Granulosa-Theca Cell Tumors  

 

Background:

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 group and include tumors made up 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 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.

Pathophysiology: 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. Initiation of growth in GCTs likely is multifactorial.

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. Metastatic disease can involve any organ system, although tumor growth usually is confined to the abdomen and pelvis.

Frequency:

  • Internationally: 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.

Mortality/Morbidity: 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.

  • Only 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. Of patients, 30-50% 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.

Age:

  • 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 persons.

 

CLINICAL FEATURES

History: Many patients with GCTs 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, often they 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 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.

  • 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 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.
  • Postmenopausal 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.
    Physical Examination:
  • 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. During the rectal examination, 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 examination should be performed to help rule out infectious etiologies. Wet preparation and cultures for Neisseria gonorrhoeae 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.

Causes:

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.

DIFFERENTIAL DIAGNOSIS

Adnexal Tumors
Anovulation
Appendicitis
Ascites
Cervicitis
Colon Cancer, Adenocarcinoma
Colonic Obstruction
Ectopic Pregnancy
Ovarian Cysts
Pelvic Inflammatory Disease
Polycystic Ovarian Syndrome
Urinary Tract Obstruction
Uterine Cancer


Other Problems to be Considered:

The differential diagnosis for any pelvic mass can include, but is not limited to, the following:

Gastrointestinal

Fecal impaction
Low-lying cecum
Bowel/omental adhesions

Genitourinary

Endometriosis
Ovarian torsion
Hydrosalpinx/pyosalpinx
Pelvic abscess
Uterine fibroids
Uterine anomalies
Embryologic remnants
Bladder distention/urinary retention
Pelvic kidney
Urachal cyst

Other

Retroperitoneal mass
Peritoneal cyst
Benign lesions of the uterine corpus

The differential diagnosis for patients presenting with endocrine manifestations includes, but is not limited to, the following:

Pregnancy
True precocious puberty
Exogenous hormone administration
Polycystic ovary syndrome
Adrenal tumors

 

 

 

LABORATORY STUDIES

  • Order a pregnancy test in all reproductive-aged patients (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 beta human chorionic gonadotropin (bhCG), alpha-fetoprotein (AFP), lactate dehydrogenase (LDH), and cancer antigen 125 (CA125). Levels of bhCG, AFP, and LDH can be elevated in patients with ovarian germ cell tumors and in patients with a normal or abnormal pregnancy. CA125 levels in menstruating women can be slightly to moderately elevated due to a host of benign disorders including, but not limited to, endometriosis, uterine leiomyoma, appendicitis, pancreatitis, and inflammatory bowel disease. In this group of patients, CA125 is not as useful as a diagnostic test but may be helpful in monitoring patients long-term if they are found to have a tumor that causes elevation of this tumor marker.
    • In reproductive-aged women older than 30 years, no lab study results are specific for GCTs. A CA125 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 can be drawn if elevation of these hormones is suggested 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 CA125 test. A CA125 level higher 60 U/mL in a postmenopausal woman 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 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.
    • GCTs 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 type of testing lacks sensitivity and specificity.
    • Inhibin also has been studied in these patients. Inhibin is a peptide hormone produced by ovarian granulosa cells that are made up of an alpha subunit and 1 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 GI tracts. Studies of inhibin in patients with GCTs 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.
    • Müllerian-inhibiting substance (MIS), or antimüllerian hormone (AMH), has been studied more recently.
      • This hormone is produced exclusively by granulosa cells in postnatal females and both prenatally and postnatally by the Sertoli cells in the male testis. Normally, MIS is found in very low levels in females, but in patients with GCTs, levels have been shown to parallel the extent of disease.

§         Serum MIS levels correlate well with tumor presence in patients with GCTs. This marker is not found exclusively in GCTs; it is limited to tumors of ovarian origin. This is in sharp contrast to inhibin and estradiol, both of which may be elevated in a variety of other extraovarian disorders. Future use of these markers likely will be important in follow-up evaluations, rather than diagnosis, of patients with GCTs.

Imaging Studies:

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, 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.
  • Roentgenography
    • Chest radiographs are useful in helping exclude pulmonary spread of malignant diseases of the ovary. Abdominopelvic CT 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 evaluations to confirm the presence of recurrent tumor identified after clinical examination.
    • Abdominal radiographs, 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 35 years. However, if an abdominopelvic CT 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 because these may increase the risk of breast malignancies.

 

Histologic Findings:

 

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. 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. 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. Watered-silk and gyriform patterns have cells that often line up single-file in undulating lines.

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. 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. Nuclear atypia often is more severe with more mitotic figures than are found in the adult type, consistent with a more aggressive tumor type. The cytoplasm often is more abundant and dense in JGCTs.

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. Luteinized thecomas also contain cells with a lipid-rich cytoplasm but are set within a more fibromatous stroma. 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.

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 I: Tumor is confined to the ovaries.
    • 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.

o        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.

o        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 II: Tumor involves one or both ovaries, with pelvic extension.

o        Stage IIa: Extension and/or metastases to the uterus and/or fallopian tubes are present.

o        Stage IIb: Extension to the bladder, rectum, or other pelvic tissues occurs.

o        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 III: Tumor involves 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.

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

o        Stage IIIb: Tumor implants are present on the abdominal peritoneum, none larger than 2 cm in diameter. Lymph nodes are negative.

o        Stage IIIc: Tumor implants on the abdominal peritoneum 2 cm or more are present, and/or retroperitoneal or inguinal nodes are positive.

·         Stage IV: Distant metastases are present.

o        Pleural effusions must be confirmed cytologically to classify a case as stage IV.

o        Metastases to the liver parenchyma also are included in stage IV.

TREATMENT

Medical Care:

  • Primary treatment for 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.
  • Treatment for patients postoperatively consists of frequent pelvic examinations and assessment of tumor markers (if applicable) in order to detect recurrences at an early stage. 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.

 

  •  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 suggested to have GCTs begins with a thorough preoperative evaluation and preparation.
  • Preoperative imaging and laboratory studies are helpful for measuring the extent of disease so that patients may be counseled appropriately.
  • Appropriate staging with intact removal of the tumor and optimal cytoreduction are the main goals of surgical therapy.
  • 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 so that all remaining tumor nodules are smaller than 1 cm 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.
    • Staging should be performed and consists of pelvic washings, selective pelvic and periaortic lymph node sampling on the ipsilateral side, 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 fewer than 5% of tumors are bilateral.
    • 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.
  • 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.

Consultations:

  • Gynecologic oncologist or surgical oncologist
    • 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.
    • 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 and patients with endocrinologic symptoms and an adnexal mass should have the benefit of a preoperative consultation with a gynecologic oncologist.
  • Gastroenterologist
    • Patients with primarily GI complaints may benefit from a consultation with a gastroenterologist.

o        This helps rule out a primary GI source for symptoms prior to surgical exploration because endoscopy can be performed during this preoperative evaluation.

Diet:

  • No dietary restrictions or requirements are needed.

Activity:

  • No activity restrictions are needed, outside of the normal postoperative recovery time.


MEDICATION

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 for improving both disease-free and long-term survival. 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 their agents.

Cisplatin, vinblastine, and bleomycin regimen

The cisplatin (Platinol), vinblastine, and bleomycin (PVB) regimen has been studied most recently and shows moderately high response rates.

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 eighth course during the 10th week; and vinblastine at 12 mg/m2 IV q3wk for 3-4 courses.

Bleomycin, etoposide, and cisplatin regimen

Bleomycin, etoposide, and cisplatin (BEP) regimen also has been studied in patients with advanced and recurrent GCTs. 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 GCTs. Patients with gross residual disease, positive findings on peritoneal cytology, and recurrent tumors were included. No recurrence or progression of disease was observed in 68% and 51% of patients with primary and recurrent disease, respectively. 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.

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.

Drug Category: Antineoplastic agents -- Adjunct chemotherapy for GCTs that are higher than stage Ia and for recurrent tumors.

CISPLATIN:

20 mg/m2 IV over 15-30 min days on 1-5 q3-4wk

VINBLASTIN:

0.15 mg/m2 IV days 1-2 q3-4wk

BLEOMYCIN:

10-20 U/m2 (not to exceed 30 U/dose) IV/IM/SC usually given on day 1 or 2 of cycle q3-4wk; not to exceed 400 U

CYCLOPHOSPHAMIDE:

60-120 mg/m2 PO qd; 50-1500 mg/m2 IV q3-4wk

DOXORUBICIN:

60-100 mg/m2 IV q3wk for 4-6 cycles; cumulative dose not to exceed 450-550 mg/m2

ACTINOMYCIN-D:

15 mcg/kg/d IV q3-4wk or 0.5 mg/d on days 1-5 q3-4wk

5-FLUOROURACIL:

12 mg/kg/d for 3-5 d followed by weekly maintenance dose of 12-15 mg/kg until toxic adverse effects become limiting; not to exceed 800 mg/d; 500 mg/m2 IV q3-4wk

ETOPOSIDE:

75 mg/m2 PO/IV on days 1-5 q4wk  

 

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

MESNA:

20% of alkylating agent dose IV prior to chemotherapy, then equivalent doses at 4 and 8 h  

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

ONDANSETRON:

32 mg IV 30 min prior to chemotherapy, then 8-16 mg PO bid; 0.15 mg/kg IV 30 min before chemotherapy, then at 4 and 8 h

GRANISETRON:

10 mcg/kg IV over 5 min, 30 min prior to chemotherapy, then 1-2 mg PO bid for 1 d

PALONOSETRON:

0.25 mg IV once (30 min before chemotherapy); administer over 30 sec; do not repeat dose within 7 d

DEXAMETHASONE:

20 mg PO/IV prior to chemotherapy or 8 mg PO/IV prior to chemotherapy, then 4 mg PO q4h for 2 more doses  

 

 

 

FOLLOW-UP

 

Further Outpatient Care:

  • 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, estrogen, inhibin, AMH/MIS 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.
  • In patients undergoing chemotherapy, follow-up blood tests and examinations are dictated by the type of chemotherapy regimen used. 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 examinations generally are performed as indicated previously once chemotherapy has been completed.
  • 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.

In/Out Patient Meds:

  • Antiemetics
    • 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 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-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), erythropoietin (red cell–specific), and interleukin-11 (thrombopoietic). Indications for each are patient-dependent.

Transfer:

  • 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.

Deterrence/Prevention:

  • No means of preventing sex cord–stromal tumors of the ovary are known.

Complications:

  • 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.

Prognosis:

  • Prognosis for granulosa-theca cell tumors generally is very favorable. Approximately 90% of GCTs are at stage I at the time of diagnosis . The 10-year survival rate for stage I tumors in adults is 90-96%. GCTs of more advanced stages are associated with 5-year 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. 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. 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. 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 has been found to be the most important prognostic variable. 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.
  • 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.

 

MISCELLANEOUS  

Medical Pitfalls:

  • In all cases in which reproductive-aged women (even at the extremes) present with abdominopelvic complaints, a pregnancy test should be ordered to help exclude the possibility of pregnancy. Occasionally, patients with other tumors, such as carcinoma of the pancreas or other GI tumors, have an elevated bhCG level in the absence of pregnancy.
  • Pelvic and rectal examinations should not be deferred in reproductive-aged patients who present with vague abdominal complaints. Pelvic masses are not palpable upon abdominal examination until they reach 8-10 cm and are pushed up out of the pelvis. Failure to perform pelvic and rectal examinations 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:

  • Ovarian tumors occur or can be found during pregnancy. Because only 2% of masses in pregnant women are malignant, these masses can be followed expectantly if diagnosed in the first trimester because most masses resolve spontaneously. Tumors that persist into the second trimester, especially if complex or larger 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:
    • The optimal time for abdominal exploration is approximately 16-18 weeks of gestation. The incidence of fetal loss, preterm labor, and maternal morbidity appears to be lower at this gestational age. A high vertical incision should be employed because the adnexa are out of the pelvis at this point in pregnancy. Because most tumors are stage Ia ,a unilateral salpingo-oophorectomy is sufficient treatment for most patients. In cases in which spread outside of the ovary already has occurred, treatment recommendations become unclear. Total abdominal hysterectomy and bilateral salpingo-oophorectomy, with removal of the fetus and placenta in toto, is another option to be considered. Some patients have been treated with unilateral salpingo-oophorectomy, resection of all visible tumor, and adjunct chemotherapy.
    • The decision to begin chemotherapy during pregnancy rests with the patient and physician because all chemotherapy agents are potential teratogens. Reports of chemotherapeutic agent use in the second and third trimester for other ovarian tumors exist, but caution should be taken because little is known about the long-term effects on the developing fetus. Delaying adjunct therapy until after delivery is not well studied but could be considered because many of these tumors exhibit indolent growth.
  • A higher propensity for torsion exists in pregnant patients because the adnexa become abdominal structures early in the second trimester. In pregnant patients presenting with acute abdominal pain and a palpable mass, sonographic evaluation of the adnexa can help confirm the presence of an adnexal mass.