2/19/2015 Sex cord­stromal tumors of the ovary: Granulosa­stromal cell tumors

http://www.uptodate.com/contents/sex­cord­stromal­tumors­of­the­ovary­granulosa­stromal­cell­tumors?source=machineLearning&search=granulosa+… 1/13

Official reprint from UpToDate www.uptodate.com ©2015 UpToDate

AuthorDavid M Gershenson, MD

Section EditorsBarbara Goff, MDRochelle L Garcia, MD

Deputy EditorSandy J Falk, MD, FACOG

Disclosures: David M Gershenson, MD Grant/Research/Clinical Trial Support: NCI (ovarian cancer). Employment: TheUniversity of Texas MD Anderson Cancer Center. Equity OwnerShip/Stock Options: Johnson & Johnson; Procter & Gamble.Barbara Goff, MD Nothing to disclose. Rochelle L Garcia, MD Nothing to disclose. Sandy J Falk, MD, FACOG Employee ofUpToDate, Inc.Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vettingthrough a multi­level review process, and through requirements for references to be provided to support the content.Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.Conflict of interest policy

Sex cord­stromal tumors of the ovary: Granulosa­stromal cell tumors

All topics are updated as new evidence becomes available and our peer review process is complete.Literature review current through: Jan 2015. | This topic last updated: Oct 03, 2014.

INTRODUCTION — Ovarian sex cord­stromal tumors are a heterogeneous group of benign or malignanttumors that develop from the dividing cell population that would normally produce cells that support andsurround the oocytes, including the cells that produce ovarian hormones (the nongerm cell and nonepithelialcomponents of the gonads) (figure 1) [1]. Ovarian sex cord­stromal tumors are rare, comprising only 1.2 percentof all primary ovarian cancers [2].

In contrast with epithelial ovarian cancer, most patients with malignant sex cord­stromal tumors are diagnosedwith early­stage disease; the tumors are generally considered to be low­grade malignancies.

Sex cord­stromal tumors include granulosa cell tumors (which differentiate toward female characteristics),fibroma­thecomas, and Sertoli­Leydig cell tumors (which differentiate toward male characteristics). Granulosa­stromal cell tumors include granulosa cell tumors, thecomas, and fibromas [3]. They account for 70 percent ofovarian sex cord­stromal tumors. Among granulosa­stromal cell tumors, fibromas are the most commonhistology. These tumors occur with equal frequency among pre­ and postmenopausal women.

Granulosa cell, theca cell, and mixed tumors are usually hormonally active, in contrast to fibromas, which donot produce hormones. Granulosa cell tumors are more often malignant than thecomas or fibromas, which aremost often benign.

Ovarian sex cord­stromal tumors of the granulosa­stromal cell type (granulosa cell tumors, fibromas, andthecomas) are reviewed here. An overview of sex cord­stromal tumors and other types of sex cord­stromaltumors of the ovary (Sertoli­stromal cell tumors and tumors with granulosa and Sertoli­Leydig elements), aswell as epithelial ovarian cancer, are discussed separately. (See "Overview of sex cord­stromal tumors of theovary" and "Sex cord­stromal tumors of the ovary: Sertoli­stromal cell tumors" and "Sex cord­stromal tumors ofthe ovary: Tumors with granulosa and Sertoli­Leydig elements" and "Epithelial carcinoma of the ovary, fallopiantube, and peritoneum: Histopathology" and "Epithelial carcinoma of the ovary, fallopian tube, and peritoneum:Clinical features and diagnosis".)

GRANULOSA CELL TUMOR — Granulosa cell tumors have malignant potential (ie, the ability tometastasize). They are the most common type of potentially malignant ovarian sex cord­stromal tumor; theycomprise 2 to 5 percent of all ovarian malignancies [1].

There are two subtypes, adult and juvenile. The adult subtype, which occurs most commonly in middle agedand older women (median age 50 to 54 years), comprises 95 percent of these neoplasms.

The juvenile type comprises 5 percent of all granulosa cell tumors [4]. They typically develop before puberty,and thus, are more common among children and young women. This subtype tends to have a higherproliferative rate than the adult type and a lower risk for late recurrences.

The discussion below relates mainly to the adult subtype.

Granulosa cell tumors appear to be more common in women who are non­white, obese (body mass index >30),and have a family history of breast or ovarian cancer [5]. The risk appears to be decreased in women who arecurrent or past smokers or users of oral contraceptive pills, and in those who are parous.

®®

2/19/2015 Sex cord­stromal tumors of the ovary: Granulosa­stromal cell tumors

http://www.uptodate.com/contents/sex­cord­stromal­tumors­of­the­ovary­granulosa­stromal­cell­tumors?source=machineLearning&search=granulosa+… 2/13

Histopathology — The gross appearance of granulosa cell tumors is variable. The neoplasms are usuallylarge and unilateral, and can be soft or firm depending upon the relationships of stroma, particularly collagen toneoplastic cells. They are often multicystic and may resemble a mucinous cystadenoma or be filled withserous fluid or clotted blood. Accumulation of lipids results in yellow color.

Histologically, granulosa cells of the adult subtype appear round, pale, with scant cytoplasm, and classic"coffee­bean" grooved nuclei; atypia and mitoses are typically not frequent, but do occur (picture 1). The cellsmay arrange themselves in small clusters or rosettes around a central cavity. These arrangements, which aretermed "Call­Exner bodies", resemble primordial follicles and, when diffusely present, constitute amicrofollicular pattern [6]. Lack of Call­exner bodies is not infrequent.

In contrast, the juvenile subtype has a macrofollicular or cystic pattern and is comprised of immature granulosacells with frequent mitoses; Call­Exner bodies and coffee­bean grooved nuclei are not frequent.

While the better differentiated granulosa cell tumors may have various patterns, including microfollicular,macrofollicular, trabecular, solid­trabecular, and insular, less well­differentiated tumors have a more diffusepattern, designated as sarcomatoid. Other pattern types are diffuse, cylindroid, pseudoadenomatous, or mixed,depending upon the predominant histological elements. These various patterns are not particularly important,but can render recognition as granulosa cell tumor difficult.

Theca cells, which are luteinized cells within the stroma, are present in about 70 percent of cases. Theca cellsproduce androstenedione, a weak androgen, and granulosa cells convert the androstenedione to estradiol.Significant hormone production is responsible for the clinical phenotype associated with the neoplasm. (See'Clinical features' below.)

The histologic diagnosis is facilitated by immunohistochemical staining (IHC) using antibodies against markersof sex cord­stromal differentiation. Inhibin is the most sensitive and specific [7,8]. Calretinin is typicallypositive, but is not specific for sex cord­stromal differentiation. Other markers, including CD99, müllerianinhibiting substance, vimentin, WT1, SF­1, cytokeratin, S­100 protein, and smooth muscle actin, are notspecific and are not particularly helpful in distinguishing between granulosa cell tumor and its mimics [9­11].However, even positivity for inhibin is not absolutely specific for an ovarian sex cord tumor, as sex cord­stromal differentiation can be seen in other neoplasms. As an example, in one report, positive IHC for inhibinwas present in 94 percent of granulosa cell tumors and in 10 to 20 percent of ovarian endometrioid tumors andmetastatic carcinomas to the ovary (although with significantly weaker staining intensity) [10].

In the future, molecular testing for mutations in the FOXL2 gene may improve diagnostic accuracy in patientswith sex cord­stromal tumors. Somatic mutations in this gene, which play a role in the development of normalgranulosa cells, have been identified in 97 percent of adult­type granulosa cell tumors [12,13]. In contrast, themutation was identified in only 1 of 10 juvenile­type granulosa cell tumors and 3 of 14 thecomas (21 percent),while it was absent in sex cord­stromal tumors of other types and in other ovarian neoplasms.

Clinical features — Granulosa cell tumors typically present as large masses; the mean diameter is 12 cm.Women may present with an asymptomatic mass noted on abdominal or pelvic examination.

Granulosa cell tumors often produce estrogen and/or progesterone; consequently, symptoms related tohyperestrogenism are common at diagnosis. In a review of 118 patients with granulosa cell tumors, 55 percenthad hyperestrogenic findings, including hyperplastic endometrium and abnormal uterine bleeding [14]. Increasedproduction of estrogen may also cause breast tenderness, postmenopausal bleeding, menstrual abnormalities,and, in children, sexual precocity. (See "Definition, etiology, and evaluation of precocious puberty".)

There is a well­documented association between granulosa cell tumors and endometrial neoplasms (complexendometrial hyperplasia and adenocarcinoma) [15]. For this reason, as noted in a preceding section,preoperative endometrial biopsy is suggested in all women with abnormal uterine bleeding, all postmenopausalwomen with an adnexal mass and a thickened (≥5 mm) endometrial stripe, and in the occasional patient whohas a preoperative diagnosis of ovarian granulosa cell tumor. Endometrial biopsy will detect endometrialhyperplasia/intraepithelial neoplasia in 25 to 50 percent of women with granulosa cell tumors and carcinoma in5 to 10 percent [16­18]. The endometrial adenocarcinomas that are associated with granulosa­stromal celltumors are usually early stage and well differentiated [14].

2/19/2015 Sex cord­stromal tumors of the ovary: Granulosa­stromal cell tumors

http://www.uptodate.com/contents/sex­cord­stromal­tumors­of­the­ovary­granulosa­stromal­cell­tumors?source=machineLearning&search=granulosa+… 3/13

Nonspecific symptoms or signs associated with these neoplasms include ascites, increasing abdominal girth,abdominal pain due to torsion, intraneoplasmal hemorrhage, or tumor rupture and hemoperitoneum.

Diagnosis — Diagnosis of a granulosa cell tumor is made by histology at the time of surgical excision.Preoperatively, a granulosa cell tumor should be suspected based upon the presence of a large adnexal mass,if accompanied by the signs of hyperestrogenism described in the preceding section. Ultrasonographic findings(an echogenic, septated cystic or solid mass related to the ovary) are typically nonspecific. Surgery is requiredfor histologic diagnosis as well as staging (staging is the best determination of potential malignant behavior)and treatment.

The differential diagnosis of a woman who presents with both an adnexal mass and abnormal vaginal bleedingshould also include ovarian metastasis from a primary uterine cancer, an endometrial metastasis from aprimary ovarian malignant neoplasm, and separate primary ovarian and endometrial carcinomas.

The hormonal activity of granulosa cell tumors permits the use of a variety of serum tumor markers in thediagnostic evaluation (table 1). These markers include [18­21]:

Management

Surgical staging and treatment — Granulosa cell tumors are staged surgically according to theInternational Federation of Gynecology and Obstetrics (FIGO) ovarian cancer staging system (table 2). A totalabdominal hysterectomy and bilateral salpingo­oophorectomy is recommended for women who are done withchildbearing. Assessment of stage is the most important factor in determining prognosis and to guidepostoperative treatment recommendations [33].

The rarity of lymph node metastasis at initial diagnosis suggests that pelvic and paraaortic lymphadenectomymay be omitted as part of surgical staging for these neoplasms [34,35]. However, this is dependent upon

Inhibin – Clinically, the most useful serum marker for granulosa cell tumors is inhibin, a peptide that isproduced by the ovaries in response to follicle stimulating hormone and luteinizing hormone. Inhibinusually becomes undetectable after menopause, unless produced by certain ovarian tumors, mostlymucinous epithelial ovarian carcinomas and granulosa cell tumors [22­27].

Inhibin exists as two different isoforms, inhibin A and inhibin B. Both isoforms consist of a dimer of twosubunits, the alpha and beta subunits. The alpha subunit is the same for both isoforms, while the betasubunits differ (beta A and beta B); they show about 64 percent homology. The three subunits (alpha,beta A, beta B) are produced on separate genes located on chromosomes 2 (alpha and beta B subunit)and 7 (beta A subunit).

In general, both inhibin A and inhibin B should be ordered, if possible, when following patients withgranulosa cell tumors. Although most commercial laboratories only provide assays for inhibin A, serumlevels of inhibin B seem to be more frequently elevated [28]. The free alpha subunit can also be measured[29].

The diagnostic performance of inhibin levels is poor. An elevated inhibin level in a premenopausal womanpresenting with amenorrhea and infertility or in a postmenopausal woman is suggestive of the presence ofa granulosa cell tumor, but not specific. Conversely, both inhibin A and B may be negative in patientswith active granulosa cell tumors.

Estradiol was one of the first markers identified in the serum of patients with granulosa cell tumors. Ingeneral, however, estradiol is not a sensitive marker for the presence of a granulosa cell tumor.Approximately 30 percent of these neoplasms do not produce estradiol, perhaps related to the lack oftheca cells, which produce androstenedione, a necessary precursor for estradiol synthesis.

Müllerian inhibiting substance (MIS), which is produced by granulosa cells in the developing follicles, hasemerged as a potential tumor marker for granulosa cell tumors. As with inhibin, MIS is typicallyundetectable in postmenopausal women. Although an elevated MIS level appears to be highly specific forovarian granulosa cell tumors [30­32], this test is not available for clinical use.

2/19/2015 Sex cord­stromal tumors of the ovary: Granulosa­stromal cell tumors

http://www.uptodate.com/contents/sex­cord­stromal­tumors­of­the­ovary­granulosa­stromal­cell­tumors?source=machineLearning&search=granulosa+… 4/13

whether an intraoperative diagnosis of a granulosa cell tumor can be made, since the diagnosis may not havebeen made preoperatively and is difficult to confirm during surgery.

Granulosa cell tumors are generally confined to one ovary. For women with stage I disease who wish topreserve fertility or avoid exogenous hormone replacement, a unilateral salpingo­oophorectomy and uterinepreservation with other procedures for complete surgical staging are appropriate (table 3) [36]. Retrospectivestudies suggest an equivalent cure rate for early­stage disease whether treated by unilateral salpingo­oophorectomy or bilateral salpingo­oophorectomy [37,38]. The contralateral ovary should be carefully inspected;biopsy is necessary only if an abnormality is found.

Due to the risk of endometrial neoplasia, if an endometrial biopsy was not performed preoperatively, a dilationand curettage should be performed during surgery.

Adjuvant therapy — Surgery alone is acceptable treatment for most women with granulosa cell tumors,since the majority are stage IA and confined to one ovary at the time of diagnosis (table 2) [37]. Long­termdisease­free survival rates are approximately 90 percent.

Outcomes are less favorable for women with higher­stage disease and for those with stage I disease whosetumor has ruptured, has nuclear atypia, or a high mitotic index. There are conflicting reports regarding theprognostic influence of other factors such as positive cytology, tumor size, ovarian surface involvement, andploidy status. Further studies are needed in this area. (See 'Prognosis and follow­up' below.)

Although postoperative or adjuvant therapy is often considered for such patients, the rarity of these neoplasmsmakes it difficult to conduct well­designed randomized studies to define the value of any such strategy. As aresult, the benefit of postoperative treatment for women with stage IB to IV disease is unclear, and practice isvariable. Some centers recommend adjuvant therapy for all women with stage IC to IV disease, othersrecommend adjuvant therapy only for women with residual disease after surgery, and still others do notrecommend adjuvant therapy for any stage of disease, treating only at the time of a recurrence.

The following represents the range of findings regarding the benefit of adjuvant therapy from observationalstudies:

Nevertheless, despite the absence of data supporting a survival benefit, some experts recommendpostoperative chemotherapy for women with resected stage IC to IV disease because of the high risk ofdisease progression (table 4) and the potential for long­term survival in women with advanced disease whoreceive modern platinum­based chemotherapy [17,39,49­53]. (See 'Metastatic or recurrent disease' below.)

Some reserve this recommendation for women over the age of 40 at diagnosis, who, in one early series, had ahigher risk of disease recurrences compared to younger women [54]. However, other reports have failed toconfirm the adverse impact of older age on outcomes [14,55­60].

Guidelines from the National Comprehensive Cancer Network (NCCN) recommend platinum­basedchemotherapy (or radiation therapy [RT] for limited disease, see below) in women with stage II to IV ovarianstromal tumors and that these options be "considered" in women with high­risk stage I disease (ie, rupturedstage IC tumors) [36].

The most commonly used regimen is a combination of bleomycin, etoposide, and cisplatin (BEP) (table 4) as is

For children with advanced­stage juvenile granulosa cell tumors, adjuvant chemotherapy appears tocontribute to long­lasting complete remission and is usually recommended for those with stage ICdisease and a high mitotic index (≥20 per 10 high power fields [HPF]), as well as those with moreadvanced­stage disease [39­45]. However, it is difficult to extrapolate these results to adult­type tumors,which have a different biology (ie, lower proliferative rate and greater risk of late recurrences) than thejuvenile type.

Some retrospective series of adults with granulosa cell tumor suggest that women with advanced (stageIII/IV) disease who receive postoperative chemotherapy have a longer progression­free interval than thosewho do not [46]. However, others have failed to show that the use of chemotherapy is associated withbetter survival [18,47,48].

2/19/2015 Sex cord­stromal tumors of the ovary: Granulosa­stromal cell tumors

http://www.uptodate.com/contents/sex­cord­stromal­tumors­of­the­ovary­granulosa­stromal­cell­tumors?source=machineLearning&search=granulosa+… 5/13

used for testicular and ovarian germ cell tumors [17]. (See "Initial risk­stratified treatment for advancedtesticular germ cell tumors" and "Treatment of malignant germ cell tumors of the ovary".)

Alternative chemotherapy options include etoposide plus cisplatin (EP); cyclophosphamide, doxorubicin andcisplatin (CAP); paclitaxel and carboplatin; or a platinum agent alone. The Gynecologic Oncology Group iscurrently conducting a randomized phase II trial of BEP versus the combination of paclitaxel and carboplatin forpatients with newly diagnosed and chemo­naive recurrent metastatic sex cord­stromal tumors of the ovary.

As with chemotherapy, there are no prospective randomized trials that define the value of postoperative RT.Granulosa cell tumors are radioresponsive in that RT can induce clinical responses and occasional long­termremission in patients with persistent or recurrent granulosa cell tumors. (See 'Metastatic or recurrent disease'below.)

In the adjuvant setting, an older retrospective series is often quoted as supporting benefit from radiotherapy[56]. However, insufficient data were provided to determine whether the differences in outcome betweenirradiated and nonirradiated women were attributable to therapy. Several later observational series fail to showany benefit from adjuvant radiation [14,51,55,57,61].

In summary, beyond primary surgery, there is no standard for postoperative therapy. For patients with stage IAgranulosa cell tumor, surgery alone is the preferred treatment. For women with stage IC to IV disease, somegroups do not recommend postoperative therapy, while others recommend platinum­based chemotherapy, mostfrequently BEP [16,62]. As noted above, NCCN guidelines recommend platinum­based chemotherapy (or RTfor limited disease, see below) in women with stage II to IV ovarian stromal tumors and that these options be"considered" in women with high­risk stage I disease (ie, ruptured stage IC tumors) [36].

Metastatic or recurrent disease — A common site of recurrence is the pelvis, although the retroperitoneumand upper abdomen may be involved, as well [35].

There is no standard approach to the management of advanced unresectable or relapsed disease. Completeresection may provide long­term disease control if the neoplasm is localized [60], but diffuse intraabdominaldisease is difficult to treat effectively.

RT can induce clinical responses and occasional long­term remission in women with persistent or recurrentgranulosa cell tumors, particularly if the disease is surgically cytoreduced [17,51,63]. In one review of 34patients treated at a single center over a 40­year period with radiation alone, 3 of the 14 who were treated formeasurable disease were alive without progression 10 to 21 years following treatment [63].

For patients with metastatic or suboptimally cytoreduced disease, chemotherapy regimens similar to thoseused for germ cell tumors (eg, bleomycin etoposide cisplatin or (table 4)) are active, producing overall responserates of 58 to 84 percent (table 4) [50,52,64]. In one study, 14 of 38 patients (37 percent) undergoing second­look laparotomy following four courses of BEP had negative findings [50]. The median survival of patients whohad a complete clinical response (n = 6) was over two years.

Unfortunately, the majority of patients with advanced disease do not have durable remissions [50,64]. In acombined series of patients treated with BEP for sex cord­stromal tumors, only one of seven women withmetastatic disease had a durable remission [64]. Furthermore, treatment­related toxicity (especially frombleomycin) may be prominent [52]. (See "Bleomycin­induced lung injury".)

Other chemotherapeutic regimens with reported therapeutic efficacy include doxorubicin alone [65]; carboplatinplus etoposide [66]; cisplatin, vinblastine, plus bleomycin (PVB or VBP) [3]; and cyclophosphamide,doxorubicin, plus cisplatin (CAP) [67­69]. None of these regimens have produced consistently better resultsthan seen with BEP, but may be considered for second­line therapy. The value of taxanes, particularly incombination with cisplatin, is under active investigation [70­73].

Experimental data and small clinical series suggest that hormonal agents such as luteinizing hormone releasinghormone agonists (eg, leuprolide) might have been effective through the suppression of gonadotropin secretion[74­78]. However, others have failed to document efficacy [51,79].

Treatment of recurrent disease with tamoxifen alone, progesterone alone, or a combination of the two agents

2/19/2015 Sex cord­stromal tumors of the ovary: Granulosa­stromal cell tumors

http://www.uptodate.com/contents/sex­cord­stromal­tumors­of­the­ovary­granulosa­stromal­cell­tumors?source=machineLearning&search=granulosa+… 6/13

occasionally yields long­term clinical responses. In one case report, a complete clinical response in a patientwith recurrent granulosa cell tumor was achieved using alternating biweekly cycles of megestrol 40 mg twicedaily for two weeks, alternating with two­week courses of tamoxifen 10 mg twice daily [78].

Antiangiogenic therapy also appears promising. In an early report of eight patients with granulosa cell tumors,bevacizumab, a monoclonal antibody directed against the vascular endothelial growth factor (VEGF), induced acomplete clinical response in one patient, partial responses in two, and stable disease in two others [80]. TheGynecologic Oncology Group is currently conducting a phase II trial of bevacizumab for women with recurrentsex cord­stromal ovarian tumors.

Prognosis and follow­up — The prognosis of ovarian granulosa cell tumor depends upon the stage of diseaseat diagnosis and the presence of residual disease after surgery (table 5) [17,48,61,81­83].

Five­year survival rates for completely resected stage I disease are approximately 90 percent [48,49,61], butoutcomes tend to be less favorable in the presence of a large tumor size (10 to 15 cm) or (in many but not allseries [60]) tumor rupture [14,57,58,61,84].

A number of histologic features have also been examined for their prognostic significance. In adult neoplasms,cellular atypia, high mitotic index (4 to 10 mitoses per 10 HPF), and the absence of Call­Exner bodies are theonly significant histologic predictors of early recurrence [33,60,61]. Abnormal karyotype, p53 overexpression,and ploidy do not appear to be of prognostic value [85,86].

Ovarian granulosa cell tumors have metastatic potential and a tendency for late relapse. In one report of 37women with stage I disease, survival rates at 5, 10, and 20 years were 94, 82, and 62 percent, respectively[49]. The median time to relapse is approximately four to six years after initial diagnosis; however, laterecurrences have been reported after as many as 40 years [14,33,49,61,87,88]. Thus, prolonged surveillancewith serial physical examinations and serum tumor markers (particularly inhibin) [36] should be performed.

After primary therapy, prolonged surveillance with serial physical examinations and serum tumor marker levelsis indicated because of the indolent growth pattern of these neoplasms. There is no consensus on thefrequency of postoperative surveillance. In general, we follow patients with pelvic examinations and seruminhibin levels every three months for the first two years, every four to six months during years three to five, andyearly thereafter since recurrences can occur many years after initial diagnosis. In addition, following serumestradiol levels postoperatively may be useful for detecting recurrence of an estradiol­secreting neoplasm[3,14].

Radiographic imaging studies such as computed tomography (CT) or chest radiographs are performed only ifclinically indicated (eg, evaluation of specific symptoms or an elevated inhibin level), but are not recommendedfor routine follow­up [17,89].

An overview of posttreatment surveillance for sex cord­stromal tumors can be found separately. (See"Overview of sex cord­stromal tumors of the ovary", section on 'Posttreatment surveillance'.)

FIBROMA — Fibromas are the most common of the sex cord­stromal tumors. Pure fibromas are benign solidneoplasms, usually unilateral, that primarily occur in postmenopausal women. They are not hormonally active.

Cellular fibromas are characterized by mildly increased cellular density, mild nuclear atypia, and an average ofthree or fewer mitotic figures per 10 high power fields (HPF). In contrast, fibrosarcomas (which have four ormore mitotic figures per 10 HPF plus marked cellular density and nuclear atypia) are very rare malignantovarian sarcomas whose aggressiveness correlates with the number of mitoses and the degree of anaplasia.

On ultrasound examination, an ovarian fibroma may appear as a mass that is either hyper­ or hypoechoic,which may be calcified and/or exhibit cystic degeneration [90]. Ascites is present in 10 to 15 percent of casesand hydrothorax in 1 percent, especially with larger lesions.

The association of ovarian fibroma with ascites and/or pleural effusion is termed Meigs' syndrome [91]. Fluidaccumulation is probably related to substances like vascular endothelial growth factor (VEGF) that raisecapillary permeability [24,88]. Removal of the neoplasm results in elimination of ascites and pleural effusion[92]. Several cases of Meigs' syndrome have been reported in association with elevated serum CA 125 levels

2/19/2015 Sex cord­stromal tumors of the ovary: Granulosa­stromal cell tumors

http://www.uptodate.com/contents/sex­cord­stromal­tumors­of­the­ovary­granulosa­stromal­cell­tumors?source=machineLearning&search=granulosa+… 7/13

[93]. Thus, neither ascites or pleural effusion, nor an elevated CA 125 is necessarily indicative of an advancedepithelial ovarian carcinoma in a woman with a pelvic mass.

Pseudo­Meigs' syndrome (a clinical syndrome of pleural effusion, ascites, and an ovarian mass that is not afibroma or fibroma­like mass/tumor) has been reported from a number of sources, such as leiomyomas, strumaovarii, mucinous cystadenoma, teratoma, and malignancies that are metastatic to the ovary (particularlycolorectal cancer) [94].

Ovarian fibromas associated with basal cell cancers are called nevoid basal cell carcinoma syndrome or Gorlinsyndrome. Other associated findings include odontogenic keratocysts, brain neoplasms, and mesenteric cysts.Gorlin syndrome is inherited as an autosomal dominant trait with high degree of penetrance (97 percent), butvariable expressivity. Whether the inherited germline abnormality responsible for Gorlin syndrome (a mutation inthe patched or PTCH1 gene on chromosome 9) is related to the development of ovarian fibromas as well isunclear [95]. (See "Nevoid basal cell carcinoma syndrome".)

The most common treatment for an ovarian fibroma is unilateral salpingo­oophorectomy. For women who desirepreservation of the ovary, an ovarian cystectomy may be performed with complete excision of the fibromatoustissue.

THECOMA — Thecomas are solid, fibromatous neoplasms and are generally benign. They are composed oftheca cells and arise from the ovarian stroma [96]. Thecomas are almost exclusively confined to one ovary andoccur predominantly in postmenopausal women (average age 59 years). Thecomas may produce estrogen, andup to 20 percent of patients present with a synchronous endometrial cancer.

Grossly, they have a yellowish appearance from accumulated lipids (also seen in granulosa cell tumors) andcan become very large (up to 40 cm). Histologically, they are primarily composed of theca cells, but may alsocontain granulosa cell components. The tumors are designated granulosa­theca cell tumors or granulosa celltumors depending upon the relative amount of granulosa versus theca cells [81]. Malignant thecomas are rare,and may be interpreted as fibrosarcomas or a diffuse form of a granulosa cell tumor.

The most common symptom of thecomas is abnormal uterine bleeding as a result of endometrial stimulationfrom estrogen produced by theca cells. Endometrial hyperplasia and carcinoma are present in approximately 15and 25 percent of cases, respectively [23]. Ascites is rare. Ultrasound generally reveals a nonspecific ovarianmass.

We suggest that treatment of thecomas in women in the menopausal transition and postmenopausal womeninclude a total abdominal hysterectomy with bilateral salpingo­oophorectomy (TAH­BSO). This recommendationtakes into account the possible presence of a synchronous endometrial malignancy, as well as the rareoccurrence of ovarian fibrosarcoma, a malignant mixed Müllerian neoplasm of the uterus, or endometrialstromal sarcoma.

Unilateral oophorectomy is an option in young women when preservation of fertility or avoidance of exogenoushormone replacement is desired [37].

All women with a thecoma should have pre­ or intraoperative endometrial sampling to exclude the presence ofa synchronous endometrial malignancy.

FIBROTHECOMA — The term fibrothecoma is used by some experts to refer to a neoplasm with features thatare intermediate between a fibroma and a thecoma [97]. There is no universal agreement on which neoplasmsshould be classified as a fibrothecoma rather than either a fibroma or thecoma; however, many neoplasmshave mixtures of these cell types.

Hormonal activity of these neoplasms depends upon the extent to which they resemble fibromas (lipid­poor,hormonally inert) or thecomas (lipid­containing, hormonally active) [97,98]. Fibrothecomas may be either benignor malignant, although they are most commonly benign [99,100]. The risk of malignancy is difficult to predictdue to inconsistent classification and the paucity of data regarding these neoplasms. Of note, women with asignificant amount of hormonally active thecoma elements are at risk for endometrial neoplasia, similar to purethecomas. (See 'Thecoma' above.)

2/19/2015 Sex cord­stromal tumors of the ovary: Granulosa­stromal cell tumors

http://www.uptodate.com/contents/sex­cord­stromal­tumors­of­the­ovary­granulosa­stromal­cell­tumors?source=machineLearning&search=granulosa+… 8/13

Pelvic imaging can certainly narrow the differential diagnosis of an adnexal mass, but there is nothingpathognomonic about the ultrasound or magnetic resonance imaging (MRI) appearance of fibrothecomas.Typically, they appear as a solid ovarian mass and are considered worrisome for malignant neoplasm. Thesonographic appearance of these neoplasms is usually nonspecific. On MRI, fibrothecomas typically have lowsignal intensity on T1­weighted images and very low signal intensity on T2­weighted images [101­103]. Largefibrothecomas may have areas of edema and cystic degeneration. However, there is one report indicating thatdual­echo chemical shift MRI may be a useful method for detecting small amounts of lipid in thecomas versusthe fibrous tissue in fibromas [104]. But once again, stromal tumors may contain both thecoma elements andfibroma elements (hence "fibrothecoma"), so this distinction is probably of very limited clinical benefit.

Ultimately, regardless of imaging findings, removal of the mass is required, since these lesions are neoplastic.The diagnosis is made based upon histology.

SUMMARY AND RECOMMENDATIONS

Granulosa cell tumor

Fibroma

Granulosa cell tumors are generally large and unilateral and have malignant potential. They arecategorized into two subtypes, adult and juvenile. The adult subtype is more common and occurs mostlyin middle aged and older women, while the juvenile subtype occurs mostly in children and young women.(See 'Histopathology' above.)

These neoplasms often produce estrogen (table 1). Granulosa cell tumors typically present as a largeadnexal mass frequently with signs of hyperestrogenism (abnormal uterine bleeding, endometrialneoplasia, breast tenderness, and, in children, precocious puberty). We recommend endometrial samplingpre­ or intraoperatively to exclude asymptomatic endometrial neoplasm (carcinoma or its precursor)(Grade 1B). (See 'Clinical features' above and 'Surgical staging and treatment' above.)

We suggest total abdominal hysterectomy and bilateral salpingo­oophorectomy for women with granulosacell tumors who have completed childbearing (Grade 2B). For women with stage I disease (table 2) whowish to preserve childbearing capacity or avoid estrogen therapy, we suggest unilateral oophorectomyalone (Grade 2C). (See 'Surgical staging and treatment' above.)

We suggest a course of postoperative platinum­based chemotherapy for all women with resected stageIC to IV disease because of the high risk of disease progression and the potential for long­term survival inwomen with advanced disease who receive modern platinum­based chemotherapy (Grade 2B). However,others disagree, either recommending chemotherapy only for women who are left with measurableresidual disease following surgery, or withholding adjuvant chemotherapy for all women regardless ofstage, and treating only at the time of recurrence. (See 'Adjuvant therapy' above.)

For recurrent localized disease, we suggest surgical resection, if feasible (Grade 2B). We suggestchemotherapy rather than surgery alone for patients with metastatic or suboptimally cytoreduced disease(Grade 2B). Radiation may be appropriate as primary treatment or as an adjunctive therapy followingsurgery in selected patients with recurrence confined to the pelvis. (See 'Metastatic or recurrent disease'above.)

After primary therapy, prolonged surveillance with serial physical examinations and serum tumor markerlevels (if elevated, (table 1)) is indicated because of the indolent growth pattern of these neoplasms. (See'Prognosis and follow­up' above.)

Fibromas are the most common of the sex cord­stromal tumors. Pure fibromas are benign, solid, usuallyunilateral neoplasms that primarily occur in postmenopausal women. They are not hormonally active.

Fibromas are rarely associated with Meigs' syndrome (ie, ovarian fibroma, ascites, pleural effusion).

We recommend oophorectomy for diagnosis and cure for women with ovarian fibromas (Grade 1B). (See'Fibroma' above.)

2/19/2015 Sex cord­stromal tumors of the ovary: Granulosa­stromal cell tumors

http://www.uptodate.com/contents/sex­cord­stromal­tumors­of­the­ovary­granulosa­stromal­cell­tumors?source=machineLearning&search=granulosa+… 9/13

Thecoma

Fibrothecoma

Use of UpToDate is subject to the Subscription and License Agreement.

REFERENCES

1. Young RH. Sex cord­stromal tumors of the ovary and testis: their similarities and differences withconsideration of selected problems. Mod Pathol 2005; 18 Suppl 2:S81.

2. Quirk JT, Natarajan N. Ovarian cancer incidence in the United States, 1992­1999. Gynecol Oncol 2005;97:519.

3. Segal R, DePetrillo AD, Thomas G. Clinical review of adult granulosa cell tumors of the ovary. GynecolOncol 1995; 56:338.

4. Lack EE, Perez­Atayde AR, Murthy AS, et al. Granulosa theca cell tumors in premenarchal girls: aclinical and pathologic study of ten cases. Cancer 1981; 48:1846.

5. Boyce EA, Costaggini I, Vitonis A, et al. The epidemiology of ovarian granulosa cell tumors: a case­control study. Gynecol Oncol 2009; 115:221.

6. Young R, Clement PB, Scully RE. The ovary. In: Surgical Pathology, Sternberg SS (Ed), Raven Press,New York 1989. p.1687.

7. McCluggage WG. Recent advances in immunohistochemistry in the diagnosis of ovarian neoplasms. JClin Pathol 2000; 53:327.

8. Movahedi­Lankarani S, Kurman RJ. Calretinin, a more sensitive but less specific marker than alpha­inhibin for ovarian sex cord­stromal neoplasms: an immunohistochemical study of 215 cases. Am J SurgPathol 2002; 26:1477.

9. Matias­Guiu X, Pons C, Prat J. Müllerian inhibiting substance, alpha­inhibin, and CD99 expression in sexcord­stromal tumors and endometrioid ovarian carcinomas resembling sex cord­stromal tumors. HumPathol 1998; 29:840.

10. Hildebrandt RH, Rouse RV, Longacre TA. Value of inhibin in the identification of granulosa cell tumors ofthe ovary. Hum Pathol 1997; 28:1387.

11. Zhao C, Vinh TN, McManus K, et al. Identification of the most sensitive and robustimmunohistochemical markers in different categories of ovarian sex cord­stromal tumors. Am J SurgPathol 2009; 33:354.

12. Shah SP, Köbel M, Senz J, et al. Mutation of FOXL2 in granulosa­cell tumors of the ovary. N Engl J Med2009; 360:2719.

13. Köbel M, Gilks CB, Huntsman DG. Adult­type granulosa cell tumors and FOXL2 mutation. Cancer Res2009; 69:9160.

14. Evans AT 3rd, Gaffey TA, Malkasian GD Jr, Annegers JF. Clinicopathologic review of 118 granulosa and82 theca cell tumors. Obstet Gynecol 1980; 55:231.

15. Adamian RT. [Hyperplastic processes and endometrial cancer in patients with hormone­producingovarian tumors]. Vopr Onkol 1991; 37:48.

16. Berek JS, Hacker NF. Nonepithelial ovarian and fallopian tube cancers. In: Practical GynecologicOncology, 3rd, Berek JS, Hacker NF (Eds), Lippincott Williams & Wilkins, Philadelphia 2000. p.539.

Thecomas are usually benign neoplasms; like granulosa cell tumors, thecomas may produce estrogen(table 1) and usually present as abnormal uterine bleeding in a postmenopausal woman.

We suggest unilateral oophorectomy and endometrial sampling for women with thecomas who have notcompleted childbearing or wish to avoid exogenous hormone replacement (Grade 2B). We suggest totalabdominal hysterectomy with bilateral salpingo­oophorectomy for all other women (Grade 2B). (See'Thecoma' above.)

The term fibrothecoma is used by some experts to refer to a neoplasm with features that are intermediatebetween a fibroma and a thecoma. Hormonal activity of these neoplasms depends upon the extent towhich they resemble fibromas (lipid­poor, hormonally inert) or thecomas (lipid­containing, hormonallyactive). Fibrothecomas are usually benign. (See 'Fibrothecoma' above.)

2/19/2015 Sex cord­stromal tumors of the ovary: Granulosa­stromal cell tumors

http://www.uptodate.com/contents/sex­cord­stromal­tumors­of­the­ovary­granulosa­stromal­cell­tumors?source=machineLearning&search=granulosa… 10/13

17. Schumer ST, Cannistra SA. Granulosa cell tumor of the ovary. J Clin Oncol 2003; 21:1180.18. Zanagnolo V, Pasinetti B, Sartori E. Clinical review of 63 cases of sex cord stromal tumors. Eur J

Gynaecol Oncol 2004; 25:431.19. Nakashima N, Young RH, Scully RE. Androgenic granulosa cell tumors of the ovary. A clinicopathologic

analysis of 17 cases and review of the literature. Arch Pathol Lab Med 1984; 108:786.20. Norris HJ, Taylor HB. Virilization associated with cystic granulosa tumors. Obstet Gynecol 1969; 34:629.21. Castro CY, Malpica A, Hearne RH, Silva EG. Androgenic adult granulosa cell tumor in a 13­year­old

prepubertal patient: a case report and review of the literature. Int J Gynecol Pathol 2000; 19:266.22. Lappöhn RE, Burger HG, Bouma J, et al. Inhibin as a marker for granulosa­cell tumors. N Engl J Med

1989; 321:790.23. Jobling T, Mamers P, Healy DL, et al. A prospective study of inhibin in granulosa cell tumors of the

ovary. Gynecol Oncol 1994; 55:285.24. Boggess JF, Soules MR, Goff BA, et al. Serum inhibin and disease status in women with ovarian

granulosa cell tumors. Gynecol Oncol 1997; 64:64.25. Healy DL, Burger HG, Mamers P, et al. Elevated serum inhibin concentrations in postmenopausal

women with ovarian tumors. N Engl J Med 1993; 329:1539.26. Gustafson ML, Lee MM, Scully RE, et al. Müllerian inhibiting substance as a marker for ovarian sex­cord

tumor. N Engl J Med 1992; 326:466.27. Robertson DM, Stephenson T, Pruysers E, et al. Characterization of inhibin forms and their

measurement by an inhibin alpha­subunit ELISA in serum from postmenopausal women with ovariancancer. J Clin Endocrinol Metab 2002; 87:816.

28. Mom CH, Engelen MJ, Willemse PH, et al. Granulosa cell tumors of the ovary: the clinical value ofserum inhibin A and B levels in a large single center cohort. Gynecol Oncol 2007; 105:365.

29. Robertson DM, Stephenson T, Pruysers E, et al. Inhibins/activins as diagnostic markers for ovariancancer. Mol Cell Endocrinol 2002; 191:97.

30. Rey RA, Lhommé C, Marcillac I, et al. Antimüllerian hormone as a serum marker of granulosa celltumorsof the ovary: comparative study with serum alpha­inhibin and estradiol. Am J Obstet Gynecol1996; 174:958.

31. Lane AH, Lee MM, Fuller AF Jr, et al. Diagnostic utility of Müllerian inhibiting substance determination inpatients with primary and recurrent granulosa cell tumors. Gynecol Oncol 1999; 73:51.

32. Chang HL, Pahlavan N, Halpern EF, MacLaughlin DT. Serum Müllerian Inhibiting Substance/anti­Müllerian hormone levels in patients with adult granulosa cell tumors directly correlate with aggregatetumor mass as determined by pathology or radiology. Gynecol Oncol 2009; 114:57.

33. Miller BE, Barron BA, Wan JY, et al. Prognostic factors in adult granulosa cell tumor of the ovary.Cancer 1997; 79:1951.

34. Brown J, Sood AK, Deavers MT, et al. Patterns of metastasis in sex cord­stromal tumors of the ovary:can routine staging lymphadenectomy be omitted? Gynecol Oncol 2009; 113:86.

35. Abu­Rustum NR, Restivo A, Ivy J, et al. Retroperitoneal nodal metastasis in primary and recurrentgranulosa cell tumors of the ovary. Gynecol Oncol 2006; 103:31.

36. National Comprehensive Cancer Network (NCCN). NCCN Clinical practice guidelines in oncology.http://www.nccn.org/professionals/physician_gls/f_guidelines.asp (Accessed on April 01, 2014).

37. Gershenson DM. Management of early ovarian cancer: germ cell and sex cord­stromal tumors. GynecolOncol 1994; 55:S62.

38. Zhang M, Cheung MK, Shin JY, et al. Prognostic factors responsible for survival in sex cord stromaltumors of the ovary­­an analysis of 376 women. Gynecol Oncol 2007; 104:396.

39. Schneider DT, Calaminus G, Wessalowski R, et al. Ovarian sex cord­stromal tumors in children andadolescents. J Clin Oncol 2003; 21:2357.

40. Young RH, Scully RE. Ovarian Sertoli­Leydig cell tumors. A clinicopathological analysis of 207 cases.Am J Surg Pathol 1985; 9:543.

41. Young RH, Dickersin GR, Scully RE. Juvenile granulosa cell tumor of the ovary. A clinicopathologicalanalysis of 125 cases. Am J Surg Pathol 1984; 8:575.

42. Calaminus G, Wessalowski R, Harms D, Göbel U. Juvenile granulosa cell tumors of the ovary inchildren and adolescents: results from 33 patients registered in a prospective cooperative study. GynecolOncol 1997; 65:447.

2/19/2015 Sex cord­stromal tumors of the ovary: Granulosa­stromal cell tumors

http://www.uptodate.com/contents/sex­cord­stromal­tumors­of­the­ovary­granulosa­stromal­cell­tumors?source=machineLearning&search=granulosa… 11/13

43. Schneider DT, Calaminus G, Wessalowski R, et al. Therapy of advanced ovarian juvenile granulosa celltumors. Klin Padiatr 2002; 214:173.

44. Schneider DT, Jänig U, Calaminus G, et al. Ovarian sex cord­stromal tumors­­a clinicopathological studyof 72 cases from the Kiel Pediatric Tumor Registry. Virchows Arch 2003; 443:549.

45. Plantaz D, Flamant F, Vassal G, et al. [Granulosa cell tumors of the ovary in children and adolescents.Multicenter retrospective study in 40 patients aged 7 months to 22 years]. Arch Fr Pediatr 1992; 49:793.

46. Uygun K, Aydiner A, Saip P, et al. Clinical parameters and treatment results in recurrent granulosa celltumor of the ovary. Gynecol Oncol 2003; 88:400.

47. Al­Badawi IA, Brasher PM, Ghatage P, et al. Postoperative chemotherapy in advanced ovarian granulosacell tumors. Int J Gynecol Cancer 2002; 12:119.

48. Chan JK, Zhang M, Kaleb V, et al. Prognostic factors responsible for survival in sex cord stromal tumorsof the ovary­­a multivariate analysis. Gynecol Oncol 2005; 96:204.

49. Lauszus FF, Petersen AC, Greisen J, Jakobsen A. Granulosa cell tumor of the ovary: a population­basedstudy of 37 women with stage I disease. Gynecol Oncol 2001; 81:456.

50. Homesley HD, Bundy BN, Hurteau JA, Roth LM. Bleomycin, etoposide, and cisplatin combinationtherapy of ovarian granulosa cell tumors and other stromal malignancies: A Gynecologic Oncology Groupstudy. Gynecol Oncol 1999; 72:131.

51. Savage P, Constenla D, Fisher C, et al. Granulosa cell tumours of the ovary: demographics, survival andthe management of advanced disease. Clin Oncol (R Coll Radiol) 1998; 10:242.

52. Colombo N, Sessa C, Landoni F, et al. Cisplatin, vinblastine, and bleomycin combination chemotherapyin metastatic granulosa cell tumor of the ovary. Obstet Gynecol 1986; 67:265.

53. Zambetti M, Escobedo A, Pilotti S, De Palo G. cis­platinum/vinblastine/bleomycin combinationchemotherapy in advanced or recurrent granulosa cell tumors of the ovary. Gynecol Oncol 1990; 36:317.

54. Schwartz PE, Smith JP. Treatment of ovarian stromal tumors. Am J Obstet Gynecol 1976; 125:402.55. Ohel G, Kaneti H, Schenker JG. Granulosa cell tumors in Israel: a study of 172 cases. Gynecol Oncol

1983; 15:278.56. Pankratz E, Boyes DA, White GW, et al. Granulosa cell tumors. A clinical review of 61 cases. Obstet

Gynecol 1978; 52:718.57. Björkholm E, Silfverswärd C. Prognostic factors in granulosa­cell tumors. Gynecol Oncol 1981; 11:261.58. Stenwig JT, Hazekamp JT, Beecham JB. Granulosa cell tumors of the ovary. A clinicopathological study

of 118 cases with long­term follow­up. Gynecol Oncol 1979; 7:136.59. Fox H, Agrawal K, Langley FA. A clinicopathologic study of 92 cases of granulosa cell tumor of the

ovary with special reference to the factors influencing prognosis. Cancer 1975; 35:231.60. Sehouli J, Drescher FS, Mustea A, et al. Granulosa cell tumor of the ovary: 10 years follow­up data of 65

patients. Anticancer Res 2004; 24:1223.61. Malmström H, Högberg T, Risberg B, Simonsen E. Granulosa cell tumors of the ovary: prognostic

factors and outcome. Gynecol Oncol 1994; 52:50.62. Gershenson DM, Hartmann LC, Young RH. Ovarian sex cord­stromal tumors. In: Principles and Practice

of Gynecologic Oncology, WJ, Young RC, Markman M, Perez CA, Barakat R, Randall M (Eds),Lippincott Williams & Wilkins, Philadelphia 2005. p.1011.

63. Wolf JK, Mullen J, Eifel PJ, et al. Radiation treatment of advanced or recurrent granulosa cell tumor ofthe ovary. Gynecol Oncol 1999; 73:35.

64. Gershenson DM, Morris M, Burke TW, et al. Treatment of poor­prognosis sex cord­stromal tumors of theovary with the combination of bleomycin, etoposide, and cisplatin. Obstet Gynecol 1996; 87:527.

65. Disaia P, Saltz A, Kagan AR, Rich W. A temporary response of recurrent granulosa cell tumor toadriamycin. Obstet Gynecol 1978; 52:355.

66. Powell JL, Otis CN. Management of advanced juvenile granulosa cell tumor of the ovary. Gynecol Oncol1997; 64:282.

67. Muntz HG, Goff BA, Fuller AF Jr. Recurrent ovarian granulosa cell tumor: role of combinationchemotherapy with report of a long­term response to a cyclophosphamide, doxorubicin and cisplatinregimen. Eur J Gynaecol Oncol 1990; 11:263.

68. Gershenson DM, Copeland LJ, Kavanagh JJ, et al. Treatment of metastatic stromal tumors of the ovarywith cisplatin, doxorubicin, and cyclophosphamide. Obstet Gynecol 1987; 70:765.

69. Pectasides D, Alevizakos N, Athanassiou AE. Cisplatin­containing regimen in advanced or recurrent

2/19/2015 Sex cord­stromal tumors of the ovary: Granulosa­stromal cell tumors

http://www.uptodate.com/contents/sex­cord­stromal­tumors­of­the­ovary­granulosa­stromal­cell­tumors?source=machineLearning&search=granulosa… 12/13

granulosa cell tumours of the ovary. Ann Oncol 1992; 3:316.70. Tresukosol D, Kudelka AP, Edwards CL, et al. Recurrent ovarian granulosa cell tumor: a case report of a

dramatic response to Taxol. Int J Gynecol Cancer 1995; 5:156.71. Brown J, Shvartsman HS, Deavers MT, et al. The activity of taxanes in the treatment of sex cord­

stromal ovarian tumors. J Clin Oncol 2004; 22:3517.72. Brown J, Shvartsman HS, Deavers MT, et al. The activity of taxanes compared with bleomycin,

etoposide, and cisplatin in the treatment of sex cord­stromal ovarian tumors. Gynecol Oncol 2005;97:489.

73. Powell JL, Connor GP, Henderson GS. Management of recurrent juvenile granulosa cell tumor of theovary. Gynecol Oncol 2001; 81:113.

74. Emons G, Schally AV. The use of luteinizing hormone releasing hormone agonists and antagonists ingynaecological cancers. Hum Reprod 1994; 9:1364.

75. Martikainen H, Penttinen J, Huhtaniemi I, Kauppila A. Gonadotropin­releasing hormone agonist analogtherapy effective in ovarian granulosa cell malignancy. Gynecol Oncol 1989; 35:406.

76. Fishman A, Kudelka AP, Tresukosol D, et al. Leuprolide acetate for treating refractory or persistentovarian granulosa cell tumor. J Reprod Med 1996; 41:393.

77. Briasoulis E, Karavasilis V, Pavlidis N. Megestrol activity in recurrent adult type granulosa cell tumour ofthe ovary. Ann Oncol 1997; 8:811.

78. Hardy RD, Bell JG, Nicely CJ, Reid GC. Hormonal treatment of a recurrent granulosa cell tumor of theovary: case report and review of the literature. Gynecol Oncol 2005; 96:865.

79. Maxwell GL, Soisson AP, Miles P. Failure of gonadotropin releasing hormone therapy in patients withmetastatic ovarian sex cord stromal tumors. Oncology 1994; 51:356.

80. Tao X, Sood AK, Deavers MT, et al. Anti­angiogenesis therapy with bevacizumab for patients withovarian granulosa cell tumors. Gynecol Oncol 2009; 114:431.

81. Cronjé HS, Niemand I, Bam RH, Woodruff JD. Review of the granulosa­theca cell tumors from the emilNovak ovarian tumor registry. Am J Obstet Gynecol 1999; 180:323.

82. Uygun K, Aydiner A, Saip P, et al. Granulosa cell tumor of the ovary: retrospective analysis of 45 cases.Am J Clin Oncol 2003; 26:517.

83. Lee YK, Park NH, Kim JW, et al. Characteristics of recurrence in adult­type granulosa cell tumor. Int JGynecol Cancer 2008; 18:642.

84. Auranen A, Sundström J, Ijäs J, Grénman S. Prognostic factors of ovarian granulosa cell tumor: a studyof 35 patients and review of the literature. Int J Gynecol Cancer 2007; 17:1011.

85. Ala­Fossi SL, Mäenpää J, Aine R, et al. Prognostic significance of p53 expression in ovarian granulosacell tumors. Gynecol Oncol 1997; 66:475.

86. Roush GR, el­Naggar AK, Abdul­Karim FW. Granulosa cell tumor of ovary: a clinicopathologic and flowcytometric DNA analysis. Gynecol Oncol 1995; 56:430.

87. Crew KD, Cohen MH, Smith DH, et al. Long natural history of recurrent granulosa cell tumor of the ovary23 years after initial diagnosis: a case report and review of the literature. Gynecol Oncol 2005; 96:235.

88. Ishiko O, Yoshida H, Sumi T, et al. Vascular endothelial growth factor levels in pleural and peritonealfluid in Meigs' syndrome. Eur J Obstet Gynecol Reprod Biol 2001; 98:129.

89. Stuart GC, Dawson LM. Update on granulosa cell tumours of the ovary. Curr Opin Obstet Gynecol 2003;15:33.

90. Chechia A, Attia L, Temime RB, et al. Incidence, clinical analysis, and management of ovarian fibromasand fibrothecomas. Am J Obstet Gynecol 2008; 199:473.e1.

91. Brun JL. Demons syndrome revisited: a review of the literature. Gynecol Oncol 2007; 105:796.92. MEIGS JV. Fibroma of the ovary with ascites and hydrothorax; Meigs' syndrome. Am J Obstet Gynecol

1954; 67:962.93. Timmerman D, Moerman P, Vergote I. Meigs' syndrome with elevated serum CA 125 levels: two case

reports and review of the literature. Gynecol Oncol 1995; 59:405.94. Peparini N, Chirletti P. Ovarian malignancies with cytologically negative pleural and peritoneal effusions:

demons' or meigs' pseudo­syndromes? Int J Surg Pathol 2009; 17:396.95. Tsuji T, Catasus L, Prat J. Is loss of heterozygosity at 9q22.3 (PTCH gene) and 19p13.3 (STK11 gene)

involved in the pathogenesis of ovarian stromal tumors? Hum Pathol 2005; 36:792.96. DiSaia PJ, Creasman WT. Germ cell, stromal and other ovarian tumors. In: Clinical Gynecologic

2/19/2015 Sex cord­stromal tumors of the ovary: Granulosa­stromal cell tumors

http://www.uptodate.com/contents/sex­cord­stromal­tumors­of­the­ovary­granulosa­stromal­cell­tumors?source=machineLearning&search=granulosa… 13/13

Oncology, 7th, Mosby­Elsevier, 2007. p.387.97. Roth LM, Czernobilsky B. Perspectives on pure ovarian stromal neoplasms and tumor­like proliferations

of the ovarian stroma. Am J Surg Pathol 2011; 35:e15.98. Nowak M, Podciechowski L, Krawczyk T, Wilczynski J. Meigs' syndrome and virilizing ovarian

fibrothecoma complicating pregnancy. A case report and review of the literature. Neuro Endocrinol Lett2009; 30:192.

99. Elghorori MR, Al­Taher H, Redwood NF. Ovarian fibrothecoma: a benign neoplasm with potentialadverse consequences. J Obstet Gynaecol 2003; 23:677.

100. Liu H, Hao SH, Li WM. Giant malignant ovarian fibrothecoma involved with retroperitoneal structuresmimicking a retroperitoneal sarcoma. Arch Gynecol Obstet 2009; 279:763.

101. Troiano RN, Lazzarini KM, Scoutt LM, et al. Fibroma and fibrothecoma of the ovary: MR imagingfindings. Radiology 1997; 204:795.

102. Jung SE, Rha SE, Lee JM, et al. CT and MRI findings of sex cord­stromal tumor of the ovary. AJR AmJ Roentgenol 2005; 185:207.

103. Tanaka YO, Saida TS, Minami R, et al. MR findings of ovarian tumors with hormonal activity, withemphasis on tumors other than sex cord­stromal tumors. Eur J Radiol 2007; 62:317.

104. Okajima Y, Matsuo Y, Tamura A, et al. Intracellular lipid in ovarian thecomas detected by dual­echochemical shift magnetic resonance imaging: report of 2 cases. J Comput Assist Tomogr 2010; 34:223.

Topic 3234 Version 16.0