Sex cord-stromal tumors (SCSTs) are a heterogeneous group of rare neoplasms that originate from the ovarian matrix. Cells within this matrix have the potential for hormone production, and nearly 90 percent of hormone-producing ovarian tumors are SCSTs. As a result, individuals with these tumors typically present with signs and symptoms of estrogen or androgen excess.
Surgical resection is the primary treatment, and SCSTs are generally confined to one ovary at the time of diagnosis. Moreover, most have an indolent growth pattern and low malignant potential. For these reasons, few patients ever require platinum-based chemotherapy. Although recurrent disease often responds poorly to treatment, patients may live for many years because of characteristically slow tumor progression.
The overall prognosis of ovarian SCSTs is excellent—primarily due to early-stage disease at diagnosis and curative surgery. The scarcity of these tumors, however, limits the understanding of their natural history, treatment, and prognosis.
SCSTs account for 3 to 5 percent of ovarian malignancies (Ray-Coquard, 2014). These tumors are more than twice as likely to develop in black women for reasons that are unclear (Quirk, 2005). In contrast with epithelial ovarian cancers or malignant germ cell tumors, ovarian SCSTs typically affect women of all ages. This range contains a unique bimodal distribution that reflects inherent tumor heterogeneity. For example, juvenile granulosa cell tumors, Sertoli-Leydig cell tumors, and sclerosing stromal tumors are found predominantly in prepubertal girls and women within the first three decades of life (Schneider, 2005). Adult granulosa cell tumors commonly develop in older women, at an average age in the mid-50s (van Meurs, 2013).
There are no proven risk factors for SCSTs. However, in a hypothesis-generating case-control study, Boyce and coworkers (2009) observed that obesity as a hyperestrogenic state was independently associated, whereas parity, smoking, and oral contraceptive use were protective.
The etiology of SCSTs is largely unknown. However, a single, recurrent FOXL2 gene mutation (402C>G) is present in virtually all adult-type granulosa cell tumors. Thus, mutant FOXL2 appears to be a highly specific event in the pathogenesis of these rare tumors (Schrader, 2009; Shah, 2009). The other major finding is that women with a germline DICER1 mutation are predisposed to developing SCSTs (Heravi-Moussavi, 2012). Otherwise, there is no known inherited predisposition for the development of these tumors, and familial cases are rare (Stevens, 2005). However, ovarian SCSTs do develop in association with several defined hereditary disorders at a frequency that exceeds mere chance. Associated disorders include Ollier disease, which is characterized by multiple benign but disfiguring cartilaginous neoplasms, and Peutz-Jeghers syndrome, characterized by intestinal hamartomatous polyps (Stevens, 2005).
Isosexual precocious puberty is the presenting sign in more than 80 percent of prepubertal girls ultimately diagnosed with an ovarian SCST (Kalfa, 2005). Adolescents often report secondary amenorrhea. As a result, these young individuals presenting with endocrinologic symptoms tend to be diagnosed at earlier stages. Abdominal pain and distention are other common complaints in this age group (Schneider, 2003a).
In adult women, heavy, irregular bleeding and postmenopausal bleeding are the most frequent symptoms. In addition, mild hirsutism that rapidly progresses to frank virilization should prompt evaluation to exclude these tumors. The classic presentation is a postmenopausal woman with rapidly evolving stigmata of androgen excess and a complex adnexal mass. Abdominal pain or a mass palpable by the patient herself are other telling signs and symptoms (Chan, 2005).
The size of SCSTs varies widely, but most women have a palpable abdominal or pelvic mass during examination regardless of their age. A fluid wave and other physical findings suggestive of advanced disease, however, are rare.
Elevated circulating levels of testosterone or androstenedione or both are strongly suggestive of an ovarian SCST in a woman with signs and symptoms of virilization. Clinical hyperandrogenism is more likely to be idiopathic or related to polycystic ovarian syndrome, but serum testosterone levels >150 g/dL or dehydroepiandrosterone sulfate (DHEAS) levels >8000 g/L strongly suggest the possibility of an androgen-secreting tumor (Carmina, 2006). In most instances, tumor marker studies are not obtained preoperatively, because the diagnosis of ovarian SCST is often not suspected. When the diagnosis is confirmed, the appropriate tumor markers may be drawn during or following surgery (Table 36-4).
TABLE 36-4Tumor Markers for Ovarian Sex Cord-Stromal Tumors with Malignant Potential ||Download (.pdf) TABLE 36-4 Tumor Markers for Ovarian Sex Cord-Stromal Tumors with Malignant Potential
|Granulosa cell tumors (adult and juvenile) ||Inhibin A and B; estradiol (not as reliable) |
|Sertoli-Leydig cell tumors ||Inhibin A and B; occasionally alpha-fetoprotein |
|Sex cord tumor with annular tubules ||Inhibin A and B |
|Steroid cell tumors not otherwise specified ||Steroid hormones elevated pretreatment |
The gross appearances of SCSTs range from large multicystic masses to small solid masses—effectively precluding a specific radiologic diagnosis. Granulosa cell tumors often sonographically demonstrate semisolid features but are not reliably discernible from epithelial tumors (Fig. 36-8) (Sharony, 2001). In addition, the endometrium may be thickened from increased tumor estrogen production. Although CT or MR imaging has been used to clarify indeterminate sonograms, there is no definitive radiologic study to diagnose these tumors (Jung, 2005).
Adult granulosa cell tumor. A. Abdominal sonography displays a large adnexal mass with solid and cystic areas. With application of color Doppler, thick vascular septa are seen. B. Computed tomographic (CT) scan of the same tumor. C. The tumor was opened after excision, and again its mixed architecture is noted. (Used with permission from Dr. Christa Nagel.)
Patients with an ovarian mass suspicious for malignancy based on clinical and sonographic findings require surgical resection for definitive tissue diagnosis, staging, and treatment. Sonographically or CT-guided percutaneous biopsy has no role. Moreover, diagnostic laparoscopy or laparotomy with visual assessment of the adnexal mass alone is inadequate. Thus, excision and pathologic evaluation are necessary. Following removal, ovarian SCSTs can usually be distinguished histologically from germ cell tumors, epithelial ovarian cancers, or other spindle-cell neoplasms by immunostaining for inhibin (Cathro, 2005; Schneider, 2005).
Preoperatively, patients with a potentially malignant ovarian SCST are ideally referred to a gynecologic oncologist for evaluation. Most ovarian SCSTs, however, are diagnosed by generalist gynecologists following resection of a seemingly benign but complex mass in a woman with a CA125 level that is typically normal, if known beforehand. The initial surgery is often performed in a community-based hospital and without adequate staging. In this setting, prior to referral, histologic results should be reviewed and confirmed by an experienced pathologist. Following referral to a gynecologic oncologist, surgical staging may be indicated.
Ovarian SCSTs arise from sex cord and mesenchymal cells of the embryonic gonad (Chap. 18). Granulosa and Sertoli cells develop from the sex cords and thus from the coelomic epithelium. In contrast, theca cells, Leydig cells, and fibroblasts are derived from the mesenchyme. The primitive gonadal stroma possesses sexual bipotentiality. Therefore, developing tumors may be composed of a male-directed cell type (Sertoli or Leydig cell) or a female-directed cell type (granulosa or theca cell). Although distinct categories of SCSTs have been defined, mixed tumors are relatively common (Table 36-5). For example, ovarian granulosa cell tumors may have admixed Sertoli components. Similarly, tumors that are predominantly Sertoli or Sertoli-Leydig cells may contain minor granulosa cell elements. These mixed tumors are believed to arise from a common lineage with variable differentiation and do not represent two concurrent separate entities (McKenna, 2005; Vang, 2004).
TABLE 36-5Modified WHO Classification of Ovarian Sex Cord-Stromal Tumors ||Download (.pdf) TABLE 36-5 Modified WHO Classification of Ovarian Sex Cord-Stromal Tumors
| Pure stromal tumors |
|Sclerosing stromal tumor |
|Leydig cell tumor |
|Steroid cell tumor |
| Pure sex cord tumors |
|Granulosa cell tumor |
| Adult type |
| Juvenile type |
|Sertoli cell tumor |
|Sex cord tumor with annular tubules |
| Mixed sex cord-stromal tumors |
|Sertoli-Leydig cell tumors |
|Sex cord-stromal tumors, NOS |
Ovarian granulosa cell tumors are universally considered to have malignant potential, but most other SCST subtypes do not have definitive criteria for clearly defining benign and malignant. Attempts to grade these tumors using nuclear characteristics or mitotic activity counts have produced inconsistent results (Chen, 2003).
Patterns of Growth and Spread
The natural history of SCSTs in general differs greatly from that of epithelial ovarian carcinomas. For example, most of these tumors have low malignant potential. They are typically unilateral and remain localized, retain hormone-secreting functions, and infrequently relapse. Recurrences tend to be late and usually develop in the abdomen or pelvis (Abu-Rustum, 2006). Bone metastases are rare (Dubuc-Lissoir, 2001).
Adult Granulosa Cell Tumors
Seventy percent of ovarian SCSTs are granulosa cell tumors (Colombo, 2007). These tumors are formed by cells believed to arise from those surrounding the germinal cells within ovarian follicles. There are two clinically and histologically distinct types: the adult form, which makes up 95 percent of cases, and the juvenile type, accounting for 5 percent.
With adult granulosa cell tumor, most women are diagnosed after age 30, and the average age approximates 55 years. Heavy, irregular menstrual bleeding and postmenopausal bleeding are common and reflect prolonged exposure of the endometrium to estrogen. Related to this estrogen excess, coexisting pathology such as endometrial hyperplasia or adenocarcinoma has been found in 25 to 30 percent of patients with adult granulosa cell tumor (van Meurs, 2013). Similarly, breast enlargement and tenderness are frequent associated complaints, and secondary amenorrhea has been reported (Kurihara, 2004). Alternatively, symptoms may stem from the mass of the ovary rather than from hormones produced (Ray-Coquard, 2014). An enlarging and potentially hemorrhagic tumor can cause abdominal pain and distention. Acute pelvic pain may suggest adnexal torsion, or tumor rupture with hemoperitoneum can mimic ectopic pregnancy.
During surgery, if an adult granulosa cell tumor is confirmed, tumor markers may be requested. Of these, inhibin B seems to be more accurate than inhibin A, frequently being elevated months before clinical detection of recurrence (Mom, 2007). The diagnostic value of these markers, however, is often hampered by their physiologically broad normal ranges (Schneider, 2005). Estradiol also has limited use in surveillance. This is particularly true for the younger patient wishing to preserve fertility and having the contralateral ovary left in situ.
Grossly, adult granulosa cell tumors are large and multicystic and often exceed 10 to 15 cm in diameter (see Fig. 36-8). The surface is frequently edematous and unusually adhered to other pelvic organs. For this reason, more extensive dissection is typically required than for epithelial ovarian cancers or malignant germ cell tumors. During excision, inadvertent rupture and intraoperative bleeding from the tumor itself is also common.
The interior of the tumor is highly variable. Solid components may predominate with large areas of hemorrhage and necrosis. Alternatively, it can be cystic, with numerous locules filled with serosanguinous or gelatinous fluid (Colombo, 2007). Microscopic examination shows predominately granulosa cells with pale, grooved, “coffee bean” nuclei. The characteristic microscopic feature is the Call-Exner body—a rosette arrangement of cells around an eosinophilic fluid space (Fig. 36-9).
Adult granulosa cell tumor. A. Cells are typically crowded and contain scant, pale cytoplasm. Their elongated nuclei may have a longitudinal fold or groove that gives them a “coffee bean” appearance. B. Call-Exner bodies are identified by their rosette appearance. (Used with permission from Dr. Raheela Ashfaq.)
Adult granulosa cell tumors are low-grade malignancies that typically demonstrate indolent growth. Ninety-five percent are unilateral, and 70 to 90 percent are stage I at diagnosis (Table 36-6). The 5-year survival for patients with stage I disease is 90 to 95 percent (Colombo, 2007; Zhang, 2007). However, 15 to 25 percent of stage I tumors will eventually relapse. The median time to recurrence is 5 to 6 years, but may be several decades (Abu-Rustum, 2006; East, 2005). Advantageously, these indolent tumors usually progress slowly thereafter, and the median length of survival after relapse is another 6 years. Advanced tumor stage and residual disease are poor prognostic factors (Al Badawi, 2002; Sehouli, 2004). Patients with stage II-IV tumors have a 5-year survival rate of 30 to 50 percent (Malmstrom, 1994; Miller, 1997; Piura, 1994). Cellular atypia and mitotic count may help in determining the prognosis but are difficult to reproducibly quantify (Miller, 2001).
TABLE 36-6Stage and Survival of Common Ovarian Sex Cord-Stromal Tumors ||Download (.pdf) TABLE 36-6 Stage and Survival of Common Ovarian Sex Cord-Stromal Tumors
| ||Adult Granulosa Cell ||Sertoli-Leydig Cell |
| Stage at diagnosis |
|I ||70–90% ||97% |
|II-IV ||10–20% ||2–3% |
| Five-year survival |
|Stage I ||90–95% ||90–95% |
|Stage II–IV ||30–50% ||10–20% |
Juvenile Granulosa Cell Tumors
These rare neoplasms develop primarily in children and young adults, and approximately 90 percent are diagnosed before puberty (Colombo, 2007). The mean age at diagnosis is 13 years, but patient ages range from newborn to 67 years (Young, 1984). Juvenile granulosa cell tumors are sometimes associated with Ollier disease or with Maffucci syndrome, which is characterized by endochondromas and hemangiomas (Young, 1984; Yuan, 2004).
In affected females, estrogen, progesterone, and testosterone levels may be elevated and lead to suppression of gonadotropins. As a result, menstrual irregularities or amenorrhea are common. Prepubertal girls typically display isosexual precocious puberty, which is characterized by breast enlargement and development of pubic hair, vaginal secretions, and other secondary sexual characteristics. These tumors infrequently secrete androgens, but in such cases may induce virilization. Despite these endocrinologic signs, a delayed diagnosis of juvenile granulosa cell tumors in pre- and postpubertal girls is common and associated with a higher risk of peritoneal tumor spread (Kalfa, 2005).
In addition to hormonal changes, individuals may display tumor effects. For example, older patients usually seek medical attention for abdominal pain or swelling. Preoperative rupture with resulting hemoperitoneum may create acute abdominal symptoms in 5 to 10 percent of cases (Colombo, 2007). Ascites is present in 10 percent (Young, 1984).
Juvenile granulosa cell tumors are grossly similar to the adult-type tumor and display variable solid and cystic components. They can attain significant size and have an average diameter of approximately 12 cm. Microscopically, cytologic features that distinguish these tumors from the adult type are their rounded, hyperchromatic nuclei without “coffee-bean” grooves. Call-Exner bodies are rare, but often there is a theca cell component (Young, 1984).
Prognosis is excellent, and the 5-year survival rate is 95 percent. Similar to adult-type tumors, 95 percent of juvenile granulosa cell tumors are unilateral and stage I at diagnosis (Young, 1984). However, the juvenile type is more aggressive in advanced stages, and the time to relapse and death is much shorter. Recurrences typically develop within 3 years and are highly lethal. Later recurrences are unusual (Frausto, 2004).
These are relatively common SCSTs and are rarely malignant. Thecomas are unique because they typically develop in postmenopausal women in their mid-60s and develop infrequently before age 30. These solid tumors are among the most hormonally active of the SCSTs and usually produce excess estrogen. As a result, the primary signs and symptoms are abnormal vaginal bleeding or pelvic mass or both. Many women also present with concurrent endometrial hyperplasia or adenocarcinoma (Aboud, 1997). These tumors are composed of lipid-laden stromal cells that are occasionally luteinized. Half of these luteinized thecomas are either hormonally inactive or androgenic with the potential for inducing masculinization.
Thecomas are solid tumors whose cells resemble the theca cells that normally surround the ovarian follicles (Chen, 2003). Because of this texture, these tumors appear sonographically as solid adnexal masses and may mimic extrauterine leiomyomas.
Bilateral ovarian involvement and extraovarian spread are rare. Fortunately, ovarian thecomas are clinically benign, and surgical resection is curative.
Fibromas are also relatively common, hormonally inactive SCST variants that usually occur in perimenopausal and menopausal women (Chechia, 2008). These solid, generally benign ovarian neoplasms arise from the spindled stromal cells that form collagen. Most fibromas are found incidentally during pelvic or sonographic examination. They are round, oval, or lobulated solid tumors associated with free fluid or less commonly, with frank ascites and possess minimal to moderate vascularization (Paladini, 2009).
Perhaps 1 percent of women present with Meigs syndrome, which is a triad of pleural effusion, ascites, and a solid ovarian mass (Siddiqui, 1995). Pleural effusions are usually right-sided, and these, as well as accompanying ascites, are typically transudative and resolve after tumor resection (Majzlin, 1964). Despite this association of ascites with benign fibromas, when ascites and a pelvic mass coexist, evaluation is based on an assumption of malignancy.
The prognosis following excision of fibromas is that for any benign tumor. However, 10 percent will demonstrate increased cellularity and varying degrees of pleomorphism and mitotic activity that indicate a tumor better characterized as having low malignant potential. In 1 percent of cases, malignant transformation to fibrosarcoma is found.
Sclerosing Stromal Tumors
These tumors are rare and account for less than 5 percent of SCSTs. The average patient age is approximately 20 years, and 80 percent develop before age 30. Sclerosing stromal tumors are clinically benign and typically unilateral. Menstrual irregularities and pelvic pain are both frequent symptoms (Marelli, 1998). Ascites is seldom encountered (unlike fibromas), and sclerosing stromal tumors are hormonally inactive (unlike thecomas). Tumor size ranges from microscopic to 20 cm. Histologically, the presence of pseudolobulation of cellular areas separated by edematous connective tissue, increased vascularity, and prominent areas of sclerosis are distinguishing features.
Sertoli-Stromal Cell Tumors
Ovarian Sertoli cell tumors are rare and account for less than 5 percent of all SCSTs. The mean patient age at diagnosis is 30 years, but ages range from 2 to 76 years. One quarter of patients present with estrogenic or androgenic manifestations, but most tumors are clinically nonfunctional.
Sertoli cell tumors are typically unilateral, solid, and yellow and measure 4 to 12 cm in diameter. Derived from the cell type that gives rise to the seminiferous tubules, these tumor cells often organize into histologically characteristic tubules (Young, 2005). Sertoli cell tumors, however, may also mimic many different tumors, and immunostaining in these cases is invaluable to confirm the diagnosis.
More than 80 percent are stage I at diagnosis, and most are clinically benign. Moderate cytologic atypia, brisk mitotic activity, and tumor cell necrosis are indicators of greater malignant potential and are found in 10 percent of individuals with stage I disease and most of those with stage II-IV tumors. The risk of recurrence is higher when these features are identified (Oliva, 2005).
Sertoli-Leydig Cell Tumors
Sertoli-Leydig cell tumors comprise only 5 to 10 percent of ovarian SCSTs (Zhang, 2007). Their incidence mirrors that of Sertoli cell tumors, and the average age is 25 years. Although Sertoli-Leydig cell tumors have been identified in children and postmenopausal females, more than 90 percent develop during the reproductive years.
These tumors frequently produce sex-steroid hormones, most commonly androgens. As a result, frank virilization develops in one third of affected women, and another 10 percent have clinical manifestations of androgen excess (Young, 1985). Menstrual disorders are also common. Accordingly, Sertoli-Leydig cell tumors are suspected preoperatively in a patient with a unilaterally palpable adnexal mass and with androgenic manifestations. For these women, an elevated serum testosterone-to-androstenedione ratio further suggests the diagnosis.
Although these hormonal effects frequently develop, one half of patients will have nonspecific abdominal mass symptoms as their only presenting complaint. Associated ascites is infrequent (Outwater, 2000). Thyroid abnormalities also coexist with Sertoli-Leydig cell tumors at a frequency that exceeds mere chance.
These tumors tend to be large at the time of excision with an average diameter greater than 10 cm, but ranges from 1 to 50 cm have been reported. In most cases, Sertoli-Leydig cell tumors appear yellow and lobulated. Tumors can be solid, partially cystic, or completely cystic, and they may or may not have polypoid or vesicular structures in their interior (Fig. 36-10). Microscopically, these morphologically diverse tumors contain cells resembling epithelial and stromal testicular cells in varying proportions. The five subtypes of differentiation (well, intermediate, poor, retiform, and heterologous) have considerable overlap. Well-differentiated tumors are all clinically benign (Chen, 2003; Young, 2005).
Sertoli-Leydig cell tumor (SLCT). A. SLCTs show variable gross features depending on the degree of differentiation and presence of heterologous elements. This opened surgical specimen has a predominantly solid cut surface with focal cysts, variegated yellow-brown color, and foci of hemorrhage. B. Well-differentiated SLCT composed of hollow tubules admixed with clusters of mature Leydig cells. C. This intermediate differentiated SLCT contains solid tubules, which are thought to resemble those of the fetal testis. (Used with permission from Dr. Katja Gwin.)
Overall, 15 to 20 percent of Sertoli-Leydig cell tumors are clinically malignant. Prognosis depends predominantly on the stage and degree of tumor differentiation in these malignant variants. For example, Young and Scully (1985) performed a clinicopathologic analysis of 207 cases and identified stage I disease in 97 percent. The 5-year survival rate for patients with stage I disease exceeds 90 percent (Zaloudek, 1984). Malignant features were observed in approximately 10 percent of tumors with intermediate differentiation and in 60 percent of poorly differentiated tumors. Retiform and heterologous elements are seen only in intermediate or poorly differentiated Sertoli-Leydig cell tumors and typically are associated with poorer prognosis. Overall, the 2 to 3 percent of patients with stage II-IV disease have a dismal prognosis (Young, 1985).
Sex Cord Tumors with Annular Tubules
This tumor accounts for 5 percent of SCSTs and is characterized by ring-shaped tubules and distinctive cellular elements that are histologically intermediate between Sertoli-cell and granulosa cell tumors. There are two clinically distinct types. One third are clinically benign and develop in patients with Peutz-Jeghers syndrome (PJS). These tumors are typically small, multifocal, calcified, bilateral, and diagnosed incidentally. Fifteen percent of PJS-associated cases will also develop adenoma malignum of the cervix, which is a rare, extremely well-differentiated adenocarcinoma. In contrast, two thirds of tumors are not associated with PJS. These masses are usually larger, unilateral, and symptomatic and carry a clinical malignancy rate of 15 to 20 percent (Young, 1982).
Fewer than 5 percent of SCSTs are steroid cell tumors. The average age at diagnosis is the mid-20s, but patients can present at virtually any age. These tumors are composed entirely or predominantly of cells that resemble steroid hormone-secreting cells and are categorized according to the histologic composition of these cells.
Stromal luteomas are clinically benign tumors that by definition lie completely within the ovarian stroma. They are usually seen in postmenopausal women. Estrogenic effects are common, but occasional individuals have androgenic manifestations.
Leydig cell tumors are also benign and typically are seen in postmenopausal women. They are distinguished microscopically by rectangular, crystal-like cytoplasmic inclusions, termed crystals of Reinke. Leydig cells secrete testosterone, and these tumors are usually associated with androgenic effects.
Steroid cell tumors not otherwise specified (NOS) are the most common subtype within this group and typically present in younger reproductive-aged women. Some of these cases may represent large stromal luteomas that have grown to reach the ovarian surface or Leydig-cell tumors in which Reinke crystals cannot be identified. These tumors are typically associated with androgen excess, but estrogen or cortisol overproduction (i.e., Cushing syndrome) has also been reported. One third of steroid cell tumors NOS are clinically malignant and have a dismal prognosis (Oliva, 2005).
Unclassified Sex Cord-Stromal Tumors
Unclassified tumors account for 5 percent of SCSTs and have no clearly predominant pattern of testicular (Sertoli cells) or ovarian (granulosa cells) differentiation. These ill-defined tumors are especially common during pregnancy due to alterations in their usual clinical and pathologic features (Young, 2005). They may be estrogenic, androgenic, or nonfunctional. The prognosis is similar to that of granulosa cell tumors and Sertoli-Leydig cell tumors of similar degrees of differentiation.
These are the rarest type of ovarian SCST. Patients present at a mean age of 30 years and typically have menstrual irregularities or evidence of hormonal excess. The tumors are characterized by intermingled granulosa cells and tubules of Sertoli cells. Theca or Leydig cells or both may also be present in varying degrees. Gynandroblastomas have low malignant potential, and only one death has been reported (Martin-Jimenez, 1994).
The mainstay of treatment for patients with an ovarian SCST is complete surgical resection. This group shows relative insensitivity to adjuvant chemotherapy or radiation. Thus, operative goals are to establish a definitive tissue diagnosis, determine the extent of disease, and also remove all grossly visible tumors in those infrequent patients with advanced-stage disease. Moreover, during preoperative planning, clinicians should consider the patient’s age and desire for future fertility. Hysterectomy with BSO is performed for those who have completed childbearing, whereas fertility-sparing USO with preservation of the uterus and remaining ovary may be appropriate in the absence of obvious disease spread to these organs (Zanagnolo, 2004). Endometrial sampling is performed, especially if fertility-sparing surgery is planned in women with granulosa cell tumors or thecomas. This is because many of these patients will have coexisting endometrial hyperplasia or adenocarcinoma that may affect the decision for hysterectomy.
Minimally invasive laparoscopic surgery has a variety of relevant applications. For some, the diagnosis of SCST may not be discovered until the mass is laparoscopically removed and sent for frozen section analysis. Laparoscopic surgical staging can then proceed. When the diagnosis is not made until the final pathology report is confirmed postoperatively, laparoscopic staging may be proposed to determine whether metastatic disease is present. This can reduce the morbidity of a second operation (Shim, 2013).
Surgical staging is essential to determine the extent of disease and the need for adjuvant therapy in most individuals with potentially malignant SCST subtypes (Fig. 36-11). That said, only approximately 20 percent of cases have complete staging (Abu-Rustum, 2006; Brown, 2009). More recent data suggest that, due to surface and hematogenous routes of spread, the standard ovarian cancer procedure can be modified. Pelvic washings, exploration of the abdomen, peritoneal biopsies, and partial omentectomy remain important. However, the utility of routine pelvic and paraaortic lymphadenectomy has been increasingly challenged. In a study of 262 ovarian SCSTs, none of the 58 patients undergoing nodal dissection had positive nodes (Brown, 2009). Additionally, performing a lymphadenectomy has not been shown to improve survival rates in those with SCSTs (Chan, 2007).
Staging of sex cord-stromal tumors. PJS = Peutz-Jeghers syndrome.
Surgical removal of hormone-producing SCSTs results in an immediate drop in elevated preoperative sex-steroid hormone levels. Physical manifestations of these elevated levels, however, partially or completely resolve more gradually.
In general, women with stage I ovarian SCSTs have an excellent prognosis following surgery alone and usually can be followed at regular intervals without the need for further treatment (Schneider, 2003a). Surveillance includes a general physical and pelvic examination, serum marker level testing, and imaging as clinically indicated.
The decision to administer postoperative therapy depends on various factors (Fig. 36-12). Although typically treated solely with surgery, malignant stage I ovarian SCSTs may require adjuvant chemotherapy when large tumor size, high mitotic index, capsular excrescences, tumor rupture, incomplete staging, or equivocal pathology results are noted. Women with one or more of these suspicious features are thought to be at higher risk of relapse and are considered for platinum-based chemotherapy (Schneider, 2003b). In addition, stage II-IV disease warrants postoperative treatment. In general, SCSTs display less sensitivity to chemotherapy than other ovarian malignancies, but most women at high risk for disease progression can be treated successfully with adjuvant platinum-based chemotherapy (van Meurs, 2014).
Postoperative treatment of sex cord-stromal tumors.
The 5-day bleomycin, etoposide, and cisplatin (BEP) regimen is the most widely used first-line chemotherapy combination (Gershenson, 1996; Homesley, 1999). For completely resected disease, three courses given every 3 weeks are sufficient. Four cycles are recommended for patients with incompletely resected tumor (Homesley, 1999). In addition to BEP, taxanes have demonstrated activity against ovarian SCSTs, and combination paclitaxel and carboplatin chemotherapy shows promising results (Brown, 2004, 2005). To determine the most effective regimen, a prospective randomized study is currently underway, comparing paclitaxel and carboplatin to BEP in those with newly diagnosed ovarian SCSTs (GOG protocol #264). Unfortunately, the relative scarcity of women who have ovarian SCST and receive chemotherapy limits the ability to conduct large randomized studies.
Postoperative radiation therapy currently has a limited role in the management of ovarian SCSTs. There is some evidence indicating a prolonged survival in at least some women with newly diagnosed disease who received whole-abdominal radiotherapy (Wolf, 1999). However, chemotherapy is usually the primary postoperative treatment because it is generally better tolerated, more widely accessible, and easier to administer. Radiation is best reserved for palliation of local symptoms (Dubuc-Lissoir, 2001).
The management of recurrent ovarian SCST depends on the clinical circumstances. Secondary surgical debulking is strongly considered due to the indolent growth pattern, the typically long disease-free interval after initial treatment, and the inherent insensitivity to chemotherapy (Crew, 2005; Powell, 2001). Platinum-based combination chemotherapy is the primary treatment chosen for recurrent disease with or without surgical debulking (Uygun, 2003). Of regimens, BEP is most frequently administered because it has the highest known response rate (Homesley, 1999). Paclitaxel is another promising agent that was evaluated as a single agent in a phase II Gynecologic Oncology Group trial (GOG protocol #187).
There is no standard treatment for women who have progressive disease despite aggressive surgery and platinum-based chemotherapy. Bevacizumab (Avastin) demonstrated a 17-percent response rate in a Phase II trial (GOG protocol #251) (Brown, 2014a). Vincristine, actinomycin D, and cyclophosphamide (VAC) regimen has limited activity (Ayhan, 1996; Zanagnolo, 2004). Hormonal therapy is minimally toxic, but the clinical experience with this approach is extremely limited (Hardy, 2005). Medroxyprogesterone acetate and the gonadotropin-releasing hormone (GnRH) agonist leuprolide acetate (Lupron) have each demonstrated activity in halting the growth of recurrent ovarian SCSTs (Fishman, 1996; Homesley, 1999). GnRH antagonists, however, may not be as effective (Ameryckx, 2005).
In addition to traditional drugs, discovery of the FOXL2 402C>G mutation occurring exclusively in all adult granulosa cell tumors may lead to the development of targeted therapies for women with advanced or recurrent disease. Currently, FOXL2 as a transcription factor does not represent a pharmacologic target. Further insights into its function and downstream effects may identify molecular alterations in these tumors that can be targeted (Kobel, 2009).
In general, ovarian SCSTs portend a much better prognosis than epithelial ovarian carcinomas chiefly because most women with SCSTs are diagnosed with stage I disease. Stage II-IV tumors are rare, but women with these cancers have a poor prognosis similar to their counterparts with epithelial disease. Unfortunately, improvements in survival rates have not been observed in ovarian SCSTs during the past few decades (Chan, 2006).
Of the clinical factors affecting prognosis, surgical stage and residual disease are the most important (Lee, 2008; Zanagnolo, 2004). Further, in a Surveillance, Epidemiology and End Results (SEER) database study, Zhang and colleagues (2007) performed a multivariate analysis of 376 women with SCSTs. They concluded that age younger than 50 years was also an independent predictor of an improved survival rate.
Management During Pregnancy
Ovarian SCSTs are rarely detected during pregnancy (Okada, 2004). In a California population-based study of more than 4 million obstetric patients, one granulosa cell tumor was diagnosed among 202 women with an ovarian malignancy (Leiserowitz, 2006). Granulosa cell tumors are most common, but only 10 percent are diagnosed during pregnancy (Hasiakos, 2006). One third of pregnant women with SCSTs are incidentally diagnosed at cesarean delivery, one third has abdominal pain or swelling, and the remainder may present with hemoperitoneum, virilization, or vaginal bleeding (Young, 1984). Surgical management should be the same as for the nonpregnant woman. For most, conservative management with USO and staging is the primary procedure, but hysterectomy and BSO may be indicated in selected circumstances (Young, 1984). Postoperative chemotherapy is typically withheld until after delivery because SCSTs have an indolent growth pattern.