Common benign epithelial neoplasms of the ovary lined by tubal-type epithelium, distinguished by the amount of fibrous stroma
Clinical ─ Can occur at any age, peak in 4th-5th decades; often asymptomatic or present with mass effect (pain, pressure, bloating); generally excellent prognosis
Macro ─ Serous Cystadenoma: Usually unilocular (can be multilocular), thin-walled cyst containing clear, watery (serous) fluid; smooth inner lining, occasional small papillae
─ Serous Adenofibroma/Cystadenofibroma: Predominantly solid and fibrous (adenofibroma) or mixed cystic and solid (cystadenofibroma); firm, white/tan cut surface
Micro ─ Lined by a single, non-stratified layer of bland epithelial cells
─ Cells are cuboidal to low columnar, often ciliated (resembling fallopian tube epithelium); non-ciliated (peg) cells also present
─ Nuclei are small, round to oval, uniform, without significant atypia
─ Mitotic activity is absent or very rare (<1 per 10 HPF)
─ Simple, non-complex, non-hierarchical papillae may be present
─ Serous Adenofibroma: Epithelial-lined glands/cysts embedded in abundant, dense fibrous stroma
Ancillary studies ─ IHC (+) WT1, PAX8, ER (usually); CK7
─ IHC (-) CK20, CDX2
DDx ─ Serous Borderline Tumor (hierarchical branching, epithelial stratification, mild-moderate atypia)
─ Low-Grade Serous Carcinoma (invasion, moderate atypia, psammoma bodies common)
─ Cortical Inclusion Cyst / Endosalpingiosis (usually small, incidental, often multiple)
─ Peritoneal Inclusion Cyst (mesothelial lining, often reactive)
─ Brenner Tumor (transitional/urothelial-like epithelium)
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Serous Borderline Tumor

A non-invasive epithelial neoplasm with serous (tubal-type) differentiation, characterized by epithelial proliferation and atypia exceeding benign tumors but lacking destructive stromal invasion
Clinical ─ Wide age range, often reproductive/perimenopausal; may present as adnexal mass or be incidental; often bilateral; prognosis generally good, but depends on micropapillary features and presence/type of implants
Macro ─ Cystic, unilocular or multilocular, often with intracystic or surface papillary excrescences; may be solid/fibrous (cystadenofibromatous type)
Micro ─ Papillary architecture, often with complex, hierarchical branching (typical SBT)
─ Epithelial stratification (usually >1 and <4 cell layers)
─ Mild to moderate nuclear atypia (more than cystadenoma, less than HGSC)
─ Epithelial tufting/detachment (small clusters of cells budding into lumen)
─ Mitotic activity generally low
─ Psammoma bodies may be present
─ No destructive stromal invasion (key feature)
─ Micropapillary (MP) Variant:
─ Non-hierarchical, slender, filiform papillae or cribriform patterns
─ Must be >5 mm in at least one dimension
─ Associated with higher risk of invasive implants (LGSC)
─ Peritoneal Implants:
─ Non-invasive: Epithelial (glands/papillae) or Desmoplastic (fibrous response); better prognosis
─ Invasive: Qualify as LGSC; poorer prognosis
Ancillary studies ─ IHC (+) WT1, PAX8, ER, PR (often)
─ IHC (-) p53 (wild-type pattern), Ki67 (low, <10%)
─ Molecular ─ KRAS or BRAF mutations common; TP53 wild-type
DDx ─ Serous Cystadenoma (single layer, bland)
─ Low-Grade Serous Carcinoma (destructive invasion)
─ High-Grade Serous Carcinoma (high-grade atypia, high mitoses, p53 aberrant)
─ Well-differentiated papillary mesothelial tumor / Peritoneal inclusion cysts (WT1+, Calretinin+, PAX8-)
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Low-Grade Serous Carcinoma

An invasive carcinoma with serous differentiation, characterized by relatively uniform nuclei, low mitotic activity, and often associated with SBT
Clinical ─ Tends to affect younger women than HGSC; often presents at advanced stage; frequently chemoresistant but indolent course; arises de novo or from SBT/implants
Macro ─ Often large, complex cystic and solid masses; extensive papillary or nodular growth; can involve ovarian surface and peritoneum extensively
Micro ─ Demonstrates destructive stromal invasion (irregular nests, single cells, micropapillae infiltrating stroma)
─ Cells are relatively uniform, with mild to moderate nuclear atypia (typically grade 1 or 2 nuclei)
─ Mitotic count is low (<12 per 10 HPF, often much lower)
─ Architectural patterns include micropapillary, glandular, and single cells
─ Psammoma bodies are very common, can be extensive
─ Often seen arising in association with or adjacent to SBT
Ancillary studies ─ IHC (+) WT1, PAX8, ER, PR (often strongly)
─ IHC (-) p53 (wild-type pattern), Ki67 (low to moderate, typically <15-20%)
─ Molecular ─ KRAS, BRAF, or NRAS mutations common; TP53 wild-type
DDx ─ Serous Borderline Tumor (lacks destructive invasion)
─ High-Grade Serous Carcinoma (high-grade atypia, high mitoses, p53 aberrant)
─ Invasive implants of SBT (are LGSC by definition)
─ Endometrioid Carcinoma (often WT1-, ER/PR+, may have squamous change)
─ Well-differentiated papillary mesothelial tumor (Calretinin+, PAX8-)
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High-Grade Serous Carcinoma (Ovary)

The most common and aggressive type of ovarian cancer, characterized by marked nuclear pleomorphism, high mitotic activity, and near-universal TP53 mutation; believed to arise primarily from the fallopian tube fimbria (STIC) or ovarian surface/cortical inclusion cysts
Clinical ─ Most common ovarian malignancy (~70%); typically affects older women (postmenopausal); often presents at advanced stage (III/IV) with widespread peritoneal carcinomatosis and ascites; high response to platinum-based chemotherapy but frequent recurrence and poor long-term prognosis
Macro ─ Often large, bilateral, solid and cystic masses with extensive papillary excrescences, necrosis, and hemorrhage; frequently involves ovarian surface and extra-ovarian sites
Micro ─ Marked nuclear atypia (pleomorphism, high N/C ratio, irregular chromatin, prominent nucleoli; grade 3 nuclei)
─ High mitotic activity (usually >12 mitoses per 10 HPF), often including atypical mitotic figures
─ Common architectural patterns: Papillary, solid sheets, glandular, cribriform, slit-like spaces (SET pattern - Solid, Endometrioid-like, Transitional-like)
─ Necrosis is common
─ Psammoma bodies can be present
Ancillary studies ─ IHC (+) WT1 (nuclear), PAX8, p53 (aberrant: >75% strong/diffuse staining OR completely negative/null pattern), Ki67 (high, often >40-50%)
─ IHC (+/-) ER, PR (often positive but can be patchy or negative, generally less intense than LGSC)
─ Molecular ─ TP53 mutations almost universal; BRCA1/BRCA2 mutations (germline or somatic) common; Homologous Recombination Deficiency (HRD) common (~50%)
DDx ─ Low-Grade Serous Carcinoma (lower grade atypia/mitoses, p53 wild-type)
─ High-Grade Endometrioid Carcinoma (often ER/PR strong+, WT1-, may have squamous/mucin)
─ Metastatic Carcinoma (eg, breast, GI - clinical history, IHC panel)
─ Undifferentiated Carcinoma
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Mucinous Tumors

Mucinous Cystadenoma / Mucinous Adenofibroma (Ovary)

Benign epithelial neoplasms of the ovary lined by mucin-secreting cells, typically of endocervical (Müllerian) or intestinal type; adenofibroma variant has prominent fibrous stroma
Clinical ─ Common, can occur at any age, often large at presentation causing mass effects; generally excellent prognosis; intestinal type must be distinguished from metastatic disease
Macro ─ Often very large (can exceed 30 cm), multilocular cystic masses; filled with thick, gelatinous, mucoid material; cyst walls are generally thin and smooth; Adenofibroma variant is more solid and fibrous
Micro ─ Lined by a single layer of bland, tall columnar mucinous epithelial cells with basal nuclei
─ No significant nuclear atypia, stratification (<3 layers thick), or mitotic activity
─ Two main types of epithelium:
─ Intestinal-type: Resembles colonic epithelium, often with goblet cells; may show Paneth cells or neuroendocrine cells
─ Endocervical-type (Müllerian): Resembles endocervical glands with pale eosinophilic or clear apical mucin, usually lacks goblet cells
─ Adenofibroma variant shows epithelial-lined glands/cysts embedded in abundant, dense fibrous stroma
Ancillary studies ─ IHC (Intestinal) (+) CK20, CDX2; (-) CK7 (or patchy), ER, PR, WT1
─ IHC (Endocervical) (+) CK7, ER, PR (often); (-) CK20, CDX2, WT1
DDx ─ Mucinous Borderline Tumor (epithelial stratification, atypia, complexity)
─ Mucinous Carcinoma (invasion, significant atypia)
─ Metastatic Mucinous Carcinoma (especially appendix, colon, pancreas - check history, bilaterality, surface involvement, IHC profile)
─ Mature Cystic Teratoma (presence of other germ cell elements)
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Mural Nodules in Mucinous Cystic Neoplasms (Ovary)

Discrete, solid nodules found within the wall of ovarian mucinous cystic tumors (usually borderline or carcinoma), which can be benign (reactive), sarcoma-like (but benign), or frankly malignant (anaplastic carcinoma or sarcoma)
Clinical ─ Found in a subset of ovarian mucinous tumors; prognostic significance depends entirely on the nature of the nodule (benign vs malignant); malignant nodules confer a worse prognosis
Macro ─ Discrete, solid, variably sized nodules (mm to cm) projecting from or within the cyst wall; can be firm, soft, gray-white, yellow, or hemorrhagic
Micro ─ Wide range of appearances depending on type:
─ Anaplastic Carcinoma: Most common malignant type; pleomorphic, bizarre, or spindled cells with high mitotic activity and necrosis; often TP53 mutated; can mimic sarcoma but usually CK+
─ Sarcoma: True sarcoma (eg, rhabdomyosarcoma, fibrosarcoma, undifferentiated) arising in the wall; rare
─ Sarcoma-like (Benign/Reactive): Can mimic sarcoma but lack high-grade features/invasion; includes:
─ Pleomorphic/Spindle Cell Nodules: Bizarre, hyperchromatic cells, but low MIB1, p53 wt, often associated with hemorrhage/inflammation
─ Rhabdomyoblastic Nodules (benign): Strap cells or rhabdomyoblasts, often reactive
Ancillary studies ─ IHC depends on suspected type: p53 (aberrant in anaplastic ca), Ki67 (high in malignant), Desmin/Myogenin (rhabdomyoblastic), CD68 (histiocytic), Cytokeratins (confirm carcinoma)
DDx ─ Based on nodule histology: Differentiating benign reactive nodules from true anaplastic carcinoma/sarcoma is crucial
─ Intracystic papillary carcinoma (part of the primary mucinous tumor)
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Mucinous Borderline Tumor (Ovary)

A non-invasive mucinous epithelial neoplasm (usually intestinal type) characterized by epithelial proliferation, architectural complexity, and nuclear atypia exceeding benign tumors but lacking destructive stromal invasion
Clinical ─ Represents ~10-15% of mucinous ovarian tumors; often presents as large adnexal masses; most are stage I and have excellent prognosis; must exclude metastasis, especially from appendix; can be associated with pseudomyxoma peritonei if ruptured or metastatic intestinal type
Macro ─ Large, multilocular cysts; often have areas with papillary projections, thickened walls, or increased complexity compared to cystadenomas
Micro ─ Increased architectural complexity (papillary, villous, or cribriform patterns)
─ Epithelial stratification (usually >1 but <4 cell layers)
─ Mild to moderate nuclear atypia (enlargement, hyperchromasia, irregular contours)
─ Mitotic figures may be present, but not usually numerous or atypical
─ No destructive stromal invasion (key feature)
─ Most are Intestinal-type; Müllerian (endocervical) type is less common and resembles seromucinous tumors
─ May have foci of Intraepithelial Carcinoma (IEC): High-grade (Grade 3) nuclei confined by basement membrane
─ May have foci of Microinvasion: Invasive focus <5 mm in greatest dimension (or <10 mm²)
Ancillary studies ─ IHC (Intestinal) (+) CK20, CDX2; (-) CK7 (or patchy), ER, PR; p53 (wt)
─ IHC (Müllerian) (+) CK7, ER, PR; (-) CK20, CDX2
─ IHC SATB2 is useful; positivity strongly favors lower GI (appendiceal) origin over primary ovarian
─ Molecular ─ KRAS mutations are common (especially intestinal type)
DDx ─ Mucinous Cystadenoma (lacks atypia/stratification/complexity)
─ Mucinous Carcinoma (frank destructive invasion)
─ Metastatic Mucinous Carcinoma (especially appendix: often bilateral, surface involvement, pseudomyxoma, SATB2+, CK20+/CK7-)
─ Seromucinous Borderline Tumor (shows mixed serous/mucinous features, more often WT1+)
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Mucinous Carcinoma (Ovary)

An invasive carcinoma composed of mucin-secreting epithelial cells, most commonly of intestinal type; primary ovarian mucinous carcinoma is rare, and metastasis must always be excluded
Clinical ─ Often large masses; if bilateral or associated with pseudomyxoma peritonei, strong consideration for metastasis (especially appendix); prognosis depends heavily on stage and whether primary or metastatic; primary cases often have better prognosis if confined to ovary
Macro ─ Large, multilocular cystic masses, often with solid, necrotic, or hemorrhagic areas; gelatinous mucin content
Micro ─ Malignant mucinous epithelial cells showing significant nuclear atypia (grade 2 or 3), stratification, and mitotic activity
─ Invasion patterns:
─ Expansile (Confluent): Large (>5 mm), complex, back-to-back glands lacking significant intervening stroma, often with 'labyrinthine' appearance
─ Infiltrative (Destructive): Irregular glands, nests, or single cells invading a desmoplastic stroma
─ Grading is based on nuclear features and architecture
─ Crucial to exclude metastasis: Features favoring primary include unilateral, large size (>13 cm), smooth surface, associated teratoma/Brenner/MBT, CK7+/CK20- profile; Features favoring metastasis include bilateral, smaller size, surface involvement, pseudomyxoma, lymphovascular invasion, CK7-/CK20+, SATB2+, CDX2+ profile
Ancillary studies ─ IHC Panel is essential for origin assessment:
─ Primary Ovarian (Intestinal) (+) CK7 (often), CK20 (variable), PAX8 (often -/weak), CDX2 (variable); (-) SATB2
─ Metastatic Appendix (+) CK20, CDX2, SATB2; (-) CK7, PAX8
─ Metastatic Colon (+) CK20, CDX2, SATB2; (-) CK7, PAX8
─ Metastatic Pancreas (+) CK7, CK20 (variable), MUC1, MUC5AC; (-) CDX2, SATB2, PAX8
─ Molecular ─ KRAS mutations common in primary and metastatic intestinal types; TP53 mutations can occur in higher grades
DDx ─ Metastatic Mucinous Carcinoma (most important DDx)
─ Mucinous Borderline Tumor (lacks invasion)
─ Endometrioid Carcinoma with mucinous features (check for typical endometrioid areas, WT1-, PAX8+)
─ Mixed Mucinous / Seromucinous tumors
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Endometrioid

Endometrioid Cystadenoma / Adenofibroma (Ovary)

Benign epithelial neoplasms of the ovary characterized by endometrial-type glands, often with squamous metaplasia, set in fibrous stroma (adenofibroma) or forming cysts (cystadenoma)
Clinical ─ Often found in association with endometriosis or endometrial carcinoma (synchronous); typically presents as an adnexal mass; benign behavior
Macro ─ Can be cystic (cystadenoma), solid/fibrous (adenofibroma), or mixed (cystadenofibroma); may contain 'chocolate-like' fluid if arising from endometriosis
Micro ─ Lined by a single layer of bland, non-stratified or minimally stratified, cuboidal to columnar endometrial-type epithelium (non-ciliated or poorly ciliated)
─ Glands are tubular or round, resembling inactive or proliferative endometrium
─ Squamous metaplasia (morules) is very common and a helpful feature
─ Ciliated cells (tubal metaplasia) can occur
─ Stroma is typically fibrous (adenofibroma)
─ No significant atypia or mitotic activity
─ May see evidence of endometriosis (stroma, hemosiderin)
Ancillary studies ─ IHC (+) PAX8, ER, PR, CK7; (-) WT1
DDx ─ Endometrioid Borderline Tumor (glandular complexity, atypia)
─ Endometriosis (presence of endometrial stroma is defining)
─ Serous Adenofibroma (ciliated cells, WT1+)
─ Brenner Tumor (urothelial-like cells, 'coffee-bean' nuclei)
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Endometrioid Borderline Tumor (Ovary)

A non-invasive (or microinvasive) epithelial neoplasm of the ovary with endometrioid differentiation, characterized by glandular proliferation and atypia exceeding benign tumors but lacking destructive stromal invasion
Clinical ─ Rare; often associated with endometriosis; may be synchronous with uterine endometrioid neoplasia; generally favorable prognosis, though recurrences can occur
Macro ─ Can be cystic (often arising from an endometriotic cyst), solid (adenofibromatous), or mixed; may have papillary or polypoid areas
Micro ─ Proliferation of endometrioid-type glands showing architectural complexity (crowding, back-to-back arrangement, cribriforming, villoglandular patterns)
─ Mild to moderate nuclear atypia
─ Mitotic figures can be present but are not usually numerous or atypical
─ Squamous metaplasia (morules) is common and characteristic
─ Ciliated metaplasia can be seen
─ No destructive stromal invasion (key feature); microinvasion (<5 mm) is allowed
─ Often arises in association with endometriosis
─ Two patterns described: Adenofibromatous (exophytic) and Intracystic (papillary)
Ancillary studies ─ IHC (+) PAX8, ER, PR, CK7; (-) WT1
─ IHC Beta-catenin (nuclear positivity suggests CTNNB1 mutation, common in endometrioid neoplasms)
─ Molecular ─ ARID1A loss, PTEN loss, CTNNB1 mutations can occur
DDx ─ Endometrioid Carcinoma (destructive invasion)
─ Endometrioid Cystadenoma (lacks atypia/complexity)
─ Serous Borderline Tumor (hierarchical branching, WT1+)
─ Clear Cell Borderline Tumor (clear/hobnail cells, Napsin A+, HNF1B+)
─ Brenner Borderline Tumor (urothelial-like cells)
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Endometrioid Carcinoma (Ovary)

An invasive carcinoma of the ovary resembling endometrial adenocarcinoma of the uterus, often arising in the setting of endometriosis or synchronous with a uterine primary
Clinical ─ ~10-15% of ovarian cancers; often presents at an earlier stage than serous; ~15-30% have synchronous uterine endometrioid ca; often associated with endometriosis; prognosis generally better than HGSC, grade-dependent
Macro ─ Can be cystic (often arising within an endometriotic cyst, may contain 'chocolate' material) or solid/polypoid; may show necrosis/hemorrhage
Micro ─ Resembles uterine counterpart, typically glandular architecture (back-to-back glands, cribriform, villoglandular)
─ Can have solid areas (Grade 3)
─ Squamous differentiation (morules, squamous metaplasia, or invasive squamous component) is common (~30-50%) and a helpful feature
─ Ciliated cells or mucinous differentiation can occur
─ Nuclear grading (FIGO 1-3) based on % solid growth and atypia
─ Must differentiate low-grade from borderline (invasion) and high-grade from HGSC (IHC profile)
─ Look for background endometriosis
Ancillary studies ─ IHC (+) PAX8, ER, PR, CK7
─ IHC (-) WT1 (key differentiator from serous)
─ IHC (+/-) Beta-catenin (nuclear+ in ~40-60%, indicates CTNNB1 mutation), p53 (aberrant in high-grade/dedifferentiated), ARID1A (loss in ~30-50%), PTEN (loss), MMR proteins (loss suggests Lynch syndrome/MSI)
DDx ─ High-Grade Serous Carcinoma (WT1+, p53 aberrant usually)
─ Metastatic Endometrial Carcinoma (requires clinical/imaging correlation)
─ Metastatic Colorectal Carcinoma (often CK20+, CDX2+, SATB2+; PAX8-, ER-)
─ Seromucinous Tumor (mix of cell types)
─ Sex Cord-Stromal Tumors (Inhibin+, Calretinin+, FOXL2+)
─ Brenner Tumor (urothelial-like cells, WT1+/-)
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Clear Cell Adenofibroma (Ovary)

A benign epithelial neoplasm of the ovary composed of clear cell type glands and cysts set within an abundant fibrous stroma
Clinical ─ Uncommon; often an incidental finding or presents as a mass; considered a potential precursor to atypical/borderline clear cell tumors and carcinoma; often associated with endometriosis
Macro ─ Predominantly solid, firm, white-tan fibrous tumor, may have small cystic spaces
Micro ─ Benign glands and small cysts embedded in a dense fibrous stroma
─ Glands/cysts lined by a single layer of bland epithelial cells:
─ Hobnail cells (characteristic)
─ Flat or cuboidal cells
─ Clear cells (glycogenated)
─ Eosinophilic cells
─ No significant atypia, stratification, or mitotic activity
Ancillary studies ─ IHC (+) PAX8, HNF1B, Napsin A (variable), CK7; (-) ER, PR, WT1
DDx ─ Clear Cell Borderline Tumor (atypia, complexity)
─ Brenner Tumor (urothelial-like cells, coffee-bean nuclei)
─ Serous Adenofibroma (ciliated cells, WT1+)
─ Endometrioid Adenofibroma (endometrioid glands, squamous morules common)
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Clear Cell

Clear Cell Borderline Tumor (Ovary)

A rare, non-invasive (or microinvasive) epithelial neoplasm of the ovary with clear cell differentiation, characterized by glandular/papillary proliferation and atypia exceeding benign tumors but lacking destructive stromal invasion
Clinical ─ Very rare; often associated with endometriosis and clear cell adenofibroma/carcinoma; prognosis is generally favorable but less certain than other borderline types due to rarity
Macro ─ May be cystic, solid, or mixed; often arises within an endometriotic cyst or an adenofibroma
Micro ─ Architectural complexity (glandular crowding, papillae) exceeding adenofibroma
─ Lined by clear cell types: Hobnail, clear (glycogenated), eosinophilic, or flattened cells
─ Mild to moderate nuclear atypia
─ No destructive stromal invasion (key feature); microinvasion (<5 mm) may occur
─ Often associated with endometriosis or clear cell adenofibroma
Ancillary studies ─ IHC (+) PAX8, HNF1B, Napsin A, CK7; (-) ER, PR, WT1
DDx ─ Clear Cell Carcinoma (destructive invasion, higher-grade atypia)
─ Clear Cell Adenofibroma (lacks atypia/complexity)
─ Arias-Stella Reaction (in endometriosis, associated with pregnancy/hormones, lacks mass/complexity)
─ Endometrioid Borderline Tumor (lacks hobnail/clear cells, often has morules, ER+)
─ Serous Borderline Tumor (WT1+)
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Clear Cell Carcinoma (Ovary)

A high-grade invasive carcinoma of the ovary characterized by cells with clear (glycogen-rich) cytoplasm and/or hobnail morphology
Clinical ─ ~10% of ovarian cancers; strongly associated with endometriosis (~50-70%); associated with paraneoplastic hypercalcemia and venous thromboembolism; typically presents at an earlier stage than HGSC but can be aggressive and relatively chemoresistant
Macro ─ Often large, unilocular or multilocular cysts, frequently arising from an endometriotic cyst; may have solid, fleshy, or polypoid nodules; tan-yellow cut surface
Micro ─ Diverse architectural patterns:
─ Tubulocystic (most common)
─ Papillary
─ Solid
─ Characteristic cell types:
─ Clear cells (abundant clear cytoplasm due to glycogen)
─ Hobnail cells (protruding nuclei into lumen)
─ Eosinophilic ('oxyphilic') cells
─ Flattened/cuboidal cells
─ Nuclei are typically high-grade (Grade 3) with prominent nucleoli
─ Stroma is often hyalinized; hyaline bodies/globules can be seen
─ Background endometriosis is common
Ancillary studies ─ IHC (+) Napsin A (strong & diffuse is specific), HNF1B (nuclear), PAX8, CK7, AMACR
─ IHC (-) ER, PR, WT1 (usually)
─ IHC (+/-) ARID1A (loss in ~50%)
─ PAS (+) and diastase-sensitive (confirms glycogen in clear cells)
DDx ─ Yolk Sac Tumor (younger age, Schiller-Duval bodies, AFP+, SALL4+)
─ High-Grade Serous Carcinoma (WT1+, p53 aberrant, different morphology)
─ Endometrioid Carcinoma (ER+, WT1-, often morules, different morphology)
─ Dysgerminoma with clear cells (younger age, OCT3/4+, SALL4+, KIT+)
─ Steroid Cell Tumor (Inhibin+, Calretinin+, lipid-rich)
─ Metastatic Renal Cell Carcinoma (often PAX8+, but usually CA9+, CD10+; check history)
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Seromucinous

Seromucinous Borderline Tumor (Ovary)

A non-invasive epithelial neoplasm of the ovary characterized by a mixture of cell types, typically including serous (ciliated) and endocervical-type mucinous cells, often with endometrioid or transitional features, and frequently associated with endometriosis
Clinical ─ Often occurs in women with endometriosis; generally presents as an adnexal mass; prognosis is usually excellent
Macro ─ Typically cystic, often multilocular, with intracystic papillae; may arise within an endometriotic cyst
Micro ─ Complex, branching papillary architecture (often resembles SBT)
─ Lined by a mixture of cell types, predominantly:
─ Ciliated serous-type cells
─ Endocervical-type mucinous cells (apical mucin, no goblet cells)
─ Eosinophilic ('indifferent') cells
─ May also have foci of endometrioid, transitional, or clear cells
─ Mild to moderate nuclear atypia and epithelial stratification
─ Numerous neutrophils often seen within the epithelium and stroma (characteristic but not required)
─ No destructive stromal invasion
─ Often associated with endometriosis (~40-50%)
Ancillary studies ─ IHC (+) CK7, PAX8, ER, PR (usually)
─ IHC (-) WT1 (usually, key differentiator from serous), CK20, CDX2
─ IHC (+/-) ARID1A (loss can occur, reflecting endometrioid lineage)
DDx ─ Serous Borderline Tumor (WT1+, lacks prominent mucinous component)
─ Mucinous Borderline Tumor (Intestinal type: goblet cells, CK20+, WT1-)
─ Endometrioid Borderline Tumor (predominantly endometrioid, often squamous morules, WT1-)
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Brenner

Brenner Tumor (Benign) (Ovary)

A benign epithelial-stromal neoplasm of the ovary characterized by nests of transitional-like (urothelial-like) epithelium embedded within a dense fibrous stroma
Clinical ─ Most common Brenner type; often found in older women (postmenopausal); usually unilateral and asymptomatic (incidental finding) or presents as mass; excellent prognosis
Macro ─ Typically a solid, firm, well-circumscribed, gray-white or tan-yellow mass; may have small cystic areas
Micro ─ Well-demarcated, sharply defined nests of transitional-like (urothelial-like) epithelial cells
─ Epithelial cells are typically bland, oval, with pale cytoplasm and longitudinal nuclear grooves ('coffee-bean' nuclei)
─ Nests are set within an abundant, dense, fibrous (thecoma-like) stroma
─ Glandular differentiation with mucinous cells (resembling endocervical or intestinal type) is common within the center of epithelial nests, sometimes forming cysts
─ No significant atypia, mitoses, or invasion
Ancillary studies ─ IHC (+) GATA3, p63, CK7, Uroplakin III (variable)
─ IHC (-) PAX8, WT1, ER, Inhibin (stroma can be +)
DDx ─ Fibroma / Thecoma (lacks epithelial nests)
─ Adenofibroma (Serous/Endometrioid/Clear Cell - different epithelial type & IHC)
─ Borderline / Malignant Brenner Tumor (shows atypia/papillary growth/invasion)
─ Metastatic Urothelial Carcinoma (history, higher grade, invasive features, PAX8-)
─ Granulosa Cell Tumor (Call-Exner bodies, different nuclei, Inhibin+, FOXL2+)
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Borderline Brenner Tumor (Ovary)

A rare Brenner neoplasm of the ovary characterized by papillary proliferation of low-grade transitional-like epithelium within cystic spaces, resembling low-grade non-invasive papillary urothelial carcinoma, without stromal invasion
Clinical ─ Rare; usually presents as a cystic mass; excellent prognosis when confined to the ovary
Macro ─ Usually predominantly cystic, may have papillary projections into the cyst lumen; often associated with a benign Brenner component
Micro ─ Cystic spaces lined by papillary fronds
─ Papillae are covered by thickened (multilayered) transitional-like epithelium
─ Epithelium shows mild to moderate nuclear atypia (Grade 1 or 2 nuclei)
─ Low mitotic activity
─ No stromal invasion
─ Often associated with benign Brenner tumor nests
Ancillary studies ─ IHC (+) GATA3, p63, CK7
─ IHC (-) PAX8, WT1
DDx ─ Benign Brenner Tumor with cystic change (lacks papillary architecture and significant atypia/thickening)
─ Malignant Brenner Tumor (shows stromal invasion and/or high-grade features)
─ Seromucinous Borderline Tumor (different cell types, WT1-)
─ Transitional Cell Carcinoma (usually higher grade, invasive)
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Malignant Brenner Tumor (Ovary)

A rare invasive carcinoma, usually of transitional cell type, that arises in association with a benign and/or borderline Brenner tumor component in the ovary
Clinical ─ Rare; typically occurs in older women; prognosis is generally poor, similar to other high-grade ovarian carcinomas
Macro ─ Often large, solid and cystic masses, may show necrosis or hemorrhage
Micro ─ Consists of an invasive carcinoma, typically Transitional Cell Carcinoma (TCC), but can be SCC or others
─ The invasive component shows features of malignancy: high-grade nuclear atypia, high mitotic activity, and destructive stromal invasion
─ Crucially, a coexisting benign and/or borderline Brenner tumor component must be identified for diagnosis
─ If no benign/borderline Brenner component is seen, it is classified as primary TCC of the ovary (or HGSC with TCC-like features)
Ancillary studies ─ IHC (Malignant TCC component) (+) GATA3, p63, CK7; (-) PAX8, WT1
DDx ─ Primary Transitional Cell Carcinoma of Ovary (no benign/borderline Brenner)
─ High-Grade Serous Carcinoma (WT1+, PAX8+, often p53 aberrant)
─ Metastatic Urothelial Carcinoma (history, PAX8-)
─ Undifferentiated Carcinoma
─ Squamous Cell Carcinoma (arising from teratoma or primary)
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Ovary

Inflammatory & Non-Neoplastic Conditions

Tubo-ovarian Abscess

A severe complication of pelvic inflammatory disease (PID) resulting in an abscess involving the fallopian tube and ovary
Clinical ─ Reproductive age women; risk factors include PID, multiple sexual partners, IUD use; presentation includes fever, pelvic pain, vaginal discharge, elevated WBC and CRP
Macro ─ Enlarged, matted adnexal structures, forming a complex, multiloculated cystic mass filled with pus; adhesions are common
Micro ─ Florid acute inflammation with sheets of neutrophils filling the lumen and infiltrating the wall
─ Necrosis, fibrin deposition, and abscess formation
─ Granulation tissue and fibrous tissue in the abscess wall
─ Chronic inflammatory cells (lymphocytes, plasma cells) often present
─ Ovarian parenchyma may be difficult to identify or completely destroyed
─ Look for Actinomyces (sulfur granules), especially with IUD use
Ancillary studies ─ Gram stain and culture can identify causative organisms (often polymicrobial: N gonorrhoeae, C trachomatis, anaerobes)
DDx ─ Endometriotic cyst with acute inflammation
─ Ovarian neoplasms with necrosis or infection (eg, mucinous or endometrioid carcinoma)
─ Xanthogranulomatous oophoritis
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Xanthogranulomatous Oophoritis

A rare, destructive chronic inflammatory process characterized by an abundance of lipid-laden macrophages
Clinical ─ Can mimic an ovarian neoplasm; may present as an adnexal mass with pain or fever; often associated with PID, endometriosis, IUDs, or prior surgery
Macro ─ May form a solid, yellowish mass or a cystic lesion; can be admixed with abscess formation
Micro ─ Sheets of foamy macrophages (histiocytes) with abundant granular or vacuolated cytoplasm
─ Mixed inflammatory infiltrate including lymphocytes, plasma cells, and neutrophils
─ Multinucleated giant cells are common
─ Cholesterol clefts may be present
─ Necrosis and fibrosis can occur
─ Absence of Michaelis-Gutmann bodies (distinguishes from malakoplakia)
Ancillary studies ─ IHC (+) CD68 in foamy macrophages
DDx ─ Malakoplakia (presence of Michaelis-Gutmann bodies)
─ Clear cell carcinoma (malignant features, positive for Napsin A, HNF1B)
─ Steroid cell tumor (positive for inhibin, calretinin)
─ Yolk sac tumor (younger age, Schiller-Duval bodies, AFP+)
─ Granulosa cell tumor (inhibin+, FOXL2)
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Cortical Inclusion Cyst

Common, small cysts within the ovarian cortex, lined by epithelium, thought to arise from entrapped surface epithelium or endosalpingiosis
Clinical ─ Usually an incidental finding, especially in peri- and postmenopausal women; considered potential precursors for epithelial ovarian tumors
Macro ─ Typically small (<1 cm) and not grossly identified, but can be seen as small surface irregularities or tiny cysts
Micro ─ Small, simple cysts located within the ovarian cortex, often near the surface
─ Lined by a single layer of epithelium:
─ Tubal-type (ciliated cells, secretory cells, intercalated cells) - most common
─ Endometrioid
─ Mucinous
─ Non-specific cuboidal or flattened cells
─ Psammoma bodies are frequently present within or near the cysts
─ May show reactive epithelial changes or metaplasia
Ancillary studies ─ IHC can highlight epithelial type if needed (eg, PAX8 for Mullerian, WT1 can be positive in serous-type) but rarely required
DDx ─ Endosalpingiosis (more complex, branching glands/cysts)
─ Endometriosis (presence of endometrial stroma and/or hemosiderin)
─ Cystic follicle (lined by granulosa and theca cells)
─ Rete ovarii (anastomosing channels deeper in hilum/medulla)
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Polycystic Ovary Disease

A common endocrine disorder characterized by hyperandrogenism, ovulatory dysfunction, and polycystic ovaries on ultrasound
Clinical ─ Reproductive age; presents with oligomenorrhea/amenorrhea, infertility, hirsutism, acne, obesity; associated with insulin resistance and increased risk of endometrial hyperplasia/carcinoma; diagnosis often uses Rotterdam criteria
Macro ─ Ovaries often bilaterally enlarged; smooth, thickened, pearly-white 'oyster-like' capsule
Micro ─ Numerous (often >12-20) subcapsular follicular cysts (typically 2-9 mm)
─ Thickened tunica albuginea / cortical stromal hyperplasia
─ Luteinization of theca interna cells (stromal hyperthecosis) may be present
─ Paucity or absence of corpora lutea or corpora albicantia (reflecting anovulation)
Ancillary studies ─ Lab findings support clinical diagnosis (eg, ↑ androgens, ↑ LH:FSH ratio)
DDx ─ Stromal hyperthecosis (more prominent stromal luteinization, often more severe virilization)
─ Normal ovaries (may have multiple follicles depending on cycle phase)
─ Granulosa cell tumors (neoplastic proliferation)
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Ovarian Torsion

Twisting of the adnexal structures, primarily the infundibulopelvic ligament, leading to vascular compromise and infarction
Clinical ─ Surgical emergency; presents with sudden onset of severe pelvic pain, often with nausea/vomiting; can occur at any age, more common with ovarian masses/cysts, pregnancy, or ovulation induction
Macro ─ Ovary and/or fallopian tube are enlarged, edematous, and congested to hemorrhagic and necrotic; color ranges from dark red to purple or black
Micro ─ Findings vary with duration and degree of twisting:
─ Early: Marked edema, vascular congestion, particularly of veins and lymphatics
─ Later: Interstitial hemorrhage progressing to extensive hemorrhagic infarction/necrosis
─ Fibrin thrombi are often seen in blood vessels
─ Necrotic structures may appear as 'ghost outlines'
─ A neutrophilic infiltrate may be present, especially late or with re-perfusion
─ Underlying cause (eg, cyst, tumor) may be identified, though often obscured by necrosis
Ancillary studies ─ Usually none performed on the specimen; diagnosis is clinical and radiographic, confirmed at surgery
DDx ─ Hemorrhagic cyst (hemorrhage confined to cyst)
─ Ectopic pregnancy (presence of chorionic villi/trophoblast)
─ Massive ovarian edema (marked edema without significant hemorrhage/necrosis, often preserves architecture)
─ Appendicitis / Diverticulitis (depending on presentation)
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Sex Cord-Stromal Tumors

Fibroma (Ovary)

A benign ovarian neoplasm composed of spindle cells resembling fibroblasts and producing collagen, representing the most common sex cord-stromal tumor
Clinical ─ Most common in perimenopausal and postmenopausal women; usually hormonally inactive; can be associated with Meigs syndrome (ovarian fibroma, ascites, pleural effusion) or Gorlin syndrome (nevoid basal cell carcinoma syndrome)
Macro ─ Typically unilateral, solid, firm, well-circumscribed mass; cut surface is white or tan and often whorled; calcification, edema, or cystic change can occur
Micro ─ Intersecting fascicles or storiform pattern of bland spindle cells with elongated nuclei
─ Variable amounts of intervening collagen (can be dense or scant)
─ Low mitotic activity (typically <4 per 10 HPF) and no significant atypia
─ Cellular Fibroma: Higher cellularity but still lacks significant atypia or mitoses (>3/10 HPF)
─ Mitotically Active Cellular Fibroma: Cellular with >=4 mitoses/10 HPF but <10, no significant atypia
Ancillary studies ─ IHC (-) Inhibin (usually), Calretinin (usually), SF-1, ER, PR, Desmin
─ IHC (+/-) SMA, CD34
DDx ─ Thecoma (plump cells, lipid vacuoles, Inhibin+, SF-1+)
─ Sclerosing Stromal Tumor (pseudolobular, mixed cells, prominent vasculature, Inhibin+)
─ Leiomyoma (Desmin+, SMA+)
─ Massive Ovarian Edema (preserves underlying architecture, edematous stroma)
─ Brenner Tumor (has epithelial nests)
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Microcystic Stromal Tumor

A rare, usually benign ovarian stromal tumor characterized by a distinctive pattern of microcysts, solid cellular areas, and hyalinized stroma, notable for its unique IHC profile (CD10+, Beta-catenin nuclear+, Inhibin-)

Clinical ─ Wide age range (13-83 years); usually unilateral and presents as an ovarian mass; generally considered benign, though rare malignant cases reported

Macro ─ Solid and cystic mass, often well-circumscribed; cut surface is tan-white to yellow, may show prominent cysts and fibrous bands

Micro ─

─ Triphasic appearance with variable proportions:

─ Microcysts: Small, empty-appearing or fluid-filled spaces

─ Solid Cellular Areas: Sheets or lobules of bland spindle to polygonal cells with scant cytoplasm

─ Fibrous/Hyalinized Stroma: Dense collagenous bands separating cellular/cystic areas ─ Nuclei are generally bland and oval; mitoses are rare

─ Characteristic nuclear beta-catenin expression due to CTNNB1 mutations

Ancillary studies ─

─ IHC (+) CD10, Beta-catenin (nuclear), Vimentin

─ IHC (-) Inhibin, Calretinin, SF-1, ER, PR, CK7, EMA (key negative profile distinguishing from other SCSTs and epithelial tumors)

DDx ─

─ Fibroma / Thecoma (Inhibin+/-, different morphology, lack nuclear beta-catenin)

─ Adult Granulosa Cell Tumor (FOXL2+, Inhibin+, coffee-bean nuclei)

─ Sertoli-Leydig Cell Tumor (tubules/cords, Inhibin+)

─ Yolk Sac Tumor (reticular/microcystic pattern, but AFP+, SALL4+, malignant cytology)

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Leydig Cell Tumor

A rare, pure sex cord-stromal tumor composed exclusively of Leydig cells, often hormonally active (androgenic)

Clinical

─ Can occur at any age, but most common in postmenopausal women; usually presents with signs of virilization (hirsutism, clitoromegaly, voice deepening); most are benign

Macro ─ Typically small (<5 cm), solid, well-circumscribed; cut surface is yellow, brown, or orange

Micro ─

─ Diffuse sheets, nests, or cords of large polygonal cells

─ Abundant eosinophilic, granular cytoplasm (can be vacuolated/lipid-rich) ─ Central, round nuclei, often with a prominent nucleolus

─ Reinke crystals (elongated, eosinophilic, rod-shaped cytoplasmic inclusions) are pathognomonic but found in only ~40% of cases ─ Low mitotic activity and minimal atypia (in benign cases)

Ancillary studies ─

─ IHC (+) Inhibin, Calretinin, SF-1, Melan A, HSD3B1

─ IHC (-) EMA, SALL4, Cytokeratins

DDx ─

─ Steroid Cell Tumor, NOS (histologically similar, diagnosis of exclusion if no Reinke crystals, often larger)

─ Luteoma of Pregnancy (associated with pregnancy, regresses post-partum, lacks Reinke crystals)

─ Sertoli-Leydig Cell Tumor (contains Sertoli cell component/tubules)

─ Hilus Cell Hyperplasia (microscopic finding, not a discrete mass)

─ Adrenal Rest Tumor (often subcapsular/hilar, CgA/Syn often +)

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Steroid Cell Tumor

A group of tumors composed of cells resembling steroid hormone-secreting cells (lutein, Leydig, or adrenal cortical); includes Stromal Luteoma, Leydig Cell Tumor, and Steroid Cell Tumor, NOS

Clinical ─ Steroid Cell Tumor, NOS (Not Otherwise Specified) is most common; wide age range; often androgenic (~50-75%), can be estrogenic or Cushingoid; ~25-40% are malignant, based on size and histologic features

Macro ─ Usually solid, well-circumscribed, lobulated; cut surface is yellow-orange to brown-red; larger tumors more likely malignant and may show necrosis/hemorrhage Micro ─

─ Diffuse sheets, nests, or cords of medium to large polygonal cells

─ Cytoplasm varies from eosinophilic/granular to abundant, clear/vacuolated (lipid-rich)

─ Nuclei are typically central and round, may have prominent nucleoli

─ Features suggesting malignancy: >2 mitoses/10 HPF, necrosis, significant nuclear atypia, size >7 cm, hemorrhage

Ancillary studies ─

─ IHC (+) Inhibin, Calretinin, SF-1, Melan A, HSD3B1

─ IHC (-) EMA, SALL4, Cytokeratins

DDx ─

─ Leydig Cell Tumor (presence of Reinke crystals) ─ Stromal Luteoma (postmenopausal, small, within stroma, benign)

─ Clear Cell Carcinoma (Napsin A+, PAX8+, CK7+, malignant)

─ Luteinized Thecoma (more spindle-shaped cells)

─ Luteoma of Pregnancy (pregnancy-related)

─ Metastatic Adrenal Cortical Carcinoma (history, SF-1+, Inhibin+)

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Ovarian Fibrosarcoma

A rare, malignant tumor composed of fibroblasts producing collagen, defined by significant cellularity, atypia, and mitotic activity

Clinical ─ Occurs in older women; often presents as a large ovarian mass; aggressive behavior with high risk of recurrence and metastasis

Macro ─ Large, solid, fleshy, gray-white mass, often with areas of necrosis and hemorrhage

Micro ─

─ Highly cellular proliferation of spindle cells

─ Cells arranged in a 'herringbone' pattern or intersecting fascicles

─ Marked nuclear pleomorphism and atypia (hyperchromasia, irregular contours)

─ High mitotic activity (defined as >=10 mitoses per 10 HPF, often much higher)

─ Atypical mitotic figures are common

─ Necrosis is frequently present

─ May arise de novo or from a pre-existing fibroma (rare)

Ancillary studies ─

─ IHC (-) Inhibin, Calretinin, SF-1, Desmin, S100, Cytokeratins (usually)

─ IHC (+) Vimentin

DDx ─

─ Cellular Fibroma / Mitotically Active Cellular Fibroma (lack significant atypia and meet lower mitotic criteria)

─ Leiomyosarcoma (Desmin+, SMA+) ─ Sarcomatoid Carcinoma (Cytokeratin+, PAX8+)

─ Malignant Peripheral Nerve Sheath Tumor (S100+, SOX10+)

─ Adult Granulosa Cell Tumor (FOXL2+, Inhibin+, different morphology)

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Adult Granulosa Cell Tumor

The most common malignant sex cord-stromal tumor, typically low-grade, often estrogenic, and characterized by cells with 'coffee-bean' nuclei and the FOXL2 C134W mutation
Clinical ─ Peak age 50-55 years, but wide range; often presents with signs of estrogen excess (postmenopausal bleeding, endometrial hyperplasia/carcinoma) or as a mass; late recurrences can occur (10-30 years)
Macro ─ Often large, unilateral, solid and cystic; cut surface is typically yellow-tan; hemorrhage and necrosis are common
Micro ─ Diverse architectural patterns (often mixed):
─ Microfollicular: Small rosettes with eosinophilic material (Call-Exner bodies) - most characteristic
─ Diffuse: Sheet-like growth (can mimic sarcoma/carcinoma)
─ Trabecular/Insular: Cords or islands of cells
─ Macrofollicular: Large cysts resembling follicles
─ Cells are uniform, round to oval, with scant cytoplasm and pale nuclei
─ Longitudinal nuclear grooves ('coffee-bean' nuclei) are characteristic but not always present
─ Mitotic activity is variable, usually low (<5/10 HPF), but doesn't reliably predict behavior
Ancillary studies ─ ─ IHC (+) Inhibin (often diffuse), Calretinin (often patchy), SF-1, FOXL2, CD56, Vimentin; variable CK7/EMA
─ IHC (-) PAX8 (usually)
─ Molecular ─ FOXL2 c_402C>G (p_C134W) mutation (~97%)
DDx ─ Endometrioid Carcinoma (PAX8+, often ER+, WT1-, lacks grooves/CE bodies)
─ Small Cell Carcinoma, Hypercalcemic Type (SMARCA4 loss, younger age, high grade)
─ Undifferentiated Carcinoma (lack SCST markers)
─ Thecoma (more lipid, lacks grooves/CE bodies)
─ Juvenile Granulosa Cell Tumor (younger age, lacks grooves, different follicle type)
─ Sertoli-Leydig Cell Tumor (tubules/cords, may have Leydig cells)
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Juvenile Granulosa Cell Tumor

A rare sex cord-stromal tumor, typically occurring in children and young adults, often associated with precocious puberty, and characterized by variably sized follicles and cells lacking nuclear grooves
Clinical ─ Most common in the first two decades (90% <30 years); often presents with isosexual precocious puberty due to estrogen production; can be associated with syndromes (Ollier disease, Maffucci syndrome); most are stage I and have excellent prognosis, though higher stage can be aggressive
Macro ─ Usually unilateral, large, solid and cystic mass; yellow/tan cut surface; hemorrhage/necrosis common
Micro ─ Predominantly macrofollicular or solid-follicular pattern
─ Follicles are often large, irregular, filled with basophilic or eosinophilic fluid (resembling mucin or colloid)
─ Tumor cells are larger than AGCT, polygonal, with more abundant eosinophilic or vacuolated cytoplasm (luteinized)
─ Nuclei are round, hyperchromatic, often with prominent nucleoli; lack nuclear grooves ─ Mitotic activity is often high and atypical figures can be seen (not necessarily predicting malignancy in JGCT)
Ancillary studies ─ ─ IHC (+) Inhibin, Calretinin, SF-1, CD56
─ IHC (-) FOXL2 mutation is absent (though protein may be +)
DDx ─ Adult Granulosa Cell Tumor (older age, grooves, CE bodies, FOXL2 mutation)
─ Yolk Sac Tumor (AFP+, SALL4+, Schiller-Duval bodies)
─ Clear Cell Carcinoma (Napsin A+, HNF1B+, older age)
─ Dysgerminoma (OCT3/4+, KIT+, fibrous septa with lymphocytes)
─ Thecoma (more spindle cells, lacks follicles)
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Sertoli Cell Tumor

A rare, pure sex cord-stromal tumor composed exclusively of Sertoli cells, typically forming tubules
Clinical ─ Wide age range; may be hormonally inactive or produce estrogens or androgens; most are benign and low-stage
Macro ─ Typically unilateral, solid, firm, yellow-tan lobulated mass
Micro ─ Predominantly composed of well-formed hollow or solid tubules, resembling immature seminiferous tubules
─ Tubules are lined by bland, columnar to cuboidal Sertoli cells with pale to eosinophilic cytoplasm
─ Nuclei are round to oval, without significant atypia or grooves
─ Mitotic activity is low
─ Stroma is typically fibrous, may be minimal or prominent
─ Lipid-rich variants exist
Ancillary studies ─ ─ IHC (+) Inhibin, Calretinin, SF-1, WT1 (nuclear), Androgen Receptor, SOX9
─ IHC (-) EMA, PAX8
DDx ─ Sertoli-Leydig Cell Tumor (must exclude Leydig cell component)
─ Endometrioid Carcinoma (PAX8+, ER+, often WT1-)
─ Ovarian Adenofibroma (different epithelial type)
─ Brenner Tumor (urothelial nests, GATA3+)
─ Sex Cord Tumor with Annular Tubules (annular structures, hyaline cores)
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Sex Cord Tumor with Annular Tubules (SCTAT)

A rare, distinctive sex cord-stromal tumor characterized by ring-like tubular structures, often associated with Peutz-Jeghers Syndrome (PJS)
Clinical ─ Two forms: PJS-associated (usually bilateral, multifocal, small, benign) and Sporadic (usually unilateral, larger, ~20% malignant potential); mean age ~27 (sporadic) / ~16 (PJS); can be hormonally inactive or estrogenic
Macro ─ Varies from microscopic (PJS) to large solid masses (sporadic); typically yellow-tan
Micro ─ Hallmark feature: Simple and complex annular (ring-shaped) tubules
─ Tubules are lined by columnar cells with nuclei oriented towards the periphery (antipolar) and away from the central lumen/hyaline core
─ Central lumen often contains one or more eosinophilic hyaline bodies (basement membrane material, PAS+)
─ Cytoplasm is pale to eosinophilic, may contain lipid
─ PJS-associated cases often have calcification
─ Malignant features (in sporadic cases): Large size, necrosis, high mitotic rate, nuclear atypia, invasion
Ancillary studies ─ ─ IHC (+) Inhibin, Calretinin, SF-1, WT1 (variable)
DDx ─ Sertoli Cell Tumor (lacks distinct annular tubules/hyaline cores)
─ Adult Granulosa Cell Tumor (Call-Exner bodies are different - rosettes around eosinophilic material, not hyaline basement membrane rings)
─ Endometrioid Carcinoma (PAX8+, WT1-)
─ Gonadoblastoma (must exclude germ cell component, OCT3/4+)
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Germ Cell Tumors

Immature Teratoma

A malignant germ cell tumor containing a mixture of mature and immature/embryonal tissues, with grading based on the amount of immature neuroectoderm
Clinical ─ Occurs primarily in children and young adults (mean age ~18-20 years); often presents as a large, rapidly growing mass; prognosis depends on grade and stage
Macro ─ Typically large, predominantly solid with cystic areas; may show necrosis, hemorrhage; cartilage or bone may be grossly visible
Micro ─ Haphazard mixture of tissues from all three germ layers, similar to mature teratoma, but with the presence of immature elements
─ Immature Neuroectoderm is the key component for grading:
─ Appears as small, round blue cells with hyperchromatic nuclei and scant cytoplasm
─ Forms primitive neural tubules, rosettes (Homer Wright, Flexner-Wintersteiner), or diffuse sheets
─ High mitotic activity is common
─ Other immature tissues (eg, cartilage, mesenchyme) can be present but do not contribute to grade
─ Grading (based on lowest power field with most immature neuroectoderm):
─ Grade 1: <1 low power field (LPF) of immature neuroectoderm
─ Grade 2: 1-3 LPFs of immature neuroectoderm
─ Grade 3: >3 LPFs of immature neuroectoderm
─ May contain foci of other GCTs (Yolk Sac Tumor most common)
Ancillary studies ─ ─ IHC (+) Neuroectodermal markers (Synaptophysin, GFAP, S100, SOX2) can confirm neuro-epithelium but not required for grading
─ IHC Check for other GCTs (AFP, SALL4, OCT3/4) if suspected
DDx ─ Mature Teratoma (lacks immature elements)
─ Mixed Germ Cell Tumor (requires significant other GCT components)
─ Small Cell Carcinoma, Hypercalcemic Type (SMARCA4 loss, distinct morphology)
─ High-Grade Serous Carcinoma (WT1+, PAX8+)
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Dysgerminoma

The most common malignant ovarian germ cell tumor, composed of primitive germ cells, equivalent to testicular seminoma and CNS/mediastinal germinoma
Clinical ─ Primarily affects adolescents and young women (2nd-3rd decades); often presents as a rapidly growing mass; excellent prognosis due to high chemosensitivity and radiosensitivity; elevated LDH or HCG (due to syncytiotrophoblasts) possible
Macro ─ Solid, fleshy, lobulated mass; tan, white, or pink cut surface; may have necrosis but often less than other GCTs
Micro ─ Sheets, nests, or cords of large, uniform, round-to-polygonal cells
─ Cells have distinct borders, abundant clear or eosinophilic (glycogen-rich) cytoplasm, and large central nuclei with prominent (often multiple) nucleoli ('fried egg' appearance)
─ Nests are typically separated by fibrous septa infiltrated by lymphocytes (T-cells) and sometimes granulomas
─ Syncytiotrophoblastic giant cells can be present, associated with HCG elevation
─ Mitotic figures are usually easy to find
Ancillary studies ─ ─ IHC (+) OCT3/4 (nuclear), SALL4 (nuclear), KIT (CD117, membranous), D2-40 (Podoplanin, membranous), PLAP (variable)
─ IHC (-) CK7, EMA, Inhibin, CD30, Glypican-3
DDx ─ Yolk Sac Tumor (AFP+, Glypican-3+, Schiller-Duval bodies)
─ Embryonal Carcinoma (CD30+, CK+, more pleomorphic)
─ Clear Cell Carcinoma (PAX8+, Napsin A+, older age)
─ High-Grade Serous Carcinoma (PAX8+, WT1+, older age)
─ Malignant Lymphoma (LCA+, specific B/T markers)
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Yolk Sac Tumor (Endodermal Sinus Tumor)

A malignant germ cell tumor showing differentiation towards yolk sac structures, notable for producing alpha-fetoprotein (AFP)
Clinical ─ Second most common malignant GCT, typically affects children and young women; presents as a rapidly growing mass; aggressive but chemosensitive
Macro ─ Often large, solid and cystic, friable; yellow-white cut surface, frequently with prominent hemorrhage and necrosis
Micro ─ Characterized by diverse architectural patterns (often multiple present):
─ Microcystic / Reticular (most common): Anastomosing spaces lined by flattened/cuboidal cells
─ Endodermal Sinus (Schiller-Duval bodies): Perivascular structure with a central vessel surrounded by tumor cells in a cystic space - pathognomonic but not always present
─ Solid: Sheets of polygonal cells
─ Papillary
─ Glandular (can mimic endometrioid/clear cell)
─ Hepatoid
─ Hyaline globules (PAS+, diastase resistant, AFP+) are characteristic
─ Cells can be cuboidal, flattened, or pleomorphic
Ancillary studies ─ ─ IHC (+) AFP (often patchy), SALL4 (strong nuclear), Glypican-3, Cytokeratin (AE1/AE3)
─ IHC (-) OCT3/4 (usually), CD30, Inhibin, WT1
DDx ─ Clear Cell Carcinoma (Napsin A+, HNF1B+, PAX8+, older age)
─ Dysgerminoma (OCT3/4+, KIT+, lacks AFP/Glypican-3)
─ Embryonal Carcinoma (OCT3/4+, CD30+, CK+)
─ Juvenile Granulosa Cell Tumor (Inhibin+, lacks AFP/SALL4)
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Embryonal Carcinoma

A rare, highly malignant germ cell tumor composed of primitive, pleomorphic epithelial cells resembling those of the early embryo
Clinical ─ Rare in pure form, more common as part of mixed GCT; affects adolescents/young adults (mean 15 years); highly aggressive; may have elevated AFP and/or HCG
Macro ─ Predominantly solid, gray-white mass; often shows extensive hemorrhage and necrosis
Micro ─ Sheets, nests, cords, or papillary structures of large, pleomorphic cells
─ Cells have indistinct borders, amphophilic cytoplasm, large vesicular nuclei, and prominent nucleoli
─ High N/C ratio, marked nuclear atypia, frequent and atypical mitoses, and apoptosis are characteristic
─ Glandular or tubular structures may be present
Ancillary studies ─ ─ IHC (+) OCT3/4 (nuclear), SALL4 (nuclear), CD30 (membranous/Golgi - highly characteristic), Cytokeratin (AE1/AE3), PLAP
─ IHC (+/-) AFP, HCG (if syncytiotrophoblasts present)
─ IHC (-) Inhibin, WT1
DDx ─ Dysgerminoma (more uniform, OCT3/4+, CD30-, KIT+)
─ Yolk Sac Tumor (AFP+, Glypican-3+, CD30-, different patterns)
─ Choriocarcinoma (biphasic, hCG+)
─ High-Grade Serous Carcinoma (PAX8+, WT1+, older age)
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Choriocarcinoma (Non-Gestational)

A rare, highly aggressive germ cell tumor composed of syncytiotrophoblasts and cytotrophoblasts, mimicking placental villous trophoblast, and producing high levels of HCG
Clinical ─ Very rare in pure form, more common in mixed GCTs; occurs in young individuals; highly aggressive with early metastasis (lungs, liver, brain); marked elevation of serum HCG
Macro ─ Typically a hemorrhagic and necrotic mass; often small primary with large metastases
Micro ─ Biphasic pattern is essential for diagnosis:
─ Syncytiotrophoblasts: Large, multinucleated cells with abundant eosinophilic/vacuolated cytoplasm (HCG+)
─ Cytotrophoblasts: Smaller, mononuclear cells with clear cytoplasm and distinct borders
─ Cells are arranged in sheets or plexiform patterns, often surrounding blood-filled spaces
─ Absence of chorionic villi is characteristic of choriocarcinoma (vs mole/placenta)
─ Extensive hemorrhage and necrosis are typical
Ancillary studies ─ ─ IHC (+) HCG (strong in syncytiotrophoblasts), SALL4, GATA3, Inhibin (variable)
─ IHC (-) OCT3/4 (usually)
─ Molecular ─ Genotyping can distinguish non-gestational (purely maternal DNA) from gestational (paternal DNA present)
DDx ─ Gestational Choriocarcinoma (history, genotyping)
─ Embryonal Carcinoma (CD30+, OCT3/4+, different pattern)
─ Yolk Sac Tumor (AFP+, different pattern)
─ Dysgerminoma with syncytiotrophoblasts (primary dysgerminoma pattern, HCG only in STGCs)
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Mixed Germ Cell Tumor

A germ cell tumor composed of two or more distinct types of malignant germ cell tumors
Clinical ─ Represents ~10-15% of malignant GCTs; young women/adolescents; presentation and prognosis depend on the types and proportions of components and overall stage; AFP and/or HCG may be elevated depending on components
Macro ─ Usually large, solid and cystic masses; appearance varies depending on components (eg, fleshy like dysgerminoma, hemorrhagic like chorio, cystic like teratoma)
Micro ─ Requires identification of two or more distinct GCT components (eg, Dysgerminoma + YST; Immature Teratoma + YST + Embryonal Ca)
─ The different components can be intermingled or exist as discrete nodules
─ Each component should be documented and ideally quantified (as percentage)
─ The most common components are Dysgerminoma, Yolk Sac Tumor, and Immature Teratoma
Ancillary studies ─ ─ IHC panel is crucial to identify and confirm different components:
─ Dysgerminoma: OCT3/4+, SALL4+, KIT+
─ YST: SALL4+, AFP+, Glypican-3+
─ Embryonal Ca: OCT3/4+, SALL4+, CD30+, CK+
─ Choriocarcinoma: SALL4+, HCG+
─ Immature Teratoma: Various markers depending on tissue, GCT markers usually negative in mature/immature elements
DDx ─ Pure Germ Cell Tumors (only one component identified)
─ Gonadoblastoma (requires both GCT and SCST components in nests)
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Monodermal Teratomas (e.g., Struma ovarri & carcinoid tumor)

A group of germ cell tumors composed predominantly or exclusively of a single, highly specialized tissue type, representing a one-sided development of a teratoma
Clinical ─ Variable presentation depending on tissue type; Struma Ovarii and Carcinoid are most common
Macro ─ Appearance varies with type (eg, Struma often cystic/brown; Carcinoid often solid/yellow)
Micro ─ Defined by >50% of the tumor being composed of one specialized tissue:
─ Struma Ovarii: Composed of mature (or sometimes malignant) thyroid tissue; follicles contain colloid; can be associated with hyperthyroidism; Malignant Struma Ovarii (papillary/follicular ca) can occur
─ Carcinoid Tumor: Neuroendocrine tumor; usually Insular type (nests/ribbons, resembles GI carcinoid, can cause carcinoid syndrome); Trabecular, Strumal, and Mucinous types also exist
─ Other rare types: Sebaceous tumors, Respiratory epithelial tumors, etc
─ Often found in association with a typical mature cystic teratoma
Ancillary studies ─ ─ Struma Ovarii: IHC (+) Thyroglobulin, TTF-1, PAX8
─ Carcinoid: IHC (+) Synaptophysin, Chromogranin A, CD56
DDx ─ Mature Cystic Teratoma with prominent component (<50%)
─ Metastatic Carcinoma (eg, thyroid, neuroendocrine - check history, IHC)
─ Ovarian Carcinomas with specific features (eg, Endometrioid with NE change)
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Gonadoblastoma

A rare neoplasm composed of an intimate mixture of immature germ cells and sex cord-stromal elements, almost exclusively occurring in individuals with gonadal dysgenesis and a Y chromosome
Clinical ─ Typically found in phenotypic females with virilization or primary amenorrhea, or phenotypic males with cryptorchidism/hypospadias; high risk (~50-60%) of developing an invasive GCT (usually Dysgerminoma)
Macro ─ Usually small, bilateral (1/3), solid, gray-white or yellow; often calcified
Micro ─ Circumscribed, round to oval nests separated by fibrous stroma
─ Each nest contains two cell types:
─ Large, central Germ Cells: Identical to Dysgerminoma cells (OCT3/4+, SALL4+)
─ Smaller Sex Cord Cells: Resemble immature Sertoli/Granulosa cells, often arranged peripherally or around hyaline bodies (Inhibin+, SF-1+)
─ Hyaline (PAS+) bodies and calcification (often extensive) are very common within nests
─ If germ cells overgrow and invade the stroma, it is classified as Dysgerminoma arising from Gonadoblastoma
Ancillary studies ─ ─ IHC (+) OCT3/4, SALL4 (Germ cells); Inhibin, SF-1, Calretinin (Sex cord cells)
DDx ─ Dysgerminoma (lacks SCST component in nests, no hyaline bodies/calcification usually)
─ Sex Cord Tumor with Annular Tubules (lacks germ cells, different architecture)
─ Mixed Germ Cell Tumor
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Gynandroblastoma

An extremely rare ovarian sex cord-stromal tumor containing an intimate mixture of unequivocal, well-differentiated female-directed (granulosa cell tumor) and male-directed (Sertoli cell and/or Leydig cell tumor) elements
Clinical ─ Very rare, occurs over a wide age range; hormonal activity is variable (estrogenic, androgenic, or inactive); behavior is uncertain due to rarity, generally considered low malignant potential if well differentiated
Macro ─ Usually solid or solid and cystic; appearance is variable
Micro ─

─ Requires unequivocal, clearly identifiable components of both:
─ Granulosa Cell Tumor elements (either Adult or Juvenile type, with characteristic morphology like Call-Exner bodies or typical follicular patterns respectively)
─ Sertoli cell and/or Leydig cell elements (forming tubules, cords, or nests of Leydig cells)
─ Each component must constitute at least 10% of the tumor mass
─ The components are typically intermingled but distinct
Ancillary studies ─

─ IHC can help highlight both components:
─ Granulosa cell areas: FOXL2+, Inhibin+, Calretinin+, SF-1+
─ Sertoli cell areas: Inhibin+, Calretinin+, WT1+, SOX9+
─ Leydig cell areas: Inhibin+, Calretinin+, SF-1+, Melan-A+
DDx ─

─ Granulosa Cell Tumor with luteinized/Sertoliform areas (lacks true Sertoli-Leydig component)
─ Sertoli-Leydig Cell Tumor with GCT-like areas (lacks true GCT component)
─ Poorly differentiated Sex Cord-Stromal Tumor, NOS
─ Mixed Germ Cell-Sex Cord Stromal Tumor (eg, Gonadoblastoma - contains germ cells)
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Miscellaneous Tumors of the Ovary

STK11 Adnexal Tumor

A rare tumor occurring in the adnexal region (ovary, fallopian tube, broad ligament), typically in patients with Peutz-Jeghers syndrome (PJS) due to germline STK11 mutations, or sporadically with somatic STK11 mutations
Clinical ─ Rare; strongly associated with Peutz-Jeghers syndrome; can also occur sporadically; behavior is variable, can be benign or low-grade malignant
Macro ─ Variable; may present as a solid or cystic mass in the ovary, fallopian tube, or broad ligament
Micro ─

─ Displays varied and distinctive morphologies, often not fitting neatly into other adnexal tumor categories
─ Common patterns include:
─ Sertoliform tubular structures
─ Cords and nests of cells with eosinophilic cytoplasm
─ Endometrioid-like glands
─ Small glandular or microcystic arrangements
─ Stroma is often prominent, can be hyalinized or desmoplastic
─ Cytologic atypia is usually mild to moderate
Ancillary studies ─

─ IHC: Expression can be variable depending on differentiation; may show positivity for sex cord markers (Inhibin, Calretinin, SF-1) or epithelial markers (CK7, EMA)
─ IHC: Loss of STK11 (LKB1) protein expression by IHC is a supportive feature, particularly if a germline mutation is known or suspected
─ Molecular ─ STK11 gene mutation (germline in PJS, somatic in sporadic cases)
DDx ─

─ Sex Cord Tumor with Annular Tubules (SCTAT) (also common in PJS, but has characteristic annular tubules with hyaline cores)
─ Sertoli cell tumor or Sertoli-Leydig cell tumor (may show overlapping features but typically more distinct differentiation)
─ Endometrioid tumors (if glandular component prominent)
─ Wolffian tumor (if tubular patterns are present)
─ Adenoma malignum (Minimal Deviation Adenocarcinoma) of the cervix (if cervical and in PJS patient, shares STK11 link)
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Mesonephric-like Adenocarcinoma

A rare ovarian carcinoma resembling mesonephric carcinoma of the cervix, characterized by various architectural patterns and often expressing GATA3 and TTF-1
Clinical ─ Wide age range; behavior can be aggressive; may be associated with KRAS mutations
Macro ─ Typically solid and cystic masses
Micro ─ Diverse architectural patterns:
─ Small tubules / Glands (often back-to-back)
─ Papillary or micropapillary structures
─ Glomeruloid or sieve-like formations
─ Spindled or solid areas
─ Often contains dense, eosinophilic, PAS+ luminal secretions
─ Nuclei are typically low to intermediate grade, can show grooves or overlap
Ancillary studies ─ ─ IHC (+) PAX8, GATA3, Calretinin, CD10, TTF-1 (variable), EMA
─ IHC (-) ER, PR, WT1 (usually)
DDx ─ Endometrioid Carcinoma (ER+, GATA3-, TTF-1-)
─ Serous Carcinoma (WT1+, GATA3-, TTF-1-)
─ Clear Cell Carcinoma (Napsin A+, HNF1B+, GATA3-, TTF-1-)
─ Sertoli-Leydig Cell Tumor (Inhibin+, SF-1+)
─ Wolffian Tumor (PAX8-, often Inhibin+)
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Rete Ovarii Tumors

A group of rare tumors arising from the rete ovarii (anastomosing channels in the ovarian hilum), ranging from benign cystadenomas/adenofibromas to adenocarcinomas
Clinical ─ Very rare; most are benign cystadenomas; adenocarcinomas occur in older women and can be aggressive
Macro ─ Usually located in the ovarian hilum; can be cystic or solid
Micro ─ Benign: Simple cysts or glands lined by bland cuboidal, hobnail, or flattened epithelium, resembling rete ovarii; may have a fibrous (adenofibroma) component
─ Malignant (Adenocarcinoma): Shows invasive growth with complex glandular or papillary patterns; cells have malignant cytologic features
Ancillary studies ─ ─ IHC (+) PAX8, CK7, EMA
─ IHC (-) WT1, ER, PR
DDx ─ Serous Tumors (especially hilar ones; WT1+)
─ Endometrioid Tumors (ER+, WT1-)
─ Mesonephric-like Tumors (GATA3+)
─ Sertoli Cell Tumors (Inhibin+, PAX8-)
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Wolffian Tumor

A rare, usually benign tumor arising from mesonephric (Wolffian) duct remnants, typically found in the broad ligament but occasionally in the ovary
Clinical ─ Wide age range; mostly asymptomatic or presents as a mass; majority are benign, rare malignant cases reported
Macro ─ Solid, well-circumscribed, gray-white to yellow mass
Micro ─ Diverse architectural patterns:
─ Tubular / Glandular
─ Sieve-like / Cribriform
─ Solid / Diffuse sheets
─ Cells are typically uniform, cuboidal to low columnar, with scant cytoplasm and round nuclei
─ Luminal eosinophilic material is common
─ Stroma is often fibrous, can be edematous or hyalinized
Ancillary studies ─ ─ IHC (+) Calretinin, Inhibin, CD10, GATA3, CK7 (variable)
─ IHC (-) PAX8 (usually), ER, PR, WT1
DDx ─ Sertoli Cell Tumor (PAX8-, often WT1+)
─ Endometrioid Tumor (PAX8+, ER+)
─ Mesonephric-like Adenocarcinoma (PAX8+, often TTF-1+)
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Solid Pseudopapillary Neoplasm (SPN)

A very rare ovarian neoplasm identical to its pancreatic counterpart, typically occurring in young women and characterized by low malignant potential and nuclear beta-catenin expression
Clinical ─ Very rare in ovary; most common in young women/adolescents; generally low-grade malignancy with good prognosis after resection
Macro ─ Typically large, well-encapsulated, solid and cystic mass with prominent hemorrhage and necrosis
Micro ─ Solid sheets of uniform, round to oval cells punctuated by pseudopapillae
─ Pseudopapillae formed by discohesion, leaving cells clinging to delicate fibrovascular cores
─ Cells have eosinophilic or clear/vacuolated cytoplasm, round/oval nuclei, often with longitudinal grooves
─ Mitoses are usually infrequent
─ Hyaline (PAS+) globules and cholesterol clefts/foam cells are common
Ancillary studies ─ ─ IHC (+) Beta-catenin (Nuclear & Cytoplasmic), CD10, CD56, Vimentin, PR, Cyclin D1, TFE3
─ IHC (-) Chromogranin, Synaptophysin, Cytokeratins (usually), Inhibin
DDx ─ Granulosa Cell Tumor (Inhibin+, FOXL2+, lacks nuclear beta-catenin/CD10)
─ Sertoli-Leydig Cell Tumor (Inhibin+, lacks nuclear beta-catenin)
─ Neuroendocrine Tumors (Synaptophysin+, Chromogranin+)
─ Clear Cell Carcinoma (Napsin A+, PAX8+)
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Wilms Tumor (Ovarian)

A very rare primary ovarian neoplasm, often associated with teratomas, histologically identical to renal Wilms tumor
Clinical ─ Extremely rare; usually occurs in children or young adults; prognosis is generally favorable if low stage
Macro ─ Solid, fleshy mass, can be large
Micro ─ Classically triphasic (though components vary):
─ Blastemal: Small, round blue cells in diffuse sheets
─ Epithelial: Abortive tubules and glomeruli
─ Stromal: Spindle cells, may show differentiation (muscle, cartilage)
─ Often arises within or is associated with an ovarian teratoma
Ancillary studies ─ ─ IHC (+) WT1 (nuclear - blastema, epithelial), PAX8 (epithelial), CD56 (blastema), Cytokeratin (epithelial)
DDx ─ Immature Teratoma (predominantly neuroectoderm)
─ Yolk Sac Tumor (SALL4+, AFP+)
─ Small Cell Carcinoma (SCCOHT - SMARCA4 loss; SCCOPT - NE markers)
─ Dysgerminoma (OCT3/4+, KIT+)
─ Metastatic Wilms Tumor (requires clinical exclusion)
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Small Cell Carcinoma, Hypercalcemic-Type (SCCOHT)

A highly aggressive, undifferentiated carcinoma typically affecting young women, often associated with hypercalcemia, and characterized by SMARCA4 loss
Clinical ─ Mean age 24 years; presents as large adnexal mass; ~50-60% have hypercalcemia; very poor prognosis
Macro ─ Large, solid, fleshy, gray-white mass with extensive necrosis and hemorrhage
Micro ─ Diffuse sheets, nests, or cords of small to medium-sized cells
─ Scant cytoplasm, ill-defined borders
─ Nuclei are hyperchromatic, often molded, with high mitotic rate
─ Characteristic feature: Follicle-like spaces (small cysts lined by tumor cells, may contain eosinophilic material)
─ Can have a large cell component
Ancillary studies ─ ─ IHC (-) SMARCA4 (BRG1) - loss is pathognomonic
─ IHC (+) WT1 (often), SALL4, CD10, EMA (focal), Cytokeratin (focal/variable)
─ IHC (-) Inhibin, Calretinin, Chromogranin, Synaptophysin, OCT3/4
DDx ─ Dysgerminoma (OCT3/4+, SMARCA4+)
─ Juvenile Granulosa Cell Tumor (Inhibin+, SMARCA4+, lacks follicles)
─ Adult Granulosa Cell Tumor (Inhibin+, FOXL2+, SMARCA4+)
─ Yolk Sac Tumor (AFP+, Glypican-3+, SALL4+, SMARCA4+)
─ Small Cell Carcinoma, Pulmonary-Type (NE markers+, SMARCA4+)
─ Malignant Lymphoma (LCA+, specific B/T markers)
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Small Cell Carcinoma, Pulmonary-Type (SCCOPT)

A rare ovarian neuroendocrine carcinoma histologically identical to small cell lung cancer, typically affecting older women
Clinical ─ Rare as primary ovarian tumor; usually occurs in postmenopausal women; aggressive behavior, poor prognosis; must exclude metastasis from lung or other sites
Macro ─ Solid, fleshy mass, often with necrosis
Micro ─ Sheets, nests, or cords of small cells with scant cytoplasm
─ Nuclei are hyperchromatic, oval to spindle-shaped
─ Prominent nuclear molding, crush artifact, and high mitotic/apoptotic rate
─ No follicle-like spaces (unlike SCCOHT)
Ancillary studies ─ ─ IHC (+) Synaptophysin, Chromogranin A, CD56 (at least one NE marker)
─ IHC (+) Cytokeratin (AE1/AE3, CAM5_2), TTF-1 (variable)
─ IHC (+) SMARCA4 (retained - key differentiator from SCCOHT)
─ IHC (-) WT1, SALL4, Inhibin
DDx ─ Small Cell Carcinoma, Hypercalcemic-Type (SMARCA4 loss, WT1+, younger age)
─ Metastatic Small Cell Carcinoma (Lung is most common - clinical correlation crucial)
─ Granulosa Cell Tumor (Inhibin+, FOXL2+)
─ Dysgerminoma (OCT3/4+)
─ Lymphoma (LCA+)
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Tumor-Like Lesions of the Ovary

Follicle Cyst

A common, non-neoplastic, functional ovarian cyst arising from an unruptured or incompletely involuted Graafian follicle
Clinical ─ Very common, especially in reproductive age; usually asymptomatic and resolve spontaneously; can cause pain if large, ruptured, or hemorrhagic; defined as >3 cm (smaller are considered cystic follicles)
Macro ─ Unilocular, thin-walled cyst filled with clear, serous fluid; can be hemorrhagic
Micro ─ Cyst wall lined by layers of granulosa cells (inner layer) and theca cells (outer layer)
─ Granulosa cells are small, round, often with scant cytoplasm and 'coffee-bean' nuclei (though grooves may be less obvious than GCT)
─ Theca cells are plumper, often vacuolated (luteinized)
─ With time or pressure, the lining can become attenuated or denuded
Ancillary studies ─ ─ Usually none required; IHC can show Inhibin+ in both layers
DDx ─ Corpus Luteum Cyst (convoluted wall, prominent luteinized cells)
─ Endometriotic Cyst (endometrial lining/stroma, hemosiderin)
─ Serous Cystadenoma (single layer, ciliated cells, WT1+)
─ Adult Granulosa Cell Tumor (usually solid/cystic mass, CE bodies, FOXL2+)
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Corpus Luteum Cyst

A functional ovarian cyst, typically >3 cm, formed from a corpus luteum that fails to involute normally, often becoming hemorrhagic
Clinical ─ Reproductive age; may be asymptomatic or cause pain (especially if ruptured or hemorrhagic), menstrual irregularities; regresses spontaneously but can mimic ectopic pregnancy or neoplasm
Macro ─ Cyst (often 3-8 cm) with a characteristically thick, convoluted, bright yellow wall; lumen often contains clotted blood (hemorrhagic corpus luteum)
Micro ─ Convoluted cyst wall lined by large, polygonal luteinized cells:
─ Granulosa Lutein Cells: Larger, more eosinophilic, form the bulk of the inner wall
─ Theca Lutein Cells: Smaller, paler/vacuolated, form clusters in the outer wall/folds
─ Central cavity often filled with blood, fibrin, or serous fluid
─ No significant atypia or mitotic activity beyond normal corpus luteum
Ancillary studies ─ ─ Usually none required
DDx ─ Follicle Cyst (thinner wall, less convoluted, no prominent luteinization)
─ Luteoma of Pregnancy (solid, multiple, pregnancy-related)
─ Endometriotic Cyst (endometrial lining/stroma, hemosiderin)
─ Steroid Cell Tumor (solid mass, can show atypia)
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Large Solitary Luteinized Follicle Cyst

A large, unilocular ovarian cyst, typically seen during pregnancy or postpartum, lined by prominent luteinized granulosa and theca cells
Clinical ─ Occurs almost exclusively in pregnancy/puerperium; usually asymptomatic and discovered incidentally; benign and typically regresses
Macro ─ Large (can be >20 cm), unilocular, thin-walled cyst filled with clear fluid
Micro ─ Lined by one to several layers of large, polygonal cells with abundant eosinophilic cytoplasm (luteinized cells)
─ Both granulosa and theca cell types contribute to the luteinized lining
─ Nuclei are generally bland and round
─ Lacks the convoluted appearance of a corpus luteum cyst
Ancillary studies ─ ─ Usually none required
DDx ─ Follicle Cyst (usually smaller, less prominent luteinization)
─ Corpus Luteum Cyst (convoluted wall, typically hemorrhagic)
─ Luteoma of Pregnancy (solid)
─ Cystic Granulosa Cell Tumor (neoplastic features)
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Luteoma of Pregnancy

A rare, non-neoplastic, hormone-responsive proliferation of luteinized stromal cells occurring during pregnancy, often causing maternal virilization
Clinical ─ Typically discovered in the third trimester or at C-section; ~30-50% are bilateral, ~30-50% cause maternal virilization; can cause virilization of female fetus; regresses spontaneously after delivery
Macro ─ Usually solid, well-circumscribed, brown or tan nodules; can be single or multiple, often large
Micro ─ Diffuse sheets or nodules of large, polygonal cells with abundant eosinophilic cytoplasm (luteinized cells)
─ Nuclei are round and generally bland, though some atypia can be seen; nucleoli can be prominent
─ Mitotic activity can be present but is typically low and non-atypical
─ No Reinke crystals
─ Regressing lesions show cytoplasmic vacuolization and smaller cells
Ancillary studies ─ ─ IHC (+) Inhibin, Calretinin, SF-1
DDx ─ Corpus Luteum (cyst or normal; convoluted, two cell types)
─ Steroid Cell Tumor / Leydig Cell Tumor (can be histologically very similar, but not pregnancy-related; Reinke crystals in Leydig)
─ Juvenile Granulosa Cell Tumor (follicular pattern)
─ Dysgerminoma (OCT3/4+, lymphocytes)
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Stromal Hyperplasia and Hyperthecosis

A spectrum of non-neoplastic ovarian stromal proliferation, with hyperthecosis referring to the presence of luteinized stromal cells
Clinical ─ Typically affects postmenopausal women, but can occur in younger women (often a/w PCOS); presents with signs of estrogen (bleeding) or androgen (virilization) excess; associated with insulin resistance, obesity, hypertension
Macro ─ Ovaries are usually symmetrically and bilaterally enlarged, solid, firm, and white-tan; can be nodular
Micro ─ Stromal Hyperplasia: Diffuse or nodular proliferation of ovarian stromal cells, expanding the cortex and medulla
─ Hyperthecosis: Presence of scattered nests or single luteinized stromal cells within the hyperplastic stroma; these cells have eosinophilic or vacuolated cytoplasm and round nuclei
─ Lacks significant atypia or mitotic activity
Ancillary studies ─ ─ IHC (+) Inhibin, Calretinin, SF-1 in luteinized cells
DDx ─ Fibroma / Thecoma (usually unilateral, discrete mass)
─ Polycystic Ovary Disease (PCOS) (multiple cysts, younger age, though can have hyperthecosis)
─ Steroid Cell Tumor (discrete mass)
─ Diffuse Adult Granulosa Cell Tumor (FOXL2+)
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Ovarian Fibromatosis and Massive Edema

Two related, benign tumor-like conditions characterized by proliferation of ovarian stromal fibroblasts (fibromatosis) and/or marked stromal edema (massive edema)
Clinical ─ Typically affects young women (<30 years); presents as an adnexal mass, often with abdominal pain; can cause virilization due to stromal luteinization; often unilateral
Macro ─ Enlarged, firm, white-tan ovary; cut surface may be solid and whorled (fibromatosis) or gelatinous/watery (massive edema); often overlaps
Micro ─ Fibromatosis: Proliferation of bland spindle-shaped fibroblasts and myofibroblasts with abundant collagen deposition; often surrounds and entraps follicles; may show focal luteinization
─ Massive Edema: Marked accumulation of edema fluid separating normal ovarian stromal cells and structures (follicles, vessels); often has a peripheral rim of compressed cortex; can have stromal luteinization
─ Both conditions lack significant atypia and mitotic activity
Ancillary studies ─ ─ Usually none required; IHC can show Inhibin+ in luteinized cells
DDx ─ Fibroma / Thecoma (usually more discrete mass, less edema/entrapment)
─ Sclerosing Stromal Tumor (pseudolobular, prominent vessels)
─ Krukenberg Tumor (signet ring cells, CK+)
─ Ovarian Torsion (hemorrhage, necrosis)
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Leydig Cell Hyperplasia (Hilus Cell Hyperplasia)

A non-neoplastic increase in the number of Leydig (hilus) cells within the ovarian hilum
Clinical ─ Usually an incidental microscopic finding; most common in postmenopausal women; can be associated with conditions causing androgen excess or stromal hyperplasia/hyperthecosis
Macro ─ No discrete mass; ovarian hilum may appear unremarkable
Micro ─ Increased numbers of small nests, clusters, or single Leydig cells within the ovarian hilum, often near non-myelinated nerves
─ Cells are identical to Leydig cells (large, polygonal, eosinophilic cytoplasm)
─ Reinke crystals may be present but are often absent
─ No mass formation
Ancillary studies ─ ─ IHC (+) Inhibin, Calretinin, SF-1
DDx ─ Leydig Cell Tumor (forms a discrete mass)
─ Steroid Cell Tumor (forms a discrete mass)
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Fallopian Tube & Broad Ligament

Non-Neoplastic

Chronic Salpingitis

Chronic inflammation of the fallopian tube, most often a sequela of pelvic inflammatory disease (PID)
Clinical ─ Can be asymptomatic or cause chronic pelvic pain, infertility, or increased risk of ectopic pregnancy; often due to N gonorrhoeae, C trachomatis, or polymicrobial infections
Macro ─ Tube may be thickened, adherent; fimbriae may be fused (hydrosalpinx if distended with fluid)
Micro ─ Infiltration of the tubal plicae and wall by lymphocytes and plasma cells (key feature)
─ Plical blunting, fusion (bridging), and edema
─ Follicular Salpingitis: Severe form where plical fusion creates gland-like or labyrinthine spaces filled with inflammatory cells
─ Hydrosalpinx: Distended tube with flattened, atrophic epithelium and chronic inflammation, often with plical fusion
Ancillary studies ─ ─ Usually none required; IHC can highlight plasma cells (CD138) if needed
DDx ─ Acute Salpingitis (predominantly neutrophils)
─ Salpingitis Isthmica Nodosa (diverticula within myosalpinx)
─ Tuberculous Salpingitis (caseating granulomas)
─ Endosalpingiosis (benign glands outside tube, no inflammation)
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Pseudoxanthomatous Salpingitis

A rare, usually incidental finding characterized by the accumulation of foamy macrophages within the stroma of tubal plicae
Clinical ─ Often an incidental finding in tubes removed for other reasons; may be associated with PID, endometriosis, or prior surgery; generally considered benign and clinically insignificant
Macro ─ Fallopian tube usually appears normal or shows features of underlying pathology (eg, chronic salpingitis)
Micro ─ Collections of foamy macrophages (xanthoma cells) with clear, vacuolated cytoplasm
─ Macrophages are typically confined to the lamina propria of the plical tips
─ Usually lacks significant acute inflammation, necrosis, or stromal destruction (unlike Xanthogranulomatous salpingitis)
─ Pigment (lipofuscin or hemosiderin) may be present
Ancillary studies ─ ─ IHC (+) CD68 highlights macrophages
DDx ─ Xanthogranulomatous Salpingitis (more destructive, mixed inflammation, often forms mass)
─ Malakoplakia (Michaelis-Gutmann bodies)
─ Metastatic Clear Cell Carcinoma (malignant features, PAX8+)
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Xanthogranulomatous Salpingitis

A rare, destructive chronic inflammatory process of the fallopian tube characterized by abundant foamy histiocytes, often associated with PID or endometriosis
Clinical ─ Can present as a pelvic mass mimicking malignancy, or with pain/fever; often associated with pelvic inflammatory disease, IUD use, or endometriosis
Macro ─ Tube is often thickened, indurated, and may form a mass; cut surface can be yellowish and show abscess formation
Micro ─ Destructive inflammatory infiltrate replacing normal tubal structures
─ Predominantly composed of sheets of foamy macrophages (histiocytes)
─ Mixed inflammatory cells including lymphocytes, plasma cells, and neutrophils are present
─ Multinucleated giant cells and cholesterol clefts may be seen
─ Fibrosis and abscess formation can occur
Ancillary studies ─ ─ IHC (+) CD68 highlights macrophages
DDx ─ Pseudoxanthomatous Salpingitis (macrophages confined to plicae, non-destructive)
─ Malakoplakia (Michaelis-Gutmann bodies)
─ Tuberculous Salpingitis (caseating granulomas, AFB+)
─ Metastatic Clear Cell Carcinoma (malignant features, PAX8+)
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Fallopian Tube Prolapse

A benign condition where fallopian tube epithelium herniates through the vaginal cuff, typically following hysterectomy
Clinical ─ Occurs weeks to years after hysterectomy (especially vaginal); can present as a polypoid lesion/granulation tissue at the vaginal apex, may cause spotting or discharge
Macro ─ Small, reddish, polypoid or granular lesion at the vaginal vault
Micro ─ Prolapsed tissue shows tubal plicae or isolated glands lined by tubal-type epithelium (ciliated/secretory/peg cells)
─ Epithelium often shows reactive atypia, squamous metaplasia, or mucinous metaplasia
─ Stroma is typically edematous and contains acute and chronic inflammatory cells, granulation tissue, and hemosiderin
Ancillary studies ─ ─ IHC (+) PAX8 confirms Mullerian origin; p63 can highlight squamous metaplasia
DDx ─ Vaginal Adenocarcinoma (Clear Cell or Endometrioid - invasive, malignant cytology, specific markers)
─ Endocervicosis / Endometriosis (endocervical glands or endometrial glands/stroma)
─ Microglandular Hyperplasia (if mucinous metaplasia prominent)
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Walthard Cell Nests

Common, benign, incidental nests of transitional-like (urothelial-like) epithelium typically found on the serosal surfaces of the fallopian tube, broad ligament, or ovary
Clinical ─ Incidental finding with no clinical significance; very common
Macro ─ Usually microscopic; can appear as small (<1 mm), white-yellow, solid or cystic nodules on serosal surfaces
Micro ─ Well-circumscribed nests of epithelial cells resembling urothelium
─ Cells are polygonal with oval nuclei, often showing prominent longitudinal grooves ('coffee-bean' nuclei)
─ Nests can be solid or may develop central cystic spaces (Walthard Cysts), sometimes containing mucin
─ No atypia or mitotic activity
Ancillary studies ─ ─ IHC (+) GATA3, p63, CK7
─ IHC (-) PAX8, WT1, Calretinin
DDx ─ Mesothelial Hyperplasia (Calretinin+, GATA3-)
─ Endosalpingiosis (PAX8+, GATA3-)
─ Serous Borderline Tumor / Implants (WT1+, PAX8+)
─ Brenner Tumor (ovarian location, denser stroma)
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Paratubal Cyst

Benign cysts located adjacent to the fallopian tube, most commonly Hydatids of Morgagni arising from Mullerian remnants near the fimbriae
Clinical ─ Very common, usually small and incidental; can occasionally undergo torsion, causing acute pain
Macro ─ Typically small (<2 cm), thin-walled, translucent cysts filled with clear fluid; often pedunculated, especially near fimbriae (Hydatids of Morgagni)
Micro ─ Lined by a single layer of bland epithelial cells
─ Most commonly lined by serous (tubal-type) epithelium with ciliated and non-ciliated cells (Mullerian origin)
─ Can also be lined by simple cuboidal or flattened cells (Mesonephric origin)
─ Wall is typically thin and fibrous, may contain smooth muscle
Ancillary studies ─ ─ Usually none required; Serous-type will be PAX8+, WT1+/-
DDx ─ Cystic Mesothelioma / Peritoneal Inclusion Cyst (mesothelial lining, Calretinin+)
─ Serous Cystadenoma (ovarian or tubal origin, can be larger/more complex)
─ Endosalpingiosis (more glandular/complex)
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Epithelial Tumors

Adenomatoid Tumor (Fallopian Tube)

A benign tumor of mesothelial origin, typically found on the serosal surface or within the wall of the fallopian tube or uterus
Clinical ─ Usually an incidental finding in hysterectomy/salpingectomy specimens; presents as a small, firm nodule; benign behavior
Macro ─ Small (<3 cm), solid, firm, well-circumscribed, gray-white nodule
Micro ─ Complex network of anastomosing, small, slit-like or rounded channels, tubules, and cysts
─ Lined by flattened to cuboidal mesothelial cells; cytoplasm can be eosinophilic or vacuolated ('signet ring-like', but mucin negative)
─ Set in a fibrous or fibromuscular stroma
─ Bland cytology, low/absent mitoses
Ancillary studies ─

─ IHC (+) Calretinin, WT1 (nuclear), D2-40, CK7, EMA
─ IHC (-) PAX8, Ber-EP4, MOC31 (helps exclude adenocarcinoma)
DDx ─ Salpingitis Isthmica Nodosa (tubal epithelium, within muscle layer)
─ Lymphangioma (D2-40+, but Calretinin-/WT1-)
─ Metastatic Carcinoma (malignant features, adenocarcinoma markers)
─ Mesothelioma (rare in tube, usually shows invasion/malignant features)
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Tubal Papilloma

A rare, benign epithelial proliferation of the fallopian tube characterized by distinct papillary structures
Clinical ─ Very rare; can present with vaginal discharge or be incidental
Macro ─ Small, exophytic, papillary lesion within the tubal lumen
Micro ─ Papillary fronds with fibrovascular cores
─ Lined by bland tubal-type epithelium (serous), resembling normal tubal mucosa
─ No significant atypia, stratification, or mitotic activity
Ancillary studies ─

─ IHC (+) PAX8, WT1+/-, ER/PR+
DDx ─ Metaplastic Papillary Lesion (metaplastic changes, often IUD-related)
─ Serous Borderline Tumor / STIC / Serous Carcinoma (show atypia, stratification, +/- invasion)
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Serous Adenofibroma (Fallopian Tube)

A rare, benign tumor of the fallopian tube composed of serous epithelial-lined glands and cysts set within a prominent fibrous stroma
Clinical ─ Very rare; usually an incidental finding or presents as a small mass
Macro ─ Small, firm, solid or solid/cystic mass, often near fimbriae
Micro ─ Glandular or cystic structures embedded in abundant, dense fibrous stroma
─ Lined by a single layer of bland serous (tubal-type) epithelium, often ciliated
─ No atypia, stratification, or mitotic activity
Ancillary studies ─

─ IHC (+) PAX8, WT1+/-, ER/PR+ (epithelium)
DDx ─ Brenner Tumor (transitional nests, GATA3+)
─ Serous Borderline Tumor / Carcinoma (atypia, complexity, +/- invasion)
─ Endometrioid Adenofibroma (WT1-, ER+)
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p53 Signature

A segment of morphologically benign-appearing fallopian tube epithelium (usually fimbrial secretory cells) with strong nuclear p53 protein accumulation, considered an early precursor lesion to pelvic high-grade serous carcinoma
Clinical ─ Microscopic finding, often identified in fallopian tubes removed prophylactically (eg, BRCA mutation carriers) or incidentally; considered the earliest recognizable precursor of many pelvic high-grade serous carcinomas
Macro ─ N/A (microscopic finding)
Micro ─

─ Morphologically unremarkable or very subtly altered tubal epithelium, typically involving secretory cells
─ Defined by a linear stretch of at least 12 consecutive secretory cells showing strong, diffuse nuclear p53 expression by immunohistochemistry
─ Lacks significant cytological atypia (ie, cells do not appear overtly malignant on H&E)
─ No significant increase in proliferation index (Ki67 is low)
Ancillary studies ─

─ IHC (+) p53 (strong, diffuse nuclear staining in ≥12 consecutive cells)
─ IHC (-) Ki67 (low proliferation index, typically <10%)
DDx ─

─ Serous Tubal Intraepithelial Carcinoma (STIC) (shows significant cytologic atypia, higher Ki67, often more extensive p53 abnormality)
─ Serous Tubal Intraepithelial Lesion of Uncertain Significance (SCOUT) (more p53 staining/atypia than p53 signature but less than STIC)
─ Reactive atypia (may show some p53 staining but typically not the continuous, strong pattern of a p53 signature)
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Serous Tubal Intraepithelial Lesion of Uncertain Significance (SCOUT)

A diagnostic category for tubal epithelial alterations that show some atypia or p53 expression but do not meet the full criteria for Serous Tubal Intraepithelial Carcinoma (STIC) or a p53 signature
Clinical ─ Represents an indeterminate lesion found in the fallopian tube, often during risk-reducing surgery or incidental salpingectomy; its biological behavior and risk of progression are less defined than STIC or p53 signature, requiring careful assessment and sometimes further investigation
Macro ─ N/A (microscopic finding)
Micro ─

─ Epithelial alterations in fallopian tube lining, usually fimbrial secretory cells
─ Features fall short of diagnostic criteria for STIC or p53 signature
─ May show focal cytologic atypia that is more than reactive but less than STIC
─ May exhibit more extensive p53 immunohistochemical staining than a typical p53 signature but without the marked atypia or high proliferation of STIC
─ The epithelium is not morphologically normal but lacks definitive features of STIC
Ancillary studies ─

─ IHC (+) p53 (may show overexpression or aberrant patterns that are more extensive than a p53 signature but less conclusive than in STIC)
─ IHC Ki67 (proliferation index may be mildly elevated but typically not as high as in STIC)
DDx ─

─ p53 signature (strong p53 staining in morphologically bland epithelium, ≥12 consecutive cells)
─ Serous Tubal Intraepithelial Carcinoma (STIC) (significant cytologic atypia, high N/C ratio, loss of polarity, aberrant p53, high Ki67)
─ Reactive atypia (usually less p53 expression, associated inflammation or repair)
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Serous Tubal Intraepithelial Carcinoma (STIC)

A non-invasive high-grade serous carcinoma confined to the fallopian tube epithelium, considered the precursor lesion for many pelvic high-grade serous carcinomas
Clinical ─ Microscopic finding, usually in tubes removed for other reasons (especially BSO/RRSO for BRCA carriers); high-risk patients; crucial diagnosis
Macro ─ Usually invisible; tube may appear normal or subtly thickened
Micro ─ Non-invasive epithelial proliferation replacing normal tubal lining, often fimbrial
─ Cells show high-grade nuclear features: Marked pleomorphism, high N/C ratio, irregular chromatin, prominent nucleoli
─ Epithelial stratification and loss of polarity
─ Increased mitotic activity, often atypical forms
─ Detached cell clusters or 'tufts' may be seen
─ Often occurs in a background of 'p53 signature' (linear stretches of p53+ cells)
─ Serous Borderline Tumor (SBT) of the tube is rare and shows lower-grade atypia/papillary growth without invasion
Ancillary studies ─

─ IHC (+) p53 (aberrant: >75% strong/diffuse OR null/absent); Ki67 (high proliferation index, often >10-20%); WT1; PAX8
DDx ─ Reactive Atypia / Metaplasia (less atypia, p53 wt, low Ki67)
─ p53 Signature (p53+, but lacks atypia/stratification/high Ki67)
─ Serous Borderline Tumor (lower-grade atypia, lacks aberrant p53)
─ Invasive High-Grade Serous Carcinoma (stromal invasion)
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Endometrioid Carcinoma (Fallopian Tube)

A rare primary invasive carcinoma of the fallopian tube with endometrioid differentiation
Clinical ─ Rare; often presents similarly to ovarian cancer (mass, pain); may be associated with tubal endometriosis; prognosis depends on stage
Macro ─ May present as a mass or thickening within the tube
Micro ─ Histologically identical to endometrioid carcinoma of the uterus or ovary
─ Glandular, villoglandular, or solid patterns
─ Lined by malignant cells with oval/elongated nuclei, resembling endometrial cells
─ Squamous differentiation may occur
─ Must be distinguished from direct extension or metastasis from ovary/uterus
Ancillary studies ─

─ IHC (+) PAX8, ER, PR
─ IHC (-) WT1
DDx ─ High-Grade Serous Carcinoma (WT1+, p53 aberrant)
─ Metastatic Endometrioid Carcinoma (clinical/imaging correlation needed)
─ Endometriosis with atypia (lacks invasion)
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Carcinosarcoma (Fallopian Tube)

A rare, highly aggressive biphasic malignancy of the fallopian tube containing both malignant epithelial (carcinoma) and malignant mesenchymal (sarcoma) components
Clinical ─ Very rare; typically affects postmenopausal women; presents with mass, pain, or bleeding; poor prognosis
Macro ─ Often large, bulky mass, may show necrosis and hemorrhage
Micro ─ Intimate mixture of carcinomatous and sarcomatous elements
─ Carcinomatous component is usually high-grade serous or endometrioid type
─ Sarcomatous component is usually high-grade, undifferentiated, or may show specific differentiation (eg, rhabdomyosarcoma, chondrosarcoma)
Ancillary studies ─

─ IHC panel to highlight both components:
─ Carcinoma: PAX8, Cytokeratins, EMA
─ Sarcoma: Vimentin, Desmin (muscle), S100 (chondroid), Myogenin (rhabdo)
DDx ─ High-Grade Serous Carcinoma with spindle cells (CK+, Vimentin-)
─ Endometrioid Carcinoma with spindle cells
─ Primary Tubal Sarcoma (lacks epithelial component)
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Tumor-like lesions

Tubal Hyperplasia

An incidental finding characterized by increased complexity and crowding of tubal epithelial folds, but lacking significant cytologic atypia
Clinical ─ Usually an incidental microscopic finding; no known clinical significance, but needs to be distinguished from STIC
Macro ─ Fallopian tube usually appears normal
Micro ─ Increased number and branching of tubal plicae, leading to crowding and pseudostratification
─ Epithelium consists of bland ciliated and secretory cells, similar to normal tubal lining
─ Lacks significant nuclear atypia, hyperchromasia, or increased mitotic activity
Ancillary studies ─ ─ IHC (+) p53 (wild-type pattern); Ki67 (low proliferation index)
DDx ─ Serous Tubal Intraepithelial Carcinoma (STIC) (high-grade atypia, aberrant p53, high Ki67)
─ Serous Borderline Tumor (papillary growth, mild-moderate atypia)
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Salpingitis Isthmica Nodosa (SIN)

A condition characterized by diverticula or outpouchings of the fallopian tube epithelium extending into the myosalpinx, often associated with hypertrophy of the surrounding muscle
Clinical ─ Often seen in young women; strongly associated with infertility and ectopic pregnancy; cause is debated (inflammation vs congenital vs adenomyosis-like)
Macro ─ Typically involves the isthmic (proximal) portion of the tube, causing nodular thickening
Micro ─ Benign-appearing tubal-type epithelial glands or gland-like spaces located within the muscular wall (myosalpinx)
─ Glands may or may not connect to the main tubal lumen
─ Surrounding smooth muscle is often hyperplastic and hypertrophied
─ May have associated chronic inflammation
Ancillary studies ─ ─ Usually none required
DDx ─ Adenomyosis extending to tube (endometrial stroma required)
─ Endometriosis involving tubal wall (endometrial stroma required)
─ Adenocarcinoma (malignant features)
─ Chronic Salpingitis (inflammation without diverticula)
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Metaplastic Papillary Lesion (Fallopian Tube)

A benign, usually incidental papillary proliferation within the tubal lumen, often characterized by eosinophilic or syncytial-like metaplasia
Clinical ─ Often an incidental finding; sometimes associated with IUDs, PID, or pregnancy; benign
Macro ─ Can be microscopic or form small, visible papillary tufts
Micro ─ Small, non-complex papillary structures within the tubal lumen
─ Lined by cuboidal to columnar cells, often showing prominent eosinophilic cytoplasm, sometimes forming syncytial-like aggregates
─ Nuclei are generally bland, though can show reactive atypia or smudging
─ Inflammation may be present
Ancillary studies ─ ─ IHC (+) PAX8, Cytokeratins
DDx ─ Tubal Papilloma (more distinct papillae, typical serous lining)
─ Serous Borderline Tumor / Carcinoma (atypia, complexity, specific IHC)
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Placental Site Nodule (Fallopian Tube)

An ectopic, non-neoplastic residue of intermediate trophoblasts from a prior gestation, occurring within the fallopian tube wall or lumen
Clinical ─ Rare in the fallopian tube; can occur years after a pregnancy (tubal or uterine); usually an incidental finding
Macro ─ Small, well-circumscribed, yellowish or tan nodule
Micro ─ Well-demarcated nodule composed of intermediate trophoblast cells set in an extensively hyalinized stroma
─ Trophoblast cells are polygonal with eosinophilic or amphophilic cytoplasm; nuclei can be irregular but lack high-grade features or significant mitoses
Ancillary studies ─ ─ IHC (+) Inhibin, hPL, Mel-CAM (CD146), CK18
─ IHC (-) hCG (usually), SALL4
─ IHC Ki67 (low)
DDx ─ Placental Site Trophoblastic Tumor / Epithelioid Trophoblastic Tumor (larger, invasive, higher Ki67, different IHC profile)
─ Ectopic Pregnancy (chorionic villi, acute changes)
─ Squamous Cell Carcinoma (p63+, CK5/6+, SCST markers-)
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Mucinous Metaplasia (Fallopian Tube)

Replacement of the normal serous epithelium of the fallopian tube with mucin-secreting cells, resembling either endocervical or intestinal epithelium
Clinical ─ Usually an incidental finding; can be associated with chronic inflammation, PID, or nearby tumors
Macro ─ Fallopian tube usually appears normal
Micro ─ Replacement of ciliated/secretory cells by tall columnar cells containing apical or cytoplasmic mucin
─ Can resemble endocervical epithelium (pale apical mucin) or intestinal epithelium (goblet cells)
─ Lacks significant atypia, stratification, or architectural complexity
Ancillary studies ─ ─ Mucin stains (Alcian Blue, PAS) confirm mucin
─ IHC can show CK7+/CK20- (Mullerian) or CK20+/CK7- (Intestinal)
DDx ─ Mucinous adenocarcinoma (rare in tube, shows malignant features)
─ Metastatic mucinous carcinoma
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Other Tumors

Endosalpingiosis (Fallopian Tube)

The presence of benign glands lined by tubal-type epithelium (ciliated, secretory, and peg cells) in ectopic locations, often on the tubal serosa or within the tubal wall but outside the lumen
Clinical ─ Common incidental finding; usually asymptomatic; rarely can form cystic masses; its presence on peritoneal surfaces is common, but here it refers specifically to the tube context
Macro ─ Usually microscopic; can form small, clear cysts or surface granularity
Micro
─ Glandular or cystic structures lined by bland epithelium identical to fallopian tube lining (ciliated, secretory, peg cells)
─ Found on the tubal serosa, within the tubal wall (myosalpinx or subserosa), or in paratubal tissues
─ Psammoma bodies are frequently associated
─ No endometrial stroma (distinguishes from endometriosis)
─ No significant atypia or inflammation (usually)
Ancillary studies ─ ─ IHC (+) PAX8, WT1 (variable), ER, PR, CK7
DDx
─ Endometriosis (must have endometrial stroma)
─ Peritoneal Inclusion Cyst / Cystic Mesothelioma (lined by mesothelium, Calretinin+)
─ Serous Borderline Tumor / Adenocarcinoma (atypia, complexity, invasion)
─ Walthard Nests (transitional epithelium, GATA3+)
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Leiomyoma (Broad Ligament)

A benign smooth muscle tumor arising from the smooth muscle within the broad ligament, distinct from uterine or ovarian origin
Clinical ─ Most common primary tumor of the broad ligament; usually asymptomatic and incidental; can cause mass effect or pain if large; hormonally responsive (estrogen/progesterone)
Macro ─ Well-circumscribed, firm, white-tan, whorled mass located within the leaves of the broad ligament, separate from the uterus and ovary
Micro
─ Intersecting fascicles of bland, uniform spindle-shaped smooth muscle cells
─ Cells have eosinophilic cytoplasm and elongated 'cigar-shaped' nuclei
─ Low mitotic activity, no significant atypia or tumor cell necrosis
─ Variants (cellular, myxoid, etc) similar to uterine leiomyomas can occur
Ancillary studies
─ IHC (+) Desmin, SMA (Smooth Muscle Actin), Caldesmon
─ IHC (-) CD10, Inhibin, Cytokeratins
DDx
─ Uterine Leiomyoma (pedunculated/intraligamentary extension)
─ Leiomyosarcoma of broad ligament (atypia, necrosis, high mitoses)
─ Ovarian Fibroma/Thecoma (different IHC profile)
─ Wolffian Tumor (different morphology/IHC)
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Adenomyoma (Broad Ligament)

A rare, benign biphasic tumor composed of benign endometrial-type glands set within a prominent smooth muscle stroma, occurring in the broad ligament
Clinical ─ Rare; usually asymptomatic or presents as a mass separate from the uterus
Macro ─ Well-circumscribed, solid mass, may have small cystic areas, located within the broad ligament
Micro
─ Benign endometrial-type glands (can show proliferative, secretory, or inactive patterns)
─ Surrounded by abundant, interlacing fascicles of benign smooth muscle
─ Lacks endometrial stroma (distinguishing it from endometriosis with smooth muscle metaplasia or an adenomyotic nodule extending into the broad ligament)
Ancillary studies
─ IHC (+) Glands (CK7, PAX8, ER/PR); Stroma (Desmin, SMA)
DDx
─ Endometriosis involving broad ligament (requires endometrial stroma)
─ Leiomyoma (lacks glands)
─ Adenosarcoma of broad ligament (malignant stroma)
─ Wolffian tumor (different gland morphology/IHC)
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Adenosarcoma (Broad Ligament)

A rare biphasic malignancy arising in the broad ligament, composed of benign epithelial glands and a malignant (usually low-grade) mesenchymal stromal component
Clinical ─ Very rare primary broad ligament tumor; may present as a mass; behavior similar to uterine/ovarian counterparts, with risk of recurrence, especially with stromal overgrowth
Macro ─ Solid or cystic mass in the broad ligament, may have polypoid fronds
Micro ─

─ Biphasic pattern: Benign glands and malignant sarcoma
─ Glands often cystically dilated, lined by benign epithelium (endometrial, endocervical, or tubal type)
─ Sarcomatous stroma shows periglandular cuffing/condensation, atypia, and mitotic activity (usually low-grade)
─ Stromal overgrowth (>25% of tumor volume) signifies higher risk of recurrence/metastasis
Ancillary studies
─ IHC (Stroma) (+) CD10, Vimentin; variable ER/PR, Desmin, SMA
─ IHC (Epithelium) (+) Cytokeratins, PAX8
DDx
─ Adenomyoma of broad ligament (benign stroma)
─ Carcinosarcoma of broad ligament (malignant glands and stroma)
─ Leiomyosarcoma with entrapped benign glands
─ Malignant Phyllodes Tumor (if breast-like elements are prominent and stroma is specific)
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Leiomyosarcoma (Broad Ligament)

A rare malignant tumor of smooth muscle origin arising primarily within the broad ligament
Clinical ─ Rare; typically affects older women; aggressive behavior with high risk of recurrence and metastasis
Macro ─ Often large, fleshy mass with hemorrhage and necrosis, arising in the broad ligament, separate from uterine/ovarian primaries
Micro
─ Malignant spindle cell proliferation showing smooth muscle differentiation
─ Meets criteria for malignancy: Significant nuclear atypia, high mitotic activity (often >=10/10 HPF in uterine criteria, applied by analogy), and tumor cell necrosis
Ancillary studies
─ IHC (+) Desmin, SMA, Caldesmon
─ IHC (-) CD10, Inhibin, Cytokeratins, STAT6
DDx ─

─ Leiomyoma of broad ligament (lacks malignant features)
─ Endometrial Stromal Sarcoma extending into broad ligament (CD10+)
─ Solitary Fibrous Tumor (STAT6+)
─ Sarcomatoid Carcinoma (CK+)
─ Metastatic Leiomyosarcoma from uterus
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Wolffian Tumor (Broad Ligament)

A rare, usually benign tumor arising from mesonephric (Wolffian) duct remnants, typically found in the broad ligament or other adnexal structures
Clinical ─ Wide age range; mostly asymptomatic or presents as a mass; vast majority are benign, rare malignant cases reported
Macro ─ Solid, well-circumscribed, gray-white to yellow mass, typically within the broad ligament or paratubal/paraovarian region
Micro
─ Diverse architectural patterns:
─ Tubular / Glandular: Small, closely packed tubules or glands
─ Sieve-like / Cribriform: Fenestrated appearance
─ Solid / Diffuse sheets
─ Cells are typically uniform, cuboidal to low columnar, with scant eosinophilic cytoplasm and round, bland nuclei
─ Luminal eosinophilic, PAS-positive material is common
─ Stroma is often fibrous or hyalinized
Ancillary studies
─ IHC (+) Calretinin (often strong), Inhibin (variable), CD10 (variable), GATA3, CK7 (variable)
─ IHC (-) PAX8 (usually negative, a key point if distinguishing from Müllerian lesions), ER, PR, WT1
DDx
─ Sertoli Cell Tumor / Sertoli-Leydig Cell Tumor (different IHC profile, PAX8-, WT1 variable, SF1+)
─ Endometrioid Tumors (PAX8+, ER+, GATA3-)
─ Mesonephric-like Adenocarcinoma (PAX8+, GATA3+, more atypia/invasion if malignant)
─ Paratubal cysts (simple lining, not a solid tumor)
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Papillary Cystadenoma (Broad Ligament)

A rare, benign epithelial tumor of presumed mesonephric origin, often associated with Von Hippel-Lindau (VHL) disease, arising in the broad ligament or other adnexal sites
Clinical ─ Rare; strongly associated with VHL disease (consider screening if found, especially if bilateral or in a male epididymis); benign, no malignant potential reported
Macro ─ Small, cystic or solid mass, typically in the broad ligament or near epididymis/testis in males
Micro
─ Complex papillary structures projecting into cystic spaces
─ Papillae lined by a single layer of cuboidal cells with abundant clear cytoplasm (glycogen-rich)
─ Nuclei are typically small, round, and bland, often basally located
─ Stroma of papillae is delicate and fibrovascular
─ Histologically identical to Papillary Cystadenoma of the Epididymis
Ancillary studies
─ IHC (+) PAX8, PAX2, CK7, EMA, CD10, CAIX (Carbonic Anhydrase IX)
─ IHC (-) ER, PR, WT1, Inhibin, Calretinin, Chromogranin
DDx
─ Clear Cell Carcinoma (ovarian/tubal/peritoneal - malignant features, HNF1B+, Napsin A+)
─ Serous Tumors (WT1+, often ER+)
─ Metastatic Renal Cell Carcinoma, Clear Cell Type (history, often larger, more atypia, different IHC profile, but CAIX can overlap)
─ Wolffian Tumor (lacks prominent clear cells and papillary architecture usually)
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Ependymoma (Broad Ligament)

An extremely rare neuroectodermal tumor identical to CNS ependymoma, occurring as a primary tumor within the broad ligament or pelvis, presumed to arise from heterotopic glial tissue or germ cell origin
Clinical ─ Extremely rare; can occur at any age; behavior is variable, can be low-grade or anaplastic
Macro ─ Solid, well-circumscribed mass in the broad ligament
Micro
─ Resembles CNS ependymoma:
─ Sheets or lobules of cells with uniform, round to oval nuclei and fibrillary cytoplasm
─ Characteristic perivascular pseudorosettes (tumor cells arranged radially around blood vessels with an intervening anuclear zone)
─ True ependymal rosettes/canals may be present
─ Grading based on CNS criteria (mitoses, atypia, necrosis)
Ancillary studies
─ IHC (+) GFAP (Glial Fibrillary Acidic Protein - characteristic), S100
─ IHC (+/-) EMA (dot-like positivity)
DDx
─ Other primary pelvic sarcomas or spindle cell tumors (IHC will differ)
─ Metastatic CNS Ependymoma (clinical history crucial)
─ Sex Cord-Stromal Tumors (GFAP-, SCST markers+)
─ Smooth Muscle Tumors (Desmin+, SMA+, GFAP-)
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Adrenocortical Remnants (Broad Ligament) / Adrenal Rest

Ectopic nodules of benign adrenocortical tissue found incidentally within the broad ligament or other adnexal structures
Clinical ─ Common incidental finding, especially in infants or during surgery; no clinical significance unless they rarely undergo hyperplasia or neoplasia (extremely rare)
Macro ─ Small (<5mm), bright yellow, well-circumscribed nodules on serosal surfaces or within connective tissue of the broad ligament, near ovary or tube
Micro
─ Nodules of cells identical to normal adrenal cortex, often showing zonation:
─ Outer zone of small cells with scant cytoplasm (zona glomerulosa-like)
─ Inner zone of larger polygonal cells with abundant eosinophilic or vacuolated (lipid-rich) cytoplasm (zona fasciculata/reticularis-like)
─ Cells are bland with round nuclei
─ No medulla is present
Ancillary studies
─ IHC (+) Inhibin, Calretinin, SF-1, Melan-A (similar to adrenal cortex)
─ IHC (-) Cytokeratins, PAX8
DDx
─ Luteinized Theca Cells / Hilus Cell Hyperplasia (different location/context, less distinct zonation)
─ Steroid Cell Tumor (forms a distinct tumor mass, may lack clear zonation)
─ Metastatic Clear Cell Carcinoma (malignant, PAX8+)
─ Walthard Nests (transitional epithelium, GATA3+)
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Uterus

Non-Neoplastic Endometrium

Adenomyosis / Adenomyoma

The presence of endometrial glands and stroma within the myometrium, which can be diffuse (adenomyosis) or form a discrete nodule (adenomyoma)
Clinical ─ Common, often middle-aged women; presents with menorrhagia, dysmenorrhea, dyspareunia, or can be asymptomatic; associated with infertility
Macro ─ Uterus often globularly enlarged; myometrium appears thickened and trabeculated, may contain small cysts (can be hemorrhagic); Adenomyoma is a circumscribed, non-encapsulated, whorled nodule resembling a leiomyoma but less well-defined
Micro ─ Nests of endometrial glands and associated endometrial stroma located within the myometrium
─ Diagnosis usually requires glands/stroma to be at least 2_5 mm (or 1 LPF) below the endomyometrial junction
─ Glands can be proliferative, secretory, or inactive/atrophic
─ Surrounding myometrium often shows reactive hypertrophy/hyperplasia
─ Adenomyoma shows glands/stroma within a leiomyomatous proliferation
Ancillary studies ─ ─ Usually none required
DDx ─ Leiomyoma (lacks glands/stroma)
─ Endometrioid Carcinoma invading myometrium (malignant glands, often complex/back-to-back, desmoplasia)
─ Endometrial Hyperplasia involving adenomyosis
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Arias-Stella Reaction

Benign, non-neoplastic changes in endometrial (or endocervical/tubal/vaginal) epithelium due to high progesterone levels, most commonly associated with pregnancy
Clinical ─ Associated with intrauterine/ectopic pregnancy, gestational trophoblastic disease, or exogenous progestin therapy; important to recognize as benign and not mistake for carcinoma
Macro ─ Endometrium may appear thick/secretory
Micro ─ Glands often show secretory 'exhaustion' or hypersecretory changes
─ Key feature: Marked nuclear atypia, including:
─ Enlargement and hyperchromasia
─ Irregular nuclear contours, smudged chromatin
─ Intranuclear cytoplasmic pseudoinclusions
─ Cells often have abundant clear or eosinophilic cytoplasm
─ Hobnail or 'peg' cells projecting into glandular lumens are common
─ Crucially, there is a lack of significant mitotic activity Ancillary studies ─ ─ Usually none required; IHC (-) Ki67 (low index) can help if malignancy is considered
DDx ─ Clear Cell Carcinoma (invasive, high Ki67, Napsin A+)
─ Endometrioid Carcinoma (invasive, higher Ki67)
─ Microglandular Hyperplasia (neutrophils, lacks severe atypia)
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Atrophy (Endometrium)

A thin, inactive endometrium, typically seen in postmenopausal women due to estrogen deficiency, or resulting from hormonal therapies
Clinical ─ Common cause of postmenopausal bleeding (due to fragile vessels); can also be seen in reproductive age (eg, OCP use, anorexia)
Macro ─ Endometrium appears thin, pale, and smooth
Micro ─ Scant, inactive, simple endometrial glands, often widely spaced
─ Glands lined by low cuboidal to flattened, inactive epithelial cells
─ Stroma is typically dense and spindled
─ Cystic Atrophy: A common variant where glands become cystically dilated but remain lined by bland, atrophic epithelium
─ No mitotic activity
Ancillary studies ─ ─ Usually none required
DDx ─ Endometrial Hyperplasia (especially cystic variant; shows glandular crowding, ↑ gland:stroma ratio)
─ Endometrial Polyp (polypoid shape, fibrous stroma, thick vessels)
─ Progestin effect (decidualized stroma, inactive glands)
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Disordered Proliferative Endometrium (DPE)

An architectural alteration of proliferative endometrium due to prolonged unopposed estrogen (anovulation), characterized by glandular crowding and variation without significant cytologic atypia
Clinical ─ Common cause of abnormal uterine bleeding, especially in perimenopausal women or those with PCOS; considered a precursor/part of spectrum with endometrial hyperplasia
Macro ─ Endometrium may appear thickened
Micro ─ Variation in glandular size and shape, some glands may be cystically dilated
─ Increased gland-to-stroma ratio, but stroma is still prominent
─ Glands are generally proliferative, with stratified columnar cells and mitotic figures
─ Lacks significant cytologic atypia (distinguishes from EIN/Atypical Hyperplasia)
─ Breakdown changes (stromal condensation, hemorrhage) are common due to anovulation
Ancillary studies ─ ─ Usually none required
DDx ─ Normal Proliferative Endometrium (uniform glands, <50% gland:stroma)
─ Endometrial Hyperplasia without Atypia (more pronounced crowding, often >50% gland:stroma)
─ Endometrial Intraepithelial Neoplasia / Atypical Hyperplasia (cytologic atypia)
─ Endometrial Polyp (polypoid structure)
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Endometrial Metaplasia

The replacement of normal endometrial epithelium by another mature cell type, often seen in response to hormones, inflammation, or associated with polyps/hyperplasia/carcinoma
Clinical ─ Common finding; significance varies - some are benign (ciliated), others associated with hyperplasia/carcinoma (squamous, mucinous)
Macro ─ Usually no specific gross findings, depends on underlying condition
Micro ─ Various types can occur, often mixed:
─ Squamous Metaplasia (Morules): Nests of bland squamous cells, often non-keratinizing; common in hyperplasia/carcinoma
─ Ciliated (Tubal) Metaplasia: Presence of ciliated cells; common and benign
─ Eosinophilic Metaplasia: Cells with abundant, granular eosinophilic cytoplasm; often surface change
─ Papillary Metaplasia (Syncytial): Papillary tufts or syncytia of cells; can mimic serous tumors
─ Clear Cell Metaplasia: Cells with clear cytoplasm; must distinguish from clear cell carcinoma
─ Hobnail Metaplasia: Hobnail cells; must distinguish from clear cell/Arias-Stella
─ Mucinous Metaplasia: Mucin-secreting cells (endocervical or intestinal); must distinguish from mucinous carcinoma
Ancillary studies ─ ─ IHC can help in difficult cases (eg, Napsin A for clear cell, MUC stains, p63 for squamous)
DDx ─ Endometrial Hyperplasia / Carcinoma (assess background)
─ Arias-Stella Reaction (hobnail/clear cells, pregnancy/progestin effect)
─ Clear Cell / Serous / Mucinous Carcinoma (malignant features)
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Endometrial Polyp

A common, localized, benign overgrowth of endometrial glands and stroma, projecting into the uterine cavity
Clinical ─ Can be asymptomatic or cause abnormal uterine bleeding (intermenstrual, postmenopausal); common; can rarely harbor hyperplasia or carcinoma
Macro ─ Smooth, sessile or pedunculated mass within the endometrial cavity; size varies greatly
Micro ─ Three key components:
─ Endometrial Glands: Often irregular, cystically dilated, lined by inactive or proliferative epithelium
─ Fibrous Stroma: Dense, collagenous stroma (unlike normal functionalis)
─ Thick-Walled Blood Vessels: Prominent, often hyalinized vessels
─ Covered by endometrial epithelium on at least three sides
─ Glands often 'out of phase' with background endometrium
─ Can show metaplasia, hyperplasia, or carcinoma (requires assessment)
Ancillary studies ─ ─ Usually none required
DDx ─ Adenomyoma (within myometrium)
─ Submucosal Leiomyoma (predominantly smooth muscle)
─ Endometrial Hyperplasia / Carcinoma (assess glandular features)
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Endometritis

Inflammation of the endometrial lining, classified as acute or chronic
Clinical ─ Can cause abnormal bleeding, pain, discharge, infertility; associated with PID, IUDs, post-partum/post-abortion states, instrumentation
Macro ─ Endometrium may appear hyperemic or normal; pyometra may occur if severe
Micro ─ Acute Endometritis: Presence of neutrophils within endometrial glands and/or stroma; often seen with menstruation or breakdown, but significant infiltration outside these settings is diagnostic
─ Chronic Endometritis: Defined by the presence of plasma cells within the endometrial stroma; often accompanied by lymphocytes, eosinophils, and stromal changes (spindling, edema)
─ Lymphoid aggregates are common but not specific unless plasma cells are present
─ Specific causes (eg, TB, HSV, CMV) have characteristic features but are rare
Ancillary studies ─ ─ IHC (+) CD138 can highlight plasma cells, useful in subtle cases
DDx ─ Normal Menstrual Endometrium (shows 'stromal crumble', neutrophils, but plasma cells are rare/absent)
─ Ectopic Pregnancy / Retained Products (trophoblasts, chorionic villi)
─ Malignancy (can have associated inflammation)
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Exogenous Hormone Effects (Endometrium)

Changes in endometrial morphology resulting from the use of hormones like oral contraceptives, progestins, tamoxifen, or aromatase inhibitors
Clinical ─ History of medication use is key; used for contraception, HRT, AUB treatment, breast cancer treatment, etc
Macro ─ Varies: Can be thin (OCPs, progestins) or thickened/polypoid (Tamoxifen)
Micro ─ Oral Contraceptives / Progestins:
─ Early: Subnuclear vacuoles (secretory), stromal edema
─ Later/Prolonged: Glandular atrophy (small, inactive glands), prominent decidualized stroma, thin-walled 'chicken-wire' vasculature
─ Tamoxifen (SERM):
─ Effects are mixed (estrogenic on endometrium); can cause polyps, hyperplasia (often cystic/atypical), and carcinoma (usually endometrioid or serous); subepithelial stromal condensation
─ Aromatase Inhibitors:
─ Primarily cause atrophy; can sometimes be associated with polyps
─ Mirena IUD (Progestin):
─ Marked decidualization, glandular atrophy, superficial stromal changes (mucin, inflammation)
Ancillary studies ─ ─ Usually none required, correlation with history is paramount
DDx ─ Normal cycle phases
─ Endometrial Hyperplasia / Carcinoma (assess atypia/architecture independent of hormone effect)
─ Endometrial Atrophy / Polyps (can be hormone-induced but also occur independently)
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Endometrial Hyperplasia +/- Atypia (EIN)

A spectrum of endometrial proliferation ranging from an increase in gland-to-stroma ratio without significant atypia, to a premalignant lesion (EIN) with cytologic atypia
Clinical ─ Often presents with abnormal uterine bleeding; risk factors include unopposed estrogen (obesity, anovulation/PCOS, estrogen therapy, tamoxifen); Atypical Hyperplasia/EIN carries significant risk of progressing to/coexisting with carcinoma
Macro ─ Endometrium often appears thickened and lush, may be polypoid
Micro ─ Hyperplasia without Atypia:
─ Increased gland-to-stroma ratio (>50%)
─ Glands vary in size/shape, may be dilated or crowded, but retain distinct stroma between them
─ Epithelium resembles proliferative endometrium, lacks significant cytologic atypia ─ Mitoses common
─ Atypical Hyperplasia / Endometrial Intraepithelial Neoplasia (EIN):
─ Glandular crowding often pronounced, but key is cytologic atypia ─ Nuclei are enlarged, rounded, vesicular, or hyperchromatic, losing polarity; differ from background
─ Usually a clonal proliferation >1 mm
Ancillary studies ─ ─ IHC PAX2 (loss supports EIN), PTEN (loss supports EIN), MMR proteins (loss can occur)
DDx ─ Disordered Proliferative Endometrium (less crowding, no atypia)
─ Well-Differentiated Endometrioid Carcinoma (confluent/cribriform growth, stromal invasion - though distinction can be difficult)
─ Endometrial Polyp (fibrous stroma, thick vessels)
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Endometrial Carcinomas

Endometrial Carcinoma-General (Molecular)

The current classification incorporates molecular features (TCGA/ProMisE) stratifying tumors into four main groups with prognostic significance
Clinical ─ Provides prognostic information independent of grade/stage and guides therapy (eg, immunotherapy for MSI-H)
Macro ─ N/A
Micro ─ POLE (ultramutated):
─ Often high-grade endometrioid, abundant TILs, bizarre nuclei; excellent prognosis
─ Dx: POLE exonuclease domain sequencing
─ MSI-H (hypermutated):
─ Often endometrioid, lower uterine segment, dedifferentiated; intermediate prognosis
─ Dx: IHC for MMR proteins (MSH6, PMS2, MSH2, MLH1); loss of one/more indicates dMMR/MSI-H
─ NSMP (No Specific Molecular Profile / Copy-number low):
─ Mostly low-grade endometrioid; good-intermediate prognosis
─ Dx: p53 wild-type by IHC, MMR proficient, POLE wild-type
─ p53 abnormal (Copy-number high / Serous-like):
─ Mostly serous, high-grade endometrioid, carcinosarcomas; poor prognosis
─ Dx: p53 aberrant (overexpression or null) by IHC
Ancillary studies ─ ─ IHC: p53, MSH6, PMS2 (screening)
─ Molecular: POLE sequencing
DDx ─ N/A - it's a classification system
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Endometrioid Carcinoma (Uterus)

The most common type of endometrial carcinoma, characterized by glandular differentiation resembling proliferative endometrium
Clinical ─ Most common endometrial cancer; typically presents with postmenopausal bleeding; often arises from hyperplasia/EIN; associated with unopposed estrogen; usually low grade (1/2) and good prognosis (Type I)
Macro ─ Polypoid or diffuse mass filling endometrial cavity, may invade myometrium
Micro ─ Gland-forming carcinoma (back-to-back glands, cribriform, villoglandular)
─ FIGO grading (based on % solid growth):
─ Grade 1: <=5% solid non-squamous/non-morular growth
─ Grade 2: 6-50% solid growth
─ Grade 3: >50% solid growth (or significant nuclear atypia)
─ Nuclei typically oval, stratified, with moderate chromatin; low-grade unless >50% solid growth
─ Variants: Villoglandular, Secretory, Ciliated, with Squamous differentiation
Ancillary studies ─ ─ IHC (+) PAX8, ER, PR, CK7; (-) WT1
─ Molecular: Often NSMP or MSI-H; POLE can occur; usually p53 wt (low grade)
DDx ─ Atypical Hyperplasia / EIN (lacks invasion/confluent growth)
─ Serous Carcinoma (high-grade atypia, p53 aberrant, often WT1+)
─ Clear Cell Carcinoma (Napsin A+, HNF1B+)
─ Adenomyosis (benign glands/stroma in myometrium)
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Serous Carcinoma (Uterus)

An aggressive (Type II) endometrial carcinoma, histologically identical to ovarian HGSC, characterized by high-grade atypia and papillary/glandular architecture, typically TP53 mutated
Clinical ─ Less common (~10%), typically affects older, postmenopausal women; often arises in atrophic endometrium via Serous EIC; aggressive, presents at higher stage, poor prognosis
Macro ─ Can be small/polypoid or large/invasive; often deep myometrial/LVI
Micro ─ Complex papillary, glandular, or solid patterns
─ High-grade nuclear features: Marked pleomorphism, high N/C ratio, irregular chromatin, prominent nucleoli
─ High mitotic activity, often atypical figures
─ Psammoma bodies can be seen
─ Background endometrium often atrophic, look for Serous EIC (surface replacement by malignant cells)
Ancillary studies ─ ─ IHC (+) p53 (aberrant: >75% strong OR null), p16 (diffuse block-like), PAX8
─ IHC (+/-) WT1 (30-50%), ER, PR (often weak/patchy/negative), high Ki67
DDx ─ High-Grade Endometrioid Carcinoma (often ER+, p53 wt, WT1-)
─ Clear Cell Carcinoma (Napsin A+, HNF1B+)
─ Metastatic Ovarian HGSC (indistinguishable histologically; clinical/site correlation)
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Clear Cell Carcinoma (Uterus)

A rare, aggressive (Type II) endometrial carcinoma characterized by clear, hobnail, or eosinophilic cells, similar to its ovarian counterpart
Clinical ─ Uncommon (~<5%); affects older women; aggressive, often presents at higher stage; not strongly linked to estrogen/hyperplasia
Macro ─ Bulky polypoid mass, often with necrosis
Micro ─ Architectural patterns: Tubulocystic, papillary, solid
─ Characteristic cell types: Clear (glycogenated), Hobnail, Eosinophilic, Flattened
─ High-grade nuclear features, prominent nucleoli
─ Hyalinized stroma is common
Ancillary studies ─ ─ IHC (+) Napsin A, HNF1B, PAX8, AMACR, CK7
─ IHC (-) ER, PR (usually), WT1
DDx ─ Serous Carcinoma (p53 aberrant, different morphology)
─ Endometrioid Carcinoma (ER+, different morphology)
─ Arias-Stella Reaction / Secretory changes (benign, history, low Ki67)
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Undifferentiated & Dedifferentiated Carcinomas (Uterus)

High-grade malignancies, where undifferentiated lacks clear differentiation, and dedifferentiated shows an undifferentiated component alongside a low-grade endometrioid carcinoma
Clinical ─ Rare, aggressive, poor prognosis; often associated with MSI-H (Lynch syndrome)
Macro ─ Large, fleshy masses with necrosis
Micro ─ Undifferentiated: Diffuse sheets or nests of monomorphic or pleomorphic cells; lacks glandular/squamous/other differentiation; can have rhabdoid features
─ Dedifferentiated: Sharply demarcated juxtaposition of:
─ Low-grade (FIGO 1 or 2) Endometrioid Carcinoma
─ Undifferentiated Carcinoma
Ancillary studies ─ ─ IHC (Undiff/Dediff comp): Often loss of ER, PR, PAX8 (can be focal); variable CK+; common loss of SWI/SNF proteins (SMARCB1/INI1, SMARCA4/BRG1, ARID1A); frequent MMR protein loss
─ IHC (LG Endometrioid comp): Retains ER, PR, PAX8; intact SWI/SNF; may show MMR loss
DDx ─ High-Grade Endometrioid / Serous Carcinoma (more differentiation/structure)
─ Carcinosarcoma (distinct malignant stroma)
─ Endometrial Stromal Sarcoma (CD10+, CK-)
─ Lymphoma (LCA+)
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Mixed Carcinoma (Uterus)

An endometrial carcinoma composed of at least two distinct types, with at least one usually being high-grade, and each component comprising at least 10% of the tumor
Clinical ─ Prognosis and treatment usually driven by the highest-grade or most aggressive component; relatively common, often Serous + Endometrioid
Macro ─ Varies depending on components
Micro ─ Two or more distinct histologic types of carcinoma present
─ Most common mix: High-Grade Serous + Endometrioid
─ Other mixes: Clear Cell + Endometrioid, Serous + Clear Cell, etc
─ Each component must meet its diagnostic criteria and exceed 10% volume
Ancillary studies ─ ─ IHC panel is essential to confirm and delineate the different components (eg, p53, WT1 for serous; ER/PR for endometrioid; Napsin A for clear cell)
DDx ─ Carcinoma with divergent differentiation (eg, endometrioid with mucinous)
─ Dedifferentiated Carcinoma (specific LG + Undiff pattern)
─ Carcinosarcoma (requires malignant stroma)
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Carcinosarcoma (MMMT) (Uterus)

A highly aggressive uterine malignancy composed of an admixture of malignant epithelial (carcinoma) and malignant mesenchymal (sarcoma) components
Clinical ─ Typically affects older, postmenopausal women; poor prognosis; now considered a high-grade 'metaplastic' or 'sarcomatoid' carcinoma rather than a true mixed tumor
Macro ─ Large, bulky, polypoid mass often filling the cavity; prominent necrosis and hemorrhage
Micro ─ Biphasic tumor with both malignant epithelial and mesenchymal elements:
─ Carcinomatous: Usually high-grade (serous, endometrioid G3, clear cell, or undifferentiated)
─ Sarcomatous: Often high-grade, undifferentiated/NOS; can show homologous (ESS, LMS) or heterologous (rhabdomyosarcoma, chondrosarcoma, osteosarcoma) differentiation
Ancillary studies ─ ─ IHC panel to highlight both:
─ Carcinoma: PAX8, Cytokeratins, EMA
─ Sarcoma: Vimentin; specific markers if differentiated (Desmin, Myogenin, S100)
─ Often p53 aberrant in both components
DDx ─ Dedifferentiated Carcinoma (lacks true malignant stroma)
─ Endometrioid Carcinoma with spindle cell features (stroma is CK-)
─ Adenosarcoma (benign glands, low-grade stroma usually)
─ Pure Sarcoma (lacks carcinoma)
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Myometrial Mesenchymal Tumors

Uterine Leiomyoma

A benign smooth muscle neoplasm arising from the myometrium, the most common tumor in women
Clinical ─ Very common, especially in reproductive age; can be asymptomatic or cause abnormal bleeding, pain, pressure, or infertility; estrogen/progesterone sensitive
Macro ─ Well-circumscribed, firm, white-tan, whorled masses; can be intramural, submucosal, or subserosal; variants exist (red degeneration, calcification, cystic, etc)
Micro ─ Intersecting fascicles of bland, uniform spindle-shaped smooth muscle cells
─ Cells have eosinophilic cytoplasm and elongated 'cigar-shaped' nuclei
─ Key Benign Features: No significant atypia, no tumor cell necrosis, low mitotic activity (typically <5 /10 HPF, though higher allowed in some variants if no atypia/necrosis)
─ Common variants: Cellular, Myxoid, Hydropic, Apoplectic/Hemorrhagic, Lipoleiomyoma, Bizarre/Symplastic (atypia but no mitoses/necrosis)
Ancillary studies ─ ─ IHC (+) Desmin, SMA, Caldesmon, HMB45 (in PEComa-like variants)
─ IHC (-) CD10, Inhibin
DDx ─ Leiomyosarcoma (requires atypia + necrosis and/or high mitoses)
─ Smooth Muscle Tumor of Uncertain Malignant Potential (STUMP) (fails to meet criteria for LMS but has concerning features)
─ Cellular Leiomyoma (distinguish from ESS)
─ Endometrial Stromal Nodule/Sarcoma (CD10+)
─ Adenomyoma (contains glands)
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Intravenous Leiomyomatosis (IVL)

A rare condition characterized by the intravascular growth of histologically benign smooth muscle, typically arising from a uterine leiomyoma and extending into uterine and pelvic veins
Clinical ─ Can extend significantly, sometimes reaching the inferior vena cava and right atrium; presents with pelvic mass or cardiovascular symptoms; usually benign but can be fatal due to cardiac involvement
Macro ─ Worm-like, rubbery plugs of tumor seen within dilated blood vessels, often extending from uterus
Micro ─ Nodules of bland, benign-appearing smooth muscle tissue located within vascular lumens
─ Histology resembles a typical leiomyoma (no atypia, necrosis, or high mitoses)
─ Tumor is often attached to or growing within the vessel wall
Ancillary studies ─ ─ IHC (+) Desmin, SMA, Caldesmon; ER, PR often positive
DDx ─ Leiomyosarcoma with vascular invasion (shows malignant features)
─ Endometrial Stromal Sarcoma (CD10+, often more infiltrative)
─ Thrombus (fibrin, organized blood elements)
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Metastasizing Leiomyoma (Benign)

A rare condition where histologically benign-appearing leiomyomas are found in extrauterine sites, most commonly the lungs
Clinical ─ Almost always occurs in women with a history of uterine leiomyomas (often post-hysterectomy); lung lesions often multiple and asymptomatic; debate whether true metastasis or multifocal origin/embolization
Macro ─ Multiple, well-circumscribed, firm nodules in lungs or other sites
Micro ─ Nodules are histologically identical to benign uterine leiomyomas
─ Composed of bland spindle smooth muscle cells
─ No atypia, tumor cell necrosis, or significant mitotic activity
Ancillary studies ─ ─ IHC (+) Desmin, SMA, Caldesmon, ER, PR
DDx ─ Leiomyosarcoma metastasis (must rule out by reviewing primary/mets for malignant features)
─ Primary Lung Tumors
─ Other Spindle Cell Tumors
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Uterine Leiomyosarcoma (LMS)

A malignant neoplasm showing smooth muscle differentiation, typically arising de novo in the myometrium
Clinical ─ Rare (<5% of uterine cancers); affects older women (mean 55-60); aggressive, high recurrence rate, hematogenous spread (lungs); poor prognosis
Macro ─ Often large (>10 cm), solitary, fleshy, poorly circumscribed mass; prominent hemorrhage and necrosis are common
Micro ─ Diagnosis requires at least two of the following three features (Stanford criteria):
─ Diffuse moderate to severe cytologic atypia
─ Tumor cell necrosis
─ High mitotic index (>= 10 mitoses per 10 HPF)
─ Composed of intersecting fascicles of atypical spindle cells
─ Epithelioid and Myxoid variants exist (Myxoid LMS requires only atypia + >=2 mitoses/10 HPF + invasion)
Ancillary studies ─ ─ IHC (+) Desmin, SMA, Caldesmon, HMB45 (occasionally)
─ IHC (-) CD10, Cytokeratins, S100
─ IHC (+/-) p53 (often aberrant), high Ki67
DDx ─ Leiomyoma (and variants, especially bizarre/mitotically active)
─ STUMP (borderline category)
─ Endometrial Stromal Sarcoma (CD10+)
─ Undifferentiated Uterine Sarcoma (lacks SM markers)
─ Carcinosarcoma (PAX8+/CK+)
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Endometrial Stromal Tumors

Endometrial Stromal Nodule (ESN)

A benign neoplasm composed of cells resembling proliferative-phase endometrial stroma, characterized by well-circumscribed, non-infiltrative borders
Clinical ─ Uncommon; can occur at any age but often perimenopausal; usually presents with AUB or as a mass; benign, non-recurring
Macro ─ Well-demarcated, solid, tan-yellow, fleshy mass; usually intramural or submucosal
Micro ─ Composed of uniform, small oval cells with scant cytoplasm, resembling proliferative endometrial stroma
─ Prominent network of small arterioles (spiral artery-like)
─ Key Feature: Well-circumscribed, 'pushing' borders with the surrounding myometrium; no significant infiltration (<3 protrusions or <3 mm depth)
─ Mitotic activity is typically low (<10/10 HPF)
─ No significant atypia; foam cells common
Ancillary studies ─ ─ IHC (+) CD10, ER, PR, Cyclin D1 (variable), Vimentin
─ IHC (-) Desmin, Caldesmon, HMB45
DDx ─ Low-Grade Endometrial Stromal Sarcoma (infiltrative borders)
─ Cellular Leiomyoma (Desmin+, CD10-)
─ Undifferentiated Uterine Sarcoma (higher grade, lacks CD10/ER/PR)
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Low-Grade Endometrial Stromal Sarcoma (LG-ESS)

An infiltrative, low-grade malignant neoplasm resembling proliferative endometrial stroma, often characterized by JAZF1 fusions
Clinical ─ Uncommon; median age 45-55; presents with AUB, pain, or mass; indolent course but prone to late recurrences and metastasis; often estrogen/progesterone sensitive
Macro ─ Often poorly circumscribed, fleshy, tan-yellow mass; frequently shows prominent 'worm-like' plugs of tumor within myometrial vessels (lymphovascular invasion)
Micro ─ Monotonous population of small oval cells resembling ESN/proliferative stroma
─ Key Feature: Irregular, 'tongue-like' infiltration into the myometrium and prominent lymphovascular space invasion
─ Prominent network of small arterioles
─ Mitotic activity is usually low (<10/10 HPF)
─ Myxoid, fibrous, or sex cord-like differentiation can occur
Ancillary studies ─ ─ IHC (+) CD10, ER, PR, Cyclin D1 (usually strong/diffuse), Vimentin
─ IHC (-) Desmin, Caldesmon, HMB45
─ Molecular ─ JAZF1-SUZ12 (~50%), JAZF1-PHF1, EPC1-PHF1 fusions common
DDx ─ Endometrial Stromal Nodule (non-infiltrative)
─ High-Grade ESS (different morphology/IHC/molecular)
─ Uterine PEComa (HMB45+, SMA+)
─ Undifferentiated Uterine Sarcoma (lacks CD10/ER/PR)
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High-Grade Endometrial Stromal Sarcoma, YWHAE fusion (HG-ESS, YWHAE)

An aggressive uterine sarcoma characterized by a YWHAE-NUTM2 (or rarely YWHAE-FAM22) gene fusion and often a biphasic morphology
Clinical ─ Rare, aggressive; affects a slightly younger age group than LG-ESS; poor prognosis
Macro ─ Large, fleshy mass with necrosis and hemorrhage
Micro ─ Often shows a distinctive biphasic pattern:
─ Small Cell Component: Uniform, small round blue cells with high N/C ratio, scant cytoplasm
─ Spindle Cell Component: Larger, fascicular spindle cells resembling fibrosarcoma
─ Can be predominantly small cell or spindle cell
─ High mitotic activity and necrosis common
Ancillary studies ─ ─ IHC (+) Cyclin D1 (strong and diffuse - key feature)
─ IHC (-) ER, PR, CD10 (usually)
─ IHC (+/-) BCOR (variable)
─ Molecular ─ YWHAE-NUTM2 or YWHAE-FAM22 fusion confirmed by FISH or RT-PCR
DDx ─ HG-ESS, BCOR (BCOR+, Cyclin D1 patchy)
─ LG-ESS (CD10+, ER/PR+, lacks small cell component)
─ Undifferentiated Uterine Sarcoma (diagnosis of exclusion)
─ Carcinosarcoma (CK+, PAX8+)
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High-Grade Endometrial Stromal Sarcoma, BCOR alt (HG-ESS, BCOR)

An aggressive uterine sarcoma defined by BCOR gene alterations, most commonly internal tandem duplications (ITD)
Clinical ─ Rare, aggressive; affects a wide age range; poor prognosis
Macro ─ Large, fleshy mass with necrosis and hemorrhage
Micro ─ Typically composed of monomorphic spindle cells arranged in fascicles or sheets, resembling fibrosarcoma or monophasic synovial sarcoma
─ Can have a prominent myxoid stroma
─ Nuclei are oval to spindle-shaped, with moderate atypia
─ High mitotic activity
─ Lacks the small round cell component of YWHAE-rearranged HG-ESS
Ancillary studies ─ ─ IHC (+) BCOR (strong, diffuse nuclear staining - key feature)
─ IHC (+/-) CD10 (often positive), Cyclin D1 (often patchy/focal, not diffuse like YWHAE type)
─ IHC (-) ER, PR
─ Molecular ─ BCOR ITD or ZC3H7B-BCOR fusion
DDx ─ HG-ESS, YWHAE (biphasic, diffuse Cyclin D1+)
─ LG-ESS (lower grade, CD10/ER/PR+, lacks strong BCOR)
─ Leiomyosarcoma (Desmin+, BCOR-)
─ Undifferentiated Uterine Sarcoma
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Undifferentiated Uterine Sarcoma

A high-grade malignant mesenchymal neoplasm lacking any specific line of differentiation (smooth muscle, endometrial stromal, etc), representing a diagnosis of exclusion
Clinical ─ Rare; typically affects postmenopausal women; highly aggressive with poor prognosis
Macro ─ Large, fleshy mass, often with extensive necrosis and hemorrhage
Micro ─ Lacks recognizable differentiation; can be monomorphic or highly pleomorphic
─ Often composed of sheets of round, spindle, or epithelioid cells
─ Marked nuclear atypia, high mitotic activity, and tumor cell necrosis are characteristic
─ Must exclude poorly differentiated LMS, high-grade ESS, carcinosarcoma, and poorly differentiated carcinoma through extensive sampling and IHC
Ancillary studies ─ ─ IHC (+) Vimentin
─ IHC (-) Desmin, Caldesmon, CD10, ER, PR, Cytokeratins, S100, HMB45 (by definition)
─ IHC (+/-) MDM2 amplification can occur
DDx ─ Leiomyosarcoma (Desmin+)
─ High-Grade ESS (BCOR+ or Cyclin D1+)
─ Carcinosarcoma / Dedifferentiated Carcinoma (CK+, PAX8+)
─ PEComa (HMB45+)
─ Melanoma (S100+, SOX10+)
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Other Uterine Mesenchymal & Mixed Tumors

Uterine Tumor Resembling Ovarian Sex Cord Tumor (UTROSCT)

A rare uterine neoplasm with a mixed epithelial and sex cord-like stromal appearance, typically behaving in a benign or low-grade malignant fashion
Clinical ─ Wide age range, often perimenopausal; usually presents with AUB or as a mass; most are benign, but recurrences/metastases can occur
Macro ─ Well-circumscribed, solid, tan-yellow mass, often intramural or polypoid
Micro ─ Biphasic appearance:
─ Epithelial Component: Benign-appearing endometrial-type glands or clefts
─ Sex Cord-Like Component: Cords, nests, tubules, or diffuse sheets of cells resembling granulosa, Sertoli, or indifferent sex cord cells
─ Stroma is often fibrous or hyalinized
Ancillary studies ─ ─ IHC (+) SCST markers (Inhibin, Calretinin, SF-1, CD99 - often patchy)
─ IHC (+) Epithelial markers (CK7, EMA - in glands)
─ IHC (+/-) ER, PR, CD10
DDx ─ Endometrial Stromal Sarcoma with sex cord-like features (prominent ESS pattern, CD10+)
─ Adenosarcoma (malignant stroma, periglandular cuffing)
─ Adenomyoma (benign SM stroma)
─ Epithelioid Smooth Muscle Tumors
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SMARCA4-Deficient Uterine Sarcoma

A recently described, aggressive, high-grade uterine sarcoma characterized by loss of SMARCA4 (BRG1) expression, often with rhabdoid features
Clinical ─ Rare; affects a wide age range; highly aggressive with poor prognosis
Macro ─ Large, fleshy mass with necrosis
Micro ─ Often shows undifferentiated or rhabdoid morphology
─ Sheets of large, discohesive cells with eccentric nuclei, prominent nucleoli, and eosinophilic cytoplasm (rhabdoid)
─ Can also have sheets of small round blue cells or pleomorphic cells
─ High mitotic rate and necrosis
Ancillary studies ─ ─ IHC (-) SMARCA4 (BRG1) - complete loss is defining feature
─ IHC (+/-) Cytokeratins (can be +), SALL4 (can be +), CD34
─ IHC (-) SMARCB1 (INI1) (usually intact), ER, PR, Desmin, CD10
DDx ─ Small Cell Carcinoma, Hypercalcemic Type (SCCOHT) (also SMARCA4 loss, but often WT1+, SALL4+; primarily ovarian)
─ Rhabdoid Tumors (check other SWI/SNF components)
─ Undifferentiated Carcinoma / Sarcoma (SMARCA4 intact)
─ Epithelioid Sarcoma (SMARCB1 loss)
─ PEComa (HMB45+)
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Atypical Polypoid Adenomyoma (APA)

A polypoid uterine lesion characterized by atypical endometrioid glands mixed with a prominent smooth muscle stromal component
Clinical ─ Typically occurs in premenopausal women; presents with AUB or infertility; considered benign but has potential for recurrence and association/progression to endometrioid carcinoma
Macro ─ Polypoid, exophytic mass, usually in the lower uterine segment or cervix
Micro ─ Irregularly shaped, crowded endometrioid glands showing architectural complexity
─ Glands often show squamous metaplasia (morules)
─ Glandular epithelium shows cytologic atypia (can range from mild to significant)
─ Glands are set within a prominent stroma composed of interlacing fascicles of smooth muscle (myofibromatous stroma)
─ Lacks features of frank carcinoma (eg, confluent growth, significant invasion)
Ancillary studies ─ ─ IHC (+) Glands (CK7, PAX8, ER/PR); Stroma (Desmin, SMA)
DDx ─ Endometrial Polyp (fibrous stroma, no atypia)
─ Adenomyoma (benign glands)
─ Endometrioid Carcinoma (invasive growth)
─ Adenosarcoma (malignant stroma, periglandular cuffing)
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Müllerian Adenosarcoma (Uterus)

A biphasic uterine neoplasm characterized by benign epithelial glands and a malignant (usually low-grade) mesenchymal stromal component
Clinical ─ Most common in perimenopausal/postmenopausal women; usually presents with AUB or as a polypoid mass protruding through cervix; generally low-grade, but can recur, especially with stromal overgrowth
Macro ─ Large, polypoid, bulky mass, often with cystic changes; 'leaf-like' fronds similar to phyllodes tumor of breast
Micro ─ Biphasic pattern:
─ Epithelial Component: Benign glands, often cystically dilated, lined by various Mullerian types (endometrioid, ciliated, mucinous, inactive)
─ Stromal Component: Malignant mesenchymal proliferation, typically low-grade (resembling LG-ESS); key feature is periglandular stromal cuffing (condensation of stromal cells around glands)
─ Mitotic activity usually present in stroma, but low (<10/10 HPF) unless high-grade
─ Stromal Overgrowth: Defined as pure sarcoma comprising >25% of the tumor; signifies higher risk of recurrence/metastasis
Ancillary studies ─ ─ IHC (Stroma) (+) CD10, ER, PR, Vimentin; WT1 (variable)
─ IHC (Epithelium) (+) Cytokeratins, PAX8
DDx ─ Adenofibroma (benign stroma)
─ Atypical Polypoid Adenomyoma (SM stroma)
─ Endometrial Polyp (fibrous stroma)
─ Carcinosarcoma (malignant glands and stroma)
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Adenomatoid Tumor (Uterus)

A benign tumor of mesothelial origin, typically found within the myometrium or on the uterine serosa
Clinical ─ Common incidental finding in hysterectomy specimens; usually small and asymptomatic; benign behavior
Macro ─ Small (<3 cm), solid, firm, well-circumscribed, gray-white nodule; often subserosal or intramural
Micro ─ Complex network of anastomosing, small, slit-like or rounded channels, tubules, and cysts
─ Lined by flattened to cuboidal mesothelial cells; cytoplasm can be eosinophilic or vacuolated ('signet ring-like', but mucin negative)
─ Set in a fibrous or fibromuscular stroma, often with prominent smooth muscle bundles
─ Bland cytology, low/absent mitoses
Ancillary studies ─ ─ IHC (+) Calretinin, WT1 (nuclear), D2-40, CK7, EMA
─ IHC (-) PAX8, Ber-EP4, MOC31, CD10, Desmin (except in stroma)
DDx ─ Adenomyosis (endometrial glands/stroma)
─ Leiomyoma with cystic change (Desmin+)
─ Angioma / Lymphangioma (vascular markers, Calretinin-)
─ Metastatic Carcinoma (malignant features, adenocarcinoma markers)
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Central Primitive NET / CNS Embryonal Tumor (Uterus)

An extremely rare, highly aggressive uterine neoplasm resembling primary central nervous system (CNS) embryonal tumors
Clinical ─ Extremely rare; usually affects young women; very poor prognosis
Macro ─ Large, fleshy mass with necrosis
Micro ─ Composed of undifferentiated small round blue cells
─ Cells have scant cytoplasm, hyperchromatic nuclei, and high N/C ratio
─ Often shows features of neuroectodermal differentiation, such as Homer Wright rosettes or neuropil
─ High mitotic rate and extensive apoptosis/necrosis are common
Ancillary studies ─ ─ IHC (+) Neuroectodermal markers (Synaptophysin, Chromogranin A, CD56, Nestin, GFAP - variable)
─ Molecular: May show CNS-type alterations (DICER1 in some PNET-like tumors, CIC, etc) but distinct from Ewing/other SRBCTs
DDx ─ Ewing Sarcoma (CD99+, NKX2_2+, EWSR1 rearranged)
─ High-Grade ESS (BCOR+ or Cyclin D1+)
─ Undifferentiated Uterine Sarcoma
─ Small Cell Carcinoma (Pulmonary type - NE markers+ but older; Hypercalcemic - SMARCA4 loss)
─ Lymphoma (LCA+)
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Cervix

Squamous Metaplasia (Cervix)

A benign process where the native endocervical columnar (glandular) epithelium is replaced by stratified squamous epithelium
Clinical ─ Physiologic process, most active during puberty and first pregnancy; defines the Transformation Zone (TZ), the area most susceptible to HPV infection and subsequent neoplasia; benign itself
Macro ─ Transformation zone appears as a variably sized area between the original and new squamocolumnar junction (SCJ)
Micro ─ Immature Squamous Metaplasia: Proliferation of subcolumnar reserve cells forming multiple layers of small, uniform squamous cells with scant cytoplasm; lacks maturation/stratification; can mimic HSIL but lacks atypia/high Ki67
─ Mature Squamous Metaplasia: Fully developed stratified squamous epithelium resembling native ectocervical lining, often non-keratinizing; may cover/occlude endocervical gland openings (Nabothian cysts)
─ Glycogenation increases with maturity
Ancillary studies ─ ─ IHC (-) p16 (usually negative or patchy, unlike HSIL's block positivity); Ki67 (low, basal/parabasal only, unlike HSIL's full thickness)
DDx ─ High-Grade Squamous Intraepithelial Lesion (HSIL) (nuclear atypia, high N/C ratio, high mitoses, p16 block+, high Ki67)
─ Low-Grade Squamous Intraepithelial Lesion (LSIL) (koilocytosis, mild atypia)
─ Atrophy (thin epithelium, lacks maturation)
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Atrophy (Cervix)

Physiologic thinning of the cervical epithelium (both squamous and glandular) due to decreased estrogen levels, primarily in postmenopausal women
Clinical ─ Postmenopausal state; can lead to atrophic vaginitis/cervicitis symptoms; can cause cytologic changes mimicking HSIL on Pap tests
Macro ─ Cervix may appear pale, thin, and fragile; SCJ often recedes into the canal
Micro ─ Squamous Epithelium: Thinned, lacks maturation and glycogenation; composed mainly of basal/parabasal cells with scant cytoplasm and relatively high N/C ratio; can show reactive atypia but lacks high-grade features
─ Glandular Epithelium: Endocervical glands become smaller, less numerous, with scant mucin production; lining cells are low cuboidal/flattened
─ Stroma often appears more prominent and dense
Ancillary studies ─ IHC p16 (negative or patchy), Ki67 (low, basal only) - helps distinguish from HSIL
DDx ─ High-Grade Squamous Intraepithelial Lesion (HSIL) (true high N/C ratio, hyperchromasia, mitoses, p16 block+, high Ki67)
─ Immature Squamous Metaplasia (more cellular, lacks significant thinning)
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Transitional Metaplasia (Cervix)

A benign replacement of normal cervical (squamous or glandular) epithelium by multiple layers of cells resembling urothelium
Clinical ─ Usually an incidental finding; benign; can mimic HSIL cytologically and histologically
Macro ─ Usually no specific gross findings
Micro ─ Multilayered epithelium resembling urothelium (transitional cells)
─ Cells have oval 'coffee-bean' nuclei with longitudinal grooves
─ Surface may show 'umbrella-like' cells
─ Can involve ectocervix, transformation zone, or endocervical glands
─ Lacks significant atypia, high N/C ratio, hyperchromasia, and mitoses seen in HSIL
Ancillary studies ─ IHC (+) GATA3, p63, CK7
─ IHC (-) p16 (or patchy)
DDx ─ High-Grade Squamous Intraepithelial Lesion (HSIL) (p16 block+, lacks GATA3, lacks coffee-bean nuclei)
─ Squamous Metaplasia
─ Atrophy (thinned, lacks transitional features)
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Squamous Lesions

Squamous Intraepithelial Lesions (LSIL & HSIL)

A spectrum of HPV-induced pre-neoplastic changes in the cervical squamous epithelium, classified by the 2-tiered LAST terminology
Clinical ─ Caused by Human Papillomavirus (HPV); LSIL often represents transient infection, HSIL is a true precursor to SCC; detected by Pap test/HPV testing, confirmed by biopsy
Macro ─ Often invisible, may cause subtle whitening (acetowhitening) on colposcopy
Micro ─ Low-Grade Squamous Intraepithelial Lesion (LSIL):
─ Proliferation of basal/parabasal cells confined to the lower one-third
─ Koilocytosis in upper layers (perinuclear halo, wrinkled 'raisinoid' nucleus, binucleation)
─ Mild nuclear atypia (enlargement, hyperchromasia)
─ p16 is usually negative or patchy; Ki67 only in lower third
─ High-Grade Squamous Intraepithelial Lesion (HSIL):
─ Atypia (high N/C ratio, hyperchromasia, irregular contours) involving > lower one-third (HSIL/CIN2 = lower 2/3; HSIL/CIN3 = full thickness)
─ Increased mitotic activity, often suprabasal; atypical mitoses possible
─ Loss of maturation, disordered polarity
─ p16 block positivity (>70% strong/diffuse nuclear+cytoplasmic) strongly supports HSIL
─ Ki67 shows high index extending into upper layers
Ancillary studies ─ IHC p16 and Ki67 (especially useful for differentiating HSIL/CIN2 from mimics)
DDx ─ Immature Squamous Metaplasia / Atrophy / Transitional Metaplasia (vs HSIL)
─ Reactive changes (vs LSIL/HSIL)
─ Squamous Cell Carcinoma (invasion)
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Squamous Cell Carcinoma, HPV-Associated (Cervix)

An invasive malignancy of squamous cells driven by persistent high-risk HPV infection, the most common type of cervical cancer
Clinical ─ Arises from HSIL; major risk factor is high-risk HPV (16, 18, 31, 33, etc); presents with abnormal bleeding, discharge, or mass; screening (Pap/HPV) has reduced incidence
Macro ─ Can be exophytic, endophytic, or ulcerative; often firm and indurated
Micro ─ Invasive nests, sheets, or single cells of malignant squamous epithelium penetrating the basement membrane into the cervical stroma
─ Tumor cells show varying degrees of squamous differentiation (keratin pearls, intercellular bridges) and atypia (pleomorphism, high N/C, hyperchromasia)
─ Types:
─ Keratinizing SCC: Prominent keratin pearls and individual cell keratinization
─ Non-Keratinizing SCC: Less keratin, cells grow in nests with distinct borders
─ Papillary, Verrucous, Warty variants exist
─ Stroma often shows desmoplastic response or inflammation
─ Lymphovascular invasion is common
Ancillary studies ─ IHC (+) p16 (diffuse block positivity - indicates HPV E7 activity)
─ IHC (+) Cytokeratins (eg, AE1/AE3, CK5/6), p63
DDx ─ High-Grade Squamous Intraepithelial Lesion (HSIL) (lacks invasion)
─ HPV-Independent SCC (p16 negative/patchy)
─ Adenocarcinoma / Adenosquamous Carcinoma (glandular component, mucin+)
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Squamous Cell Carcinoma, HPV-Independent (Cervix)

A rare subtype of cervical squamous cell carcinoma not associated with HPV infection
Clinical ─ Accounts for ~5-10% of cervical SCCs; tends to occur in older women; may have a worse prognosis than HPV+ SCC; not linked to HSIL
Macro ─ Similar to HPV+ SCC, can be exophytic or endophytic
Micro ─ Invasive squamous cell carcinoma, often well-differentiated and keratinizing
─ Lacks the features of HPV-associated neoplasia ─ Does not arise from typical HSIL (may arise from dVIN-like lesions or de novo)
Ancillary studies ─ IHC (-) p16 (Negative or patchy/weak staining - key feature)
─ IHC (+/-) TP53 mutations are common (aberrant p53 expression)
─ HPV testing (ISH or PCR) is negative
DDx ─ HPV-Associated SCC (p16 block positive)
─ Metastatic SCC from other sites
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Benign Glandular Lesions

Endocervical Polyps

Common, benign, localized overgrowths of endocervical glands and stroma, projecting from the endocervical canal
Clinical ─ Very common; can be asymptomatic or cause intermenstrual bleeding, postcoital spotting, or discharge; usually benign, rarely harbor malignancy
Macro ─ Smooth, soft, reddish-pink, sessile or pedunculated mass; usually <3 cm; may protrude from os
Micro ─ Polypoid structure covered by endocervical epithelium
─ Core composed of fibrous or edematous stroma, often with chronic inflammation and dilated blood vessels
─ Contains benign endocervical glands, often cystically dilated and filled with mucin
─ Can show metaplasia (squamous, tubal) or reactive changes
─ Atypical changes or carcinoma are rare but must be excluded
Ancillary studies ─ Usually none required
DDx ─ Polypoid Adenocarcinoma (malignant glands)
─ Adenosarcoma / Carcinosarcoma (malignant stroma +/- glands)
─ Prolapsed Endometrial Polyp (endometrial glands/stroma)
─ Microglandular Hyperplasia (can be polypoid, but different glandular pattern)
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Nabothian Cyst

A common, benign retention cyst formed when squamous metaplasia occludes the opening of an endocervical gland, causing mucin accumulation
Clinical ─ Very common, especially in adult women; asymptomatic and clinically insignificant; detected on pelvic exam or imaging
Macro ─ Small (mm to cm), smooth, translucent or yellowish cysts on the ectocervix or within the transformation zone
Micro ─ Cystically dilated endocervical gland located within the cervical stroma
─ Lined by a single layer of bland, flattened to low cuboidal endocervical epithelium
─ Lumen is filled with pale, inspissated mucin
─ Often seen beneath areas of mature squamous metaplasia
Ancillary studies ─ Usually none required
DDx ─ Adenoma Malignum (Minimal Deviation Adenocarcinoma) (infiltrative, atypical glands, desmoplasia)
─ Tunnel Clusters (multiple small glands, can be deep)
─ Mesonephric Cysts (deep, often GATA3+)
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Tunnel Clusters

A benign proliferation of small, closely packed endocervical glands located relatively deep within the cervical stroma, often seen in multiparous women
Clinical ─ Incidental finding; benign; important to distinguish from adenoma malignum
Macro ─ Usually microscopic; can cause slight induration or small cystic areas
Micro ─ Well-circumscribed, lobulated clusters of small to medium-sized endocervical glands
─ Located deeper in the stroma than typical endocervical glands
─ Glands are lined by bland, mucin-producing columnar cells
─ Type A (Non-cystic): Small, closely packed glands
─ Type B (Cystic): Glands show cystic dilation
─ Crucially, lacks significant cytologic atypia, infiltrative growth pattern, or desmoplastic stromal reaction (unlike Adenoma Malignum)
Ancillary studies ─ Usually none required; IHC can show normal p53, low Ki67 if needed
DDx ─ Adenoma Malignum (Minimal Deviation Adenocarcinoma) (infiltrative, variable gland shape, desmoplasia, cytologic atypia - often subtle)
─ Nabothian Cysts (larger, single/few cysts)
─ Microglandular Hyperplasia (different pattern, often neutrophils)
─ Mesonephric Hyperplasia (different location/morphology/IHC)
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Microglandular Hyperplasia (MGH)

A benign proliferation of small, tightly packed endocervical glands, often associated with progestin exposure (OCPs, pregnancy)
Clinical ─ Common; usually asymptomatic or may present as polyp/abnormal bleeding; associated with oral contraceptives and pregnancy
Macro ─ Can be polypoid, granular, or macroscopically unremarkable
Micro ─ Densely packed, small, round glands with scant intervening stroma
─ Glands lined by cuboidal to low columnar cells, often with clear or eosinophilic cytoplasm
─ Subnuclear vacuoles are common
─ Hobnail cells can be present
─ Luminal neutrophils are a frequent finding
─ Lacks significant cytologic atypia or high mitotic activity
Ancillary studies ─ IHC (-) p16, CEA (usually); ER/PR often negative
DDx ─ Clear Cell Carcinoma (invasive, malignant atypia, Napsin A+)
─ Endometrioid Carcinoma (atypia, invasion)
─ Arias-Stella Reaction (marked atypia, lacks neutrophils, pregnancy-related)
─ Mesonephric Hyperplasia (deep, different morphology, GATA3+)
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Lobular Endocervical Glandular Hyperplasia (LEGH)

A benign proliferation of endocervical glands arranged in a distinct lobular pattern, often showing gastric-type differentiation and considered a potential precursor to gastric-type adenocarcinoma
Clinical ─ Often incidental; can cause discharge or bleeding; may be associated with Peutz-Jeghers syndrome
Macro ─ May cause cervical enlargement or be invisible; can be cystic
Micro ─ Well-circumscribed, lobular proliferation of endocervical glands centered around a larger, often dilated central duct
─ Glands are lined by tall columnar cells with abundant, pale, 'foamy' or clear cytoplasm, resembling gastric foveolar or pyloric glands
─ Nuclei are typically small, round, and basally located; minimal atypia
Ancillary studies ─ IHC (+) HIK1083 (gastric mucin), MUC6
─ IHC (-) p16, CEA (usually)
DDx ─ Adenoma Malignum / Gastric-Type Adenocarcinoma (invasive, desmoplasia, atypia)
─ Tunnel Clusters (not lobular, lacks gastric features)
─ Endocervical Adenocarcinoma, Usual Type (HPV+, p16+, lacks gastric features)
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Mesonephric Remnants and Mesonephric Hyperplasia (Cervix)

Benign remnants of the mesonephric (Wolffian) duct system, typically found deep within the lateral cervical walls, which can undergo hyperplasia
Clinical ─ Common incidental finding; benign; can rarely give rise to mesonephric adenocarcinoma
Macro ─ Usually microscopic; hyperplasia may cause induration or small cysts
Micro ─ Remnants: Small, scattered tubules or lobules deep in the lateral stroma
─ Hyperplasia: Increased number and size of lobules, can show various patterns (tubular, ductal, retiform)
─ Glands are small, round, lined by bland, low cuboidal to flattened cells
─ Characteristic feature: Dense, eosinophilic, PAS-positive luminal secretions
─ No significant atypia or mitoses
Ancillary studies ─ IHC (+) GATA3, CD10, PAX8, Calretinin (variable)
─ IHC (-) ER, PR, p16, CEA
DDx ─ Microglandular Hyperplasia (superficial, neutrophils)
─ Tunnel Clusters (endocervical mucin, GATA3-)
─ Mesonephric Adenocarcinoma (infiltration, atypia, mitoses)
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Arias-Stella Reaction (Cervix)

Benign, non-neoplastic changes in endocervical glandular epithelium due to high progesterone levels, identical to the reaction seen in the endometrium
Clinical ─ Associated with pregnancy (intrauterine/ectopic), gestational trophoblastic disease, or progestin therapy; important not to misdiagnose as carcinoma
Macro ─ Usually no specific gross findings
Micro ─ Endocervical glands show enlarged cells with:
─ Marked nuclear atypia (enlargement, hyperchromasia, irregular contours)
─ Abundant clear or eosinophilic cytoplasm
─ Hobnail cells projecting into lumens
─ Lack of mitotic activity is key
Ancillary studies ─ Usually none required; IHC (-) Ki67 (low index)
DDx ─ Clear Cell Carcinoma (invasive, high Ki67, Napsin A+)
─ Adenocarcinoma in situ / Invasive Adenocarcinoma (mitoses, higher Ki67)
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Tuboendometrioid Metaplasia (Cervix)

A benign condition where endocervical glands are replaced by epithelium resembling fallopian tube (ciliated cells) or endometrium
Clinical ─ Common incidental finding; benign; often associated with inflammation or prior procedures
Macro ─ No specific gross findings
Micro ─ Endocervical glands lined partly or wholly by:
─ Tubal Type: Ciliated cells, non-ciliated secretory (peg) cells, and intercalated cells
─ Endometrioid Type: Non-ciliated columnar cells resembling inactive or proliferative endometrium (must lack endometrial stroma)
─ No significant atypia
Ancillary studies ─ IHC (+) PAX8, ER, PR; Tubal type may show WT1
DDx ─ Adenocarcinoma in situ (atypia, mitoses, p16+)
─ Endometriosis (requires endometrial stroma)
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Glandular Neoplasia

Adenocarcinoma, Usual Type (HPV-Associated, Cervix)

The most common type of endocervical adenocarcinoma, driven by high-risk HPV, and often arising from Adenocarcinoma in situ (AIS)
Clinical ─ Associated with HPV 16 & 18; presents with bleeding/discharge; prognosis depends on stage and Silva pattern
Macro ─ Can be exophytic, endophytic, or ulcerative; may form 'barrel cervix'
Micro ─ Invasive glands, often with complex, branching, or cribriform patterns
─ Lined by columnar cells with elongated, hyperchromatic, stratified nuclei
─ Prominent mitotic activity and apoptosis ('apoptotic bodies') are characteristic
─ Silva Pattern (Invasion Pattern Based)

Prognostic:
─ Pattern A: Well-demarcated glands, no LVI, minimal invasion (<5mm) - Excellent prognosis
─ Pattern B: Focal destructive invasion admixed with A - Low recurrence risk
─ Pattern C: Diffuse destructive stromal invasion - Higher risk
Ancillary studies ─ IHC (+) p16 (diffuse block positivity), CEA, PAX8, ER/PR (variable)
─ HPV ISH/PCR (+) High-risk HPV
DDx ─ Adenocarcinoma in situ (AIS) (lacks invasion)
─ Gastric-Type Adenocarcinoma (HPV-, p16-, gastric mucin+)
─ Endometrioid Carcinoma (usually uterine primary, WT1-)
─ Clear Cell / Mesonephric Carcinoma (specific features/IHC)
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Adenocarcinoma in situ (AIS, Cervix)

A precursor lesion to HPV-associated endocervical adenocarcinoma, characterized by replacement of normal endocervical glands by atypical columnar epithelium without invasion
Clinical ─ Asymptomatic, detected by Pap test or colpo; associated with high-risk HPV (18 > 16); risk of concurrent/subsequent invasive cancer
Macro ─ Usually invisible
Micro ─ Partial or complete replacement of native endocervical glandular epithelium (surface and/or glands) by atypical cells
─ Atypical cells show enlarged, hyperchromatic, elongated nuclei, often stratified ('picket fence')
─ Increased mitotic activity (often suprabasal) and apoptosis are common
─ Glandular architecture can be complex but no stromal invasion (preserved basement membrane)
─ Often coexists with HSIL
Ancillary studies ─ IHC (+) p16 (strong, diffuse block positivity), Ki67 (high index, full thickness), BCL2
─ IHC (-) CEA (usually negative or focal, unlike invasive)
DDx ─ Invasive Adenocarcinoma, Usual Type (stromal invasion)
─ Tuboendometrioid Metaplasia / Reactive Atypia (lacks significant atypia, p16-, low Ki67)
─ Arias-Stella Reaction (pregnancy-related, lacks mitoses)
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Gastric-Type Adenocarcinoma (GAC, Cervix)

An aggressive, HPV-independent subtype of cervical adenocarcinoma characterized by cells with abundant clear or pale eosinophilic cytoplasm resembling gastric epithelium
Clinical ─ HPV-negative; often affects older women; poor prognosis, often resistant to standard chemo/radiation; can arise from LEGH/Adenoma Malignum
Macro ─ Often large, 'barrel-shaped' cervix; mucoid cut surface
Micro ─ Glands or single cells infiltrating stroma, often with marked desmoplastic reaction ─ Tumor cells have abundant, pale eosinophilic, foamy, or clear cytoplasm
─ Nuclei are typically pleomorphic with prominent nucleoli (high-grade atypia)
─ Can show various patterns (glandular, papillary, signet ring)
─ Often has intracytoplasmic mucin (PAS+/Alcian Blue+)
─ Adenoma Malignum (Minimal Deviation GAC) is a very well-differentiated variant
Ancillary studies ─ IHC (+) HIK1083 (gastric mucin), MUC6, CEA
─ IHC (-) p16 (negative or patchy/non-block), ER, PR
─ IHC (+/-) PAX8 (can be neg), GATA3
DDx ─ Adenocarcinoma, Usual Type (HPV+, p16 block+, lacks gastric mucin)
─ Clear Cell Carcinoma (Napsin A+, HNF1B+)
─ Lobular Endocervical Glandular Hyperplasia (LEGH) (lacks invasion/atypia)
─ Microglandular Hyperplasia (benign, neutrophils)
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Clear Cell Adenocarcinoma (Cervix)

A rare, HPV-independent adenocarcinoma of the cervix characterized by cells with clear or hobnail cytoplasm, historically associated with in utero DES exposure but also occurs sporadically
Clinical ─ Rare (<5% of cervical adenocarcinomas); can occur in young women (DES-related) or older women (sporadic); aggressive behavior
Macro ─ Polypoid or ulcerative mass
Micro ─ Architectural patterns: Tubulocystic (most common), papillary, solid
─ Characteristic cell types:
─ Clear cells (abundant clear cytoplasm due to glycogen)
─ Hobnail cells (protruding nuclei into lumen)
─ Eosinophilic or flattened cells
─ High-grade nuclear features
─ Hyalinized stroma may be present
Ancillary studies ─ IHC (+) Napsin A, HNF1B, PAX8, CK7
─ IHC (-) p16 (negative or patchy/non-block), ER, PR, WT1
DDx ─ Arias-Stella Reaction (pregnancy/progestin effect, lacks invasion/mitoses)
─ Microglandular Hyperplasia (benign, neutrophils, lacks atypia)
─ Serous Carcinoma (p53 aberrant, WT1 variable, different morphology)
─ Endometrioid Carcinoma with clear cell change
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Mesonephric Adenocarcinoma (Cervix)

A rare, HPV-independent adenocarcinoma arising from mesonephric (Wolffian) remnants in the cervical wall
Clinical ─ Rare; occurs over a wide age range; variable behavior, can be aggressive
Macro ─ Often deep-seated mass within cervical wall, may be polypoid
Micro ─ Diverse architectural patterns:
─ Small tubules / Glands (often closely packed)
─ Ductal or retiform patterns
─ Papillary or glomeruloid structures
─ Cells are typically cuboidal with scant cytoplasm; nuclei are usually low to intermediate grade
─ Characteristic dense, eosinophilic, PAS-positive luminal secretions
Ancillary studies ─ IHC (+) GATA3, CD10, PAX8, Calretinin (variable), TTF-1 (variable)
─ IHC (-) p16 (negative or patchy), ER, PR, CEA
DDx ─ Usual Type (HPV+) Endocervical Adenocarcinoma (p16 block+, lacks GATA3/CD10)
─ Mesonephric Hyperplasia (lacks invasion, atypia, mitoses)
─ Clear Cell Carcinoma (Napsin A+, HNF1B+)
─ Endometrioid Carcinoma
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Endometrioid Adenocarcinoma (Cervix)

A rare primary adenocarcinoma of the cervix with endometrioid morphology, usually HPV-independent
Clinical ─ Rare as primary cervical cancer (<5%); must exclude extension from uterine corpus or metastasis; prognosis similar to usual type adenocarcinoma of similar stage
Macro ─ Polypoid or infiltrative mass
Micro ─ Glandular architecture resembling uterine endometrioid carcinoma
─ Can show squamous differentiation (adenoacanthoma if benign squamous, adenosquamous if malignant squamous)
─ Grading similar to uterine endometrioid (FIGO grade 1-3)
Ancillary studies ─ IHC (+) PAX8, ER, PR, Vimentin (variable), CK7
─ IHC (-) p16 (usually negative or patchy), WT1, CEA (often)
─ Molecular: May show PTEN, ARID1A, KRAS mutations similar to uterine counterparts
DDx ─ Usual Type (HPV+) Endocervical Adenocarcinoma (p16 block+, ER/PR often weaker)
─ Endometrial Adenocarcinoma extending to cervix (most common scenario)
─ Clear Cell / Serous / Gastric Type Adenocarcinoma (specific features/IHC)
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Other Epithelial Tumors of Cervix

Carcinosarcoma (Cervix)

A rare, highly aggressive biphasic malignancy of the cervix containing both malignant epithelial (carcinoma) and malignant mesenchymal (sarcoma) components
Clinical ─ Very rare; typically affects postmenopausal women; poor prognosis, similar to uterine carcinosarcoma
Macro ─ Often large, polypoid, bulky mass with necrosis and hemorrhage
Micro ─ Intimate admixture of carcinomatous and sarcomatous elements
─ Carcinomatous component: Usually high-grade (squamous, adenocarcinoma, or undifferentiated)
─ Sarcomatous component: High-grade, undifferentiated, or may show heterologous differentiation (eg, rhabdomyosarcoma, chondrosarcoma)
Ancillary studies ─ IHC panel to highlight both:
─ Carcinoma: PAX8, Cytokeratins, EMA, p16 (if HPV-related carcinoma component)
─ Sarcoma: Vimentin; specific markers if differentiated (Desmin, Myogenin, S100)
DDx ─ Poorly Differentiated Carcinoma with spindle cells (sarcomatoid carcinoma)
─ Adenosarcoma (benign glands, low-grade stroma usually)
─ Pure Sarcoma (lacks epithelial malignancy)
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Adenosquamous Carcinoma (Cervix)

A malignant cervical tumor with intimately mixed, clearly recognizable invasive glandular (adenocarcinoma) and invasive squamous cell carcinoma components
Clinical ─ HPV-associated; behavior is generally considered more aggressive than pure SCC or usual type adenocarcinoma of similar stage
Macro ─ Exophytic or endophytic mass
Micro ─ Both malignant squamous and malignant glandular components are present and intermingled
─ Each component must be unequivocally malignant and invasive
─ Squamous component is usually non-keratinizing or keratinizing SCC
─ Glandular component is usually usual endocervical type adenocarcinoma
Ancillary studies ─ IHC (+) p16 (diffuse block positive in both components)
─ IHC (+) Squamous: p63, CK5/6
─ IHC (+) Glandular: CEA, PAX8, CK7
DDx ─ Squamous Cell Carcinoma with glandular involvement/extension
─ Adenocarcinoma with squamous metaplasia (metaplasia is benign)
─ Adenoid Basal Carcinoma (basaloid cells + benign glands)
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Adenoid Basal Carcinoma (Cervix)

A rare, low-grade malignant epithelial tumor of the cervix, characterized by nests of small basaloid cells often admixed with benign-appearing squamous or glandular elements
Clinical ─ Typically affects older women; often associated with HSIL or SCC; excellent prognosis, very low metastatic potential
Macro ─ Usually small, incidental finding; can be a superficial ulcer or plaque
Micro ─ Nests and cords of small, uniform basaloid cells with scant cytoplasm and dark nuclei
─ Peripheral palisading of nuclei in the nests is common
─ Minimal stroma between nests
─ Often admixed with or arises in conjunction with HSIL or invasive SCC
─ May contain small, benign-appearing squamous pearls or glandular lumens within the basaloid nests
─ Lacks high-grade atypia, significant mitoses, or desmoplastic stromal reaction typically seen in adenoid cystic or high-grade basaloid SCC
Ancillary studies ─ IHC (+) Basaloid cells: p63, CK5/6, SOX2, BCL2
─ IHC (+) Glandular areas (if present): CEA, CK7
─ IHC p16 (variable, can be positive)
DDx ─ Adenoid Cystic Carcinoma (more infiltrative, cribriform, perineural invasion, MYB+)
─ Basaloid Squamous Cell Carcinoma (more atypia, mitoses, infiltrative)
─ HSIL involving glands (lacks true basaloid nests)
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Vagina

Benign Squamous & Glandular Lesions

Squamous Papilloma (Vagina)

A benign exophytic lesion of the vagina composed of papillary fronds lined by mature stratified squamous epithelium
Clinical ─ Uncommon; can occur at any age; may be associated with HPV (condylomatous type) or be non-HPV related; benign
Macro ─ Small, warty, finger-like, or cauliflower-like projection from the vaginal mucosa
Micro ─ Papillary fronds with fibrovascular cores
─ Lined by mature, stratified squamous epithelium, often with koilocytotic changes if HPV-related
─ No significant atypia or disordered maturation (unlike VAIN or SCC)
Ancillary studies ─ IHC p16 (usually negative or patchy, unless HPV-driven koilocytosis is prominent then may be +)
DDx ─ Condyloma Acuminatum (HPV-driven, prominent koilocytosis)
─ Verrucous Carcinoma (invasive, bulbous rete ridges)
─ Squamous Cell Carcinoma, Papillary Type (malignant atypia, invasion)
─ Vaginal Intraepithelial Neoplasia (VAIN) (atypia, disordered maturation)
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Atrophy (Vagina)

Thinning of the vaginal squamous epithelium due to decreased estrogen levels, primarily in postmenopausal women
Clinical ─ Common in postmenopausal women or those with estrogen deficiency (eg, oophorectomy, lactation, anti-estrogen therapy); symptoms include dryness, itching, dyspareunia, spotting; increased susceptibility to infection/inflammation
Macro ─ Vaginal mucosa appears pale, thin, smooth, and sometimes friable or inflamed
Micro ─ Marked thinning of the stratified squamous epithelium
─ Loss of normal maturation sequence; epithelium composed mainly of basal and parabasal cells
─ Reduced or absent glycogen content in cells
─ Cells have scant cytoplasm and relatively high N/C ratio, which can mimic HSIL/VAIN cytologically
─ Underlying stroma may show inflammation (atrophic vaginitis)
Ancillary studies ─ IHC p16 (negative or patchy), Ki67 (low, basal only) - helps distinguish from VAIN
DDx ─ Vaginal Intraepithelial Neoplasia (VAIN) (true atypia, high N/C, hyperchromasia, abnormal mitoses, p16 variable but can be +, high Ki67)
─ Lichen Sclerosus (sclerosis, inflammation, distinct epithelial changes)
─ Inflammatory conditions
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Tubulosquamous Polyp (Vagina)

A benign polypoid lesion of the vagina characterized by squamous epithelium with underlying tubular or cleft-like glandular structures
Clinical ─ Uncommon; may present as a small vaginal polyp or be an incidental finding
Macro ─ Small, exophytic, polypoid lesion
Micro ─ Surface composed of bland, mature stratified squamous epithelium, often forming papillary fronds
─ Underlying stroma contains benign tubular or cleft-like glandular structures lined by cuboidal, columnar, or squamous epithelium
─ Lacks atypia, significant mitotic activity, or invasion
Ancillary studies ─ Usually none required
DDx ─ Squamous Papilloma (lacks prominent tubular/glandular component)
─ Verrucous Carcinoma / Squamous Cell Carcinoma (malignant features, invasion)
─ Vaginal Adenosis involving a papilloma
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Squamous Tumors & Precursors (Vagina)

Vaginal Intraepithelial Neoplasia (VAIN)

A pre-neoplastic lesion characterized by atypical squamous cells confined to the vaginal epithelium, analogous to CIN (cervical) and VIN (vulvar)
Clinical ─ Associated with HPV infection (especially high-risk types); risk factors include history of CIN/VIN, immunosuppression; often asymptomatic, detected by cytology/colposcopy
Macro ─ Often invisible; may appear as white, red, or pigmented plaques on colposcopy
Micro ─ Spectrum of atypia similar to cervical lesions:
─ Low-Grade VAIN (VAIN 1): Atypia confined to lower one-third of epithelium; koilocytotic changes common
─ High-Grade VAIN (VAIN 2 & 3): Atypia extends to middle third/upper third (VAIN 2) or full thickness (VAIN 3); increased N/C ratio, hyperchromasia, disordered maturation, mitotic activity (can be suprabasal)
─ p16 block positivity is characteristic of high-grade VAIN (HPV-driven)
Ancillary studies ─ IHC (+) p16 (block positive in high-grade VAIN), Ki67 (increased proliferation, suprabasal staining in high-grade)
DDx ─ Reactive Atypia / Atrophy (lacks true high-grade atypia, p16-, low Ki67)
─ Squamous Cell Carcinoma (invasion beyond basement membrane)
─ Immature Squamous Metaplasia / Transitional Metaplasia
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Squamous Cell Carcinoma, HPV-Associated (Vagina)

An invasive malignancy of vaginal squamous cells driven by persistent high-risk HPV infection, representing the most common type of primary vaginal cancer
Clinical ─ Most common vaginal cancer (~85-90%); often arises from high-grade VAIN; risk factors include HPV infection, history of cervical/vulvar cancer/precancer, immunosuppression; presents with abnormal bleeding, discharge, or mass
Macro ─ Exophytic, endophytic, or ulcerative lesion, most commonly in posterior wall of upper third
Micro ─ Invasive nests, sheets, or single cells of malignant squamous epithelium penetrating the basement membrane into the vaginal stroma
─ Varying degrees of squamous differentiation (keratinizing, non-keratinizing) and atypia
Ancillary studies ─ IHC (+) p16 (diffuse block positivity)
─ IHC (+) Cytokeratins (eg, AE1/AE3, CK5/6), p63
DDx ─ High-Grade VAIN (lacks invasion)
─ HPV-Independent Vaginal SCC (p16 negative/patchy)
─ Metastatic SCC (eg, from cervix, vulva, anus - clinical history crucial)
─ Adenocarcinoma with squamous features
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Squamous Cell Carcinoma, HPV-Independent (Vagina)

A rare subtype of vaginal squamous cell carcinoma not associated with HPV infection
Clinical ─ Accounts for a small percentage of vaginal SCCs; tends to occur in older women; may be associated with chronic inflammation or lichen sclerosus; prognosis can be poor
Macro ─ Similar to HPV+ SCC; ulcerative or infiltrative mass
Micro ─ Invasive squamous cell carcinoma, often well-differentiated and keratinizing
─ Lacks features of HPV-driven neoplasia; does not typically arise from usual VAIN
Ancillary studies ─ IHC (-) p16 (Negative or patchy/weak, non-block staining - key feature)
─ IHC (+/-) TP53 mutations common (aberrant p53 expression)
─ HPV testing (ISH or PCR) is negative
DDx ─ HPV-Associated SCC (p16 block positive)
─ Metastatic SCC from other sites (especially skin if p16-)
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Glandular Tumors (Vagina)

Villous Adenoma (Vagina)

A rare, benign glandular tumor of the vagina characterized by papillary fronds lined by mucinous (often intestinal-type) epithelium, resembling colorectal villous adenoma
Clinical ─ Very rare; typically affects older women; can present with discharge or bleeding; low risk of malignant transformation, but can recur or harbor adenocarcinoma
Macro ─ Polypoid, papillary, or velvety lesion in the vagina
Micro ─ Finger-like papillary fronds with fibrovascular cores
─ Lined by tall columnar mucinous epithelium, usually intestinal type (goblet cells) or gastric foveolar type
─ Epithelium may show varying degrees of dysplasia (low-grade or high-grade)
Ancillary studies ─ IHC (+) CK20, CDX2 (intestinal type); CK7 (variable); MUC2, MUC5AC
─ IHC (-) p16 (usually)
DDx ─ Mucinous Adenocarcinoma (invasive growth, high-grade atypia)
─ Vaginal Adenosis (glands, not typically villous or as complex)
─ Squamous Papilloma with mucinous metaplasia
─ Metastatic Villous Adenoma/Adenocarcinoma from colorectum (clinical history crucial)
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Mullerian Papilloma (Vagina)

A rare, benign papillary tumor of the vagina, typically occurring in infants and young children, composed of glands and papillae lined by Mullerian-type epithelium
Clinical ─ Rare; almost exclusively in female infants/children (<10 years); presents as a polypoid vaginal mass or bleeding; benign, but local recurrence possible
Macro ─ Small, reddish, polypoid, grape-like, or papillary mass
Micro ─ Complex, branching papillary fronds and glandular structures
─ Lined by a single layer of bland cuboidal, columnar, or hobnail cells (Mullerian type)
─ Stroma is often edematous and may contain inflammatory cells
─ No significant atypia or mitotic activity
Ancillary studies ─ IHC (+) PAX8, ER, PR (variable), CK7
DDx ─ Embryonal Rhabdomyosarcoma (Botryoid type) (cambium layer, rhabdomyoblasts, Myogenin/Desmin+) - CRITICAL DDX
─ Clear Cell Carcinoma (malignant, DES history, Napsin A+)
─ Villous Adenoma (mucinous epithelium, older patients)
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Vaginal Adenosis

A condition characterized by the presence of benign glandular (columnar) epithelium in the vagina, where normally stratified squamous epithelium is found
Clinical ─ Common; strongly associated with in utero Diethylstilbestrol (DES) exposure, but also occurs sporadically/congenitally; usually asymptomatic; DES-related adenosis is a risk factor for vaginal Clear Cell Carcinoma
Macro ─ May appear as red, granular patches or be invisible; Lugol's iodine non-staining areas
Micro ─ Presence of glandular epithelium (mucinous endocervical-type, tuboendometrioid-type, or endometrial-type) on the vaginal surface or within the superficial stroma (lamina propria)
─ Glands are lined by benign columnar cells
─ Squamous metaplasia is often seen replacing the glandular epithelium
Ancillary studies ─ IHC (+) PAX8, CK7; ER/PR (variable); Mucinous type: MUC5AC/MUC6
DDx ─ Endocervicosis (deeper glands in vaginal wall)
─ Clear Cell Carcinoma (malignant features, especially in DES context)
─ Arias-Stella Reaction (pregnancy/progestin effect, specific atypia)
─ Microglandular Hyperplasia (cervical origin, different pattern)
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Endocervicosis (Vagina)

A benign condition characterized by the presence of endocervical-type mucinous glands located deep within the vaginal wall, distinct from superficial adenosis
Clinical ─ Uncommon; can occur in women with history of endometriosis, surgery, or trauma; may present as a cystic mass or be an incidental finding; benign
Macro ─ May form a firm nodule or cystic lesion in the vaginal wall, often posterior/lateral
Micro ─ Clusters of well-formed, benign endocervical-type glands located deep in the vaginal fibromuscular wall
─ Glands are lined by tall columnar mucinous cells with basal nuclei, similar to normal endocervix
─ Minimal or no associated stroma (unlike endometriosis)
─ No significant atypia or mitotic activity
Ancillary studies ─ IHC (+) CK7, CEA (luminal), ER/PR (variable), PAX8
DDx ─ Vaginal Adenosis (superficial glands)
─ Mucinous Adenocarcinoma (invasive, atypia, desmoplasia)
─ Gartner Duct Cyst (mesonephric origin, GATA3+, CD10+)
─ Endometriosis (requires endometrial stroma)
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Cysts of the Vagina

Benign cystic structures occurring within the vaginal wall or mucosa, arising from various embryologic remnants or acquired processes
Clinical ─ Common; often asymptomatic and incidental; can present as a palpable nodule or mass; rarely symptomatic unless large or infected
Macro ─ Usually small, thin-walled, fluid-filled cysts; content can be clear, mucoid, or keratinaceous
Micro ─ Lining varies by type:
─ Gartner Duct Cyst: Most common; from mesonephric (Wolffian) duct remnants; anterolateral wall; lined by low cuboidal, non-mucinous, non-ciliated epithelium, may have eosinophilic luminal secretions
─ Epidermal Inclusion Cyst: From traumatic implantation of epidermis or squamous metaplasia of other cysts; lined by stratified squamous epithelium, filled with keratin debris
─ Müllerian Cyst: Lined by endocervical-type (mucinous), tubal-type (ciliated), or endometrial-type epithelium; can include endometriosis (if stroma present) or endocervicosis
─ Bartholin Duct Cyst (technically vulvovaginal): Obstruction of Bartholin gland duct; posterolateral introitus/lower vagina; lined by transitional or squamous epithelium proximally, mucinous acini distally
Ancillary studies ─ Gartner: IHC (+) PAX8, GATA3, CD10 (variable)
─ Müllerian: IHC (+) PAX8, ER/PR (variable), CK7
DDx ─ Adenocarcinoma (eg, Clear Cell, Mesonephric - if atypia/invasion)
─ Vaginal Adenosis / Endocervicosis (solid/glandular proliferation vs discrete cyst)
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Adenocarcinoma, HPV-Associated (Vagina)

A rare type of primary vaginal adenocarcinoma driven by high-risk HPV, histologically resembling HPV-associated endocervical adenocarcinoma
Clinical ─ Very rare; presumed to arise from vaginal adenosis or tuboendometrioid metaplasia infected with HPV; risk factors similar to HPV-related cervical/vaginal SCC
Macro ─ May present as an ulcerative, infiltrative, or exophytic mass
Micro ─ Invasive adenocarcinoma with features similar to usual type (HPV+) endocervical adenocarcinoma
─ Glandular, papillary, or cribriform architecture
─ Cells show columnar morphology, nuclear atypia, stratification, mitoses, and apoptosis
─ Silva-like invasion patterns may be described
Ancillary studies ─ IHC (+) p16 (diffuse block positivity), PAX8, CEA
─ HPV ISH/PCR (+) High-risk HPV
DDx ─ HPV-Independent Vaginal Adenocarcinomas (eg, Clear Cell, Gastric - p16 neg/patchy)
─ Metastatic HPV+ Adenocarcinoma from Cervix (most common consideration)
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Endometrioid Carcinoma (Vagina)

A rare primary adenocarcinoma of the vagina with endometrioid morphology, often arising from vaginal endometriosis
Clinical ─ Rare; typically affects older women; can arise from pre-existing vaginal endometriosis; prognosis depends on stage
Macro ─ Infiltrative or polypoid mass
Micro ─ Glandular architecture resembling uterine or ovarian endometrioid carcinoma
─ Can show squamous differentiation
─ Grading similar to uterine endometrioid (FIGO grade 1-3)
─ Must exclude metastasis from uterus or ovary
Ancillary studies ─ IHC (+) PAX8, ER, PR, CK7
─ IHC (-) WT1, p16 (usually patchy/negative)
DDx ─ Metastatic Endometrioid Carcinoma (clinical history crucial)
─ Vaginal Adenosis with atypia / Endometriosis with atypia (lacks invasion)
─ Clear Cell / Serous / Mucinous Adenocarcinoma of Vagina (specific features/IHC)
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Clear Cell Carcinoma (Vagina)

A rare, aggressive adenocarcinoma of the vagina characterized by cells with clear or hobnail cytoplasm, historically associated with in utero DES exposure
Clinical ─ Rare; classic association with Diethylstilbestrol (DES) exposure in utero (daughters of women who took DES), but also occurs sporadically in older women (non-DES related); aggressive, with risk of recurrence/metastasis
Macro ─ Polypoid, nodular, or ulcerative mass, often in upper third/anterior wall
Micro ─ Architectural patterns: Tubulocystic (most common), papillary, solid
─ Characteristic cell types: Clear (glycogen-rich), Hobnail, Eosinophilic, Flattened
─ High-grade nuclear features; hyalinized stroma common
─ Often arises from vaginal adenosis (especially DES-related)
Ancillary studies ─ IHC (+) Napsin A, HNF1B, PAX8, CK7, AMACR
─ IHC (-) p16 (usually patchy/negative), ER, PR, WT1
DDx ─ Arias-Stella Reaction (pregnancy/progestin, benign, lacks invasion)
─ Microglandular Hyperplasia (cervical origin, benign, neutrophils)
─ Metastatic Clear Cell Carcinoma (eg, ovary, kidney - clinical history)
─ Yolk Sac Tumor (AFP+, SALL4+, younger age)
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Mucinous Carcinoma, Gastric Type (Vagina)

An extremely rare, HPV-independent primary vaginal adenocarcinoma resembling gastric-type adenocarcinoma of the cervix or stomach
Clinical ─ Very rare; aggressive behavior; not associated with HPV
Macro ─ Ulcerative or infiltrative mass
Micro ─ Glands or single cells infiltrating stroma, often with marked desmoplasia
─ Tumor cells have abundant, pale eosinophilic, foamy, or clear cytoplasm, resembling gastric epithelium
─ Marked nuclear atypia is characteristic
─ May show intracytoplasmic mucin
Ancillary studies ─ IHC (+) HIK1083 (gastric mucin), MUC6, CEA
─ IHC (-) p16 (negative or patchy), ER, PR
─ IHC (+/-) PAX8 (can be negative)
DDx ─ Metastatic Gastric or Pancreaticobiliary Adenocarcinoma
─ Mucinous Carcinoma, Intestinal Type (Vagina) (CDX2+, CK20+)
─ Clear Cell Carcinoma (Napsin A+, HNF1B+)
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Mucinous Carcinoma, Intestinal Type (Vagina)

An extremely rare primary vaginal adenocarcinoma with features resembling colorectal or intestinal adenocarcinoma
Clinical ─ Very rare; may arise from vaginal endometriosis with intestinal metaplasia, villous adenoma, or cloacal remnants; variable prognosis
Macro ─ Polypoid or infiltrative mass
Micro ─ Glandular structures lined by tall columnar cells with goblet cells, resembling intestinal epithelium
─ May show 'dirty necrosis' within glandular lumens
─ Variable degrees of atypia and complexity
Ancillary studies ─ IHC (+) CK20, CDX2, MUC2
─ IHC (-) CK7 (often), PAX8 (often)
DDx ─ Metastatic Colorectal Adenocarcinoma (most important DDx; history, identical IHC)
─ Villous Adenoma with invasion
─ Mucinous Carcinoma, Gastric Type (Vagina) (CK20-, CDX2-, HIK1083+)
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Mesonephric Adenocarcinoma (Vagina)

An extremely rare adenocarcinoma arising from mesonephric (Gartner duct) remnants in the vaginal wall
Clinical ─ Extremely rare; occurs over a wide age range; variable behavior
Macro ─ Firm, infiltrative mass, often in anterolateral vaginal wall
Micro ─ Similar to cervical mesonephric adenocarcinoma; diverse patterns (tubular, ductal, papillary, retiform)
─ Small tubules lined by bland cuboidal cells; dense eosinophilic luminal secretions
Ancillary studies ─ IHC (+) GATA3, CD10, PAX8, Calretinin (variable)
─ IHC (-) ER, PR, p16
DDx ─ Gartner Duct Cyst with hyperplasia (lacks invasion/atypia)
─ Clear Cell Carcinoma (Napsin A+, HNF1B+)
─ Endometrioid Carcinoma
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Carcinosarcoma (Vagina)

An extremely rare, highly aggressive biphasic malignancy of the vagina containing both malignant epithelial (carcinoma) and malignant mesenchymal (sarcoma) components
Clinical ─ Very rare; typically affects older women; poor prognosis
Macro ─ Often large, polypoid, bulky mass with necrosis and hemorrhage
Micro ─ Intimate admixture of carcinomatous and sarcomatous elements
─ Carcinomatous component: Usually high-grade (squamous, adenocarcinoma, or undifferentiated)
─ Sarcomatous component: High-grade, undifferentiated, or may show heterologous differentiation
Ancillary studies ─ IHC panel to highlight both:
─ Carcinoma: PAX8, Cytokeratins, EMA
─ Sarcoma: Vimentin; specific markers if differentiated
DDx ─ Poorly Differentiated Carcinoma with spindle cells
─ Adenosarcoma (benign glands)
─ Pure Sarcoma
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Other Epithelial Tumors (Vagina)

Mixed Tumor (Vagina)

A rare, usually benign biphasic tumor of the vagina, composed of epithelial (glandular and/or squamous) and stromal (spindle cell) components, analogous to pleomorphic adenoma of salivary glands
Clinical ─ Rare; typically occurs in adult women; usually benign but malignant transformation (carcinoma ex mixed tumor) can occur; presents as a submucosal nodule
Macro ─ Well-circumscribed, firm, gray-white nodule, often <3 cm
Micro ─ Intimate admixture of:
─ Epithelial Component: Glands, tubules, nests, or squamous areas; cells are bland
─ Stromal Component: Spindle cells, often with myxoid, chondroid, or osseous metaplasia
─ Myoepithelial cells may be present
─ Lacks significant atypia or high mitotic activity in benign forms
Ancillary studies ─ IHC (Epithelial) (+) Cytokeratins, EMA
─ IHC (Stromal/Myoepithelial) (+) S100, SMA, GFAP (variable)
DDx ─ Adenosarcoma (malignant stroma, periglandular cuffing)
─ Spindle Cell Carcinoma / Carcinosarcoma (frank malignancy)
─ Botryoid Rhabdomyosarcoma (children, cambium layer, rhabdomyoblasts)
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Adenocarcinoma of Skene Gland Origin

A rare adenocarcinoma arising from the paraurethral Skene glands, which can present as a vaginal or urethral mass
Clinical ─ Rare; typically affects adult women; can present with dysuria, mass, or bleeding
Macro ─ Periurethral or vaginal mass, often infiltrative
Micro ─ Histologic type can vary:
─ Prostatic-type Adenocarcinoma: Resembles prostatic acinar adenocarcinoma; glands lined by cells with prominent nucleoli (PSA+, PAP+)
─ Clear Cell Carcinoma
─ Endometrioid Carcinoma
─ Mucinous Carcinoma
Ancillary studies ─ IHC Depends on type: PSA, PSAP, P501S (prostatic type); Napsin A (clear cell); ER/PR (endometrioid)
DDx ─ Metastatic Carcinoma (eg, prostate, colorectal, urothelial)
─ Primary Vaginal Adenocarcinomas of other types
─ Urethral Carcinoma
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Adenosquamous Carcinoma (Vagina)

A malignant vaginal tumor with intimately mixed, clearly recognizable invasive glandular (adenocarcinoma) and invasive squamous cell carcinoma components
Clinical ─ Rare; HPV-association is common, similar to cervical adenosquamous ca; behavior is generally aggressive
Macro ─ Exophytic, endophytic, or ulcerative mass
Micro ─ Both malignant squamous and malignant glandular components are present and intermingled
─ Each component must be unequivocally malignant and invasive
─ Squamous component is usually non-keratinizing or keratinizing SCC
─ Glandular component is usually endocervical-like or endometrioid adenocarcinoma
Ancillary studies ─ IHC (+) p16 (diffuse block positive if HPV-driven)
─ IHC (+) Squamous: p63, CK5/6
─ IHC (+) Glandular: CEA, PAX8, CK7
DDx ─ Squamous Cell Carcinoma with glandular involvement/extension
─ Adenocarcinoma with squamous metaplasia (metaplasia is benign)
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Adenoid Cystic Carcinoma (Vagina)

A rare malignant glandular tumor, typically arising from Bartholin gland extension or de novo in the vagina, characterized by cribriform, tubular, and solid patterns
Clinical ─ Rare in vagina; more common in vulva (Bartholin gland); indolent but with high propensity for local recurrence and late distant metastases; perineural invasion is common
Macro ─ Firm, infiltrative mass
Micro ─ Characteristic patterns:
─ Cribriform: Nests with multiple, rounded, 'punched-out' spaces containing hyaline or mucoid material
─ Tubular: Small tubules lined by basaloid cells
─ Solid: Sheets of basaloid cells
─ Composed of two cell types: ductal cells and myoepithelial/basaloid cells
─ Perineural and lymphovascular invasion are common
Ancillary studies ─ IHC (+) MYB or MYBL1 (nuclear, due to gene fusion), CK7, CD117 (c-kit), S100, SMA (myoepithelial)
─ IHC (-) p16, ER, PR
─ Molecular ─ MYB::NFIB or MYBL1 rearrangements common
DDx ─ Adenoid Basal Carcinoma (cervix, less aggressive, lacks MYB)
─ Basaloid Squamous Cell Carcinoma (more atypia, lacks cribriform/MYB)
─ Collagenous Spherulosis (benign)
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Miscellaneous Tumors (Vagina)

Adenosarcoma (Vagina)

A rare biphasic tumor of the vagina with benign epithelial glands and a malignant (usually low-grade) stromal component
Clinical ─ Very rare; occurs over a wide age range; may present as a polypoid mass; generally low-grade but can recur, especially with stromal overgrowth
Macro ─ Polypoid mass, often large and friable
Micro ─ Biphasic tumor similar to uterine/cervical counterpart:
─ Epithelial Component: Benign glands, often cystically dilated, lined by various Mullerian types
─ Stromal Component: Malignant mesenchymal proliferation, typically low-grade; characteristic periglandular stromal cuffing
─ Stromal overgrowth (>25% of tumor volume) indicates higher risk
Ancillary studies ─ IHC (Stroma) (+) CD10, Vimentin; variable ER/PR
─ IHC (Epithelium) (+) Cytokeratins, PAX8
DDx ─ Benign Mixed Tumor / Fibroepithelial Polyp (benign stroma)
─ Carcinosarcoma (malignant epithelium and stroma)
─ Embryonal Rhabdomyosarcoma (cambium layer, rhabdomyoblasts)
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Germ Cell Tumors (Vagina)

Exceedingly rare primary vaginal neoplasms derived from germ cells, with Yolk Sac Tumor being the most common type in this location
Clinical ─ Predominantly affects infants and young children (Yolk Sac Tumor); other types (mature teratoma, dysgerminoma) are exceptionally rare; highly malignant but chemosensitive
Macro ─ Polypoid, friable mass, often in anterior vaginal wall
Micro ─ Yolk Sac Tumor (Endodermal Sinus Tumor):
─ Most common type; histologically identical to ovarian YST
─ Diverse patterns: Reticular/microcystic, Schiller-Duval bodies, solid, papillary
─ Hyaline globules common
─ Other rare GCTs (eg, mature teratoma, embryonal carcinoma) would resemble their ovarian counterparts
Ancillary studies ─ Yolk Sac Tumor: IHC (+) AFP, SALL4, Glypican-3, Cytokeratin
DDx ─ Embryonal Rhabdomyosarcoma (infants/children, rhabdomyoblasts, Myogenin+)
─ Clear Cell Carcinoma (older patients, Napsin A+, HNF1B+)
─ Mullerian Papilloma (benign, children)
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Vulva

Squamous Lesions (Vulva)

HPV-Associated Squamous Intraepithelial Lesion (VIN)

A pre-neoplastic lesion of the vulvar squamous epithelium caused by HPV, encompassing LSIL and HSIL (also known as usual VIN or uVIN)
Clinical ─ Risk factors: HPV infection (esp_ 16, 6, 11), smoking, immunosuppression; LSIL often flat condyloma, HSIL is precursor to HPV+ SCC; presents as plaques, papules, or macules, often multifocal; can be itchy/painful
Macro ─ White, red, or pigmented lesions; flat, papular, or warty
Micro ─ Low-Grade Squamous Intraepithelial Lesion (LSIL) / Flat Condyloma:
─ Mild atypia, usually confined to lower 1/3; Koilocytosis often prominent in upper layers
─ Acanthosis, papillomatosis, hyperkeratosis variable
─ p16 negative or patchy
─ High-Grade Squamous Intraepithelial Lesion (HSIL) / Usual VIN (uVIN):
─ Moderate to severe atypia involving > lower 1/3 (HSIL/VIN2) or full thickness (HSIL/VIN3)
─ High N/C ratio, hyperchromasia, disordered maturation, increased/abnormal mitoses
─ Bowenoid papulosis (pigmented papules) is a clinical variant of HSIL
─ p16 block positivity is characteristic
Ancillary studies ─ IHC (+) p16 (diffuse block positive in HSIL), Ki67 (increased, suprabasal in HSIL)
DDx ─ Reactive Atypia / Lichen Simplex Chronicus (vs LSIL/low-grade HSIL)
─ Differentiated VIN (dVIN) (p16 negative, basal atypia)
─ Squamous Cell Carcinoma (invasion)
─ Psoriasis / Spongiotic Dermatitis (inflammatory changes)
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Differentiated-Type Vulvar Intraepithelial Neoplasia (dVIN)

An HPV-independent precursor lesion to HPV-independent squamous cell carcinoma of the vulva, often associated with lichen sclerosus or lichen simplex chronicus
Clinical ─ Less common than uVIN/HSIL; typically affects older women; associated with chronic dermatoses (lichen sclerosus); HPV-negative
Macro ─ Often poorly defined white or red plaques, may be ulcerated or hyperkeratotic
Micro ─ Characterized by basal layer atypia: Enlarged, hyperchromatic nuclei, prominent nucleoli in basal/parabasal cells
─ Abundant eosinophilic cytoplasm in superficial cells, often with premature keratinization (dyskeratosis) and prominent intercellular bridges
─ Elongated/anastomosing rete ridges may be present
─ Lacks koilocytosis or features of viral cytopathic effect
Ancillary studies ─ IHC (-) p16 (Negative or patchy/weak - key feature)
─ IHC (+/-) TP53 mutations are common (aberrant p53 expression - can be overexpression or null)
DDx ─ Usual VIN (HSIL) (p16 block positive, full-thickness or >1/3 atypia)
─ Lichen Sclerosus / Lichen Simplex Chronicus with reactive atypia (less severe atypia, p53 wt)
─ Invasive Squamous Cell Carcinoma (stromal invasion)
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Differentiated Exophytic Vulvar Intraepithelial Lesion (deVIL)

An HPV-negative precursor lesion to vulvar squamous cell carcinoma, characterized by exophytic growth and features of well-differentiated SCC but confined to the epithelium
Clinical ─ Rare, HPV-negative; may be associated with lichen sclerosus or chronic inflammation; potential precursor to invasive well-differentiated SCC
Macro ─ Exophytic, warty, or papillary lesion
Micro ─ Exophytic, verruciform acanthosis with papillomatosis
─ Squamous epithelium shows features resembling well-differentiated SCC:
─ Elongated, sometimes anastomosing rete ridges
─ Abundant eosinophilic cytoplasm, prominent intercellular bridges
─ Basal layer atypia (enlarged nuclei, hyperchromasia)
─ Variable parakeratosis and hyperkeratosis
─ No stromal invasion
Ancillary studies ─ IHC (-) p16 (Negative or patchy)
─ IHC (+/-) p53 (may show aberrant expression)
DDx ─ Condyloma Acuminatum / LSIL (HPV-driven, koilocytosis, p16 variable)
─ Verrucous Carcinoma (invasive, bulbous rete ridges)
─ Squamous Cell Carcinoma, well-differentiated (stromal invasion)
─ Differentiated VIN (dVIN) (more often flat, less exophytic)
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Vulvar Acanthosis with Altered Differentiation (VAAD)

An HPV-negative vulvar epithelial alteration characterized by acanthosis and disordered keratinocyte maturation, with minimal atypia; its precursor potential is debated
Clinical ─ HPV-negative; may be seen in association with chronic dermatoses or as an isolated finding; relationship to dVIN and SCC is under investigation, may represent a very early precursor or reactive change
Macro ─ Often subtle; may appear as white or thickened plaques
Micro ─ Acanthosis (epidermal thickening) with elongated rete ridges
─ Altered keratinocyte maturation: Disordered arrangement, cytoplasmic eosinophilia, some nuclear crowding but minimal atypia
─ Variable hyperkeratosis and parakeratosis
─ Lacks prominent basal atypia of dVIN or significant cytologic features of HSIL
─ Does not meet criteria for specific dermatoses like lichen sclerosus, lichen simplex chronicus, or psoriasis
Ancillary studies ─ IHC (-) p16 (Negative or patchy)
─ IHC (+/-) p53 (usually wild-type)
DDx ─ Lichen Simplex Chronicus (more hyperkeratosis, less specific maturation alteration)
─ Psoriasis (neutrophils in stratum corneum, Munro microabscesses)
─ Differentiated VIN (dVIN) (more pronounced basal atypia)
─ Early/Subtle HSIL (would show some p16 expression)
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Squamous Cell Carcinoma, HPV-Associated (Vulva)

An invasive malignancy of vulvar squamous cells driven by persistent high-risk HPV infection, typically arising from HSIL (usual VIN)
Clinical ─ Accounts for ~30-40% of vulvar SCCs; often affects younger women (compared to HPV-neg); risk factors include HPV, smoking, immunosuppression; often multifocal
Macro ─ Can be exophytic, ulcerative, or infiltrative; may appear warty or basaloid
Micro ─ Invasive nests, sheets, or single cells of malignant squamous epithelium
─ Often shows basaloid, warty, or less differentiated features compared to HPV-independent SCC
─ High N/C ratio, nuclear atypia, increased mitoses
─ Often arises from adjacent HSIL (uVIN)
Ancillary studies ─ IHC (+) p16 (diffuse block positivity - surrogate for HPV E7 activity)
─ IHC (+) Cytokeratins, p63
DDx ─ HSIL (uVIN) (lacks stromal invasion)
─ HPV-Independent SCC (p16 negative/patchy)
─ Verrucous Carcinoma (locally invasive, very well-differentiated, p16-)
─ Basal Cell Carcinoma (peripheral palisading, stromal retraction, BerEP4+)
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Squamous Cell Carcinoma, HPV-Independent (Vulva)

An invasive malignancy of vulvar squamous cells not associated with HPV infection, typically arising from dVIN or in the setting of chronic dermatoses like lichen sclerosus
Clinical ─ Accounts for ~60-70% of vulvar SCCs; typically affects older women; associated with lichen sclerosus, lichen simplex chronicus, or dVIN; usually unifocal
Macro ─ Often well-differentiated, keratinizing, ulcerative, or indurated plaque/nodule
Micro ─ Invasive squamous cell carcinoma, usually well-differentiated and keratinizing
─ Tumor cells often have more abundant eosinophilic cytoplasm and prominent intercellular bridges
─ Basal atypia in adjacent epithelium may suggest origin from dVIN
─ Lacks features of HPV infection (no koilocytosis)
Ancillary studies ─ IHC (-) p16 (Negative or patchy/weak, non-block staining - key feature)
─ IHC (+/-) TP53 mutations common (aberrant p53 expression - overexpression or null)
DDx ─ HPV-Associated SCC (p16 block positive)
─ Differentiated VIN (dVIN) (lacks stromal invasion)
─ Keratoacanthoma (crateriform, rapid growth - rare in vulva)
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Glandular Tumors and Cysts (Vulva)

Mammary-Type Glandular Lesions (Vulva)

Lesions arising from ectopic mammary tissue or anogenital mammary-like glands in the vulva, ranging from benign (fibroadenoma) to malignant (ductal carcinoma)
Clinical ─ Uncommon; ectopic breast tissue most common in axilla, but can occur in vulva (milk line remnant); can respond to hormonal changes
Macro ─ Variable; firm nodule (fibroadenoma, carcinoma) or ill-defined thickening
Micro ─ Spectrum of lesions identical to those seen in the breast:
─ Ectopic Breast Tissue: Normal ducts and lobules
─ Fibroadenoma: Biphasic tumor with benign glands and fibrous stroma
─ Phyllodes Tumor: Biphasic with more cellular stroma, leaf-like architecture
─ Ductal Carcinoma In Situ (DCIS): Malignant cells within ducts, preserved basement membrane
─ Invasive Ductal Carcinoma: Infiltrating malignant glands
Ancillary studies ─ IHC (+) ER, PR, GATA3, Mammaglobin, GCDFP-15 (mammary markers)
─ IHC (+) PAX8 (can be positive in some Mullerian-derived lesions too)
DDx ─ Primary Vulvar Adenocarcinoma (eg, sweat gland origin - different IHC)
─ Metastatic Breast Carcinoma (clinical history, rule out primary vulvar mammary-like)
─ Hidradenoma Papilliferum (benign apocrine tumor)
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Bartholin Gland Cyst

A common cyst of the vulva resulting from obstruction of the Bartholin gland duct, leading to accumulation of mucinous secretions
Clinical ─ Common; occurs in women of reproductive age; can be asymptomatic or cause pain/discomfort, especially if large or infected (Bartholin gland abscess)
Macro ─ Unilateral, fluctuant, spherical swelling in the posterolateral aspect of the vaginal introitus/vulva
Micro ─ Cyst lined by various epithelia depending on location and pressure:
─ Transitional epithelium (near duct opening)
─ Stratified squamous epithelium (may undergo metaplasia)
─ Cuboidal or flattened ductal epithelium
─ Mucin-secreting columnar cells (if acini involved or prominent)
─ Wall is fibrous, may contain chronic inflammation or Bartholin gland acini
Ancillary studies ─ Usually none required
DDx ─ Epidermal Inclusion Cyst (keratin contents, squamous lining)
─ Skene Duct Cyst (paraurethral)
─ Mucinous Cyst of the vulva (other origins)
─ Bartholin Gland Carcinoma (malignant features, solid areas)
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Bartholin Gland Hyperplasia, Adenoma, Adenomyoma

Benign proliferative lesions of the Bartholin gland involving its acini and/or ducts
Clinical ─ Uncommon; usually present as a firm nodule or swelling in the Bartholin gland area; benign
Macro ─ Small, firm, circumscribed nodule
Micro ─ Hyperplasia: Increased number of benign-appearing mucinous acini and ducts, maintaining a lobular architecture
─ Adenoma: Well-circumscribed proliferation of benign glands (mucinous acini and small ducts) with minimal intervening stroma
─ Adenomyoma: Similar to adenoma but with a prominent smooth muscle stromal component
─ All show bland cytology without atypia or significant mitoses
Ancillary studies ─ IHC (Glands) (+) CK7, CEA (variable)
─ IHC (Stroma in Adenomyoma) (+) Desmin, SMA
DDx ─ Bartholin Gland Carcinoma (especially Adenocarcinoma - atypia, invasion)
─ Normal Bartholin Gland tissue
─ Nodular Hidradenoma (different morphology)
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Bartholin Gland Carcinomas

Malignant neoplasms arising from the Bartholin gland, with Squamous Cell Carcinoma and Adenocarcinoma being the most common types
Clinical ─ Rare (~2-7% of vulvar cancers); typically affects older women (adenocarcinoma) or middle-aged (SCC); presents as a persistent, indurated mass in Bartholin gland area
Macro ─ Firm, infiltrative mass, may be ulcerated or cystic
Micro ─ Histologic type varies:
─ Squamous Cell Carcinoma: Arises from ductal epithelium; similar to other vulvar SCCs (HPV+ or HPV-)
─ Adenocarcinoma: Arises from glandular acini; can be mucinous, endometrioid, or NOS type
─ Adenoid Cystic Carcinoma: Cribriform, tubular, solid patterns; perineural invasion common; MYB driven
─ Other rare types: Transitional cell, Undifferentiated
Ancillary studies ─ IHC depends on type:
─ SCC: p16 (if HPV+), p63, CK5/6
─ Adeno: CK7, CEA, PAX8 (variable)
─ ACC: MYB, CD117, S100
DDx ─ Benign Bartholin Gland Lesions (cyst, adenoma - lack malignancy)
─ Metastatic Carcinoma to vulva
─ Primary Vulvar SCC/Adenocarcinoma not of Bartholin origin (location is key)
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Adenocarcinoma of Intestinal Type (Vulva)

A rare primary vulvar adenocarcinoma resembling colorectal adenocarcinoma, often arising from cloacal remnants or intestinal metaplasia
Clinical ─ Rare; typically affects older women; prognosis is variable, often depends on stage
Macro ─ Ulcerative, polypoid, or infiltrative mass, may be perianal or involve Bartholin gland area
Micro ─ Glandular architecture resembling intestinal adenocarcinoma (colorectal type)
─ Lined by tall columnar cells with goblet cells, often with dirty necrosis in glandular lumens
─ Variable degrees of atypia and complexity
Ancillary studies ─ IHC (+) CK20, CDX2, MUC2
─ IHC (-) CK7 (usually), PAX8
DDx ─ Metastatic Colorectal Adenocarcinoma (most important DDx; clinical history crucial, identical IHC)
─ Extramammary Paget Disease with underlying adenocarcinoma (Pagetoid spread in epidermis)
─ Adenocarcinoma of Skene Gland (prostatic markers like PSA if that type)
─ Bartholin Gland Adenocarcinoma (location specific, can be intestinal type)
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Miscellaneous Tumors (Vulva)

Germ Cell Tumors (Vulva)

Exceedingly rare primary vulvar neoplasms derived from germ cells, with Yolk Sac Tumor being the most reported type in this location, typically in infants/young children
Clinical ─ Predominantly affects infants and young children (Yolk Sac Tumor); other types are exceptionally rare; can be aggressive
Macro ─ Polypoid, friable mass
Micro ─ Yolk Sac Tumor (Endodermal Sinus Tumor) is the most common:
─ Histologically identical to ovarian/vaginal/testicular YST
─ Diverse patterns: Reticular/microcystic, Schiller-Duval bodies, solid, papillary
─ Hyaline globules common
─ Mature cystic teratomas are also reported but are extremely rare
Ancillary studies ─ Yolk Sac Tumor: IHC (+) AFP, SALL4, Glypican-3, Cytokeratin
DDx ─ Embryonal Rhabdomyosarcoma (infants/children, rhabdomyoblasts, Myogenin+)
─ Clear Cell Carcinoma (older patients, Napsin A+, HNF1B+)
─ Other benign or malignant vulvar masses depending on morphology
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Lower Genital Tract Mesenchymal Tumors

Adipocytic

Lipoblastoma-like Tumor (Vulva)

A rare, benign adipocytic neoplasm of the vulva, typically occurring in young children, characterized by lobules of immature fat cells including lipoblasts, and often PLAG1 gene rearrangement
Clinical ─ Rare; almost exclusively in infants and young children (usually <3 years); presents as a painless, slow-growing vulvar mass; benign with excellent prognosis after complete excision
Macro ─ Well-circumscribed, lobulated, soft, yellow-tan mass
Micro ─ Lobulated architecture with fibrous septa
─ Composed of immature adipocytes at various stages of differentiation, including multivacuolated lipoblasts
─ Stroma can be myxoid or fibrous
─ Plexiform vascular pattern common
─ Lacks significant atypia or high mitotic activity
Ancillary studies ─ Molecular ─ PLAG1 gene rearrangements (8q12) are characteristic
DDx ─ Myxoid Liposarcoma (older age group, lacks PLAG1 rearrangement, DDIT3 fusions, more atypia)
─ Lipoma (mature fat, no lipoblasts)
─ Embryonal Rhabdomyosarcoma (myxoid variants can mimic, but Myogenin+)
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Fibroblastic and Myofibroblastic

Postoperative Spindle Cell Nodule (PSCN) (Lower Genital Tract)

A benign, reactive proliferation of spindle cells (myofibroblasts) that typically occurs following surgery or trauma in the lower genital tract
Clinical ─ History of prior surgery or trauma at the site is key; presents as a rapidly growing but small (<5 cm) nodule or polyp; can occur in vagina, vulva, or cervix; benign, self-limited, or resolves with excision
Macro ─ Small, firm, polypoid or nodular lesion, may be ulcerated
Micro ─ Highly cellular proliferation of plump spindle cells arranged in short fascicles or a storiform pattern, often with a 'tissue culture-like' appearance
─ Cells have vesicular nuclei, prominent nucleoli, and eosinophilic cytoplasm
─ Mitotic activity can be brisk, but atypical mitoses are absent
─ No significant cytologic atypia or necrosis
─ Background often shows granulation tissue, inflammation, and hemorrhage
Ancillary studies ─ IHC (+) SMA, Desmin, Vimentin (myofibroblastic differentiation)
─ IHC (-) Cytokeratins, S100
DDx ─ Leiomyosarcoma / Other Sarcomas (more atypia, necrosis, infiltrative growth)
─ Nodular Fasciitis (similar features, less common in this specific site)
─ Spindle Cell Carcinoma (CK+)
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Prepubertal Fibroma (Vulva/Lower Genital Tract)

A rare, benign fibroblastic/myofibroblastic tumor typically occurring in the vulva or perineum of prepubertal girls
Clinical ─ Rare; presents as a painless, firm, well-circumscribed subcutaneous nodule in prepubertal girls; benign with low recurrence risk after excision
Macro ─ Well-circumscribed, firm, gray-white nodule
Micro ─ Cellular proliferation of bland spindle to stellate cells (fibroblasts/myofibroblasts)
─ Cells are arranged in short fascicles or a patternless pattern within a collagenous or myxoid stroma
─ No significant cytologic atypia or mitotic activity
─ May show infiltrative edges into surrounding fat
Ancillary studies ─ IHC (+) Vimentin
─ IHC (+/-) SMA, CD34, ER, PR
─ IHC (-) Desmin, S100
DDx ─ Infantile Fibromatosis / Desmoid-type Fibromatosis (more infiltrative, Beta-catenin nuclear+ in desmoid)
─ Superficial Angiomyxoma (more myxoid, prominent vessels)
─ Low-Grade Sarcomas (would show more atypia/mitoses)
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Superficial Myofibroblastoma (Vulva/Lower Genital Tract)

A benign mesenchymal tumor composed of myofibroblasts, a superficial variant of myofibroblastoma more commonly described in other sites, occurring in the vulvovaginal region
Clinical ─ Rare in vulva; typically affects adults; presents as a slow-growing, painless, well-circumscribed nodule
Macro ─ Small, firm, well-demarcated nodule, often subcutaneous
Micro ─ Well-circumscribed proliferation of bland spindle cells arranged in short fascicles
─ Cells have eosinophilic cytoplasm and oval to spindle nuclei
─ Stroma is often collagenous, can be hyalinized
─ Low mitotic activity, no significant atypia
─ Distinguished from deeper myofibroblastoma by superficial location if criteria are strictly applied
Ancillary studies ─ IHC (+) CD34, Desmin, SMA (variable), ER, PR, BCL2
─ IHC (-) S100
DDx ─ Cellular Angiofibroma (more vascular, distinct vessel hyalinization)
─ Angiomyofibroblastoma (more myxoid, prominent vessels, often perivascular cuffing)
─ Leiomyoma (Desmin strong+, CD34-)
─ Solitary Fibrous Tumor (STAT6+)
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Cellular Angiofibroma (Vulva/Lower Genital Tract)

A benign mesenchymal neoplasm, typically occurring in the vulvovaginal region of adult women, characterized by cellular spindle cell areas and prominent small to medium-sized hyalinized blood vessels
Clinical ─ Benign; most common in adult women (4th-6th decades); presents as a well-circumscribed, slow-growing subcutaneous mass in vulva, perineum, or inguinal region
Macro ─ Well-demarcated, firm, rubbery, gray-white to tan nodule, usually <5 cm
Micro ─ Alternating hypercellular and hypocellular areas
─ Cellular areas composed of bland spindle cells with scant cytoplasm, often arranged around vessels
─ Numerous small to medium-sized blood vessels, often with thick, hyalinized walls (characteristic)
─ Stroma can be edematous or collagenous
─ Adipocytes may be scattered within the lesion
─ Low mitotic activity, no significant atypia or necrosis
Ancillary studies ─ IHC (+) CD34, Vimentin, ER, PR
─ IHC (-) Desmin (usually), SMA (variable, often perivascular), S100
─ Molecular ─ Loss of RB1 gene/locus (13q14) is common
DDx ─ Angiomyofibroblastoma (more myxoid, less cellular usually, perivascular stromal cell condensation)
─ Aggressive Angiomyxoma (infiltrative, larger, more myxoid, CD34 variable)
─ Superficial Myofibroblastoma (less vascular, Desmin+)
─ Solitary Fibrous Tumor (STAT6+)
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NTRK-Rearranged Spindle Cell Neoplasm (Lower Genital Tract)

A group of mesenchymal tumors defined by gene fusions involving one of the neurotrophic tyrosine receptor kinase genes (NTRK1, NTRK2, or NTRK3), occurring in various sites including the lower genital tract
Clinical ─ Rare in GYN tract; can occur at any age, including congenital/infantile (infantile fibrosarcoma-like); behavior varies from locally aggressive to metastatic depending on specific histology/fusion; highly responsive to TRK inhibitor therapy
Macro ─ Variable; often fleshy, infiltrative masses
Micro ─ Histology can be diverse, often resembling infantile fibrosarcoma or other spindle cell sarcomas:
─ Cellular proliferation of spindle cells arranged in fascicles, herringbone pattern, or diffuse sheets
─ Can have myxoid stroma, prominent vasculature, or primitive round cell areas
─ Atypia and mitotic activity are variable
Ancillary studies ─ IHC (+) Pan-TRK (immunohistochemical screen for NTRK protein overexpression due to fusion)
─ IHC (+/-) S100, CD34, SMA (variable, depends on differentiation)
─ Molecular ─ Definitive diagnosis requires detection of NTRK gene fusion (eg, ETV6::NTRK3) via FISH, RT-PCR, or NGS
DDx ─ Other Spindle Cell Sarcomas (eg, Fibrosarcoma, MPNST, Leiomyosarcoma - distinguished by IHC and lack of NTRK fusion)
─ Myofibroblastic tumors
─ Solitary Fibrous Tumor (STAT6+)
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Leiomyoma (Lower Genital Tract, Non-Uterine)

A benign smooth muscle neoplasm arising in the cervix, vagina, or vulva, histologically identical to uterine leiomyomas
Clinical ─ Most common mesenchymal tumor of the vulva; can occur in cervix (most common benign cervical tumor) or vagina; often asymptomatic, can cause mass effect, pain, or dyspareunia depending on size/location
Macro ─ Well-circumscribed, firm, white-tan, whorled mass; size varies
Micro
─ Intersecting fascicles of bland, uniform spindle-shaped smooth muscle cells
─ Cells have eosinophilic cytoplasm and elongated 'cigar-shaped' nuclei
─ No significant atypia, no tumor cell necrosis, and low mitotic activity (typically <5 /10 HPF)
─ Variants similar to uterine leiomyomas can occur (eg, cellular, epithelioid)
Ancillary studies
─ IHC (+) Desmin, SMA (Smooth Muscle Actin), Caldesmon
─ IHC (-) CD10, Inhibin, Cytokeratins
DDx
─ Leiomyosarcoma (atypia, necrosis, high mitoses)
─ STUMP of lower genital tract (borderline features)
─ Other mesenchymal tumors (eg, Angiomyofibroblastoma, Cellular Angiofibroma - distinct morphology/IHC)
─ Fibroepithelial stromal polyp (if polypoid and stromal predominant)
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Smooth Muscle Tumor of Uncertain Malignant Potential (STUMP)

A rare smooth muscle tumor of the cervix, vagina, or vulva whose histologic features are concerning but do not unequivocally meet criteria for leiomyosarcoma, nor can it be confidently diagnosed as benign leiomyoma
Clinical ─ Very rare in these locations; biologic behavior is uncertain; requires close follow-up; diagnosis of exclusion after thorough sampling
Macro ─ Usually a fleshy or firm mass; may show areas of softening or hemorrhage
Micro
─ Diagnosis applies to smooth muscle tumors that exhibit features exceeding those of benign leiomyoma variants but fall short of leiomyosarcoma criteria for that specific site (extrapolating from uterine STUMP criteria)
─ May show combinations such as:
─ Focal or multifocal moderate to severe atypia with low mitotic count and no necrosis
─ Necrosis (non-infarct type) with low atypia and low mitotic count
─ Higher mitotic counts (eg, 5-9/10HPF) with no or mild atypia and no necrosis
─ Uncertainty in assessing atypia, necrosis, or mitotic counts definitively
─ Extensive sampling is crucial
Ancillary studies
─ IHC (+) Desmin, SMA, Caldesmon
─ IHC (-) CD10, Cytokeratins
─ IHC (+/-) p16, p53 (may show alterations in some cases, but not diagnostic alone)
DDx
─ Leiomyoma (and its variants - clearly benign features)
─ Leiomyosarcoma (meets full criteria for malignancy: atypia + necrosis and/or high mitoses)
─ Other spindle cell neoplasms
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Peritoneum

Mesothelial Hyperplasia (Peritoneum)

A benign, reactive proliferation of mesothelial cells lining the peritoneum, typically occurring in response to underlying irritation or fluid accumulation
Clinical ─ Common incidental finding; associated with inflammation (PID, peritonitis), surgery, endometriosis, ascites, ovarian tumors; not pre-malignant
Macro ─ May be grossly unremarkable or show subtle granularity, small papillae, or opacification of peritoneal surfaces
Micro ─ Proliferation of mesothelial cells, typically one to few layers thick
─ Cells are bland, cuboidal to flattened, with eosinophilic cytoplasm and uniform nuclei
─ Can form small, simple papillae, tufts, or solid nests
─ Lacks significant atypia, high mitotic activity, necrosis, or stromal invasion (distinguishes from mesothelioma)
─ Underlying stroma may show inflammation or edema
Ancillary studies ─ IHC (+) Calretinin, WT1 (nuclear), CK5/6, D2-40
─ IHC (-) BAP1 (retained expression)
DDx ─ Well-Differentiated Papillary Mesothelial Tumor (more complex, persistent papillae)
─ Malignant Mesothelioma (invasion, atypia, BAP1 loss)
─ Serous Borderline Tumor / Carcinoma implants (PAX8+, Calretinin-)
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Peritoneal Inclusion Cyst (Benign Cystic Mesothelioma)

Benign, often multilocular cystic structures lined by bland mesothelial cells, typically occurring in women of reproductive age with a history of prior surgery, PID, or endometriosis

Clinical ─ May be asymptomatic or cause chronic pelvic pain; often found incidentally; can recur if incompletely excised but no malignant potential

Macro ─ Single or multiple thin-walled, translucent cysts filled with clear serous fluid; can form large, multiloculated masses

Micro

─ Cysts lined by a single layer of flattened to cuboidal, bland mesothelial cells

─ Cyst walls are thin, composed of fibrous tissue, may contain scant chronic inflammation or entrapped normal structures

─ No atypia, mitoses, or stromal invasion

Ancillary studies

─ IHC (+) Calretinin, WT1 (nuclear), D2-40, CK7

DDx

─ Lymphangioma (D2-40+, but Calretinin-/WT1-)

─ Cystic Serous Tumors (PAX8+, Calretinin-)

─ Malignant Cystic Mesothelioma (rare, shows atypia/invasion)

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Adenomatoid Tumor (Peritoneum)

A benign neoplasm of mesothelial origin, most commonly found in the male and female genital tracts, but can occasionally occur as a primary peritoneal lesion
Clinical ─ Usually an incidental finding; presents as a small, firm nodule; benign behavior with no malignant potential
Macro ─ Small (<5 cm, often <2 cm), solid, well-circumscribed, gray-white, firm nodule on peritoneal surfaces
Micro ─ Complex network of anastomosing, small, slit-like or rounded channels, tubules, and cysts, sometimes forming cord-like structures
─ Lined by flattened to cuboidal mesothelial cells; cytoplasm can be eosinophilic or vacuolated (can mimic signet rings, but mucin negative)
─ Set in a fibrous or fibromuscular stroma
─ Bland cytology, low/absent mitoses
Ancillary studies ─ IHC (+) Calretinin, WT1 (nuclear), D2-40, CK7, EMA
─ IHC (-) PAX8, Ber-EP4, MOC31, CEA (helps exclude adenocarcinoma)
DDx ─ Malignant Mesothelioma (infiltrative, atypia, necrosis, higher mitoses)
─ Well-Differentiated Papillary Mesothelial Tumor (papillary architecture)
─ Metastatic Adenocarcinoma (malignant features, adenocarcinoma markers positive)
─ Lymphangioma (D2-40+, but Calretinin-/WT1-)
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Well-Differentiated Papillary Mesothelial Tumor (WDPMT) (Peritoneum)

A rare mesothelial neoplasm of low malignant potential characterized by a superficial papillary architecture lined by bland mesothelial cells
Clinical ─ Can occur in peritoneum of both sexes, more common in women; often an incidental finding or associated with ascites; usually indolent, but rare recurrences or progression to mesothelioma reported
Macro ─ Multiple small (mm to cm), firm, gray-white papillary nodules or plaques on peritoneal surfaces
Micro ─ Simple, non-hierarchical papillary structures with fibrovascular cores
─ Papillae lined by a single layer of bland, flattened to cuboidal mesothelial cells
─ No significant cytologic atypia, high mitotic activity, or stromal invasion (key features)
─ Psammoma bodies may be present
Ancillary studies ─ IHC (+) Calretinin, WT1 (nuclear), D2-40, CK5/6
─ IHC (-) BAP1 (loss is rare, if lost, consider mesothelioma)
─ IHC (-) Adenocarcinoma markers (PAX8, CEA, BerEP4)
DDx ─ Malignant Mesothelioma, epithelioid type (shows invasion, complex architecture, atypia)
─ Reactive Mesothelial Hyperplasia (less complex, often history of irritation)
─ Serous Borderline Tumor / Low-Grade Serous Carcinoma (PAX8+, WT1+, Calretinin-)
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Malignant Mesothelioma (Peritoneum)

An aggressive malignant neoplasm arising from the mesothelial lining of the peritoneum, less common than pleural mesothelioma
Clinical ─ Associated with asbestos exposure (though less strongly than pleural); presents with abdominal pain, distension, ascites, weight loss; poor prognosis
Macro ─ Diffuse thickening of peritoneal surfaces, multiple nodules, or large dominant masses; omentum often heavily involved ('omental cake')
Micro ─ Main histologic types:
─ Epithelioid: Most common; tubules, papillae, glands, solid sheets; cells cuboidal/polygonal, moderate atypia
─ Sarcomatoid: Spindle cells resembling fibrosarcoma or other sarcomas; highly aggressive
─ Biphasic: Mixture of epithelioid and sarcomatoid components (at least 10% of each)
─ Features of malignancy: Stromal invasion, necrosis, significant atypia, increased mitoses
Ancillary studies ─ IHC (+) Calretinin, WT1 (nuclear), CK5/6, D2-40, Podoplanin
─ IHC (-) BAP1 (loss is common and supports malignancy)
─ IHC (-) Adenocarcinoma markers: CEA, Ber-EP4, MOC31, PAX8, TTF-1 (crucial for DDx)
DDx ─ Metastatic Carcinoma (especially serous, ovarian, GI - use IHC panel)
─ Well-Differentiated Papillary Mesothelial Tumor (lacks invasion/high-grade features)
─ Reactive Mesothelial Hyperplasia (lacks invasion/malignant features)
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Epithelial Tumors of Müllerian Type (Peritoneum)

Serous Borderline Tumor of the Peritoneum (Primary)

A non-invasive serous epithelial neoplasm arising primarily from the peritoneum, histologically identical to ovarian serous borderline tumor
Clinical ─ Rare as primary peritoneal tumor; usually affects women of reproductive age; often widespread peritoneal involvement (omental caking); prognosis generally good if implants are non-invasive
Macro ─ Multiple small nodules, plaques, or papillary excrescences on peritoneal surfaces, omentum, bowel serosa
Micro ─ Hierarchical branching papillae lined by stratified serous epithelium (ciliated/secretory cells)
─ Mild to moderate nuclear atypia
─ Detached epithelial cell clusters/tufts common
─ No destructive stromal invasion (by definition)
─ Often associated with psammoma bodies
─ Implants can be non-invasive (epithelial or desmoplastic) or invasive (classified as LGSC)
Ancillary studies ─ IHC (+) WT1, PAX8, ER, PR
─ IHC (-) Calretinin (distinguishes from mesothelial lesions)
DDx ─ Low-Grade Serous Carcinoma (shows stromal invasion)
─ High-Grade Serous Carcinoma (high-grade atypia, p53 aberrant)
─ Well-Differentiated Papillary Mesothelial Tumor (Calretinin+, WT1+, PAX8-)
─ Endosalpingiosis (bland glands, often psammoma bodies)
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Low-Grade Serous Carcinoma of the Peritoneum (Primary)

An invasive serous carcinoma arising primarily from the peritoneum, characterized by relatively uniform nuclei and low mitotic activity, often associated with psammoma bodies
Clinical ─ Rare as primary; typically affects women; often presents at advanced stage with diffuse peritoneal involvement; relatively chemoresistant but can have indolent course; may arise from primary peritoneal SBT
Macro ─ Diffuse peritoneal studding, nodules, plaques, omental caking
Micro ─ Invasive growth pattern (irregular nests, glands, micropapillae infiltrating stroma)
─ Cells are relatively uniform with mild to moderate nuclear atypia (less than HGSC)
─ Mitotic count is low (<12 per 10 HPF)
─ Psammoma bodies are very common and can be extensive
─ Often associated with a Serous Borderline Tumor component
Ancillary studies ─ IHC (+) WT1, PAX8, ER, PR (often strongly)
─ IHC (-) p53 (wild-type pattern), Calretinin
─ Molecular ─ KRAS, BRAF, or NRAS mutations common
DDx ─ Serous Borderline Tumor (lacks destructive invasion)
─ High-Grade Serous Carcinoma (high-grade atypia, p53 aberrant)
─ Malignant Mesothelioma (Calretinin+, PAX8-)
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High-Grade Serous Carcinoma of the Peritoneum (Primary)

An aggressive carcinoma arising primarily from the peritoneum, histologically identical to ovarian/tubal HGSC, defined by high-grade nuclear features and TP53 mutation
Clinical ─ Represents a significant portion of 'ovarian cancer' presentations when ovaries/tubes are minimally involved; older women; aggressive, presents at high stage; often responsive to platinum but high recurrence
Macro ─ Widespread peritoneal/omental disease, ascites common; ovaries/tubes may be normal or superficially involved
Micro ─ Marked nuclear atypia (pleomorphism, high N/C ratio, irregular chromatin)
─ High mitotic activity, atypical mitoses
─ Architectural patterns: Papillary, solid, glandular, slit-like spaces
─ Must exclude origin from fallopian tube (STIC) or ovary
Ancillary studies ─ IHC (+) p53 (aberrant: overexpression or null), WT1, PAX8
─ IHC (+/-) ER, PR (often weaker/patchier than LGSC)
─ IHC (-) Calretinin
─ Molecular ─ TP53 mutation is near-universal
DDx ─ Metastatic HGSC from ovary/tube (often indistinguishable without careful grossing/sampling of adnexa)
─ Low-Grade Serous Carcinoma (lower grade atypia, p53 wt)
─ Malignant Mesothelioma (Calretinin+, PAX8-)
─ Metastatic Adenocarcinoma from other sites (GI, breast - use IHC panel)
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Other Primary Peritoneal Conditions & Tumors

Leiomyomatosis Peritonealis Disseminata (LPD)

A rare, benign condition characterized by multiple, small smooth muscle nodules studding the peritoneal surfaces, typically in women of reproductive age
Clinical ─ Often asymptomatic and incidental finding during surgery; associated with high estrogen states (pregnancy, OCPs, functioning ovarian tumors); generally benign, but rare malignant transformation reported
Macro ─ Numerous small (<1 cm to several cm), firm, gray-white nodules scattered over peritoneum, omentum, mesentery
Micro ─ Nodules composed of bland, benign-appearing smooth muscle cells arranged in fascicles
─ Histology resembles typical leiomyoma (no atypia, necrosis, or significant mitoses)
─ Can show hydropic change, hyalinization, or focal decidualization if pregnant
Ancillary studies ─ IHC (+) Desmin, SMA, Caldesmon, ER, PR
─ IHC (-) CD10, Cytokeratins
DDx ─ Metastatic Leiomyosarcoma (malignant features in nodules)
─ Peritoneal Mesothelioma, sarcomatoid type (CK+, mesothelial markers+)
─ Desmoplastic Small Round Cell Tumor (young males, EWS::WT1 fusion, specific IHC)
─ Diffuse Peritoneal Deciduosis (pregnancy, sheets of decidual cells, no SM)
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Extragastrointestinal Stromal Tumor (EGIST) (Peritoneum)

A mesenchymal neoplasm identical to Gastrointestinal Stromal Tumor (GIST) in morphology and immunophenotype, but arising in the peritoneum or intra-abdominally without a primary GI tract connection
Clinical ─ Rare; occurs in adults; most common in omentum or mesentery; behavior similar to GIST (risk stratification by size, mitoses, location); often driven by KIT or PDGFRA mutations
Macro ─ Well-circumscribed, fleshy mass; can be large
Micro ─ Spindle cell, epithelioid, or mixed morphology, identical to GISTs:
─ Spindle Cell: Fascicles of uniform spindle cells with pale eosinophilic cytoplasm
─ Epithelioid: Sheets of round/polygonal cells with clear or eosinophilic cytoplasm
─ Mitotic activity varies
Ancillary studies ─ IHC (+) CD117 (KIT) - strong membranous/Golgi (95%)
─ IHC (+) DOG1 (90-95%)
─ IHC (+/-) CD34 (70%), SMA (30%), S100 (5%), Desmin (-)
─ Molecular ─ KIT or PDGFRA mutations are common
DDx ─ Leiomyoma / Leiomyosarcoma (Desmin+, CD117-/DOG1-)
─ Solitary Fibrous Tumor (STAT6+, CD34+, CD117-)
─ Fibromatosis (Beta-catenin nuclear+, CD117-)
─ Sarcomatoid Mesothelioma / Carcinoma (CK+, mesothelial markers or specific carcinoma markers)
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Endometrioid Stromal Sarcoma (Primary Peritoneal)

A rare malignant mesenchymal tumor arising directly from peritoneal endometriosis, histologically and immunophenotypically similar to uterine low-grade endometrioid stromal sarcoma
Clinical ─ Extremely rare; typically occurs in women with extensive endometriosis; often presents with diffuse peritoneal disease or masses; behavior similar to uterine LG-ESS (indolent but prone to recurrence)
Macro ─ Multiple nodules or diffuse thickening involving peritoneal surfaces, omentum
Micro ─ Monotonous population of small oval to spindle cells resembling proliferative endometrial stroma
─ Infiltrative growth pattern into underlying tissues
─ Prominent network of small arterioles is characteristic
─ Mitotic activity is usually low
─ Background endometriosis is usually identifiable
Ancillary studies ─ IHC (+) CD10, ER, PR, Cyclin D1 (often)
─ IHC (-) Desmin, Caldesmon, Cytokeratins
─ Molecular ─ May show JAZF1 or other ESS-related fusions
DDx ─ Metastatic Uterine LG-ESS (more common than primary peritoneal)
─ Leiomyomatosis Peritonealis Disseminata (Desmin+, CD10-)
─ Desmoplastic Small Round Cell Tumor (EWS::WT1 fusion, different IHC)
─ Mesothelioma (Calretinin+, WT1+)
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Transitional Cell Metaplasia (Peritoneum) / Walthard Nests

Benign nests of transitional-like (urothelial-like) epithelium on the peritoneal surface or within submesothelial stroma, identical to Walthard nests of the adnexa
Clinical ─ Common incidental finding; no clinical significance
Macro ─ Usually microscopic; may appear as tiny (<1 mm) white-yellow solid or cystic nodules
Micro ─ Well-circumscribed nests of epithelial cells resembling urothelium
─ Cells are polygonal with oval nuclei, often showing longitudinal nuclear grooves ('coffee-bean' nuclei)
─ Nests can be solid or develop central cystic spaces, sometimes containing mucin
─ No atypia or mitotic activity
Ancillary studies ─ IHC (+) GATA3, p63, CK7
─ IHC (-) PAX8, WT1, Calretinin
DDx ─ Mesothelial Hyperplasia (Calretinin+, GATA3-)
─ Endosalpingiosis (PAX8+, GATA3-)
─ Serous Tumor Implants (PAX8+, WT1+)
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Endosalpingiosis (Peritoneum)

The presence of benign glands lined by tubal-type epithelium (ciliated, secretory, and peg cells) within the peritoneum or on its surface
Clinical ─ Common incidental finding, especially in women of reproductive age; usually asymptomatic; rarely can form cystic masses; not considered pre-malignant
Macro ─ Often microscopic; can form small, clear, thin-walled cysts or superficial plaques
Micro ─ Glandular or cystic structures lined by bland epithelium identical to fallopian tube lining:
─ Ciliated columnar cells
─ Non-ciliated secretory (peg) cells
─ Intercalated cells
─ Psammoma bodies are frequently associated
─ Stroma is usually minimal or fibrous, lacks endometrial-type stroma
Ancillary studies ─ IHC (+) PAX8, WT1 (variable), ER, PR, CK7
─ IHC (-) Calretinin
DDx ─ Endometriosis (requires endometrial stroma)
─ Peritoneal Inclusion Cyst (mesothelial lining, Calretinin+)
─ Serous Borderline Tumor / Adenocarcinoma (atypia, complexity, invasion)
─ Walthard Nests (transitional epithelium, GATA3+)
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Histiocytic Nodule / Foreign Body Granuloma (Peritoneum)

A reactive nodular aggregate of histiocytes, often with multinucleated giant cells and chronic inflammation, typically formed in response to prior surgery, hemorrhage, or foreign material (eg, talc, suture)
Clinical ─ History of surgery or irritant exposure; usually an incidental finding; benign
Macro ─ Small, firm, white-gray nodules or plaques on peritoneal surfaces
Micro ─ Nodular collections of epithelioid histiocytes (macrophages)
─ Multinucleated foreign body-type giant cells are common
─ Variable chronic inflammatory infiltrate (lymphocytes, plasma cells)
─ Foreign material (suture, talc crystals - birefringent on polarization) may be identified
─ Hemosiderin deposition if related to prior hemorrhage
─ Fibrosis can occur in older lesions
Ancillary studies ─ IHC (+) CD68 highlights histiocytes
DDx ─ Tuberculous Peritonitis (caseating granulomas, AFB+)
─ Sarcoidosis (non-caseating granulomas, clinical context)
─ Metastatic Carcinoma (malignant cells, CK+)
─ Mesothelioma (mesothelial markers+)
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Ectopic Decidua (Peritoneal Deciduosis)

The presence of decidualized stromal cells on peritoneal surfaces or within submesothelial stroma, occurring during pregnancy or in response to exogenous progestin therapy
Clinical ─ Common incidental finding during pregnancy (especially at C-section) or in patients on high-dose progestins; usually asymptomatic; regresses postpartum or after cessation of progestins
Macro ─ Multiple small (mm to cm), slightly raised, pink, tan, or hemorrhagic plaques or nodules on peritoneal surfaces
Micro ─ Sheets or nodules of large, polygonal decidual cells
─ Cells have abundant eosinophilic to amphophilic cytoplasm, distinct cell borders, and round, vesicular nuclei
─ No glands are present (distinguishes from endometriosis with decidual change)
─ May show minimal atypia related to hormonal effect, but lacks mitoses
─ Underlying stroma often vascular and edematous
Ancillary studies ─ IHC (+) Vimentin, PR
─ IHC (+/-) Desmin, Inhibin
─ IHC (-) Cytokeratins
DDx ─ Endometriosis with decidual change (must have endometrial glands)
─ Metastatic Carcinoma (CK+, malignant features)
─ Mesothelioma (mesothelial markers+)
─ Luteoma of Pregnancy (ovarian mass)
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Splenosis (Peritoneum)

Autotransplantation of splenic tissue onto peritoneal or serosal surfaces, typically occurring after splenic trauma or splenectomy
Clinical ─ History of splenic rupture or surgery; usually asymptomatic and incidental; can rarely cause pain or intestinal obstruction if large or strategically located
Macro ─ Multiple small (mm to several cm), dark red-blue, well-circumscribed nodules or plaques on peritoneal surfaces, omentum, bowel serosa, or diaphragm
Micro ─ Ectopic splenic tissue showing normal splenic architecture:
─ Red pulp (sinusoids, macrophages, RBCs)
─ White pulp (lymphoid follicles with germinal centers, periarteriolar lymphoid sheaths - PALS)
─ Trabeculae and vessels
─ Often surrounded by a fibrous pseudocapsule
Ancillary studies ─ Usually none required if histology is classic
─ IHC (+) CD8 (highlights sinusoids), CD20/CD3 (lymphocytes) - can confirm splenic elements
DDx ─ Endometriosis (endometrial glands/stroma, can be reddish)
─ Hemangioma (vascular proliferation)
─ Metastatic Carcinoma (malignant cells)
─ Peritoneal Mesothelioma
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Pseudomyxoma Peritonei (PMP)

A clinical syndrome characterized by abundant gelatinous (mucinous) ascites and peritoneal/omental implants, typically arising from a ruptured appendiceal mucinous neoplasm
Clinical ─ Often presents with abdominal distension, pain, or as an incidental finding; ovaries are frequently secondarily involved (mucinous ovarian tumors); behavior depends on grade of underlying neoplasm
Macro ─ Abdominal cavity filled with voluminous, thick, gelatinous material; omentum often massively thickened ('omental cake'); multiple peritoneal and serosal implants
Micro ─ Pools of extracellular mucin, often dissecting tissue planes
─ Within mucin, variable amounts of neoplastic mucinous epithelium:
─ Low-Grade (DPAM - Disseminated Peritoneal Adenomucinosis): Scant, bland, strip-like or glandular mucinous epithelium with minimal atypia, often floating in mucin
─ High-Grade (PMCA - Peritoneal Mucinous Carcinomatosis): More abundant, atypical mucinous epithelium (glands, papillae, cribriform), often with higher grade atypia and mitotic activity
─ PMCA with Signet Ring Cells: Worst prognosis
─ Fibrous stroma may be present
Ancillary studies ─ IHC (+) CK20, CDX2 (usually intestinal phenotype)
─ IHC (-) CK7 (often, helps distinguish from many Mullerian primaries)
DDx ─ Primary Peritoneal Mucinous Tumors (rare, eg, mucinous mesothelioma)
─ Metastatic Mucinous Carcinoma from other sites (eg, colon, pancreas, ovary - clinical/IHC correlation)
─ Gelatinous ascites from non-neoplastic causes (rare)
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Gliomatosis Peritonei

A rare condition characterized by implants of mature glial tissue on peritoneal surfaces, almost always associated with an ovarian teratoma (usually immature)
Clinical ─ Typically an incidental finding during surgery for an ovarian teratoma in young women/adolescents; generally considered a benign condition (mature glial tissue) with excellent prognosis if associated teratoma is low grade
Macro ─ Multiple small (mm), firm, gray-white nodules or plaques on peritoneal surfaces, omentum, bowel serosa
Micro ─ Nodules composed exclusively of mature glial tissue (astrocytes, oligodendrocytes, ependymal cells)
─ Glial tissue is typically fibrillary or pilocytic, resembling normal brain tissue
─ No immature neuroectodermal elements or other teratomatous components (by definition in pure gliomatosis peritonei)
─ Mitotic activity is absent or very low; no necrosis
Ancillary studies ─ IHC (+) GFAP, S100 (glial markers)
DDx ─ Metastatic Immature Teratoma (would contain immature neuroectoderm)
─ Metastatic Low-Grade Glioma (extremely rare, history crucial)
─ Peritoneal Mesothelioma / Carcinomatosis (different morphology/IHC)
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Placenta

Infections

Chorioamnionitis

Inflammation of the chorioamniotic membranes, typically due to ascending microbial infection from the lower genital tract
Clinical ─ Associated with preterm labor, premature rupture of membranes (PROM), neonatal sepsis, and cerebral palsy; can be clinical or subclinical
Macro ─ Membranes may appear opaque, cloudy, or purulent; amniotic fluid may be turbid or foul-smelling
Micro ─ Maternal Inflammatory Response (graded by stage):
─ Stage 1 (Early): Neutrophils in subchorionic plate or chorion/decidua (Subchorionitis / Chorionitis)
─ Stage 2 (Intermediate): Neutrophils extend into amniotic connective tissue (Amnionitis)
─ Stage 3 (Late): Necrotizing chorioamnionitis with amniotic epithelial necrosis/squames
─ Fetal Inflammatory Response: See Funisitis; also includes chorionic vasculitis (neutrophils in chorionic plate vessels)
─ Organisms (bacteria, Candida) may be visible with special stains
Ancillary studies ─ Gram stain, GMS/PAS (for organisms) - rarely done now unless specific suspicion
DDx ─ Meconium effect (pigmented macrophages, no significant neutrophilic infiltrate unless superimposed infection)
─ Intrauterine fetal demise (non-inflammatory changes unless infection)
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Funisitis

Inflammation of the umbilical cord, representing a fetal inflammatory response, usually secondary to chorioamnionitis
Clinical ─ Component of fetal inflammatory response syndrome (FIRS); associated with adverse neonatal outcomes (sepsis, neurologic injury)
Macro ─ Cord may appear edematous, opaque, or have vascular thrombi
Micro ─ Neutrophilic infiltration of:
─ Umbilical vessels (vasculitis): Phlebitis (umbilical vein) and/or Arteritis (umbilical arteries)
─ Wharton's jelly (inflammation surrounding vessels)
─ Necrotizing Funisitis: Severe form with concentric rings of neutrophils and necrotic debris around vessels; strongly associated with Candida or specific bacterial infections
─ Neutrophils migrate from fetal circulation through vessel walls into Wharton's jelly
Ancillary studies ─ None usually specific for funisitis itself, part of chorioamnionitis workup if done
DDx ─ Umbilical cord knots/torsion (vascular compromise without primary inflammation)
─ Meconium staining of cord (pigment, no neutrophils unless secondary infection)
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Maternal & Fetal Vascular Malperfusion

Maternal Vascular Malperfusion (MVM)

A pattern of placental injury resulting from abnormal or reduced blood flow from the uterus to the placenta, often seen in conditions like preeclampsia, hypertension, or thrombophilias
Clinical ─ Associated with preeclampsia, chronic hypertension, diabetes, autoimmune disease, IUGR, stillbirth, abruption
Macro ─ Placenta may be small; infarcts, retroplacental hematoma (abruption) may be visible
Micro ─ Key features include:
─ Decidual Arteriopathy: Atherosis (fibrinoid necrosis, foamy macrophages in vessel walls), mural hypertrophy, thrombosis of maternal spiral arteries
─ Placental Infarcts: Areas of ischemic villous necrosis (villous agglutination, syncytial knots, ghost villi)
─ Increased Syncytial Knots / Syncytial Sprouting
─ Villous Agglutination
─ Accelerated Villous Maturation (see separate entry)
─ Distal Villous Hypoplasia (see separate entry)
Ancillary studies ─ Usually none; diagnosis based on constellation of morphologic findings
DDx ─ Fetal Vascular Malperfusion (different set of villous changes)
─ Chronic Villitis (inflammatory infiltrate in villi)
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Accelerated Villous Maturation

A placental finding characterized by villi that appear more mature (smaller, more syncytial knots, prominent vasculosyncytial membranes) than expected for gestational age; often a feature of Maternal Vascular Malperfusion
Clinical ─ Associated with conditions causing chronic uteroplacental ischemia (eg, preeclampsia, hypertension, smoking); can be focal or diffuse
Macro ─ Placenta may be small or unremarkable
Micro ─ Terminal villi are smaller and more numerous than expected for gestational age
─ Increased number of syncytial knots (aggregates of syncytiotrophoblast nuclei)
─ Increased vasculosyncytial membranes (areas where fetal capillaries are apposed to overlying syncytiotrophoblast, facilitating exchange)
─ Decreased villous stromal cellularity
Ancillary studies ─ None specific
DDx ─ Normal term placenta (features are appropriate for term, but not preterm)
─ Distal Villous Hypoplasia (small, poorly vascularized villi, less prominent knots)
─ Confined Placental Mosaicism (can affect villous size/maturation)
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Distal Villous Hypoplasia (DVH)

A placental lesion characterized by abnormally small, poorly branched, and often poorly vascularized terminal villi, usually a manifestation of Maternal Vascular Malperfusion
Clinical ─ Associated with severe, early-onset Maternal Vascular Malperfusion, leading to chronic uteroplacental ischemia; linked to severe IUGR and poor perinatal outcomes
Macro ─ Placenta is often small
Micro ─ Terminal villi are small, thin, and poorly branched (reduced complexity)
─ Villi show reduced stromal cellularity and vascularity (avascular or hypovascular villi)
─ Syncytial knots may be present but are not as prominent as in AVM alone
─ Intervillous space may appear relatively increased
Ancillary studies ─ None specific
DDx ─ Accelerated Villous Maturation (villi also small, but more knots/vasculosyncytial membranes)
─ Fetal Vascular Malperfusion (avascular villi, but different underlying cause/associated features like thrombosis)
─ Trisomies (can cause small placenta with dysmorphic villi)
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Fetal Vascular Malperfusion (FVM) / Fetal Thrombotic Vasculopathy (FTV)

A pattern of placental injury due to obstruction of fetal blood flow within the umbilical cord or placental fetal vessels
Clinical ─ Associated with umbilical cord abnormalities (knots, strictures, velamentous insertion), fetal cardiac dysfunction, hypercoagulable states, IUGR, stillbirth, neonatal neurologic injury
Macro ─ May see cord lesions, fetal vessel thrombi, pale areas (avascular) in placenta; fetal membranes may show amnion nodosum if oligohydramnios results
Micro ─ Key features due to obstructed fetal circulation:
─ Avascular Villi: Clusters of chorionic villi lacking fetal capillaries or containing karyorrhectic stromal cells (hallmark)
─ Intimal Fibrin Cushions: Eccentric fibrin deposition in fetal vessel walls
─ Thrombosis: Occlusive or non-occlusive thrombi in fetal arteries or veins (chorionic plate, stem villi)
─ Villous Stromal Karyorrhexis: Degenerating stromal cells in avascular villi
─ Chorangiosis (increased capillaries) can be seen in areas of compensatory flow
Ancillary studies ─ None specific; diagnosis is morphologic
DDx ─ Maternal Vascular Malperfusion (different villous changes, decidual arteriopathy)
─ Massive Perivillous Fibrin Deposition (fibrin encases villi, often associated with fetal demise)
─ Villitis of Unknown Etiology (inflammatory infiltrate in villi)
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Abnormal Villous Development & Maturation

Delayed Villous Maturation / Villous Dysmaturity

A placental finding characterized by the persistence of immature intermediate villi at or near term, reflecting impaired villous development
Clinical ─ Associated with maternal conditions like gestational diabetes mellitus (GDM), fetal hydrops, and some fetal anomalies; can lead to impaired placental function and adverse fetal outcomes
Macro ─ Placenta may be large, pale, and edematous
Micro ─ Persistence of immature intermediate villi with:
─ Larger villous diameter than expected for gestational age
─ Increased stromal cellularity and edema
─ Fetal capillaries that are often centrally located within the stroma (not apposed to syncytiotrophoblast)
─ Fewer syncytial knots and vasculosyncytial membranes than expected
Ancillary studies ─ None specific
DDx ─ Normal early third trimester placenta (features are appropriate for that GA)
─ Placental Mesenchymal Dysplasia (more pronounced cystic changes in stem villi, abnormal vessels)
─ Hydropic abortion (generalized villous edema, often early gestation)
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Villous Chorangiosis / Chorangiomatosis

An increase in the number of fetal capillaries within terminal chorionic villi (chorangiosis) or a focal nodular proliferation of capillaries (chorangiomatosis)
Clinical ─ Chorangiosis is associated with chronic placental hypoxia (eg, maternal diabetes, preeclampsia, smoking, high altitude); Chorangiomatosis is less common, significance less clear but also linked to hypoxia; both can be associated with adverse perinatal outcomes
Macro ─ Usually no specific gross findings for chorangiosis; Chorangiomatosis may appear as small, firm, reddish nodules
Micro ─ Chorangiosis: Defined as >10 terminal villi containing >10 capillaries each, observed in >10 non-infarcted areas using a 10x objective
─ Capillaries are often congested and may protrude into the intervillous space
─ Chorangiomatosis: More localized, nodular proliferation of villous capillaries, forming larger, more complex vascular channels than seen in chorangiosis, but lacking features of true chorangioma
Ancillary studies ─ IHC (+) CD31, CD34 highlight endothelial cells
DDx ─ Chorangioma (a discrete benign vascular neoplasm of the placenta, larger, often solitary)
─ Congested villi (capillaries engorged but not necessarily increased in number)
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Dysmorphic Villi

Chorionic villi with abnormal shapes, contours, stromal characteristics, or trophoblast morphology, often associated with chromosomal abnormalities or specific syndromes
Clinical ─ Finding raises suspicion for fetal aneuploidy (eg, Trisomy 13, 18, 21, Turner syndrome), genetic syndromes, or confined placental mosaicism; may be associated with IUGR or fetal demise
Macro ─ Placenta may be small or show other gross abnormalities depending on underlying condition
Micro ─ Features are variable and can include:
─ Irregular, 'scalloped', or 'geographic' villous contours
─ Villous stromal fibrosis, edema, or hypercellularity
─ Trophoblast pseudoinclusions (invaginations of trophoblast into stroma)
─ Atypical or immature trophoblast
─ Poorly vascularized or avascular villi (can overlap with FVM if specific)
─ Specific patterns may suggest certain aneuploidies (eg, 'grape-like' villi in some trisomies)
Ancillary studies ─ Karyotyping/genetic studies of fetal tissue or amniocytes if suspected clinically or based on severe dysmorphism
DDx ─ Normal variation in villous morphology
─ Other specific placental lesions (eg, villitis, MVM, FVM) which may show some overlapping features
─ Molar pregnancy (specific trophoblastic changes and villous hydrops)
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Placental Mesenchymal Dysplasia (PMD)

A rare placental abnormality characterized by a large placenta with diffuse cystic/grape-like changes in stem villi, normal trophoblast proliferation, and often associated with adverse fetal outcomes including Beckwith-Wiedemann syndrome
Clinical ─ Can mimic partial hydatidiform mole on ultrasound; associated with IUGR, fetal demise, preeclampsia, and Beckwith-Wiedemann syndrome (BWS) or other androgenetic/biparental mosaicism/chimerism; female fetuses more common
Macro ─ Large, edematous placenta; multiple grape-like cystic vesicles (hydropic stem villi); areas of normal-appearing placental tissue may be present
Micro ─ Marked hydropic swelling and cistern formation primarily in stem villi
─ Stroma of affected villi is loose, myxoid, and edematous, with abnormal thick-walled or ectatic blood vessels
─ Crucially, trophoblast proliferation is absent or minimal (distinguishes from molar pregnancy)
─ Terminal villi may appear normal or show chorangiosis
Ancillary studies ─ IHC (+) p57KIP2 is expressed in cytotrophoblast and villous stromal cells (helps rule out complete mole and some partial moles)
─ Molecular ─ Karyotype is typically diploid (46,XX or 46,XY), though mosaicism/chimerism can occur
DDx ─ Partial Hydatidiform Mole (triploid, focal trophoblast proliferation, some villi p57 negative depending on androgenetic contribution)
─ Complete Hydatidiform Mole (diffuse trophoblast proliferation, p57 negative)
─ Twin pregnancy with one normal placenta and one complete mole
─ Hydropic abortion (generalized villous edema, usually early gestation)
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Other Placental Pathology

Chronic Villitis (of Unknown Etiology - VUE)

An inflammatory condition of the placenta characterized by a lymphohistiocytic infiltrate within chorionic villi, with no identifiable infectious cause
Clinical ─ Common (5-15% of term placentas); often an incidental finding but associated with IUGR, preterm delivery, recurrent pregnancy loss, and neurodevelopmental delay; presumed maternal alloimmune or autoimmune response against fetal antigens
Macro ─ Usually no specific gross findings; placenta may be small if associated with IUGR
Micro ─ Infiltration of chorionic villi by lymphocytes (predominantly T-cells) and histiocytes (macrophages)
─ Plasma cells are typically absent (distinguishes from infectious villitis like CMV)
─ Can be focal, multifocal, or diffuse
─ Graded based on extent and severity (eg, Low-grade vs High-grade)
─ Chronic intervillositis (maternal inflammatory cells in intervillous space) may be associated
Ancillary studies ─ IHC can confirm lymphocyte (CD3, CD8) and histiocyte (CD68) presence
─ Special stains for organisms (eg, CMV, Toxoplasma) are negative by definition of VUE
DDx ─ Infectious Villitis (eg, CMV, Toxoplasma, Rubella, Syphilis - specific organisms/inclusions, often plasma cells)
─ Villitis associated with meconium exposure
─ Intervillositis of Unknown Etiology (inflammation primarily in intervillous space)
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Perivillous Fibrin Deposition / Maternal Floor Infarct (MFI)

A spectrum of placental injury characterized by excessive deposition of fibrinoid material in the intervillous space, leading to encasement and atrophy of chorionic villi; MFI represents the most severe end of this spectrum involving the basal plate
Clinical ─ Associated with recurrent pregnancy loss, stillbirth, severe IUGR, and preeclampsia; high recurrence risk in subsequent pregnancies
Macro ─ Maternal Floor Infarct: Placental basal plate is thickened, firm, pale yellow-white, and relatively homogeneous; villous tissue may appear compressed
─ Perivillous Fibrin Deposition: Less extensive, may show focal pale areas or be grossly unremarkable
Micro ─ Extensive deposition of eosinophilic, acellular fibrinoid material within the intervillous space, surrounding and entrapping chorionic villi
─ Entrapped villi become atrophic, fibrotic, and avascular
─ Increased numbers of cytotrophoblast cells (X-cells) may be seen within the fibrinoid material
─ In MFI, this process is diffuse and predominantly involves the maternal floor (basal plate) extending upwards
Ancillary studies ─ None specific; diagnosis is morphologic
DDx ─ Placental Infarct (ischemic necrosis of villi, ghosts of villi, often wedge-shaped)
─ Normal fibrin deposition (minor, focal fibrin is physiologic)
─ Intervillous Thrombus (laminated blood clot in intervillous space)
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Gestational Trophoblastic Disease

Partial Hydatidiform Mole

An abnormal molar pregnancy resulting from diandric triploidy (typically two paternal and one maternal sets of chromosomes), characterized by focal villous hydrops and mild trophoblastic proliferation
Clinical ─ Less common than complete mole; often presents as missed or incomplete abortion; fetal parts may be present; lower risk of persistent gestational trophoblastic neoplasia (GTN) than complete mole; serum hCG often elevated but usually lower than complete mole
Macro ─ Placenta is often bulky with an admixture of normal-appearing small villi and scattered, variably sized hydropic (cystic) villi; fetal sac/parts may be identified
Micro ─ Two distinct populations of chorionic villi:
─ Small, fibrotic, normal-appearing villi
─ Large, edematous, hydropic villi, often with central cistern formation (cavitation)
─ Characteristic scalloped or irregular villous outlines ─ Mild to moderate, often focal trophoblastic proliferation, typically involving syncytiotrophoblast more than cytotrophoblast
─ Villous stromal capillaries often present, may contain fetal red blood cells
Ancillary studies ─ IHC (+) p57KIP2 is expressed in villous stromal cells and cytotrophoblast (paternally imprinted, maternally expressed gene - helps distinguish from complete mole)
─ Molecular ─ Karyotyping shows triploidy (eg, 69,XXY or 69,XXX)
DDx ─ Complete Hydatidiform Mole (diffuse hydrops/proliferation, p57 negative)
─ Hydropic Abortion (diffuse villous edema, no significant trophoblast proliferation, diploid)
─ Placental Mesenchymal Dysplasia (normal trophoblast, p57 positive, diploid)
─ Twin pregnancy with normal fetus and complete mole
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Complete Hydatidiform Mole

An abnormal molar pregnancy resulting from androgenetic diploidy (all chromosomes paternally derived), characterized by diffuse villous hydrops and marked trophoblastic proliferation, with no fetal development
Clinical ─ Presents with vaginal bleeding, uterine size greater than dates, markedly elevated serum hCG, preeclampsia before 20 weeks; higher risk of developing persistent GTN (invasive mole, choriocarcinoma) than partial mole
Macro ─ Uterine cavity filled with diffusely swollen, vesicular (grape-like) chorionic villi; no fetus or amniotic sac usually identified
Micro ─ Diffuse, marked hydropic swelling of virtually all chorionic villi, often with central cistern formation
─ Circumferential, marked proliferation of both cytotrophoblast and syncytiotrophoblast, often with atypia
─ Absence of fetal stromal blood vessels or fetal red blood cells (avascular villi)
─ Villous outlines are typically smooth (not scalloped)
Ancillary studies ─ IHC (-) p57KIP2 is negative in villous stromal cells and cytotrophoblast (key diagnostic feature)
─ Molecular ─ Karyotyping shows diploidy (most commonly 46,XX, all paternal; rarely 46,XY)
DDx ─ Partial Hydatidiform Mole (focal hydrops/proliferation, p57 positive, triploid)
─ Hydropic Abortion (less trophoblast proliferation, diploid biparental)
─ Placental Mesenchymal Dysplasia (normal trophoblast, p57 positive)
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Epithelioid Trophoblastic Tumor (ETT)

A rare gestational trophoblastic neoplasm derived from chorionic-type intermediate trophoblasts, often occurring years after an antecedent pregnancy
Clinical ─ Rare; can occur remote from pregnancy (mean interval ~6-7 years, range up to 20+ years); presents with AUB, mass, or metastasis; serum hCG usually low to moderately elevated; generally less aggressive than choriocarcinoma or PSTT if localized
Macro ─ Well-circumscribed, solid or cystic mass; cut surface often tan-yellow, hemorrhagic, or necrotic
Micro ─ Grows as nodules or sheets of relatively uniform, medium-sized epithelioid cells
─ Cells have distinct borders, eosinophilic to clear cytoplasm, and round nuclei with vesicular chromatin
─ Characterized by geographic (map-like) necrosis and abundant hyaline-like extracellular matrix material
─ Mitotic activity is variable, usually low to moderate
─ Perivascular growth common
Ancillary studies ─ IHC (+) Cytokeratin (AE1/AE3, CAM5_2, CK18), EMA, Inhibin-alpha, GATA3, p63 (diffuse nuclear)
─ IHC (+/-) hCG (focal/weak), hPL (focal/weak), CD146 (variable)
─ IHC (-) SALL4 (usually)
─ Ki67 usually 10-25%
DDx ─ Placental Site Trophoblastic Tumor (PSTT) (more infiltrative, HPL diffuse, p63-)
─ Choriocarcinoma (biphasic, diffuse hCG+, p63-)
─ Squamous Cell Carcinoma (especially cervical; p63+ but lacks other trophoblastic markers, history)
─ Placental Site Nodule (benign, more hyalinization, lower Ki67)
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Placental Site Trophoblastic Tumor (PSTT)

A rare gestational trophoblastic neoplasm derived from implantation site intermediate trophoblasts, characterized by infiltrative growth into the myometrium
Clinical ─ Rare; typically occurs within months to years after a term pregnancy (most common), mole, or abortion; presents with AUB or amenorrhea; serum hCG is usually only mildly elevated; potentially malignant, with ~10-15% metastatic rate
Macro ─ Polypoid or intramural uterine mass, often ill-defined; tan-yellow, fleshy cut surface
Micro ─ Infiltrative growth pattern, with tumor cells dissecting between myometrial fibers (muscle splitting)
─ Composed of sheets, cords, or single polygonal intermediate trophoblast cells
─ Cells have abundant eosinophilic or amphophilic cytoplasm, large irregular nuclei
─ Prominent deposition of fibrinoid material around tumor cells and vessels
─ Vascular invasion is common
─ Mitotic activity is variable, usually <5/10 HPF; higher counts suggest worse prognosis
Ancillary studies ─ IHC (+) hPL (human placental lactogen - diffuse), CD146 (Mel-CAM), Cytokeratin (AE1/AE3, CK18)
─ IHC (+/-) hCG (usually focal/weak), Inhibin (variable)
─ IHC (-) p63 (usually), SALL4
─ Ki67 typically <30%
DDx ─ Exaggerated Placental Site (EPS) (non-neoplastic, lacks mass, less atypia/infiltration)
─ Epithelioid Trophoblastic Tumor (ETT) (nodular, p63+, less HPL)
─ Choriocarcinoma (biphasic, diffuse hCG+)
─ Poorly Differentiated Carcinoma / Sarcoma
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Choriocarcinoma (Gestational)

A highly malignant gestational trophoblastic neoplasm composed of a biphasic proliferation of syncytiotrophoblasts and cytotrophoblasts, without formation of chorionic villi
Clinical ─ Rare; can follow any type of gestation (mole > abortion > ectopic > term); presents with AUB, markedly elevated serum hCG, or symptoms of early metastases (lungs, brain, liver); highly aggressive but very chemosensitive
Macro ─ Often a hemorrhagic, necrotic, friable mass within the uterus or at metastatic sites; primary uterine lesion may be small
Micro ─ Biphasic pattern is essential:
─ Syncytiotrophoblasts: Large, multinucleated cells with dense eosinophilic/vacuolated cytoplasm; produce hCG
─ Cytotrophoblasts: Smaller, monomorphic, mononuclear cells with clear or pale cytoplasm and distinct borders
─ These two cell types are intimately admixed, often with cytotrophoblasts capped by syncytiotrophoblasts, recapitulating early villous trophoblast
─ Absence of chorionic villi distinguishes from hydatidiform mole or chorioadenoma destruens (invasive mole)
─ Extensive hemorrhage and necrosis are characteristic; vascular invasion is common
Ancillary studies ─ IHC (+) hCG (strong and diffuse in syncytiotrophoblasts), SALL4, GATA3, Inhibin (variable in syncytiotrophoblasts)
─ IHC Cytokeratins (AE1/AE3, CAM5_2) positive in both components
─ Molecular ─ Genotyping can confirm gestational origin (presence of paternal DNA distinct from maternal)
DDx ─ Invasive Hydatidiform Mole (chorionic villi present)
─ Placental Site Trophoblastic Tumor (PSTT) / Epithelioid Trophoblastic Tumor (ETT) (monophasic intermediate trophoblast, different IHC)
─ Non-Gestational Choriocarcinoma (ovarian/testicular primary - clinically distinct, pure maternal DNA if ovarian)
─ Poorly Differentiated Carcinoma with STGCs
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Exaggerated Placental Site (EPS)

A non-neoplastic, exuberant infiltration of implantation site intermediate trophoblasts into the decidua and superficial myometrium, seen in association with normal pregnancy or other gestations
Clinical ─ Incidental microscopic finding in curettings or hysterectomy specimens related to pregnancy, abortion, or molar pregnancy; benign, self-limited physiologic process
Macro ─ Usually no discrete mass; endometrium/myometrium may appear thickened or unremarkable
Micro ─ Scattered or small clusters of implantation site intermediate trophoblast cells infiltrating decidua and superficial myometrium
─ Cells are large, polygonal, with eosinophilic cytoplasm and pleomorphic nuclei (can appear atypical)
─ Lacks true tumor mass formation, deep myometrial invasion, significant necrosis, or high mitotic activity seen in PSTT
─ Often associated with fibrinoid material and decidual cells
Ancillary studies ─ IHC (+) hPL, CD146, CK18 (similar to PSTT cells, but distribution is key)
DDx ─ Placental Site Trophoblastic Tumor (PSTT) (forms a discrete tumor mass, more extensive/destructive infiltration, higher Ki67)
─ Decidual Reaction (lacks trophoblasts)
─ Arias-Stella Reaction (glandular atypia, pregnancy hormone effect)
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Placental Site Nodule (PSN)

A benign, small, well-circumscribed, hyalinized nodule composed of chorionic-type intermediate trophoblasts, usually an incidental finding in the endometrium or cervix remote from pregnancy
Clinical ─ Usually an asymptomatic, incidental microscopic finding in curettings or biopsies, often years after a previous gestation; benign
Macro ─ Usually microscopic; if visible, a tiny, firm, yellowish-white nodule
Micro ─ Well-demarcated, often round to oval nodule
─ Composed of scattered, degenerating intermediate trophoblast cells (chorionic type) embedded in an abundant, dense, hyalinized (acellular eosinophilic) stroma
─ Trophoblast cells have eosinophilic to clear cytoplasm, nuclei can be irregular or pyknotic
─ Minimal to absent mitotic activity
Ancillary studies ─ IHC (+) Inhibin, p63 (variable), CK18, EMA, PLAP (variable)
─ IHC (-) hPL, CD146 (usually negative, unlike PSTT/EPS)
─ Ki67 index is very low
DDx ─ Epithelioid Trophoblastic Tumor (ETT) (larger, viable cells, geographic necrosis, less hyalinization, different IHC)
─ Placental Site Trophoblastic Tumor (PSTT) (infiltrative, viable cells, hPL+)
─ Squamous Cell Carcinoma (especially if cervical - keratin pearls, intercellular bridges)
─ Decidual Nodule (lacks trophoblasts)
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Chorangioma

The most common benign vascular neoplasm of the placenta, essentially a hemangioma of chorionic villous origin
Clinical ─ Most are small (<4 cm) and clinically insignificant, found incidentally; large chorangiomas (>4-5 cm) can be associated with fetal complications (eg, hydrops, IUGR, polyhydramnios, preterm labor) due to AV shunting or mass effect
Macro ─ Well-circumscribed, firm, red-purple to tan nodule, usually on fetal surface or within placental disc; can be single or multiple
Micro ─ Well-demarcated nodular proliferation of benign capillaries within a villous stroma
─ Two main histologic patterns (often mixed):
─ Angiomatous (Capillary): Numerous small, back-to-back capillaries lined by bland endothelial cells
─ Cellular: More cellular with less distinct lumina, plump endothelial cells, and pericytes
─ Stroma can be fibrous or edematous
─ May show secondary changes: thrombosis, infarction, calcification, hyalinization
Ancillary studies ─ IHC (+) CD31, CD34, Factor VIII-related antigen, GLUT1 (endothelial cells)
DDx ─ Chorangiosis (diffuse increase in villous capillaries, not a discrete mass)
─ Chorangiomatosis (focal nodular capillary proliferation but less discrete/organized than chorangioma)
─ Umbilical Cord Hemangioma (similar histology, different location)
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Hepatocellular Adenoma-like Lesion of Placenta

An extremely rare, benign lesion of the placenta composed of cells resembling hepatocytes
Clinical ─ Extremely rare; usually an incidental finding; clinical significance is uncertain due to rarity, presumed benign
Macro ─ May appear as a small, well-circumscribed, tan or yellowish nodule
Micro ─ Well-demarcated nodule composed of sheets or cords of polygonal cells with abundant eosinophilic, granular cytoplasm, resembling hepatocytes
─ Nuclei are round with inconspicuous nucleoli; minimal atypia
─ Lacks portal tracts or normal liver architecture
─ May contain bile pigment
Ancillary studies ─ IHC (+) HepPar-1, Arginase-1 (hepatocyte markers)
─ IHC (+/-) AFP (can be positive)
─ IHC (-) Glypican-3 (unlike hepatocellular carcinoma)
DDx ─ Decidual Nodule (decidual cells, PR+)
─ Metastatic Hepatocellular Carcinoma (extremely rare, would show malignant features)
─ Yolk Sac Tumor, Hepatoid variant (AFP strong+, SALL4+, malignant)
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Placental Site Subinvolution (Subinvolution of Uteroplacental Arteries)

Failure of physiologic remodeling and involution of spiral arteries at the placental implantation site postpartum, leading to persistent large, ectatic vessels
Clinical ─ Important cause of delayed postpartum hemorrhage (usually 1-2 weeks to months after delivery); can also present with AUB
Macro ─ Uterus may be boggy; implantation site may appear shaggy or contain protruding vessels
Micro ─ Persistence of large, thick-walled, poorly involuted spiral arteries within the superficial myometrium and endometrium at the placental site
─ Vessels are often ectatic, with hyalinized or muscular walls, and may lack an endothelial lining or contain thrombi
─ Surrounding stroma often shows decidual change, fibrin deposition, and scattered intermediate trophoblast cells
─ No chorionic villi are present
Ancillary studies ─ Usually none required; diagnosis based on H&E in clinical context of PPH
DDx ─ Retained Products of Conception (chorionic villi present)
─ Arteriovenous Malformation (complex tangle of abnormal arteries/veins, not just spiral arteries)
─ Gestational Trophoblastic Neoplasia (eg, PSTT - infiltrative trophoblastic tumor)
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