Volume 69, Number 1 OBSTETRICAL AND GYNECOLOGICAL SURVEY Copyright * 2014 by Lippincott Williams & Wilkins

CME REVIEW ARTICLE

CHIEF EDITOR’S NOTE: This article is part of a series of continuing education activities in this Journal through which a total of 36 AMA PRA Category 1 Creditsi can be earned in 2014. Instructions for how CME credits can be earned appear on the last page of the Table of Contents.

A Comprehensive Review of Diagnostic and Treatment Options for Granulosa Cell Tumors of the Ovary Jessica E. Stine, MD(* Stuart Pierce, MD(† and John T. Soper, MD‡ *Fellow Gynecologic Oncology, †Resident Obstetrics and Gynecology, and ‡Professor Gynecologic Oncology, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of North Carolina, Chapel Hill, NC Granulosa cell tumors are rare and comprise approximately 2% to 8% of all ovarian malignancies. Research dedicated to these tumors is rare given the low incidence. These tumors are more difficult to diagnose than epithelial ovarian tumors, and understanding how they present may aid in appropriate referral to a gynecologic oncologist. The aim of this review was to summarize the epidemiology, risk factors, and clinical presentation of granulosa cell tumors to aid in provider recognition. We will also explore current diagnostic and treatment modalities with examination of newer, novel treatments. At the end of this review, the reader should understand how to appropriately diagnose and treat these rare malignancies. Target Audience: Obstetricians and gynecologists, family physicians Learning Objectives: After completing this CME activity, physicians should be better able to summarize the epidemiology, risk factors, and clinical presentation of granulosa cell tumors of the ovary, identify current diagnostic modalities to aid in provider recognition, and apply treatment options including examination of newer, novel treatments, to care for patients.

Stromal cell tumors comprise approximately 8% of all ovarian malignancies. Of stromal cell tumors, 70% are tumors of granulosa cells, with the remainder involving fibroblasts and theca cells.1,2 Thus, granulosa cell tumors (GCTs) are uncommon, representing only 2% to 8% of all ovarian malignancies.1Y8 There are 2 distinct forms of GCTs, adult and juvenile, based primarily on clinical presentation and histopathologic differences. The adult form comprises approximately 95% of GCT and frequently presents with perimenopausal or postmenopausal uterine bleeding related to the estrogen effects on the endometrium. The juvenile form is much more rare, affecting both premenarchal All authors and staff in a position to control the content of this CME activity and their spouses/life partners (if any) have disclosed that they have no financial relationships with, or financial interests in, any commercial organizations pertaining to this educational activity. Correspondence requests to: Jessica E. Stine, MD, Lineberger Comprehensive Cancer Center, Obstetrics and Gynecology, Campus Box 7572, Chapel Hill, NC. E-mail: [email protected].

and premenopausal women. Generally, both forms are characterized by favorable prognosis, slow growth, and indolent patterns of relapse. The majority of patients present with stage I disease (71%Y98%)1Y3,6 and have excellent prognosis with surgical treatment alone. Chemotherapy has proven less effective for treating advanced or recurrent GCT than for germ cell tumors or epithelial ovarian carcinoma, sparking investigation into molecular biology of these tumors to develop novel, effective treatments. We review the epidemiology, risk factors, and clinical presentation of GCTs to aid in provider recognition. We will explore current diagnostic and treatment modalities with examination of newer, novel treatments. EPIDEMIOLOGY The American Cancer Society estimates 22,240 new cases of ovarian cancer in 2013,9 with estimated deaths reaching 14,000. Although most of these will be epithelial ovarian malignancies, approximately 1200 will

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be GCTs.1,10 Estimated incidence is thought to be near 0.99/100,000 in the United States, whereas incidence for other developed countries ranges from 0.4 to 1.7/ 100,000.2,4Y7,11,12 Although it can present at any age, 80% of the more common adult form of GCT presents in women older than 40 years, most frequently in perimenopausal or postmenopausal women between 50 and 54 years old.2,4Y7,11Y15 Half of juvenile GCTs are diagnosed in girls younger than 10 years, with studies showing a mean age at diagnosis of 8 to 13 years.16,17 Case reports describe juvenile GCTs found in infants.18 Young et al13 reported that 34% of cases present between 11 and 20 years of age, 18% between 21 and 30 years, and 3% in women older than 30 years. ETIOLOGY AND RISK FACTORS Current studies are inconclusive in describing risk factors associated with GCTs. Menopausal status, race, and parity do not appear to elevate risk of developing GCTs.1,2 There are inconsistent data on the role of oral contraceptive pills or hormone replacement and GCT. Some studies have shown an increased incidence of ovarian tumors in women with ovarian stimulation with selective estrogen receptor modulators, such as clomiphene citrate, or with high-dose pituitary gonadatropins. However, there are likely confounding factors. For example, the thorough ultrasound evaluations for these women may have increased detection rates of ovarian tumors including GCT.2,19 Historically, others have postulated that this association was causative with 2 possible explanations: that tumor was present and waiting for the hormonal trigger or that elevations in folliclestimulating hormone are oncogenic to the granulosa cells.20 There are reported nonmodifiable risk factors related to development of GCTs. Genetic syndromes are associated with increased risk for ovarian stromal tumors. Peutz-Jeghers syndrome, a rare autosomal dominant disorder involving mutations in STK11/LBK1 tumor suppressor gene, is characterized by multiple gastrointestinal hamartomatous polyps, mucocutaneous manifestations, and risk for benign and malignant tumors of many other organs.19,21 Peutz-Jeghers syndrome is associated with an increased risk for GCTs. Nearly a third of women with Peutz-Jeghers syndrome develop a unique ovarian sex cord stromal tumor intermediate between GCT and Sertoli cell tumors.19,22Y24 Case studies have also shown association between the juvenile form of GCT and Maffucci syndrome/Ollier disease, a rare genetic disorder marked by tumors of cartilage and bone marrow.19 BRCA1 and BRCA2, which have a

known relationship with epithelial ovarian carcinoma, have not been shown to increase risk of developing GCTs.25,26 MOLECULAR BIOLOGY Recent developments in GCT molecular biology may have significant implications for diagnosis, assessing prognosis, future therapies, and surveillance. Several researchers confirm that 94% to 97% of adult-form GCT carries a specific missense mutation in FOXL2, although the exact mechanism or role in oncogenesis is unknown.19,25,27,28 FOXL2 mutations occur exclusively in the adult form, so while distinction between juvenile and adult has historically relied on histopathologic differences, FOXL2 mutation status may provide a more accurate discrimination between these 2 entities.13,19,29 Kalfa et al30 showed that 30% of juvenile GCTs display constitutive activation of the gsp oncogene, portending poor prognosis. Moreover, dysregulation of mTOR, a major regulator of cell proliferation, can be seen in GCT. Everolimus, an mTORspecific inhibitor, has been shown to slow but not stop growth of primary tumor and peritoneal implants in mouse models of GCT.8,10 Certain distinct cytogenetic abnormalities and chromosomal aberrations have been seen in GCTs. These tumors have a relatively stable, predictable karyotype, with 14% to 33% displaying trisomy 12, 25% to 33% with trisomy 14, and 35% to 40% with monosomy 22. However, there is little prognostic difference attributable to these karyotypes.19,31 CLINICAL PRESENTATION Presenting symptoms are often nonspecific in GCT patients, for example, abdominal pain, swelling, or bloating. However, most tumors (70%-100%) produce estrogen,1,19,32 consistent with the steroid synthesis of late preovulatory follicles, making vaginal bleeding a common presenting complaint. Most patients with adult-form GCTs present with postmenopausal bleeding or premenopausal abnormal uterine bleeding.2,3,5Y7,12 Endometrial biopsies often reveal glandular hyperplasia, atypical adenomatous hyperplasia, or adenocarcinoma in situ or invasive carcinoma.20 As many as 25% to 50% of adult-form GCTs are associated with development of endometrial hyperplasia caused by tumor estrogen secretion; 5% to 13% develop well-differentiated, usually early-stage endometrial adenocarcinoma.2Y4,11,33 However, 10% of GCTs are not diagnosed until patients undergo surgery for abnormal uterine bleeding.4 Imaging with transvaginal ultrasound occasionally identifies these tumors

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Granulosa Cell Tumors of the Ovary

before surgery as they can become large, up to more than 10 to 15 cm.2 Anywhere from 3% to 27% of patients with a GCT will have a synchronous adenocarcinoma of the endometrium.6,7,12,15 The differential diagnosis of uterine adenocarcinoma with an ovarian mass should include (1) synchronous GCT, (2) primary uterine carcinoma with metastases to the ovary, and (3) synchronous development of primary endometrial and ovarian malignancies.34 Patients can present with pain and abdominal distension related to the size of these tumors or the presence of hemoperitoneum.6 Granulosa cell tumors are highly vascularized, and signs of an acute abdomen could be due to GCT rupture and hemoperitoneum. Approximately 10% of GCTs will rupture with subsequent hemorrhage that can be significant in causing peritonitis and risk for forming peritoneal or visceral abdominal organ implants.8,19 Virilization is uncommon but can be seen with large GCTs, especially those with a Sertoli-Leydig component.35 The majority (78%Y91%) of adult form is confined to the ovary and unilateral at presentation.11 Fotopoulou et al,27 in a retrospective evaluation of 18 primary tumors, report stage IA presentation in 47.4% of cases, IB in 5.3%, IC in 21.1%, IIB in 5.3%, and IIIB in 10.5%. Grossly, these tumors tend to be predominantly solid with hemorrhagic areas. Thecomatous components (granulosa-thecomas) may result in areas of yellow coloration. Histologically, the characteristic findings include cells arranged in rosettes called Call-Exner bodies and cells containing pale cytoplasm with ‘‘coffeebean’’Yshaped grooved nuclei. These histological findings are frequently found in the adult variety of GCT, but rarely observed in the juvenile subtype. Pure thecomas are highly hormonally active but benign solid tumors, which feature luteinized cells.3,5 Spread of GCT is primarily through peritoneal seeding and direct, local extension. However, hematogenous spread has been observed with metastasis in liver, lungs, and brain.4 Seventy percent of adult-form GCTs contain a mixture of granulosa cells and theca cells. Theca cells are lipid-laden (luteinized) ovarian stromal cells. It is the androstenedione produced by these theca cells, which is converted into estradiol by the granulosa cells. Therefore, it is the theca cell component of the granulosatheca cell tumor that in turn produces many of the clinical manifestations of these tumors such as sexual precocity in children, abnormal uterine bleeding in premenopausal women, and postmenopausal bleeding in an older population. The juvenile form, a rare presentation of GCT (5%), differs from the adult form. The average age at

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diagnosis is 8 to 13 years. Histopathology reveals round hyperchromatic nuclei lacking ‘‘coffee bean’’ nuclear grooves and rare or absent Call-Exner bodies.3,5 They lack FOXL2 mutations and g-protein mutations (gsp).1,2,16,19 Most patients with juvenile GCTs will present in prepuberty with greater than 50% of patients younger than 10 years.4 Eighty percent of premenarchal girls with GCTs will present with isosexual precocious puberty2,4,16 related to hormonal activity of the tumor. Juvenile GCTs are seen also in young women younger than 30 years, with 10% of tumors being diagnosed in pregnancy during routine ultrasound screening.36 Recurrence and metastasis are rare and usually occur earlier in comparison to the adult form of GCT.25,37 DIAGNOSIS Imaging Because of its relative rarity, there are limited published reports focusing on preoperative diagnosis of GCT. Few small retrospective studies highlight the appearance of these tumors on preoperative imaging (Table 1). Only 7 retrospective studies describe the preoperative appearance of GCTs on either ultrasound or computed tomography (CT) scan.25,37 The majority of published reports have used ultrasound as the diagnostic tool to evaluate these masses.38Y41,44 Ko et al42 divided GCTs into 5 distinct morphologic patterns: multilocular cystic, thick-walled unilocular cystic, thinwalled unilocular cystic, homogeneously, and heterogeneously solid. This system was simplified by Kim et al,39 who described GCTs as most commonly multiseptated cystic masses or unlobulated solid masses with internal cystic portions. One review by MacSweeney and King43 focused only on CT scan appearance and described GCTs as solid well-defined masses with low attenuation. The largest review by Stine et al44 concluded that GCTs are almost exclusively complex in appearance and frequently greater than 10 cm. Each of the studies contained a slightly different approach to characterizing the morphology of GCTs, although when pooling the data, most GCTs are complex in appearance, being described as multilocular (cystic) and solid (Table 1). A minority of tumors can appear homogeneous or simple in appearance. In suspected epithelial ovarian cancer, CT scan is often used as a preoperative modality to evaluate for metastatic disease, including lymphadenopathy, peritoneal or omental nodularity, and presence of ascites. In contrast, the incidence of lymphadenopathy associated with GCTs appears to be low. A study by Ayhan et al45 retrospectively evaluated 80 patients with GCTs and found that lymphadenopathy was present in only

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TABLE 1 Literature Review of Ultrasound and CT Scan in GCTs Reference

Study Design

n

Ultrasound/CT/Both

Findings

MacSweeney and King43 (1994) Hong et al38 (1996) Ko et al42 (1999)

Retrospective Retrospective Retrospective

15 9 13

CT Ultrasound Both

Sharony et al40 (2001) van Holsbeke et al41 (2008)

Retrospective Retrospective

7 23

Ultrasound Ultrasound

Kim et al39 (2010)

Retrospective

16

Ultrasound

Stine et al44 (2013)

Retrospective

63

Both

GCTs solid well-defined masses with low attenuation GCTs complex and multicystic 5 Morphologic patterns observed; mean size 10 cm 1. Multilocular cystic (n = 6) 2. Thick-walled unilocular cystic (n = 2) 3. Thin-walled unilocular cystic (n = 1) 4. Homogeneously solid (n = 2) 5. Heterogeneously solid (n = 2) 6/7 GCTs were semisolid in appearance 5 Morphologic patterns observed. 52% 910 cm 1. Unilocular (n = 0) 2. Unilocular solid (n = 1) 3. Multilocular (n = 1) 4. Multilocular solid (n = 12) 5. Solid (n = 9) 3 morphologic patterns observed. 1. Solid and cystic (n = 10) 2. Solid with a sponge form appearance (n = 4) 3. Solid (n = 2) 4 Morphologic patterns observed. 70% 910 cm 1. Unilocular cystic (n = 1) 2. Multicystic (n = 10) 3. Solid and cystic (n = 44) 4. Solid (n = 8)

7 patients (8.8%). Stine et al44 reported only 7% of patients with lymphadenopathy on CT scan.44 The same series by Ayhan et al45 and another review of 106 patients with GCT performed by Park et al46 reported the presence of ascites to range from 16% to 28%. Finally, as a derivative of the granulosa cell in the ovarian stroma, many GCTs have produced estradiol, which may lead to thickened endometrium on imaging and symptoms of abnormal vaginal bleeding.47 TUMOR MARKERS Estradiol is responsible for the estrogenic effects associated with GCTs. The problem with the use of estradiol as a marker for these tumors is the lack of reliability and fluctuating levels that do not necessarily correlate with tumor volume or indicate treatment response. In addition, approximately 30% of GCTs do not produce estradiol48 or any detectable forms of estrogen. Inhibin is a protein complex that down-regulates the synthesis and inhibits the secretion of follicle-stimulating hormone.49 It is a dimeric protein composed of 2 homologous > and A subunits.50,51 Inhibin is produced in the gonads, pituitary gland, placenta, and corpus luteum. Follicle-stimulating hormone stimulates the secretion of inhibin from the granulosa cells of the ovarian follicles, with inhibin B reaching its peak in the early follicular to midfollicular phase and inhibin A in the midluteal

phase. Detection of elevated serum inhibin levels in patients with GCTs was first reported in 1989.52 This study reviewed 6 patients with GCT and reported elevated inhibin levels in 2 women with residual or recurrence disease that preceded clinical detection by 5 to 20 months.52 Several studies have confirmed these observations in both premenopausal and postmenopausal patients.53Y56 The literature has progressed throughout the years to further guide recommendations for evaluating patients with GCT. In 1998, Petraglia et al53 identified inhibin B as the preferred subunit in the detection of GCTs. Mom et al54 verified these findings in 30 patients with GCTs. The sensitivity and specificity of inhibin B exceeded that of inhibin A at 89% and 100% versus 67% and 100%, respectively. In practice, inhibin is most consistently elevated in the preoperative setting and undergoes a sharp decline postoperatively, making it the most ideal marker for surveillance.52 Levels of inhibin typically fall to undetectable 1 week after excision. It is important to note that total inhibin is the sum of not only the mature inhibin molecules but also the precursors and subunits. If a total inhibin is sent for postexcision surveillance, there is the potential it can be in reference range even in the presence of an elevated inhibin B. Follicle regulatory protein has been found in menstruating women and is produced by granulosa cells. Levels have been found to be elevated in select patients

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Granulosa Cell Tumors of the Ovary

with GCTs. The significance of follicle regulatory protein as a tumor marker has yet to be determined. Mu¨llerian inhibitory substance (MIS) is also produced by granulosa cells in developing ovarian follicles.2 Mu¨llerian inhibitory substance is cyclically elevated in premenopausal females and undetectable after menopause. Rey et al48 found that levels were elevated in GCTs. In this study, serum antimu¨llerian hormone concentrations were measured in 16 patients with GCT and 75 with ovarian adenocarcinoma, extraovarian cancers, or benign ovarian cysts.48 Levels were also determined in 58 postmenopausal and premenopausal control patients without identified pathology. Mu¨llerian inhibitory substance was consistently less than 5 Hg/L in premenopausal patients and undetectable in postmenopausal patients. Nine of the patients with GCT were followed up for 6 to 47 months. In this group, 8 of 9 had detectable levels between 6.8 and 117.9 Hg/L in the presence of progressive tumor. Only 1 patient had normal levels. On average, MIS serum levels became elevated at least 11 months before recurrence was clinically detectable.48 Mu¨llerian inhibitory substance levels were within reference range in 93% of other gynecologic and nongynecologic cancers. Currently, MIS is available for use only in the research setting.57 Further investigations need to be performed to validate these findings on a larger scale; however, MIS may be a useful marker for GCTs in the future. CA-125 is a commonly used tumor marker in the presence of abnormal-appearing ovarian masses. A recent review by Stine et al44 evaluated the use of CA-125 as a marker for GCTs. This study found that only approximately half of the study group had a CA-125 value that was considered to be elevated (935 U/mL). CA125 is not proven to be helpful in the diagnosis or clinical management of patients with GCTs.44 TREATMENT Surgery As with other forms of ovarian cancer, staging laparotomy is recommended as initial therapy to include hysterectomy, bilateral salpingo-oophorectomy as well as pelvic and para-aortic lymphadenectomy and omentetcomy. A vertical midline or paramedian incision would be preferred for maximal exposure. A common surgical finding is hemoperitoneum. Ascites, if present, should be sent for cytology, and if not present pelvic washings should be performed.34 A biopsy should be performed on any grossly suspicious lesion. Multiple peritoneal biopsies are often performed to include the diaphragm, small and large bowel serosa, pelvic sidewall, lateral paracolic gutters, and cul-de-sac.

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The role of pelvic and para-aortic staging lymphadenectomy in the absence of suspicious lymph node enlargement is less well defined for GCT than for epithelial ovarian cancers. Brown et al58 reviewed 262 patients treated for GCT and other stromal tumors at MD Anderson to determine the incidence of lymph node metastasis detected at primary staging surgery or at recurrence. Although other stromal tumor types were included, GCT comprised 78% of their cohort of patients. Among 58 patients who underwent lymph node sampling as part of the staging procedure, no occult node metastases were detected. Furthermore, only 6 (5.1%) of 117 patients treated for recurrent disease had nodal metastases as their site of recurrence, and 3 of those had negative lymph nodes at their initial staging procedure. They concluded that intraperitoneal and hematogenous metastases were the predominant routes of spread for these tumors and that lymph node sampling could be safely omitted from the initial staging procedure.58 For reproductive-age women, there is a role for conservative surgery including unilateral salpingooophorectomy (USO) without hysterectomy in early stages.59,60 The frequency of bilaterality with GCTs is low, in the 2% to 7% range. Wedge biopsy of the contralateral ovary is not recommended, given low yields of positive findings and potential for adhesion formation that might interfere with future fertility. In the event of more advanced disease, a complete debulking procedure should be performed with the goal of resecting all gross disease. Data regarding recurrence rates for patients who initially received conservative surgery versus complete staging are conflicting.61 Ohel et al12 and Evans et al3 found recurrence rates were higher, and overall survival (OS) was lower in patients who underwent USO compared with those who had a total abdominal hysterectomy bilateral salpingo-oophorectomy. In Ohel and colleagues’ review,12 the 5-year survival rate was 75% for those with a complete surgery versus 59% in the USO group. Evans et al3 found that recurrence rates jumped from 17% to 24% in patients with more conservative surgery. Another review by Pankratz et al15 showed striking differences in recurrence rates with 57% in the USO group and 26% in the total abdominal hysterectomy bilateral salpingo-oophorectomy group. Despite these findings, we believe that in those patients desiring future fertility, USO is a viable option keeping in mind the increased risk of recurrence in the future. Chemotherapy The majority of patients with GCTs have an excellent long-term prognosis and are diagnosed as stage I

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tumors. Thus, many patients do not require adjuvant treatment.3,6,11,12,14 Some form of either single agent or combination chemotherapy is an option for patients with residual tumor or a high risk of recurrence. Highrisk groups include those with tumor rupture, stage IC or greater, poorly differentiated tumors, or a tumor diameter of greater than 10 to 15 cm.2 Again, the relatively small number of patients in the current literature precludes a definitive recommendation, as there has been no proof of survival advantage. Historically, commonly used drugs included doxorubicin and alkylating agents. Unfortunately, results were less than desirable, and responses when achieved were short in duration.2,62Y66 Barlow et al62 combined doxorubicin and bleomycin. Schwartz et al67 used a 3drug regimen of dactinomycin, cyclophosphamide, and 5-fluourouracil. Once platinum agents became available, several alternative regimens were introduced. BEP (bleomycin + etoposide + cisplatin) and PVB (cisplatin + vinblastine + bleomycin) are both studied and effective regimens.59,68Y70 Response rates in these series are reported as high as 37% to 60.5%. Columbo et al59 treated 11 patients with stage III/IV recurrent GCT with PVB. The group received a median of 4 cycles. Six had a complete response, and 3 demonstrated a partial response with a median follow-up of 23 months.59 Among patients with germ cell tumors, dose-limiting neurotoxicity with PVB led to a preference for BEP, in which etoposide is substituted for vinblastine.71 Although the BEP regimen can be myelotoxic and is associated with secondary leukemias, it is much better tolerated, with fewer patients suffering from doselimiting peripheral neuropathy. Of note, these patients should be followed up with pulmonary function tests at least every other cycle to monitor for pulmonary fibrosis related to bleomycin.72 A regimen of bleomycin 10 to 15 mg/d given by continuous intravenous (IV) infusion on days 1 to 3, etoposide 100 mg/m2 IV on days 1 to 3, and cisplatin 100 mg/m2 IV on day 1 was used by the MD Anderson group to treat 9 patients with metastatic sex cord stromal tumors.73 Two patients developed pulmonary toxicity, with neutropenia being the most common adverse effect; however, overall toxicity was acceptable. Median progression-free survival was 14 months with a median survival of 28 months. The Gynecologic Oncology Group evaluated BEP in a prospective phase II clinical trial in patients with ovarian stromal tumors for a median follow-up of 3 years.69 This is the largest prospective study of chemotherapy in GCT with 75 patients enrolled. Eligibility criteria included incompletely resected stage II-IV or recurrent disease, positive

peritoneal washings, or radiographic evidence of tumor. The primary study endpoint was response at time of second-look surgery. Of the 38 patients who underwent second-look laparotomy, 14 (37%) did not show evidence of disease. The remaining 17 patients did not have additional surgery but were clinically free of disease at the end of the study. The overall response rate was 40% with a median duration of a complete response of 24.4 months. There was a high rate of myelosuppression at 61%.69 In an attempt to decrease toxicity from the above combination regimens, there has been evaluation of platinum- and taxane-based chemotherapy.59,74 Brown et al74 directly compared taxanes with BEP. Two hundred twenty-two patients both recurrent and newly diagnosed with GCT were included in the analysis. Forty-four were treated with taxanes, and 21 were treated with BEP. For those patients with newly diagnosed disease, there was no significant difference in response rate at 82%. Median progression-free survival was reported as 46 months for BEP and more than 52 months for taxanes, and OS was 97.2 and more than 52 months, respectively. In patients with recurrent disease, there was also no statistical difference in response rates (71% vs 37%) or PFS (11.2 vs 7.2 months).74 Radiotherapy Radiation therapy has been used in the adjuvant and recurrent setting, but a lack of randomized controlled data leaves its use to the judgment of the practitioner. There are retrospective studies that suggest a possible survival benefit or improved disease-free interval when given postoperatively or for recurrent/advanced disease when compared with no further treatment.15,64Y66,75,76 To date, there are no prospective randomized trials to define the exact value in the adjuvant or recurrent setting. Savage et al76 used radiation in the setting of inoperable disease and had 3 of 8 patients disease-free for up to 4 years with an overall response of 50%. Pankratz et al15 reviewed 61 cases of GCT.15 Of these, 48 underwent adjuvant radiation therapy. Treatment in individual patients included whole pelvic as well as whole abdominal radiation fields. There was an increase in OS in the radiation group compared with patients treated with surgery alone. Their study also included patients who received pelvic and or abdominal adjuvant radiation after optimal debulking surgery (G1-cm disease). The median follow-up time was 13 years. Of the 14 patients, 6 (43%) had a complete clinical response, 3 of whom had a relapse 4 to 5 years later. In the recurrence group, 2 died of disease, and 1 survived. Patients who did not respond to radiotherapy had a median survival of 12.3 months (range, 91Y60 months).76

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Granulosa Cell Tumors of the Ovary

However, several studies have shown no survival benefit with radiation.3,7,11 In as series of 42 patients treated with either external beam radiation or radioactive isotope, 20% recurred versus 13% of those treated with surgery alone.3 At this point, there is not enough evidence to recommend for or against radiation therapy. We suggest it be considered on a case-by-case basis in the recurrent setting as well as in patients with inoperable disease for palliation, as surgery and chemotherapy remain the mainstay of treatment. Novel/New Treatments Alternative treatment strategies have been evaluated especially in the setting of recurrent GCT. Aromatase inhibitors bind to aromatase and produce an antiestrogen effect that would theoretically be a treatment strategy for tumors that produce estradiol. There are case reports of the use of aromatase inhibitors such as anastrozole in GCTs to treat recurrences with some success.77,78 There have also been published reports on the use of megestrol and tamoxifen offering a diseasefree survival of 5 years.79 It is important to note that these treatments are supported only by case reports, and there are a number of reports that come to the opposite conclusion.76 At this stage in the literature, there is no conclusive evidence to or to not recommend hormonal therapies as a treatment option. Another novel option is the use of tyrosine kinase inhibitors. Imatinib mesylate (Gleevec) is a tyrosine kinase inhibitor most commonly used in the treatment of leukemias (and gastrointestinal stromal tumors).80

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It works by preventing a tyrosine kinaseYmediated phosphorylation, thus inhibiting the signaling cascade necessary for cancer development leading to apoptosis of cancer cells. Chu et al81 evaluated the in vitro response of imatinib mesylate and nilotinib in 2 human derived ovarian GCT cell lines. Both cell lines responded with dose-dependent decreases in cell proliferation and viability; however, this effect was shown only at high doses. The authors concluded that tyrosine kinase inhibitors might represent a future treatment in GCTs, but that more research was necessary to develop more specific targets. The most recent publication of the use of tyrosine kinase inhibitors in clinical practice is by Raspagliesi et al.82 Their experience was with a single patient who suffered from heavily treated recurrent GCT. A regimen of imatinib using 400 mg/d during the first 2 months, escalated to 800 mg/d, showed a marked reduction of disease after 6 months of treatment. While the use of tyrosine kinase inhibitors may be promising, further research is needed before these agents can be considered for widespread use. At this time, we would recommend it only for patients with recurrent GCT who have been exposed to multiple prior regimens and who have exhausted other treatment options. SURVIVAL The staging for GCTs is the same as the system for epithelial ovarian cancer used by the International Federation of Gynecology and Obstetrics (Table 2).The majority of GCTs are diagnosed in stage I (78%Y91%).2 Survival declines with increasing stage. Overall 5-year

TABLE 2 Staging of GCTs Stage I The cancer is still contained within the ovary (or ovaries). It has not spread outside the ovary. Stage IA: Cancer has developed in 1 ovary, and the tumor is confined to the inside of the ovary. Stage IB: Cancer has developed in both ovaries but not on their outer surfaces. Stage IC: The cancer is present in 1 or both ovaries and Q1 of the following are present: cancer is on the outer surface of at least one of the ovaries, the capsule has ruptured, positive pelvic washings, or ascites. Stage II The cancer is in 1 or both ovaries and has spread to other organs (such as the uterus, fallopian tubes, bladder, the sigmoid colon, or the rectum) within the pelvis. It has not spread to lymph nodes, the lining of the abdomen or distant sites. Stage IIA: The cancer has spread to or has invaded the uterus or the fallopian tubes, or both. Stage IIB: The cancer has spread to other nearby pelvic organs such as the bladder, the sigmoid colon, or the rectum. Stage IIC: The cancer has spread to pelvic organs as in stage IIA or IIB, and cancer cells were found in pelvic washings. Stage III The cancer is in 1 or both ovaries, and 1 or both of the following are present: (1) cancer has spread beyond the pelvis to the lining of the abdomen; (2) cancer has spread to lymph nodes. Stage IIIA: Microscopic disease in the upper abdomen. Stage IIIB: Metastatic disease 92 cm in the upper abdomen Stage IIIC: The cancer is in 1 or both ovaries, and 1 or both of the following are present: cancer has spread to lymph nodes, metastatic disease 92 cm in the abdomen Stage IV Distant metastasis including liver parenchyma and pleural fluid.

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TABLE 3 GCTs Survival by Stage Stage

5-y Survival

10-y Survival

I II III/IV

90%Y100% 55%Y75% 22%Y59%

84%Y95% 50%Y65% 17%Y33%

survival for stage I is 90% to 100%; stage II, 55% to 75%; and stage III-IV, 22% to 59%.2,60 Ten-year survival rates for stages I, II, III, and IV are 84% to 95%, 50% to 65%, and 17% to 33%, respectively.2,15,67 Because the majority of GCT is diagnosed at earlier stages, survival exceeds that of epithelial ovarian cancers (Table 3). POSTTREATMENT SURVEILLANCE Guidelines Because of the natural history of GCTs, typical median time to relapse is reported as 4 to 6 years. For this reason, long-term semiannual follow-up beyond 5 years is recommended to monitor for recurrences.3,7,14,83,84 A unique feature of GCTs is their ability to relapse more than 20 years after initial treatment.83 The most common site of recurrence is the pelvis, with 30% to 45% recurring in the upper abdomen.3,5,84,85 More rarely seen are distant metastases in the lungs, liver, and bony skeleton. Recent data published by Mangili et al86 in the British Journal of Cancer further solidified the need for long-term follow-up in these tumors. Longterm outcomes were evaluated retrospectively in a total of 97 patients treated in MITO (Multicentre Italian Trials in Ovarian Cancer) centers. This study confirmed the generally favorable prognosis of GCTs of the ovary with a 5-year survival approaching 97%. Despite this, survival after 20 years was significantly less at 66.8%. Their findings support the need for lifelong follow-up even in cases of early-stage GCT.86 Follow-up includes a thorough interval history, physical examination, and tumor markers (currently inhibin). In patients with early-stage disease, routine imaging is not helpful for follow-up, but CT scans are useful to evaluate unusual symptoms or physical findings. Given the natural history of the disease, patients may undergo multiple surgical procedures for separate recurrences over their lifetime. CONCLUSIONS In conclusion, GCT is a rare ovarian malignancy that does not usually present with the clinical scenario typical for an epithelial ovarian cancer. Vaginal bleeding and precocious puberty may be a result of estradiol

secretion. Many patients present with a pelvic mass and some rupture, resulting in acute pelvic pain and hemoperitoneum. Surgery remains the mainstay of initial management and is necessary for diagnosis, staging, and tumor debulking. In women who have completed childbearing, a total abdominal hysterectomy and bilateral salpingo-oophorectomy are typically performed in addition to a staging procedure to evaluate thoroughly for metastatic disease that requires debulking. There is a role for conservative USO in women who have early-stage disease and desire future fertility. Because the majority of patients present with earlystage disease, most patients with GCT do not require adjuvant therapy. Patients at higher risk for recurrence may benefit from postoperative adjuvant therapy with either chemotherapy or radiation, although these have not been validated by prospective trials. Some retrospective studies have shown that use of adjuvant chemotherapy or radiation may improve progression-free survival. The natural history of a GCT is associated with late recurrences. For this reason, patients should be followed up with a thorough history, physical examination, and tumor markers backed up by symptomdirected radiologic surveillance indefinitely.

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