoid Hamartoma (REAH): Glandular proliferation below intact surface, prominent basement membranes

Papillary Sinonasal Adenocarcinoma (Intestinal or Non-Intestinal Type): Usually higher grade cytology, invasive growth

Media ─ placeholder

Intestinal-Type Sinonasal Adenocarcinoma (ITAC)

Malignant epithelial glandular tumors of sinonasal tract that histologically resemble intestinal adenocarcinoma.

Clinical ─

Age: Wide range, most common 5th-7th decades

Site: Ethmoid sinus > nasal cavity > maxillary sinus; sporadic cases often involve maxillary antrum

Etiology: Strong association with occupational exposure (wood dust, leather dust); may occur sporadically

Presentation: Nasal obstruction, epistaxis, facial pain/swelling; often advanced at diagnosis

Treatment: Complete surgical resection +/- radiation therapy; neck dissection generally not indicated

Prognosis: Aggressive; 5-year survival ~40%; papillary type has better prognosis; no difference between occupational and sporadic cases

Micro ─

─ Colonic type (~40%): Tubuloglandular architecture, resembles colorectal adenocarcinoma; increased atypia/mitoses

─ Papillary type (~18%): Predominantly papillary architecture, minimal atypia, rare mitoses; best prognosis

─ Solid type (~20%): Solid/trabecular growth, loss of differentiation, marked atypia/mitoses

─ Mucinous type (Uncommon): Extracellular mucin pools (>50%) or intracellular mucin/signet ring cells

─ Mixed type (Rare): Admixture of ≥2 patterns

─ May show features simulating intestinal mucosa (villi, Paneth cells, enterochromaffin cells)

Molecular ─

KRAS mutations (~25%); TP53 mutations (14-44%); BRAF mutations rare; microsatellite instability usually absent

IHC ─

(+) CK20 (most), CDX2 (nuclear), Villin, MUC2; Variable CK7

DDx ─

Metastatic Colorectal Adenocarcinoma: Clinically exclude primary; identical histology/IHC

Non-Intestinal Sinonasal Adenocarcinoma: Lacks intestinal morphology and markers (CK20-, CDX2-)

Salivary Gland Adenocarcinomas (e.g., ACC): Different morphology, IHC profile, +/- specific molecular alterations

Media ─ placeholder

Non-Intestinal-Type Sinonasal Adenocarcinoma (non-ITAC)

Sinonasal tract adenocarcinomas lacking features of intestinal differentiation or specific minor salivary gland types; divided into low-grade and high-grade.

Clinical ─

Age: Adults; Low-grade mean ~55-65 yrs; High-grade mean ~59 yrs

Site: Low-grade: Nasal cavity, ethmoid sinus; High-grade: Maxillary sinus predilection

Presentation: Low-grade: Nasal obstruction, epistaxis, pain infrequent; High-grade: Nasal obstruction, epistaxis, pain, facial deformity common

Treatment: Complete surgical excision +/- radiation (esp for high-grade or extensive disease)

Prognosis: Low-grade: Excellent (~80% 3-yr survival), recurrence ~30%, metastasis rare; High-grade: Poor (~20% 3-yr survival), frequent metastasis

Micro ─

─ Low-grade: Submucosal, often circumscribed glandular/papillary proliferation; back-to-back glands common; single layer of cuboidal/columnar cells; minimal atypia/mitoses; necrosis absent; invasion may be present.

─ High-grade: Invasive tumor, often solid/sheet-like with focal glands/papillae; moderate to marked nuclear pleomorphism; increased/atypical mitoses; necrosis common; angiolymphatic/perineural invasion possible.

IHC ─

(+) CK7, Pan-CK; (-) CK20, CDX2, Villin; Variable S100; p63 usually (-)

DDx ─

Intestinal-Type Adenocarcinoma (ITAC): Intestinal morphology; (+) CK20, CDX2

Salivary Gland Carcinomas (esp ACC, PLGA): Specific morphology (cribriform, targetoid PNI), IHC (e.g., S100, p63 patterns), +/- molecular (MYB fusions in ACC)

Respiratory Epithelial Adenomatoid Hamartoma (REAH)/Seromucinous Hamartoma: Non-invasive, characteristic glandular patterns (surface origin/thick BM in REAH, submucosal origin in SH), bland cytology

Schneiderian Papilloma: Surface epithelial origin, characteristic papillary/inverted/oncocytic patterns

Metastatic Adenocarcinoma (non-GIT): Clinical history; site-specific markers (e.g., TTF-1 for lung, GATA3/mammaglobin for breast)

Media ─ placeholder

Other Carcinomas

NUT Carcinoma (NUT Midline Carcinoma)

Poorly differentiated carcinoma with NUTM1 rearrangement.

Clinical ─

Age: often adolescents and young adults

Site: Midline, esp head and neck (sinonasal, nasopharynx, salivary glands) and mediastinum

Presentation: Rapidly growing, advanced stage at presentation

Prognosis: Rapidly fatal

Micro ─

─ Infiltrative sheets &, lobules of undifferentiated cells, extensive necrosis

─ Focal abrupt squamous differentiation without squamous maturations,

─ Monotonous population of round to oval cells, medium-sized, scant cytoplasm, indistinct cell borders, round nuclei

─ Numerous mitoses, frequent apoptosis

─ Minimal stromal reaction

Molecular ─

─ most common BRD4::NUTM1

IHC ─

─ NUT: (+) Nuclear staining (speckled pattern)

─ Epithelial Markers: (+) Pan-Cytokeratin, EMA, p63 (TP63), p40 (patchy)

─ Squamous Markers: (+) CK5/6 in squamous differentiation

─ p16: Variable

─ Neuroendocrine Markers: (-)

DDx ─

Poorly diff SCC/Basaloid SCC: NUT(-), more gradual squamous maturation

Sinonasal Undifferentiated Carcinoma (SNUC): NUT(-), more pleomorphic

Small Cell Neuroendocrine Carcinoma: nuclear features (molding, salt-and-pepper

Olfactory Neuroblastoma: (+) S100, Neuroendocrine markers; fibrillary background

Melanoma: (+) S100, SOX10, Melan-A/HMB45; (-) Cytokeratins

Media ─ placeholder

SWI/SNF Complex-Deficient Sinonasal Carcinoma

High-grade carcinomas with loss of SMARCB1 (INI1) or SMARCA4 (BRG1).

Clinical ─

Age: Wide range

Site: Sinonasal tract

Presentation: Nasal obstruction, epistaxis, mass effect; aggressive presentation

Treatment: Multimodality (surgery, chemo, radiation)

Prognosis: poor

Micro ─

─ Varied patterns: sheets, nests, cords, rhabdoid features, plasmacytoid features

─ Undifferentiated to poorly differentiated cells

─ Marked pleomorphism, nucleoli; rhabdoid cells common (esp SMARCB1-deficient)

─ High mitotic rate, necrosis common

Molecular ─

─ Inactivating mutations or deletions in SWI/SNF (SMARCB1, SMARCA4)

IHC ─

─ (-) SMARCB1 (INI1) or SMARCA4 (BRG1)

─ Epithelial Markers: (+) Cytokeratins (patchy or dot-like), EMA

─ Variable S100, Synaptophysin, CD99

DDx ─

Media ─ placeholder

Sinonasal Lymphoepithelial Carcinoma

Undifferentiated carcinoma in sinonasal tract with prominent lymphoplasmacytic infiltrate, similar to nasopharyngeal carcinoma.

Clinical ─

Age: Wide range

Site: Sinonasal tract (rare primary site)

Etiology: EBV

Treatment: radiation therapy +/- chemotherapy

Prognosis: better than SNUC, worse than conventional SCC

Micro ─

─ Syncytial sheets, nests, islands, or trabeculae of neoplastic cells

─ Intimately admixed with dense, nonneoplastic lymphoplasmacytic infiltrate

─ Desmoplastic stromal reaction often minimal or absent

─ Large, undifferentiated polygonal cells with indistinct borders

─ Nuclei are large, round to oval, vesicular chromatin, prominent eosinophilic nucleoli

─ Moderate amount of amphophilic cytoplasm

─ Mitoses frequent; necrosis may be present

─ Squamous differentiation (keratinization) is absent by definition

Molecular ─

─ EBV infection

IHC ─

─ Epithelial Cells: (+) Pan-Cytokeratin, EMA, p63 (TP63), p40

─ Lymphoid Stroma: (+) CD45, mixture of CD3(+) T cells and CD20(+) B cells (polyclonal)

─ EBV (EBER): (+) Nuclear signal by ISH in tumor cells (defining feature)

─ p16: Variable

DDx ─

Nasopharyngeal Carcinoma (Metastatic): clinically/radiographically exclude

Sinonasal Undifferentiated Carcinoma (SNUC): More pleomorphic, lacks prominent lymphoid stroma

Poorly Differentiated SCC: squamous differentiation; lymphoid stroma less prominent

Malignant Melanoma: melanocytic markers

Olfactory Neuroblastoma: Fibrillary stroma, neuroendocrine markers

Media ─ placeholder

Sinonasal Undifferentiated Carcinoma (SNUC)

Highly aggressive, poorly differentiated carcinoma lacking features of specific differentiation (squamous, glandular, neuroendocrine, olfactory). Diagnosis of exclusion.

Clinical ─

Age: Wide range

Sex: Male > female

Site: Nasal cavity, ethmoid sinuses most common; extensive involvement

Etiology: Unknown

Presentation: Rapid onset, often advanced stage (T3/T4)

Treatment: Aggressive multimodality therapy (surgery, chemoradiation)

Prognosis: Very poor

Micro ─:

─ Infiltrative sheets, nests, ribbons, trabeculae, extensive necrosis and apoptosis, vascular invasion frequent

─ Medium to large cells, round to polygonal, marked nuclear pleomorphism, irregular contours, coarse chromatin, prominent nucleoli

─ Scant to moderate cytoplasm, indistinct cell borders

─ High mitotic rate, numerous atypical mitoses

─ Lacks definitive squamous, glandular, or neuroendocrine features

Molecular ─

─ Complex karyotypes common

─ IDH2 R172 reported in a subset (~15-20%)

IHC ─

─ Epithelial Markers: (+) Cytokeratins (AE1/AE3, CAM5.2, CK7 often), EMA (variable intensity/extent)

─ (-) p63/p40: Usually negative or only focally positive (helps exclude SCC)

─ (-) Neuroendocrine Markers:

─ (-) S100, SOX10, Melan-A/HMB45

DDx ─

Poorly Differentiated SCC/Basaloid SCC: (+) p63/p40, may show focal squamous features

NUT Carcinoma: NUT(+) nuclear staining, NUTM1 rearranged

SWI/SNF Complex-Deficient Sinonasal Carcinoma: Loss of SMARCB1 or SMARCA4

Olfactory Neuroblastoma: (+) S100, Neuroendocrine markers, fibrillary background

Small Cell Neuroendocrine Carcinoma: Neuroendocrine markers (+), characteristic nuclear features

Malignant Melanoma: (+) S100, SOX10, Melan-A/HMB45

High-Grade Lymphoma: (+) CD45, specific lymphoid markers

Metastatic Carcinoma: Clinical history, different IHC profile

Rhabdomyosarcoma: (+) Desmin, Myogenin, MyoD1

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Teratocarcinosarcoma (Malignant Teratoma with Somatic-Type Malignancy)

Highly aggressive neoplasm composed of intimately admixed malignant epithelial, mesenchymal, and immature neuroectodermal/germ cell elements.

Clinical ─

Age: Wide range, often adults (mean 5th-6th decades)

Sex: Male predominance

Site: Sinonasal tract (esp maxillary sinus)

Presentation: Nasal obstruction, epistaxis, pain, mass effect

Treatment: Aggressive multimodality therapy (surgery, chemoradiation)

Prognosis: Very poor; highly aggressive with frequent recurrence and metastasis

Micro ─

Architecture:

─ Disorganized, haphazard mixture of malignant components

Components:

─ Epithelial Malignancy: Adenocarcinoma (various types), Squamous cell carcinoma, Undifferentiated carcinoma

─ Mesenchymal Malignancy (Sarcoma): Chondrosarcoma, Osteosarcoma, Rhabdomyosarcoma, Fibrosarcoma, Undifferentiated sarcoma

─ Immature Neuroectodermal/Germ Cell Elements: Primitive neuroepithelium (rosettes, tubules), Immature glial tissue, Fetal-type cartilage, Yolk sac tumor elements (less common)

─ Benign teratomatous elements (mature cartilage, glands, squamous epithelium) may also be present

IHC ─

(Reflects the different components present)

─ Epithelial areas: (+) Cytokeratins, EMA

─ Sarcomatous areas: Variable depending on type (e.g., Desmin/Myogenin for RMS, S100 for chondrosarcoma)

─ Neuroectodermal areas: (+) Synaptophysin, CD56, GFAP (glial), S100

─ Germ cell markers (OCT4, SALL4, Glypican-3): May be (+) if yolk sac/germ cell elements present

DDx ─

Carcinosarcoma (SCC with Sarcomatoid Transformation): Lacks immature neuroectodermal/germ cell elements

Poorly Differentiated Carcinoma (e.g., SNUC): Lacks distinct malignant mesenchymal or immature elements

High-Grade Sarcoma with Entrapped Epithelium: Epithelium is benign/reactive, lacks malignant epithelial component

Germ Cell Tumor (e.g., Teratoma with Malignant Transformation): Malignancy arises from one germ cell component within a background teratoma; TCS has admixed malignant elements from outset

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HPV-Associated Multiphenotypic Sinonasal Carcinoma

Distinctive sinonasal carcinoma associated with high-risk HPV, characterized by mixture of surface squamous dysplasia/CIS and invasive carcinoma often showing basaloid features and focal ductal/adenoid cystic-like patterns.

Clinical ─

Age: Wide range, often middle-aged adults

Site: Sinonasal tract, nasopharynx

Etiology: High-risk HPV (esp type 33, also 16, 35, 56)

Presentation: Nasal obstruction, epistaxis, mass

Treatment: Surgery +/- radiation

Prognosis: Generally considered indolent compared to conventional SCC or ACC; local recurrence common, metastasis rare

Micro ─

Architecture:

─ Often arises from surface squamous dysplasia or carcinoma in situ

─ Invasive component shows nests, lobules, cribriform or solid patterns

─ May have adenoid cystic-like features (pseudoglands, hyaline globules) but lacks true biphasic ductal-myoepithelial pattern of ACC

Cytology:

─ Basaloid cells with scant cytoplasm, hyperchromatic nuclei, inconspicuous nucleoli

─ May show focal squamous or ductal differentiation

─ Mitoses variable, atypia usually mild to moderate

─ Necrosis uncommon

Molecular ─

─ High-risk HPV consistently present (detected by ISH or PCR)

─ Lacks MYB or MYBL1 rearrangements seen in ACC

IHC ─

─ p16: Strong, diffuse block positivity (surrogate for HPV)

─ Epithelial Markers: (+) CK5/6, p63, p40

─ Myoepithelial Markers (SMA, Calponin, S100): Negative or only rare focal cells around nests (unlike true ACC)

─ CD117 (KIT): Often positive (overlap with ACC)

DDx ─

Adenoid Cystic Carcinoma (ACC): True biphasic pattern, cribriform spaces with basement membrane material, lacks surface dysplasia, MYB rearranged, p16(-)

Basaloid SCC: More atypia/mitoses, comedonecrosis common, usually p16(-) unless HPV+ oropharyngeal primary

Conventional SCC with Basaloid Features: Less organized growth, more atypia, usually p16(-)

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Nasopharyngeal Carcinoma (NPC)

Carcinoma arising from the epithelial lining of the nasopharynx, strongly associated with Epstein-Barr Virus (EBV) in endemic regions. Classified by WHO into nonkeratinizing (differentiated and undifferentiated subtypes) and keratinizing SCC.

Clinical ─

Age: Bimodal peaks (adolescents/young adults and older adults ~50-60 yrs) in endemic areas; primarily older adults in non-endemic areas

Site: Nasopharynx, esp fossa of Rosenmüller

Etiology: EBV infection (esp nonkeratinizing types), genetic susceptibility, environmental factors (dietary nitrosamines)

Presentation: Often subtle early symptoms; neck mass (metastatic nodes) most common presentation; also nasal obstruction, epistaxis, hearing loss (Eustachian tube dysfunction), cranial nerve palsies

Treatment: Primarily radiation therapy +/- chemotherapy (highly radiosensitive)

Prognosis: Depends on stage and histologic type; nonkeratinizing types generally have better response to RT and better prognosis than keratinizing SCC

Micro ─

WHO Classification:

─ Nonkeratinizing Carcinoma, Differentiated: Cohesive cells in trabecular or plexiform pattern; distinct cell margins; vesicular nuclei, prominent nucleoli; minimal lymphoid stroma.

─ Nonkeratinizing Carcinoma, Undifferentiated (Lymphoepithelial Carcinoma): Syncytial growth of large, undifferentiated cells with indistinct borders, vesicular nuclei, prominent nucleoli; intimately admixed with dense lymphoplasmacytic infiltrate (lymphoepithelial pattern).

─ Keratinizing Squamous Cell Carcinoma: Morphologically similar to conventional SCC elsewhere; shows keratinization (pearls, dyskeratosis); less association with EBV; worse prognosis.

─ Basaloid Squamous Cell Carcinoma: Rare variant in nasopharynx.

Molecular ─

─ EBV: Integral to pathogenesis of nonkeratinizing types; detected by EBER ISH

─ Complex genetic alterations in both EBV(+) and EBV(-) NPC

IHC ─

─ Epithelial Cells: (+) Pan-Cytokeratin, EMA, p63 (TP63), p40 (stronger in keratinizing SCC)

─ EBV (EBER): (+) Nuclear signal by ISH in tumor cells (hallmark of nonkeratinizing types)

─ p16: Variable, often patchy; not a reliable surrogate for HPV in this site

─ Lymphoid Stroma: (+) CD45, mixture of T and B cells

DDx ─

Sinonasal Lymphoepithelial Carcinoma: Arises in sinonasal tract, may also be EBER(+)

Lymphoma (esp Extranodal NK/T-cell Lymphoma, Nasal Type): Angiocentric/destructive, atypical lymphoid cells (+CD56, cytoplasmic CD3, EBER+); (-) Cytokeratins

Poorly Differentiated SCC from other sites: EBER(-)

Malignant Melanoma: (+) S100, SOX10, melanocytic markers; (-) Cytokeratins

Olfactory Neuroblastoma: Arises high in nasal cavity, (+) S100, neuroendocrine markers; EBER(-)

Pituitary Adenoma/Craniopharyngioma: Location, specific histology, pituitary hormones (+)

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Mesenchymal & Other Malignancies

Juvenile Nasopharyngeal Angiofibroma (JNA)

Benign, highly cellular and richly vascularized mesenchymal neoplasm arising in nasopharynx exclusively in males.

Clinical ─

Age: Adolescents to young men (peak: 2nd decade)

Sex: Males exclusively

Site: Nasopharynx affected; pterygoid region usually affected; may expand to involve surrounding structures (30% of cases)

Presentation: Recurrent, spontaneous epistaxis; nasal obstruction, discharge, sinusitis, rhinolalia; facial deformity (proptosis), exophthalmia, diplopia; otitis media, tinnitus, deafness; headaches

Treatment: Surgery is treatment of choice, with endoscopic resection preferred; biopsy is contraindicated due to potential exsanguination; selective angiography allows presurgical embolization

Prognosis: Good; recurrences in ~10-20% of patients (usually with intracranial extension); may have fatal exsanguination if incorrectly managed

Micro ─

─ Submucosal proliferation of vascular component within fibrous stroma

─ Many variably sized disorganized vessels; varying thickness of vessel wall with patchy muscle content

─ Vessels are mostly thin-walled, slit-like (staghorn); range from capillary size to large, dilated, patulous vessels

─ Focal, pad-like, smooth muscle thickenings within vessel walls

─ Endothelial cells may be plump but are usually attenuated

─ Fibrous stroma consists of plump spindle, angular, or stellate-shaped cells

─ Variable amounts of fine and coarse collagen fibers; elastic tissue is not identified within stroma

─ Stromal cells may be angulated, multinucleated, and pleomorphic; mitotic figures are sparse

─ Mast cells may be seen

─ Myxoid degeneration common (esp in embolized specimens)

─ Sarcomatous transformation exceedingly uncommon (usually post-radiation)

Molecular ─ Activating CTNNB1 (β-catenin) gene mutations

IHC ─

─ Stromal Cells: (+) Nuclear β-catenin, Androgen receptor (nuclear)

─ Endothelial Cells: (+) CD31, CD34, FVIIIRAg, Androgen receptor (nuclear); (-) β-catenin

─ Smooth Muscle: (+) Actin-sm, Desmin (larger vessels)

DDx ─

Lobular Capillary Hemangioma: Ulcerated; different site; granulation tissue, inflammation; organized vessels

Inflammatory Polyp: Edematous; lacks rich/characteristic vascular investment

Antrochoanal Polyp: Different location; fibrotic stroma; lacks characteristic vascular pattern

Glomangiopericytoma: Patternless/fascicular oval/spindle cells; perivascular hyalinization; (+) Actins, β-catenin; (-) CD34

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Sinonasal Glomangiopericytoma

Soft tissue tumor showing perivascular myoid differentiation defined by glomus (myoid) and hemangiopericytoma (pericyte) features.

Clinical ─

Age: Broad range (5-90 years); mean in 7th decade

Sex: Female > male (1.2:1)

Site: Nasal cavity usually affected in isolation (turbinate, septum); less often maxillary/ethmoid sinuses

Presentation: Nasal obstruction, mass, polyps, difficulty breathing; sinusitis, discharge, changes in smell; epistaxis uncommon; headache, congestion, pain

Treatment: Complete surgical excision

Prognosis: Excellent long-term survival (~90% 5-yr); recurrences (~27%) associated with long symptom duration, bone invasion, pleomorphism; metastasis rare

Micro ─

─ Surface epithelium usually intact (respiratory or metaplastic squamous); subepithelial proliferation separated from surface (grenz zone)

─ Cellular, diffuse, syncytial arrangement; patternless or short fascicles, storiform, solid, whorled

─ Spindled, epithelioid, or rounded cells with indistinct borders; clear to amphophilic/eosinophilic cytoplasm

─ Absent to mild pleomorphism; oval to spindle nuclei with coarse chromatin; mitoses uncommon (<1/10 HPF); atypical mitoses absent

─ Ramifying, branching pattern of thin-walled vessels (staghorn/antler-like)

─ Peritheliomatous (perivascular) hyalinization is characteristic

─ Extravasated erythrocytes common

─ Mixture of inflammatory cells in background (eosinophils, mast cells predominate over lymphocytes)

─ Tumor giant cells uncommon; necrosis rare (consider malignant if present)

Molecular ─ CTNNB1 mutations reported

IHC ─

─ Tumor Cells: (+) Nuclear & cytoplasmic β-catenin, Nuclear Cyclin-D1, Cytoplasmic Actin-sm, Cytoplasmic Actin-HHF-35; Negative CD34, S100, Desmin, Cytokeratins, EMA, CD31, FVIIIRAg, CD117

DDx ─

Solitary Fibrous Tumor: Spindle cells, ropy/keloid collagen, hemangiopericytoma-like vessels; (+) Nuclear STAT6, CD34, Bcl-2; (-) Actins, β-catenin

Leiomyoma: Fascicles of spindle cells with cigar-shaped nuclei, perinuclear vacuoles; (+) Desmin; (-) β-catenin

Schwannoma: Antoni A/B areas, Verocay bodies, perivascular hyalinization; (+) S100, SOX10; (-) Actins, β-catenin

Fibrosarcoma: Herringbone fascicles, more atypia/mitoses; IHC negative except vimentin

Meningioma: Whorled meningothelial cells, psammoma bodies, intranuclear inclusions; (+) EMA

Lobular Capillary Hemangioma: Lobular architecture, ulceration common, inflammation prominent; lacks diffuse myoid cells

Nasopharyngeal Angiofibroma: Nasopharynx site, adolescent males, distinct stromal/vascular features; (+) AR; nuclear β-catenin only in stromal cells

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Biphenotypic Sinonasal Sarcoma (BSNS)

Low-grade spindle cell neoplasm of sinonasal tract associated with respiratory epithelium and showing S100 protein and actin reactivity.

Clinical ─

Age: Range 24-85 years; mean 52 years

Sex: Female > males (3:1)

Site: Superior nasal cavity and ethmoid sinus most common; multiple sites often affected, extension into orbit (25%) or through cribriform plate (11%) possible

Presentation: Nasal obstruction, difficulty breathing, facial pressure, congestion, pain, mild epiphora; concurrent benign polyps may be seen

Treatment: Surgery, often accompanied by radiation

Prognosis: Local recurrences common (44%), 1-9 years post-treatment; no reported regional or distant metastases; no reported deaths from disease

Micro ─

─ Infiltrative, highly cellular spindled cell proliferation; poorly circumscribed, unencapsulated

─ Bone invasion may be seen (21%)

─ Medium to long fascicles, often with herringbone pattern

─ Highly uniform cells with elongate nuclei; focally wavy nuclei; mitoses are rare

─ Delicate strands of intercellular collagen; lacks ropy/dense collagen

─ Concurrent surface-type respiratory epithelial proliferation invaginated from surface or in small cystic spaces within proliferation is characteristic

─ Glandular structures intimately associated with spindled cells in several areas

─ Focal areas of hemangiopericytoma-like vascularity may be present

─ Scattered lymphocytes often present; necrosis, ulceration, hemorrhage inconspicuous

─ Rhabdomyoblastic differentiation (large eosinophilic cells +/- cross striations) rarely seen

Molecular ─ PAX3::MAML3 fusion t(2;4)(q35;q31.1) characteristic; rarely PAX3::NCOA1

IHC ─

─ Spindle Cells: (+) S100 (focal, patchy to diffuse), SMA/MSA (variable, strong/diffuse in ~50%); Focal (+) CD34, Desmin, EMA (weak), AE1/AE3; (-) SOX10, Myogenin

─ Epithelial/Glandular Component: (+) Cytokeratins, EMA

DDx ─

Fibrosarcoma: Longer fascicles, more collagen, lacks epithelial component; (-) S100

Synovial Sarcoma: Monophasic or biphasic; (+) TLE1, Cytokeratins, EMA; characteristic t(X;18) (SS18::SSX)

Malignant Peripheral Nerve Sheath Tumor (MPNST): Alternating cellularity, nerve association, often NF1 related, higher grade features common; (+) S100, SOX10; (-) Actins

Leiomyosarcoma: Fascicular, cigar-shaped nuclei, perinuclear halos; (+) Desmin; (-) S100

Mucosal Melanoma: Spindle cell variant; (+) SOX10, HMB45, Melan-A; (-) Actins

Glomangiopericytoma: Patternless/syncytial, perivascular hyalinization, eosinophils/mast cells; (+) β-catenin; (-) S100, CD34

Solitary Fibrous Tumor: Patternless, ropy collagen, hemangiopericytoma-like vessels; (+) Nuclear STAT6, CD34, Bcl-2; (-) S100, Actins

Schwannoma: Antoni A/B, Verocay bodies; (+) S100, SOX10; (-) Actins

Respiratory Epithelial Adenomatoid Hamartoma (REAH): Benign glandular proliferation from surface, thick basement membranes; lacks spindle cell sarcoma component

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