This group of tumors includes granulosa cell tumors, thecomas, and fibromas. The granulosa cell tumor is a low-grade malignancy, and rarely thecomas and fibromas become malignant and are called fibrosarcomas.

Granulosa cell tumors, which are estrogen secreting, are seen in women of all ages (

Figure 118-9). They are found in prepubertal females in 5% of cases, and the rest throughout the reproductive and postmenopausal years. They are bilateral in 2% of patients. In the rare prepubertal lesion, three fourths are associated with sexual pseudoprecocity because of the estrogen secretion. In the reproductive age group, most patients present with menstrual irregularities or secondary amenorrhea, and cystic hyperplasia of the endometrium may accompany these lesions. In postmenopausal women, abnormal uterine bleeding is frequently the presenting symptom. Indeed, the estrogen secretion in these patients can be sufficient to stimulate the development of endometrial cancer. Endometrial cancer occurs in association with granulosa cell tumors in about 5% of cases; 25% are associated with endometrial hyperplasia. The other symptoms and signs of granulosa cell tumors are nonspecific and are the same as for most ovarian malignancies. Ascites is present in about 10% of cases, and, rarely, a pleural effusion is present. Granulosa tumors tend to be hemorrhagic, and occasionally rupture and produce a hemoperitoneum. Inhibin is secreted by granulosa cell tumors and is a useful marker for the disease.

Granulosa cell tumors are usually stage I at diagnosis, but they may recur 5 to 30 years after initial diagnosis. The tumors also may spread hematogenously, and patients can develop metastases years after initial diagnosis in the lungs, liver, and brain. When they do recur, they can progress rapidly. Malignant thecomas are extremely rare, and their presentation, management, and outcome are similar to those of the granulosa cell tumors.

Surgery
The treatment of a granulosa cell tumor depends on the age of the patient and the extent of disease. For most patients, surgery alone is sufficient primary therapy. The performance of a unilateral oophorectomy or salpingo-oophorectomy is appropriate therapy for stage IA tumors in children or in women of reproductive age. If a granulosa cell tumor is identified by frozen section at laparotomy, a staging operation is performed, including an assessment of the contralateral ovary. If the opposite ovary appears enlarged, it should be biopsied. In perimenopausal and postmenopausal women for whom ovarian preservation is not important, a hysterectomy and bilateral salpingo-oophorectomy should be performed. In premenopausal patients in whom the uterus is not removed, a dilation and curettage of the uterus should be carried out because of a possible coexistent adenocarcinoma of the endometrium.

Treatment
There is no evidence to support the use of adjuvant radiation therapy for granulosa cell tumors, although pelvic radiation may help to palliate isolated pelvic recurrences. Furthermore, it is unclear that adjuvant chemotherapy will prevent recurrence of disease. However, metastatic lesions and recurrences have been treated with a variety of different antineoplastic drugs. There is no consistently effective regimen in these patients, although complete responses have been reported anecdotally in patients treated with a single alkylating agent, cyclophosphamide or melphalan, as well as those treated with combinations, VAC (vincristine, Adriamycin, cyclophosphamide) and PAC (cisplatin, Adriamycin, cyclophosphamide). The AcFuCy regimen (actinomycin D, 5-fluorouracil, and cyclophosphamide) has been used by the GOG and has been associated with approximately a 20% response rate. The use of hormonal agents, such as progestins or antiestrogens, has been suggested, but there are no data available.

Prognosis
Granulosa cell tumors have a prolonged natural history and a tendency for late relapse, reflecting their low grade. As such, 10-year survivals of about 90% have been reported, with 20-year survivals of 75%. Most histologic types have the same prognosis, but the more poorly differentiated diffuse or sarcomatoid type tends to do worse.

The DNA ploidy of the tumors has been correlated with survival. Holland and colleagues reported DNA aneuploidy in 13 of 37 patients (35%) with primary granulosa cell tumors. The presence of residual disease was found to be the most important predictor of progression-free survival, but DNA ploidy was an independent prognostic factor. Patients with no residual disease and DNA diploid tumors had a 10-year progression-free survival of 96%.

Sertoli-Leydig Cell Tumors. This group of tumors occurs most frequently in the third and fourth decades, with 75% of the lesions seen in women younger than 40 years. They are rare, representing less than 0.2% of ovarian cancers. Sertoli-Leydig cell tumors are usually low-grade malignancies, although a poorly differentiated variety may behave more aggressively.

The tumors typically produce androgens, and clinical virilization is noted in 70% to 85% of patients. Signs of virilization include oligomenorrhea, amenorrhea, breast atrophy, acne, hirsutism, clitoromegaly, a deepening voice, and a receding hairline. Measurement of plasma androgens may reveal an elevated testosterone and androstenedione, with normal or slightly elevated dehydroepiandrosterone sulfate.2 Rarely, the Sertoli-Leydig tumor can be associated with manifestations of estrogenization, such as, isosexual precocity or irregular or postmenopausal bleeding.

Because these low-grade lesions are only rarely bilateral (under 1%), the usual treatment for patients in their reproductive years is a unilateral oophorectomy or salpingo-oophorectomy and evaluation of the contralateral ovary. In older patients for whom fertility is not an issue, the performance of a hysterectomy and bilateral salpingo-oophorectomy is appropriate. There are insufficient data to document the value of radiation or chemotherapy in patients with persistent disease, but some responses in those with measurable disease have been reported with pelvic radiation and the VAC chemotherapy regimen. The 5-year survival is 70% to 90%, and recurrences thereafter are uncommon. Poorly differentiated lesions account for the majority of fatalities.