What is the treatment approach for a patient with a primary adult granulosa cell tumor characterized by a TERT c228t promoter mutation, PIK3CA mutation, microsatellite stable (MSS) status, and low tumor mutational burden (TMB of 0.8)?

Treatment Approach for Primary Adult Granulosa Cell Tumor with TERT c228t, PIK3CA Mutation, MSS, and Low TMB

Primary Treatment: Surgery is Definitive

Complete surgical staging with total abdominal hysterectomy and bilateral salpingo-oophorectomy (if postmenopausal) or fertility-sparing unilateral salpingo-oophorectomy (if premenopausal) represents the cornerstone of treatment for primary adult granulosa cell tumors, regardless of molecular profile. 1, 2

Surgical Staging Components

• Perform infracolic omentectomy, biopsies of diaphragmatic peritoneum, paracolic gutters, pelvic peritoneum, and peritoneal washings 2
• Lymph node dissection only if nodes appear grossly abnormal on inspection, as retroperitoneal evaluation is not mandatory for sex cord-stromal tumors 2
• Endometrial curettage to exclude concomitant uterine cancer, which can occur with estrogen-secreting granulosa cell tumors 2

Molecular Profile Interpretation

TERT c228t Promoter Mutation Significance

The TERT promoter mutation you describe is strongly associated with disease recurrence and progression in adult granulosa cell tumors. 3 Research demonstrates TERT promoter mutations occur in 64% of recurrent aGCTs versus only 26% of primary non-recurrent tumors (p = 0.017). 3 This mutation indicates higher-risk disease biology, though it does not currently change initial surgical management.

PIK3CA Mutation Context

The PIK3CA mutation identified in this tumor may contribute to tumor progression through PI3K/AKT/mTOR pathway activation. 4 However, PIK3CA mutations do not define hormone sensitivity in granulosa cell tumors and should not be confused with their role in breast cancer treatment selection. 1, 5 In the context of adult granulosa cell tumors, PIK3CA alterations have been documented in aggressive/transformed cases but do not currently have established targeted therapy applications outside clinical trials. 4

MSS Status and Low TMB

The microsatellite stable status and low tumor mutational burden (0.8) indicate this tumor would not be a candidate for immune checkpoint inhibitor therapy, as these biomarkers predict lack of response to immunotherapy. 1

Adjuvant Therapy Decision Algorithm

Stage IA Disease

• No adjuvant therapy required - surgery alone is curative with excellent prognosis 6, 2
• The presence of TERT promoter mutation does not override this recommendation for stage IA disease, though it warrants more intensive surveillance 3

Stage IC or Higher Disease

• Consider platinum-based chemotherapy with BEP regimen (bleomycin, etoposide, cisplatin) for 3-4 cycles for stage IC with high mitotic index, ruptured tumor capsule, or any stage II-IV disease 2, 7
• Alternative regimen: carboplatin/paclitaxel for 6 cycles 2
• The TERT promoter mutation strengthens the indication for adjuvant chemotherapy in borderline cases (stage IC) given its association with recurrence 3

Surveillance Strategy (Critical Given TERT Mutation)

Lifelong follow-up is mandatory, as granulosa cell tumors can recur 20-37 years after initial diagnosis, with your molecular profile suggesting higher recurrence risk. 2, 8

Surveillance Schedule

• Inhibin B levels every 2-4 months for first 2 years (most sensitive tumor marker) 6, 2
• CT abdomen/pelvis/chest every 3-6 months for first 2 years 2
• Continue surveillance every 6 months beyond 5 years indefinitely 2
• Pelvic ultrasound and clinical pelvic examination at each visit 6

Management if Recurrence Occurs

Surgical Approach First

• Attempt complete surgical cytoreduction whenever feasible - this remains the most effective treatment for recurrence 6, 2

Systemic Therapy Options for Unresectable/Metastatic Disease

Platinum-based chemotherapy (BEP or carboplatin/paclitaxel) should be first-line systemic therapy for treatment-naive advanced or recurrent disease. 2, 7

Hormone Therapy (Second-Line or Beyond)

Hormone therapy should only be considered for recurrent disease after failure of or ineligibility for surgery and chemotherapy: 6

• Aromatase inhibitors (letrozole) have shown responses 6
• Tamoxifen has documented activity 6
• Progestins have demonstrated responses 6

Potential Targeted Therapy Consideration

Given the PIK3CA mutation, PI3K/AKT/mTOR pathway inhibitors could theoretically be considered in a clinical trial setting for refractory disease, as these alterations have been documented in aggressive granulosa cell tumors. 4 However, there are no established protocols outside investigational settings, and alpelisib (the PIK3CA inhibitor approved for breast cancer) has no data in granulosa cell tumors. 1

Critical Pitfalls to Avoid

• Do not use hormone therapy as primary treatment - surgery is curative for early-stage disease 6
• Do not substitute hormone therapy for platinum-based chemotherapy in treatment-naive advanced disease 6
• Do not perform routine lymphadenectomy in absence of suspicious nodes, as this adds morbidity without proven benefit 2
• Do not discontinue surveillance after 5 years - recurrences occur decades later, and your TERT mutation increases this risk 2, 3
• Do not assume MSS/low TMB tumors will respond to immunotherapy - they will not 1