Susan C. Modesitt and Jubilee Brown
Germ Cell Tumors
Germ cell tumors of the ovary comprise fewer than 5% of all malignant ovarian tumors. Germ cell tumors arise from the primordial germ cells and sex cord-stromal derivatives; they are exceedingly common in that they account for approximately one-quarter of all ovarian tumors, yet only 1% to 5% of germ cell tumors are malignant.1-5 This disease is characterized by a young age at diagnosis. Survival is excellent due to the typically early stage at diagnosis and the relative chemosensitivity of even advanced disease, especially in comparison with epithelial ovarian, tubal, and peritoneal cancers.
EPIDEMIOLOGY
Key Points
1. The peak incidence of these tumors occurs in the 15- to 19-year-old age range.
2. Germ cell tumors may occur in setting of dysgenetic gonads, so karyotype testing may be warranted.
Within the United States, the incidence (age-adjusted) of malignant germ cell tumors is estimated at between 0.34 to 0.41 per 100,000, and rates appear to have declined over the last 30 years.1,2 Risk factors are not well understood, but include younger age; the 15- to 19-year-old age group has by far the highest incidence rates. Studies have not consistently confirmed other specific demographic characteristics, such as in utero exposures (hormones, pesticides, smoking, or alcohol), maternal reproductive history, parental occupation, or congenital abnormalities as associated risk factors for germ cell tumors.6-8 Racial differences exist in that dysgerminoma occurs twice as often in whites and other nonwhites as compared with blacks, and teratoma incidence is increased for blacks and other nonwhites as compared with whites; there appear to be no significant differences for the remainder of types.2,9
As opposed to some epithelial and stromal ovarian malignancies, germ cell tumors in females do not appear to be related to any yet-identified inherited cancer susceptibility syndromes (eg, BRCA mutations for epithelial ovarian, tubal, and peritoneal cancers and Peutz-Jegher syndrome for certain ovarian stromal tumors).10 Surprisingly, in a recent review of pediatric germ cell tumors, a family history of testicular cancer was correlated with an increased risk of male germ cell tumors; however, a family history of ovarian or uterine cancer was inversely correlated with female germ cell tumors.10 In contrast, there have been several case reports of familial clustering of germ cell tumors, and authors have hypothesized that a fraction of ovarian germ cell tumors could be a rare manifestation of a familial gonadal tumor syndrome.11
Of particular note, however, is that women with gonadal dysgenesis are at very high risk for the development of germ cell tumors. Gonadal dysgenesis is defined as a defect in development that causes abnormal sex steroid production and subsequent clinical manifestations such as delayed puberty or primary amenorrhea. In general, Turner syndrome (normally 45 X, or rarely a mosaic form of 45 X with a partial Y fragment) accounts for approximately two-thirds of diagnosed dysgenetic gonads. The majority of patients with Turner syndrome who develop tumors have the mosaic karyotype. Gonadal dysgenesis may also occur in 46 XX or 46 XY individuals. The greatest risk for germ cell tumors, especially dysgerminomas, is found in patients with Swyer syndrome (complete gonadal dysgenesis with 46 XY, but a female phenotype) and may affect more than 30% of patients12; prophylactic removal of both gonads should be strongly considered as soon as one of these syndromes is diagnosed.13
DIAGNOSIS
Key Points
1. Pelvic pain or mass is the most common presenting symptom of women with germ cell tumors.
2. The majority of germ cell tumors are stage IA at diagnosis.
3. Malignant germ cell tumors characteristically appear solid on imaging ultrasonography.
Most women with germ cell tumors present during the reproductive years, with a mean age in the early 20s. The most frequent symptoms are pelvic pain and/or mass (up to 85% of patients) followed by abdominal distension (30%), fever (10%), vaginal bleeding (10%), or ovarian torsion.1,3,5 Of note, in ovarian torsion cases, up to 10% of adult cases but fewer than 2% of pediatric cases are ultimately proven to be caused by a malignant process. 5,14,15
As part of the initial work-up for a pelvic mass in a young woman, ultrasound is the preferred radiographic modality due to the information gleaned regarding ovarian morphology and the lack of radiation. The majority of germ cell tumors are also unilateral. Only dysgerminomas are observed to be bilateral in 10% to 15% of cases.3,5
In addition, the majority of the malignant germ cell tumors will be predominantly solid (Figure 14-1).16,17 Ultrasound alone may be able to raise the suspicion for an immature teratoma (or other malignant germ cell tumor) as opposed to its far more common benign counterpart, a mature cystic teratoma. A recent study from Canada evaluating ultrasound characteristics in teratomas found that benign cystic teratomas were more commonly predominantly cystic (77% vs. 18%), and the entirely solid tumors were all immature teratomas.17 Another recent study in the pediatric population also observed that the benign ovarian germ cell tumors were smaller (7.65 cm vs. 16.9 cm; P < .001) and more often cystic compared with their malignant counterparts.16 For evaluation of extraovarian disease, magnetic resonance imaging (MRI), computed tomography (CT), and positron emission tomography (PET) may be used, but due to the relatively low likelihood of malignancy and incidence of extraovarian metastases in germ cell tumors, this is often omitted during the initial mass evaluation.
FIGURE 14-1. Ultrasound demonstrating a dysgerminoma of the ovary (white solid arrow) with the adjacent normal ovarian tissue with follicles (white dashed arrow).
Diagnostic testing should include preoperative evaluation of tumor markers and should include quantitative human chorionic gonadotropin (hCG), lactate dehydrogenase, α-fetoprotein (AFP), CA-125, and baseline blood work for surgery.1,3,5,18,19 The most commonly abnormal tumor markers are hCG and AFP, and elevations are virtually diagnostic of a malignant germ cell tumor; specific patterns of tumor markers vary by tumor types (Table 14-1). Newer tumor markers may help differentiate malignant from benign masses; for example, the newly US Food and Drug Administration–approved OVA1 test (representing a combination of 5 immunoassays, including CA-125, transthyretin, apolipoprotein A1, β-2 microglobulin, and transferrin) demonstrated a 78% sensitivity for malignant nonepithelial ovarian cancers. Further research is needed, however, before applying the OVA1 test to these rare tumor types.20 For patients with suspected gonadal dysgenesis, a karyotype should be performed before surgery, if possible, to ensure both ovaries are removed if indicated.
Table 14-1 Tumor Markers in Germ Cell Tumors
Definitive diagnosis is via surgical removal using a method that allows full surgical staging if necessary and can be done via laparotomy or laparoscopy, depending on patient and mass characteristics, as well as surgeon preference. The ovary should be removed intact (ie, no intra-abdominal morcellation). Frozen section can confirm the diagnosis and further surgical management undertaken as appropriate (see Treatment section).
PATHOLOGY
Key Points
1. Dysgerminoma and immature teratoma are most common malignant types of germ cell tumors.
2. Immature teratomas are defined by the presence of immature neural elements.
3. The hallmark histopathologic feature of endodermal sinus tumors is the Schiller-Duval body.
In the latest World Health Organization (WHO) classification, germ cell tumors are categorized into 3 broad categories (Table 14-2) that include (1) primitive germ cell tumors, (2) biphasic or triphasic teratoma, and (3) monodermal teratomas (including somatic tumors arising within teratomas). Malignant germ cell tumors include immature teratomas, dysgerminomas, and endodermal sinus tumors, along with the less common types. A recent Surveillance, Epidemiology, and End Results (SEER) data review of malignant germ cell tumors found that the most frequently diagnosed subtypes were immature teratoma (36%), dysgerminoma (33%), endodermal sinus tumor (15%), mixed non-dysgerminoma types (5%), embryonal (4%), mature teratoma with malignant degeneration (3%), and choriocarcinoma (2%).2
Table 14-2 Categories of Germ Cell Tumors
|
I. Primitive germ cell tumors |
|
Dysgerminoma |
|
II. Biphasic or triphasic teratoma |
|
Immature teratoma |
|
Solid |
|
III. Monodermal teratoma and somatic-type tumors associated with group II (above) |
|
Thyroid (struma ovarii) |
Adapted from World Health Organization classification of tumors: Tavassoli FA, Deville P. Pathology and Genetics of Tumors of the Breast and Female Genital Organs. Lyon, France: International Agency for Research on Cancer; 2003.
Grossly and histologically, several tumor types have distinctive appearances. Dysgerminomas are primarily solid tumors with a gray/white appearance and microscopically have sheets of vesicular cells with large nuclei with a fibrous stroma separating them (Figure 14-2). Immature teratomas are usually more solid than cystic and may contain hair or sebaceous material in a similar manner to mature teratomas; there is often extensive necrosis and hemorrhage. The immature components are comprised of neural tissue (required for diagnosis; Figure 14-3); they may also include glands, bone, or muscle.20 Endodermal sinus tumors may be both solid and cystic with soft, friable tissue that may often be either hemorrhagic or necrotic (Figure 14-4). The hallmark histologic feature associated with endodermal sinus tumors is the Schiller-Duval body, which most closely resembles a renal glomerulus. Embryonal carcinomas maybe histologically solid (with diffuse sheets of ana-plastic cells), tubular, or papillary; frequently there is a combination of these patterns (Figure 14-5). There is commonly foci of coagulative necrosis, and spindle cell stroma around tumor nests.
FIGURE 14-2. Dysgerminoma. A. Gross picture of dysgerminoma. B. Micrograph of dysgerminoma. (Image contributed by Dr. Kristen Atkins, Department of Pathology, University of Virginia Health System.)
FIGURE 14-3. Micrograph of immature teratoma. (Image contributed by Dr. Kristen Atkins, Department of Pathology, University of Virginia Health System.)
FIGURE 14-4. Endodermal sinus tumor. A. Micrograph of endodermal sinus tumor with typical vitelline growth pattern. (Image contributed by Dr. Kristen Atkins, Department of Pathology, University of Virginia Health System.) B. Micrograph of endodermal sinus tumor with associated Schiller-Duval body.
FIGURE 14-5. Micrograph of embryonal carcinoma.
TREATMENT
Key Points
1. Complete surgical resection is critical in the management of germ cell tumors.
2. Controversy exists regarding the need for comprehensive surgical staging in the pediatric population.
3. Adjuvant platinum-based chemotherapy has been recommended for treatment of all malignant germ cell tumors except stage I dysgerminoma and stage I, grade 1 immature teratomas.
4. In general, germ cell tumors are both chemo- and radiosensitive, even in advanced or recurrent disease.
Surgery
The mainstay of treatment for malignant germ cell tumors is surgery, as approximately 60% of all germ cell tumors will be confined to the ovary, and most (except dysgerminomas) are unilateral.3,5 Although ovarian cystectomy is not recommended if the diagnosis is known intraoperatively, excellent survival rates after cystectomy for immature teratoma have been reported, but notably, most patients received adjuvant chemotherapy.21 Few dispute the necessity of removal of the involved ovary, but there are divergent opinions regarding the extent (or necessity) of comprehensive surgical staging. In the gynecologiconcology community, the standard recommended surgery has included a unilateral salpingo-oophorectomy (and bilateral salpingo-oophorectomy with hysterectomy if future fertility is not desired), peritoneal cytology, peritoneal biopsies, omentectomy, and retroperitoneal lymphadenectomy, including removal of bilateral pelvic and para-aortic nodes and any abnormal tissue. Because of the extremely chemosensitive nature of the disease, extensive and aggressive surgical resection procedures may not be advised if they increase morbidity or would delay chemotherapy.
In one of the largest reviews of lymph node metastasis, Kumar et al4 found that approximately half of all patients with germ cell tumor in the SEER database diagnosed between 1988 and 2004 did not have lymph node dissection done as part of their surgery. Of the patients who did undergo lymph node dissection, overall 18% had positive nodes, and women with dysgerminoma had the highest rate of node metastases at 28%. Positive lymph nodes, not surprisingly, were an independent negative predictor of survival. Another study by Palenzuela et al22 noted that only approximately half of the malignant germ cell tumors underwent comprehensive staging; none of the stage IA patients who underwent complete surgical staging experienced recurrence during observation without adjuvant chemotherapy, and none of the stage I patients who received adjuvant chemotherapy experienced recurrence, whereas approximately 40% of the patients with presumed (but not fully staged) stage I disease had recurrence.
In the pediatric oncology and surgery community, there has been a potential shift toward even more minimal surgery (unilateral salpingo-oophorectomy, washings, directed peritoneal biopsies, and careful abdominal inspection without retroperitoneal lymphadenectomy or omentectomy unless abnormalities are detected/palpated).23 This change has occurred, in large part, from a study by Billmire et al24 that reviewed the role and outcomes of surgical staging in germ cell tumors in children and adolescents enrolled in 2 large intergroup trials that involved postoperative chemotherapy treatment (bleomycin, etoposide, and cisplatin [BEP] or high-dose cisplatin with etoposide and bleomycin). They found that deviations from standard surgical guidelines were the norm (most often the omission of lymphadenectomy), but that survival was excellent regardless of the extent of staging. They concluded that surgery should include washings, excision of any abnormal peritoneal surfaces, biopsy of any abnormal nodes or an abnormal contralateral ovary, and removal of the tumor-containing ovary. 23,24 However, all of the participants in this study received adjuvant platinum-based chemotherapy, which may have minimized any benefit of surgical staging in this very chemosensitive group of tumors.24,25
Most recently, a large Children’s Oncology Group (COG) study examining surveillance of patients with stage I germ cell tumors who did not undergo chemotherapy closed to accrual in 2010; however, these data are not yet available. Of note, the COG uses a modified staging system (not the standard International Federation of Gynecology and Obstetrics [FIGO] staging26) in which lymphadenectomy and omentectomy are not routinely performed, tumor markers and radiographic imaging are employed as part of the staging assignment process, and patients who have positive washings/cytology/ascites are classified as having a stage III tumor25(Table 14-3, COG staging; Table 14-4, FIGO staging).
Table 14-3 Children’s Oncology Group Staging for Ovarian Germ Cell Tumor
Table 14-4 FIGO Staging for Ovarian Tumors
In summary, in adult women, full staging including lymphadenectomy allows better counseling regarding the need for postoperative adjuvant therapy; however, gynecologic oncologists need to be aware that this may not be the standard practice in pediatric patients who undergo surgery with other specialists.
Chemotherapy
Postoperative chemotherapy has been generally recommended for all malignant germ cell tumors with the exception of stage I dysgerminomas and stage I immature teratomas (low grade). There has been a recent trend toward the consideration of surveillance in all stage I germ cell tumors, as many contend that recurrences are almost always successfully treated with salvage therapy; this would obviate the need for initial adjuvant chemotherapy and eliminate chemotherapy-associated short- and long-term adverse sequelae.1,3,27 Given the rarity of this disease and the overall excellent prognosis of patients with stage I disease, no randomized trial comparing surveillance with adjuvant therapy in adults will likely ever be undertaken, although a surveillance study has been completed (but not reported) in the COG for all stage I malignant germ cell tumors.
To evaluate the strategy of surveillance after surgery for all stage IA germ cell patients, Patterson et al27 reported a recurrence rate of 22% in dysgerminomas and a 36% recurrence rate for the other types. Additionally, they reported a salvage/cure rate of 90% in patients with recurrent disease. The authors concluded that all patients with stage I disease may be safely observed; however, their recurrence rates are much higher than those reported for stage I patients receiving adjuvant treatment, and not all recurrences were cured. Further, this was a small study with 37 patients (some previously reported), and this limits the conclusions.27 In other studies reported in the late 1990s and early 2000s, 3 groups evaluated surveillance alone in stage I germ cell tumors (83 patients), with an overall survival rate of 97%; 92% (12 of 13) of those patients who experienced disease recurrence were subsequently cured with chemotherapy.3,28-31 A recent study by Vicus et al32 of pure dysgerminomas found that the recurrence rate for stage IA patients without adjuvant therapy was 22% compared with 0 for those who received adjuvant treatment; again, all patients who experienced recurrence were cured. Of note, only 4 patients of the entire 65 patients in that study underwent full surgical staging (including lymphadenectomy and omentectomy).
Ultimately, the choice of adjuvant chemotherapy for stage I germ cell malignancy remains controversial and is influenced by both patient and physician preferences. Chemotherapy may be overtreatment for many women, whereas surveillance may represent undertreatment for others who might not be cured at the time of recurrence. Especially, in the absence of full surgical staging, the recurrence rates for presumed stage I malignant germ cell tumors will be approximately 20% to 40%.
Historically, the cure rate for malignant germ cell tumors has been exceedingly poor, as all women with advanced-stage disease died, and a minority of even patients with presumed stage I disease survived before the advent of chemotherapy.3 Initially, vincristine, actinomycin D, and cyclophosphamide (VAC) was used, and cure rates improved. With the advent of platinum agents, cure for this disease, even in advanced stages, is the rule rather than the exception. The mainstay of platinum-based regimens for this disease is currently BEP, and this is the recommended primary adjuvant therapy according to several large Gynecologic Oncology Group studies as well as the National Comprehensive Cancer Network guidelines.1,3,5,18,25 A common adult regimen is bleomycin 30 units/wk, etoposide 100 mg/m2/d for 5 days, and cisplatin 20 mg/m2/d for 5 days on a 4-week schedule, but multiple other dosing schemes are reported. For other patients for whom toxicity concerns are a priority, an alternate regimen is etoposide (120 mg/m2/d for 3 days) and carboplatin (400 mg/m2 on day 1) for 3 cycles on a 4-week schedule or EP (BEP regimen without the bleomycin). Other active regimens that have been used include cisplatin, vincristine, methotrexate, and bleomycin (POMB); vinblastine, bleomycin, and cisplatin; actinomycin D, cyclophosphamide, and etoposide (ACE); or vincristine, ifosfamide, and cisplatin (VIP).
Most women who present with advanced-stage disease at diagnosis still undergo surgical staging and/or debulking followed by chemotherapy. Given the extremely chemosensitive nature of the disease, however, there have been recent reports advocating the possible use of neoadjuvant chemotherapy (where chemotherapy is given before surgical resection) and fertility preservation. Raveendran et al33 reported 2 patients with advanced germ cell tumors who underwent neoadjuvant chemotherapy (BEP) and had no viable tumor at interval surgery with excellent survival.
Radiation
Germ cell tumors are also very radiosensitive, with excellent responses after radiation therapy. Since the advent of effective chemotherapy, however, the use of radiation in the adjuvant setting for germ cell tumors has been largely abandoned due to the detrimental effects on future fertility and the potential for late side effects. In the past, women with dysgerminomas were treated with either pelvic and para-aortic radiation or whole abdominal radiation with cure rates approaching 100% for early stage and approximately 60% for advanced disease.5,32
SURVIVAL AND PROGNOSIS
Key Points
1. In general, survival for germ cell tumors is excellent, and most women are cured with surgery and chemotherapy.
2. Advanced stage remains the most important negative prognostic factor.
3. Elevated initial tumor markers may portend worse prognosis.
The overall survival for malignant ovarian germ cell tumors remains excellent, and the reported 5-year survival rates range from 80% to 97% and vary according to well-established prognostic factors, particularly stage.2,4,9,14,24,27,34-36 Since the advent of platinum-based chemotherapy, cure rates for stage I disease are almost 100%, and even in advanced disease, cure rates approach 75%.3
Stage remains the most important prognostic factor in determining both recurrence risk and overall survival.1,3,5,35-37 Almost all stage I/II cancers are cured, but patients with advanced-stage disease are more likely to experience recurrence. For example, Chan et al36 reported a significant survival difference (97.6% for stage I/II vs. 85.5% for stage III/IV); 
) for all germ cell tumors in a recent SEER analysis. All advanced-stage tumors were treated with adjuvant chemotherapy as described previously. Similarly, the presence of lymph node involvement (denoting advanced stage) in a recent SEER analysis conferred a 3-fold increase risk of death compared with women without lymph node involvement.4
Tumor marker elevation (primarily hCG and AFP) at diagnosis has been relatively consistently linked to increased recurrence rates (3- to 4-fold relative risk), but although this finding has been consistent, it is not necessarily universal.5,37,38 Failure to normalize tumor markers indicates persistent disease and mandates further treatment.
Histologic type has also been found to be indicative of recurrence. Dysgerminomas have a better prognosis than the other types and have less recurrence risk.3,5,35,36 In a comparison of the impact of the 3 main histologic types, dysgerminomas appear to have the best 5-year survival rates, followed by immature teratomas and then endodermal sinus tumors (99.5% vs. 94.3% vs. 85.5%; 
).36 Lai et al35 found a 100% 5-year overall survival rate for the dysgerminoma and immature teratoma patients compared with 80% other types combined 
. Data on endodermal sinus tumors are limited to case series from single institutions or SEER data but indicate a 5-year survival rate of 72% to 90%.36,39-41 Of note, these tumors may more often be late stage; in one series, 31% of patients with endodermal sinus tumors experienced recurrence (all within 8 months), and only 1 patient was cured.39
Racial disparities have also been documented, with black and white women having lower survival rates compared with other nonwhites; it has been hypothesized that this discrepancy for black women may represent diminished access to treatment.2 Another study found a difference in survival for white compared with blacks (92% vs. 86%; P = .02) . However, on multivariate analysis that controlled for complete surgical staging, stage, and histologic type, this difference was no longer significant.9
MANAGEMENT OF RECURRENT DISEASE
Key Points
1. The majority of women with recurrent disease naïve to chemotherapy can be treated and cured.
2. Most recurrences are diagnosed within a year and very rarely after 2 years. Options for platinum-resistant disease are limited.
Most recurrences of germ cell tumors occur within the first year, and almost none is ever reported after 2 years of follow-up.1,3,5,35,37,38 Recurrences are most often detected by tumor markers but also are detected on physical or radiographic imaging. For those patients who did not receive initial chemotherapy and then experience recurrence during surveillance, BEP remains the drug regimen of choice, with an almost 100% cure rate. When including all patients with recurrent germ cell tumors, the overall salvage rate for recurrence, however, is approximately 50%.3 The optimal treatment of recurrent cancer in those women previously treated with BEP is less clear, in part due to the paucity of patients, and regimens have been adopted based on the testicular germ cell trials. Some small studies suggest a role for high-dose salvage chemotherapy with stem cell transplant, with successful long-term cures documented, but most data on this modality are from the testicular germ cell tumors.35,42 Other options that have been reported with varying success include all the previously mentioned chemotherapeutic combinations in upfront therapy (eg, BEP, VIP, PVB, POMB, ACE) as well as some new regimens undergoing evaluation, including paclitaxel/carboplatin/ifosfamide, gemcitabine, oxaliplatin/paclitaxel, and targeted therapies including bevacizumab, sunitinib, and flavopiridol.
Data supporting a role for surgical resection for chemotherapy-refractory recurrent disease are limited. In one of the only case series reported, Munkarah et al43 demonstrated limited efficacy and suggested that the role of secondary cytoreductive surgery might be limited to immature teratoma.
SPECIAL MANAGEMENT ISSUES
Fertility Preservation
Because most women with germ cell tumors are of reproductive age, fertility-sparing surgery has become the standard of care and does not adversely affect clinical outcomes.1,3,5,14,18,22-24,27,36,37,44 Fertility-sparing surgery is defined as preserving the uterus at a minimum and usually preserving the normal contralateral ovary as well. A recent SEER database review found that the median age of patients with germ cell tumors in the United States was 23 years, and the vast majority of patients had stage I or II disease. In this review, 41% received fertility-preserving surgery; this percentage increased over the time period studied, with almost half (48.4%) having fertility preservation for the most recent time period examined (1998-2001).36 There were no significant survival differences observed between women treated with fertility-preserving surgery compared with those undergoing hysterectomy and bilateral salpingo-oophorectomy.
For those young women who undergo fertility preservation, several studies have documented that most will return or attain normal menstrual function, even after chemotherapy administration.14,44,45 Yoo et al45 found that 89% of prepubertal girls and 94% of adolescents treated with chemotherapy (primarily BEP), subsequently experienced normal menses; similarly, Biswajit14 reported 100% resumption of normal menses after treatment with chemotherapy. Gershenson et al44 surveyed 132 women who had undergone treatment for germ cell malignancies and found that approximately 54% had fertility preservation and 87% of those still reported normal menstrual function; successful pregnancies were reported in approximately a third of the fertile women (of note, almost 40% were using birth control at the time of the survey). Several other authors have also reported that women can achieve pregnancy after treatment for germ cell tumors: Tangir et al46 reported 76%, Zanetta et al47 reported 86%, and de La Motte Rouge40 reported that 75% of women who attempted pregnancy were able to conceive.
Long-Term Sequelae of Treatment
Given the young age at diagnosis, women undergoing treatment for germ cell tumors also can develop late effects relating to therapy (primarily chemotherapy). In addition to the hormonal and reproductive factors addressed previously, women can develop from delayed puberty, irregular menses, and premature menopause. Of note, germ cell cancer survivors who were younger at diagnosis and report fewer gynecologic symptoms have associated better physical functioning.48 Additionally, women may develop neurotoxicity due to chemotherapy, and this finding is the most highly predictable for decreased physical quality of life.48 In comparing germ cell survivors with controls, survivors were more likely to report high blood pressure, high cholesterol, and chronic functional problems, including numbness, tinnitus, or nausea, but were less likely to report joint pain or muscle cramps.49 Most survivors have a quality of life comparable to that of controls with these minimal exceptions.
One of the most devastating potential late toxicities is the development of a secondary malignancy; this is most commonly attributed to etoposide and/or cisplatin and may approach 1% of all patients.5
FUTURE DIRECTIONS
Young women with malignant germ cell tumors have generally excellent cancer-specific outcomes and can return to almost normal life after treatment. Further research needs to confirm whether surveillance can replace adjuvant chemotherapy in all presumed stage I cancers, even if comprehensive surgical staging has not been performed. Additional therapies are needed for the rare platinum-refractory recurrences, and this may be anti-angiogenesis agents or other targeted therapies.
Sex Cord-Stromal Ovarian Tumors
Sex cord-stromal ovarian tumors are considered rare ovarian tumors and comprise between 3% and 10% of all ovarian malignancies. Because of their relative rarity, treatment guidelines are based on limited data that combine histologic subtypes. In general, most ovarian stromal tumors are clinically indolent and are reported to have excellent long-term prognoses. However, many occur in adolescent and reproductive-aged women, and therefore, individualized treatment with consideration for fertility preservation is of great importance. Appropriate treatment guidelines are based on individual factors and consist of surgical staging, tumor reduction, and systemic therapy. Stromal tumors of the ovary represent a small portion of ovarian cancers, but are important to distinguish from other types of ovarian neoplasms, because their histologic origin, natural history, and treatment recommendations are distinct from other ovarian cancer histologies.
EPIDEMIOLOGY
Key Points
1. The majority of sex cord-stromal cell tumors occur in women of reproductive age.
2. Sex cord-stromal tumors account for 10% to 15% of all childhood ovarian malignancies.
3. Adult granulosa cell tumors represent the most common histologic subtype.
Ninety percent of ovarian malignancies are epithelial in origin, with the remaining 10% comprising sex cord-stromal tumors, germ cell tumors, soft tissue tumors not specific to the ovary, unclassified tumors, and metastatic tumors.50The histologic classification of ovarian stromal tumors is presented in Table 14-5.50 Estimates from the SEER database between 1975 and 1998 suggest that for each 5-year interval between ages 15 and 40 years, the incidence of non–germ cell ovarian malignancy increases from 8 per million to 79 per million women per year.51 However, these data are not specific for stromal ovarian tumors. In general, it has been estimated that malignant stromal tumors of the ovary account for between 3% and 10% of all ovarian malignancies.52-54
Table 14-5 World Health Organization for Classification of Stromal Tumors of the Ovary
Granulosa cell tumors, the most common histo-logic subtype, comprise between 2% and 5% of all ovarian cancers and represent 90% of stromal ovarian tumors, yielding an incidence of 0.58 to 1.6 cases per 100,000 women.55-57Both adult- and juvenile granulosa cell tumors occur, with the adult subtype representing 95% of all granulosa cell tumors. Most adult granulosa cell tumors occur during the reproductive or perimenopausal years, whereas most juvenile types occur during childhood and adolescence. The designation of juvenile versus adult granulosa cell tumors is not based on age alone, as they are distinct in natural history and pathologic characteristics.
Many of these tumors occur in adolescent and young women and require special consideration with regard to fertility preservation. Although most adolescents and young adults with ovarian malignancies do have ovarian germ cell tumors, 10% to 15% of childhood ovarian tumors are sex cord-stromal,58 with juvenile granulosa cell tumors most often occurring in childhood and Sertoli-Leydig cell tumors and unclassified sex cord-stromal tumors occurring during puberty.59 One study identified 38 cases of pediatric ovarian tumors, and 15% were stromal ovarian tumors, all of which were juvenile granulosa cell tumors.60 Neonatal presentations of juvenile granulosa cell tumors also occur.11
Thecomas, fibromas, and fibrothecomas usually occur in postmenopausal women. The mean age at diagnosis is 48 years, and only 10% of patients are less than 30 years of age.61,62 These tumors are most often benign and are not usually considered to be malignant. However, ovarian fibromas are the most common type of ovarian stromal tumor, and when combined, these tumors account for 1% of all ovarian neoplasms.
Sertoli-Leydig cell tumors may contain only Sertoli cells, only Leydig cells, or both. These rare tumors represent fewer than 1% of all ovarian tumors. They are classified into 5 groups: well differentiated, intermediately differentiated, poorly differentiated, retiform, and mixed. Sertoli-Leydig cell tumors tend to occur in young adult women with a mean age of 25 years. Intermediate and poorly differentiated tumors tend to be more aggressive and occur approximately 10 years earlier than intermediate or poorly differentiated tumors. The retiform type is usually diagnosed at an even younger age than intermediate or poorly differentiated types.63,64 Both isolated Sertoli tumors and Sertoli-Leydig tumors usually occur in women in their teens and 20s. Thus fertility preservation is an important consideration in many of these patients, and this is usually appropriate, as more than 95% of all tumors are unilateral with a normal uterus.65-67
Sex cord tumor with annular tubules (SCTAT), first described by Scully68 in 1970, was identified in association with Peutz-Jeghers syndrome. Approximately 15% of these tumors are associated with adenoma malignum of the cervix.69 These tumors are uncommon in adolescents, but have been reported to present with isosexual precocity.70
Gynandroblastomas are a separate, rare type of stromal tumor, which occur most often during the third to fifth decades of life and account for fewer than 1% of all ovarian stromal tumors.71
Steroid (lipid) cell tumors consist of stromal luteomas, Leydig cell tumors, and steroid cell tumors not otherwise specified. In combination, these 3 neoplasms represent fewer than 0.1% of all ovarian tumors. Stromal luteomas are benign lesions that represent approximately one-fourth of steroid cell tumors. These may occur during pregnancy but are most common during the postmenopausal years. Leydig cell tumors represent 15% to 20% of all steroid cell tumors of the ovary and usually occur in postmenopausal women. Steroid cell tumors not otherwise specified are the most common type of steroid cell tumor and can be malignant and quite aggressive. Steroid cell tumors not otherwise specified present at a mean age of 43 years.
Sclerosing stromal tumor of the ovary is an extremely rare benign ovarian neoplasm that occurs primarily in women under 30 years of age and is usually unilateral.72
DIAGNOSIS
Key Points
1. Women with sex cord-stromal tumors typically present with signs and symptoms of a pelvic mass.
2. Women with granulosa cell tumors may present with hemoperitoneum.
3. Elevations in inhibin A, inhibin B, and/or CA-125 serum levels may suggest a sex cord-stromal tumor preoperatively.
The definitive diagnosis of an ovarian sex cord-stromal tumor is based on histologic evaluation of the removed tumor specimen. However, the history and physical examination, radiographic imaging, and laboratory testing may suggest the diagnosis preoperatively.
In a woman with a pelvic mass, a detailed patient history may offer suggestions regarding the tumor histology. The patient is often in her adolescent or young adult years, as noted previously. She may present with symptoms of a pelvic mass, including bloating, pelvic pressure or pain, increase in abdominal girth, and gastrointestinal or urinary symptoms. Abdominal pain may be a presenting complaint, especially in patients with hemoperitoneum resulting from a granulosa cell tumor. The physical examination usually suggests a pelvic mass. In the case of a ruptured granulosa cell tumor, signs of hemoperitoneum can include abdominal tenderness, peritoneal signs, a fluid wave, and even hemo-dynamic instability.
Because stromal tumors of the ovary arise from steroid-producing cells, these tumors are often hormonally active, producing estrogen, progesterone, and androgens. Therefore, hirsutism, virilism, and/or isosexual precocious puberty may be present.73 During the reproductive years, patients may present with menorrhagia, irregular menstrual bleeding, and amenorrhea. Postmenopausal patients may report vaginal bleeding, breast enlargement or tenderness, and vaginal cornification.74
Patients with adult granulosa cell tumors can frequently present with abnormal vaginal bleeding, abdominal distention and/or pain, and occasionally signs of virilism and usually present with a unilateral pelvic mass.74,75 The potential for a hereditary component has been suggested in a report regarding 2 first-degree relatives, but this observation is isolated. Therefore, family history should not be assumed to be a risk factor or suggest a diagnosis.76
Patients with a juvenile granulosa cell tumor typically present with a palpable mass on pelvic or rectal examination, and more than 95% are unilateral.77,78 An association has been described between juvenile granulosa cell tumors and Ollier disease (enchondromatosis) and Maffucci syndrome (enchondromatosis and hemangiomatosis). An increased risk for the development of breast cancer has also been reported.79
Thecomas are often hormonally active and may cause abnormal vaginal bleeding as the most common presenting symptom. Endometrial hyperplasia occurs in 37% to 50% of patients with thecomas, and up to 27% have an associated endometrial carcinoma.61,62,80 Therefore, any patient presenting with abnormal bleeding should always have the endometrium sampled preoperatively. Thecomas may also be luteinized, which may cause androgen production and virilization.81
In contrast, fibromas are usually benign, unilateral, and hormonally inactive tumors, and therefore, patients may present with pelvic pressure or pain and a mass. Approximately 30% of patients with tumors more than 6 cm in size have ascites. This can lead to hydrothorax in 1% of patients with fibromas; the constellation of hydrothorax, ascites, and ovarian fibroma is known as Meigs syndrome.82
Sertoli-Leydig cell tumors cause virilization in approximately 50% of patients. This finding is independent of tumor size.63 Patients with SCTAT usually present with abnormal vaginal bleeding, and abdominal pain and intussusception have been reported. Gynandroblastomas present with symptoms and signs related to estrogen and androgen overproduction in 60% of patients. These patients may have virilization in the setting of endometrial hyperplasia.83 Also, most gynandroblastomas are appreciated on the pelvic examination because of their size. Approximately 50% of patients with steroid cell tumors demonstrate androgenic changes.84
During the diagnostic and/or preoperative evaluation, abnormal uterine bleeding should prompt consideration for an endometrial biopsy. In women of reproductive age, pregnancy must first be excluded. Because endometrial hyperplasia can result from excess estrogen production by the ovarian stromal tumor, the endometrium must be evaluated, either preoperatively or intraoperatively upon the diagnosis of an ovarian stromal tumor.85
Imaging tests, including transvaginal ultrasound, CT, and MRI, may prove useful in the diagnosis of the adnexal mass but are nonspecific for ovarian sex cord-stromal tumors. The findings may also identify hemoperitoneum or ascites. Adult granulosa cell tumors have variable amounts of solid, cystic, hemorrhagic, and necrotic components, so they may appear as solid masses, multilocular cystic lesions, or completely cystic tumors.86 Ultrasound often shows increased vascularity by color flow Doppler.87
In contrast, Sertoli-Leydig cell tumors often appear as well-defined solid enhancing mass with cysts within the tumor on CT and appear hypointense with multiple variable-sized cystic areas on MRI. The amount of fibrous stroma determines the low-signal intensity on T2-weighted MRI.86 Radiographically, 79% of thecomas are solid on CT and show delayed accumulation of contrast material.88 Fibromas appear as hypointense on T1-weighted MRI with very low-signal intensity on T2-weighted imaging, often with dense calcifications.86
Preoperative laboratory tests that may be helpful include inhibin A, inhibin B, and, less often, CA-125, in addition to routine preoperative laboratory testing. These levels may act as tumor markers, facilitating preoperative diagnosis but more importantly serving as a baseline by which to judge efficacy of therapy.89,90
PATHOLOGY
Key Points
1. Adult-type granulosa cells demonstrate grooved “coffee-bean” nuclei, and frequently exhibit Call-Exner bodies.
2. Leydig cell tumors may exhibit crystals of Reinke.
Specialized gonadal stromal cells and their precursors can give rise to sex cord-stromal tumors of the ovary, originating within one or both ovaries, either as an isolated histologic subtype or in combination. The WHO classification is presented in Table 14-5.50 Specifically, granulosa cells and Sertoli cells arise from sex cord cells, whereas theca cells, Leydig cells, lipid cells, and fibroblasts arise from stromal cells and their pluripotential mesenchymal precursors.
Adult granulosa cell tumors represent 95% of granulosa cell tumors, whereas juvenile granulosa cell tumors represent 5% of granulosa cell tumors. The gross appearance of both subtypes is similar, most commonly presenting with a tumor with cystic and solid components. Microscopic examination reveals 2 characteristics that distinguish juvenile from adult granulosa cell tumors: the nuclei of juvenile granulosa cell tumors are rounded and hyperchromatic with moderate to abundant eosinophilic or vacuolated cytoplasm, and the theca cell component is luteinized in juvenile granulosa cell tumors (Figures 14-6 and 14-7).91 Adult type tumors demonstrate granulosa cells with grooved “coffee bean” nuclei; furthermore, they may exhibit Call-Exner bodies, a histologic finding characterized by a rosette arrangement of cells around a central eosinophilic fluid space.
FIGURE 14-6. Adult granulosa cell tumor. Hematoxylin and eosin stain, ×100. Insulae of uniformly staining cells are seen with Call-Exner bodies throughout.
FIGURE 14-7. Juvenile granulosa cell tumor immunostained for inhibin A. Hematoxylin and eosin stain, ×100. Uniform cells are seen amid an edematous, loose stroma. Cytoplasmic staining for inhibin A is present in the majority of cells.
Thecomas and fibromas have significant overlap. Often, these tumors cannot be assigned to either the distinct thecoma or fibroma category based on the clinical or microscopic examination.91 Thecomas are composed of lipid-laden stromal cells that may or may not demonstrate luteinization. When these tumors exhibit nuclear atypia and mitoses, they may represent low-grade stromal sarcomas or fibrosarcomas and may have a malignant course.92Fibromas are usually solid and white, with an average size of 6 cm.93 Approximately 10% of fibromas show light microscope evidence of hypercellularity, as well as pleomorphism and mitoses. Tumors of low malignant potential (cellular fibromas) are designated as those with an increased cellular density, mild nuclear atypia, and fewer than 3 mitotic figures per high-power field. Fully malignant fibrosarcomas have greater cellular density, marked pleomorphism, and more than 10 mitoses per high-power field. These tumors are highly aggressive and are usually large, unilateral, and highly vascular, with rupture, adhesions, hemorrhage, and necrosis often seen at the time of surgery.94
Sertoli-stromal cell tumors, or androblastomas, represent a group of tumors that differentiate toward testicular structures. These tumors were originally named arrhenoblastomas in 1931 by Meyer, but were renamed Sertoli-Leydig cell tumors in 1958 by Morris and Scully.95 On gross examination, Sertoli-Leydig cell tumors are solid or mixed cystic and solid (Figure 14-8). There are no features pathognomonic for Sertoli-Leydig cell tumors grossly. The size ranges from microscopic to 25 cm.63 Well-differentiated tumors tend to be smaller than poorly differentiated tumors.64 Well-differentiated tumors, which account for 11% of cases, have a predominantly tubular pattern on light microscopy. The Sertoli cells are cuboidal or columnar with round nuclei, but with no prominent nucleoli. Atypical nuclei are absent or rare, and few mitotic figures are seen. The stroma consists of nest of Leydig cells. As seen in Table 14-1, the most common variants are intermediate differentiation (54%) and poor differentiation (13%). These subgroups are characterized by a continuum of different patterns and combinations of cell types, with both Sertoli and Leydig components exhibiting various degrees of maturity. A retiform component is present in 15% of tumors, demonstrating tubules and cysts arranged in a pattern that resembles the rete testis (Figure 14-9).
FIGURE 14-8. Gross photograph of Sertoli-Leydig cell tumor. Recurrent tumor filled the abdomen and pelvis, invading small bowel, diaphragm, and liver. Tumor appears as dark maroon, hemorrhagic, fleshy, and solid.
FIGURE 14-9. Sertoli-Leydig cell tumor demonstrates both Sertoli and Leydig cells in trabeculae. Hematoxylin and eosin stain, ×100.
SCTATs are characterized by either simple or complex ring-shaped tubules. It is controversial whether these tumors are more closely related to granulosa cell tumors or Sertoli-Leydig cell tumors, as the cellular elements appear to be somewhat intermediate in nature, but they do seem to represent a distinct entity.91
Gynandroblastomas comprise granulosa cell elements, tubules, and Leydig cells. The specific cell of origin remains debated, but it may arise from undifferentiated mesenchyme.71 Most of these tumors are solid and large, measuring between 7 and 10 cm in size, with yellow-white cystic areas present. Microscopically, these tumors show unequivocal granulosa/theca cell elements, must be well differentiated, and must demonstrate intimate mixing of all the constituent cell types.71
Steroid cell tumors consist of stromal luteomas, Leydig cell tumors, and steroid cell tumors not otherwise specified. Stromal luteomas are often small; half measure less than 5 cm.96 Microscopically, they consist of large, rounded or polyhedral cell resembling Leydig cells, luteinized ovarian stromal cells, and adrenocortical cells. Leydig cell tumors are subdivided into tumors of hilar and non-hilar type, and both are benign. Inspection reveals small, unilateral tumors with a median size less than 3 cm.97 Histologically, they consist solely of Leydig cells, and crystals of Reinke are seen. These crystals are intracytoplasmic rectangular structures seen in up to 40% of Leydig tumors. Steroid cell tumors not otherwise specified are larger than the other steroid cell tumors with an average size of 8.5 cm and are often bilateral. These lipid cell tumors lack the specific characteristics of stromal luteomas or Leydig cell tumors. The strongest prognostic factor other than stage is the number of mitotic figures, because more than 90% of tumors with more than 2 mitoses per 10 high-power fields are malignant.96
Vascular endothelial growth factor is overexpressed in a majority of stromal ovarian tumors, which may account for the vascularity, angiogenesis, and response to anti-angiogenic agents.98 Inhibin and calretinin may also be helpful immunohistochemical stains to aid in the pathologic diagnosis of sex cord-stromal ovarian tumors.99,100 SF-1 is a diagnostically useful immunohistochemical marker that aids in the differential diagnosis of Sertoli cell tumors.101
Of interest, a single recurrent somatic mutation (402 C to G) in the FOXL2 gene has been identified as occurring in adult granulosa cell tumors.102 Validation and confirmation as a driver mutation have yet to be published.
TREATMENT
Key Points
1. Staging and tumor cytoreductive surgery (with metastatic disease) is essential at the time of diagnosis of a sex cord-stromal tumor.
2. Routine lymphadenectomy is not required for a complete staging procedure, as lymphatic metastases are exceedingly rare.
3. Adjuvant chemotherapy consists of bleomycin, etoposide, and cisplatin versus paclitaxel and a platinum agent; these regimens are currently being compared in a randomized trial.
Surgical Therapy and Staging
The appropriate treatment of stromal ovarian tumors is determined by patient age, parity, desire for future fertility, extent of disease, and comorbid conditions. The goals of surgical therapy are accurate diagnosis, removal of the mass, comprehensive staging, tumor cytoreduction when disseminated disease is present, and preservation of fertility when desired and feasible in patients of reproductive age.
Intraoperative pathologic diagnosis is often difficult, and intraoperative determination of the precise histology may be impossible. Therefore, general guidelines should be applied for nonepithelial ovarian tumors during the initial operative management, and the need for adjuvant or additional therapy should be determined based on the final pathology results. With close attention to detail, the need for reoperation and more extensive surgery can be minimized. Alternatively, the frozen section diagnosis may be rendered in the intra-operative setting, in which case guidelines for specific stromal ovarian tumors can be followed.
In general, a preoperative discussion should be held with any woman of childbearing age who has an adnexal mass regarding her wishes for future fertility depending on operative findings. This conversation, although difficult, is better discussed preoperatively with the patient than intraoperatively with the next of kin when a malignancy is encountered.67
Minimally invasive surgery (laparoscopy with or without robotic assistance) is appropriate in the occasional patient with a small solid adnexal mass or complex ovarian cyst.103,104 However, any patient with a large, solid adnexal mass or evidence of hemodynamic instability should undergo laparotomy through a vertical skin incision to remove the mass without morcellation and allow for appropriate surgical staging or tumor reductive surgery.56
The surgical procedure consists of pelvic washings and evacuation of hemoperitoneum, if present. The site of hemorrhage is most commonly the mass itself, and therefore surgical removal may stop the bleeding. A unilateral mass in a patient of any age should be removed by unilateral salpingo-oophorectomy and sent for immediate intraoperative histologic evaluation.56,67 Cystectomy, rupture, and morcellation of suspicious masses should be avoided.105Intraoperative rupture of granulosa cell tumors during laparoscopic management can result in subsequent peritoneal seeding and convert an early-stage malignancy to one with disseminated disease.105 When laparoscopy is the initial approach, a bag with an extended incision should be used or the procedure should be converted to a laparotomy to avoid morcellation. If a cystectomy is initially performed and the frozen section returns as a stromal ovarian tumor, the remainder of the adnexa should immediately be removed, as cystectomy is not adequate therapy.67,106 It should be noted that “conservative management” of these tumors invariably describes unilateral salpingo-oophorectomy with conservation of the uterus and normal-appearing contralateral ovary in the setting of limited disease. Therefore, unilateral salpingo-oophorectomy is the initial step in the treatment of patients with disease apparently confined to 1 ovary.67,106
Once an ovarian sex cord-stromal tumor is diagnosed, exploration of the abdominopelvic cavity should be performed, inspecting all peritoneal surfaces and abdominopelvic organs. A complete staging procedure should be performed, including cytologic evaluation of each hemidiaphragm, infracolic omentectomy, and peritoneal biopsies from each paracolic gutter, the vesicouterine fold, and the pouch of Douglas. Additionally, biopsies of any suspicious areas should be performed. The bowel should be inspected from the ileocecal valve to the ligament of Treitz, with specific evaluation for tumor implants and sites of obstruction. Maximal tumor cytoreductive surgery should be performed in patients with advanced disease, preferably leaving the patient with no macroscopic disease.67,106
Historically, pelvic and para-aortic lymphadenectomy were performed as a component of surgical staging. However, lymph node metastasis in stromal ovarian tumors is extremely rare.107,108 In one report examining 58 patients with sex cord-stromal ovarian tumors who had lymph nodes sampled during primary surgery, none had positive nodes.108 Therefore, lymph-adenectomy may be omitted in the staging of patients with this disease.
Patients who have completed childbearing should undergo total abdominal hysterectomy and bilateral salpingo-oophorectomy, regardless of the stage of disease. However, preservation of fertility should always be attempted in young patients seeking future fertility.67 If the contralateral ovary and/or uterine serosa are grossly involved by tumor, the uterus and both adnexae should be removed. If the contralateral ovary and uterine serosa appear normal, conservative management with preservation of the uterus and contralateral adnexa is safe and appropriate, as 95% of sex cord-stromal tumors are unilateral.66,67,74,106 Staging should still be performed. Fertility-sparing surgery does not obviate the need for staging and refers to the safe preservation of a normal-appearing contralateral ovary and uterus in the setting of apparent limited disease.
Some sex cord-stromal tumors may present with abnormal uterine bleeding. In this case, a preoperative endometrial biopsy or intraoperative endometrial curettage should be performed to exclude endometrial hyperplasia or malignancy. If a uterine malignancy is encountered, the uterus should be removed regardless of patient age.85
When juvenile granulosa cell tumors are diagnosed intraoperatively, most are diagnosed as stage IA tumors.77,78 It is essential to stage each of these patients, because platinum-based chemotherapy is recommended for any patient with disease over stage IA.
Conversely, thecomas, fibromas, and fibrothecomas are uniformly benign, so surgical resection alone without staging or adjuvant treatment is the appropriate therapy. Because many of these patients are diagnosed after their reproductive years, fertility preservation is rarely appropriate.74
The management of patients with Sertoli-Leydig cell tumors follows the preceding guidelines, and fertility preservation is important for many of these patients. In patients of reproductive age, a unilateral salpingo-oophorectomy and staging is usually appropriate, as 95% of lesions are unilateral.66,67 In patients finished with childbearing, a total hysterectomy and bilateral salpingo-oophorectomy with staging procedure is indicated.74
Ovarian SCTATs occur in 2 clinical subgroups. The first is associated with Peutz-Jeghers syndrome and is typically multifocal, bilateral, small, and almost always benign. Such patients should be carefully assessed for adenoma malignum of the cervix, as 15% of patients have an occult lesion,69 and hysterectomy should be strongly considered. The second subgroup of ovarian SCTATs is unrelated to Peutz-Jeghers syndrome and presents with larger tumors with a significant potential for malignant behavior. The basis of treatment remains surgical resection.
Patients with gynandroblastomas require surgical staging, and metastatic tumor should be resected. However, stromal luteomas and Leydig cell tumors are benign and do not require staging or postoperative therapy. Childbearing potential should be maintained in the occasional young patient with this diagnosis. Conversely, steroid cell tumors not otherwise specified can be malignant and aggressive, and therefore, when a steroid cell tumor is diagnosed intraoperatively, staging and aggressive surgical resection of metastases should be performed.
Adjuvant Therapy
Because sex cord-stromal tumors are rare ovarian neoplasms, clinical trials designed to determine which treatment regimens are best for specific histologic subtypes of this disease are not feasible. Most published studies combine most or all subtypes of stromal ovarian tumors, and therefore treatment recommendations are based on limited data. Most data have been gathered from patients with adult granulosa cell tumors, but occasionally other tumor types are encountered, and treatment is generalized to these types as well.67,75
Adjuvant therapy is not indicated for patients with surgically staged stage I disease.109 Patients with stage IC disease may benefit from some adjuvant therapy, either using platinum-based chemotherapy or hormonal therapy with leuprolide acetate.62
Patients with more advanced disease are typically treated with combination chemotherapy. The data regarding platinum-based therapy originated in the 1970s and 1980s. Several investigators published anecdotal reports of several complete and partial responses to platinum-containing regimens, including VAC, doxorubicin/cisplatin, cyclophosphamide/doxorubicin/cisplatin, and altretamine/cisplatin.110-112 Colombo113 subsequently investigated bleomycin, vinblastine, and cisplatin in patients with newly diagnosed advanced disease and found that 9 of 11 patients responded but with severe toxicity. Later trials used etoposide in place of vinblastine, and in 1996, Gershenson114 reported an 83% response rate in 9 patients with advanced stromal tumors of the ovary. In 1999, Homesley115 reported the utility of bleomycin, etoposide, and cisplatin (BEP) in 57 evaluable patients with stage II to IV disease. Sixty-one percent of patients experienced grade 4 myelotoxicity, and several cases of pulmonary toxicity occurred, but 69% of patients with advanced-stage primary and 51% of patients with recurrent disease remained progression free. The progression-free interval was 24 months. As a result, many patients have been treated with 3 to 4 courses of BEP, and this has become a commonly used treatment for patients with stromal ovarian tumors. Most recently, paclitaxel and carboplatin combination therapy have been reported to be effective in stromal tumors with fewer toxic effects compared with BEP.116,117 Of 22 newly diagnosed patients, 11 treated with BEP and 11 treated with a taxane/platinum regimen, 9 patients in each group were without evidence of disease at the completion of chemotherapy. No differences were detected in response rate, progression-free survival, or overall survival.117 Confirmation of equivalent outcomes between these 2 regimens awaits performance of a larger prospective randomized trial, which is currently underway.
More than 90% of patients with Sertoli-Leydig cell tumors have stage IA disease. This is largely dependent on grade, with well-differentiated tumors tending to be of limited stage. Only one death from disease has been reported in a patient with a well-differentiated tumor. However, 10% of intermediate, 60% of poorly differentiated, and 20% of retiform and heterologous subtypes show malignant behavior. Therefore, patients with Sertoli-Leydig cell tumors staged IC disease or greater, with poorly differentiated tumors of any stage, or with heterologous elements should receive adjuvant therapy with either BEP or paclitaxel and carboplatin.118 Radiation and hormone therapy have been described,64 but there is very limited information on which to base treatment.
Patients with steroid cell tumors not otherwise specified who have tumors that are pleomorphic, have an increased mitotic count, are large, or are at an advanced stage should be treated with additional postoperative platinum-based chemotherapy.119
No prospective randomized studies showing the value of radiotherapy in stromal ovarian tumors exist, but several retrospective studies have demonstrated the utility of radiation therapy in select patients with advanced disease.120,121
SURVIVAL AND PROGNOSIS
Key Points
1. In general, ovarian sex cord-stromal tumors follow an indolent clinical course.
2. These tumors may recur on multiple occasions with long disease-free intervals.
3. Juvenile granulosa cell tumors, Sertoli-Leydig cell tumors with poor prognostic factors, and steroid cell tumors not otherwise specified can be aggressive.
4. Stromal luteomas, fibromas, and thecomas follow a benign course.
Several large series have reported on survival and prognostic factors of ovarian sex cord-stromal tumors.55,62 The overall 20-year survival rate of women with this disease approximates 40%. The strongest prognostic factor is the stage at presentation, with the 5- to 10-year survival rate being more than 90% for stage I, 55% for stage II, and 25% for stage III tumors. The natural history of adult granulosa cell tumors is characterized by late recurrence, sometimes over a decade after the initial diagnosis. The average time to recurrence is 5 to 10 years. Poor prognostic factors include tumor size, rupture, and bilaterality. In patients with stage I disease, the recurrence rate is rare in tumors less than 5 cm, 20% in tumors 5 to 15 cm in size, and more than 30% in tumors greater than 15 cm.122
Overall, the prognosis for patients with juvenile granulosa cell tumor is favorable but is related to stage. The 5-year survival rate for patients with stage IA disease is 99%, but this declines to 60% for patients with advanced disease.71
The prognosis of patients with Sertoli-Leydig cell tumors is related to grade, stage, and histologic subtype. Patients with well-differentiated tumors tend to be of early stage. Such patients have an excellent prognosis, with no reports of advanced stage or recurrence, and only 1 death from disease has been reported in a patient with a well-differentiated tumor. However, 10% of intermediate, 60% of poorly differentiated, and 20% of retiform and heterologous subtypes show malignant behavior.118
Unfortunately, eventual prognosis is poor for recurrent stromal ovarian tumors, and the overall mortality rate is 70% in the recurrent setting despite treatment.62
MANAGEMENT OF RECURRENT DISEASE
Key Points
1. Multiple tumor cytoreductive surgeries may be employed in the treatment of recurrent sex cord-stromal tumors.
2. Chemotherapy, radiation therapy, and hormonal therapy may be useful in treating recurrent disease.
3. Anti-angiogenic therapy has a biologic basis and may be an option for treating recurrent disease refractory to traditional chemotherapy regimens.
Patients with recurrent disease may achieve long-term survival through secondary cytoreductive surgery, sometimes on multiple occasions after long treatment-free intervals.116 In cases of widespread disease or disease refractory to surgery, chemotherapy and hormonal therapy are options for treatment. The most effective chemotherapeutic regimens appear to be platinum-based, with either BEP or a taxane-platinum combination most commonly used, yielding similar response rates of 54% and 72%, respectively.117
Other chemotherapeutic agents with demonstrated response include carboplatin; cisplatin, doxorubicin, and cyclophosphamide; etoposide and cisplatin; VAC; oral etoposide; topotecan; liposomal doxorubicin; paclitaxel; and ifosfamide and etoposide. Paclitaxel and carboplatin remain the most commonly used single agents at first and second relapse.116
Likely due to the expression of steroid receptors, responses have been reported after treatment with gonadotropin-releasing hormone antagonists, progestins, and aromatase inhibitors.123,124
The use of radiation for the treatment of recurrent disease has also been reported, with some responses noted in patients with localized or symptomatic disease. However, based on the small numbers of patients, the data are anecdotal, the response rates are short, and the impact on survival remains unknown.125
Antiangiogenic agents have also been investigated in patients with recurrent adult granulosa cell tumor, due to the overexpression of vascular endothelial growth factor and vascularity of these tumors. Promising results have been noted, and a cooperative group trial investigating bevacizumab is currently underway.98
SPECIAL MANAGEMENT PROBLEMS
Key Points
1. Consideration of fertility preservation is key in patients with limited disease.
2. Inadequate staging at the initial surgery may require consideration of repeat surgery for staging versus careful observation.
Fertility preservation has been discussed under Surgical Considerations. This is an important issue in many patients with ovarian sex cord-stromal tumors, as the age distribution is often among women of reproductive age. Because the majority of tumors are unilateral and disease is often grossly confined, unilateral salpingo-oophorectomy can safely be performed with preservation of a normal-appearing contralateral adnexa and uterus. In the unlikely event of bilateral ovarian involvement with a normal-appearing uterus, both adnexae should be removed and the uterus can be preserved for consideration of donor egg–assisted reproduction post-treatment. A key feature of such conservative management is a preoperative discussion with any patient in whom a stromal ovarian tumor is suspected.67
The treatment of patients who have had inadequate staging is a difficult issue. Limited information exists regarding the best course of action for these patients. If the patient has documented large amounts of residual disease after a limited initial attempt at tumor reduction, repeat surgical exploration with staging and tumor-reductive surgery would be reasonable. If the patient has had an inadequate exploration, such as through a small Pfannenstiel incision or through a limited laparoscopy, more information needs to be collected before making a decision about postsurgical treatment. Several options may be considered, including repeat laparoscopic or open exploration with full surgical staging or, in some circumstances, a physical examination, CT, and measurement of serum inhibin and serum CA-125 levels. If the results of all of these are negative, the decision may be made to observe the patient clinically, with or without hormonal suppression therapy using leuprolide acetate. Lack of lymphadenectomy during staging, however, should not warrant reoperation, as the risk of nodal involvement approaches zero.108
FUTURE DIRECTIONS
Research in rare tumors is a difficult issue and is best performed in a cooperative group setting. Currently, the Gynecologic Oncology Group is partnering internationally in a randomized phase II trial to determine the most effective therapy—BEP versus paclitaxel and carboplatin—for patients with newly diagnosed advanced and recurrent chemotherapy-naive patients with ovarian sex cord-stromal tumors. Additionally, bevacizumab is being investigated for use in patients with recurrent ovarian sex cord-stromal tumors in a phase II trial of the Gynecologic Oncology Group. The results of these trials will provide solid recommendations for treatment in patients with newly diagnosed and recurrent disease.
One of the most interesting facets of recent research has been the elucidation of the FOXL2 gene mutation as a suspected driver mutation for the development of adult granulosa cell tumors.102 Further research into the mechanism of this mutation and targeted therapy directed against this gene may provide new avenues of understanding and novel therapy for patients with ovarian stromal tumors.
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