Clinical Management and Pathological Assessment of Ovarian, Fallopian Tube, and Primary Peritoneal Cancers

Pathology and Histological Classification

Accurate pathologic diagnosis is essential, as the histological subtype dictates the entire treatment trajectory. Ovarian cancers are broadly categorized into epithelial and non-epithelial tumors.

Epithelial Ovarian Cancer

This is the most prevalent category and includes several distinct subtypes:

• Serous: Often categorized into high-grade (aggressive) and low-grade.
• Endometrioid: Includes various grades, with Grade 1 being less aggressive than Grade 2 or 3.
• Mucinous: These can be difficult to distinguish from gastrointestinal (GI) metastases.
• Clear Cell: A distinct subtype that may benefit from specific immunotherapy in recurrence.

Borderline and Other Epithelial Lesions

Borderline epithelial tumors (also known as low malignant potential tumors) are characterized by cytologic malignancy but lack frank tumor invasion. While they do not typically require adjuvant therapy, they require extended clinical follow-up because noninvasive implants carry a 15% to 20% increased risk of progression to low-grade serous carcinoma.

Non-Epithelial Tumors

• Germ Cell Tumors: Including dysgerminomas and yolk sac tumors.
• Malignant Sex Cord-Stromal Tumors: Such as granulosa cell tumors.
• Carcinosarcomas (MMMTs): Aggressive biphasic tumors containing both malignant epithelial and sarcomatous components.

Diagnostic Immunohistochemistry (IHC)

Pathologists utilize IHC to differentiate between primary ovarian tumors and metastatic disease:

• PAX8: Typically positive in primary ovarian tumors; its absence may suggest a different primary site.
• WT1: Often positive in serous carcinomas.
• Napsin A: A specific marker for clear cell carcinomas.
• SATB2: Often consistent with a colonic (GI) origin, helping to rule out primary ovarian cancer.

Molecular Testing and Biomarkers

Modern management relies heavily on molecular profiling to guide maintenance and targeted therapies. Upon pathologic confirmation, patients should undergo both germline and somatic testing.

Key Molecular Targets

1. BRCA1/2 and HRD Status: Testing for $BRCA1/2$ mutations and Homologous Recombination Deficiency (HRD) is critical. Patients with these markers are prime candidates for PARP inhibitor (PARPi) maintenance therapy.
2. Targeted Biomarkers in Recurrence: For patients with recurrent disease, testing for a variety of markers is recommended to identify opportunities for precision medicine:
   • FR$\alpha$ (Folate Receptor Alpha): Positive disease may be treated with mirvetuximab soravtansine.
   • MSI/MMR and TMB: To assess eligibility for immunotherapy.
   • Other targets: HER2, BRAF, RET, and NTRK.

Exam Tip: Remember that in the absence of a $BRCA1/2$ mutation, HRD testing is still highly valuable. It can provide information on the potential magnitude of benefit from PARP inhibitor maintenance therapy.

Staging and Monitoring

Staging is performed using the FIGO system. It is important to note that approximately 30% of patients initially suspected of having early-stage disease are upstaged after complete surgical staging. Therefore, comprehensive surgical staging is recommended for most patients to ensure appropriate postoperative management, including the selection of adjuvant and maintenance therapies.

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References NCCN Guidelines Version 4.2026: Ovarian Cancer Including Fallopian Tube Cancer and Primary Peritoneal Cancer.