Cancer Treatment Reviews (2008) 34, 1 12

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TUMOUR REVIEW

Granulosa cell tumor of the ovary

D. Pectasides *, E. Pectasides, A. Psyrri
Second Department of Internal Medicine, Propaeduetic, Oncology Section, University of Athens, Attikon University Hospital, Haidari, 1 Rimini, Athens, Greece Received 27 July 2007; received in revised form 27 August 2007; accepted 29 August 2007

KEYWORDS Granulosa cell tumors; Pathology; Prognosis; Tumor markers; Management

Summary Ovarian granulosa cell tumors (GCTs) are uncommon neoplasms that arise from the sex-cord stromal cells of the ovary. GCTs are characterized by long natural history and their tendency to recur years after the initial diagnosis. They present with symptoms and signs due to estradiol secretion, including vaginal bleeding and precocious puberty. Occasionally, tumor rupture causes abdominal pain and hemoperitoneum. GCT is usually associated with a mass on pelvic examination which is subsequently conrmed with imagine techniques. Surgery is the mainstay of initial management for histological diagnosis, appropriate staging and debulking surgery. In patients with stage I disease and those in reproductive age a more conservative unilateral salpingo-oophorectomy is indicated. In postmenopausal women and those with more advanced disease a total abdominal hysterectomy with bilateral salpingo-oophorectomy is the appropriate surgical treatment. The most important prognostic factor associated with a higher risk of relapse is the stage of disease. The role of post-operative chemo- or radiotherapy in stage I disease and those with completely resected tumor has not been dened. Nevertheless, the use of adjuvant chemotherapy or radiotherapy has sometimes been associated with prolonged disease-free survival and possibly overall survival. Chemotherapy should be considered for patients with advanced, recurrent or metastatic disease and the BEP (bleomycin, etoposide, cisplatin) is the currently preferable regimen. Although overall response rate (RR) is high, the impact on disease-free or overall survival is unknown. Due to their tendency to recur years after the initial diagnosis, prolonged surveillance is essential. c 2007 Elsevier Ltd. All rights reserved.


Introduction

Ovarian granulosa cell tumors (GCTs) are uncommon neoplasms that arise from the sex-cord stromal cells of the
* Corresponding author. Tel.: +30 210 5831691/6008610; fax: +30 210 5831690/6008610. E-mail address: pectasid@otenet.gr (D. Pectasides).

ovary and represent 2% to 5% of all ovarian cancers.14 GCTs are divided into two subgroups based on clinical presentation and histologic characteristics: juvenile GCTs and adult GCTs. The majority of the patients are adults but 5% are prepubertal.5 The uvenile form of GCTs (JGCTs) is diagnosed in patients under 30, 20, and 10 years of age in 90%, 80%, and 50% of the cases, respectively, thus justifying its juvenile prex.6 However, adult GCTs can also be

0305-7372/$ - see front matter c 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.ctrv.2007.08.007

2 found in children, even though this is rare. The mean age at diagnosis of JGCTs has been reported as 89 years and 13 17 years in series consisting of girls less than 16 years of age,7 and in series that included adults,8 respectively. Since all GCTs are nearly hormonally active producing estradiol, 8090% of patients under 8 years of age have signs of isosexual precocious pseudopuberty.7 On examination, these patients may have precocious breast development, increased pubic hair, vaginal bleeding, or advanced growth and bone age. In the older patients, hormonally active JGCTs may cause menstrual irregularities and rarely, virilization. In all patients, abdominal swelling, pain, and a palpable mass in the lower abdomen are important presenting symptoms. In 10% of the cases, JGCT may rupture and thus the rst presenting symptom may be acute abdominal pain. Ascites is present in 10% of patients.9 GCTs are bilateral in only 3% of patients and in most cases are limited to the ovary at the time of diagnosis (FIGO stage I). The JGCTs are usually large, averaging 12 cm in diameter and either solid or partly, or entirely cystic. The cystic uid is most often serous. There are no differences in tumor size between preand post-menarchal patients. The majority of women with adult GCTs are also diagnosed as having stage I disease (7891%).2,10 The natural history of these neoplasms is generally one of slow growth, with a tendency for late recurrence.1,10 This review analyses the clinical features of adult GCTs and describes the treatment modalities of patients with newly diagnosed and recurrent disease.

D. Pectasides et al. of the granulosa-cell tumour during ovarian stimulation is coincidental. It has been reported that mutations of BRCA1 or BRCA2 have not been associated with a higher risk of developing GCTs.3

Clinical presentation
The most common presenting symptoms of GCTs are abnormal uterine bleeding and pain due to their large size. In the reproductive age group, patients may have menstrual irregularities, menorrhagia, intermenstrual bleeding or amenorrhea, and in postmenopausal women, abnormal uterine bleeding, may be the presenting symptoms.2,9,12,15,20 In older patients, the symptoms of GCTs may mimic those of common epithelial cancer, such as vague abdominal discomfort, increasing abdominal girth, and weight loss. Schwartz and Smith,21 were treated 51 patients with GCTs and noted that the majority of patients were in the 5th and 6th decades of life. The most common presenting symptoms were postmenopausal bleeding, the presence of a mass, and pelvic or abdominal mass. Similar presenting symptoms were reported by Fox et al.2 and Ohel et al.11 In approximately 10% of patients, the tumor is either discovered at the time of surgery for abnormal bleeding, or found only after histologic examination of the specimen.22 Because of the endogenous estrogen effect, endometrial hyperplasia is also frequently present. Approximately 2550% of GCTs are associated with endometrial hyperplasia, whereas 513% are associated with an endometrial carcinoma.1,2,12,15,23 Occasionally, endometrial carcinoma may be diagnosed incidentally at the time of surgical staging performed for GCTs. Endometrial carcinoma related to GCTs is usually well differentiated, early stage and associated with a good prognosis.1,10,22 GCTs may also be associated with breast enlargement and tenderness due to the endogenous estrogen effect. The juvenile variant of GCTs usually occurs before the normal age of puberty and is associated with histologic features that distinguished it from the adult GCTs. Patients with juvenile GCTs often present with isosexual precocity.2,9,24 An association has been found with Potters syndrome,25 multiple congenital abnormalities,26 Olliers disease (multiple enchondromarosis),27,28 and Maffuccis syndrome (Olliers disease with hemangiomas).29 Approximately 90% of GCTs found in prebubertal patients, and many tumors found in women under age 30, will be juvenile GCTs.6 Rare cases have also been reported of androgensecreting GCTs causing the development of virilizing features or hirsutism.30,31 Patients may describe persistent, localized abdominal or pelvic pain, sometimes associated with abdominal distension from a large ovarian mass. More acute onset of pelvic pain may be the result of an ovarian torsion. Torsion can produce acute abdominal signs and symptoms,2 but huge hemorrhagic GCTs may be relatively asymptomatic.32 Rupture of adult GCTs was reported by Stenwig et al.15 to occur in 10% of patients. In the series of Schwartz and Smith,21 35% of the tumors ruptured (13 of 37). Five of these ruptured within 24 h of surgery and 8 ruptured at the time of surgery. Premenopausal women who present with ruptured GCTs experience acute onset of abdominal pain, abdominal

Epidemiology
GCTs occur at any age but most commonly in women in the reproductive age and as well as in women who are postmenopausal.13,1015 Over a 15-year period in Israel, 172 cases of GCTs were diagnosed, for an incidence of 0.9 cases/100,000 women/year.11 The incidence in women of European and American background was almost twice that of women of African and Asian descent (0.98 versus 0.552/100,000/year). The reported incidence of GCTs has varied from 0.58/ 100,000 to 1.6/100,000 women/year,10,11,15 and was reported as 0.62/100,000 women/year in Finland.11 The calculated incidence of GCTs is 0.99/100,000 white females/year in United States.3,11 The more common adult form generally presents in the peri- or postmenopausal women with a median age at presentation of 50 years,2,10,11 and a span between 40 and 70 years.16 GCTs have been reported to be associated with endometrial hyrperplasia due to stimulation of the endometrium by the estrogen production. Up to 13% of these patients develop well-differentiated endometrial adenocarcinoma.1,2,17 Rarely, virilizing effects have been observed, usually in association with very large unilocular or multilocular thin-walled cystic masses.2,18 Patients with GCTs have not demonstrated an increased incidence of infertility, despite association with excessive hormone production.11 Willemsen et al.19 were treated 12 GCTs with clomiphen and gonadotrophins or both for ovarian hyperstimulation. They postulate three explanations for the possible relation of ovarian stimulation and GCTs; rst, the granulosa-cell tumour is present in the ovary, waiting for a hormonal trigger; second, increased follicle stimulating hormone concentrations are oncogenic to granulosa cell; and third, the onset

Granulosa cell tumor of the ovary distention and hypotension caused by the development of hemoperitoneum. Spread of GCTs is local, direct extension and intraperitoneal seeding. The tumors may also spread hematogenously, and patients can develop metastases in the lungs, liver, and brain years after initial diagnosis. Diddle,33 found that 8% of 110 cases had lymph node metastasis at postmortem examination. GCTs are the most classic late-recurring malignancies in gynecology.2 Recurrences may not be detected for more than 5 years after the initial diagnosis. The longest reported time period before recurrence was 37 years.34 However, 14 of 19 patients with recurrent GCTs were identied within 3 years in the series of Schwartz and Smith,21 and more than half of the recurrences were identied within 2 years in the series of Fox et al.2 Most patients have a palpable abdominal or pelvic mass.2,11 Between 80% and 90% of GCTs are conned to the ovary. Advanced metastatic disease with ascites is present in about 10% of cases.

3 but not in extraovarian tumors) which are responsible for the androstenedione production (estradiol precursor) which is converted to estradiol through the aromatase action present in granulose cells.40 Thus, although estradiol may be helpful in monitoring the course of disease, it is not sensitive enough to serve as a reliable tumor marker in this disease.

Inhibin
Inhibin is a dimeric, ovarian glycoprotein hormone consisting of an a- and one of two b-subunits (bA giving inhibin-A or bB giving inhibin-B).42 It is a member of the transforming growth factor b-family of growth factors. The major biological property of inhibin is to suppress the synthesis and secretion of pituitary follicle-stimulating hormone (FSH) and it serves as a component of the pituitarygonadal feedback system. Its role in that system has been established particularly in the female.43 A related member of the inhibin superfamily is activin which consists of three possible forms (bAbA; bAbB; bBbB). Activin, in contrast to inhibin, stimulates the secretion of FSH and has actions in a variety of other tissues. The granulosa cell tumor has shown positive staining for inhibin-A and the activins.44 To date no assay suitable for measurement of circulating activin concentrations is available.44 Either or both inhibin species may be secreted by GCTs and serve as useful tumor markers, although inhibin B may be more frequently elevated in patients with GCTs.4547 It has been reported that patients with GCTs had elevated serum concentrations which fell following tumor removal and which could serve as a marker of tumor recurrence.40 More recently, it was reported that 82% of postmenopausal women with mucinous carcinoma of the ovary had elevated serum immunoreactive inhibin concentrations.48 These levels became undetectable 1 week following tumor removal. The observation that serum inhibin levels fall following tumor removal was consistent with the possibility that the elevated inhibin concentrations were the result of secretion of the hormone, either by the tumor tissue or by neighboring normal ovarian tissue. Lappohn et al.40 reported elevated inhibin levels and low FSH levels in 2 patients with residual or recurrent disease. The authors concluded that inhibin was a more reliable tumor marker of disease activity than estradiol. These results were conrmed by other investigators.48,49

Radiographic ndings
Imaging ndings in adult GCTs vary widely and range from solid masses, to tumors with varying degrees of hemorrhagic or brotic changes, to multilocular cystic lesions to completely cystic tumors. Ko et al.35 categorized 13 adult GCTs into 5 morphologic patterns based on echographic and CT scan ndings: multilocular cystic, thick-walled unilocular cystic, thin-walled unilocular cystic, homogenously solid, and heterogeneously solid and Kim,36 simplied the categories into two most common forms: multiseptated cystic masses and unlobulated solid masses with internal cystic portions. Intratumoral bleeding, infarcts, brous degeneration, and irregularly arranged tumor cells have yielded heterogeneously solid tumors.35,37 Evidence of hemorrhage has been reported in 6071.4% of cases.36,37 On CT scan hemorrhage is difcult to identify due to absence of precontrast images In contrast with epithelial neoplasms, GCTs do not have intracystic papillary projections, less propensity for peritoneal seeding, and are conned to the ovary at the time of diagnosis. Estrogenic effects on the uterus may manifest as uterine enlargement or as endometrial thickening or hemorrhage.38

Tumor markers
Estradiol
Estradiol has been identied as one of the substances secreted by GCTs and is responsible for the clinical signs of hyperestrogenism. This secretion may serve as a possible tumor marker for GCTs.39 Elevated estradiol levels have been found in patients with known GCTs. However, estradiol levels are not a reliable marker of disease activity, since uctuated levels of estradiol have been found in patients with bulky disease or patients responded or not to treatment.40,41 Rey et al.41 found no correlation between estradiol levels and course of the disease. GCTs do not produce estradiol in approximately 30% of cases due to the lack of theca cells in the tumor stroma. The GCTs produce estradiol in the presence of theca cells (are present in some ovarian

Follicle regulatory protein (FRP)

FRP is secreted by the granulose cells and is normally presenting the serum of a regularly menstruating woman. The regulation of FRP secretion occurs with the differentiation of granulose cell. Elevated levels of FRP have been detected in some patients with GCTs.50 The clinical importance of this marker is not yet known.

Mullerian inhibitory substance (MIS)

Mullerian inhibitory substance is a new possible tumor marker for GCTs. In females, MIS is produced by the granulose cells in the developing follicles of the ovary. Rey et al.41 evaluated serum MIS as a marker for granulosa cell tumors. Serum antimullerian hormone concentrations were determined in 16 patients with an adult-type granulosa cell

4 tumor; in 75 female patients with ovarian adenocarcinoma, benign ovarian cysts, or extraovarian cancers; and in 58 normal premenopausal and postmenopausal women. Serum MIS, a-inhibin, and estradiol levels were compared in 10 patients with a granulosa cell tumor during 647 months of follow-up. Serum MIS was undetectable in normal postmenopausal women and was <5 lg/L in premenopausal women. Normal serum levels were found in patients with ovarian cancers or cysts or with extraovarian cancers. Levels were between 6.8 and 117.9 microg/L in 8 of 9 patients with a progressive granulosa cell tumor. In the remaining case MIS, a-inhibin and estradiol concentrations were normal. Serum MIS and a-inhibin levels became elevated at least 11 months before the recurrence was clinically detectable. During clinical remission serum MIS, b-inhibin, and estradiol were normal in most cases. Although the clinical usefulness of MIS is still under investigation, these studies indicate that this hormone may be a useful marker of GCTs activity.

D. Pectasides et al. factors have, however, commonly frustrated not only by their relative rarity but also by the very long period for which follow-up observation is required. Their clinical course is characterized by indolent growth leading to large tumor size at the time of diagnosis, although in most patients the tumor is still conned to the ovary. The only clinical factor unequivocally related to recurrence is stage.2,1012,14,50 Overall 10-year survival rates for patients with GCTs have been reported as being between 60% and 90%,9,12,15,50,51 but the 25-year survival rate is only in the range of 4060%.2,9,5052 The 5-year survival rate for patients with stage I ranged from 90% to 95% (>90% survival rate in the majority of the studies).1,2,10,12,13,15,50 The 10-year survival rate is between 85% and 95%.10,13,53 As 6090% of patients present with stage I disease,1,2,10,13 the denition of pathologic prognostic factors relates principally to stage I tumors. The 5-year survival rates for stage II and stage III/IV have been reported 5575% and 2250%, respectively and the 10-year survival rates for stage I, stage II and stage III/IV 8495%, 5065% and 1733%, respectively,10,13,16,21,54 (Table 1). Conicting data exist regarding the prognostic signicance of age.1,10,11,16,33 Some studies showed an improved prognosis in GCTs patients with age less than 40 years,15 whereas others reported a more favorable outcome in patients aged greater than 40 years.16 GCTs tend to run an indolently malignant course and recurrences following initial therapy commonly occur after more than 5 years, not infrequently after more than 10 years, sometimes after 20 years and very occasionally after more than 25 years.2,12,55,56 Therefore even after a diseasefree period of 20-years it is not possible to reassure the patient with absolute with dogmatism that she is cured with no chance of recurrence. Nevertheless most recurrences occur within 510-years following initial therapy and the role of dening pathologic prognostic factors is to identify patients with a very long-term risk of recurrence.2,10,11,14,52 Tumor size has been reported of prognostic signicance. Patients with tumors measuring 5 cm or less have a better progression-free survival and 10-year survival than those with tumors greater than 5 cm and as well as with women whose tumors measured in excess of 10 cm, independent of stage.1,2,15 However, other investigators did not nd the tumor size as a prognostic factor for the outcome.10,12,14 In another study tumors which recurred early were larger than those which recurred after 10 years and these, in turn, were larger than those which did not recur.14 In contrast, other investigators showed no signicant difference in mean tumor size between those cases which recurred and those without evidence of recurrence.57 It

Pathology
GCTs vary greatly in gross appearance. Sometimes they are solid tumors that are soft or rm, depending on the relative amounts of neoplastic cells and brothecomatous stroma they contain, and are yellow or grey, depending on amount of intracellular lipid in the lesion. More commonly, the GCT is predominantly cystic, and, on external examination, may resemble mucinous cystadenoma or cystadenocarcinoma. However, when sectioned, this cyst is generally found to be lled with serous uid or clotted blood. About 15% of patients with cystic GCTs are rst examined for acute abdomens associated with hemoperitoneum. On the basis of their differentiation, GCTs should be divided into 2 general categories: well and moderately differentiated. The former pattern may have various presentations, including microfolicular, trabecular, solid tubular, diffuse, and water-silk. However, a mixture of these patterns is often found in an individual tumor.1,10,15,50 Tumors in the moderately differentiated category have a diffuse pattern that has been designated sarcomatoid. Occasionally, GCTs with a diffuse pattern can be mistaken for a poorly differentiated carcinoma on intraoperative frozen section. The nuclear appearance can be very helpful in making this distinction. It is important that undifferentiated carcinomas, adenocarcinomas, and carcinoids not be misdiagnosed as GCTs, which they may supercially resemble. Each of these tumors has a strikingly different prognosis. One characteristic feature is the appearance of the nuclei. Oval or angular, uniform and pale, grooved nuclei are typical of GCTs (coffe-bean appearance). The nuclei of undifferentiated carcinomas are frequently hyperchromatic, ungrooved, and unequal in size and shape. Nuclear atypia and multiple mitotic gures are also less common in GCTs but more frequently observed in undifferentiated carcinomas. Call-Exner bodies are also of diagnostic importance, but unfortunately are not often sharply dened.

Table 1 Figo stage I II III IV

Survival by stage Five-year survival (%) 90100 5575 2250 Ten-year survival (%) 8495 5065 1733 (combined data for stages III/IV)

Prognostic factors
Several factors of prognostic signicance have been reported for GCTs. Studies aimed at dening prognostic

Granulosa cell tumor of the ovary should be noted that even microscopic tumors may recur after some years.58 Another of prognostic signicance factor in GCTs is tumor rupture. In one study, patients with intact stage I tumors had a 25-year survival rate of 86% while those with ruptured tumors of the same stage had a survival rate of 60%.10 In another study, Schneider et al.59 reported no relapses among 12 patients who had accidental stage IC disease due to intraoperative of the tumor capsule. Among these were 3 bilateral tumors treated with adjuvant chemotherapy. In contrast, 5 of 9 patients with stage IC disease who experienced preoperative tumor rupture or malignant ascites relapsed (p = 0.001). These patients were treated with adjuvant chemotherapy, among whom, three developed a recurrence.59 It has been reported that patients whose tumors had a follicular pattern showed a 10-year survival rate of 82% compared to 29% in those with tumors with diffuse pattern.52 It has also been claimed that both insular and diffuse histologic patterns are associated with a poor prognosis.60 However, other investigators have not validated the histologic pattern as a prognostic factor in GCTs.2,10,12,15,30,50,51 Several studies have reported an association between the mitotic activity-index (MI) of GCTs and survival or recurrence.10,12,14,15,55,58,61 In one study, patients whose tumors had a low MI [<3 MI per 10 high power elds (HPFs)] had a 10-year survival of 70% compared to 37% for those whose tumors had higher MI.15 In a series in which tumors had P4 mitoses/10HPFs had a more than times risk of recurrence than did those with 63 mitoses/10HPFs.53 Furthermore, the disease-free survival rate at 80 months for patients with tumors containing <4 mitoses/10HPFs, compared with 25% for patients whose tumors showed P4 mitoses/10HPFs (p < 0.0005). In another study MI tended to correlate with stage and was not a prognostic factor in stage I tumors.2 Similar results have been reported in studies in which MI either was not a prognostic factor,9 or correlated with the disease stage but was not clearly a predictor for recurrence.12,62,63 Malmstrom et al.12 determined the MI in 42 of 54 cases with GCTs and demonstrated in patients with stage I that survival was signicantly superior in patients whose tumors had 610 mitoses/10HPFs. Nuclear atypia has been reported to be one of the most signicant prognostic factor in stage I disease.15,54 In one study the 25-year survival rate was 80% for patients whose tumors demonstrated slight nuclear atypia compared to 60% for those whose tumors showed more marked atypia.10 Similar results have been reported by Stenwig et al.15 Recently, nuclear atypia has been found as the most important pathologic factor predicting tumor recurrence.14,57 It was also found signicant difference in the outcome between tumors which had recurred early [nuclear atypia in 77%] and those which had recurred late [nuclear atypia in 33%].14,57 In contrast, other investigators were unable to show that nuclear atypia was of any prognostic signicance.2,48,61 DNA analysis revealed that 520% of GCTs are aneuploid. Some investigators demonstrated that aneuploidy was not a predictor for recurrence,58,6264 while others found that aneuploidy was associated with high risk for recurrence.6568 Conicting results have also been reported for p53 overexpression, where some investigators demon-

5 strated that this was an adverse prognostic factor,62,69,70 while others showed no association with the outcome.54,57,61,71 Staining of GCTs for Ki-67 showed that a high Ki-67 index was correlated with an adverse prognosis in some studies,6062 but not in others.71,72

Treatment
Surgical management
Surgical treatment has traditionally been similar to that used for epithelial ovarian cancer. Patients with GCTs generally present with stage I disease (7891%), while the remainders have advanced disease.1,2,12,15,20,54 Rarely, patients can present with metastatic disease involving the liver, lung or bone. The staging system used for GCTs is that applied for epithelial ovarian cancer (FIGO staging system). Surgical staging at the time of initial operation is important for determining which patients are likely to have recurrence. The initial operation should be performed through a vertical midline or paramedian incision to allow adequate exposure of the upper abdomen and the pelvis. On entry into the peritoneal cavity, ascites or free uid should be aspirated and sent for cytology and cell block analysis. If no uid is present, approximately 100 ml of normal saline should be instilled into the pelvis and each lateral paracolic space. The irrigant should be aspirated and sent for cytology and cell block analysis. If the patient is young, desires to preserve fertility, and appears to have disease conned to one ovary (incidence of bilaterality is approximately 2 8%), a unilateral salpingo-oophorectomy (USO) should be performed. Because the incidence of bilaterality is low, a wedge biopsy of the opposite ovary is controversial and should be performed with caution to preserve fertility. The specimen should be sent for frozen section to rule out the presence of microscopic disease. An omentectomy and samples of multiple intraperitoneal sites should be taken, including the diaphragm peritoneum, lateral paracolic peritoneum, small and large bowel serosa, cul-de-sac, and pelvic sidewall peritoneum; and para-aortic and pelvic lymph nodes should be biopsied. In these instances, it is important to perform an endometrial biopsy to rule out a concomitant uterine cancer. If all biopsy specimens and washings are disease-free, no further therapy is recommended. For patients whose fertility is not an issue and for postmenopausal women a total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAH BSO) should be performed. Debulking surgery should be performed to remove as much gross tumor as possible. Management of recurrence should involve aggressive debulking surgery followed by combination chemotherapy. Most recurrences are present in the peritoneal cavity, although liver, lung and skeletal metastases can occur.2,73 Given the long natural history of GCTs, repeated surgical debulking, depending on age, performance status and resectability of the disease, as a useful method of both symptom control and prolonging survival has been used.1,16,19,73 Evans et al.1 reported that extend of the initial surgery appeared to affect recurrence rates. The reported recurrence rate was 17% for those patients who underwent TAH BSO and 24% for those who had a less extensive procedure. However, details relating the surgical

6
Table 2 Management of stage I GCTs Unilateral salpingo-oophoorectomy endometrial biopsy Total abdominal hysterectomy, bilateral salpingo-oophorectomy Total abdominal hysterectomy, bilateral salpingo-oophorectomy

D. Pectasides et al.

Stage IA tumors Age 40 and under, desiring preservation of reproductive function Under age 40, not desiring preservation of reproductive function Over age 40

Observation indenitely Observation indenitely Observation indenitely

procedure to the stage of disease were lacking. Therefore, no conclusions can be drawn concerning the relative values of a USO and other forms of surgery. Similarly, Ohel et al.11 reported a 5-year survival rate of 75% in patients who underwent a TAH BSO and 59% in those women who had only USO. In this study again, no conclusions about the relative value of conservative versus more extensive surgery cannot be made. In another study, the recurrence rates were 57% in patients treated with USO and 26% in those undergoing TAH BSO.16 However, a review of the data showed that 10/19 that underwent a USO and 4/9 that had a BSO, had by denition either stage II/III and therefore were at obvious higher risk for recurrence with conservative surgery. In the study by Schneider et al.59 33 patients underwent adnectomy (salpingo-oophorectomy), which was complete in 18 and incomplete in 15 patients. Sixteen patients had stage IA tumors, 13 had stage IC tumors, and 1 patient had a stage III tumor. Four patients experienced disease recurrence after incomplete resection, whereas all completely resected patients are remaining disease-free. In conclusion, since the majority of patients present with early-stage disease, usually conned to the ovary, a USO should be performed, particularly if the patient wishes to preserve her fertility. In those patients whose fertility is not an issue or those with more advanced disease it would seem reasonable to complete TAH BSO with removal of all visible disease (Table 2).

Radiotherapy
Radiotherapy has been used either in the adjuvant setting or for recurrent disease.13,16,7477 However, no randomized trials exist for dening the role of radiotherapy in the treatment of GCTs. The post-operative radiation therapy is associated with improved survival.16,74,75 Pankratz et al.16 treated 48 of 61 GCTs patients with radiotherapy post-surgery. The administered dose in the upper abdomen ranged from 2000 cGy to 3000 cGy and in the pelvis from 3000 cGy to 5000 cGy. The authors concluded that the group of patients receiving radiation therapy had an improved survival compared with those who did not receive radiotherapy. Savage et al.13 treated 62 patients with GCTs, 8 of whom received radiotherapy for advanced inoperable disease. Radiotherapy produced a number of long-term remissions with an overall response rate of 50%, with 3 of them remaining disease-free for at least 4 years. Fourteen received treatment for clinically measurable disease; 20 received adjuvant radiotherapy after surgery for minimal residual (<1 cm) or microscopic residual disease. Ten of 14 patients were treated with moving-strip whole-abdomen

radiation (2728 Gy) and a pelvic boost of 28 Gy. The other 4 patients were treated with pelvic radiotherapy (45 61 Gy). Six of 14 patients (43%) had a clinical complete response to radiotherapy, with a median follow-up of 13 years (range, 521 years). Three of 6 who responded to radiation had relapse 45 years later; 2 of these 3 died of disease and 1 was alive with disease at last follow-up. Three responders remain alive without evidence of disease 1021 years after treatment. The eight non-responders had a median survival of 12.3 months (range, 160 months). Although radiation therapy is associated with improved survival in newly diagnosed, high-risk patients or patients with recurrent disease,21,33,75,77 other studies suggest no survival benet from radiotherapy.1,1012 Its role in the palliative setting may be for symptomatic disease which can be encompassed by tolerable radiotherapy and in those patients who are suitable for surgical debulking or treatment modalities. Evans et al.1 treated 118 patients with GCTs of whom 42 received pre- or post-operatively external beam radiotherapy or radioactive isotope (gold). Radiotherapy appeared to have no effect on recurrence rate, since 20% of patients receiving radiotherapy developed recurrence, while only 13% of those treated with surgery alone recurred. In conclusion, there are no convincing data to support the use of radiotherapy in the adjuvant setting. Furthermore, it is unclear whether whole abdominal radiotherapy is required if radiotherapy is considered in the adjuvant setting. It is also unclear the dose required to be administered to treat these patients.

Chemotherapy
GCT is a potentially responsive tumor to single agent and combination chemotherapy. Patients with stage I disease have an excellent prognosis (long-term disease-free status is about 90%) and very often do not require further adjuvant treatment.1,10,13,15 However, some stage I disease patients with large tumor size, tumors with high MI or ruptured tumors may have a higher risk of relapse and may require post-operative chemotherapy, since agents with known activity in GCT exist. Post-operative adjuvant therapy remains controversial because of the small number of patients in any reported series. For patients deemed to be good candidates for post-operative treatment, platinum-based chemotherapy is often considered. Although it may be reasonable to consider adjuvant radiotherapy for patients with low-volume residual tumor, the data from the literature do not permit rm conclusions to be made regarding whether radiation therapy is superior to chemotherapy in the adjuvant setting. For patients with gross residual tumor or those

Granulosa cell tumor of the ovary with stage IV disease, the use of platinum-based chemotherapy is the treatment of choice. Bjorkholm and Silfversward,10 reported that patients with clinical stage I disease whose tumors ruptured should be treated with 3 courses of BEP. Chemotherapy and hormonal therapy has been often considered for patients who have advanced/inoperable (stages II, III, IV) or recurrent disease where further surgery or radiotherapy cannot be given for medical or technical reason. In the pre-platinum era alkylating agents and doxorubicin has been reported to have modest activity in GCTs, but the responses were short-lived.21,74,75,7880 Thereafter, reports appeared on the use of combination chemotherapy consisting of doxorubicin/bleomycin,79 and dactinomycin/ cyclophosphamide/5-uoruracil.21 The introduction of cisplatin led to the development of cisplatin/doxorubicin,81 CAP (cyclophosphamide/doxorubicin/cisplatin),13,39,8185 (Table 3), PVB (cisplatin/vinblasine/bleomycin),13,8688 and BEP (bleomycin/etoposide/cisplatin),13,86,87 (Table 4). Ten patients with advanced or recurrent granulosa cell tumours were treated with CAP.85 Five complete responses (CR) (three pathologically documented) and one partial response (PR) were obtained for a total response rate of 60%. One pathologically-complete responder relapsed after 48 months from the onset of chemotherapy, but responded completely to debulking surgery and radiotherapy and remains well with no evidence of disease 87+ months. Similarly, Gerscenson et al.82 were treated 8 patients with metastatic ovarian stromal tumors. Three patients (38%) had a CR to therapy (two conrmed by second-look laparotomy), and two patients (25%) achieved a PR (one veried by sec-

7 ond-look laparotomy). The overall response rate (RR) was 63%. Recent data showed that PVB is active in patients with previously untreated GCTs, but some dose-limiting neurotoxicity and fatalities have been reported.8385 Colombo et al.86 were treated 11 patients with recurrent and/or metastatic GCTs. Six patients achieved a CR, while an additional 3 patients achieved a PR, for an overall RR of 74%. Of the complete responders, 5 of 6 remain disease-free at a median follow-up of 17.8 months. Zambetti et al.87 were treated 7 patients with advanced/recurrent GCTs with PVB. Three CRs (one pathologically documented) and 1 PR were observed, for an overall RR of 66%. Two complete responders were alive without evidence of disease 7 and 26 months from the start of treatment; the remaining patient relapsed at 15 months. In another series 13 patients with advanced or recurrent GCTs were treated with PVB.88 The reported CR was 54%, PR was 39% and the overall RR was 93%, respectively. These series established PVB as an active regimen in the treatment of advanced and/or recurrent GCTs. Toxicity, however, was signicant and included neutropenic sepsis and bleomycin-induced pneumonitis.86,87 The BEP regimen which substitutes etoposide for vinblasine is better tolerated. Although BEP is signicantly myelotoxic and is associated with a risk of secondary acute myelogenous leukemia due to the inclusion of etoposide, it is associated with decreased peripheral neuropathy BEP regimen is currently recommended for adjuvant post-operative chemotherapy and for patients with advanced or recurrent disease. Recurrence should involve aggressive

Table 3 Author Barlow

75

Combination chemotherapy for GCTs Regimen ADR/BLEO ADR/5-FU/CTX Previous treatment None None Response 1/1 CR 2/2 CR Comment Stage III Duration 5 months Stage III NED 35, 27 months Advanced disease Duration not evaluable Recurrent/advanced disease Duration not evaluable Stage IV Duration 2 months Recurrent disease Median survival 11 months

Schwartz20

Schulman78 Jacobs77 Camlibel80 Neville71

CAP CDDP/ADR CAP CTX/ADR CDDP/HEXA CTX/ML/5-FU/P CTX/ML/5-FU/VCR/P CTX/ADR/VCR/CDDP CAP CAP

None None None DRX and Chemo

1/1 PR 2/2 PR 1/1 PR 2/2 2/3 0/1 1/2 0/1 2/2 PR PR PR PR PR PR

Kaye37 Gershenson79

DRX and Chemo DRX

3/8 CR

Pectasides81

CAP

None

5 CR 1 PR

Recurrent disease Duration 8 months Stage II(2), III(1) Recurrent(5) 4 DF, 1 AWD, 3 DOD Advanced/Recurrent

Abbreviations. ADR: doxorubicin, BLEO: bleomycin, 5-FU: 5-uoruracil, CTX: cyclophosphamide, CAP: cyclophosphamide, doxorubicin, cisplatin, CDDP: cisplatin, HEXA: hexamethylmelamine, ML: melphalan, P: prednisone, VCR: vincristine, CR: complete response, PR: partial response, SD: stable disease, NED: no evidence of disease, DF: disease-free, DOD: died of disease, AWD: alive with disease, DRX: radiotherapy, Chemo: chemotherapy.

8
Table 4 Author Colombo
82

D. Pectasides et al.
Combination Chemotherapy with PVB, BEP Regimen PVB Previous treatment 2 Chemo Response 6/11 CR (54%) 3/11 PR (20%) Comment Stage III(4), IV(2), Recurrent (5) 6 NED 2 Alive with disease 2 toxic deaths 1 Died with disease Stage III(5), IV(1), Recurrent (9) Stage II(3) Recurrent (4) 2 NED 2 PD 1 Toxic death 1 Death reason unknown Stage IIIV Stage IIC(1), IIIC(1), Recurrent(3) Stage IIIV Stage IIIV Recurrent

Pecorelli84 Zambetti83

PVB PVB

DRX (6) Chemo(1) None

7/13 CR (54%) 5/13 PR (39%) 3/7 CR (42%)

Savage13 Gershenson85 Savage13 Homesley86

PVB BEP BEP BEP

None None None DRX

1/5 CR 3/5 PR 2/5 CR 3/5 PR 1/3 PR 6 CR, 4 PR

Abbreviations. PVB: cisplatin, vinblastine, bleomycin, BEP: bleomycin, etoposide, cisplatin, Chemo: chemotherapy, CR: complete response, PR: partial response, PD: progressive disease, NED: no evidence of disease, DRX: radiotherapy.

debulking surgery followed by combination chemotherapy. Gershenson et al.89 were treated 9 patients with metastatic ovarian sex cord-stromal tumors of all types with bleomycin 1015 mg/day by continuous intravenous (IV) infusion on days 13; etoposide 100 mg/m2 IV per day on days 13; cisplatin 100 mg/m2 IV on day 1. Of the six patients with measurable disease, two (33%) had a CR (one surgical and one clinical), and three (50%) had a PR, for an overall RR of 83%. Toxicity was acceptable; two patients had mild bleomycin pulmonary toxicity. Of the seven patients with metastatic disease, only one (14%) had a durable remission. Median progression-free survival was 14 months. Median survival time was 28 months. The Gynecologic Oncology Group evaluated in a phase II trial the BEP regimen as rst-line therapy for ovarian stromal malignancies.90 Thirty-seven percent (14/38) of the patients undergoing second-look laparotomy had negative ndings. The six complete responders were of long median duration (24.4 months). Patients with measurable disease were at the highest risk of progression and death. Grade 4 myelotoxicity occurred in 61% of the patients. The authors reported that 69% of patients with advanced disease and 51% of those with recurrent disease remained progression-free, with a relatively short median follow-up of 3 years. Although platinum-based chemotherapy is clearly active, the efcacy of newer agents, such as gemcitabine, oxaliplatin, is not known. Only paclitaxel has been used in a woman with recurrent GCT with a dramatic response.91 The potential activity of paclitaxel has been conrmed by the study of Brown et al.92 Of 222 patients identied, 21 were treated with BEP (10 newly diagnosed patients, 11 patients with recurrent disease) and 44 with taxane (11 newly diagnosed patients, 37 patients with recurrent disease). For newly diagnosed patients treated with BEP compared with those treated with taxane, no signicant differences in response

rate (82% for both regimens), median progression-free survival (46.1 months for BEP, >52 months for taxane), and median overall survival (97.2 months for BEP, >52 months for taxane) were found. For recurrent measurable disease, the response rate (71% versus 37%) and the median progression-free survival (11.2 months versus 7.2 months) were also not statistically signicant. It is possible that the combination of carboplatin plus paclitaxel which has been established in the treatment of epithelial ovarian cancer could have a role in the management of GCTs. The management of recurrence should include aggressive surgery followed by either radiotherapy or chemotherapy. These treatment modalities have been associated with prolonged disease-free survival.21,39,76,77,81,8387 For patients previously treated with BEP, the VAC (vincristine/dactinomycin/cyclophosphamide) regimen is offered. Radiation may play a role in the treatment of recurrent GCT if the patient is found to have an isolated metastasis that can be completely resected. A small eld of intense radiation therapy has been associated with prolonged survival.93 Another treatment option is chemotherapy with BEP for patients with more widespread disease or disease that is suboptimally cytoreduced at the time of relapse. Recurrent disease may also be managed with hormonal therapy, but experience is limited. Schwartz et al.94,95 reported the presence of estrogen and progesterone receptors in GCTs. One of their patients with progesterone receptorpositive tumor was treated for advanced recurrent disease with oral progestins, and her disease was stable for 10 months. Her disease was again stabilized on tamoxifen.94 Malik and Slavin,96 reported 2 patients treated with high doses of medroxyprogesterone acetate who responded with prolonged remissions after documented widespread recurrence. Similarly, Briasoulis et al.97 reported a PR in an elderly woman with GCT and lung metastases lasting for

Granulosa cell tumor of the ovary

Table 5 GCTs Recommendations for follow-up of patients with

9 completely resected tumor has not been dened. Nevertheless, the use of adjuvant therapy has sometimes been associated with prolonged disease-free survival and possibly overall survival. Chemotherapy should be considered for patients with advanced, recurrent or metastatic disease and the BEP is the currently preferable regimen. Although overall RR is high, the impact on disease-free or overall survival is unknown. Newer cytotoxic agents, such as paclitaxel, have shown promising activity in patients with advanced or recurrent GCTs. Due to their tendency to recur years after the initial diagnosis, prolonged surveillance is essential. Recommendations during follow-up are shown in Table 5.

Physical examination including pelvic exam First year: every 3 months Second to fth year: every 4 months After fth year: every 6 months Computed tomography (CT) scan After completion of therapy as baseline study For unexplained abdominal symptoms or hormonal changes Chest X-ray Annually Tumor markers As available

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20 months with megestrol acetate who had a recurrence after carboplatin chemotherapy. Treatment with a gonadotropin releasing hormone (GnRH-goserelin) analog achieved a transient PR in 1 patient who had a recurrence after cytotoxic platinum-based chemotherapy.98 Similarly, Fishman et al.99 were treated 6 patients with refractory or progressive GCTs after cytotoxic chemotherapy with leuprolide acetate. Among the 5 evaluable patients, two achieved a PR lasting 3 and 11 months, with disease progression-free intervals of 4 and 12 months. The other three patients, including two whose disease had progressed on chemotherapy, had stable disease with disease progression-free intervals of 3+, 3+ and 13+ months. The objective response rate was 40%. Cessation of disease progression was noted in all 5 of the evaluable patients. The sixth patient, whose disease could not be evaluated, was treated with leuprolide acetate and had no clinical evidence of disease for 24 months. The therapy was convenient to administer, and no major side effects were noted. In contrast, others have found no benet of these agents in the setting of recurrent disease.13 In conclusion, GCTs are uncommon neoplasms that are characterized by long natural history and their tendency to recur years after the initial diagnosis. They present with symptoms and signs due to estradiol secretion, including vaginal bleeding and precocious puberty. Occasionally, tumor rupture causes abdominal pain and hemoperitoneum. GCT is usually associated with a mass on pelvic examination which is subsequently conrmed with imagine techniques. The initial treatment of choice is surgery which is necessary for histological diagnosis, appropriate staging and debulking surgery. In patients with stage I disease and those in reproductive age a more conservative surgery, including unilateral salpingo-oophorectomy, is indicated. In postmenopausal women and those with more advanced disease a total abdominal hysterectomy with bilateral salpingo-oophorectomy is the appropriate surgical treatment. Since most of the patients with GCTs present with stage I disease, prognosis is excellent. In more advanced stages and in those with high-risk stage I disease (large tumor size, high MI, ruptured tumor) prognosis is less favorable. Due to the rarity of these tumors, randomized trials in order to assess the relative benets of different treatment modalities are not feasible. The role of post-operative chemo- or radiotherapy in stage I disease and those with

10
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56.

57.

58.

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