Granulosa Cell Tumour

Granulosa cell tumours are sex cord stromal tumours of the ovary that arise from granulosa cells and secrete oestrogen (and inhibin). They account for about 2 to 5 percent of ovarian malignancies.

Two types are distinguished:

• The adult type (95 percent) occurs at a mean age of 50 to 54 years, with FOXL2 C134W mutation present in nearly all.
• The juvenile type (5 percent) occurs in children and young women under 30 years. It is characterised by AKT1 and other mutations, with a more aggressive histology but a better prognosis at early stage.

Tumours are usually unilateral (over 95 percent) and large (about 12 cm on average), solid and cystic. About 90 percent are stage I at presentation.

They are low grade malignancies with late recurrence (the median to recurrence is 4 to 6 years, and up to 20 to 30 years). Stage is the most important prognostic factor; 10-year survival is 90 percent for stage I and 50 to 60 percent for advanced stages.

Associations include endometrial hyperplasia (25 to 50 percent), endometrial carcinoma (5 to 10 percent), and breast disease.

• Hyperoestrogenism: abnormal uterine bleeding (menorrhagia, intermenstrual or postmenopausal bleeding), oligomenorrhoea or amenorrhoea, breast tenderness and enlargement.
• Juvenile type: isosexual precocious puberty (breast development, vaginal bleeding, and accelerated growth) in prepubertal girls.
• Pelvic mass, abdominal distension, pain, or an acute abdomen from tumour rupture (haemoperitoneum in about 10 to 15 percent) or torsion.
• Examination: palpable solid or cystic pelvic mass, and signs of oestrogen effect.
• Endometrial thickening on ultrasound.
• Ascites in advanced disease; Meigs syndrome features are possible.

• Ultrasound: large solid or multicystic ovarian mass with a "Swiss cheese" appearance, thickened endometrium; Doppler shows vascular flow; MRI and CT define extent.
• Tumour markers: inhibin B (most sensitive and specific, raised in about 90 percent) and inhibin A, anti-Müllerian hormone (raised, useful for surveillance), and oestradiol; CA-125 may be raised in advanced disease.
• Endometrial biopsy in women with abnormal bleeding, because of concurrent hyperplasia or carcinoma.
• Histology: Call-Exner bodies (rosette like arrangement of granulosa cells around eosinophilic material) in about 50 percent, and coffee bean nuclei with longitudinal grooves.
• Histology shows positivity for inhibin, calretinin, SF-1, FOXL2 and CD56.
• The main differentials are thecoma, undifferentiated carcinoma, and endometrioid carcinoma.
• Preoperative evaluation: chest and abdominal CT, endometrial sampling, and tumour markers.

• Surgery is the mainstay.
• Stage I disease in women who have completed childbearing: total abdominal hysterectomy, bilateral salpingo oophorectomy and complete surgical staging (washings, omentectomy, peritoneal biopsies). Lymphadenectomy is not routinely needed because nodal spread is rare (below 5 percent).
• Fertility sparing surgery in young women with stage IA disease: unilateral salpingo oophorectomy with preservation of the uterus and contralateral ovary, endometrial sampling to exclude hyperplasia or carcinoma, and staging. Completion surgery after childbearing.
• Intraoperative rupture, which upstages the disease to IC, must be avoided; the tumour is removed intact in a bag.
• Adjuvant therapy: stage I low risk, observation only.
• Stage IC (rupture or capsule breach), high mitotic activity, poorly differentiated, or stage II to IV: chemotherapy with bleomycin 15 units/m2 (maximum 30 units) on day 1 to 3 or weekly, etoposide 100 mg/m2 on days 1 to 5, and cisplatin 20 mg/m2 on days 1 to 5 (BEP), every 21 days for 4 cycles.
• The alternative is carboplatin AUC 6 with paclitaxel 175 mg/m2 every 21 days for 6 cycles (preferred for less toxicity and similar response). Pulmonary function is monitored with bleomycin.
• Recurrent disease: secondary cytoreductive surgery when localised and late recurrence is present.
• Hormonal therapy (letrozole 2.5 mg daily, anastrozole 1 mg daily, tamoxifen 20 mg daily, medroxyprogesterone, or leuprolide 3.75 mg monthly) in the relapsed or indolent setting, with response rates 20 to 30 percent.
• Other options for recurrence: chemotherapy with carboplatin AUC 6 and paclitaxel 175 mg/m2 every 21 days; bevacizumab 15 mg/kg every 3 weeks; and radiotherapy for localised recurrence.
• Surveillance: clinical examination and inhibin B or AMH every 3 to 6 months for 5 years then every 6 to 12 months, for at least 10 years and often lifelong, because recurrence can occur more than 20 years later. Image if markers rise or symptoms arise.
• Juvenile type: unilateral oophorectomy with staging is sufficient for stage IA, with BEP chemotherapy for advanced disease. A favourable outcome is expected, with relapses occurring early (within 3 years).
• Endometrial hyperplasia or carcinoma found alongside is treated according to its own grade, with hysterectomy typically when childbearing is done.
• Bone and cardiovascular health care follow oophorectomy; hormone replacement is generally withheld due to a theoretical risk, though evidence of harm is limited.