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.
Many patients with GCTs present with manifestations of hyperestrogenism. Approximately 70% of these tumors are hormonally active. Hormonal influences can cause different presenting symptoms depending on patient age and menstrual status. Although these symptoms can be quite profound, often they may be secondary findings in patients with complaints relating to the abdomen and pelvis.
Reports of increasing abdominal girth and abdominal discomfort are quite common. Most patients have a palpable mass found during examination. Abdominal symptoms may be due to enlargement of the mass but also can be due to the production of ascites, which occurs in approximately 10% of patients. Increasing size of the mass also can lead to symptoms associated with compression of adjacent structures, such as abdominal pain, dysuria, urinary frequency, and constipation.
Acute onset of abdominal pain also can occur, although rarely. Acute abdominal or pelvic pain may be observed in combination with nausea, vomiting, dizziness, and shoulder pain. These symptoms may be due to adnexal torsion, rupture of a partially cystic GCT, or hemorrhage either within the tumor or into the peritoneum.
Patients usually present with precocious pseudopuberty (70-80%) and have secondary sex characteristics at a very early age. These may include increased linear growth, breast enlargement, clitoral enlargement, pubic hair development, increased vaginal secretions, and vaginal bleeding.
In a few instances, patients present with virilizing symptoms as a result of testosterone production by the tumor cells. Many of these hormone-induced symptoms abate following resection of the tumor.
Increasing abdominal girth and other symptoms related to an enlarging adnexal mass may be seen in this group of patients. Menstrual irregularities such as oligomenorrhea, menorrhagia, and secondary amenorrhea tend to be the hallmark of these tumors in reproductive-aged women.
The most common endocrine manifestation of GCTs in postmenopausal women is abnormal uterine bleeding. This is caused by resumption of endometrial proliferation due to estrogen production by the tumor. For this reason, endometrial hyperplasia and/or endometrial adenocarcinoma may be a concomitant finding in women with GCT.
Patients also can have breast tenderness and increased vaginal secretions from estrogenic stimulation of the breast and vaginal tissues, respectively.
Rarely, a patient may present with virilizing symptoms such as acne, hirsutism, deepening of the voice, and clitoral enlargement. This is due to testosterone and/or androstenedione production in a minority of these tumors.
Pelvic mass is the most consistent finding on pelvic and rectal examination in patients of all ages with GCT. A palpable mass can be found in 85-97% of patients. A bimanual examination and a rectovaginal examination should be performed to evaluate the pelvis and lower abdomen for masses, the posterior cul-de-sac for nodularity, and any other areas associated with tenderness.
For patients presenting with acute abdominal pain, a careful speculum examination should be performed to help rule out infectious etiologies. Wet preparation and testing for Neisseria gonorrhoeae and Chlamydia trachomatis should be considered. Gram stain for gram-negative diplococci can be helpful if other findings are consistent with a diagnosis of pelvic inflammatory disease and/or cervicitis.
Other findings generally relate to endocrine manifestations of hyperestrogenic and/or hyperandrogenic states.
No definite etiologies for GCTs have been found. Proposed etiologies include chromosomal anomalies and/or autocrine and endocrine signaling abnormalities. A multifactorial etiology has been postulated.
Order a pregnancy test in all reproductive-aged patients (even at the extremes of reproductive age) who present with abdominopelvic symptoms.
The standard workup for a patient with an adnexal mass varies depending on patient age, as follows:
Other ancillary laboratory studies that may be useful in narrowing the differential include stool guaiac testing, CBC count with differential, blood chemistries, urinalysis, and cervical cultures for gonorrhea and chlamydia.
Several other tumor markers have been evaluated in patients with GCTs.
Inhibin has been studied in women with granulosa cell tumors. It is a peptide hormone produced by ovarian granulosa cells that plays a role in regulation of FSH secretion by the pituitary. It is composed of an alpha subunit and 1 of 2 beta subunits (BA or BB). Although inhibin A and inhibin B levels can both be elevated in patients with granulosa cell tumors, inhibin B level is usually elevated in a higher proportion of these tumors. Furthermore, this increase in serum levels from baseline is often higher as well. Typical cutoffs for normal inhibin levels in postmenopausal or oophorectomized women are less than or equal to 5 ng/L and 15 ng/L for inhibin A and B, respectively.
Studies of inhibin in patients with GCTs have shown that levels are elevated preoperatively and return to the reference range postoperatively in both adult and juvenile types of tumors. In a 2002 study by Robertson et al, total serum inhibin level was elevated in 100% of GCTs and 100% of thecomas.[5] Additionally, 84% of patients with mucinous ovarian carcinomas had elevated inhibin levels. However, only 18% of patients with serous and 54% of patients with endometrioid ovarian cancers had elevation of total serum inhibin level. Current inhibin assays allow us to distinguish between inhibin A and inhibin B.
Mom et al evaluated the use of serum inhibin levels in 30 women with granulosa cell tumors. The sensitivities and specificities for inhibin A were 67 and 100% and for inhibin B were 89 and 100%, respectively. They also noted that inhibin A level was elevated before or at the time of first clinical recurrence in 58% of patients while inhibin B level was elevated in 85%. Lead time from elevation of inhibin levels to clinical recurrence was estimated to be 11 months. Inhibin A and B levels were not elevated in any of the 17 patients who were postoperatively disease free. Serum inhibin levels are currently available for diagnosis and clinical follow-up of women with granulosa cell tumors of the ovary.[6]
This hormone is produced exclusively by granulosa cells in postnatal females and both prenatally and postnatally by the Sertoli cells in the male testis. This hormone functions in male fetuses to induce regression of the mullerian system. Normally, MIS/AMH is found in low levels in reproductive-aged females and functions as a paracrine inhibitory factor decreasing resting ovarian follicle response to follicle stimulating hormone (FSH). This insures the emergence of a single dominant follicle. Serum MIS/AMH may be a marker of ovarian reserve and typically disappears from the serum after menopause or bilateral oophorectomy. However, in patients with GCTs, levels have been shown to parallel the extent of disease.[7]
Lane et al found that 76% of patients with GCTs had elevated MIS/AMH levels preoperatively.[8] No patient with levels within the reference range postoperatively experienced recurrence, whereas 6 of 15 patients with elevated levels had a recurrence. On average, elevated levels were detected 3 months before clinical evidence of recurrence was found. In 2000, Long et al used an ultrasensitive ELISA and found that AMH levels became undetectable in 15 of 16 women treated for GCTs and were elevated in 14 of 15 women (sensitivity 93%) with recurrent granulosa cell tumors.[9]
Anttonen et al reported that MIS gene expression was significantly decreased in 87% of tumors greater than 10 cm.[10] This inverse relationship between MIS expression and tumor size raised concerns that MIS/AMH may not be a useful marker in advanced cases of GCT.
Serum MIS/AMH levels correlate well with tumor presence in patients with GCTs. This marker is highly specific for GCT in postmenopausal or oophorectomized women. It may also be elevated in women with Sertoli-Leydig cell tumors of the ovary, but is not typically produced by other gonadal or extragonadal tumors. This is in sharp contrast to inhibin and estradiol levels, both of which may be elevated in a variety of other extraovarian disorders. This makes AMH/MIS attractive as a marker for diagnosis and prospective follow-up of patients with GCTs. However, studies have been limited to retrospective trials. With widespread clinical availability of AMH testing, this marker may gain ground in the management of women with GCTs and perhaps could be a molecular target in the future.
GCTs are the most common estrogen-producing neoplasms in females and are found to produce estradiol in approximately 40-60% of patients. This estradiol production is dependent on stimulation by testosterone secreted by the theca cells. However, not all GCTs are hormonally active or have theca cells that secrete testosterone, and this type of testing lacks sensitivity and specificity.
Transvaginal sonography (TVS) is by far the best primary modality for imaging pelvic structures. This may allow for delineation between ovarian, tubal, uterine, and other pelvic masses. If an adnexal mass is identified, the presence of cystic or solid components should be noted and remarks on the internal architecture of cystic structures (eg, septations, excrescences) should be made. Free pelvic fluid also can be identified readily on TVS images. The presence of solid, complex, cystic, or bilateral masses, with or without free fluid, increases the possibility of malignancy.
GCTs have a heterogeneous appearance on both sonographic and CT imaging, depending on the histologic pattern. Most commonly, they appear as round-to-ovoid masses that are multicystic, sometimes with solid components at the center or periphery. Fewer cases appear as unilocular simple or complex cysts or even homogeneous solid masses. The average size of these tumors is 12 cm, but they can range from 2-50 cm.
Chest radiography is useful in helping exclude pulmonary spread of malignant diseases of the ovary. Abdominopelvic CT scanning or MRI may help in diagnosing intraperitoneal spread or involvement of other organ systems prior to surgery. Abdominopelvic imaging also can be used in follow-up evaluations to confirm the presence of recurrent tumor identified after clinical examination.
Abdominal radiography, intravenous pyelography (IVP), barium enemas, and upper GI series also can be useful adjuncts in patients with symptoms involving the GI or genitourinary tracts.
Perform a barium enema or colonoscopy in any patient with a pelvic mass prior to surgical intervention to help rule out colonic involvement, colon cancer, or both as the primary tumor in women older than 40 years. However, if abdominopelvic CT scanning with oral and intravenous contrast already has been performed, IVP, colonoscopy, and barium enema are not required.
The preoperative workup also should include mammography for women older than 40 years who have not had one in the preceding 6-12 months. This is especially important in women with estrogen-producing tumors because these may increase the risk of breast malignancies.
Additionally, breast cancers can metastasize to the ovaries and are often bilateral. Mammography can help rule out the possibility of a nongynecologic primary neoplasm in the breast.
Grossly, tumors can be cystic, solid, or a mixture of both. On cut section, they usually are multicystic and may contain areas of hemorrhage. Solid tumors appear grayish if they are nonsteroidogenic or yellow if they are steroid-producing neoplasms. Androgen-producing tumors more commonly are unilocular or solid in contrast to the multilocular tumors that make up most GCTs.
Microscopically, GCTs are composed of granulosa cells, theca cells, and fibroblasts in varying amounts and combinations. The term granulosa-theca cell tumor had been applied to all tumors in which both cell types were identified, regardless of the amounts present. Young and Scully proposed a system that required a tumor to be composed of at least 25% of the second cell type before the tumor could be designated as a true granulosa-theca cell tumor.[11] Otherwise, the tumor would be designated as a granulosa cell tumor or a theca cell tumor based on the predominant cell type. This has led to some confusion in the literature because some theca cell tumors, which are essentially benign neoplasms, have been given the dual designation of granulosa-theca cell tumors, suggesting a malignant potential among this benign group of tumors.
AGCTs have multiple histomorphologies, including well-differentiated and less well-differentiated types. The well-differentiated group is composed of microfollicular, macrofollicular, trabecular, and insular patterns. Microfollicular is the most common pattern of all of these subtypes and contains characteristic Call-Exner bodies. These bodies consist of small rings of granulosa cells surrounding eosinophilic fluid and basement membrane material (see image below).
View Image | Microfollicular pattern of an adult granulosa cell tumor at 100X magnification. Inset is characteristic Call-Exner bodies and nuclear grooves (400X). .... |
Macrofollicular GCTs are composed of a large cyst or collection of large cysts, each lined by a single layer of granulosa cells. Trabecular and insular patterns have cells arranged in nests and bands, with an intervening fibrothecomatous stroma found in the trabecular type.
The less well-differentiated group includes diffuse and watered-silk (moiré) or gyriform patterns. Monotonous sheets of cells arranged in no distinguishable pattern characterize the diffuse subtype (see image below).
View Image | Less well-differentiated diffuse pattern of adult granulosa cell tumor. Monotonous pattern can be confused with low-grade stromal sarcoma (200X). Inse.... |
Watered-silk and gyriform patterns have cells that often line up single-file in undulating lines (see image below).
View Image | Gyriform pattern of adult granulosa cell tumor. Undulating single-file rows of granulosa cells (200X). Image courtesy of James B. Farnum, MD, TriHealt.... |
The nuclear appearance is the same in both groups of adult GCTs. The nuclei usually are large pale ovoid or angular structures containing nuclear grooves that give them a "coffee-bean" appearance (see image below).
View Image | Microfollicular pattern of an adult granulosa cell tumor at 100X magnification. Inset is characteristic Call-Exner bodies and nuclear grooves (400X). .... |
Usually only a small amount of cytoplasm is present, although luteinization of the tumor, characterized by larger amounts of dense cytoplasm with occasional vacuoles, sometimes can be found. Mitotic figures generally are few in number, and only mild nuclear atypia is found in most cases. Nuclear appearance and mitotic rate often are the key elements differentiating GCTs from other malignant tumors. Low-grade stromal sarcomas, small cell carcinomas, carcinoid tumors, and melanomas may look similar to GCTs on low power, but these other tumors lack nuclear grooves, are more hyperchromatic, and often contain more mitotic figures than GCTs.
JGCTs have little morphologic similarity to those of the adult type. However, their gross appearance can be similar to AGCTs in that they often are a mixture of solid and cystic components with many areas of hemorrhage. Microscopically, they have a distinct appearance with round hyperchromatic nuclei, most often lacking the nuclear grooves found in the adult type (see image below). Nuclear atypia often is more severe with more mitotic figures than are found in the adult type, consistent with their more aggressive phenotype. The cytoplasm often is more abundant and dense in JGCTs.
View Image | Juvenile granulosa cell tumor. Multiple follicles in various shapes and sizes (200X). Inset shows nuclei that are rounded, hyperchromatic, lacking gro.... |
Thecomas usually are tan or yellow with an average size of 7-8 cm. These tumors are bilateral in fewer than 3% of cases. Microscopically, they are composed of round or ovoid cells with pale nuclei and a lipid-rich cytoplasm. Mitoses usually are less than 4 per 10 high-power fields. Hyaline bands often are found interspersed between cells (see image below).
View Image | Theca cell tumor. Typical thecoma with lipid-rich cytoplasm, pale nuclei, and intervening hyaline bands (200X). Image courtesy of James B. Farnum, MD,.... |
Luteinized thecomas also contain cells with a lipid-rich cytoplasm but are set within a more fibromatous stroma (see image below). Most of these tumors are hormone-producing tumors and cause postmenopausal bleeding in as many as two thirds of patients. Luteinized thecomas also may be androgenic and, if so, tend to occur in younger women.
View Image | Luteinized thecoma. Vacuolated theca cells with an abundant fibromatous stroma (200X). Image courtesy of James B. Farnum, MD, TriHealth Department of .... |
Ovarian carcinoma is a surgically staged disease. The current staging classification system is based on 1987 International Federation of Gynecology and Obstetrics (FIGO) nomenclature.
Stage Ia: Tumor is limited to one ovary with an intact capsule. No tumor is present on the external surface of the capsule, and no ascites containing malignant cells are present.
Stage Ib: Tumor involves both ovaries, with intact capsules. No tumor is present on the external surface of the capsule, and no ascites containing malignant cells are present.
Stage Ic: Tumor is stage Ia or Ib with tumor on the external surface of one or both ovaries, or ruptured capsule(s) or malignant cells are present in ascitic fluid or peritoneal washings.
Stage IIa: Extension and/or metastases to the uterus and/or fallopian tubes are present.
Stage IIb: Extension to the bladder, rectum, or other pelvic tissues occurs.
Stage IIc: Tumor is stage IIa or IIb, with tumor on the external surface of one or both ovaries or ruptured capsule(s), or malignant cells are present in ascitic fluid or peritoneal washings.
Stage IIIa: Tumor is grossly confined to the pelvis but with microscopic seeding of the abdominal peritoneal surfaces. Lymph nodes are negative.
Stage IIIb: Tumor implants are present on the abdominal peritoneum, none larger than 2 cm in diameter. Lymph nodes are negative.
Stage IIIc: Tumor implants on the abdominal peritoneum 2 cm or more are present, and/or retroperitoneal or inguinal nodes are positive.
Pleural effusions must be confirmed cytologically to classify a case as stage IV. Metastases to the liver parenchyma also are included in stage IV.
Primary treatment for patients with GCTs is surgical. Chemotherapy and/or radiotherapy are reserved for patients with advanced disease by surgical staging, and for patients with recurrent tumor.
Surveillance for patients postoperatively consists of frequent pelvic examinations and assessment of tumor markers (if applicable) to detect recurrences as early as possible. Findings from physical examination or laboratory studies that are suggestive of recurrence should be further evaluated with abdominopelvic CT scan or other diagnostic imaging modalities.
Radiotherapy for patients with advanced or recurrent GCTs has been studied and appears to have limited efficacy.
In a 1999 study by Wolf et al at the MD Anderson Cancer Center, 6 of 14 patients with measurable disease had complete clinical responses to pelvic radiation and 3 patients were without evidence of disease 10-21 years after radiation. However, 3 patients experienced a recurrence 4-5 years after radiation.[12] Eight of 14 had no response to treatment and had a median survival of 12.3 months overall.
A more recent study by Hauspy et al reviewed 45 years of GCT treatment at Princess Margaret Hospital. Thirty-one of 103 women received abdominal and/or pelvic radiation as adjuvant therapy. Multivariate analysis showed that adjuvant radiation significantly improved survival and that stage III disease was independently predictive of a poor response. They concluded that patients receiving radiation had better disease-free survival (251 mo vs 114 mo for those not receiving radiation). However, 86% of those receiving radiation were stage I versus only 52% of those who did not receive radiation. Moreover, only 2 of the 103 patients received chemotherapy.[13]
Currently, radiation is considered an option for advanced-stage patients and, in patients with pelvic recurrence, radiotherapy should be considered because a clinical response occurs in almost half of patients treated with radiation therapy.
Adjuvant therapy for GCTs has typically been carried out using chemotherapy. There is also data available regarding hormonal manipulation of these tumors using GnRH analogues and aromatase inhibitors. See additional discussion under "Experimental medications" below.
Standard of care for initial management of GCTs remains surgical.[14, 15] Surgical management allows for staging and tissue diagnosis.
Surgical management of patients who present with signs and symptoms concerning for GCTs begins with a thorough preoperative evaluation.
Preoperative imaging and laboratory studies are helpful for measuring the extent of disease permitting proper patient counseling (see Lab Studies and Imaging Studies).
Appropriate staging with intact removal of the tumor and optimal cytoreduction are the main goals of surgical therapy. Several studies have shown that FIGO stage is the most prognostic factor for granulosa cell tumors.
In a 2003 study, Uygun et al showed a definite survival benefit for patients with lower-stage tumors and for patients who had no residual disease at surgery (mean overall survival 108 mo) versus those with residual disease at the end of surgery (mean 42 mo, p = 0.001).[16]
Prepare patients for the possibility of bowel resection and/or ostomy placement if diffuse spread is suggested following the preoperative assessment. A mechanical bowel preparation, with or without antibiotics, should be used in all patients undergoing surgery for a pelvic mass.
Complete surgical staging consists of a thorough examination of the pelvic and intra-abdominal structures. If disease is identified outside the ovary, optimal debulking should be performed so that all remaining tumor nodules are smaller than 1 cm, but goal should still be complete resection of all visible tumor. Optimal tumor debulking improves overall survival and decreases recurrences.
In younger patients who desire future fertility, a unilateral salpingo-oophorectomy almost always provides sufficient treatment because most of these tumors are stage I (see Staging). Zanagnolo et al, in a review of 63 cases of sex cord stromal tumors, reported that conservative surgical management was performed in 23% of early stage tumors. No recurrences were noted and 5 out of 11 patients became pregnant.[17]
Staging should generally be performed and consists of pelvic washings, selective ipsilateral pelvic and bilateral periaortic lymph node sampling, peritoneal biopsies, partial omentectomy, and biopsy of the contralateral ovary (only if it appears abnormal). Previously, biopsy of the contralateral ovary was considered a routine part of the staging procedure but now is not required because only approximately 2% of tumors are bilateral and biopsy may lead to adhesion formation and subsequent problems with pain and/or fertility.
A retrospective study from MD Anderson has called into question the need for lymphadenectomy to be routinely performed as part of the standard staging procedure for GCTs due to the low risk of lymph node metastasis even in cases of advanced stage disease. Because hormone overproduction is common with GCTs, dilatation and curettage should be considered to help rule out a neoplastic process of the endometrium in younger patients undergoing fertility-sparing surgery, especially if abnormal uterine bleeding was part of their clinical presentation.[18]
A more recent study by Thrall et al supports the concept of avoiding lymphadenectomy. In their study, there were no lymph node metastases in 47 patients who had at least some lymph nodes removed, with a median lymph node count of 14 in 36 of these patients. However, 2 of 18 patients who recurred did not undergo initial nodal dissection. Moreover, they noted that 60% of patients who were stage II or higher had only microscopic extraovarian disease.[19]
Although data on the clinical utility of lymphadenectomy in sex cord stromal tumors is mounting, there are no uniform recommendations and there remains an important role for surgical staging/biopsy based on incidence of microscopic extraovarian disease.
For patients in whom future fertility is not a concern, surgical therapy should consist of bilateral salpingo-oophorectomy and total abdominal hysterectomy, in addition to the staging procedures.
Treatment of recurrent GCTs is not as uniform as it is for the primary tumors. Surgical debulking can be of value if the tumor appears to be focal on imaging studies. Chemotherapy, radiotherapy, and hormonal treatments have been used with variable success. All appear to have some benefit for improving long-term survival and the progression-free interval. Mean survival after a recurrence has been diagnosed is approximately 5 years for adult GCTs.[20]
Consultation is appropriate to help treat patients with GCTs. Unfortunately, the diagnosis of GCT usually is not made until the histologic review is completed. Therefore, appropriate preoperative consultation and intraoperative frozen sections help to ensure that patients are appropriately staged and have the best chance to be optimally debulked during their initial laparotomy.
For patients in whom the diagnosis is made postoperatively, consultation with a gynecologic oncologist or hematologic oncologist still should be pursued.
The question of when to obtain preoperative consultation with a gynecologic oncologist can be difficult to delineate. A good rule of thumb is that all postmenopausal and premenarchal patients with adnexal masses should have the benefit of a consultation with an oncologist because the risk of malignancy is greater.
In reproductive-aged patients, the vast majority of adnexal masses are benign. Patients with radiologic or sonographic findings suggestive of malignancy (solid or mixed solid and cystic tumors, ascites, etc) and patients with endocrinologic symptoms and an adnexal mass should have the benefit of a preoperative consultation with a gynecologic oncologist. Patients with a question of malignancy preoperatively can also be evaluated with serum tumor markers including CA125, CA19-9, LDH, AFP, beta-hCG, and inhibin levels. Appropriate referral should be made if any of these are significantly elevated.
Patients with primarily GI complaints may benefit from a consultation with a gastroenterologist to rule out a primary GI source prior to surgical exploration. Endoscopy can be performed during this preoperative evaluation if indicated.
No activity restrictions are needed, outside of the normal postoperative recovery time.
Surgical treatment is considered first-line therapy for patients with GCTs. Chemotherapy can be used as adjuvant therapy in patients with advanced or recurrent disease and has been effective for improving the disease-free survival. The rarity of this tumor has precluded randomized control trials; therefore, no prospective data are available regarding overall survival in high-risk patients who receive adjuvant chemotherapy compared to those who have not.
The optimal chemotherapy regimen has been hard to identify given that the overall incidence of GCTs is relatively low. Various chemotherapy regimens have been used in patients with GCTs, with varying toxicity and response rates.
Single-agent chemotherapy with alkylating agents has been used in patients with GCTs with only modest partial response rates. Current chemotherapy regimens usually consist of multidrug regimens and most commonly include platinum as one of the agents. The most frequent combination therapy given currently is the bleomycin, etoposide, and cisplatin (BEP) regimen. The Gynecologic Oncology Group (GOG) is currently conducting a randomized phase II trial (Clinical trial ID: NCT104522) comparing BEP with carboplatin and paclitaxel for patients with advanced or recurrent chemotherapy-naive sex cord stromal tumors.
Bleomycin, etoposide, and cisplatin regimen
The BEP regimen also has been studied in patients with advanced and recurrent GCTs. In 1999, Homesley et al reported the Gynecologic Oncology Group's experience using this regimen and included patients with all types of ovarian sex cord–stromal tumors, although 48 patients had GCTs. Patients with gross residual disease, positive findings on peritoneal cytology, and recurrent tumors were included.[21]
Of patients undergoing second-look surgery, 14 of 38 (37%) had a complete response on second look laparotomy. Additionally, 40% of the 25 patients with measurable disease had an objective response to this regimen. No recurrence or progression of disease was observed in 11 of 16 patients with primary advanced disease (68%) and 21 of 41 patients with recurrent disease (51%). However, only half the patients had follow-up of 3 years or longer. Only measurable disease was found to be a predictor of both overall survival and progression-free interval. Again, significant toxicity was noted, with bone marrow suppression being most common (79%), followed by GI toxicity.
The BEP regimen is bleomycin at 20 U/m2 (not to exceed 30 U) IV q3wk for 4 courses, etoposide at 75 mg/m2 IV on days 1-5 q3wk for 4 courses, and cisplatin at 20 mg/m2 IV on days 1-5 q3wk for 4 courses.
Cisplatin, vinblastine, and bleomycin regimen
The cisplatin (Platinol), vinblastine, and bleomycin (PVB) regimen has been studied most recently and shows moderately high response rates. Pecorelli et al showed complete and partial response rates of 28% and 24%, respectively, with 25.4-month median survival in patients who had not received prior chemotherapy or radiation. An additional 13 patients in their study received prior radiation. Their complete, partial, and overall response rates were 38%, 38%, and 77%, respectively. Median survival in this group was 41.1 months. Hematologic toxicity, nausea, vomiting, and peripheral neuropathy were common, and pulmonary toxicity due to bleomycin was observed in a few patients.[22] Earlier studies by Zambetti et al[23] and Colombo et al[24] showed similar response rates but with severe bone marrow and pulmonary toxicity.
The PVB regimen is cisplatin at 20 mg/m2/d IV for 5 days q3wk for 3-4 courses; bleomycin at 20 U/m2 (not to exceed 30 U) IV qwk for 7 courses, followed by an 8th course during the 10th week; and vinblastine at 12 mg/m2 IV q3wk for 3-4 courses.
Other regimens
Older multidrug regimens included (1) cyclophosphamide, doxorubicin (Adriamycin), and cisplatin regimen, which includes cyclophosphamide at 500 mg/m2 IV, Adriamycin at 40-50 mg/m2 IV, and cisplatin at 40-50 mg/m2 IV all given q4wk for 4-6 courses; (2) cisplatin and doxorubicin; and (3) cyclophosphamide, actinomycin, and 5-fluorouracil. These regimens have the benefit of fewer and less serious adverse effects. However, response rates often were poorer than for those of the newer cisplatin-based regimens.
Much less information is available for JGCTs with regard to treatment of advanced disease and recurrences. These tumors tend to behave more aggressively, with earlier recurrences and poorer responses to chemotherapeutic agents. Case reports detailing complete responders can be found for patients treated with carboplatin and etoposide; methotrexate, actinomycin D, and chlorambucil; and methotrexate, actinomycin D, and cyclophosphamide. However, long-term survival rates in patients with JGCTs have been disappointing.
Current research includes the activity of taxanes in the treatment of GCTs, particularly for recurrence in patients previously treated with BEP. A retrospective review from the MD Anderson Cancer Center suggests that response to taxanes with or without platinum may be similar to that of the BEP regimen with less toxicity.
Experimental medications
There has been increasing interest in the use of antiangiogenic therapy in GCTs due to accumulating evidence on the role of angiogenesis in this class of tumors. Case reports and 1 case series show potentially promising results, with 1 patient having a complete and 2 patients having partial responses out of 8 patients with GCTs treated with bevacizumab at MD Anderson Cancer Center.[25]
Several recent case reports have raised the possibility of the use of hormonal therapy in the management of recurrent GCTs. Responses to medroxyprogesterone acetate, GnRH agonists, and megestrol (Megace)[26] have all been reported in a small number of patients with progressive disease not responsive to chemotherapy.
Treatment of recurrent GCTs with leuprolide acetate has been described but exhibited only marginal success in a small number of patients. Several recent reports have documented the use of the aromatase inhibitors, which inhibit the conversion of androstenedione to estrone, in the management of patients who previously received surgery and chemotherapy. To date, there are less than 10 patients published in the literature who received aromatase inhibitors as part of their treatment strategy. Several patients have shown durable responses and 1 patient treated after surgical resection of a second recurrence remained disease free for at least 54 months.[27] Another case report used an aromatase inhibitor as a rescue therapy for tamoxifen-refractory disease.[28] Although interesting, the role of aromatase inhibitors in GCTs remains investigational.
Clinical Context: Inhibits DNA synthesis and, thus, cell proliferation by causing DNA crosslinks and denaturation of double helix. Platinum-based alkylating agent. Found in most currently prescribed regimens for ovarian sex cord–stromal tumors. Treatment should be delayed if leukocyte count is < 4000/µL or if platelet count is < 100,000/µL.
Clinical Context: Plant-based vinca-alkaloid. Inhibits microtubule formation, which, in turn, disrupts the formation of mitotic spindle, causing cell proliferation to arrest at metaphase.
Clinical Context: Glycopeptide antibiotic that inhibits DNA synthesis.
Clinical Context: Alkylating agent that inhibits tumor growth by binding to DNA. Limited use currently, but could be tried in second-line regimens.
Clinical Context: Antitumor antibiotic that works by irreversibly binding to DNA, thereby inhibiting transcription.
Clinical Context: Antitumor antibiotic that is second-line treatment for ovarian germ cell tumors. Mechanism of action is through binding to guanine, thereby preventing DNA transcription.
Clinical Context: Cycle-specific antimetabolite that interferes with DNA synthesis by blocking methylation of deoxyuridylic acid. Used in various dosages in a variety of combination chemotherapy regimens.
Clinical Context: Plant-alkaloid derivative that exerts inhibitory activity at S-G2 phase of the cell cycle.
Adjunct chemotherapy for GCTs that are higher than stage Ia and for recurrent tumors.
Clinical Context: Detoxifies metabolites of ifosfamide and cyclophosphamide.
Somewhat controversial but commonly accepted that total dose should be at least 60% of total dose of alkylating agent.
Prevention of hemorrhagic cystitis in patients being treated with ifosfamide and cyclophosphamide.
Clinical Context: Selective 5-HT3-receptor antagonist that blocks serotonin both peripherally and centrally. Prevents nausea and vomiting associated with emetogenic cancer chemotherapy (eg, high-dose cisplatin) and complete body radiotherapy.
Clinical Context: 5-HT3-receptor antagonist.
Clinical Context: Selective 5-HT3 receptor antagonist with long half-life (40 h). Indicated for prevention and treatment of chemotherapy-induced nausea and vomiting. Blocks 5-HT3 receptors peripherally and centrally in chemoreceptor trigger zone.
Clinical Context: Used as antiemetic in low doses during chemotherapy. Usually used in multiagent antiemetic regimens with 5HT-3 receptor antagonists.
Prevention and treatment of nausea and vomiting associated with chemotherapy.
Follow-up should occur at 2- to 3-month intervals for the first 2 years for patients not undergoing chemotherapy. Then, this can be spaced out to every 4-6 months for the next 3 years, then yearly thereafter.
A history should be obtained and pelvic examination should be performed at each visit. Also, serum determination of tumor markers (ie, inhibin levels) should be performed if these were elevated preoperatively or immediately postoperatively.
If any evidence of recurrence arises during follow-up, imaging studies, usually an abdominopelvic CT scan should be performed to look for recurrent tumors. Most recurrences are confined to the abdomen and pelvis. Other imaging studies may be ordered as dictated by physical examination findings.
Long-term follow-up is required in all patients with GCTs because at least 50% of recurrences are found more than 5 years after initial treatment.[29]
Ondansetron, granisetron, metoclopramide, and prochlorperazine can be used to treat or prevent emesis in an inpatient or outpatient setting. Note that some chemotherapeutic agents (eg, cisplatin, cyclophosphamide) cause a delayed emesis (>24 h after chemotherapy).
The adult dose of metoclopramide is 30-40 mg PO bid or 10 mg qid for 3 days. The pediatric dose is 10-20 mg PO bid for 3 days.
The adult dose of prochlorperazine is 5-10 mg PO q6-8h or 25 mg PR bid. The pediatric dose is 0.1-0.15 mg/kg PO q6-8h or 0.2-0.3 mg/kg PR bid.
Note that metoclopramide and prochlorperazine may cause sedation and dystonic reactions.
A host of growth factors now can be given in place of antibiotics and transfusion of blood products to treat severe chemotherapy-induced or radiation-induced bone marrow suppression.
Available agents include granulocyte colony-stimulating factor (neutrophil-specific), granulocyte-macrophage colony-stimulating factor (neutrophil-, eosinophil-, and monocyte-specific), and erythropoietin (red cell–specific). Indications for each are patient-dependent.
Patients admitted with nonspecific complaints who are found later to have a pelvic mass and/or other signs of malignancy (ie, ascites, elevated tumor marker levels, outward signs of abnormal sex hormone production) should be transferred for operative and postoperative management by a trained gynecologic oncologist if one is not available at the current facility. Otherwise, consultation generally can be performed on an outpatient basis, preferably preoperatively in women with pelvic masses.
No means of preventing sex cord–stromal tumors of the ovary are known.
In 10%-15% of cases, acute abdominal symptoms may be the presenting complaints for patients with rupture of their mass, hemorrhage into the mass, or torsion of the ovary.
Adverse effects from chemotherapy can be expected but generally are well tolerated. Specific adverse effects vary with the type of chemotherapy given and have been discussed in In/Out Patient Meds and Medication.
The prognosis for granulosa-theca cell tumors generally is very favorable. GCTs are considered to be tumors of low malignant potential. Approximately 90% of GCTs are at stage I at the time of diagnosis (see Staging). The 10-year survival rate for stage I tumors in adults is 90-96%. GCTs of more advanced stages are associated with 5- and 10-year survival rates of 33-44%. The overall 5-year survival rates for patients with AGCTs or JGCTs are 90% and 95-97%, respectively. The 10-year survival rate for AGCTs is approximately 76%. In contrast, the overall 5-year survival rate for patients with epithelial ovarian cancer is only 30-50% because only one quarter of patients present with stage I disease.
Recurrences in patients with AGCTs tend to be later than in patients with JGCTs. Mom et al reported a recurrence rate of 43% in 30 patients with stage I-III GCT observed over 10 years. Mom states that while the recurrence rate might be high, it falls within the range of 9-39% cited in other studies.[30] Average recurrence for the adult type is approximately 5 years after treatment, with more than half of these occurring more than 5 years after primary treatment. These tumors tend to follow an indolent course, with a mean survival of 5 years after the recurrence is diagnosed. The 10-year overall survival after an AGCT recurrence is in the 50-60% range.
More recently, van Meurs et al developed a prognostic model for the prediction of recurrence-free survival using BMI, clinical stage, tumor diameter, and mitotic index.[31] This model may provide useful information in the surveillance of AGCTs.
JGCTs recur much sooner, with more than 90% of recurrences occurring in the first 2 years. Recurrence in these patients is rapidly fatal.
Tumor stage at the time of initial surgery is the most important prognostic variable. Besides stage, Zhang et al found early stage disease and age younger than 50 years to be statistically significant factors in predicting survival. Other features associated with a poorer prognosis include high mitotic rates, moderate-to-severe atypia, preoperative spontaneous rupture of the capsule, and tumors larger than 15 cm. The presence of bizarre nuclei and tumor rupture intraoperatively does not appear to affect prognosis.[32] A study by Bryk et al reported tumor rupture as the strongest predictive factor for AGCT recurrence.[33]
Approximately 10% of tumors occur during pregnancy, but this does not affect prognosis. Perform surgical treatment for an adnexal mass in pregnancy early in the second trimester in order to minimize surgical and pregnancy risks.
True thecomas have an excellent prognosis, with 5-year survival rates of nearly 100%. However, their estrogen-producing capabilities may cause increased overall morbidity due to endometrial hyperplasia, endometrial adenocarcinoma, and possibly, breast carcinoma.
Patients must be educated about the need for long-term follow-up, especially those with AGCTs. Early diagnosis and treatment can lead to prolonged survival in this group of patients.
For patient education resources, see the Women's Health Center and Cancer and Tumors Center, as well as Ovarian Cancer.
Less well-differentiated diffuse pattern of adult granulosa cell tumor. Monotonous pattern can be confused with low-grade stromal sarcoma (200X). Inset is high-power magnification demonstrating nuclear grooves and nuclear atypia. Image courtesy of James B. Farnum, MD, TriHealth Department of Pathology.
Less well-differentiated diffuse pattern of adult granulosa cell tumor. Monotonous pattern can be confused with low-grade stromal sarcoma (200X). Inset is high-power magnification demonstrating nuclear grooves and nuclear atypia. Image courtesy of James B. Farnum, MD, TriHealth Department of Pathology.