Classification of Ovarian Tumors

Introduction

1. Surface epithelial-stromal tumors (from müllerian/surface epithelium)
2. Sex cord-stromal tumors (from gonadal stroma and sex cords)
3. Germ cell tumors (from primordial germ cells)
4. Metastatic tumors (from non-ovarian primaries)

I. Surface Epithelial-Stromal Tumors

General Behavior Grading

• Benign: Well-differentiated, confined, no invasion - lined by well-formed glandular epithelium without atypia
• Borderline (Low Malignant Potential): Show epithelial proliferation with cytologic atypia but without stromal invasion - significant clinical intermediate category
• Malignant (Carcinoma): Show frank stromal invasion, cytologic atypia, and metastatic potential

Type I vs. Type II Carcinomas

• Type I tumors progress stepwise from benign cystadenoma → borderline tumor → low-grade carcinoma. They harbor mutations in KRAS, BRAF, or ERBB2 and are typically TP53 wild-type. They include low-grade serous, endometrioid, and mucinous carcinomas.
• Type II tumors arise de novo from in situ lesions (serous tubal intraepithelial carcinoma, STIC) without a recognizable precursor. They carry TP53 mutations in >95% of cases and frequently have BRCA1/2 dysfunction. High-grade serous carcinoma is the prototype.

1. Serous Tumors

• Benign serous cystadenoma: Thin-walled unilocular cysts lined by columnar, ciliated, tubal-type epithelium resembling fallopian tube mucosa. Often bilateral (~20%). Composed of clear, straw-colored serous fluid.
• Borderline serous tumor: Show complex papillary architecture and epithelial stratification (2-3 layers) with mild to moderate cytologic atypia but no destructive stromal invasion. Behavior is indolent; even when peritoneal implants are present, prognosis is generally favorable.
• Low-grade serous carcinoma (LGSC): Arises from borderline tumors; mild nuclear atypia, KRAS/BRAF mutations, indolent behavior, relatively chemo-resistant.
• High-grade serous carcinoma (HGSC): The most common and lethal ovarian malignancy. Composed of cells with severe nuclear atypia, high mitotic activity, and frequent psammoma bodies (concentric calcified laminations). TP53 mutations present in >95%. Now thought to arise largely from STIC at the fimbriated end of the fallopian tube, not the ovarian surface itself.

2. Mucinous Tumors

• Benign mucinous cystadenoma: The largest ovarian tumors ever recorded (weights over 100 kg have been reported). Multilocular with locules containing thick, gelatinous mucin. Lined by tall columnar cells with basally placed nuclei.
• Borderline mucinous tumor: More common as the intestinal type. Proliferative glandular architecture without invasion.
• Mucinous adenocarcinoma: Malignant form with destructive invasion. Must be distinguished from Krukenberg tumors (bilateral ovarian metastases from a gastric or colorectal primary showing signet-ring cells). Primary ovarian mucinous carcinomas are almost always unilateral; bilateral mucinous tumors should raise suspicion for metastasis.
• Pseudomyxoma peritonei: A complication seen when mucinous tumors rupture, seeding the peritoneum with mucin-secreting cells. Now understood to arise predominantly from appendiceal primaries, not ovarian primaries.

3. Endometrioid Tumors

• Benign endometrioid tumors: Rare; include cystadenomas and adenofibromas.
• Endometrioid adenocarcinoma: Accounts for ~20% of ovarian carcinomas. Importantly, about 15-20% are associated with endometriosis, and 15-30% have a synchronous endometrial carcinoma. They arise from endometriosis or from inclusion cysts with endometrioid metaplasia. Mutations include CTNNB1 (beta-catenin), PTEN, KRAS, ARID1A, and mismatch repair gene defects (Lynch syndrome).

4. Clear Cell Tumors

• Lined by cells with abundant clear cytoplasm (due to glycogen) and a "hobnail" pattern of cells protruding into glandular lumens.
• Most are malignant (clear cell adenocarcinoma) and arise from endometriosis.
• Associated with hypercalcemia and a higher rate of thromboembolic events.
• Relatively resistant to platinum-based chemotherapy compared to serous carcinoma.
• Mutation hallmark: ARID1A (chromatin remodeling gene) mutations in ~50% of cases.

5. Brenner Tumors

• Contain nests of epithelial cells resembling urothelium (transitional cell epithelium) embedded in dense fibrous stroma - sometimes described as "coffee bean" nuclei.
• Benign Brenner tumors are the vast majority; often incidental findings.
• Borderline and malignant Brenner tumors are rare.
• Thought to arise from metaplasia of the surface epithelium or from Walthard cell rests.

II. Sex Cord-Stromal Tumors

1. Granulosa Cell Tumors

• Adult granulosa cell tumor (AGCT): The most common malignant sex cord-stromal tumor. Accounts for ~2% of all ovarian tumors. Occurs predominantly in postmenopausal women.
  • Secrete estrogen → causes endometrial hyperplasia, postmenopausal bleeding, and has association with endometrial carcinoma (5%).
  • Histology: Call-Exner bodies (small follicle-like structures with eosinophilic secretion) are pathognomonic. Coffee-bean nuclei with nuclear grooves.
  • Molecular hallmark: FOXL2 mutation (C134W) is present in >95% of AGCTs.
  • Behavior is low-grade malignant with late recurrences (10-30 years); inhibin is a tumor marker.
• Juvenile granulosa cell tumor (JGCT): Occurs before puberty; causes isosexual precocious puberty. Lacks FOXL2 mutations.

2. Thecomas and Fibromas

• Thecoma: Composed of lipid-laden stromal cells resembling theca interna. Virtually always benign. Estrogenic (endometrial stimulation).
• Fibroma: Composed of spindle-shaped fibroblasts; no hormonal activity. Associated with Meigs syndrome (fibroma + ascites + right-sided pleural effusion - all resolve after tumor removal) and with Gorlin syndrome (basal cell nevus syndrome).
• Fibrothecoma: Mixed features of both.

3. Sertoli-Leydig Cell Tumors (Androblastoma)

• Recapitulate testicular tubular architecture with Sertoli cells and Leydig cells.
• Typically produce androgens → virilization (hirsutism, clitoromegaly, deepening of voice, amenorrhea).
• Mostly occur in young women (second and third decades).
• Most are of low malignant potential; ~20% are malignant.
• Molecular feature: DICER1 mutations in a subset.

4. Steroid (Lipid) Cell Tumors

• Stromal luteoma, Leydig cell tumors, or steroid cell tumors NOS.
• Produce steroid hormones; may cause virilization or, rarely, Cushing syndrome.

III. Germ Cell Tumors

1. Teratomas

a) Mature Cystic Teratoma (Dermoid Cyst)

• The most common ovarian tumor overall in women of reproductive age.
• Benign, predominantly ectodermal tissue: lined by skin (squamous epithelium) with appendages, hair, teeth, sebaceous material.
• Other tissues present: thyroid, neural, gastrointestinal, respiratory.
• Bilateral in ~15% of cases.
• Complication: malignant transformation in <2% (usually squamous cell carcinoma).
• Can undergo torsion, rupture causing chemical peritonitis.

b) Immature Teratoma

• Contains immature (embryonal) tissue, most notably immature neuroepithelium (primitive neural elements).
• Malignant, occurring in the first two decades of life.
• Graded 1-3 based on the amount of immature neural tissue per slide.
  • Grade 1: Rare foci of immature tissue, <1 LPF per slide - best prognosis
  • Grade 3: Abundant immature neuroepithelium, >3 LPF per slide - worst prognosis
• Grows rapidly, penetrates capsule, spreads locally and distantly.
• Stage I, grade 1 has excellent prognosis; higher grades require adjuvant chemotherapy.

c) Monodermal (Specialized) Teratomas

• Composed almost entirely of a single tissue type:
  • Struma ovarii: Entirely mature thyroid tissue; may cause hyperthyroidism
  • Ovarian carcinoid: Arises from intestinal tissue within a teratoma; may cause carcinoid syndrome (even without liver metastases, as ovarian veins drain directly into the systemic circulation)
  • Strumal carcinoid: Combined struma ovarii and carcinoid

2. Dysgerminoma

• The ovarian counterpart of testicular seminoma - the most common malignant germ cell tumor of the ovary.
• Accounts for ~50% of malignant ovarian germ cell tumors.
• Predominantly occurs in the second and third decades. May occur in gonadal dysgenesis (XY gonadal dysgenesis) where risk of malignancy is ~30%.
• Morphology: Large, solid, lobulated tumors with gray-white to yellow-white cut surface. Histologically: sheets of large cells with vesicular nuclei, prominent nucleoli, clear cytoplasm, separated by fibrous septa infiltrated by lymphocytes.
• Expresses OCT3/4, OCT4, NANOG, PLAP (placental alkaline phosphatase).
• Associated with isochromosome 12p and KIT mutations/amplification (~30-50%).
• Most are non-functional (no hormone secretion), though some with syncytiotrophoblastic giant cells may produce hCG.
• Highly radiosensitive and chemosensitive - 5-year survival of early-stage tumors approaches 95%.
• LDH serves as a serum tumor marker.

3. Yolk Sac Tumor (Endodermal Sinus Tumor)

• Recapitulates the yolk sac (extraembryonic endoderm).
• Predominantly affects women under 30 years.
• Characterized histologically by Schiller-Duval bodies (perivascular structures resembling the endodermal sinuses of the rat placenta).
• Produces alpha-fetoprotein (AFP) - the key serum tumor marker.
• Highly aggressive but responds well to BEP chemotherapy (bleomycin, etoposide, cisplatin).

4. Choriocarcinoma (Non-gestational)

• Rare primary ovarian tumor composed of cytotrophoblast and syncytiotrophoblast.
• Produces hCG (beta-hCG) in large amounts → isosexual precocious puberty in young girls.
• Highly malignant.

5. Embryonal Carcinoma

• Very rare, highly malignant.
• Produces both AFP and hCG.
• Occurs in young women; histologically resembles embryonal carcinoma of testis.

6. Mixed Germ Cell Tumors

• Combinations of two or more germ cell tumor types in a single tumor.
• The most common combination is dysgerminoma + yolk sac tumor.
• Management is guided by the most malignant component present.

IV. Metastatic Tumors (Secondary Ovarian Tumors)

• Colorectal and appendiceal carcinomas (most common overall)
• Gastric carcinoma - classic source of Krukenberg tumor
• Breast carcinoma
• Endometrial carcinoma

• Bilateral ovarian metastases (usually symmetric enlargement)
• Characterized histologically by mucin-filled signet ring cells within a cellular ovarian stroma (desmoplastic reaction)
• Most commonly from gastric primary, also colorectal and appendix
• Usually presents as diffuse peritoneal carcinomatosis with poor prognosis

• Bilateral involvement
• Small ovarian size
• Nodular growth pattern
• Surface involvement
• Associated peritoneal implants

V. Epidemiology and Clinical Correlations

VI. FIGO Staging (Brief Overview)

• Stage I: Confined to ovary/ovaries
• Stage II: Pelvic extension
• Stage III: Peritoneal metastases beyond the pelvis or retroperitoneal lymph node involvement
• Stage IV: Distant metastases (including pleural effusion with cytology-positive cells, liver parenchyma)

Conclusion

Classification of Ovarian Tumors with Morphological Features

Introduction

I. SURFACE EPITHELIAL-STROMAL TUMORS

1. Serous Tumors

Gross Morphology

• Serous tumors present as unilocular or multilocular cystic masses
• Benign serous cystadenoma: Thin-walled, smooth-surfaced cyst with a glistening inner wall; minimal or no papillary projections; filled with clear watery (serous) fluid; typically 5-15 cm
• Borderline serous tumor: Cyst lined by numerous delicate papillary projections projecting into the lumen; may grow on the outer surface (exophytic); complex but no solid areas of invasion
• Serous carcinoma: Large, bulky solid-cystic masses; irregular nodular capsule; areas of hemorrhage and necrosis; may have surface excrescences; large papillary masses filling the cyst
• Bilaterality: 20% of benign, 30% of borderline, ~66% of serous carcinomas are bilateral

Microscopic Morphology

• Benign: Cysts lined by a single layer of columnar epithelium with abundant cilia, resembling fallopian tube (endosalpingeal) epithelium; simple microscopic papillae; no atypia
• Borderline: Increased complexity of papillae with hierarchical (arborescent) branching; pseudostratification (2-3 cell layers); epithelial tufting and detached cell clusters; mild nuclear atypia and slightly increased mitoses; NO stromal invasion - the basement membrane remains intact (key diagnostic criterion)
  • Micropapillary variant: Non-hierarchical, filiform papillae arising directly from large fibrovascular cores ("Medusa head" pattern); higher risk of invasive implants
• Low-grade serous carcinoma (LGSC): Small, uniform nests and papillae invading stroma; mild nuclear atypia; low mitotic rate; KRAS/BRAF mutations; arises from borderline tumors
• High-grade serous carcinoma (HGSC): Complex glandular, papillary, and solid architecture; marked nuclear pleomorphism (≥3-fold size variation); numerous mitoses (>12/10 HPF); prominent nucleoli; areas of necrosis; frequently shows psammoma bodies (concentric laminated calcifications - pathognomonic of serous type); TP53 mutations in >95%
• Psammoma bodies: Round, laminated, calcified concretions within papillary structures - form from apoptotic tumor cells and are a hallmark of serous differentiation

2. Mucinous Tumors

Gross Morphology

• Multilocular cystic masses with compartments containing thick, viscid, gelatinous mucin
• Locules vary in size and number; the overall tumor can be massive (>50 cm, >100 kg recorded)
• Benign cystadenoma: Smooth inner walls, no solid areas; contents are gelatinous/honey-like
• Borderline: Papillary excrescences on inner wall; soft pale areas
• Mucinous carcinoma: Solid areas, hemorrhage, necrosis; irregular friable inner surface
• Predominantly unilateral (bilateral mucinous tumors raise suspicion of metastasis - especially Krukenberg)

Microscopic Morphology

• Intestinal type (more common): Lined by columnar mucin-secreting cells resembling colonic or gastric epithelium; goblet cells present; interspersed Paneth cells
• Endocervical (müllerian) type: Lined by cells resembling endocervical mucosa; often associated with pseudomyxoma peritonei
• Benign: Single layer of tall columnar cells with basal nuclei and apical mucin vacuoles; minimal atypia
• Borderline: Epithelial stratification (2-3 layers), nuclear atypia, increased mitoses, papillary tufting; no destructive invasion
• Mucinous carcinoma: Glands lined by markedly atypical mucin-secreting cells invading stroma with desmoplastic reaction; may show back-to-back glands with little intervening stroma (confluent glandular pattern)
• Pseudomyxoma peritonei: Peritoneal surface implants of mucin-secreting cells; produces jelly-like material filling the abdomen; usually from appendiceal primary (not truly ovarian)

3. Endometrioid Tumors

Gross Morphology

• Predominantly solid and cystic tumors; cut surface shows both cystic areas (often blood-tinged, from associated endometriosis) and solid tan-white regions
• Often arise within a background of endometriosis (chocolate cyst/endometrioma)
• Size varies from small to large masses; 40% are bilateral (suggesting extraovarian spread)
• Inner surface may show polypoid, friable solid components

Microscopic Morphology

• Contain tubular glands closely resembling endometrial glands - the diagnostic hallmark
• Benign: Glands lined by columnar endometrioid cells; no atypia; may have endometrial stroma
• Borderline: Stratification and mild atypia without invasion
• Carcinoma: Well-formed glands or solid sheets of cells; may show squamous differentiation (squamous morules - adenoacanthoma pattern) or mucinous areas - squamous differentiation in endometrioid carcinoma is a diagnostically helpful feature
• Nuclei: Elongated, pseudostratified, with moderate atypia; mitoses variable
• Often graded as FIGO grade 1, 2, or 3 based on solid component proportion
• Key mutations: CTNNB1 (beta-catenin), PTEN, ARID1A, KRAS; mismatch repair deficiency in Lynch syndrome cases

4. Clear Cell Carcinoma

Gross Morphology

• Can be predominantly solid or cystic
• Often arise within an endometriotic cyst (the cyst wall shows clear cell carcinoma nodules)
• Solid areas appear tan-yellow; hemorrhagic foci common
• Mostly unilateral

Microscopic Morphology

• Two characteristic cell types:
  • Clear cells: Large polygonal cells with abundant optically clear cytoplasm (due to glycogen - PAS-positive, diastase-labile); nuclei pushed to the periphery; cells arranged in sheets, tubules, or glands
  • "Hobnail cells": Cells with bulging nuclei that protrude into glandular lumens like a hobnail - the pathognomonic feature; scant cytoplasm; the nucleus sticks out above the apical cytoplasm
• Growth patterns: Tubulo-cystic, papillary (with hobnail cells lining papillae), and solid - all three often coexist in the same tumor
• Stroma: Hyalinized basement membrane-like material around tubules is characteristic
• High nuclear grade; numerous mitoses
• ARID1A mutations in ~50%; shared mutations with endometrioid carcinoma (PIK3CA, KRAS, PTEN)
• Associated with hypercalcemia (paraneoplastic) and thromboembolic events

5. Brenner Tumors (Transitional Cell Tumors)

Gross Morphology

• Typically solid, small (<2 cm), firm, gray-white masses with a gritty consistency on cut section (due to calcifications)
• Well-encapsulated; dense fibrous consistency resembling a fibroma
• Usually unilateral (~90%)
• Rarely large (up to 30 cm in malignant variants)
• Often found incidentally alongside another ovarian tumor (mucinous cystadenoma frequently co-occurs)

Microscopic Morphology

• Characteristic sharply demarcated nests of epithelial cells (Walthard nests) embedded in dense fibrous stroma
• Epithelial nests resemble urothelium (transitional cell epithelium):
  • Cells have oval nuclei with characteristic longitudinal grooves ("coffee bean nuclei")
  • Central mucinous glands within nests are common
  • Nuclei are bland with inconspicuous nucleoli
• Surrounding fibrous stroma resembles normal ovarian stroma; may contain plump theca-like cells (occasionally estrogenic)
• Malignant Brenner tumor: Recognizable benign Brenner nests adjacent to clearly malignant transitional cell carcinoma areas
• Transitional cell carcinoma (without Brenner component): Similar to high-grade serous carcinoma; treated identically

II. SEX CORD-STROMAL TUMORS

1. Granulosa Cell Tumors

Gross Morphology

• Adult type (AGCT): Variable size; may be large (up to 20 cm); typically encapsulated
• Cut surface shows yellow-tan to white lobulated tissue alternating with cystic, often hemorrhagic areas; the yellow color reflects steroid-producing cells with lipid
• Juvenile type (JGCT): Predominantly solid, may have cystic areas
• May show hemorrhage into cysts causing a blood-filled mass (hemoperitoneum from rupture is a complication)

Microscopic Morphology

• Call-Exner bodies: Small follicle-like structures with a central round space filled with eosinophilic secretion (degenerated nuclear material) surrounded by granulosa cells arranged in a rosette pattern - pathognomonic
• Nuclear grooves: Characteristic "coffee bean" or "cleaved" nuclei - pale, angular nuclei with a longitudinal groove
• Growth patterns: microfollicular (most common, Call-Exner bodies), macrofollicular, trabecular, insular, diffuse (sarcomatoid - least differentiated)
• Cells are small with pale-to-clear cytoplasm and scant stroma
• Immunohistochemistry: Strongly positive for inhibin and calretinin; negative for EMA and keratin
• FOXL2 mutation (C134W) in 97% of adult GCT - molecular hallmark
• Juvenile GCT: Follicles with abundant pale secretions and more luteinized cells; lacks Call-Exner bodies; nuclear grooves less prominent; AKT1 and GNAS mutations

2. Thecomas and Fibromas

Gross Morphology

• Thecoma: Solid, yellow (lipid-rich) to white tumor; usually <10 cm; unilateral; encapsulated; cut surface bright yellow due to lipid content
• Fibroma: Solid, hard, gray-white mass; firm, rubbery to stony consistency; glistening intact serosa; cut surface shows dense white whorled appearance similar to a uterine leiomyoma; usually unilateral (~90%); size 1-10 cm typically but can exceed 20 cm
• Calcification may be present (especially in Gorlin syndrome-associated fibromas)

Microscopic Morphology

• Thecoma: Sheets of plump spindle-to-round cells with abundant pale, lipid-laden cytoplasm (clear on H&E, positive for Oil-Red-O); interspersed hyaline plaques; estrogenic (positive for inhibin)
• Fibroma: Well-differentiated spindle-shaped fibroblasts with scant collagenous stroma in an intersecting fascicular pattern; scant cytoplasm; bland nuclei; no significant atypia; may show edema (cellular fibroma)
• Fibrothecoma: Mixed features - fibrous spindle cells plus lipid-laden thecomatous foci
• Mitoses very rare; if >4/10 HPF → fibrosarcoma territory

3. Sertoli-Leydig Cell Tumors (Androblastoma)

Gross Morphology

• Predominantly solid, lobulated, yellow-brown tumors
• Cut surface shows solid tan-yellow lobules (due to lipid in Leydig cells)
• Usually unilateral, small to medium size; occasionally large
• May have cystic components (especially poorly differentiated types)
• Associated with virilization

Microscopic Morphology

• Sertoli cells: Arranged in hollow or solid tubules (recapitulating seminiferous tubules); columnar cells with pale cytoplasm, round-oval nuclei
• Leydig cells: Large polygonal cells with abundant eosinophilic granular cytoplasm, round nuclei with prominent nucleoli; often have Reinke crystals (eosinophilic rod-shaped intracytoplasmic crystalloids - pathognomonic of Leydig cell differentiation)
• Graded by differentiation:
  • Well-differentiated: Distinct tubular structures, both cell types clearly identifiable
  • Moderately differentiated: Cords and trabeculae; incomplete tubule formation; immature Sertoli cells
  • Poorly differentiated: Sarcomatoid pattern; diagnosis challenging; heterologous elements (cartilage, skeletal muscle, mucinous epithelium) may occur in ~20%
• DICER1 mutations in a subset; particularly in those with heterologous elements

III. GERM CELL TUMORS

1. Mature Cystic Teratoma (Dermoid Cyst)

Gross Morphology

• Unilocular or occasionally multilocular cyst; size typically 5-10 cm
• Outer surface: Smooth, glistening, pearly-white capsule
• Inner surface: Lined by skin-like tissue - pale, wrinkled, resembling the scalp
• Content: Sebaceous material (thick, greasy, yellow), matted hair (tufts of hair a characteristic finding), sometimes teeth or calcified bone visible on imaging/gross
• A localized thickening of the cyst wall called the Rokitansky protuberance (dermoid plug / mamilla) is characteristic - this is where most mature tissues are concentrated (teeth, hair follicles, thyroid, neural tissue)
• Cut surface: May reveal solid nodular areas, teeth embedded in gritty material

Microscopic Morphology

• Ectodermal components: Stratified squamous epithelium with hair follicles, sebaceous glands, sweat glands, neural tissue - the dominant component
• Mesodermal components: Smooth muscle, cartilage, bone, connective tissue
• Endodermal components: Respiratory epithelium, gastrointestinal mucosa, thyroid follicles
• All tissues are mature (fully differentiated) - absence of immature/embryonic tissue defines this as benign
• Malignant transformation (<2%): Most commonly squamous cell carcinoma arising from the squamous lining; rarely basal cell carcinoma, adenocarcinoma, carcinoid
• Chemical peritonitis can occur if the cyst ruptures, due to spillage of sebaceous material

2. Immature Teratoma

Gross Morphology

• Large, predominantly solid tumors with some cystic areas
• Cut surface: Variegated appearance - mixed solid gray-white (neural tissue), glistening (cartilage), gritty (bone) areas interspersed with cystic spaces
• May show areas of hemorrhage and necrosis
• Rapidly growing; capsule may be breached

Microscopic Morphology

• Contains immature (embryonal) tissues from all three germ layers; the crucial diagnostic element is immature neuroepithelium
• Immature neuroepithelium: Primitive neural tubules and rosettes lined by small, dark, mitotically active cells, resembling fetal neural tissue - the grading element
• Also contains immature skeletal muscle, cartilage, glandular epithelium
• Grading (1-3) based on amount of immature neural tissue per low-power field:
  • Grade 1: Rare foci, <1 low-power field (LPF) of immature neuroepithelium per slide
  • Grade 2: 1-3 LPF per slide
  • Grade 3: >3 LPF per slide - worst prognosis
• Mixed with mature components - the immature elements alone determine grade
• Fig. 22.38 (Robbins): "Primitive neuroepithelium" forming rosette-like structures - key microscopic feature

3. Dysgerminoma

Gross Morphology

• Solid, lobulated tumor with gray-white to gray-pink ("fish-flesh") cut surface
• Soft and fleshy consistency
• May be small or fill the entire abdomen
• 80-90% are unilateral; 10-15% bilateral
• Capsule often intact; if ruptured → peritoneal spread

Microscopic Morphology

• Sheets and nests of large, uniform round cells with abundant clear to pale cytoplasm (glycogen-rich) and prominent, centrally placed round nuclei with 1-2 prominent nucleoli
• Cells show a "fried egg" appearance - round cell with prominent nucleus surrounded by clear cytoplasm
• Fibrous septa subdivide tumor into lobules; septa are infiltrated by lymphocytes (T cells) - immune response analogous to seminoma
• Granulomatous reaction within septa (histiocytes, giant cells) in some areas
• Scattered syncytiotrophoblastic giant cells in ~5-10% - associated with elevated hCG
• Mitoses are frequent
• Immunohistochemistry: Positive for PLAP (placental alkaline phosphatase), OCT3/4, OCT4, NANOG, CD117 (KIT), D2-40 (podoplanin); negative for AFP, hCG (unless syncytiotrophoblastic cells present)
• Isochromosome 12p [i(12p)] - cytogenetic hallmark (shared with testicular seminoma)

4. Yolk Sac Tumor (Endodermal Sinus Tumor)

Gross Morphology

• Large, predominantly solid tumors with variable cystic areas
• Cut surface: Gray-white to yellow, soft, often with prominent hemorrhage and necrosis (highly vascular, aggressive tumor)
• Predominantly unilateral; may show rupture with hemoperitoneum

Microscopic Morphology

• Most characteristic structure: Schiller-Duval bodies - glomerulus-like structures with a central fibrovascular core lined by tumor cells, surrounded by a cystic space lined by tumor cells (resembling endodermal sinuses of the rat placenta - pathognomonic)
• Reticular (mesh-like) pattern: Most common pattern - anastomosing spaces and channels lined by flattened or cuboidal tumor cells in a loose myxoid stroma
• Periodic acid-Schiff (PAS)-positive, diastase-resistant hyaline globules within tumor cells and intercellular spaces - represent AFP
• Other patterns: polyvesicular vitelline, hepatoid, glandular (endometrioid-like), solid
• AFP immunoreactivity in tumor cells - diagnostic marker (serum AFP elevated)
• Cells have primitive appearance with large pleomorphic nuclei and conspicuous nucleoli

5. Choriocarcinoma (Non-Gestational, Primary Ovarian)

Microscopic Morphology

• Biphasic pattern: Cytotrophoblast (mononuclear pale cells) + syncytiotrophoblast (multinuclear giant cells with dark vacuolated cytoplasm)
• Extensive hemorrhage and necrosis throughout
• Produces hCG (elevated in serum)
• Must be distinguished from gestational choriocarcinoma

IV. METASTATIC TUMORS - KRUKENBERG TUMOR

Gross Morphology

• Bilateral (almost always), symmetrical ovarian enlargement - key clue to metastasis
• Ovaries usually preserve their shape but are markedly enlarged
• Cut surface: Solid, firm, white to yellow nodular masses; gelatinous mucin-filled areas

Microscopic Morphology

• Characteristic signet ring cells: Large mucin-filled vacuoles that compress and displace the nucleus to the periphery, giving the cell a "signet ring" appearance
• Signet ring cells scattered individually or in clusters within a cellular, fibromatous (desmoplastic) ovarian stroma that shows reactive proliferation - the stroma is characteristically cellular, not fibrous and acellular
• The cellular stromal reaction distinguishes Krukenberg tumor from other mucinous metastases
• Mucin stains (Alcian blue, mucicarmine) highlight the intracytoplasmic mucin

Summary Table of Key Morphological Features