In a postmenopausal woman with a large complex pelvic mass, peritoneal dissemination, and markedly abnormal tumor‑marker profile, what is the most likely diagnosis and what work‑up and management should be pursued?

Diagnosis: Advanced-Stage High-Grade Serous Ovarian Carcinoma

The clinical triad of a large complex pelvic mass, peritoneal spread, and markedly elevated tumor markers in a postmenopausal woman is pathognomonic for advanced-stage epithelial ovarian carcinoma, most commonly high-grade serous carcinoma. 1

Most Likely Diagnosis

• High-grade serous ovarian carcinoma is the most probable diagnosis given this presentation, accounting for the majority of advanced epithelial ovarian cancers in postmenopausal women. 1
• Primary peritoneal serous carcinoma is the second consideration, presenting identically with peritoneal carcinomatosis, ascites, and elevated CA125 despite minimal or absent ovarian enlargement. 2
• Fallopian tube carcinoma should be considered but is rare; it presents similarly and is managed identically to ovarian cancer. 3

Essential Diagnostic Work-Up

Immediate Laboratory Assessment

• CA125 measurement is mandatory—levels markedly above 65 U/mL (typically >500 U/mL) provide 100% specificity for malignancy in postmenopausal women with complex adnexal masses. 1, 4
• HE4 (human epididymis protein 4) should be measured in conjunction with CA125; the dual-marker ROMA (Risk of Ovarian Malignancy Algorithm) achieves 94.3% sensitivity at 75% specificity for distinguishing benign from malignant disease. 4
• Complete blood count to assess for anemia from chronic disease or occult bleeding. 1
• Comprehensive metabolic panel, liver function tests, and coagulation profile are required before surgical intervention. 1
• CEA measurement may help differentiate primary ovarian/peritoneal carcinoma from gastrointestinal metastases to the ovary. 2

Imaging Studies

• Transvaginal ultrasound with Doppler is the first-line imaging modality to characterize the adnexal mass, documenting size, complexity, solid components, septations, excrescences, and vascular flow patterns. 5
• Contrast-enhanced CT of chest, abdomen, and pelvis is essential to document peritoneal carcinomatosis, omental caking, hepatic surface nodules (confirming Stage IV disease), pleural effusion, and lymphadenopathy. 3, 1
• MRI is not routinely necessary for preoperative evaluation when CT demonstrates obvious advanced disease; it should not delay surgical referral. 3, 1
• PET/CT is not recommended for primary cancer detection due to high false-positive rates, though it may provide additional staging information in select cases. 3

Tissue Diagnosis Considerations

• Cytology from ascitic fluid or pleural effusion can confirm adenocarcinoma with Müllerian features, supporting the diagnosis. 1
• Image-guided biopsy of peritoneal implants may be performed if neoadjuvant chemotherapy is being considered, but should not delay referral to a gynecologic oncologist. 1
• Definitive histologic diagnosis and molecular testing (BRCA, HRD) require adequate tissue from the primary ovarian tumor obtained at surgery, not solely from peritoneal biopsies. 1

Immediate Management Steps

Urgent Referral

• Immediate referral to a gynecologic oncologist is mandatory—this improves overall survival in patients with suspected advanced ovarian cancer. 1, 5
• Referral should occur before any surgical intervention by a general gynecologist, as optimal cytoreduction by a specialist significantly impacts prognosis. 5

Surgical Management

• Primary cytoreductive (debulking) surgery is the standard initial treatment for advanced-stage high-grade serous ovarian carcinoma. 1
• The surgical goal is complete macroscopic resection of all visible disease—achieving no residual tumor is the strongest prognostic factor for overall survival. 1
• Comprehensive surgical staging includes: total abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy, peritoneal biopsies (diaphragm, paracolic gutters, pelvic peritoneum), pelvic and para-aortic lymphadenectomy, and peritoneal washings for cytology. 3
• Appendectomy is indicated only if mucinous histology is suspected; it is not routinely performed for serous carcinoma. 3, 1
• Procedures for optimal cytoreduction may include: bowel resection, diaphragm stripping, splenectomy, partial hepatectomy, or distal pancreatectomy as needed to achieve complete resection. 3

Neoadjuvant Chemotherapy Alternative

• Neoadjuvant chemotherapy followed by interval debulking surgery is appropriate when:
  • Performance status is too poor for immediate surgery
  • Disease is deemed unresectable at initial exploration
  • Significant comorbidities preclude safe primary cytoreduction 1
• If optimal debulking (residual disease <1 cm) cannot be achieved during primary surgery, conversion to neoadjuvant chemotherapy with planned interval debulking is advised. 1

Adjuvant Chemotherapy

• Platinum-based combination chemotherapy (carboplatin plus paclitaxel) for six cycles is the standard adjuvant regimen after optimal cytoreduction. 1
• CA125 should be measured before each chemotherapy cycle; a declining trend indicates treatment response. 1

Management of Complications

Pre-Operative Optimization

• Bilateral hydronephrosis from tumor compression requires urologic consultation and possible ureteral stent placement to preserve renal function before surgery. 1
• Therapeutic paracentesis is recommended for massive ascites causing respiratory compromise or severe discomfort. 1
• Anemia (hemoglobin <8 g/dL) warrants transfusion if symptomatic or peri-operatively. 1
• Nutritional optimization and correction of hypoalbuminemia/electrolyte disturbances are essential before major surgery. 1

Differential Diagnosis Considerations

Distinguishing Primary Ovarian from Metastatic Disease

• Gastrointestinal metastases to the ovary (Krukenberg tumors) can mimic primary ovarian cancer; gastrointestinal tract evaluation with endoscopy and elevated CEA suggest this diagnosis. 3, 2
• Immunohistochemistry is critical: CA125+/CK7+/WT1+/PAX8+ profile strongly supports ovarian serous carcinoma, while CK20+/CDX2+ suggests gastrointestinal origin. 6, 2
• WT1 is positive in 80-90% of high-grade serous carcinomas; its absence makes this diagnosis less likely. 6
• PAX8 is highly sensitive for ovarian and Müllerian-derived carcinomas; negativity supports a non-ovarian origin. 6

Other Müllerian Carcinomas

• Uterine serous carcinoma or carcinosarcoma can present with peritoneal spread mimicking ovarian cancer; these are high-grade tumors with patterns of failure similar to ovarian cancer. 3
• Clear cell carcinoma of the ovary is less common, typically presents at earlier stages, and is associated with endometriosis; it is WT1-negative and estrogen receptor-negative. 3
• Mucinous carcinoma of the ovary is rare; it presents as very large cystic masses and requires appendectomy to exclude gastrointestinal primary. 3

Prognostic Factors

• FIGO Stage IV ovarian cancer has markedly lower 5-year survival compared with early-stage disease, but maximal cytoreduction combined with platinum-based chemotherapy offers the best chance for prolonged survival. 1
• Achieving complete cytoreduction (no visible residual disease) is the single most important prognostic factor for overall survival. 1
• Up to 22% of apparent early-stage ovarian cancers are upstaged after comprehensive surgical staging, emphasizing the importance of thorough exploration. 3

Common Pitfalls to Avoid

• Do not delay referral to a gynecologic oncologist for biopsy confirmation—the clinical presentation is sufficient to warrant immediate specialist consultation. 5
• Do not perform surgery without adequate staging procedures—incomplete staging leads to undertreatment and worse outcomes. 3
• Do not rely solely on CA125—the addition of HE4 significantly improves diagnostic accuracy, particularly for early-stage disease. 4, 7
• Do not assume all pelvic masses with peritoneal spread are ovarian—always consider metastatic gastrointestinal or breast cancer, especially if immunohistochemistry is atypical. 6, 2