Ovarian Tumor Pathology (Harsh Mohan / WHO Classification)

Note: Harsh Mohan's Textbook of Pathology is not directly available in this library, but it follows the WHO classification identical to Robbins & Cotran. The content below is drawn from Robbins & Cotran Pathologic Basis of Disease and Robbins & Kumar Basic Pathology, which are the primary reference sources Harsh Mohan cites throughout his text.

Overview and Classification

1. Surface/fallopian tube epithelium (and endometriosis)
2. Germ cells
3. Gonadal stroma (sex cord-stromal cells)

WHO Classification of Ovarian Neoplasms

Type I vs. Type II Ovarian Carcinoma (Pathogenesis)

I. Surface Epithelial Tumors (~65% of all ovarian tumors; 90% of malignancies)

A. Serous Tumors (most common epithelial tumor)

• 70% benign or borderline, 30% malignant
• Benign/borderline: ages 20-45; serous carcinomas: older (familial cases earlier)
• Risk factors: increasing age, nulliparity, early menarche/late menopause, BRCA1/BRCA2 mutations (20-60% lifetime risk by age 70)
• OCP use reduces risk (suppression of ovulation)

• Serous cystadenoma (benign): lined by single layer of columnar, ciliated cells resembling fallopian tube epithelium; may be papillary; bilateral in 20%
• Borderline serous tumor: increased architectural complexity, epithelial stratification without stromal invasion; psammoma bodies common
• Low-grade serous carcinoma: complex micropapillary growth; KRAS/BRAF mutations
• High-grade serous carcinoma: marked nuclear atypia, brisk mitoses, stromal invasion; TP53 mutations (>95%); often bilateral; frequently diagnosed at advanced stage; psammoma bodies (calcified concentric laminations) are a hallmark

B. Mucinous Tumors

• Less common than serous; can grow to enormous size (>25 kg recorded)
• Bilateral in only 5% (vs. 20-25% for serous) - ovarian surface rarely involved
• Key mutation: KRAS (present in benign, borderline, and malignant mucinous tumors - suggests a stepwise progression)
• Origin: likely from mucinous glands of teratomas, Brenner tumors, or Müllerian epithelium with mucinous differentiation

• Benign: tall columnar cells with apical mucin, no cilia; gastric/intestinal differentiation; multiloculated, filled with sticky gelatinous fluid
• Borderline: epithelial stratification, tufting, papillary intraglandular growth; resembles intestinal villous adenoma
• Malignant: confluent glandular "expansive" invasion or desmoplastic stromal invasion
• Pseudomyxoma peritonei: gelatinous mucinous implants in peritoneum - usually from appendiceal primary, not ovarian

C. Endometrioid Tumors

• Distinguished by tubular glands resembling endometrium
• 40% bilateral at presentation
• Associated with endometriosis (precursor in 15-20% of cases)
• Share molecular features with endometrial carcinoma: PTEN, PIK3CA, ARID1A, KRAS mutations
• 5-year survival for stage I: ~75%

D. Clear Cell Carcinoma

• Large epithelial cells with abundant clear cytoplasm (resembles hypersecretory gestational endometrium)
• Now regarded as a variant of endometrioid adenocarcinoma
• Shared mutations: PIK3CA, ARID1A, KRAS, PTEN, TP53
• Often associated with endometriosis or endometrioid carcinoma
• Confined to ovary: 90% 5-year survival; advanced stage: poor prognosis

E. Brenner Tumors (Transitional Cell Tumors)

• ~10% of ovarian epithelial tumors
• Usually unilateral (~90%); 90% are benign
• Solid or cystic; range from <1 cm to 20-30 cm
• Morphology: fibrous stroma (resembling normal ovary) with sharply demarcated nests of transitional (urothelium-like) epithelial cells, often with mucinous glands in centers (the "Walthard cell nests")
• Malignant Brenner: rare; show invasion

II. Germ Cell Tumors (~15-20% of ovarian tumors)

A. Teratomas

• Most common ovarian tumor in women <30 years
• Contains well-differentiated tissues from all three germ layers: skin, hair follicles, sebaceous glands, teeth, bone, brain, thyroid
• Benign in >99% of cases; malignant transformation in <1% (usually squamous cell carcinoma)
• Bilateral in 10-15%

• Contains immature (embryonic) tissue, particularly primitive neuroepithelium
• Graded 1-3 based on amount of immature neural tissue
• Rapidly growing, penetrates capsule, local/distant spread
• Stage I, grade 1: excellent prognosis
• Grade 2-3: treated with adjuvant chemotherapy

• Struma ovarii: composed entirely of thyroid tissue; may cause hyperthyroidism
• Carcinoid: from intestinal tissue; if >7 cm, may cause carcinoid syndrome even without hepatic metastases (ovarian veins → systemic circulation directly)
• Strumal carcinoid: combination of both

B. Dysgerminoma

• Ovarian counterpart of testicular seminoma
• Most common malignant germ cell tumor (~50% of malignant GCTs)
• 75% occur in 2nd and 3rd decades; may arise in gonadal dysgenesis
• Most have no endocrine activity; a few produce hCG (syncytiotrophoblastic giant cells)
• Markers: OCT3, OCT4, NANOG (stem cell); KIT (receptor tyrosine kinase) - KIT mutations in 30-50%
• Associated with isochromosome 12p

• 80-90% unilateral; solid, yellow-white to gray-pink, soft and fleshy
• Large vesicular cells (resembling primordial germ cells) with distinct cell membranes and centrally placed nuclei
• Divided into lobules by fibrous septa infiltrated by lymphocytes (identical histology to seminoma)
• Excellent prognosis - highly radiosensitive; 5-year survival >90%

C. Yolk Sac Tumor (Endodermal Sinus Tumor)

• Second most common malignant GCT in children/young women
• Produces AFP (alpha-fetoprotein) - used as tumor marker
• Schiller-Duval bodies (perivascular pseudorosettes) - pathognomonic
• Aggressive; treated with BEP chemotherapy (Bleomycin-Etoposide-Cisplatin)

D. Choriocarcinoma (Non-gestational)

• Extremely rare, highly malignant
• Produces hCG (beta-hCG tumor marker)
• Composed of cytotrophoblasts and syncytiotrophoblasts
• Occurs in young girls; causes isosexual precocious puberty

E. Embryonal Carcinoma

• Rare, highly malignant
• Produces both AFP and hCG
• Large primitive cells with prominent nucleoli

III. Sex Cord-Stromal Tumors (~5-10% of ovarian tumors)

A. Granulosa Cell Tumor

• Most common malignant sex cord-stromal tumor
• Functionally active: secretes estrogens - leads to:
  • Precocious puberty (in children)
  • Menstrual irregularities, endometrial hyperplasia/carcinoma (in adults)
  • Postmenopausal bleeding (in elderly)
• Call-Exner bodies: small follicle-like spaces filled with eosinophilic secretion surrounded by granulosa cells - pathognomonic
• FOXL2 mutation (C134W) in ~97% - molecular marker
• Indolent but late recurrences possible (up to 30 years); 5-year survival ~90%

B. Thecoma

• Usually benign, unilateral, occurs in postmenopausal women
• Estrogen-secreting → endometrial hyperplasia
• Lipid-laden stromal cells; yellow cut surface

C. Fibroma

• Benign, most common sex cord-stromal tumor (overall)
• Meigs Syndrome: fibroma + ascites + right pleural effusion (resolves after tumor removal)
• Non-functional (no hormone secretion)
• Firm, white, whorled on cut section

D. Sertoli-Leydig Cell Tumor (Androblastoma)

• Rare; occurs in young women (20-30 years)
• Androgen-secreting → virilization: hirsutism, voice deepening, clitoromegaly, breast atrophy
• Well-differentiated: tubules lined by Sertoli cells with clusters of Leydig cells
• Usually benign/low-grade malignancy

IV. Metastatic Tumors (Krukenberg Tumor)

• Secondary tumors to ovary from primary sites: stomach (most common), colon, breast, appendix
• Krukenberg tumor: bilateral ovarian metastases characterized by mucin-secreting signet ring cells in a cellular ovarian stroma
• Stomach is the most common primary site (~70%)
• Presents with bilateral solid ovarian masses
• Poor prognosis (usually indicates systemic disease)

Key Tumor Markers Summary

Important Histological Landmarks