What is the optimal treatment approach for a premenopausal woman with an Adult Granulosa Cell Tumor (AGCT) that is positive for Follicle-Stimulating Hormone (FSH) receptors, Progesterone (PR) receptors, and Estrogen (ER) receptors, and also has a TERT c228t promoter mutation and PIK3CA mutation?

Treatment Approach for ER+/PR+ Adult Granulosa Cell Tumor

For a premenopausal woman with ER+/PR+ adult granulosa cell tumor (AGCT), complete surgical staging with fertility-sparing unilateral salpingo-oophorectomy is the definitive primary treatment, and the presence of TERT c228t and PIK3CA mutations indicates high-risk disease requiring platinum-based adjuvant chemotherapy rather than hormone therapy, which should only be reserved for chemotherapy-refractory recurrent disease. 1

Primary Treatment: Surgery First

• Complete surgical staging is mandatory and represents the cornerstone of treatment regardless of hormone receptor status or molecular profile 1
• For premenopausal women desiring fertility preservation, perform unilateral salpingo-oophorectomy with comprehensive staging including infracolic omentectomy, biopsies of diaphragmatic peritoneum, paracolic gutters, pelvic peritoneum, and peritoneal washings 1
• Lymph node dissection should only be performed if nodes appear grossly abnormal, as routine lymphadenectomy adds morbidity without proven benefit 1
• Endometrial curettage is essential to exclude concomitant uterine cancer, which can occur with estrogen-secreting granulosa cell tumors 1

Critical Molecular Profile Interpretation

• The TERT c228t promoter mutation is strongly associated with disease recurrence and progression, with 64% incidence in recurrent tumors versus 26% in primary non-recurrent tumors 1
• PIK3CA mutations in AGCT do not define hormone sensitivity and should not be confused with their role in breast cancer treatment selection 1, 2
• The PIK3CA mutation in this context may contribute to tumor progression through PI3K/AKT/mTOR pathway activation, potentially making this tumor more aggressive 2
• The combination of TERT and PIK3CA mutations suggests this is a high-risk tumor requiring aggressive systemic therapy 2

Adjuvant Therapy Decision Algorithm

Given the high-risk molecular profile (TERT + PIK3CA mutations), platinum-based chemotherapy is indicated even if stage IA:

• BEP regimen (bleomycin, etoposide, cisplatin) for 3-4 cycles is the preferred first-line adjuvant chemotherapy for high-risk features 3, 1
• Alternative option: carboplatin/paclitaxel for 6 cycles if BEP is contraindicated 3
• The overall response rate to platinum-based chemotherapy is 63-80% in advanced disease 3

Why Hormone Therapy Should NOT Be Primary Treatment

Critical pitfall to avoid: Despite ER+/PR+ status, hormone therapy should NOT be used as primary adjuvant treatment 1, 4

• Hormone therapy is only appropriate for recurrent disease after failure of or ineligibility for surgery and chemotherapy 4
• The objective response rate to hormone therapy is only 18% (95% CI: 6-41%) in measurable disease, with 64% achieving only stable disease 5
• Do not substitute hormone therapy for platinum-based chemotherapy in treatment-naive disease, as chemotherapy has superior response rates (63-80% vs 18%) 3, 5
• The presence of hormone receptors does not predict response to hormone therapy in AGCT, unlike in breast cancer 1

Surveillance Strategy for High-Risk Disease

Lifelong follow-up is mandatory as AGCTs can recur 20-37 years after initial diagnosis, and the TERT mutation significantly increases recurrence risk 1, 4

• Inhibin B levels every 2-4 months for the first 2 years, as it is the most sensitive tumor marker 1, 4
• CT abdomen/pelvis/chest every 3-6 months for the first 2 years 1
• Continue surveillance every 6 months beyond 5 years—do not discontinue after 5 years 1
• Pelvic ultrasound every 6 months if fertility-sparing surgery was performed 6

Management Strategy if Recurrence Occurs

Given the high-risk molecular profile, early recurrence is more likely:

• Attempt complete surgical cytoreduction whenever feasible, as it remains the most effective treatment for recurrence 3, 6
• After surgical cytoreduction, reinitiate platinum-based chemotherapy (BEP or carboplatin/paclitaxel) 6
• Only consider hormone therapy after failure of both surgery and chemotherapy 4

Hormone Therapy Options (Only for Chemotherapy-Refractory Recurrent Disease)

If the patient eventually develops chemotherapy-resistant recurrent disease, hormone therapy options include:

• Aromatase inhibitors (letrozole) have shown responses in recurrent disease 3, 4
• Tamoxifen has documented responses 3, 4, 7
• Progestins (megestrol acetate) have shown activity 3, 4, 7
• One case report demonstrated complete response with alternating biweekly cycles of megestrol and tamoxifen after 22 months of treatment 7
• GnRH agonists are another option with reported responses 3

Alternative Regimens for Chemotherapy-Resistant Disease

• Paclitaxel/ifosfamide/cisplatin (TIP) 6
• Vincristine/dactinomycin/cyclophosphamide (VAC) 6
• Paclitaxel/gemcitabine 6
• Weekly paclitaxel for relapsed patients after platinum failure 3

Key Clinical Pitfalls to Avoid

• Do not use hormone therapy as primary adjuvant treatment despite ER+/PR+ status—surgery followed by platinum-based chemotherapy is the standard of care for high-risk disease 1, 4
• Do not assume hormone receptor positivity predicts hormone therapy response in AGCT as it does in breast cancer 1
• Do not perform routine lymphadenectomy in absence of suspicious nodes 1
• Do not discontinue surveillance after 5 years—the TERT mutation increases late recurrence risk 1
• Do not assume PIK3CA mutations indicate hormone sensitivity in AGCT—they indicate aggressive biology requiring chemotherapy 1, 2