In a 73‑year‑old post‑menopausal woman with cancer antigen 125 (CA‑125) 6 U/mL, carcinoembryonic antigen (CEA) 4.9 ng/mL, alpha‑fetoprotein (AFP) 4.2 ng/mL, estradiol 3300 pg/mL, follicle‑stimulating hormone (FSH) 3.7 IU/L, luteinizing hormone (LH) 1.1 IU/L, prolactin 16.1 ng/mL and total cortisol 2.8 µg/dL, what is the most likely diagnosis?

Diagnosis: Estrogen-Secreting Ovarian Sex Cord-Stromal Tumor (Most Likely Granulosa Cell Tumor)

The markedly elevated estradiol (3301.6 pg/mL) with suppressed FSH (3.7 IU/L) and LH (1.1 IU/L) in a 73-year-old postmenopausal woman strongly indicates an estrogen-secreting ovarian sex cord-stromal tumor, most commonly a granulosa cell tumor. 1

Key Diagnostic Features Supporting This Diagnosis

Hormonal Pattern Analysis

• Extremely elevated estradiol (3301.6 pg/mL): This level is approximately 165-fold higher than the expected postmenopausal range (typically <20 pg/mL), which is pathognomonic for an estrogen-secreting ovarian tumor in this age group 1, 2

• Suppressed gonadotropins (FSH 3.7 IU/L, LH 1.1 IU/L): These values are inappropriately low for a postmenopausal woman, who should have FSH >40 IU/L and LH >30 IU/L. The suppression occurs via negative feedback from the massively elevated estradiol, confirming autonomous estrogen production 1

• Normal prolactin (16.1 ng/mL): This excludes pituitary pathology as the cause of the hormonal abnormalities 1

• Low cortisol (2.8 µg/dL): While this is below the normal morning range (5-25 µg/dL), it may reflect the time of day of collection or mild adrenal suppression, but does not suggest a cortisol-secreting tumor 1

Tumor Marker Profile

• Normal CA-125 (6 U/mL): This is reassuring and argues against epithelial ovarian cancer, which would typically show elevation in 80-90% of serous carcinomas. However, sex cord-stromal tumors characteristically have normal CA-125 levels 1, 3

• Normal CEA (4.9 ng/mL) and AFP (4.2 ng/mL): These exclude germ cell tumors and gastrointestinal metastases 1, 3

Clinical Presentation and Associated Findings

Expected Clinical Manifestations

• Postmenopausal bleeding: The extremely high estradiol level typically causes endometrial hyperplasia or even endometrial cancer, presenting as vaginal bleeding in postmenopausal women 1

• Estrogenic symptoms: Breast tenderness, vaginal discharge, or return of premenopausal symptoms may occur 1

• Virilization is absent: The normal testosterone markers and lack of androgen excess distinguish this from Sertoli-Leydig cell tumors 1

Granulosa Cell Tumor Characteristics

Pathophysiology

• Granulosa cell tumors are the most common malignant sex cord-stromal tumor, accounting for approximately 70% of this category 1

• The adult form (as opposed to juvenile) occurs predominantly in postmenopausal women and characteristically secretes estrogen, causing the hormonal pattern seen in this patient 1

• These tumors appear as circumscribed, soft, focally hemorrhagic, distinctly yellow masses on gross examination 1

Diagnostic Markers Specific to Granulosa Cell Tumors

• Inhibin and estradiol: These are the most useful tumor markers for granulosa cell tumors and should be measured for serial follow-up after diagnosis 1

• Immunohistochemistry: Positive staining with α-inhibin, calretinin, CD99, and melan-A confirms the diagnosis on tissue examination 1

Immediate Diagnostic Work-Up Required

Imaging Studies

• Transvaginal ultrasound with color Doppler: First-line imaging to identify the ovarian mass, assess for hemorrhage (which suggests granulosa cell tumor), and evaluate vascularity 1, 3

• CT or MRI of abdomen/pelvis: Required for staging, as these tumors can rupture and cause hemoperitoneum 1

• Endometrial evaluation: Hysteroscopy with endometrial biopsy or dilation and curettage is mandatory to assess for endometrial hyperplasia or carcinoma, which occurs in up to 50% of cases due to unopposed estrogen stimulation 1

Additional Laboratory Tests

• Inhibin A and B levels: These are elevated in granulosa cell tumors and serve as useful markers for monitoring disease 1

• Repeat estradiol measurement: To confirm the markedly elevated level and establish a baseline for post-treatment monitoring 1

Differential Diagnosis (Less Likely)

Thecoma or Fibrothecoma

• These are typically benign sex cord-stromal tumors that can also produce estrogen, but usually cause less dramatic elevations 1

• The clinical presentation would be identical, and definitive diagnosis requires histopathology 1

Testosterone-Producing Adrenal Adenoma (Excluded)

• The low cortisol and absence of virilization make this diagnosis extremely unlikely 4

• Adrenal tumors would not suppress gonadotropins in this manner 4

Critical Management Considerations

Surgical Approach

• Comprehensive staging surgery: Total hysterectomy with bilateral salpingo-oophorectomy is standard, as the tumor is typically unilateral but the contralateral ovary and uterus are at risk from estrogen exposure 1

• Complete surgical staging: Includes peritoneal washings, omentectomy, peritoneal biopsies, and lymph node assessment, as tumor stage is the most important prognostic factor 1

• Referral to gynecologic oncologist: Mandatory for appropriate surgical management and staging 1

Prognosis and Follow-Up

• Stage at diagnosis is the most critical prognostic factor, with the majority of tumors being unilateral and confined to the ovary at presentation 1

• Granulosa cell tumors have a tendency for late recurrence (even 10-20 years later), requiring long-term surveillance with serial estradiol and inhibin measurements 1

• Adjuvant chemotherapy may be indicated for advanced-stage disease, though the optimal regimen remains debated 1

Common Pitfalls to Avoid

• Do not assume normal CA-125 excludes ovarian malignancy: Sex cord-stromal tumors characteristically have normal CA-125 levels, unlike epithelial ovarian cancers 1, 3

• Do not delay endometrial evaluation: The risk of concurrent endometrial hyperplasia or carcinoma is substantial with this degree of estrogen elevation and must be assessed preoperatively 1

• Do not attribute the hormonal pattern to exogenous hormone use: Always verify medication history, but this degree of estradiol elevation with gonadotropin suppression in a postmenopausal woman is pathologic 1