Sex cord-stromal tumors of the ovary: Management in adults

INTRODUCTION — Ovarian sex cord-stromal tumors (SCSTs) (table 1) are a group of benign and malignant neoplasms that develop from the sex cord (eg, Sertoli cell tumor, granulosa cell tumor), stromal cells (eg, fibroma, thecoma, Leydig cell tumor), or both (eg, Sertoli-Leydig cell tumor). They may be benign or malignant. In contrast to the more common epithelial ovarian cancer, malignant SCSTs are often diagnosed at an early stage, histology is generally low grade, lymph node metastases are rare, and prognosis is good.

This topic will discuss the management and follow-up of patients with ovarian SCSTs. The epidemiology, clinical features, and diagnosis of ovarian SCSTs are reviewed separately. (See "Sex cord-stromal tumors of the ovary: Epidemiology, clinical features, and diagnosis in adults".)

INITIAL PRESENTATION

General surgical considerations for patients with an ovarian neoplasm — In all patients with an ovarian mass, surgery is performed for diagnosis and initial treatment if ultrasound findings suggest the mass has some reasonable chance of being malignant (table 2). Surgery to resect the mass is also performed if there are other risks associated with it (eg, torsion) or if the mass is causing symptoms. Patients with SCSTs generally meet one or more of these criteria.

Preoperative patient preparation is routine, except in patients with virilization or signs of estrogen excess in whom assessing for tumor markers and performing endometrial sampling to detect a possible endometrial neoplasm may be indicated. (See "Sex cord-stromal tumors of the ovary: Epidemiology, clinical features, and diagnosis in adults", section on 'Diagnostic evaluation'.)

Preoperative counseling and informed consent should include the planned procedure for benign, malignant, or indeterminate intraoperative findings and issues regarding fertility preservation. This discussion should be documented in the medical record.

Oophorectomy is adequate therapy for a benign SCST; ovarian cystectomy may be performed if complete excision is possible and the patient desires preservation of the ovary. An exception is patients with a thecoma in the menopausal transition or postmenopause. Although thecomas are benign, we suggest a total hysterectomy with bilateral salpingo-oophorectomy for these patients because thecomas commonly cause estrogenic effects, so a synchronous endometrial neoplasm may be present (eg, endometrial cancer, endometrial stromal sarcoma) [1,2]. However, unilateral oophorectomy is an option in young patients when preservation of fertility or avoidance of exogenous hormone replacement is desired [3].

Management of malignant SCSTs is more aggressive and varies with the histologic diagnosis. Since a definitive diagnosis is often not made pre- or intraoperatively, the surgeon will need to make an intraoperative decision about which surgical option to employ based on imperfect histologic information, gross operative findings (eg, disease beyond the ovary), and the patient's preferences. Since these are rare neoplasms, even expert gynecologic pathologists may not provide a definite diagnosis based on intraoperative frozen section examination. Epithelial neoplasms (particularly endometrioid carcinoma) can mimic SCST neoplasms, and, if the diagnosis is uncertain, the pathologist should communicate this to the surgeon (and patient).

When an intraoperative frozen section is indeterminate, a young patient with a unilateral ovarian mass desirous of fertility preservation may opt for conservative surgery (oophorectomy), whereas a postmenopausal patient with a unilateral ovarian mass may prefer a hysterectomy with bilateral salpingo-oophorectomy. In patients who opt for conservative surgery, issues regarding incomplete staging and the potential need for further surgery if the definitive diagnosis is malignant neoplasm should be discussed.

Surgical management of patients with malignant SCSTs — Malignant ovarian SCSTs are surgically staged, which can be done by an open procedure or laparoscopically.

The staging system for all primary ovarian cancers is the same (table 3) regardless of histology (SCST, epithelial cell, germ cell). The stage is the most important factor in determining prognosis and guiding postoperative treatment recommendations [4].

Complete surgical staging is generally similar to that for patients with ovarian carcinoma (see "Epithelial carcinoma of the ovary, fallopian tube, and peritoneum: Surgical staging"). One notable difference is that we suggest not performing pelvic and paraaortic lymphadenectomy in most patients with confirmed or suspected SCSTs because lymph node metastases are rare with these tumors [5], and lymphadenectomy may result in lymphedema that impacts quality of life [6,7]. Instead, the pelvic and paraaortic nodes should be palpated and lymphadenectomy limited to those with palpable nodal enlargement or a definitive histologic diagnosis of a non-SCST ovarian tumor. (See "Clinical features and diagnosis of peripheral lymphedema" and "Cellulitis following pelvic lymph node dissection".)

Total hysterectomy and bilateral salpingo-oophorectomy is a component of surgical staging and treatment of ovarian cancer, but fertility preservation is an acceptable option for young patients with ovarian tumors confined to the ovary. For example, granulosa cell and Sertoli-Leydig cell tumors are generally confined to one ovary. For patients with apparent stage I disease who wish to preserve fertility or avoid exogenous hormone replacement, a unilateral salpingo-oophorectomy and uterine preservation with other procedures for complete surgical staging are appropriate (table 4) [3,8,9]. Retrospective studies suggest an equivalent cure rate for early-stage disease whether treated by unilateral salpingo-oophorectomy or bilateral salpingo-oophorectomy [3,8,10]. The contralateral ovary should be carefully inspected; biopsy is necessary only if an abnormality is found. If hysterectomy is not performed and endometrial sampling was not performed preoperatively, it should be performed intraoperatively to rule out an endometrial neoplasm in the setting of an estrogen-secreting SCST, particularly granulosa cell tumors.

Surgical management is similar for other SCSTs. The National Comprehensive Cancer Network (NCCN) recommends consideration of total hysterectomy with bilateral salpingo-oophorectomy after childbearing is completed [9]. When surgical staging is performed, it can often be completed laparoscopically. In a retrospective study of 81 patients undergoing a re-staging procedure for incompletely staged granulosa cell tumors, laparoscopy was similar to an open approach in terms of ability to complete the staging procedure and percentage of patients who were upstaged; no major intraoperative or postoperative complications occurred in either group [11]. A concern among gynecologic oncologists has been ovarian rupture during minimally invasive surgery for an unexpected ovarian malignancy, potentially converting stage IA to IC [12,13]. However, further study is required to understand whether the rate of ovarian rupture is higher with minimally invasive versus open surgery. (See "Epithelial carcinoma of the ovary, fallopian tube, and peritoneum: Surgical staging", section on 'Open laparotomy versus minimally invasive surgery'.)

Adjuvant therapy — The choice to proceed with adjuvant treatment should be guided by an individualized discussion of goals and preferences, acknowledging the lack of data to support its use. Due to the rarity of ovarian SCSTs, no prospective, randomized clinical trial data exist.

Granulosa cell tumors — Surgery alone is acceptable treatment for most patients with granulosa cell tumors since the majority are stage IA and confined to one ovary at the time of diagnosis (table 3) [3]. Long-term, disease-free survival rates are approximately 90 percent. For those with stage IC and higher disease, we suggest adjuvant chemotherapy given evidence suggesting this is a risk factor for recurrence [14], although the approach to such patients is controversial, and observation is also an acceptable strategy in patients with IC disease, per NCCN guidelines [9].

The rarity of granulosa cell tumors makes it difficult to conduct well-designed randomized studies to define the value of any strategy. As a result, the benefit of postoperative treatment is unclear, and practice is variable. While some centers recommend adjuvant therapy for all patients with stage IC to IV disease, others reserve this recommendation for patients over the age of 40 at diagnosis who, in one early series, had a higher risk of disease recurrences compared with younger patients [15], though other reports have failed to confirm the adverse impact of older age on outcomes [16-22]. Other centers recommend adjuvant therapy only for patients with residual disease after surgery, and still others do not recommend adjuvant therapy for any stage of disease, treating only at the time of a recurrence.

Although adjuvant chemotherapy has been associated with longer progression-free survival (PFS) among those with advanced granulosa cell tumors, there is no evidence supporting an overall survival benefit. The following represents the range of findings regarding the benefit of adjuvant therapy from observational studies:

●For children with advanced-stage juvenile granulosa cell tumors, adjuvant chemotherapy appears to contribute to long-lasting complete remission and is usually recommended for those with stage IC disease and a high mitotic index (≥20 per 10 high power fields), as well as those with more advanced-stage disease [23-29]. However, it is difficult to extrapolate these results to adult-type tumors, which have a different biology (ie, lower proliferative rate and greater risk of late recurrences) than the juvenile type.

●Excellent outcomes were demonstrated in an observational study of 160 patients with stage I granulosa cell tumors, most of whom (98 percent) did not receive adjuvant chemotherapy [30]. At a median follow-up of 7 years, 32 percent had relapsed, but median overall survival was similar in patients with (24 years) and without relapse (22 years). Surgery was the main therapeutic modality at relapse, although most patients (86 percent) also received some form of nonsurgical therapy. Similarly, in the MITO-9 study, among 35 patients with recurrent granulosa cell tumors, receipt of adjuvant chemotherapy at initial presentation was associated with improvements in recurrence-free survival (73 versus 48 months) but not overall survival.

●Some retrospective series of adults with granulosa cell tumor suggest that patients with advanced (stage III/IV) disease who receive postoperative chemotherapy have a longer progression-free interval than those who do not [31]. However, others have failed to show that the use of chemotherapy is associated with better survival [32-36].

●A retrospective study including data from 13 centers of the French reference network for Rare Malignant Gynecological Tumors (TMRG) evaluated 469 adult patients with malignant SCSTs treated with primary surgery between 2011 to 2015; the majority of patients had adult granulosa cell tumors [37]. Adjuvant chemotherapy was administered in only 15 percent of patients at initial diagnosis. First, second, and third relapses occurred in 33, 17, and 10 percent of patients, in whom perioperative chemotherapy was administered in 59, 28, and 24 percent of patients, respectively. Chemotherapy did not impact survival in the first-line or relapse settings.

Despite the lack of survival benefit, we and others suggest postoperative chemotherapy for patients with resected stage IC to IV disease because of the high risk of disease progression and the potential for long-term survival in patients with advanced disease who receive modern platinum-based chemotherapy [23,38-43].

Sertoli-Leydig cell tumors — The available data evaluating the benefit of chemotherapy in Sertoli-Leydig cell tumors are scant, with most of the literature consisting of isolated case reports. Together, these data suggest the following:

●For most patients with well-differentiated, stage I tumors, we suggest surgery alone (without adjuvant chemotherapy), given that such tumors have a typically good prognosis. However, for tumors that contain either heterologous elements or retiform pattern, the relapse rate is as high as 20 percent; for patients with these histologies, we suggest platinum-based chemotherapy [24].

●For patients with poorly differentiated Sertoli-Leydig cell tumors, the relapse rate is up to 60 percent; therefore, for patients with intermediate- to high-grade, stage I tumors, or higher stage tumors of any grade, we suggest adjuvant platinum-based chemotherapy [24].

Examples of outcomes with adjuvant chemotherapy in Sertoli-Leydig cell tumors are as follows for stage I disease:

●One series included three patients with stage IC Sertoli-Leydig cell tumor, two of which were poorly differentiated and one of which had intermediate differentiation [23]. Despite the early use of platinum-based chemotherapy, only the patient with a tumor of intermediate differentiation was disease-free at 47 months.

●In a multi-institutional Italian study including 21 patients with nonmetastatic Sertoli-Leydig cell tumors, five patients received adjuvant chemotherapy [44]. Of the three patients with stage IA tumors of intermediate differentiation who relapsed (none of whom received initial chemotherapy), two died of disease. Of four patients with stage IA poorly differentiated tumors, only one received adjuvant chemotherapy, and all four were alive and free of disease at the time of the report.

For those with higher stage tumors, although objective response rates are high [40], responses are typically not durable. For example, in an observational study of nine patients with metastatic ovarian SCSTs of all types and poorly differentiated Sertoli-Leydig cell tumors confined to the ovary, overall response rate was 83 percent, but PFS was just 14 months [45].

Other types of SCST — Patients with stage II to IV disease of any cell type have an increased risk of recurrence compared with those with stage I disease. Therefore, adjuvant platinum-based chemotherapy is generally offered [40,45,46], although there are other data to suggest that it may not provide a survival advantage [47]. In the absence of a randomized trial comparing chemotherapy with observation, we continue to suggest adjuvant chemotherapy to these patients.

Choice of regimen — The most commonly used regimens for patients with SCSTs are bleomycin, cisplatin, plus etoposide (BEP) (table 5), as is used for testicular and ovarian germ cell tumors, or paclitaxel plus carboplatin (PC) [38]. For younger, fit patients, we typically opt for BEP, while we prefer PC for patients >40 years old, due to toxicity concerns. (See "Initial risk-stratified treatment for advanced testicular germ cell tumors" and "Treatment of malignant germ cell tumors of the ovary".)

GOG 264 was a phase II trial to determine the PFS of PC versus BEP for treatment of newly diagnosed stage IIA to IV or recurrent chemotherapy-naïve ovarian SCSTs. Sixty-three patients were accrued at the interim futility analysis. The study was closed early for futility because compared with BEP, PC failed to improve PFS [48]. However, as presented at the 2020 International Gynecologic Cancer Society meeting, PC showed a more favorable side effect profile (hazard ratio 1.12, 95% CI 0.58-2.16). Median PFS was 27.7 months for PC and 19.7 months for BEP (95% CI 10.4-52.7).

Role for radiation therapy? — As with chemotherapy, there are no prospective randomized trials that define the value of postoperative radiation therapy (RT). RT has been used for both granulosa cell tumors and Sertoli-Leydig cell tumors. However, most reports have evaluated only granulosa cell tumors and are not contemporary. As such, RT is rarely used. For those with granulosa cell tumors who are appropriate candidates for adjuvant treatment, we typically suggest chemotherapy alone, although some experts may offer radiation as an acceptable alternative for those with disease limited to the pelvis.

In the adjuvant setting, an older retrospective series is often quoted as supporting benefit from RT [18]. However, insufficient data were provided to determine whether the differences in outcome between irradiated and nonirradiated patients were attributable to therapy. Several later observational series fail to show any benefit from adjuvant radiation [16,17,19,41,49].

Posttreatment surveillance — There is no high-quality evidence to support one posttreatment surveillance strategy over another for ovarian SCSTs. We follow guidelines from the Society of Gynecologic Oncologists and the NCCN [9,50]:

●Review of symptoms and physical examination – For the first two years, every two to four months; then every six months thereafter.

●Serum tumor markers – For patients in whom one or more tumor markers (eg, testosterone, inhibin, alpha-fetoprotein, anti-müllerian hormone) were elevated at diagnosis, the same markers should be repeated every two to four months for the first two years and then every six months thereafter. Monitoring multiple markers rather than a single marker appears to be superior for detection of macroscopic disease [51].

Symptoms are also an indication for checking serum tumor marker levels.

●Routine use of imaging studies is not recommended. Computed tomography or other imaging is usually reserved for evaluation of patients with symptoms or elevation in a serum tumor marker level.

RECURRENT DISEASE

Surgery — There are few data on the optimal management of patients who experience recurrent disease. However, if the recurrence appears resectable, low-quality data primarily obtained in studies of patients with recurrent granulosa cell tumors suggest that surgical treatment may afford a survival advantage [22,52]. In a series of 16 patients with recurrent adult granulosa cell tumor who underwent salvage surgery, maximal debulking was achieved in 13 patients [53]. Multifocal recurrent disease and residual tumor after surgery were associated with diminished progression-free and overall survival (31 versus 207 months and 22 versus 220 months, respectively). Use of adjuvant systemic treatment is discussed below. (See 'Systemic therapy' below.)

Systemic therapy

Choice of regimen — For most patients, adjuvant systemic treatment is suggested. For patients who are not candidates for surgery (either due to performance status or extent of disease) or for those who experience multiple recurrences, medical therapy alone is generally suggested.

Based on their use in the adjuvant setting [40,42,45,46], bleomycin, etoposide, plus cisplatin (BEP) and paclitaxel plus carboplatin (PC) are the most commonly utilized platinum-based regimens for these patients. Although the data are limited, angiogenesis inhibitors, hormonal therapy (including leuprolide acetate, tamoxifen, or the aromatase inhibitors), and radiation therapy (RT) have also demonstrated activity, particularly for the treatment of adult-type granulosa cell tumors [38,41,54-59]. (See 'Granulosa cell tumors' below.)

Granulosa cell tumors — As discussed above, adjuvant chemotherapy is typically offered to those who have undergone surgery for relapsed disease. It is also used for those who are not appropriate candidates for surgery or have unresectable disease. This and other options are discussed below.

●Chemotherapy – Chemotherapeutic options may include retreatment with a platinum-based regimen (BEP or PC). Typically, if BEP was used previously, PC is chosen at relapse and vice versa (although BEP is often avoided in patients older than 40 years due to toxicity concerns). The value of taxanes, particularly in combination with platinum agents, has been reported [46,60-62].

A response rate of 29 percent has been reported in patients with recurrent SCSTs treated with single-agent paclitaxel [63]. Other chemotherapeutic regimens with reported therapeutic efficacy include doxorubicin alone [64]; carboplatin plus etoposide [65]; cisplatin, vinblastine, plus bleomycin (PVB or VBP) [66]; and cyclophosphamide, doxorubicin, plus cisplatin (CAP) [67-69]. None of these regimens have produced consistently better results than those seen with BEP, but they may be considered for second-line therapy. Other empirical options include drugs used for platinum-resistant epithelial ovarian cancer, including pegylated liposomal doxorubicin, gemcitabine/cisplatin, or topotecan.

In an international randomized phase 2 trial (ALIENOR), 60 patients with relapsed sex cord-stromal ovarian tumors (the majority of which were granulosa cell tumors) were randomly assigned to receive weekly paclitaxel alone or weekly paclitaxel with bevacizumab. The estimated six-month progression-free rate with paclitaxel alone or combination therapy was 71 and 72 percent, respectively. Although the objective response rate increased from 25 to 44 percent with the addition of bevacizumab, the addition of bevacizumab to weekly paclitaxel did not improve overall clinical benefit [70].

●Hormonal therapy – Experimental data and small clinical series suggest that hormonal agents such as luteinizing hormone-releasing hormone agonists (eg, leuprolide) might be effective in granulosa cell tumors through the suppression of gonadotropin secretion [55,56,71-73]. However, others have failed to document efficacy [41,74].

In a phase 2 study of anastrozole in patients with estrogen receptor and progesterone receptor positive recurrent/metastatic granulosa cell tumors (PARAGON/ANZGOG 0903 trial), the primary endpoint was clinical benefit rate at 12 weeks evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. The clinical benefit rate at 12 weeks in 38 evaluable patients was 79 percent, which included one patient (2.6 percent) with partial response and 76 percent of patients with stable disease. The authors of the study concluded that although there was a high clinical benefit rate, the objective response rate to anastrozole was low, pointing to the need to reconsider the role of aromatase inhibitors as single agents in granulosa cell tumors [75]. RECIST 1.1 criteria are discussed in detail separately (table 6).

Low-quality data indicate that treatment of recurrent disease with aromatase inhibitors, tamoxifen alone, progesterone alone, or a combination of tamoxifen and progesterone occasionally can result in long-term clinical responses. In a systematic review including nine patients with granulosa cell tumors receiving an aromatase inhibitor, all experienced a complete or partial response [76]. Similarly, in one case report, a complete clinical response in a patient with recurrent granulosa cell tumor was achieved using alternating biweekly cycles of megestrol 40 mg twice daily for two weeks, alternating with two week courses of tamoxifen 10 mg twice daily [73].

●Other systemic agents – Antiangiogenic therapy appears promising. In an early report of eight patients with granulosa cell tumors, bevacizumab, a monoclonal antibody directed against the vascular endothelial growth factor, induced a complete clinical response in one patient, partial responses in two, and stable disease in two others [77]. A GOG phase II trial of bevacizumab in patients with metastatic SCSTs was reported [59]. Of the 36 patients enrolled, 88.9 percent had granulosa cell tumors. The response rate was 16.7 percent, and 77.8 percent had stable disease. The median progression-free survival was 9.3 months.

Because available effective therapies for patients with metastatic disease are limited, genomic profiling may be pursued to identify common mutations that may be targetable by novel agents, either off-label or in clinical trials [78]. In a study reporting the largest molecularly profiling dataset described to date for adult granulosa cell tumor, genomic profiling of 423 tumors revealed no tumors with microsatellite instability, and none had high genomic loss of heterozygosity [79]. The most common aberrations included TERT promoter mutations, 9.2 percent; KMT2D mutations, 16.8 percent; TP53 mutations, 8.3 percent; CDKN2A and/or CDKN2B deletions, 10.2 percent; and activating PIK3CA mutations, 5.4 percent. This information will hopefully serve as hypothesis-generating data for future clinical trials.

●Radiation therapy – RT can induce clinical responses and occasional long-term remission in patients with persistent or recurrent granulosa cell tumors [38,41,54]. In one review of 34 patients treated at a single center over a 40-year period with radiation alone, 3 of the 14 who were treated for measurable disease were alive without progression 10 to 21 years following treatment [54].

Sertoli-Leydig cell tumors — For those with relapsed Sertoli-Leydig cell tumors who have undergone repeat surgical resection, chemotherapy is typically offered adjuvantly, though a possible exception is for patients with well-differentiated Sertoli-Leydig cell tumors who relapse and have no change in histology; for such patients, surgery alone may be sufficient. Chemotherapy is also used as primary treatment for those with unresectable disease or for those who are poor surgical candidates [40,45,46,68,80-82]. This and other options are discussed below.

●Chemotherapy – As with granulosa cell tumors, the optimal regimen for treatment of advanced Sertoli-Leydig cell tumors is unknown. However, we suggest platinum-based chemotherapy. If BEP has not been used, and the patient is ≤40 years old, it is our preferred option. For those over 40 years of age or those who have previously been treated with BEP, we opt for PC. Other platinum-based regimens are alternatives. These include CAP; carboplatin, epirubicin, plus etoposide; PVB or VBP; and taxane/platinum combination therapy [40,45,46,68,80-82].

●Other systemic agents – Although chemotherapy is typically preferred, other agents may be appropriate as later line therapy: for example, angiogenesis inhibitors as for granulosa cell tumors. (See 'Granulosa cell tumors' above.)

However, endocrine therapy is typically not used for Sertoli-Leydig cell tumors.

●Radiation therapy – Extrapolating from data in recurrent granulosa cell tumors, RT may be offered for those with multiply relapsed Sertoli-Leydig cell tumors, though data are limited. (See 'Granulosa cell tumors' above.)

PROGNOSIS — Generally, malignant SCSTs are diagnosed at an early stage and have low-grade histology, and thus have a good prognosis. However, some tumors are aggressive and have a lethal outcome. Outcomes related to specific histologies are discussed below.

●Granulosa cell tumors – The prognosis of ovarian granulosa cell tumor depends on the stage of disease at diagnosis and the presence of residual disease after surgery (table 7) [34,38,49,83-85]. Five-year survival rates for completely resected stage I disease are approximately 90 percent [34,39,49], but outcomes tend to be less favorable in the presence of a large tumor size (10 to 15 cm) or (in many but not all series [22]) tumor rupture [14,16,19,20,49].

A number of histologic features have also been examined for their prognostic significance. In adults, cellular atypia, high mitotic index (4 to 10 mitoses per 10 high power fields), and the absence of Call-Exner bodies are the only significant histologic predictors of early recurrence [4,22,49]. Abnormal karyotype, p53 overexpression, and ploidy do not appear to be of prognostic value [86,87]. There are conflicting reports regarding the prognostic influence of other factors, such as positive cytology, tumor size, ovarian surface involvement, and ploidy status. Further studies are needed in this area.

Ovarian granulosa cell tumors have metastatic potential and a tendency for late relapse. In one report of 37 patients with stage I disease, survival rates at 5, 10, and 20 years were 94, 82, and 62 percent, respectively [39]. The median time to relapse is approximately four to six years after initial diagnosis; however, late recurrences have been reported after as many as 40 years [4,16,39,49,88,89]. Thus, prolonged surveillance with serial physical examinations and serum tumor markers (particularly inhibin) should be performed [9].

●Sertoli-Leydig cell tumors – The overall five-year survival is 70 to 90 percent and is related to stage and degree of histologic differentiation [44,90].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Ovarian, fallopian tube, and peritoneal cancer".)

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SUMMARY AND RECOMMENDATIONS

●Surgical management – Surgical staging of malignant sex cord-stromal tumors (SCSTs) is generally the same as for other primary ovarian malignant neoplasms (table 3) and typically includes total hysterectomy and bilateral salpingo-oophorectomy. (See 'Surgical management of patients with malignant SCSTs' above.)

•However, conservation of a contralateral ovary and/or the uterus if it has no evidence of disease is possible in patients who wish to preserve fertility, but the feasibility varies by tumor histology. (See 'Surgical management of patients with malignant SCSTs' above.)

•For most patients with malignant sex cord-stromal neoplasms, we suggest not performing pelvic and paraaortic lymphadenectomy (Grade 2C). Lymphadenectomy is performed, however, for patients with palpable enlargement of these nodes and may be performed in patients in whom there is a suspicion of diagnosis of another histologic type of ovarian malignant neoplasm. (See 'Surgical management of patients with malignant SCSTs' above and "Sex cord-stromal tumors of the ovary: Epidemiology, clinical features, and diagnosis in adults", section on 'Diagnosis'.)

●Postoperative approach

•For patients with stage IA disease who have completed surgical treatment, our postoperative approach is as follows, though we recognize that alternative strategies are reasonable in the setting of limited data:

-For those with granulosa cell tumors, we suggest posttreatment surveillance rather than adjuvant chemotherapy (Grade 2C). (See 'Granulosa cell tumors' above.)

-For those with Sertoli-Leydig cell tumors that are intermediate to high grade, or have heterologous or retiform pattern, we suggest adjuvant chemotherapy (Grade 2C). For those with well-differentiated tumors, observation alone is sufficient. (See 'Sertoli-Leydig cell tumors' above.)

•For patients whose neoplasm involves the ovarian surface (stage IC) or is more advanced (stage II or greater), we suggest adjuvant chemotherapy (Grade 2C), although this is particularly controversial for those with stage IC disease, and observation is also an acceptable strategy in such patients. Note that stage IB disease is essentially nonexistent. (See 'Adjuvant therapy' above.)

•Regarding choice of regimen, for patients who are ≤40 years old, we suggest bleomycin, etoposide, plus cisplatin (BEP) (Grade 2C), while for those who are >40 years old, we suggest paclitaxel plus carboplatin (PC) (Grade 2C), given better tolerability than with BEP in this older subset. (See 'Choice of regimen' above.)

●Recurrent disease

•For most patients with recurrent disease that is resectable, we suggest surgical treatment (Grade 2C). For patients who have undergone resection, we suggest postoperative platinum-based chemotherapy rather than other regimens, postoperative radiation, or observation only (Grade 2C). (See 'Recurrent disease' above.)

•For most patients with recurrent disease who are not surgical candidates, we suggest platinum-based chemotherapy rather than other radiation therapy or other forms of medical therapy (Grade 2C), although reasonable alternatives include endocrine therapy (for granulosa cell tumors) or angiogenesis inhibitors. Because available effective therapies for patients with metastatic disease are limited, genomic profiling may be pursued to identify common mutations that may be targetable by novel agents in clinical trials. (See 'Granulosa cell tumors' above.)