Granulosa-theca Cell Tumors

INTRODUCTION

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Background: Three major types of ovarian neoplasms exist, 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 group and include tumors made up of granulosa cells, theca cells, and fibroblasts in varying degrees and combinations. Granulosa cell tumors 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 are commonly estrogen producing, and it is the estrogen production that is often the reason for early diagnosis. However, while adult granulosa cell tumors usually occur in postmenopausal women and have late recurrences, most juvenile granulosa cell tumors occur before the age of 30 and 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 chapter focuses on granulosa cell tumors 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 granulosa cell tumors.

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Pathophysiology: Two theories exist as to 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 believes 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 for differentiation of normal granulosa and/or stromal cells into neoplastic entities exist. To date no clear etiologic process has been identified. It is likely that initiation of growth in GCTs is a multifactorial event.

GCTs are thought to be tumors of low malignant potential. Most of these tumors will follow a benign course with only a small percentage showing aggressive behavior. Metastatic disease can involve any organ system, although tumor growth usually is confined to the abdomen and pelvis.

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Frequency:
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• In the US: Approximately 25,000 new cases of ovarian cancer are diagnosed in the US each year. This disease accounts for over 14,000 deaths in the US annually and is the leading cause of death from gynecologic malignancies.

  Since 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 US.

• Internationally: Unlike epithelial ovarian cancers, no racial 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.

Mortality/Morbidity: GCTs of both the adult (AGCT) and juvenile (JGCT) types have very good cure rates due to the early stage of disease at diagnosis. Over 90% of AGCTs and JGCTs are diagnosed before spread outside the ovary has occurred.

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.

Only about 20% of patients diagnosed with GCT die of their disease over the course of their lifetime.

• Morbidity related to GCT is primarily 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 effect can occur in various end organs. Unopposed estrogen production by these tumors has been shown to cause stimulation of the endometrium. Thirty to 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 direct correlation has been difficult to prove.

Race: Limited data available show that this class of neoplasms makes up a similar proportion of ovarian malignancies in the US, Europe, the Far East, and the West Indies.

Sex: Authors are unaware of any case reports of granulosa–theca cell tumors in adult males. Sertoli cell tumors are the male homologue to GCTs in females.

Age:

• AGCT: Accounts for 95% of all granulosa cell tumors and usually is seen in postmenopausal women, with a median age at diagnosis of 52 years.

• JGCT: Comprise only 5% of all GCTs, and almost all of these tumors are found in patients younger than 30 years.

• Theca cell tumor: Thecomas account for less than 1% of all ovarian tumors and have a mean age at diagnosis of 53 years. These tumors are rare in women younger than 30 years with the exception of the luteinized thecoma, which tends to occur in a younger age group.

CLINICAL

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History: Many patients with GCT present with manifestations of hyperestrogenism. Approximately 70% of these tumors are hormonally active. Hormonal influences can cause very different presenting symptoms depending on patient age and menstrual status. Although these symptoms can be quite profound, they often may be secondary findings in patients with complaints relating to the abdomen and pelvis.

Complaints of increasing abdominal girth and abdominal discomfort are quite common. Most patients will have a palpable mass on exam. Abdominal symptoms may be due to enlargement of the mass but also can be due to the production of ascites that is present 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, though rarely. Acute abdominal or pelvic pain may be seen along 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.

• Prepubertal girls

  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.

• Premenopausal women

  Increasing abdominal girth and other symptoms related to enlarging adnexal mass may be seen in this group of patients. However, menstrual irregularities such as oligomenorrhea, menorrhagia, and secondary amenorrhea tend to be the hallmark of these tumors in women of reproductive age.

• Postmenopausal women

  The most common endocrine manifestation of GCT 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.

Physical:

• 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 exam, as well as a rectovaginal exam, should be employed to evaluate the pelvis and lower abdomen for masses, nodularity in the posterior cul-de-sac, and any areas of tenderness. During the time of the rectal exam, a stool sample should be obtained for guaiac testing, which can be helpful in narrowing the differential of GI disorders.

• For patients presenting with acute abdominal pain, a careful speculum exam should be performed to rule out infectious etiologies. Wet prep and cultures for Neisseria gonorrhea and Chlamydia trachomatis should be obtained. 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 discussed previously.

WORKUP

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Lab Studies:
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• Order a pregnancy test in all patients of reproductive age (even at the extremes of reproductive age) who present with abdominopelvic complaints.

• The standard workup for a patient with an adnexal mass varies depending on patient age.

• In patients who are prepubertal or younger than 30 years, obtain blood to check for human chorionic gonadotropin (bhCG), alpha-fetoprotein (AFP), lactate dehydrogenase (LDH), and cancer antigen 125 (CA-125). Levels of bhCG, AFP, and LDH can be elevated in ovarian germ cell tumors as well as in normal and abnormal pregnancies. CA-125 levels in menstruating women can be slightly to moderately elevated in a host of benign disorders including, but not limited to, endometriosis, uterine leiomyoma, appendicitis, pancreatitis, and inflammatory bowel disease. In this group of patients, CA-125 is not as useful as a diagnostic test but may be helpful in following patients long-term if they are found to have a tumor that causes elevation of this tumor marker.

• In reproductive-age women older than 30 years no lab studies are specific to GCTs. A CA-125 should be drawn, recalling that this can be elevated in benign disorders in women who still are menstruating. Serum levels for estrogen, testosterone, and dehydroepiandrosterone (DHEAS) can be drawn if elevation of these hormones is suspected based on clinical findings. Abrupt onset or rapid progression of endocrinologic manifestations should heighten the suspicion for a neoplastic process.

• In postmenopausal women, obtain blood for a CA-125 test. A CA-125 level above 60 U/mL in postmenopausal women has a very good positive predictive value for malignancy. Again, serum sex hormone levels can be ordered based on clinical findings consistent with excess hormone production.

• Other ancillary laboratory studies that may be useful in narrowing the differential include stool guaiac, CBC with differential, blood chemistries, urinalysis, and cervical cultures for gonorrhea and chlamydia.

• Several other tumor markers have been evaluated in patients with GCTs.

• Granulosa cell tumors are the most common estrogen-producing neoplasms in females and are found to produce estradiol in approximately 40-60% of patients. However, not all GCTs are hormonally active, and this test lacks sensitivity as well as specificity.

• Inhibin has been studied in these patients as well. Inhibin is a peptide hormone produced by ovarian granulosa cells that are made up of an alpha and one of 2 beta subunits. The alpha subunit is confined largely to tumors in the sex cord–stromal group whereas the beta subunit can be found in a multitude of tumors originating from the genitourinary and gastrointestinal tracts.

  Studies of inhibin in patients with granulosa cell tumors have shown that levels were elevated preoperatively and returned to normal postoperatively in both adult and juvenile types of tumors. Elevated levels have been shown to precede clinical recurrence of disease by as long as 22 months.

Imaging Studies:
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• Sonography

• 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, presence of cystic or solid components should be noted and remarks on the internal architecture of cystic structures, such as septations and excrescences, should be made. Free pelvic fluid can be identified readily on TVS, as well. Presence of solid, complex, cystic, or bilateral masses, with or without free fluid, increase suspicion for malignancy.

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• 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.

• Roentgenography

• Chest radiographs are useful in ruling out pulmonary spread of malignant diseases of the ovary. Abdominopelvic computer-assisted tomography (CAT) scan 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 to confirm presence of recurrent tumor identified on clinical exam.

• Abdominal radiographs, intravenous pyelography (IVP), barium enemas, and upper GI series also can be useful adjuncts in patients with symptoms involving the gastrointestinal or genitourinary tracts.

• Perform a barium enema or colonoscopy in any patient with a pelvic mass prior to surgical intervention to rule out colonic involvement and/or colon cancer as the primary tumor in women older than 35 years. However, if an abdominopelvic CAT scan with oral and intravenous contrast already has been performed, IVP, colonoscopy, and barium enema are not required.

• Mammography

• The preoperative workup also should include a mammogram for women older than 35 years who have not had one in the preceding 6-12 months. This becomes especially important in women with estrogen-producing tumors since this may increase the risk of breast malignancies.

Histologic Findings: Grossly, tumors can be cystic, solid, or a mixture of the two. 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. 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 since 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.

Adult granulosa cell tumors have multiple histo-morphologies 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 (figure 1). 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 (moir? or gyriform patterns. Monotonous sheets of cells arranged in no distinguishable pattern characterize the diffuse subtype (figure 2). Watered-silk and gyriform patterns have cells that often line up single file in undulating lines (figure 4).

Nuclear appearance is the same in both groups of adult GCTs. The nuclei are usually large, pale, ovoid or angular structures containing nuclear grooves that give them a “coffee bean?appearance (figure 1). 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 are often 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 granulose cell tumors.

Juvenile granulosa cell tumors have little morphologic similarity to those of the adult type. However, their gross appearance can be similar to adult GCTs in that they are often 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 (figure 3). Nuclear atypia is often more severe with more mitotic figures than found in the adult type, consistent with a more aggressive tumor type. The cytoplasm is often more abundant and dense in juvenile GCTs.

Thecomas are usually tan or yellow in color with an average size of 7-8 centimeters. These tumors are bilateral in less than 3% of cases. Microscopically they are composed of round or ovoid cells with pale nuclei and a lipid-rich cytoplasm. Mitoses are usually less than 4 per 10 high power fields. Hyaline bands are often found interspersed between cells (figure 5). Luteinized thecomas also contain cells with a lipid-rich cytoplasm, but are set within a more fibromatous stroma (figure 6). Most of these tumors are hormone-producing and cause postmenopausal bleeding in up to two-thirds of patients. Luteinized thecomas may also be androgenic and, if so, tend to occur in younger women.

Staging: 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 limited to one ovary with an intact capsule, no tumor on the external surface of the capsule and no ascites containing malignant cells

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• Stage Ib - Tumor involving both ovaries with intact capsules, no tumor on the external surface of the capsule, and no ascites containing malignant cells

• Stage Ic - Tumor stage Ia or Ib with tumor on the external surface of one or both ovaries, or ruptured capsule(s) or malignant cells in ascitic fluid or peritoneal washings

• Stage II - Tumor involving one or both ovaries with pelvic extension

• Stage IIa - Extension and/or metastases to the uterus and/or fallopian tubes

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• Stage IIb - Extension to the bladder, rectum, or other pelvic tissues

• Stage IIc - Tumor stage IIa or IIb with tumor on the external surface of one or both ovaries, or ruptured capsule(s), or malignant cells in ascitic fluid or peritoneal washings

• Stage III - Tumor involving one or both ovaries with peritoneal implants outside of the pelvis and/or positive retroperitoneal lymph nodes. Superficial liver metastases also are included in stage III.

• Stage IIIa - Tumor that is grossly confined to the pelvis but with microscopic seeding of the abdominal peritoneal surfaces. Lymph nodes are negative.

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• Stage IIIb - Tumor implants on the abdominal peritoneum, none exceeding 2 cm in diameter. Lymph nodes are negative.

• Stage IIIc - Tumor implants on the abdominal peritoneum 2 cm or greater and/or positive retroperitoneal or inguinal nodes

• Stage IV - Distant metastases. Again, pleural effusions must be confirmed cytologically to allot a case to stage IV. Metastases to the liver parenchyma also are included in stage IV.

TREATMENT

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Medical Care:

• Primary treatment in patients with GCTs always is surgical. Chemotherapy and/or radiotherapy are reserved for patients with advanced disease, as confirmed by surgical staging, and for patients with recurrent tumor.

• Management of patients postoperatively consists of frequent pelvic examinations and assessment of tumor markers (if applicable) in order to detect recurrences at an early stage. Findings on physical exam or laboratory studies that are suspicious for 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 study of 14 patients at MD Anderson Cancer Center, 6 patients responded initially, but 3 of those recurred. Eight of 14 had no response to treatment, with a median survival of 12.3 months overall. In patients with pelvic recurrences, radiotherapy can be considered since a clinical response may be noted in almost half of patients treated with radiation therapy.

• Treatment of recurrent GCTs with leuprolide acetate has been described but exhibited only marginal success in a small number of patients.

Surgical Care:

• Surgical care of patients with suspected granulosa cell tumors begins with thorough preoperative evaluation and preparation.

MEDICATION

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Surgical treatment is considered first-line therapy for patients with GCTs. Chemotherapy can be used as adjunct treatment in patients with advanced or recurrent disease and has been effective in improving both disease-free and long-term survival. The optimal chemotherapy regimen has been hard to identify given that the overall incidence of granulosa cell tumors 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 their agents.

The cisplatin, 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 had 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 seen in a few patients. Earlier studies by Zambetti et al and Columbo et al showed similar response rates but with severe bone marrow and pulmonary toxicity.

PVB therapy

Cisplatin 20 mg/m²/d IV for 5 days q3wk for 3-4 courses. Bleomycin 20 U/m² (max 30 U) IV qwk for 7 courses followed by an eighth course during the 10th week. Vinblastine 12 mg/m² IV q3wk for 3-4 courses.

Bleomycin, etoposide, and cisplatin (BEP) regimen also has been studied in patients with advanced and recurrent granulosa cell tumors. Homesley, et al reported on a multicenter study using this regimen and included patients with all types of ovarian sex cord–stromal tumors although 48 patients had GTCS. Patients with gross residual disease, positive peritoneal cytology, and recurrent tumors were included. No recurrence or progression of disease was seen in 68% and 51% of patients with primary and recurrent disease, respectively. However, only half of 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 (PFI). Again, significant toxicity was noted with bone marrow suppression being most common (79%) followed by gastrointestinal toxicity.

BEP therapy

Bleomycin 20 U/m² (max 30 U) IV q3wk for 4 courses. Etoposide 75 mg/m² IV days 1-5 q3wk for 4 courses. Cisplatin 20 mg/m² IV days 1-5 q3wk for 4 courses.

Older multidrug regimens included cyclophosphamide, doxorubicin, and cisplatin (CAP) regimen: cyclophosphamide 500 mg/m² IV, Adriamycin 40-50 mg/m² IV, and cisplatin 40-50 mg/m² IV all given q4wk for 4-6 courses; cisplatin and doxorubicin; 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 juvenile granulosa cell tumors with regard to treatment of advanced disease and recurrences. These tumors tend to behave more aggressively with earlier recurrences and poorer response to chemotherapeutic agents. Case reports detailing complete responders can be found for patients treated with carboplatin and etoposide; methotrexate, actinomycin D, and chlorambucil (MAC); and methotrexate, actinomycin D, and cyclophosphamide. However, long-term survival in patients with JGCTs has been disappointing.
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Drug Category: Antineoplastic agents -- Adjunct chemotherapy in GCTs that are greater than Ia and recurrent tumors.

Drug Category: Uroprotective agents -- Prevention of hemorrhagic cystitis in patients being treated with ifosfamide and cyclophosphamide.

Drug Category: Antiemetics -- Prevention and treatment of nausea and vomiting associated with chemotherapy.

FOLLOW-UP

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Further Outpatient Care:
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• Follow-up should be done at 2- to 3-month intervals for the first 2 years for patients not undergoing chemotherapy. This then can be spaced out to every 4-6 months for the next 3 years, then yearly thereafter.

• A history and pelvic exam should be done at each visit as well as serum determination of tumor markers (ie: estrogen, inhibin, AMH/MIS levels) 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 exam findings.

• In patients undergoing chemotherapy, follow-up blood tests and exams are dictated by the type of chemotherapy regimen. In this instance, abdominopelvic CT scans are performed at the conclusion of therapy and then at 3- to 6-month intervals to look for evidence of recurrence. Follow-up pelvic exams generally are performed as above once chemotherapy has been completed.

• In all patients with GCTs, long-term follow-up is required since at least 50% of recurrences are found more than 5 years after initial treatment.

In/Out Patient Meds:
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• Antiemetics

• Ondansetron, granisetron, metoclopramide, and prochlorperazine can be used to treat or prevent emesis as an inpatient or outpatient. It should be noted that some chemotherapeutic agents (ie: cisplatin, cyclophosphamide) cause a delayed emesis >24 hours after chemotherapy.

• The adult dose of metoclopramide is 30-40 mg PO bid 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.

  Both of these drugs may cause sedation and dystonic reactions.

• Hematopoietic growth factors

• A host of growth factors now can be given in place of antibiotics and transfusion of blood products to treat severe chemotherapy or radiation-induced bone marrow suppression.

• Available agents include G-CSF (neutrophil-specific), GM-CSF (neutrophil-, eosinophil-, and monocyte-specific), erythropoietin (red cell–specific), and IL-11 (thrombopoietic). Indications for each are patient-dependent.

Transfer:
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• Patients admitted with nonspecific complaints who are found later to have a pelvic mass and/or other signs of malignancy (ie, ascites, elevated tumor markers, 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 in your institution. Otherwise, consultation generally can be done on an outpatient basis, preferably preoperatively in women with pelvic masses.

Deterrence/Prevention:
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• No known means of preventing sex cord–stromal tumors of the ovary

Complications:
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• 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.

• Side effects from chemotherapy can be expected but generally are well tolerated. Specific side effects vary by type of chemotherapy given and have been discussed previously.

Prognosis:
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MISCELLANEOUS

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Medical/Legal Pitfalls:
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• In all cases where women of reproductive age (even at the extremes) present with abdominopelvic complaints, a pregnancy test should be ordered to exclude the possibility of pregnancy. Occasionally, other tumors, such as carcinoma of the pancreas or other gastrointestinal tumors, will have an elevated bhCG level in absence of a pregnancy.

• Pelvic and rectal exams should not be deferred in patients of reproductive age who present with vague abdominal complaints. Pelvic masses are not palpable on abdominal exam until they reach 8-10 cm in size and are pushed up out of the pelvis. Failure to perform pelvic and rectal exams may delay diagnosis of pelvic masses such as ectopic pregnancies and malignant tumors. This can have grave consequences both for patients and physicians.

• The widespread use of sonography in obstetrics has led to more frequent diagnosis of adnexal masses during pregnancy. Pregnancy is not a contraindication to proceeding with a workup of an abdominal mass. However, surgical intervention should be delayed until 16-18 weeks of gestation to decrease risks to the fetus in the embryonic stage of development.

Special Concerns:
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• As noted above, ovarian tumors occur or can be found during pregnancy. Since only 2% of masses in pregnant women are malignant, these masses can be followed expectantly if diagnosed in the first trimester since most masses will resolve spontaneously. Tumors that persist into the second trimester, especially if complex or more than 6 cm, should be managed surgically.

• Approximately 10% of GCTs occur in pregnant patients. These masses do not resolve with expectant management, and surgical therapy should be carried out as follows: