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Granulosa Cell Tumor of the Ovary: Tumor Review:

Granulosa Cell Tumor of the Ovary: Tumor Review: Integrative Cancer Therapies Volume 7 Number 3 September 2008 204-215 © 2008 Sage Publications 10.1177/1534735408322845 Granulosa Cell Tumor of the Ovary: http://ict.sagepub.com hosted at http://online.sagepub.com Tumor Review Georgios V. Koukourakis, MD, Vasilios E. Kouloulias, MD, Michael J. Koukourakis, MD, Georgios A. Zacharias, MD, Christos Papadimitriou, MD, Kyriaki Mystakidou, MD, Kyriaki Pistevou-Gompaki, MD, John Kouvaris, MD, and Athanasios Gouliamos MD Granulosa cell tumors of the ovary are rare neoplasms that the most important prognostic factor associated with the risk originate from sex-cord stromal cells. The long natural history of relapse. There are no clear conclusions regarding the role of granulosa cell tumors and their tendency to recur years of postoperative chemotherapy or radiotherapy in stage I dis- after the initial diagnosis are the most prominent of their char- ease and in those with completely resected tumor. The use of acteristics. The secretion of estradiol is the reason for signs at adjuvant chemotherapy or radiotherapy has sometimes been presentation such as vaginal bleeding and precocious puberty. associated with prolonged disease-free survival and possibly Abdominal pain and hemoperitoneum, which occasionally can overall survival. Chemotherapy is the treatment of choice for occur, are attributable to tumor rupture. The most common patients with advanced, recurrent, or metastatic disease, and finding in pelvic examination is a tumor mass, which is subse- BEP (bleomycin, etoposide, and cisplatin) is the preferred reg- quently confirmed with imaging techniques. Surgery is the imen. Although the overall rate of response to treatment is mainstay of initial management for histological diagnosis, high, the impact of treatment on disease-free or overall sur- appropriate staging, and debulking. A more conservative uni- vival is unknown. Prolonged surveillance is mandatory lateral salpingo-oophorectomy is indicated in patients with because tumors tend to recur years after the initial diagnosis. stage I disease and patients of reproductive age. Total abdom- inal hysterectomy with bilateral salpingo-oophorectomy is the appropriate surgical treatment for postmenopausal women Keywords: granulosa cell tumor; etiology; prognosis; and those with more advanced disease. The stage of disease is tumor markers; treatment varian granulosa cell tumors are rare malignan- can also be found in children, although this is rare. cies that originate from the sex-cord stromal cells Regarding the juvenile granulosa cell tumor, the mean Oof the ovary and represent 2% to 5% of all ovarian age at diagnosis has been reported as 8 to 9 years and 13 1-4 7 cancers. According to their clinical presentation and to 17 years in series of girls younger than 16 years and in histologic characteristics, they are divided into 2 sub- series that included adults, respectively. Because all groups: juvenile granulosa cell tumors and adult granu- granulosa cell tumors are hormonally active, producing losa cell tumors. The tumors most commonly affect estradiol, 80% to 90% of patients less than 8 years of age adults, but 5% present in the prepubertal period. The have signs of isosexual precocious pseudopuberty. juvenile form of tumor is diagnosed in patients less than Precocious breast development, increased pubic hair, 30, 20, and 10 years of age in 90%, 80%, and 50% of vaginal bleeding, advanced growth, and bone age may be cases, respectively. However, adult granulosa cell tumor observed on examination. A hormonally active juvenile granulosa cell tumor may cause menstrual irregularities and rarely virilization in older patients. Abdominal From the University of Ahepa Medical School, 2nd Department of swelling, pain, and a palpable mass in the lower abdomen Radiology, Radiation Therapy Unit, Attikon University Hospital, Greece are important presenting symptoms in all patients. In 10% (GKV, VEK, GAZ, KM, JK, AG); University of Thrace, Radiation Therapy Unit, Alexandroupolis, Greece (MJK); University of Athens, of cases, a juvenile granulosa cell tumor may rupture and Medical School, Alexandras Hospital, Athens, Greece (CP); and as the result acute abdominal pain may be the first pre- University of Thessaloniki, Ahepa Hospital, Thessaloniki, Greece (KPG). senting symptom. Ascites is present in 10% of patients. Address correspondence to: Georgios V. Koukourakis, Rimini 1, Haidari Bilateral granulosa cell tumors account for 3% of patients 124 64, University Hospital of Athens, Attiko; e-mail: gkoyokoyrakis @yahoo.gr. and most commonly are limited to the ovaries at the time 204 Granulosa Cell Tumor of the Ovary / Koukourakis et al 205 of diagnosis, stage I according to FIGO classification. Clinical Presentation Juvenile granulosa cell tumors are usually large, averaging 12 cm in diameter, and are either solid or partly or Abnormal uterine bleeding and pain attributable to the entirely cystic. In the majority of cases the cystic fluid is large size of granulosa cell tumors are the most common serous. Regarding tumor size, there are no differences presenting symptoms. In the reproductive age group, between premenarchal and postmenarchal patients. patients may have menstrual irregularities, menorrhagia, According to the stage at diagnosis, the majority of intermenstrual bleeding, or amenorrhea, and in post- women with adult granulosa cell tumor are also diag- menopausal women, abnormal uterine bleeding may be 2,10 2,9,12,15,20 nosed as having stage I disease (78-91%). Slow growth the presenting symptom. In older patients, the with a tendency for late recurrence characterizes the nat- symptoms of granulosa cell tumors may mimic those of 1,10 ural history of this tumor. In this review we analyze the common epithelial ovarian cancer, such as vague abdom- clinical features of adult granulosa cell tumors and men- inal discomfort, increasing abdominal girth, and weight tion the treatment modalities of patients with newly diag- loss. Schwartz and Smith treated 51 patients with gran- nosed and recurrent disease. ulosa cell tumors and noted that the majority of patients were in the fifth and sixth decades of life. The most com- mon presenting symptoms were postmenopausal bleed- Epidemiology ing, the presence of a mass, and pelvic or abdominal mass. Similar presenting symptoms were reported by Fox 2 11 Although granulosa cell tumors can occur at any age, they et al and Ohel et al. In approximately 10% of patients, present most often in women of reproductive age and the tumor is either discovered at the time of surgery for they occur as well as in women who are post- abnormal bleeding or found only after histologic exami- 1-3,10-15 22 menopausal. During a 15-year period in Israel, 172 nation of the specimen. Endometrial hyperplasia is also new cases of this tumor were diagnosed, for an incidence frequently present attributable to the endogenous estro- of 0.9 cases per 100 000 women per year. The incidence gen effect. Approximately 25% to 50% of granulosa cell of tumor in women of European and American back- tumors are associated with endometrial hyperplasia, ground was almost twice that of women of African and whereas 5% to 13% are associated with an endometrial 1,2,12,15,23 Asian origin, 0.98 versus 0.522/100 000/y. The reported carcinoma. Occasionally, endometrial carcinoma incidence of granulosa cell tumor has varied from 0.58 to may be diagnosed incidentally at the time of surgical stag- 10,11,15 1.6/100 000/y and was reported as 0.62/100 000/y ing performed for granulosa cell tumors. Endometrial car- in Finland. In United States the calculated incidence cinoma related to granulosa cell tumors is usually well 3,11 for white females is 0.99/100 000/y. The median age at differentiated, diagnosed at an early stage, and associated 1,10,22 presentation in the more common adult form, which gen- with a good prognosis. Granulosa cell tumors may erally presents in perimenopausal or postmenopausal also be associated with breast enlargement and tender- 2,10,11 16 women, is 50 years with a range of 40 to 70 years. ness attributable to the endogenous estrogen effect. Granulosa cell tumor has been reported to be associ- The juvenile variant of granulosa cell tumor usually ated with endometrial hyperplasia attributable to sti- occurs before the normal age of puberty and is associated mulation of the endometrium by estrogen production. with histologic features that distinguish it from the adult Approximately 13% of these patients develop well- granulosa cell tumor. Isosexual precocity is often present 1,2,17 2,9,24 differentiated endometrial adenocarcinoma. In very in patients with juvenile granulosa cell tumors. An large unilocular or multilocular thin-walled cystic masses, association has been found with Potter’s syndrome, mul- 2,18 26 virilism may be observed. Despite the association with tiple congenital abnormalities, Ollier’s disease (multiple 27,28 excessive hormone production, patients with granulosa enchondromatosis), and Maffucci’s syndrome (Ollier’s cell tumors have not demonstrated an increased inci- disease with hemangioma). Approximately 90% of granu- 11 19 dence of infertility. Willemsen et al treated 12 granu- losa cell tumors found in prepubertal patients, and many losa cell tumors with clomiphen, gonadotrophins, or both tumors found in women younger than 30, are juvenile for ovarian hyperstimulation. These investigators postu- granulosa cell tumors. Rare cases have also been reported lated 3 explanations for the possible relation of ovarian of androgen-secreting granulosa cell tumors causing the 30,31 stimulation and granulosa cell tumor. First, the granulosa development of virilizing features or hirsutism. cell tumor is present in the ovary, waiting for a hormonal Persistent, localized abdominal or pelvic pain, some- trigger; second, increased follicle-stimulating hormone times associated with abdominal distension from a large concentrations are oncogenic to granulosa cell tumor; ovarian mass, may be described by patient. Occasionally, and third, the onset of the granulosa cell tumor during ovarian torsion can cause more acute onset of pelvic pain. ovarian stimulation is coincidental. It has been reported Although torsion can produce acute abdominal signs and that mutations of BRCA1 or BRCA2 have not been asso- symptoms, a huge hemorrhagic granulosa cell tumor may ciated with a higher risk of developing granulosa cell be relatively asymptomatic. Rupture of adult granulosa 3 15 tumors. cell tumors was reported by Stenwig et al to occur in 10% 206 Integrative Cancer Therapies / Vol. 7, No. 3, September 2008 of patients. In the series reported by Schwartz and Tumor Markers Smith, 35% of the tumors ruptured (13/37). Five of these ruptured within 24 hours of surgery and 8 ruptured at the Estradiol time of surgery. Premenopausal women who present with One of the substances secreted by granulosa cell tumors ruptured granulosa cell tumors experience acute onset of that is responsible for the clinical signs of hyperestro- abdominal pain, abdominal distension, and hypotension genism is estradiol. This secretion may serve as a possible caused by the development of hemoperitoneum. tumor marker for granulosa cell tumors. In patients with Spread of granulosa cell tumors is local, by direct known granulosa cell tumors, elevated estradiol levels extension and intraperitoneal seeding. The tumors may have been found. However, estradiol levels are not a reli- also spread hematogenously, and patients can develop able marker of disease activity, because fluctuating metastases in the lungs, liver, and brain years after initial (instead of very high) levels of estradiol have been found diagnosis. Diddle found that 8% of 110 cases had lymph in patients with bulky disease, and patients have varied in node metastasis at postmortem examination. 40,41 41 their response to treatment. Rey et al found no cor- Granulosa cell tumors are the most classic late-recurring relation between estradiol levels and course of the dis- malignancies in gynecology. After the initial diagnosis, ease. Because of the lack of theca cells in the tumor recurrences may not be detected for more than 5 years. stroma, approximately 30% of cases of granulosa cell Thirty-seven years was the longest reported time period tumors do not produce estradiol. Granulosa cell tumors before recurrence. However, 14 of 19 patients with produce estradiol in the presence of theca cells (which recurrent granulosa cell tumors were identified within 3 are present in some ovarian but not in extraovarian years in the series reported by Schwartz and Smith, and tumors); this action is responsible for the production of more than half of the recurrences were identified within androstenedione (estradiol precursor), which is converted 2 years in the series reported by Fox et al. to estradiol through the aromatase action present in gran- Most patients have a palpable abdominal or pelvic ulosa cells. Thus, although estradiol may be helpful in 2,11 mass. Between 80% and 90% of granulosa cell tumors monitoring the course of disease, it is not sensitive are confined to the ovary. Advanced metastatic disease enough to serve as a reliable tumor marker in this disease. with ascites is present in about 10% of cases. Inhibin Radiographic Findings Inhibin is a dimeric ovarian glycoprotein hormone con- Imaging findings in adult granulosa cell tumors vary sisting of an α-subunit and 1 of 2 β-subunits (β giving widely and include solid masses, tumors with varying inhibin-A or β giving inhibin-B). Inhibin is a member of degrees of hemorrhagic or fibrotic changes, multilocular the transforming growth factor-β family of growth factors. cystic lesions, and completely cystic tumors. Using Suppression of the synthesis and secretion of the pituitary echographic and computed tomography (CT) scan find- follicle-stimulating hormone (FSH) is the major biological ings, Ko et al categorized 13 adult granulosa cell property of inhibin and serves as a component of the pitu- tumors into 5 morphologic patterns: multilocular cystic, itary gonadal feedback system. The role of Inhibin in that thick-walled unilocular cystic, thin-walled unilocular system has been established, particularly in the female. cystic, homogenously solid, and heterogeneously solid. A related member of the inhibin superfamily is activin, Kim and Kim simplified the categories into 2 most which consists of 3 possible forms (β β ; β β ; β β ). A A A B B B common forms: multiseptated cystic masses and unlob- Unlike inhibin, activin stimulates the secretion of FSH ulated solid masses with internal cystic portions. and has actions in a variety of other tissues. The granulosa Intratumoral bleeding, infarcts, fibrous degeneration, cell tumor has shown positive staining for inhibin-A and and irregularly arranged tumor cells have yielded het- the activins. Inhibin species may be secreted by granu- 35,37 erogeneously solid tumors. Evidence of hemorrhage losa cell tumors and serve as useful tumor markers, 36,37 has been reported in 60% to 71.4% of cases. On CT although inhibin-B may be more frequently elevated in 45-47 scan, hemorrhage is difficult to identify because of an patients with granulosa cell tumors. It is generally absence of precontrast images. In contrast with epithe- accepted that patients with granulosa cell tumor have ele- lial neoplasms, granulosa cell tumors do not have intra- vated serum concentrations of these substances, which cystic papillary projections, have less propensity for fall following tumor removal and could serve as a marker peritoneal seeding, and are confined to the ovary at the of tumor recurrence. More recently, it was reported that time of diagnosis. Estrogenic effects on the uterus may 82% of postmenopausal women with mucinous carcinoma manifest as uterine enlargement or as endometrial of the ovary had elevated serum immunoreactive inhibin thickening or hemorrhage. concentrations. These levels became undetectable 1 Granulosa Cell Tumor of the Ovary / Koukourakis et al 207 week following tumor removal. The observation that are solid tumors that could be soft or firm and are yellow serum inhibin levels fall following tumor removal was con- or gray, depending on amount of intracellular lipid in the sistent with the possibility that elevated inhibin concen- lesion. The majority of granulosa cell tumors are predomi- trations were the result of secretion of the hormone, either nantly cystic and on external examination may resemble by the tumor tissue or by neighboring normal ovarian tis- mucinous cystadenoma or cystadenocarcinoma. However, sue. Lappohn et al reported elevated inhibin levels and when sectioned, this cyst is generally found to be filled with low FSH levels in 2 patients with residual or recurrent dis- serous fluid or clotted blood. About 15% of patients with ease. The investigators concluded that inhibin was a more cystic granulosa cell tumors are first examined for acute reliable tumor marker of disease activity than estradiol. abdomen associated with hemoperitoneum. Granulosa cell 48,49 These results were confirmed by other investigators. tumors can be well or moderately differentiated. The for- mer pattern may have various presentations, including microfollicular, trabecular, solid tubular, diffuse, and Follicle Regulatory Protein (FRP) water-silk. However, a mixture of these patterns is often 1,10,15,50 FRP is secreted by granulosa cells and is normally pres- found in an individual tumor. Tumors in the moder- ent in the serum of a regularly menstruating woman. The ately differentiated category have a diffuse pattern that has regulation of FRP secretion occurs with differentiation of been designated “sarcomatoid.” Occasionally, granulosa granulosa cells. Elevated levels of FRP have been cell tumors with a diffuse pattern can be mistaken for a detected in some patients with granulosa cell tumors. poorly differentiated carcinoma on intraoperative frozen The clinical importance of this marker is not yet known. section. Nuclear appearance can be very helpful in distin- guishing between granulosa and carcinoma tumors. Undifferentiated carcinomas, adenocarcinomas, and carci- Mullerian Inhibitory Substance (MIS) noids may superficially resemble granulosa cell tumors, Mullerian inhibitory substance is a new potential tumor which can lead to misdiagnosis. The prognosis of these marker for granulosa cell tumors. In females, MIS is pro- tumors is strikingly different. The appearance of the nuclei duced by the granulose cells in the developing follicles of is a characteristic feature. Oval or angular, uniform, pale, the ovary. MIS as a marker for granulosa cell tumors was grooved nuclei are typical of granulosa cell tumors (coffee- evaluated by Rey et al. Serum anti-Mullerian hormone bean appearance). The nuclei of undifferentiated carcino- concentrations were determined in 16 patients with an mas are frequently hyperchromatic, ungrooved, and adult-type granulosa cell tumor; in 75 female patients unequal in size and shape. Nuclear atypia and multiple with ovarian adenocarcinoma, benign ovarian cysts, or mitotic figures are also less common in granulosa cell extraovarian cancers; and in 58 normal premenopausal tumors but more frequently observed in undifferentiated and postmenopausal women. Serum MIS, α-inhibin, and carcinomas. Call-Exner bodies are also of diagnostic impor- estradiol levels were compared in 10 patients with granu- tance but unfortunately are not often sharply defined. losa cell tumor during 6 to 47 months of follow-up. Serum MIS was undetectable in normal postmenopausal women and was less than 5 μg/L in premenopausal Prognostic Factors women. Normal serum levels were found in patients with ovarian cancers or cysts or with extraovarian cancers. For granulosa cell tumors, several factors of prognostic Levels were between 6.8 and 117.9 μg/L in 8 of 9 patients significance have been reported. However, studies aimed with a progressive granulosa cell tumor. In the remaining at defining prognostic factors have been frustrated not patient, MIS, α-inhibin, and estradiol concentrations only by the relative rarity of these tumors but also by the were normal. Serum MIS and α-inhibin levels became very long period for which follow-up observation is elevated at least 11 months before the recurrence was required. The clinical course of granulosa cell tumors is clinically detectable. During clinical remission, serum characterized by indolent growth leading to large tumor MIS, β-inhibin, and estradiol were normal in most cases. size at the time of diagnosis, although in most patients the Although the clinical usefulness of MIS is still under tumor is still confined to the ovary. The stage is unequivo- investigation, these studies indicate that this hormone 2,10-12,14,50 cally the only clinical factor related to recurrence. may be a useful marker of granulosa cell tumor activity. For patients with granulosa cell tumors, the overall 10- year survival rates have been reported as being between 60% and 90%, but the 25-year survival rate is only in the Pathology 2,9,15,50-52 range of 40% to 60%. The 5-year survival rate for The gross appearance of granulosa cell tumors varies patients with stage I ranges from 90% to 95% (>90% sur- 1-3,12,13,15,50 greatly. Depending on the relative amounts of neoplastic vival rate in the majority of the studies). The 10- 10,13,53 cells and fibrothecomatous stroma, granulosa cell tumors year survival rate is between 85% and 95%. Because 208 Integrative Cancer Therapies / Vol. 7, No. 3, September 2008 10,13,16,21,54 Table 1. Survival by Stage chemotherapy. In contrast, 5 of 9 patients with stage IC disease who experienced preoperative tumor rupture or FIGO Stage 5-Year Survival, % 10-Year Survival, % malignant ascites relapsed (P = .001). These patients I 90-100 84-95 were treated with adjuvant chemotherapy, and 3 devel- II 55-75 50-65 oped a recurrence. It has been mentioned that patients III/IV 22-50 17-33 whose tumors had a follicular pattern showed a 10-year survival rate of 82%, whereas those with tumors of diffuse pattern had a 29% survival rate. It has also been 1,2,10,13 reported that both insular and diffuse histologic patterns 60% to 90% of patients present with stage I disease, are associated with a poor prognosis. In contrary, other the definition of pathologic prognostic factors relates investigators have not recognized the histologic pattern as principally to stage I tumors. The 5-year survival rates for 50,51 a prognostic factor in granulosa cell tumors. stage II and stage III/IV have been reported as 55% to 75% An association between the mitotic activity index (MI) and 22% to 50%, respectively, and the 10-year survival of granulosa cell tumor and survival or recurrence has been rates for stage I, stage II, and stage III/IV as 84% to 95%, 10,13,16,21,54 10,12,14,15,55,58,61 reported in several studies. In one of these 50% to 65%, and 17% to 33%, respectively (Table studies, patients whose tumors had a low MI (<3 MI per 10 1). Regarding the prognostic significance of age, there are 1,10,11,16,33 high-power fields [HPFs]) had a 10-year survival of 70% conflicting data. Some studies showed an compared with 37% for those whose tumors had higher improved prognosis in granulosa cell tumor patients less 55 15 53 MI. In a series, tumors that had <4 mitoses/10 HPFs than 40 years old, whereas others reported a more favor- had a more than 2 times risk of recurrence than did those able outcome in patients older than 40 years. with <3 mitoses/10 HPFs. Furthermore, the disease-free Granulosa cell tumors usually have an indolently malig- survival rate at 80 months for patients with tumors con- nant course, and recurrences following initial therapy com- taining <4 mitoses/10 HPFs was 60% compared with 25% monly occur after more than 5 years, not infrequently after for patients whose tumors showed <4 mitoses/10 HPFs more than 10 years, sometimes after 20 years, and very (P < .0005). In another study, MI tended to correlate with occasionally after more than 25 years. Thus, even after a stage and was not a prognostic factor in stage I tumors. disease-free period of 20 years we could not state that the Studies in which MI either was not a prognostic factor or patient is cured without any chance of recurrence. correlated with the disease stage but was not clearly a pre- Nevertheless, most recurrences occur within 5 to 10 years dictor for recurrence have reported similar results. following initial therapy, and the reason for defining patho- Malmstrom et al determined the MI in 42 of 54 cases logic prognostic factors is to identify patients with a very 2,10,11,14,52 with granulosa cell tumors and demonstrated in patients long-term risk of recurrence. It has been men- with stage I that survival was significantly superior in tioned that the size of the tumor is of prognostic signifi- patients whose tumors had <10 mitoses/10 HPFs. cance. Independent of stage, patients with tumors Nuclear atypia has been reported to be one of the most measuring 5 cm or less have a better progression-free sur- 15,54 significant prognostic factors in stage I disease. In one vival rate and 10-year survival rate than those with tumors study, the 25-year survival rate for patients whose tumors greater than 5 cm and those whose tumors measured in 1,2,15 demonstrated slight atypia was 80%, whereas those whose excess of 10 cm. Nevertheless, according to other tumors showed more marked atypia had a 25-year survival investigators the tumor size was not an important prognos- 10,12,14 10 15 rate of 60%. Stenwig et al reported similar results. tic factor for outcome. In another study, tumors that Nuclear atypia has been reported to be the most important recurred early were larger than those that recurred after 10 14,57 pathologic factor predicting tumor recurrence. years, and these, in turn, were larger than those that did Researchers have found significant differences in outcome not recur. In contrast, other investigators showed no sig- between tumors that recurred early (nuclear atypia in nificant difference in mean tumor size between those cases 77%) and those that recurred late (nuclear atypia in 33%). that recurred and those without evidence of recurrence. In contrast, other investigators were unable to show that Even microscopic tumors may recur after some years. 48,61 nuclear atypia was of any prognostic significance. Tumor rupture in granulosa cell tumor is a factor of DNA analyses have indicated that 5% to 20% of granu- prognostic significance. One study showed that patients losa cell tumors are aneuploid. According to some investi- with intact stage I disease had a 25-year survival rate of 58,62-64 gators aneuploidy was not a predictor for recurrence, 86% whereas those with ruptured tumors of the same 10 59 whereas others found that aneuploidy was associated with stage had a survival rate of 60%. Schneider et al 65-68 high risk for recurrence. Similar conflicting results reported no relapses among 12 patients who had acci- have been reported for p53 overexpression; some investi- dental stage interstitial cystitis (1C) disease attributable gators demonstrated that this was an adverse prognostic to intraoperative rupture of the tumor capsule. Among 62,69,70 factor, whereas others showed no association with these were 3 bilateral tumors treated with adjuvant Granulosa Cell Tumor of the Ovary / Koukourakis et al 209 54,57,61,71 performance status, and resectability of the disease, is a outcome. Staining of granulosa cell tumors for useful method of both controlling symptoms and prolong- Ki-67 showed that a high Ki-67 index was correlated with 60-62 ing survival. The extent of the initial surgery appeared to an adverse prognosis in some studies but not in 71,72 1 affect recurrence rates, according to Evans et al. The others. reported recurrence rate was 17% for patients who under- went TAH BSO compared with 24% for those who had less Treatment extensive procedure. However, details relating the surgical procedure to the stage of disease were lacking, so no con- Surgical Management clusions can be drawn concerning the relative values of a USO and other forms of surgery. Ohel et al reported a 5- The surgical procedure for patients with granulosa cell year survival rate of 75% in patients who underwent a TAH tumors has traditionally been similar to that used for BSO and 59% in those women who had only USO. Again, epithelial ovarian cancer. The majority of patients gener- from this study, no conclusions can be made about the rel- ally present with stage I disease (78-91%), whereas the ative value of conservative versus more extensive surgery. In remainder have advanced disease. Metastatic disease at another study, the recurrence rates were 57% in patients presentation involving the liver, lung, or bone is rare. The treated with USO and 26% in those undergoing TAH FIGO staging system that is applied for epithelial ovarian BSO. However, a review of the data showed that 10 of 19 cancer is used as well for granulosa cell tumors. At the patients who underwent a USO and 4 of 9 who had a BSO time of initial operation, surgical staging is mandatory for had by definition either stage II or III and therefore were at determining which patients are likely to have recurrence. obviously higher risk for recurrence with conservative sur- The initial operation should be performed through a verti- gery. In the study by Schneider et al, 33 patients under- cal midline or paramedian incision to allow adequate went adnectomy (salpingo-oophorectomy), which was exposure of the upper abdomen and the pelvis. On entry complete in 18 and incomplete in 15 patients. Sixteen into the peritoneal cavity, ascites or free fluid should be patients had stage IA tumors, 13 patients had stage IC aspirated and sent for cytology and cell block analysis. If tumors, and 1 patient had a stage III tumor. Four patients no fluid is present, approximately 100 mL of normal saline experienced disease recurrence after incomplete resection, should be instilled into the pelvis and each lateral para- whereas all completely resected patients remained disease- colic space. The irrigant should be aspirated and sent for free. cytology and cell block analysis. Because the incidence of Because the majority of patients present with early- bilateral disease is quite low, approximately 2% to 8%, if a stage disease, usually confined to the ovary, a USO should young patient desires to preserve her fertility a unilateral be performed, particularly if the patient wishes to pre- salpingo-oophorectomy (USO) should be performed. A serve her fertility. In those patients whose fertility is not wedge biopsy of the opposite ovary is controversial and an issue or those with more advanced disease, it would should be performed with caution because the incidence seem reasonable to complete a TAH BSO with removal of of bilateral disease is low. The specimen should be sent for all visible disease. frozen section to rule out the presence of microscopic dis- ease. An omentectomy and samples of multiple intraperi- toneal sites should be taken, including the diaphragm Radiation Therapy peritoneum, lateral paracolic peritoneum, small and large bowel serosa, cul-de-sac, and pelvic sidewall peritoneum; Radiation therapy has been used to treat granulosa cell para-aortic and pelvic lymph nodes should be biopsied. tumors either in the adjuvant setting or for recurrent dis- 13,16,74-77 Concomitant uterine disease should be rule out by per- ease. Because of the lack of controlled random- forming an endometrial biopsy. If all biopsy specimens and ized trials, the role of radiation therapy is not washings are disease free, no further therapy is recom- appropriately defined. When given postoperatively, radia- 16,74,75 mended. A total abdominal hysterectomy and bilateral tion therapy is associated with improved survival. salpingo-oophorectomy (TAH BSO) should be performed Pankratz et al treated 48 of 61 cases of granulosa cell for patients whose fertility is not an issue and for post- tumors with adjuvant radiation therapy. The dose to the menopausal women. Debulking surgery should be per- upper abdomen region ranged from 2000 to 3000 cGy, formed to remove as much gross tumor as possible. whereas in the pelvic region the dose was between 3000 Management of recurrence should involve aggressive and 5000 cGy. The investigators concluded that the group debulking surgery followed by combination chemother- of patients receiving radiation therapy had an improved apy. Although liver, lung, and skeletal metastases can survival rate compared with those who did not receive occur, most recurrences are present in the peritoneal cav- radiotherapy. Of 62 patients with granulosa cell tumor 73 13 ity. Given the long natural history of granulosa cell treated by Savage et al, 8 had received radiation therapy tumors, repeated surgical debulking, depending on age, for advanced inoperable disease. As a result of radiation 210 Integrative Cancer Therapies / Vol. 7, No. 3, September 2008 therapy, 3 patients remained disease-free for at least 4 chemotherapy in the adjuvant setting. In patients with years whereas the overall response rate was 50%. stage IV disease and in those with gross residual tumor, Fourteen received treatment for clinically measurable dis- platinum-based chemotherapy is the treatment of choice. ease; 20 received adjuvant radiotherapy after surgery for According to Bjorkholm and Silfversward, patients with minimal residual (<1 cm) or microscopic residual disease. clinical stage I disease and ruptured tumor should be The moving-strip, whole-abdomen radiation technique treated with 3 courses of BEP (bleomycin, etoposide, and with a dose of 28 cGy and a pelvic boost of 28 cGy was cisplatin). Chemotherapy and hormonal therapy have used in 10 of 14 patients. The 4 remaining patients were often been often considered for patients who have treated with pelvic radiation therapy with 45 to 61 cGy. advanced/inoperable (stages II, III, IV) or recurrent dis- Six of 14 patients (43%) had a clinical complete response ease where further surgery or radiotherapy cannot be to radiotherapy, with a median follow-up of 13 years given for medical or technical reason. Before the intro- (range, 5-21 years). Three of 6 who responded to radia- duction of platinum-based chemotherapy, alkylating tion had relapse 4 to 5 years later; 2 of these 3 died of dis- agents and doxorubicin were reported to have modest ease, and 1 was alive with disease at last follow-up. Three activity in granulosa cell tumors, but the responses were 21,74,75,78-80 responders remain alive without evidence of disease 10 to short-lived. The next reports appeared on the 21 years after treatment. The 8 nonresponders had a use of combination chemotherapy consisting of doxoru- median survival of 12.3 months (range, 1-60 months). bicin and bleomycin and dactinomycin, cyclophos- Although radiation therapy is associated with phamide, and 5-fluorouracil. The introduction of improved survival in newly diagnosed, high-risk patients cisplatin has led to different combinations such as cis- 21,33,75,77 81 or patients with recurrent disease, other studies platin and doxorubicin, CAP (cyclophosphamide, dox- 1,10-12 13,39,81-85 suggest no survival benefit from radiotherapy. Its role orubicin, and cisplatin), PVB (cisplatin, 13,86-88 86,87 in the palliative setting may be for symptomatic disease vinblastine, and bleomycin), and BEP (Table 2). that can be encompassed by tolerable radiotherapy and in Ten patients with advanced or recurrent granulosa cell those patients who are suitable for surgical debulking or tumors were treated with CAP. Five complete responses treatment modalities. Evans et al treated 118 patients (CR) (3 pathologically documented) and 1 partial with granulosa cell tumors of whom 42 received preoper- response (PR) were obtained for a total response rate of ative or postoperative external beam radiotherapy or 60%. One pathologically complete responder relapsed radioactive isotope (gold). Radiotherapy appeared to have after 48 months from the onset of chemotherapy but no effect on recurrence rate: 20% of patients receiving responded completely to debulking surgery and radiother- radiotherapy developed recurrence, whereas only 13% of apy and remains well with no evidence of disease after those treated with surgery alone recurred. more than 87 months. Similarly, Gershenson et al There are not sufficient data to support the use of treated 8 patients with metastatic ovarian stromal tumors. radiation therapy in the adjuvant setting. Moreover, when Three patients (38%) had a CR to therapy (2 confirmed radiation therapy is indicated as an adjuvant treatment, it by second-look laparotomy), and 2 patients (25%) is unclear whether whole abdominal irradiation is supe- achieved a PR (1 verified by second-look laparotomy). rior to pelvic irradiation alone. The overall response rate (RR) was 63%. Although some dose-limiting neurotoxicity and fatalities have been reported, data have shown that PVB is active Chemotherapy 83-85 with previously untreated granulosa cell tumors. Granulosa cell tumor is potentially responsive to single- Colombo et al treated 11 patients with recurrent and/or agent and combination chemotherapy. In patients with metastatic granulosa cell tumors. Six patients achieved a stage I disease the prognosis is excellent, with the long- CR and 3 patients achieved a PR, for an overall RR of 74%. term disease-free survival rate said to be about 90%, and Of the complete responders, 5 of 6 remained disease-free 1,10,13,15 87 no further treatment is required after surgery. at a median follow-up of 17.8 months. Zambetti et al However, some stage I patients who have large tumors, treated 7 patients with advanced/recurrent granulosa cell tumors with high MI, or ruptured tumors may have a tumors with PVB. Three CRs (1 pathologically docu- higher risk of relapse and may require postoperative mented) and 1 PR were observed, for an overall RR of 66%. chemotherapy. Because of the small number of patients Two complete responders were alive without evidence of in any reported series, postoperative adjuvant therapy disease 7 and 26 months from the start of treatment; the remains controversial. When postoperative therapy is an remaining patient relapsed at 15 months. In another series, option, platinum-based chemotherapy is often consid- 13 patients with advanced or recurrent granulosa cell ered. Although it may be reasonable to consider adjuvant tumors were treated with PVB. The reported CR was radiotherapy for patients with low-volume residual tumor, 54%, PR 39%, and overall RR 93%. These series estab- the data from the literature do not permit firm conclu- lished PVB as an active regimen in the treatment of sions regarding whether radiation therapy is superior to advanced and/or recurrent granulosa cell tumors. Toxicity, Granulosa Cell Tumor of the Ovary / Koukourakis et al 211 Table 2. Combination Chemotherapy With PVB, BEP Study Regimen Previous Treatment Response Comments Colombo et al PVB 2 chemo 6/11 CR (54%), 3/11 PR (20%) 4 stage III, 2 stage IV, 5 recurrent, 6 NED, 2 alive with disease, 2 toxic deaths, 1 died with disease Pecorelli et al PVB 6 RT, 1 chemo 7/13 CR (54%), 5/13 PR (39%) 5 stage III, 1 stage IV, 9 recurrent Zambetti et al PVB None 3/7 CR (42%) 3 stage II, 4 recurrent, 2 NED, 2 PD, 1 toxic death, 1 death reason unknown Savage et al PVB None 1/5 CR, 3/5 PR Stage II-IV Gershenson et al BEP None 2/5 CR, 3/5 PR 1 stage IIC, 1 stage IIIC, 3 recurrent Savage et al BEP None 1/3 PR Stage II-IV Homesley et al BEP RT 6 CR, 4 PR Stage II-IV, recurrent NOTES: PVB = cisplatin, vinblastine, and bleomycin; BEP = bleomycin, etoposide, and cisplatin; chemo = chemotherapy; CR = complete response; PR = partial response; PD = progressive disease; NED = no evidence of disease; RT = radiotherapy. 91 92 however, was significant and included neutropenic sepsis cell tumor with dramatic response. Brown et al 86,87 and bleomycin-induced pneumonitis. showed the potential activity of paclitaxel: of 222 The BEP regimen in which vinblastine is substituted patients identified, 21 were treated with BEP (10 newly with etoposide is better tolerated. Although BEP is signif- diagnosed patients, 11 patients with recurrent disease) icantly myelotoxic and is associated with a risk of second- and 44 with taxanes (11 newly diagnosed patients, 37 ary acute myelogenous leukemia attributable to the patients with recurrent disease). For newly diagnosed inclusion of etoposide, it is associated with decreased patients treated with BEP compared with those treated peripheral neuropathy. For patients with advanced or with taxanes, the investigators found no significant dif- recurrent disease, the BEP regimen is recommended for ferences in response rate (82% for both regimens), adjuvant postoperative chemotherapy. In case of recur- median progression-free survival (46.1 months for BEP, rence, the optimal treatment should involve aggressive >52 months for taxanes), and median overall survival debulking surgery followed by combination chemotherapy. (97.2 months for BEP, >52 months for taxane). For Gershenson et al treated 9 patients with metastatic ovar- recurrent measurable disease, the response rate (71% vs ian sex cord-stromal tumors of all types with bleomycin 10 37%) and the median progression-free survival (11.2 to 15 mg/d by continuous intravenous (IV) infusion on months vs 7.2 months) were also not statistically signifi- days 1 to 3, etoposide 100 mg/m IV per day on days 1 to cant. It is possible that the combination of carboplatin 3, and cisplatin 100 mg/m IV on day 1. Of the 6 patients plus paclitaxel, which has been established in the treat- with measurable disease, 2 (33%) had a CR (1 surgical and ment of epithelial ovarian cancer, could have a role in 1 clinical) and 3 (50%) had a PR, for an overall RR of 83%. the management of granulosa cell tumors. Toxicity was acceptable; 2 patients had mild bleomycin In case of recurrence, aggressive treatment should pulmonary toxicity. Of the 7 patients with metastatic dis- include surgery followed by either radiation therapy or ease, only 1 (14%) had a durable remission. Median pro- chemotherapy. With these treatment modalities, the 83-87 gression-free survival was 14 months. Median survival disease-free survival is prolonged. For patients previously time was 28 months. The BEP regimen as first-line ther- treated with BEP, the VAC (vincristine, dactinomycin, apy for ovarian stromal malignancies was evaluated in a and cyclophosphamide) regimen is offered. In the treat- phase II trial by the Gynecologic Oncology Group. ment of recurrent granulosa cell tumor, if the patient is Negative findings were observed in 37% (14/38) of the found to have an isolated metastasis that can be com- patients who underwent second-look laparotomy. The 6 pletely resected, then radiation therapy may play a role. complete responses were of long median duration (24.4 One could use a small field of intense radiation therapy, months). Patients with measurable disease were at the which is associated with prolonged survival. Another highest risk of progression and death. Grade 4 myelotoxi- treatment option is chemotherapy with BEP for patients city occurred in 61% of the patients. The investigators with more widespread disease or disease that is subopti- reported that 69% of patients with advanced disease and mally cytoreduced at the time of relapse. 51% of those with recurrent disease remained progression- The treatment of recurrent disease with hormonal free, with a relatively short median follow-up of 3 years. therapy is an option, but experience is limited. Schwartz 94,95 Although the efficacy of platinum-based chemother- et al reported the presence of estrogen and progesterone apy is well established, the role of newer agents such receptors in granulosa cell tumors. Those investigators as gemsitabine and oxaliplatin is not known. Single-agent treated their patient, who presented with advanced recur- paclitaxel was used in a case report of recurrent granulosa rent disease and progesterone receptor–positive tumor, 212 Integrative Cancer Therapies / Vol. 7, No. 3, September 2008 with oral progestin, and her disease was stabilized for 10 because of the rarity of these tumors. In patients with stage months. Her disease was again stabilized on tamoxifen. I disease and those with completely resected tumor, the role Malik and Slevin reported 2 patients treated with high of postoperative chemotherapy or radiation therapy has not doses of medroxyprogesterone acetate who responded with been defined. Besides this, the use of adjuvant therapy has prolonged remissions after documented widespread recur- sometimes been associated with prolonged disease-free sur- rence. Similarly, Briasoulis et al reported a PR with vival and possibly overall survival. For patients with megestrol acetate in an elderly woman with granulosa cell advanced, recurrent, or metastatic disease, chemotherapy tumor and lung metastases lasting for 20 months who had should be considered and BEP is the preferable regimen. a recurrence after carboplatin chemotherapy. Treatment Although overall RR is high, the impact on disease-free or with a gonadotropin-releasing hormone (GnRH-goserelin) overall survival is unknown. Newer cytotoxic agents, such as analog achieved a transient PR in 1 patient who had a paclitaxel, have shown promising activity in patients with recurrence after cytotoxic platinum-based chemother- advanced or recurrent granulosa cell tumors. Finally, 98 99 apy. Similarly, Fishman et al treated 6 patients with because tumors tend to recur years after the initial diagno- refractory or progressive granulosa cell tumors after cyto- sis, prolonged surveillance is essential. toxic chemotherapy with leuprolide acetate. 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Treatment of late recurrent granulosa tive in ovarian granulosa cell malignancy. Gynecol Oncol. cell tumors of the ovary. Surg Gynecol Obstet. 1967;124:65-70. 1989;35:406-408. 94. Schwartz PE, MacLusky N, Sakamoto H, Eisenfeld A. Steroid- 99. Fishman A, Kudelka AP, Tresukosol D, et al. Leuprolide acetate receptor proteins in nonepithelial malignancies of the ovary. for treating refractory or persistent ovarian granulosa cell Gynecol Oncol. 1983;15:305-315. tumor. J Reprod Med. 1996;41:393-396. 95. Schwartz PE, MacLusky N, Naftolin F, Eisenfeld A. Tamoxifen- induced increase in cytosol progestin receptor levels in a case of metastatic endometrial cancer. Gynecol Oncol. 1983;16:41-48. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Integrative Cancer Therapies SAGE

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Integrative Cancer Therapies Volume 7 Number 3 September 2008 204-215 © 2008 Sage Publications 10.1177/1534735408322845 Granulosa Cell Tumor of the Ovary: http://ict.sagepub.com hosted at http://online.sagepub.com Tumor Review Georgios V. Koukourakis, MD, Vasilios E. Kouloulias, MD, Michael J. Koukourakis, MD, Georgios A. Zacharias, MD, Christos Papadimitriou, MD, Kyriaki Mystakidou, MD, Kyriaki Pistevou-Gompaki, MD, John Kouvaris, MD, and Athanasios Gouliamos MD Granulosa cell tumors of the ovary are rare neoplasms that the most important prognostic factor associated with the risk originate from sex-cord stromal cells. The long natural history of relapse. There are no clear conclusions regarding the role of granulosa cell tumors and their tendency to recur years of postoperative chemotherapy or radiotherapy in stage I dis- after the initial diagnosis are the most prominent of their char- ease and in those with completely resected tumor. The use of acteristics. The secretion of estradiol is the reason for signs at adjuvant chemotherapy or radiotherapy has sometimes been presentation such as vaginal bleeding and precocious puberty. associated with prolonged disease-free survival and possibly Abdominal pain and hemoperitoneum, which occasionally can overall survival. Chemotherapy is the treatment of choice for occur, are attributable to tumor rupture. The most common patients with advanced, recurrent, or metastatic disease, and finding in pelvic examination is a tumor mass, which is subse- BEP (bleomycin, etoposide, and cisplatin) is the preferred reg- quently confirmed with imaging techniques. Surgery is the imen. Although the overall rate of response to treatment is mainstay of initial management for histological diagnosis, high, the impact of treatment on disease-free or overall sur- appropriate staging, and debulking. A more conservative uni- vival is unknown. Prolonged surveillance is mandatory lateral salpingo-oophorectomy is indicated in patients with because tumors tend to recur years after the initial diagnosis. stage I disease and patients of reproductive age. Total abdom- inal hysterectomy with bilateral salpingo-oophorectomy is the appropriate surgical treatment for postmenopausal women Keywords: granulosa cell tumor; etiology; prognosis; and those with more advanced disease. The stage of disease is tumor markers; treatment varian granulosa cell tumors are rare malignan- can also be found in children, although this is rare. cies that originate from the sex-cord stromal cells Regarding the juvenile granulosa cell tumor, the mean Oof the ovary and represent 2% to 5% of all ovarian age at diagnosis has been reported as 8 to 9 years and 13 1-4 7 cancers. According to their clinical presentation and to 17 years in series of girls younger than 16 years and in histologic characteristics, they are divided into 2 sub- series that included adults, respectively. Because all groups: juvenile granulosa cell tumors and adult granu- granulosa cell tumors are hormonally active, producing losa cell tumors. The tumors most commonly affect estradiol, 80% to 90% of patients less than 8 years of age adults, but 5% present in the prepubertal period. The have signs of isosexual precocious pseudopuberty. juvenile form of tumor is diagnosed in patients less than Precocious breast development, increased pubic hair, 30, 20, and 10 years of age in 90%, 80%, and 50% of vaginal bleeding, advanced growth, and bone age may be cases, respectively. However, adult granulosa cell tumor observed on examination. A hormonally active juvenile granulosa cell tumor may cause menstrual irregularities and rarely virilization in older patients. Abdominal From the University of Ahepa Medical School, 2nd Department of swelling, pain, and a palpable mass in the lower abdomen Radiology, Radiation Therapy Unit, Attikon University Hospital, Greece are important presenting symptoms in all patients. In 10% (GKV, VEK, GAZ, KM, JK, AG); University of Thrace, Radiation Therapy Unit, Alexandroupolis, Greece (MJK); University of Athens, of cases, a juvenile granulosa cell tumor may rupture and Medical School, Alexandras Hospital, Athens, Greece (CP); and as the result acute abdominal pain may be the first pre- University of Thessaloniki, Ahepa Hospital, Thessaloniki, Greece (KPG). senting symptom. Ascites is present in 10% of patients. Address correspondence to: Georgios V. Koukourakis, Rimini 1, Haidari Bilateral granulosa cell tumors account for 3% of patients 124 64, University Hospital of Athens, Attiko; e-mail: gkoyokoyrakis @yahoo.gr. and most commonly are limited to the ovaries at the time 204 Granulosa Cell Tumor of the Ovary / Koukourakis et al 205 of diagnosis, stage I according to FIGO classification. Clinical Presentation Juvenile granulosa cell tumors are usually large, averaging 12 cm in diameter, and are either solid or partly or Abnormal uterine bleeding and pain attributable to the entirely cystic. In the majority of cases the cystic fluid is large size of granulosa cell tumors are the most common serous. Regarding tumor size, there are no differences presenting symptoms. In the reproductive age group, between premenarchal and postmenarchal patients. patients may have menstrual irregularities, menorrhagia, According to the stage at diagnosis, the majority of intermenstrual bleeding, or amenorrhea, and in post- women with adult granulosa cell tumor are also diag- menopausal women, abnormal uterine bleeding may be 2,10 2,9,12,15,20 nosed as having stage I disease (78-91%). Slow growth the presenting symptom. In older patients, the with a tendency for late recurrence characterizes the nat- symptoms of granulosa cell tumors may mimic those of 1,10 ural history of this tumor. In this review we analyze the common epithelial ovarian cancer, such as vague abdom- clinical features of adult granulosa cell tumors and men- inal discomfort, increasing abdominal girth, and weight tion the treatment modalities of patients with newly diag- loss. Schwartz and Smith treated 51 patients with gran- nosed and recurrent disease. ulosa cell tumors and noted that the majority of patients were in the fifth and sixth decades of life. The most com- mon presenting symptoms were postmenopausal bleed- Epidemiology ing, the presence of a mass, and pelvic or abdominal mass. Similar presenting symptoms were reported by Fox 2 11 Although granulosa cell tumors can occur at any age, they et al and Ohel et al. In approximately 10% of patients, present most often in women of reproductive age and the tumor is either discovered at the time of surgery for they occur as well as in women who are post- abnormal bleeding or found only after histologic exami- 1-3,10-15 22 menopausal. During a 15-year period in Israel, 172 nation of the specimen. Endometrial hyperplasia is also new cases of this tumor were diagnosed, for an incidence frequently present attributable to the endogenous estro- of 0.9 cases per 100 000 women per year. The incidence gen effect. Approximately 25% to 50% of granulosa cell of tumor in women of European and American back- tumors are associated with endometrial hyperplasia, ground was almost twice that of women of African and whereas 5% to 13% are associated with an endometrial 1,2,12,15,23 Asian origin, 0.98 versus 0.522/100 000/y. The reported carcinoma. Occasionally, endometrial carcinoma incidence of granulosa cell tumor has varied from 0.58 to may be diagnosed incidentally at the time of surgical stag- 10,11,15 1.6/100 000/y and was reported as 0.62/100 000/y ing performed for granulosa cell tumors. Endometrial car- in Finland. In United States the calculated incidence cinoma related to granulosa cell tumors is usually well 3,11 for white females is 0.99/100 000/y. The median age at differentiated, diagnosed at an early stage, and associated 1,10,22 presentation in the more common adult form, which gen- with a good prognosis. Granulosa cell tumors may erally presents in perimenopausal or postmenopausal also be associated with breast enlargement and tender- 2,10,11 16 women, is 50 years with a range of 40 to 70 years. ness attributable to the endogenous estrogen effect. Granulosa cell tumor has been reported to be associ- The juvenile variant of granulosa cell tumor usually ated with endometrial hyperplasia attributable to sti- occurs before the normal age of puberty and is associated mulation of the endometrium by estrogen production. with histologic features that distinguish it from the adult Approximately 13% of these patients develop well- granulosa cell tumor. Isosexual precocity is often present 1,2,17 2,9,24 differentiated endometrial adenocarcinoma. In very in patients with juvenile granulosa cell tumors. An large unilocular or multilocular thin-walled cystic masses, association has been found with Potter’s syndrome, mul- 2,18 26 virilism may be observed. Despite the association with tiple congenital abnormalities, Ollier’s disease (multiple 27,28 excessive hormone production, patients with granulosa enchondromatosis), and Maffucci’s syndrome (Ollier’s cell tumors have not demonstrated an increased inci- disease with hemangioma). Approximately 90% of granu- 11 19 dence of infertility. Willemsen et al treated 12 granu- losa cell tumors found in prepubertal patients, and many losa cell tumors with clomiphen, gonadotrophins, or both tumors found in women younger than 30, are juvenile for ovarian hyperstimulation. These investigators postu- granulosa cell tumors. Rare cases have also been reported lated 3 explanations for the possible relation of ovarian of androgen-secreting granulosa cell tumors causing the 30,31 stimulation and granulosa cell tumor. First, the granulosa development of virilizing features or hirsutism. cell tumor is present in the ovary, waiting for a hormonal Persistent, localized abdominal or pelvic pain, some- trigger; second, increased follicle-stimulating hormone times associated with abdominal distension from a large concentrations are oncogenic to granulosa cell tumor; ovarian mass, may be described by patient. Occasionally, and third, the onset of the granulosa cell tumor during ovarian torsion can cause more acute onset of pelvic pain. ovarian stimulation is coincidental. It has been reported Although torsion can produce acute abdominal signs and that mutations of BRCA1 or BRCA2 have not been asso- symptoms, a huge hemorrhagic granulosa cell tumor may ciated with a higher risk of developing granulosa cell be relatively asymptomatic. Rupture of adult granulosa 3 15 tumors. cell tumors was reported by Stenwig et al to occur in 10% 206 Integrative Cancer Therapies / Vol. 7, No. 3, September 2008 of patients. In the series reported by Schwartz and Tumor Markers Smith, 35% of the tumors ruptured (13/37). Five of these ruptured within 24 hours of surgery and 8 ruptured at the Estradiol time of surgery. Premenopausal women who present with One of the substances secreted by granulosa cell tumors ruptured granulosa cell tumors experience acute onset of that is responsible for the clinical signs of hyperestro- abdominal pain, abdominal distension, and hypotension genism is estradiol. This secretion may serve as a possible caused by the development of hemoperitoneum. tumor marker for granulosa cell tumors. In patients with Spread of granulosa cell tumors is local, by direct known granulosa cell tumors, elevated estradiol levels extension and intraperitoneal seeding. The tumors may have been found. However, estradiol levels are not a reli- also spread hematogenously, and patients can develop able marker of disease activity, because fluctuating metastases in the lungs, liver, and brain years after initial (instead of very high) levels of estradiol have been found diagnosis. Diddle found that 8% of 110 cases had lymph in patients with bulky disease, and patients have varied in node metastasis at postmortem examination. 40,41 41 their response to treatment. Rey et al found no cor- Granulosa cell tumors are the most classic late-recurring relation between estradiol levels and course of the dis- malignancies in gynecology. After the initial diagnosis, ease. Because of the lack of theca cells in the tumor recurrences may not be detected for more than 5 years. stroma, approximately 30% of cases of granulosa cell Thirty-seven years was the longest reported time period tumors do not produce estradiol. Granulosa cell tumors before recurrence. However, 14 of 19 patients with produce estradiol in the presence of theca cells (which recurrent granulosa cell tumors were identified within 3 are present in some ovarian but not in extraovarian years in the series reported by Schwartz and Smith, and tumors); this action is responsible for the production of more than half of the recurrences were identified within androstenedione (estradiol precursor), which is converted 2 years in the series reported by Fox et al. to estradiol through the aromatase action present in gran- Most patients have a palpable abdominal or pelvic ulosa cells. Thus, although estradiol may be helpful in 2,11 mass. Between 80% and 90% of granulosa cell tumors monitoring the course of disease, it is not sensitive are confined to the ovary. Advanced metastatic disease enough to serve as a reliable tumor marker in this disease. with ascites is present in about 10% of cases. Inhibin Radiographic Findings Inhibin is a dimeric ovarian glycoprotein hormone con- Imaging findings in adult granulosa cell tumors vary sisting of an α-subunit and 1 of 2 β-subunits (β giving widely and include solid masses, tumors with varying inhibin-A or β giving inhibin-B). Inhibin is a member of degrees of hemorrhagic or fibrotic changes, multilocular the transforming growth factor-β family of growth factors. cystic lesions, and completely cystic tumors. Using Suppression of the synthesis and secretion of the pituitary echographic and computed tomography (CT) scan find- follicle-stimulating hormone (FSH) is the major biological ings, Ko et al categorized 13 adult granulosa cell property of inhibin and serves as a component of the pitu- tumors into 5 morphologic patterns: multilocular cystic, itary gonadal feedback system. The role of Inhibin in that thick-walled unilocular cystic, thin-walled unilocular system has been established, particularly in the female. cystic, homogenously solid, and heterogeneously solid. A related member of the inhibin superfamily is activin, Kim and Kim simplified the categories into 2 most which consists of 3 possible forms (β β ; β β ; β β ). A A A B B B common forms: multiseptated cystic masses and unlob- Unlike inhibin, activin stimulates the secretion of FSH ulated solid masses with internal cystic portions. and has actions in a variety of other tissues. The granulosa Intratumoral bleeding, infarcts, fibrous degeneration, cell tumor has shown positive staining for inhibin-A and and irregularly arranged tumor cells have yielded het- the activins. Inhibin species may be secreted by granu- 35,37 erogeneously solid tumors. Evidence of hemorrhage losa cell tumors and serve as useful tumor markers, 36,37 has been reported in 60% to 71.4% of cases. On CT although inhibin-B may be more frequently elevated in 45-47 scan, hemorrhage is difficult to identify because of an patients with granulosa cell tumors. It is generally absence of precontrast images. In contrast with epithe- accepted that patients with granulosa cell tumor have ele- lial neoplasms, granulosa cell tumors do not have intra- vated serum concentrations of these substances, which cystic papillary projections, have less propensity for fall following tumor removal and could serve as a marker peritoneal seeding, and are confined to the ovary at the of tumor recurrence. More recently, it was reported that time of diagnosis. Estrogenic effects on the uterus may 82% of postmenopausal women with mucinous carcinoma manifest as uterine enlargement or as endometrial of the ovary had elevated serum immunoreactive inhibin thickening or hemorrhage. concentrations. These levels became undetectable 1 Granulosa Cell Tumor of the Ovary / Koukourakis et al 207 week following tumor removal. The observation that are solid tumors that could be soft or firm and are yellow serum inhibin levels fall following tumor removal was con- or gray, depending on amount of intracellular lipid in the sistent with the possibility that elevated inhibin concen- lesion. The majority of granulosa cell tumors are predomi- trations were the result of secretion of the hormone, either nantly cystic and on external examination may resemble by the tumor tissue or by neighboring normal ovarian tis- mucinous cystadenoma or cystadenocarcinoma. However, sue. Lappohn et al reported elevated inhibin levels and when sectioned, this cyst is generally found to be filled with low FSH levels in 2 patients with residual or recurrent dis- serous fluid or clotted blood. About 15% of patients with ease. The investigators concluded that inhibin was a more cystic granulosa cell tumors are first examined for acute reliable tumor marker of disease activity than estradiol. abdomen associated with hemoperitoneum. Granulosa cell 48,49 These results were confirmed by other investigators. tumors can be well or moderately differentiated. The for- mer pattern may have various presentations, including microfollicular, trabecular, solid tubular, diffuse, and Follicle Regulatory Protein (FRP) water-silk. However, a mixture of these patterns is often 1,10,15,50 FRP is secreted by granulosa cells and is normally pres- found in an individual tumor. Tumors in the moder- ent in the serum of a regularly menstruating woman. The ately differentiated category have a diffuse pattern that has regulation of FRP secretion occurs with differentiation of been designated “sarcomatoid.” Occasionally, granulosa granulosa cells. Elevated levels of FRP have been cell tumors with a diffuse pattern can be mistaken for a detected in some patients with granulosa cell tumors. poorly differentiated carcinoma on intraoperative frozen The clinical importance of this marker is not yet known. section. Nuclear appearance can be very helpful in distin- guishing between granulosa and carcinoma tumors. Undifferentiated carcinomas, adenocarcinomas, and carci- Mullerian Inhibitory Substance (MIS) noids may superficially resemble granulosa cell tumors, Mullerian inhibitory substance is a new potential tumor which can lead to misdiagnosis. The prognosis of these marker for granulosa cell tumors. In females, MIS is pro- tumors is strikingly different. The appearance of the nuclei duced by the granulose cells in the developing follicles of is a characteristic feature. Oval or angular, uniform, pale, the ovary. MIS as a marker for granulosa cell tumors was grooved nuclei are typical of granulosa cell tumors (coffee- evaluated by Rey et al. Serum anti-Mullerian hormone bean appearance). The nuclei of undifferentiated carcino- concentrations were determined in 16 patients with an mas are frequently hyperchromatic, ungrooved, and adult-type granulosa cell tumor; in 75 female patients unequal in size and shape. Nuclear atypia and multiple with ovarian adenocarcinoma, benign ovarian cysts, or mitotic figures are also less common in granulosa cell extraovarian cancers; and in 58 normal premenopausal tumors but more frequently observed in undifferentiated and postmenopausal women. Serum MIS, α-inhibin, and carcinomas. Call-Exner bodies are also of diagnostic impor- estradiol levels were compared in 10 patients with granu- tance but unfortunately are not often sharply defined. losa cell tumor during 6 to 47 months of follow-up. Serum MIS was undetectable in normal postmenopausal women and was less than 5 μg/L in premenopausal Prognostic Factors women. Normal serum levels were found in patients with ovarian cancers or cysts or with extraovarian cancers. For granulosa cell tumors, several factors of prognostic Levels were between 6.8 and 117.9 μg/L in 8 of 9 patients significance have been reported. However, studies aimed with a progressive granulosa cell tumor. In the remaining at defining prognostic factors have been frustrated not patient, MIS, α-inhibin, and estradiol concentrations only by the relative rarity of these tumors but also by the were normal. Serum MIS and α-inhibin levels became very long period for which follow-up observation is elevated at least 11 months before the recurrence was required. The clinical course of granulosa cell tumors is clinically detectable. During clinical remission, serum characterized by indolent growth leading to large tumor MIS, β-inhibin, and estradiol were normal in most cases. size at the time of diagnosis, although in most patients the Although the clinical usefulness of MIS is still under tumor is still confined to the ovary. The stage is unequivo- investigation, these studies indicate that this hormone 2,10-12,14,50 cally the only clinical factor related to recurrence. may be a useful marker of granulosa cell tumor activity. For patients with granulosa cell tumors, the overall 10- year survival rates have been reported as being between 60% and 90%, but the 25-year survival rate is only in the Pathology 2,9,15,50-52 range of 40% to 60%. The 5-year survival rate for The gross appearance of granulosa cell tumors varies patients with stage I ranges from 90% to 95% (>90% sur- 1-3,12,13,15,50 greatly. Depending on the relative amounts of neoplastic vival rate in the majority of the studies). The 10- 10,13,53 cells and fibrothecomatous stroma, granulosa cell tumors year survival rate is between 85% and 95%. Because 208 Integrative Cancer Therapies / Vol. 7, No. 3, September 2008 10,13,16,21,54 Table 1. Survival by Stage chemotherapy. In contrast, 5 of 9 patients with stage IC disease who experienced preoperative tumor rupture or FIGO Stage 5-Year Survival, % 10-Year Survival, % malignant ascites relapsed (P = .001). These patients I 90-100 84-95 were treated with adjuvant chemotherapy, and 3 devel- II 55-75 50-65 oped a recurrence. It has been mentioned that patients III/IV 22-50 17-33 whose tumors had a follicular pattern showed a 10-year survival rate of 82%, whereas those with tumors of diffuse pattern had a 29% survival rate. It has also been 1,2,10,13 reported that both insular and diffuse histologic patterns 60% to 90% of patients present with stage I disease, are associated with a poor prognosis. In contrary, other the definition of pathologic prognostic factors relates investigators have not recognized the histologic pattern as principally to stage I tumors. The 5-year survival rates for 50,51 a prognostic factor in granulosa cell tumors. stage II and stage III/IV have been reported as 55% to 75% An association between the mitotic activity index (MI) and 22% to 50%, respectively, and the 10-year survival of granulosa cell tumor and survival or recurrence has been rates for stage I, stage II, and stage III/IV as 84% to 95%, 10,13,16,21,54 10,12,14,15,55,58,61 reported in several studies. In one of these 50% to 65%, and 17% to 33%, respectively (Table studies, patients whose tumors had a low MI (<3 MI per 10 1). Regarding the prognostic significance of age, there are 1,10,11,16,33 high-power fields [HPFs]) had a 10-year survival of 70% conflicting data. Some studies showed an compared with 37% for those whose tumors had higher improved prognosis in granulosa cell tumor patients less 55 15 53 MI. In a series, tumors that had <4 mitoses/10 HPFs than 40 years old, whereas others reported a more favor- had a more than 2 times risk of recurrence than did those able outcome in patients older than 40 years. with <3 mitoses/10 HPFs. Furthermore, the disease-free Granulosa cell tumors usually have an indolently malig- survival rate at 80 months for patients with tumors con- nant course, and recurrences following initial therapy com- taining <4 mitoses/10 HPFs was 60% compared with 25% monly occur after more than 5 years, not infrequently after for patients whose tumors showed <4 mitoses/10 HPFs more than 10 years, sometimes after 20 years, and very (P < .0005). In another study, MI tended to correlate with occasionally after more than 25 years. Thus, even after a stage and was not a prognostic factor in stage I tumors. disease-free period of 20 years we could not state that the Studies in which MI either was not a prognostic factor or patient is cured without any chance of recurrence. correlated with the disease stage but was not clearly a pre- Nevertheless, most recurrences occur within 5 to 10 years dictor for recurrence have reported similar results. following initial therapy, and the reason for defining patho- Malmstrom et al determined the MI in 42 of 54 cases logic prognostic factors is to identify patients with a very 2,10,11,14,52 with granulosa cell tumors and demonstrated in patients long-term risk of recurrence. It has been men- with stage I that survival was significantly superior in tioned that the size of the tumor is of prognostic signifi- patients whose tumors had <10 mitoses/10 HPFs. cance. Independent of stage, patients with tumors Nuclear atypia has been reported to be one of the most measuring 5 cm or less have a better progression-free sur- 15,54 significant prognostic factors in stage I disease. In one vival rate and 10-year survival rate than those with tumors study, the 25-year survival rate for patients whose tumors greater than 5 cm and those whose tumors measured in 1,2,15 demonstrated slight atypia was 80%, whereas those whose excess of 10 cm. Nevertheless, according to other tumors showed more marked atypia had a 25-year survival investigators the tumor size was not an important prognos- 10,12,14 10 15 rate of 60%. Stenwig et al reported similar results. tic factor for outcome. In another study, tumors that Nuclear atypia has been reported to be the most important recurred early were larger than those that recurred after 10 14,57 pathologic factor predicting tumor recurrence. years, and these, in turn, were larger than those that did Researchers have found significant differences in outcome not recur. In contrast, other investigators showed no sig- between tumors that recurred early (nuclear atypia in nificant difference in mean tumor size between those cases 77%) and those that recurred late (nuclear atypia in 33%). that recurred and those without evidence of recurrence. In contrast, other investigators were unable to show that Even microscopic tumors may recur after some years. 48,61 nuclear atypia was of any prognostic significance. Tumor rupture in granulosa cell tumor is a factor of DNA analyses have indicated that 5% to 20% of granu- prognostic significance. One study showed that patients losa cell tumors are aneuploid. According to some investi- with intact stage I disease had a 25-year survival rate of 58,62-64 gators aneuploidy was not a predictor for recurrence, 86% whereas those with ruptured tumors of the same 10 59 whereas others found that aneuploidy was associated with stage had a survival rate of 60%. Schneider et al 65-68 high risk for recurrence. Similar conflicting results reported no relapses among 12 patients who had acci- have been reported for p53 overexpression; some investi- dental stage interstitial cystitis (1C) disease attributable gators demonstrated that this was an adverse prognostic to intraoperative rupture of the tumor capsule. Among 62,69,70 factor, whereas others showed no association with these were 3 bilateral tumors treated with adjuvant Granulosa Cell Tumor of the Ovary / Koukourakis et al 209 54,57,61,71 performance status, and resectability of the disease, is a outcome. Staining of granulosa cell tumors for useful method of both controlling symptoms and prolong- Ki-67 showed that a high Ki-67 index was correlated with 60-62 ing survival. The extent of the initial surgery appeared to an adverse prognosis in some studies but not in 71,72 1 affect recurrence rates, according to Evans et al. The others. reported recurrence rate was 17% for patients who under- went TAH BSO compared with 24% for those who had less Treatment extensive procedure. However, details relating the surgical procedure to the stage of disease were lacking, so no con- Surgical Management clusions can be drawn concerning the relative values of a USO and other forms of surgery. Ohel et al reported a 5- The surgical procedure for patients with granulosa cell year survival rate of 75% in patients who underwent a TAH tumors has traditionally been similar to that used for BSO and 59% in those women who had only USO. Again, epithelial ovarian cancer. The majority of patients gener- from this study, no conclusions can be made about the rel- ally present with stage I disease (78-91%), whereas the ative value of conservative versus more extensive surgery. In remainder have advanced disease. Metastatic disease at another study, the recurrence rates were 57% in patients presentation involving the liver, lung, or bone is rare. The treated with USO and 26% in those undergoing TAH FIGO staging system that is applied for epithelial ovarian BSO. However, a review of the data showed that 10 of 19 cancer is used as well for granulosa cell tumors. At the patients who underwent a USO and 4 of 9 who had a BSO time of initial operation, surgical staging is mandatory for had by definition either stage II or III and therefore were at determining which patients are likely to have recurrence. obviously higher risk for recurrence with conservative sur- The initial operation should be performed through a verti- gery. In the study by Schneider et al, 33 patients under- cal midline or paramedian incision to allow adequate went adnectomy (salpingo-oophorectomy), which was exposure of the upper abdomen and the pelvis. On entry complete in 18 and incomplete in 15 patients. Sixteen into the peritoneal cavity, ascites or free fluid should be patients had stage IA tumors, 13 patients had stage IC aspirated and sent for cytology and cell block analysis. If tumors, and 1 patient had a stage III tumor. Four patients no fluid is present, approximately 100 mL of normal saline experienced disease recurrence after incomplete resection, should be instilled into the pelvis and each lateral para- whereas all completely resected patients remained disease- colic space. The irrigant should be aspirated and sent for free. cytology and cell block analysis. Because the incidence of Because the majority of patients present with early- bilateral disease is quite low, approximately 2% to 8%, if a stage disease, usually confined to the ovary, a USO should young patient desires to preserve her fertility a unilateral be performed, particularly if the patient wishes to pre- salpingo-oophorectomy (USO) should be performed. A serve her fertility. In those patients whose fertility is not wedge biopsy of the opposite ovary is controversial and an issue or those with more advanced disease, it would should be performed with caution because the incidence seem reasonable to complete a TAH BSO with removal of of bilateral disease is low. The specimen should be sent for all visible disease. frozen section to rule out the presence of microscopic dis- ease. An omentectomy and samples of multiple intraperi- toneal sites should be taken, including the diaphragm Radiation Therapy peritoneum, lateral paracolic peritoneum, small and large bowel serosa, cul-de-sac, and pelvic sidewall peritoneum; Radiation therapy has been used to treat granulosa cell para-aortic and pelvic lymph nodes should be biopsied. tumors either in the adjuvant setting or for recurrent dis- 13,16,74-77 Concomitant uterine disease should be rule out by per- ease. Because of the lack of controlled random- forming an endometrial biopsy. If all biopsy specimens and ized trials, the role of radiation therapy is not washings are disease free, no further therapy is recom- appropriately defined. When given postoperatively, radia- 16,74,75 mended. A total abdominal hysterectomy and bilateral tion therapy is associated with improved survival. salpingo-oophorectomy (TAH BSO) should be performed Pankratz et al treated 48 of 61 cases of granulosa cell for patients whose fertility is not an issue and for post- tumors with adjuvant radiation therapy. The dose to the menopausal women. Debulking surgery should be per- upper abdomen region ranged from 2000 to 3000 cGy, formed to remove as much gross tumor as possible. whereas in the pelvic region the dose was between 3000 Management of recurrence should involve aggressive and 5000 cGy. The investigators concluded that the group debulking surgery followed by combination chemother- of patients receiving radiation therapy had an improved apy. Although liver, lung, and skeletal metastases can survival rate compared with those who did not receive occur, most recurrences are present in the peritoneal cav- radiotherapy. Of 62 patients with granulosa cell tumor 73 13 ity. Given the long natural history of granulosa cell treated by Savage et al, 8 had received radiation therapy tumors, repeated surgical debulking, depending on age, for advanced inoperable disease. As a result of radiation 210 Integrative Cancer Therapies / Vol. 7, No. 3, September 2008 therapy, 3 patients remained disease-free for at least 4 chemotherapy in the adjuvant setting. In patients with years whereas the overall response rate was 50%. stage IV disease and in those with gross residual tumor, Fourteen received treatment for clinically measurable dis- platinum-based chemotherapy is the treatment of choice. ease; 20 received adjuvant radiotherapy after surgery for According to Bjorkholm and Silfversward, patients with minimal residual (<1 cm) or microscopic residual disease. clinical stage I disease and ruptured tumor should be The moving-strip, whole-abdomen radiation technique treated with 3 courses of BEP (bleomycin, etoposide, and with a dose of 28 cGy and a pelvic boost of 28 cGy was cisplatin). Chemotherapy and hormonal therapy have used in 10 of 14 patients. The 4 remaining patients were often been often considered for patients who have treated with pelvic radiation therapy with 45 to 61 cGy. advanced/inoperable (stages II, III, IV) or recurrent dis- Six of 14 patients (43%) had a clinical complete response ease where further surgery or radiotherapy cannot be to radiotherapy, with a median follow-up of 13 years given for medical or technical reason. Before the intro- (range, 5-21 years). Three of 6 who responded to radia- duction of platinum-based chemotherapy, alkylating tion had relapse 4 to 5 years later; 2 of these 3 died of dis- agents and doxorubicin were reported to have modest ease, and 1 was alive with disease at last follow-up. Three activity in granulosa cell tumors, but the responses were 21,74,75,78-80 responders remain alive without evidence of disease 10 to short-lived. The next reports appeared on the 21 years after treatment. The 8 nonresponders had a use of combination chemotherapy consisting of doxoru- median survival of 12.3 months (range, 1-60 months). bicin and bleomycin and dactinomycin, cyclophos- Although radiation therapy is associated with phamide, and 5-fluorouracil. The introduction of improved survival in newly diagnosed, high-risk patients cisplatin has led to different combinations such as cis- 21,33,75,77 81 or patients with recurrent disease, other studies platin and doxorubicin, CAP (cyclophosphamide, dox- 1,10-12 13,39,81-85 suggest no survival benefit from radiotherapy. Its role orubicin, and cisplatin), PVB (cisplatin, 13,86-88 86,87 in the palliative setting may be for symptomatic disease vinblastine, and bleomycin), and BEP (Table 2). that can be encompassed by tolerable radiotherapy and in Ten patients with advanced or recurrent granulosa cell those patients who are suitable for surgical debulking or tumors were treated with CAP. Five complete responses treatment modalities. Evans et al treated 118 patients (CR) (3 pathologically documented) and 1 partial with granulosa cell tumors of whom 42 received preoper- response (PR) were obtained for a total response rate of ative or postoperative external beam radiotherapy or 60%. One pathologically complete responder relapsed radioactive isotope (gold). Radiotherapy appeared to have after 48 months from the onset of chemotherapy but no effect on recurrence rate: 20% of patients receiving responded completely to debulking surgery and radiother- radiotherapy developed recurrence, whereas only 13% of apy and remains well with no evidence of disease after those treated with surgery alone recurred. more than 87 months. Similarly, Gershenson et al There are not sufficient data to support the use of treated 8 patients with metastatic ovarian stromal tumors. radiation therapy in the adjuvant setting. Moreover, when Three patients (38%) had a CR to therapy (2 confirmed radiation therapy is indicated as an adjuvant treatment, it by second-look laparotomy), and 2 patients (25%) is unclear whether whole abdominal irradiation is supe- achieved a PR (1 verified by second-look laparotomy). rior to pelvic irradiation alone. The overall response rate (RR) was 63%. Although some dose-limiting neurotoxicity and fatalities have been reported, data have shown that PVB is active Chemotherapy 83-85 with previously untreated granulosa cell tumors. Granulosa cell tumor is potentially responsive to single- Colombo et al treated 11 patients with recurrent and/or agent and combination chemotherapy. In patients with metastatic granulosa cell tumors. Six patients achieved a stage I disease the prognosis is excellent, with the long- CR and 3 patients achieved a PR, for an overall RR of 74%. term disease-free survival rate said to be about 90%, and Of the complete responders, 5 of 6 remained disease-free 1,10,13,15 87 no further treatment is required after surgery. at a median follow-up of 17.8 months. Zambetti et al However, some stage I patients who have large tumors, treated 7 patients with advanced/recurrent granulosa cell tumors with high MI, or ruptured tumors may have a tumors with PVB. Three CRs (1 pathologically docu- higher risk of relapse and may require postoperative mented) and 1 PR were observed, for an overall RR of 66%. chemotherapy. Because of the small number of patients Two complete responders were alive without evidence of in any reported series, postoperative adjuvant therapy disease 7 and 26 months from the start of treatment; the remains controversial. When postoperative therapy is an remaining patient relapsed at 15 months. In another series, option, platinum-based chemotherapy is often consid- 13 patients with advanced or recurrent granulosa cell ered. Although it may be reasonable to consider adjuvant tumors were treated with PVB. The reported CR was radiotherapy for patients with low-volume residual tumor, 54%, PR 39%, and overall RR 93%. These series estab- the data from the literature do not permit firm conclu- lished PVB as an active regimen in the treatment of sions regarding whether radiation therapy is superior to advanced and/or recurrent granulosa cell tumors. Toxicity, Granulosa Cell Tumor of the Ovary / Koukourakis et al 211 Table 2. Combination Chemotherapy With PVB, BEP Study Regimen Previous Treatment Response Comments Colombo et al PVB 2 chemo 6/11 CR (54%), 3/11 PR (20%) 4 stage III, 2 stage IV, 5 recurrent, 6 NED, 2 alive with disease, 2 toxic deaths, 1 died with disease Pecorelli et al PVB 6 RT, 1 chemo 7/13 CR (54%), 5/13 PR (39%) 5 stage III, 1 stage IV, 9 recurrent Zambetti et al PVB None 3/7 CR (42%) 3 stage II, 4 recurrent, 2 NED, 2 PD, 1 toxic death, 1 death reason unknown Savage et al PVB None 1/5 CR, 3/5 PR Stage II-IV Gershenson et al BEP None 2/5 CR, 3/5 PR 1 stage IIC, 1 stage IIIC, 3 recurrent Savage et al BEP None 1/3 PR Stage II-IV Homesley et al BEP RT 6 CR, 4 PR Stage II-IV, recurrent NOTES: PVB = cisplatin, vinblastine, and bleomycin; BEP = bleomycin, etoposide, and cisplatin; chemo = chemotherapy; CR = complete response; PR = partial response; PD = progressive disease; NED = no evidence of disease; RT = radiotherapy. 91 92 however, was significant and included neutropenic sepsis cell tumor with dramatic response. Brown et al 86,87 and bleomycin-induced pneumonitis. showed the potential activity of paclitaxel: of 222 The BEP regimen in which vinblastine is substituted patients identified, 21 were treated with BEP (10 newly with etoposide is better tolerated. Although BEP is signif- diagnosed patients, 11 patients with recurrent disease) icantly myelotoxic and is associated with a risk of second- and 44 with taxanes (11 newly diagnosed patients, 37 ary acute myelogenous leukemia attributable to the patients with recurrent disease). For newly diagnosed inclusion of etoposide, it is associated with decreased patients treated with BEP compared with those treated peripheral neuropathy. For patients with advanced or with taxanes, the investigators found no significant dif- recurrent disease, the BEP regimen is recommended for ferences in response rate (82% for both regimens), adjuvant postoperative chemotherapy. In case of recur- median progression-free survival (46.1 months for BEP, rence, the optimal treatment should involve aggressive >52 months for taxanes), and median overall survival debulking surgery followed by combination chemotherapy. (97.2 months for BEP, >52 months for taxane). For Gershenson et al treated 9 patients with metastatic ovar- recurrent measurable disease, the response rate (71% vs ian sex cord-stromal tumors of all types with bleomycin 10 37%) and the median progression-free survival (11.2 to 15 mg/d by continuous intravenous (IV) infusion on months vs 7.2 months) were also not statistically signifi- days 1 to 3, etoposide 100 mg/m IV per day on days 1 to cant. It is possible that the combination of carboplatin 3, and cisplatin 100 mg/m IV on day 1. Of the 6 patients plus paclitaxel, which has been established in the treat- with measurable disease, 2 (33%) had a CR (1 surgical and ment of epithelial ovarian cancer, could have a role in 1 clinical) and 3 (50%) had a PR, for an overall RR of 83%. the management of granulosa cell tumors. Toxicity was acceptable; 2 patients had mild bleomycin In case of recurrence, aggressive treatment should pulmonary toxicity. Of the 7 patients with metastatic dis- include surgery followed by either radiation therapy or ease, only 1 (14%) had a durable remission. Median pro- chemotherapy. With these treatment modalities, the 83-87 gression-free survival was 14 months. Median survival disease-free survival is prolonged. For patients previously time was 28 months. The BEP regimen as first-line ther- treated with BEP, the VAC (vincristine, dactinomycin, apy for ovarian stromal malignancies was evaluated in a and cyclophosphamide) regimen is offered. In the treat- phase II trial by the Gynecologic Oncology Group. ment of recurrent granulosa cell tumor, if the patient is Negative findings were observed in 37% (14/38) of the found to have an isolated metastasis that can be com- patients who underwent second-look laparotomy. The 6 pletely resected, then radiation therapy may play a role. complete responses were of long median duration (24.4 One could use a small field of intense radiation therapy, months). Patients with measurable disease were at the which is associated with prolonged survival. Another highest risk of progression and death. Grade 4 myelotoxi- treatment option is chemotherapy with BEP for patients city occurred in 61% of the patients. The investigators with more widespread disease or disease that is subopti- reported that 69% of patients with advanced disease and mally cytoreduced at the time of relapse. 51% of those with recurrent disease remained progression- The treatment of recurrent disease with hormonal free, with a relatively short median follow-up of 3 years. therapy is an option, but experience is limited. Schwartz 94,95 Although the efficacy of platinum-based chemother- et al reported the presence of estrogen and progesterone apy is well established, the role of newer agents such receptors in granulosa cell tumors. Those investigators as gemsitabine and oxaliplatin is not known. Single-agent treated their patient, who presented with advanced recur- paclitaxel was used in a case report of recurrent granulosa rent disease and progesterone receptor–positive tumor, 212 Integrative Cancer Therapies / Vol. 7, No. 3, September 2008 with oral progestin, and her disease was stabilized for 10 because of the rarity of these tumors. In patients with stage months. Her disease was again stabilized on tamoxifen. I disease and those with completely resected tumor, the role Malik and Slevin reported 2 patients treated with high of postoperative chemotherapy or radiation therapy has not doses of medroxyprogesterone acetate who responded with been defined. Besides this, the use of adjuvant therapy has prolonged remissions after documented widespread recur- sometimes been associated with prolonged disease-free sur- rence. Similarly, Briasoulis et al reported a PR with vival and possibly overall survival. For patients with megestrol acetate in an elderly woman with granulosa cell advanced, recurrent, or metastatic disease, chemotherapy tumor and lung metastases lasting for 20 months who had should be considered and BEP is the preferable regimen. a recurrence after carboplatin chemotherapy. Treatment Although overall RR is high, the impact on disease-free or with a gonadotropin-releasing hormone (GnRH-goserelin) overall survival is unknown. Newer cytotoxic agents, such as analog achieved a transient PR in 1 patient who had a paclitaxel, have shown promising activity in patients with recurrence after cytotoxic platinum-based chemother- advanced or recurrent granulosa cell tumors. Finally, 98 99 apy. Similarly, Fishman et al treated 6 patients with because tumors tend to recur years after the initial diagno- refractory or progressive granulosa cell tumors after cyto- sis, prolonged surveillance is essential. toxic chemotherapy with leuprolide acetate. 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Journal

Integrative Cancer TherapiesSAGE

Published: Sep 1, 2008

Keywords: granulosa cell tumor; etiology; prognosis; tumor markers; treatment

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