Histopathological Analysis - Right Ovary

Microscopic Findings (H&E, both slides)

• Dense solid/sheet-like growth of malignant epithelioid cells forming a cohesive nest
• Cells are large and polygonal with amphophilic to eosinophilic cytoplasm
• Marked nuclear pleomorphism - anisokaryosis with coarse, vesicular chromatin
• Prominent macronucleoli (cherry-red, centrally located) in virtually every cell
• Frequent mitotic figures including atypical/multipolar forms
• Multinucleated tumor giant cells present
• Background hemorrhage and focal single-cell necrosis (karyorrhectic debris)

• Solid sheets of pleomorphic epithelioid cells infiltrating into fibromyxoid/desmoplastic stroma (visible on left)
• Same nuclear features: vesicular nuclei, macronucleoli, irregular nuclear membranes
• Highly atypical/multipolar mitotic figures (starburst pattern clearly visible)
• Sparse fibrovascular stroma traversing tumor sheets
• Scattered lymphocytic infiltrate in background

Diagnosis

Diagnostic Criteria Met (per Robbins Pathologic Basis of Disease)

• Complex growth with stromal effacement/infiltration
• Nuclear atypia: >3-fold variation in nuclear size (pleomorphism)
• >12 mitoses per 10 HPF (numerous mitoses visible)
• Atypical/multipolar mitotic figures
• Multinucleation
• Occasional areas where serous features are barely recognizable (solid undifferentiated growth)

Clinicopathological Correlation

Differential Diagnosis Considered and Excluded

Recommended IHC Panel

Staging Workup (Post-Surgery)

• Gross examination of omentum, peritoneal surfaces, and lymph nodes intraoperatively was essential
• Ascites cytology (if present) should be submitted
• BRCA1/BRCA2 germline testing strongly recommended (therapeutic implications - PARP inhibitors)
• Somatic tumor BRCA testing also recommended

Clinical Significance

• Robbins, Cotran & Kumar Pathologic Basis of Disease (10th ed.), pp. 941-943 - HGSC morphology and pathogenesis
• Robbins & Kumar Basic Pathology - Serous carcinoma of ovary, fallopian tube origin

High-Grade Serous Carcinoma (HGSC) of the Ovary

As taught by Robbins Pathologic Basis of Disease & Berek & Novak's Gynecology

1. WHO Classification - Where Does HGSC Fit?

"Most of the malignant epithelial tumors are high-grade serous carcinomas, which have a poor prognosis in large part because they are usually detected after they have spread beyond the ovary and/or the fallopian tube."

• Robbins, Cotran & Kumar

2. The Type I vs Type II Concept (The Two-Pathway Model)

Fig. 22.29 - Robbins: Schematic of pathogenesis. Type I (left) = slow stepwise progression from benign to borderline to low-grade carcinoma. Type II (right) = HGSC arising directly from STIC in fallopian tube fimbriae.

3. Origin and Pathogenesis

The Fallopian Tube Origin - STIC

"Serous tubal intraepithelial carcinoma (STIC) lesions...have since been described in association with sporadic high-grade serous ovarian cancers, suggesting that at least some high-grade serous carcinomas arise from the fallopian tube."

1. Normal secretory cells of fallopian tube fimbriae acquire TP53 mutation
2. → p53 signature (subclinical atypia)
3. → STIC (morphologically malignant cells, no invasion yet)
4. → STIC cells exfoliate and implant on ovary surface / peritoneum
5. → Cortical inclusion cysts form on ovary → frank HGSC

Why Does This Matter Clinically?

• Risk-reducing bilateral salpingo-oophorectomy (RRSO) in BRCA carriers must include the tube
• Risk-reducing salpingectomy alone is being studied as a fertility-sparing option
• Prophylactic salpingo-oophorectomy in BRCA1/2 carriers revealed STIC as the "smoking gun"

Molecular Alterations in HGSC

4. Epidemiology & Risk Factors

• Peak age: 55-65 years (postmenopausal); can occur in 40s
• Risk factors:
  • Nulliparity
  • Family history of breast/ovarian cancer
  • BRCA1 germline mutation: 20-60% lifetime risk of ovarian cancer by age 70
  • BRCA2 germline mutation: lower but significant ovarian risk
  • BRCA1 mutations present in ~5% of patients under age 70
• Protective factors:
  • Oral contraceptive use
  • Tubal ligation
  • Multiparity
  • Salpingectomy (by removing the site of STIC origin)

5. Gross Morphology

Fig. 22.31 - Robbins: (A) Serous borderline tumor with delicate papillary growths. (B) Another borderline on surface. (C) Serous CARCINOMA - opened to reveal large bulky solid-cystic tumor.

• Multiloculated cystic mass with solid areas (exactly as in this case's CT)
• Papillary excrescences inside cysts and on surface
• Capsular fixation, nodularity - signs of malignancy
• Necrosis and hemorrhage in solid areas
• Bilaterality in ~66% of serous carcinomas (vs 20% benign, 30% borderline)
• Frequently with peritoneal studding, omental "cake," ascites

6. Microscopic Morphology - The Key to Diagnosis

Fig. 22.32 - Robbins: (A) Cystadenoma - simple columnar epithelium. (B) Borderline - complex papillae, stratification, mild atypia, NO invasion. (C) Low-grade micropapillary serous carcinoma. (D) HIGH-GRADE serous carcinoma - solid nests infiltrating stroma.

Diagnostic Criteria for HGSC (Robbins + Berek & Novak)

"In malignant serous tumors, stromal invasion is present. High-grade neoplasms are characterized by solid sheets of cells, nuclear pleomorphism, and high mitotic activity."

7. Grading System

8. Immunohistochemistry Profile

9. Clinical Course and Spread

"High-grade tumors are often widely metastatic throughout the abdomen at the time of presentation, a picture associated with rapid clinical deterioration."

Routes of Spread

1. Transcoelomic (dominant): Exfoliation of tumor cells → peritoneal seeding → omental cake, diaphragmatic implants, bowel surface nodules
2. Lymphatic: Para-aortic and pelvic nodes
3. Hematogenous (late): Liver parenchyma, lungs, pleura

FIGO Staging (surgical)

Most patients present with Stage III disease - which is why early detection remains an unmet challenge.

10. Tumor Markers

11. Treatment Principles

12. Prognosis Determinants

1. FIGO stage - most important
2. Residual disease after debulking - R0 vs R1 vs R2
3. BRCA1/2 mutation status - paradoxically better prognosis (more chemo-sensitive, PARP inhibitor benefit)
4. Platinum sensitivity - responses beyond 6 months = platinum-sensitive
5. Performance status

Summary Mnemonic - "HGSC STAMP"

• S - Serous, Solid sheets, STIC origin
• T - TP53 mutation (>96%), Tubal origin
• A - Atypical mitoses, Advanced stage at presentation
• M - Macronucleoli, Marked pleomorphism, >12 Mitoses/10HPF
• P - PARP inhibitors (BRCA+), Poor prognosis (Stage III/IV most common)

• Robbins, Cotran & Kumar Pathologic Basis of Disease (10th ed.), pp. 940-945 - Epithelial Ovarian Tumors
• Berek & Novak's Gynecology, Chapter 39 - Serous Carcinomas of the Ovary

🔬 Histology Quiz: HGSC vs Borderline Serous Tumor

Based on Robbins, Cotran & Kumar & Berek & Novak's Gynecology

SECTION A - Multiple Choice Questions (1 mark each)

• A) Serous cystadenoma
• B) High-grade serous carcinoma
• C) Serous borderline tumor
• D) Low-grade serous carcinoma
• E) Endometrioid carcinoma

• A) Nuclear pleomorphism
• B) Psammoma bodies
• C) Destructive stromal invasion
• D) Papillary architecture
• E) Detached cell clusters

• A) Serous borderline tumor with microinvasion
• B) Low-grade serous carcinoma
• C) High-grade serous carcinoma
• D) Adult granulosa cell tumor
• E) Undifferentiated endometrial carcinoma

• A) Epithelial hyperplasia with pseudostratification and tufting
• B) Mild nuclear atypia and mildly increased mitotic activity
• C) Detached cell clusters
• D) Destructive stromal invasion
• E) Absence of tissue destruction at the stromal interface

• A) It shows destructive stromal invasion
• B) It has a higher mitotic count (>12/10 HPF)
• C) It is more frequently bilateral, exophytic, and high-stage
• D) It has TP53 mutations
• E) It arises from STIC lesions in the fallopian tube

• A) KRAS and BRAF mutations with TP53 wild-type
• B) CTNNB1 and PTEN mutations
• C) TP53 mutation (>96%) with frequent BRCA1/2 alterations
• D) MLH1 and MSH2 mismatch repair deficiency
• E) KRAS mutation in >85% of cases

• A) Focal weak positivity in <10% of cells (wild-type pattern)
• B) Cytoplasmic positivity only
• C) Negative staining for p53 throughout (wild-type)
• D) Either diffuse strong positivity (3+) OR complete absence of staining (null pattern)
• E) Patchy moderate positivity in ~40% of cells

• A) CK20+, CDX2+, CK7-
• B) Inhibin+, Calretinin+, p53 wild-type
• C) S100+, HMB45+, Melan-A+
• D) WT1+, PAX8+, p53 aberrant (diffuse or null)
• E) CK5/6+, p40+, p63+

• A) It automatically upgrades the diagnosis to high-grade serous carcinoma
• B) It confirms low-grade serous carcinoma at Stage III
• C) It does not change the diagnosis - the primary tumor histology determines the diagnosis
• D) It requires neoadjuvant chemotherapy before restaging
• E) It represents hematogenous spread

• A) Pathognomonic of HGSC only
• B) Never found in borderline tumors
• C) Laminated calcified concentric structures found in ~80% of serous carcinomas, also seen in borderline tumors
• D) A sign of stromal invasion
• E) Found exclusively in mucinous tumors

• A) This is normal peritoneal spread of borderline tumor with no added risk
• B) These invasive implants represent low-grade serous carcinoma and behave more aggressively (5-year OS ~50%)
• C) This confirms HGSC origin with peritoneal spread
• D) This is a Krukenberg tumor pattern
• E) This means BRCA testing is mandatory

• A) Hierarchical papillary branching with open stroma
• B) Simple cyst lining with ciliated cells
• C) Micropapillary structures without stromal cores
• D) Solid sheets of cells with effacement/infiltration of the underlying stroma
• E) Cribriform glands without nuclear atypia

SECTION B - True or False (1 mark each; correct the false statement)

SECTION C - Short Answer / Spot the Feature (2 marks each)

✅ ANSWER KEY WITH EXPLANATIONS

1. Epithelial hyperplasia - pseudostratification, tufting, cribriform, and micropapillary architecture
2. Mild nuclear atypia and mild increased mitotic activity
3. Detached cell clusters
4. Absence of destructive stromal invasion

• a) High-Grade Serous Carcinoma (HGSC)
• b) IHC panel:

• c) TP53 mutation - present in >96% of HGSC cases; reflected as aberrant p53 IHC pattern

Sources: All questions derived directly from Robbins, Cotran & Kumar Pathologic Basis of Disease (10th ed.), pp. 940-945, and Berek & Novak's Gynecology, Chapter 39 (Serous Carcinomas and Borderline Tumors of the Ovary).