Sex cord-stromal tumors are neoplasms which contain granulosa cells, Sertoli cells, Leydig cells and fibroblasts of stromal origin. These tumors are notable for their endocrine activity, with feminizing or predominantly estrogenproducing tumors or virilizing or predominantly androgen-producing tumors, and they account for 3 - 10% of gonadal tumors. Steroid dosage and specific tumor markers are useful in the follow-up after surgery. Activating mutations of the G-protein genes have been associated with the development of several endocrine neoplasms. Lyons et al. identified a special mutation at codon 179 of Gα12 (gip2) in two granulosa cell tumors and one thecoma. Other mutations were identified as gsp in Leydig cell tumors. These particular activating mutations of protein genes seem to be involved in the pathogenesis of sex cord-stromal tumors and these putative oncogenes may play a significant role in the molecular mechanism of such tumors.
Granulosa Cell Tumors. Ovarian juvenile granulosa cell tumors are usually encountered in children and adolescents and have a more favorable prognosis than the typical adult form. These tumors secrete estrogen and young girls present pseudo-precocious puberty with breast enlargement and vaginal bleeding, while adolescent patients have hypermenorrhea.
Virilization occurs in 2 - 3% of patients with granulosa tumors, especially with cystic tumors. Specific granulosa cell markers are inhibin B and MIS. Microscopically, pure granulosa cell tumors are highly differentiated and a typical microfollicular pattern consisting of Call-Exner bodies is often seen in adult tumors but is rare in juvenile cases. About 90% are diagnosed at an early stage (FIGO stage 1) and prognosis is favorable. More advanced stages have poor clinical outcome and surgery should be completed with chemotherapy (carboplatin and etoposide).
We followed an 11-year-old patient with renal failure who presented rapid breast development with metrorrhagia. Ultrasonography showed a heterogeneous right ovarian tumor (175 ml) with an enlarged uterus (55 mm). Estradiol level was high (150 pg/ml) with suppressed gonadotropin. Various tumor markers such as CEA, αFP and hCG were negative but two results were elevated: inhibin >1,000 pg/ml and MIS, 442pmol/l. This was an estrogen-producing tumor and at first we suspected a granulosa cell tumor with specific positive tumor markers. WT1 mutations have been reported in granulosa cell tumors but search for this mutation was negative. Unilateral salpingo-oophorectomy was done and confirmed FIGO stage 1. Two years later the patient is well and surveillance with inhibin B and MIS measurement and ultrasonography is negative.
fig. 2a, b). Thecomas or fibromas are uncommon before the age of 20. Pure thecomas or fibrothecomas are almost always benign but rare fibrosarcomas with nuclear atypia have a bad prognosis. Tumors may be virilizing or associated with estrogen production or Demon-Meigs syndrome (ascites and pleural effusion). In patients with nevoid basal cell carcinoma syndrome (NBCC or Gorlin syndrome), the first tumor occurs at a median age of 20 years. Gorlin syndrome is an autosomal dominant disorder linked to 9q22.3-q31 comprising ovarian fibroma, basal nevi, jaw cysts and skeletal anomalies. Pure thecomas are composed of theca cells and fibroblasts of ovarian stromal origin and luteinized thecoma.
Sertoli-Leydig Tumors. Leydig cell tumors are rare, unilateral tumors (<0.2% of all ovarian neoplasms) of the sex cord-stromal group and were previously termed androblastomas or arrhenoblastomas. They cause virilization in girls and patients complain of hirsutism, hoarseness, muscular hypertrophy and menstrual disturbances. Hormonal analysis shows a high testosterone level, only partly suppressed by the dexamethasone screening test, and suppressed LH and FSH. Ovarian vein catheterization can yield a diagnosis. These are solid yellowish nodular tumors with polygonal Leydig cells containing eosinophilic cytoplasm with lipid vacuoles. The prognosis is related to the stage and degree of tumoral differentiation. They are low-grade malignant tumors whose prognosis is usually good; unilateral salpingo-oophorectomy is necessary and sufficient. Decrease in testosterone levels and increased gonadotropins are the best markers of a favorable course.
Another Rare Tumor, the Gonadoblastoma
The gonadoblastoma is composed of germ cells mixed with sex cord derivatives and dysgerminoma. Although this tumor is benign, it may be associated with a malignant germ cell tumor. Gonadoblastoma is almost only encountered in patients with gonadal dysgenesis (Turner syndrome) associated with the Y fragment. The presence of Y chromosome material (probably not SRY) may cause the development of gonadoblastoma. The risk has recently been estimated at 7 - 10%. Gonadectomy remains the procedure of choice to exclude malignancy. If the patient or family refuse this possibility, detailed ovarian sonography supplemented with color Doppler at regular intervals may be sufficient to monitor these patients.
Revision date: June 18, 2011
Last revised: by Sebastian Scheller, MD, ScD