What are the recommended management steps for malignant sex‑cord stromal tumors of the ovary, including surgical staging, adjuvant chemotherapy regimens, fertility‑preserving options for young patients, and long‑term surveillance?

Management of Malignant Sex Cord-Stromal Tumors of the Ovary

For young patients with early-stage malignant sex cord-stromal tumors desiring fertility, perform unilateral salpingo-oophorectomy with fertility-sparing surgery, omit routine lymphadenectomy, and reserve adjuvant platinum-based chemotherapy only for high-risk features (tumor rupture, stage IC, poor differentiation, or size >10-15 cm). 1, 2

Surgical Staging and Approach

Initial Surgical Management

• Fertility-sparing surgery (unilateral salpingo-oophorectomy with preservation of contralateral ovary and uterus) is appropriate for stage IA or IC disease in patients desiring fertility 1, 3
• Complete surgical staging should include examination of the abdominal cavity, infracolic omentectomy, biopsy of diaphragmatic peritoneum, paracolic gutters, pelvic peritoneum, and peritoneal washings 3
• Lymphadenectomy may be omitted for stage IA or IC tumors, as lymph node metastases are exceedingly rare in sex cord-stromal tumors 1, 4
• A retrospective multi-institutional study of 87 patients found zero positive lymph nodes among 47 patients who had nodal tissue examined, confirming that routine lymphadenectomy provides limited additional information 4
• Laparoscopic approach is acceptable in selected cases if tumor rupture can be avoided 3

Completion Surgery

• After childbearing is complete, completion surgery (removal of remaining ovary, uterus, and contralateral tube) should be considered (Category 2B) 1

Adjuvant Chemotherapy Decision Algorithm

Low-Risk Stage I Disease (Observation Preferred)

For stage IA tumors without high-risk features, observation alone is the standard approach 1, 2

• Low-risk features include: intact capsule, well-to-moderately differentiated tumor, tumor size <10 cm, no rupture 1
• These patients achieve 90% long-term disease-free survival with surgery alone 2

High-Risk Stage I Disease (Consider Chemotherapy)

For high-risk stage I tumors, consider platinum-based chemotherapy (Category 2B), though benefit remains unproven 1, 2

High-risk features include: 1, 2

• Tumor rupture
• Stage IC disease
• Poorly differentiated tumor (Grade 3)
• Tumor size >10-15 cm

Advanced Stage Disease (Stage II-IV)

For stage II-IV tumors, platinum-based chemotherapy is recommended for all patients 1, 2

Preferred regimens (all Category 2B): 1, 2, 3

• BEP (bleomycin, etoposide, cisplatin) for 3-6 cycles is the standard first-line regimen
• Paclitaxel/carboplatin (alternative if BEP contraindicated)
• Radiation therapy for limited disease

Important caveat: Bleomycin should not be given to patients >40 years old or those with pre-existing pulmonary disease due to toxicity concerns 3

Tumor Marker Surveillance

Granulosa Cell Tumors

• Inhibin levels can be followed if initially elevated (Category 2B) 1, 2
• Inhibin A, B, and pro-AC have all been used for surveillance 1
• Estradiol, LH, and FSH may also be monitored, particularly in postmenopausal patients 1

Sertoli-Leydig Cell Tumors

• Testosterone levels should be followed if initially elevated 2, 3
• Inhibin may also be useful 3

General Markers

• CA125 may be useful in some cases 2

Long-Term Surveillance Protocol

Prolonged surveillance is mandatory because granulosa cell tumors can recur up to 30-37 years after initial diagnosis 1, 2, 3

Surveillance Schedule (Based on Society of Gynecologic Oncology Recommendations)

1, 2

• Every 3 months for the first 2 years
• Every 6 months for years 3-5
• Yearly thereafter

Imaging Surveillance

• Pelvic ultrasound every 6 months for patients who underwent fertility-sparing surgery 2
• CT abdomen/pelvis yearly or according to clinical indication 2
• Clinical examination for signs of recurrence or hormonal changes 3

Recurrence Patterns

• Median time to relapse: 4-6 years 2
• Common sites: upper abdomen and pelvis 2
• Recurrences reported as late as 37 years post-diagnosis 2

Management of Recurrent Disease

Stage II-IV Tumors with Clinical Relapse

Options include clinical trial enrollment or recurrence therapy 1

Cytotoxic Recurrence Therapy Options:

1

• Docetaxel
• Paclitaxel
• Paclitaxel/ifosfamide
• Paclitaxel/carboplatin
• VAC (vincristine, actinomycin D, cyclophosphamide)

Hormone Recurrence Therapy Options:

1

• Aromatase inhibitors
• Leuprolide
• Tamoxifen
• Single-agent bevacizumab or leuprolide specifically for recurrent granulosa cell tumors

Surgical Options:

• Secondary cytoreductive surgery may be considered, as debulking surgery is the most effective treatment for metastatic or recurrent disease 1, 2
• Palliative localized radiation therapy may also be useful 1

Prognostic Factors

Most Important Predictors of Survival

A multivariate analysis of 83 patients identified the following independent prognostic factors: 5

• Age <50 years (P = 0.003)
• Tumor size <10 cm (P = 0.003)
• Absence of residual disease (P = 0.002)

Additional Significant Factors

5, 4

• Stage at diagnosis (5-year survival: 85% for stage I-II vs. 48% for stage III-IV)
• Premenopausal status
• Lack of lymph node invasion
• Tumor size (20% increase in hazard of recurrence for each 1 cm increase)

Sertoli-Leydig Cell Tumor Specific Factors

3, 6

• Poor differentiation (Grade 3)
• Retiform pattern
• Tumor rupture or higher stage
• Presence of heterologous elements

Critical Pitfalls to Avoid

• Do NOT perform radical surgery (bilateral salpingo-oophorectomy with hysterectomy) in reproductive-age patients with stage IA disease, as this compromises fertility without improving outcomes 3
• Do NOT routinely administer adjuvant chemotherapy for stage IA well-to-moderately differentiated tumors without high-risk features, as there is no evidence of benefit 2, 3
• Do NOT perform systematic lymphadenectomy, as it does not affect prognosis and adds morbidity 1, 3, 4
• Do NOT discontinue follow-up prematurely; relapses can occur up to 20-30 years later 1, 3
• Do NOT use fine-needle or transvaginal aspiration of ovarian masses 7
• Patients should be referred to tertiary care institutions and gynecologic oncologists for treatment, as these are rare tumors requiring specialist evaluation 1, 7