Granulosa-Theca Cell Tumors
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Three major types of ovarian neoplasms are described, with epithelial cell tumors (>70%) comprising the largest group of tumors. Germ cell tumors occur less frequently (20%), while sex cord–stromal tumors make up the smallest proportion, accounting for approximately 8% of all ovarian neoplasms.
Granulosa-theca cell tumors, more commonly known as granulosa cell tumors (GCTs), belong to the sex cord–stromal category and include tumors composed of granulosa cells, theca cells, and fibroblasts in varying degrees and combinations. GCTs account for approximately 2% of all ovarian tumors and can be divided into adult (95%) and juvenile (5%) types based on histologic findings.
Both subtypes commonly produce estrogen, and estrogen production often is the reason for early diagnosis. However, while adult GCTs (AGCTs) usually occur in postmenopausal women and have late recurrences, most juvenile GCTs (JGCTs) develop in individuals younger than 30 years and often recur within the first 3 years. Theca cell tumors almost always are benign and carry an excellent prognosis. The rare malignant thecoma likely represents a tumor with a small admixture of granulosa cells. For this reason, the remainder of the article focuses on GCTs, except where indicated.
Recognition of the signs and symptoms of abnormal hormone production and consideration of these tumors in the differential diagnosis of an adnexal mass can allow for early identification, timely surgical management, and excellent cure rates. Despite the good overall prognosis, long-term follow-up always is required in patients with GCTs. [1]
Two theories exist to explain the etiology of sex cord–stromal tumors. The first proposes that these neoplasms are derived from the mesenchyme of the developing genital ridge. The second purports that sex cord and stromal cells of the mature ovary are derived from precursors found within the mesonephric and coelomic epithelium.
Reports of extraovarian GCTs can be found in the literature and may lend support to the derivation of this class of tumors from epithelium of the coelom and mesonephric duct.
Various theories propose explanations for the differentiation of normal granulosa and/or stromal cells into neoplastic entities. To date, no clear etiologic process has been identified. However, the most recent molecular data regarding these tumors have linked a missense point mutation (C402G) in the FOXL2 gene to granulosa cell tumors. [2] Using whole transcriptome sequencing of 4 adult GCTs, the mutation in FOXL2 was identified. They confirmed this mutation was present in an additional 86 of 89 adult GCTs, 3 of 14 thecomas, and 1 in 10 juvenile-type GCTs. Moreover, the mutation was not found in any of 49 sex cord stromal tumors of other types or in epithelial ovarian tumors. This suggests a potential pathogenic mutation and raises the possibility of identifying novel targeted therapies. [3]
GCTs are thought to be tumors of low malignant potential. Most of these tumors follow a benign course, with only a small percentage showing aggressive behavior, perhaps due to early stage at diagnosis. Metastatic disease can involve any organ system, although tumor growth usually is confined to the abdomen and pelvis.
United States
Approximately 25,000 new cases of ovarian cancer are diagnosed in the United States each year. This disease accounts for more than 14,000 deaths in the United States annually and is the leading cause of death from gynecologic malignancies. Because sex cord–stromal tumors account for only 5% of all ovarian tumors and approximately 8% of all malignant ovarian neoplasms, each year only 1500-2000 new cases of these tumors are diagnosed in the United States.
International
Unlike epithelial ovarian cancers, no racial or ethnic predilection is found for ovarian germ cell or sex cord–stromal tumors. The incidence of this group of tumors essentially is the same throughout the world, as witnessed by similar frequency of these tumors in Japan, Sweden, and the West Indies.
AGCTs and JGCTs have very good cure rates due to the early stage of disease at diagnosis. More than 90% of AGCTs and JGCTs are diagnosed before spread occurs outside the ovary. Five-year survival rates usually are 90-95% for stage I tumors compared to 25-50% for patients presenting with advanced-stage disease. Although 5-year survival rates are quite good, AGCTs have a propensity for late recurrence, some occurring as many as 37 years after diagnosis. Mean survival after the diagnosis of a recurrence is 5 years.
Approximately 20% of patients diagnosed with GCTs die of their disease over the course of their lifetime.
Morbidity related to GCTs primarily is due to endocrine manifestations of the disease. Physical changes brought on by high estrogen levels from the tumor usually regress upon removal of the tumor. However, a small group of patients present with symptoms of androgen excess from the tumor. Changes caused by androgen excess may be permanent or may only partially regress over time.
Serious estrogen effects can occur in various end organs. Unopposed estrogen production by these tumors has been shown to cause stimulation of the endometrium. Anywhere from 30-50% of patients develop endometrial hyperplasia and another 8-33% have endometrial adenocarcinoma. Patients also may be at an increased risk for breast cancer, although a direct correlation has been difficult to prove.
Limited available data show that this class of neoplasms makes up a similar proportion of ovarian malignancies in the United States, Europe, the Far East, and the West Indies.
Granulosa cell tumors can occur in the juvenile and adult male testes, albeit very rarely. The frequency of GCTs in the male testes is even lower than that of GCTs in females and is the least common sex cord stromal tumor in the testes.
AGCTs account for 95% of all GCTs and usually are seen in postmenopausal women, with a median age at diagnosis of 52 years.
JGCTs comprise only 5% of all GCTs, and almost all of these tumors are found in patients younger than 30 years.
Theca cell tumors (ie, thecomas) account for less than 1% of all ovarian tumors, and the mean age at diagnosis is 53 years. These tumors are rare in women younger than 30 years, with the exception of the luteinized thecoma, which tends to occur in younger women.
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David C Starks, MD, MPH Faculty Staff, Avera Medical Group Gynecologic Oncology, Avera Cancer Institute
Disclosure: Nothing to disclose.
Daniel K Chan, MD, PhD Resident Physician, Department of Obstetrics and Gynecology, Magee-Womens Hospital of UPMC
Daniel K Chan, MD, PhD is a member of the following medical societies: American Association for Cancer Research, American College of Obstetricians and Gynecologists, American Medical Association, Association of Professors of Gynecology and Obstetrics, American Congress of Obstetricians and Gynecologists, American Physician Scientists Association
Disclosure: Nothing to disclose.
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Warner K Huh, MD Professor, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Senior Scientist, Comprehensive Cancer Center, University of Alabama School of Medicine
Warner K Huh, MD is a member of the following medical societies: American College of Obstetricians and Gynecologists, American College of Surgeons, Massachusetts Medical Society, Society of Gynecologic Oncology, American Society of Clinical Oncology
Disclosure: I have received consulting fees for: Merck; THEVAX.
Bruce A Meyer, MD, MBA Executive Vice President for Health System Affairs, Executive Director, Faculty Practice Plan, Professor, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical School
Bruce A Meyer, MD, MBA is a member of the following medical societies: Medical Group Management Association, American College of Obstetricians and Gynecologists, American Association for Physician Leadership, American Institute of Ultrasound in Medicine, Association of Professors of Gynecology and Obstetrics, Massachusetts Medical Society, Society for Maternal-Fetal Medicine
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Alfonso Barnes, MD, Director of Gynecologic Oncology, Department of Obstetrics and Gynecology, Bethesda Hospitals; Director of Gynecology Service, Department of Obstetrics and Gynecology, Providence Hospital
Disclosure: Nothing to disclose.
Chad M Michener, MD Assistant Professor, Obstetrics/ Gynecology and Women’s Health Institute, Section of Gynecologic Oncology, The Cleveland Clinic
Chad M Michener, MD is a member of the following medical societies: American College of Obstetricians and Gynecologists and Society of Gynecologist Oncologists
Disclosure: Nothing to disclose.
Allan Y Wu, MD Director, The Midwest Women’s Specialty Group; Adjunct Clinical Professor, Department of Molecular Biology, The Terre Haute Center for Medical Education, Indiana University School of Medicine
Allan Y Wu, MD is a member of the following medical societies: American College of Obstetricians and Gynecologists
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