Granulosa Stromal Cell Tumors

Granulosa-stromal cell tumors account for 70% of tumors in the sex cord-stromal group, and 2% to 5% of all ovarian tumors.40 They encompass GCTs, thecomas, and fibromas. Although GCTs are considered malignant, they grow slowly and do not behave as aggressively as their epithelial counterparts. However, if not detected at an early stage they do have the potential to metastasize and recur. Unlike epithelial-type ovarian tumors, there is no racial or ethnic predilection of GCTs. There is also no identified heritable risk, particularly in the case of BRCA1 or BRCA2, which confer increased risk of epithelial ovarian carcinoma.

Granulosa Cell Tumors

The mean age of diagnosis for the adult subtype of GCT is age 50 to 54,41 which accounts for 95% of GCTs. However, the juvenile variant manifests at a young age and is responsible for 5% of granulosa-theca cell tumors. Young and associates42 studied 125 cases of juvenile GCTs and found nearly half in girls under age 10, and less than 3% in women over 30. Although the juvenile subtype falls into the classification of GCTs, histologically this tumor differs from the adult variant.

The cause of GCTs is unclear. Controversy exists as to whether granulosa cells originate from developing gonadal sex cords or from the mesenchyme of the genital ridge. Since granulosa cells proliferate in response to follicle-stimulating hormone (FSH), some have hypothesized that the elevated follicle-stimulating hormone levels observed during menopause may initiate proliferation of granulosa cells and abnormal growth. This would explain the higher incidence of GCTs in postmenopausal women, but does not account for younger women and prepubertal females who develop these tumors. Recent developments have suggested that a potential progenitor granulosa stem cell exists,43 but the subject warrants more research.

Presentation. With the exception of fibromas, GCTs tend to produce hormones and consequently are diagnosed at an early stage secondary to estrogenic effects. Women with these tumors most commonly present with menstrual cycle disruptions or postmenopausal bleeding, and over 90% of tumors are diagnosed as stage I tumors. In the prepubertal female, 70% to 80% of GCTs cause isosexual precocious puberty.42 Because of the hemorrhagic nature of GCTs, these tumors may rupture and cause hemoperitoneum; thus, patients may present with acute abdominal pain and peritonitis.

Diagnosis. Symptoms resulting from hyperestrogenism often provoke prompt investigation and early diagnosis. On physical examination, a clinician may detect the presence of an adnexal mass since the average tumor size is 12 cm. Ultrasonography usually reveals a cystic, heterogeneous mass—a nondiagnostic finding. Definitive diagnosis is made at the time of excision and rarely before then.

Histology and Pathology. Grossly, GCTs tend to be gray-to-yellow on the surface, which varies based on the lipid content of the tumor. They often appear hemorrhagic with areas of cystic necrosis (Fig. 11-2A). Most are unilateral; only 2% of GCTs are bilateral. Histologically, Call-Exner bodies are the hallmark of GCTs, occurring in 30% to 60% of GCTs,40,44,45 and appear as rosettes of granulosa cells surrounded by eosinophilic material (Fig. 11-2B). Other classic findings include the pale coffee-bean grooved nuclei. Since not all GCTs harbor Call-Exner bodies or coffee-bean nuclei, pathologic diagnosis should not rest on these characteristics alone. Some tumors possess only granulosa cells, but most contain theca cells, and some have fibroblasts. These tumors typically have a low mitotic rate, with scant nuclear atypia.

Several pattern subtypes exist: microfollicular (characterized by Call-Exner bodies), macrofollicular (more commonly found in the juvenile subtype), trabecular, and insular. The latter patterns lend themselves to well-differentiated types, whereas poorly differentiated tumors often contain a watered-silk pattern. Immunohistologic staining with inhibin proves useful for the identification of GCTs. Although other immunohistologic markers exist, inhibin remains the most sensitive of the currently available staining reagents.46

Grossly, the juvenile subtype appears similar to the adult variant. Histologically, Call-Exner bodies and coffee-bean nuclei are usually absent. In contrast to the adult variant, they are more mitotically active and favor a macrofollicular pattern.

Water The Silk Granulosa Cell Tumor
Figure 11-2. A, Gross picture of granulosa cell tumor. B, Micrograph of granulosa cell tumor (H&E, x400). (Courtesy of Dr. Kristen Atkins, Department of Pathology, University of Virginia Health System.)

Treatment. Treatment for GCTs consists of surgery with staging, including total abdominal hysterectomy and bilateral salpingo-oophorectomy. In women who desire fertility, unilateral salpingo-oophorectomy offers a cure rate comparable to complete surgical staging, hysterectomy and bilateral salpingo-oophorectomy,47,48 provided it is confined to the ovary. See Figure 11-3 for proposed management guidelines. If not performed before surgery, dilation and curettage are recommended to rule out a potential synchronous endometrial cancer. Although concurrent vaginal bleeding may elicit endometrial biopsy on initial intake, if the uterus is not excised in conjunction with the ovaries, endometrial evaluation is essential. This is especially important in the case of abnormal bleeding, or a thickened endometrial stripe larger than 4 mm in a postmenopausal woman. Approximately 30% to 55% of women with GCTs are likely to have endometrial hyperplasia on endometrial biopsy; 5% to 10% will have synchronous endometrial adenocarcinoma.40,41,44,49

Adjuvant Therapy. Stage remains the only reproducible factor determining prog-nosis50 (Table 11-4; Fig. 11-4). Other factors including age, tumor rupture, and mitotic index may influence prognosis, but these findings are inconsistent from study to study. Between 78% and 91% of GCTs are stage I at the time of initial presentation.40,45,51-53 and overall prognosis is good: Stage I 5-year survival rates range from 86% to 96%; overall 5-year survival rate for all stages is 75% to 90%. In more advanced-stage tumors, prognosis is less favorable: Stage II tumors have a 5-year survival rate of 55% to 75%; stage III/IV 22% to 50%. In the juvenile subtype, virtually all tumors are detected at an early stage, with a 5-year survival rate of 92%.42 As

Figure 11-3. Proposed surgical management algorithm for granulosa cell tumors.
Figure 11-4. Proposed adjuvant treatment algorithm for granulosa cell tumors. BEP, bleomycin/ etoposide/cisplatln; PVB, cisplatin, vinblastine, bleomycin.

Table 11-4. Survival Rates in Sex Cord-Stromal Tumors

Tumor Type

5-Year Survival Rate

Granulosa cell tumor

All stages

75-90%

Stage I

86-96%

Stage II

55-75%

Stage III/IV

22-50%

Juvenile subtype

92%

Fibroma

>90%

Thecoma

>90%

Sertoli-Leydig tumor

Stage I

70-90%

Advanced stages or poorly differentiated

<20%

in the adult subtype, these juvenile tumors may metastasize, and prognosis declines in advanced stages.

Because advanced-stage GCTs are relatively rare, there is little consensus about adjuvant therapy in the form of chemotherapy or radiation. Generally, there is agreement that if the tumor is at an early stage and excised in its entirety, there is no role for adjuvant therapy. For women with more advanced tumors (i.e., beyond stage II), intraoperative tumor rupture, large tumor (larger than 10 cm), high mitotic rate, increased cellular atypia, or residual disease, adjuvant therapy is often administered. However, the additional benefit remains unclear, since the rarity of advanced-stage disease precludes prospective randomized controlled trials. Retrospective reviews have demonstrated an improvement in progression-free interval, but no improvement in survival.54-56 Yet in the face of a known high probability of recurrence, some experts recommend adjuvant chemotherapy for these patients.

In the juvenile subtype, chemotherapy is reserved for those with stage II or greater disease, Stage IC with a high mitotic rate (more than 20 per 10 HPFs), or recurrent disease. Evidence is even more sparse in this group than the adult subtype, but chemotherapy may result in longer remission.42,57

Surveillance. Women with GCTs require lifetime surveillance owing to the potential for late recurrence of GCTs. At each patient visit we obtain a serum inhibin level and perform a pelvic examination. Granulosa cells produce inhibin, a substance normally secreted by granulosa cells in response to follicle-stimulating hormone during the luteal phase of the menstrual cycle. Inhibin is a heterodimeric polypeptide composed of alpha and beta subunits. The alpha and beta subunits are dimers; the alpha subunit dimers are identical, whereas the beta subunit dimers differ and are termed beta A and beta B. Inhibin is normally absent or undetectable in postmenopausal women, and after surgical excision of a GCT, inhibin levels become undetectable within 1 week. Inhibin remains a useful tool in surveillance for persistence or recurrence.58-60 Assays exist for both inhibin A and B; however, inhibin B appears to be more sensitive.58,61 Mucinous ovarian tumors may also produce inhibin. Thus, the molecule is not entirely specific to GCTs.

Other markers that potentially can be used include mullerian-inhibiting substance (MIS), estradiol, and CA-125. Granulosa cells secrete MIS in developing ovarian follicles, and MIS may be superior to inhibin in sensitivity.62,63 However, MIS has not yet become routinely available in laboratory assays and has not been studied extensively. Since many GCTs secrete estradiol, this could be used as a marker if elevated preoperatively, but not all GCTs produce estradiol. CA-125 is a nonspecific marker that can be elevated in certain GCTs.

Recurrent Disease. Though classified as malignant, GCTs behave indolently and tend to recur later than other ovarian malignancies, thus requiring lifetime surveillance. Most recurrences occur within 4 to 6 years after surgery, but may recur even later. Hines and colleagues64 documented the latest recorded recurrence at 37 years after surgery. The pelvis and abdomen are the most common sites of recurrence, and surgical resection is appropriate for localized recurrence. In recurrent tumors not amenable to surgical resection as further treatment, chemotherapy offers the best chance for remission. Unfortunately, most patients treated with chemotherapy do not experience long-lasting remission.65,66 The BEP regimen has shown moderate success but also considerable toxicity. Gershenson and associates66 documented an 83% response rate with a median survival time of 28 months in a study of nine patients. The GOG65 also conducted research on the use of BEP in 56 patients with stage II-IV and recurrent sex cord-stromal tumors (48 of which were GCTs) and found a 37% rate of negative findings at the time of second-look laparotomy. Of the patients with advanced stage-disease, 69% were progression-free over 3 years, and 51% of patients with recurrence were progression-free. However, this regimen was associated with significant toxicity (two deaths attributed to bleomycin) and severe granulocytopenia.

Recently, taxanes, in combination with platinum-based agent, have gained attention as potential therapeutic options. Preliminary studies show that they have an efficacy comparable to that with BEP as well as a more favorable toxicity profile.67-69 The GOG is currently conducting a phase II study of paclitaxel in recurrent ovarian stromal tumors. Less active but reasonable second-line agents include PVB70 (cisplatin, vinblastine, bleomycin), CAP (cyclophosphamide, doxorubicin, and cisplatin),71,72 doxorubicin alone,73 and carboplatin plus etoposide.74

Hormonal therapy represents a new option for recurrent GCTs. Hormonal manipulation may play a role in gonadotropin and/or direct tumor suppression. Case reports have documented a prolonged response to tamoxifen and progesterone,75 gonadotropin-releasing hormone antagonists,76 and aromatase inhibitors.77 Hormonal therapy may provide additional longevity in patients who have failed chemotherapy with a favorable side-effect profile.

Though not typically used in the setting of adjuvant therapy, radiation therapy has proved useful in treating recurrent GCTs. Wolf and associates78 reviewed 14 patients with recurrent GCTs who received external-beam radiation therapy. Of the 14, 6 patients demonstrated a complete response, with 3 patients still living at 10 to 21 years after radiation therapy. Similarly, Savage and colleagues79 found no improvement in outcomes with adjuvant radiation but found sustained remissions with recurrent disease.

Thecomas

Thecomas also originate from the ovarian stroma and occur primarily in postmeno-pausal women. They are benign solid masses that are consistently unilateral. Theca cells produce androstenedione, which undergoes conversion to estradiol, and is responsible for the hyperestrogenism. A tumor comprising solely theca cells would correspondingly produce a considerable amount of excess estrogen. Subsequently, most women present with postmenopausal bleeding from endometrial stimulation. Accordingly, the rate of synchronous endometrial adenocarcinoma is 25%.59

Thecomas may appear yellowish because of their lipid content. They consist mostly of theca cells, but may contain a few granulosa cells. Since thecomas are benign, treatment involves surgical excision only. In the case of premenopausal women, unilateral salpingo-oophorectomy is acceptable in the documented absence of endometrial hyperplasia or carcinoma. In postmenopausal women, total abdominal hysterectomy and bilateral salpingo-oophorectomy are recommended.

Fibromas

Similar to thecomas, fibromas are usually unilateral and benign and occur in post-menopausal women. Cellular-type fibromas may contain mild atypia and mitotic activity, but should not be confused with fibrosarcomas. Though not hormonally active, fibromas are interesting entities in their own right, since 10% to 15% of those affected present with ascites or Meigs syndrome, and 1% present with hydrothorax. Although the mechanism is not well understood, there is some evidence that vascular epithelial growth factor secreted by fibromas increases capillary permeability, thus contributing to fluid accumulation80 and the resultant Meigs phenomenon. Pseudo-Meigs syndrome refers to the presence of ascites from a non-fibroma-type ovarian tumor. Treatment includes unilateral salpingo-oophorectomy, which is curative for both the fibroma and the associated Meigs syndrome.

Gorlin's syndrome, an autosomal dominant syndrome also known as nevoid basal cell carcinoma, has also been associated with fibromas. The syndrome results in medul-loblastomas, mesenteric cysts, and odontogenic keratocysts. Approximately 75% of affected women develop fibromas, but this predisposition is not well understood.

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