CHAPTER 36: Ovarian Germ Cell and Sex Cord-Stromal Tumors

Three major categories account for virtually all malignant ovarian tumors. Organization of these groups is based on the anatomic structures from which the tumors originate (Fig. 36-1). Epithelial ovarian cancers account for 90 to 95 percent of malignant ovarian tumors (Chap. 35). Germ cell and sex cord-stromal ovarian tumors account for the remaining 5 to 10 percent and have unique qualities that require a special management approach (Quirk, 2005).

Germ cell tumors arise from the ovary’s germinal elements and make up one third of all ovarian neoplasms. The mature cystic teratoma, also called dermoid cyst, is by far the most common subtype. This accounts for 95 percent of all germ cell tumors, is clinically benign, and discussed in Chapter 9. In contrast, malignant germ cell tumors compose 2 to 3 percent of malignant ovarian cancers in Western countries and include dysgerminoma, yolk sac tumor, immature teratoma, and other less common types.

Three features distinguish malignant germ cell tumors from epithelial ovarian cancers. First, individuals typically present at a younger age, usually in their teens or early 20s. Second, most have stage I disease at diagnosis. Third, prognosis is excellent—even for those with advanced disease—due to exquisite tumor chemosensitivity. Fertility-sparing surgery is the primary treatment for women seeking future pregnancy, although most will require postoperative chemotherapy.

Epidemiology

The age-adjusted incidence rate of malignant ovarian germ cell tumors in the United States is much lower (0.4 per 100,000 women) than that of epithelial ovarian carcinomas (15.5) (Quirk, 2005). Smith and associates (2006) analyzed 1262 cases of malignant ovarian germ cell from 1973 to 2002 and observed that incidence rates have declined 10 percent during the past 30 years. Unlike a significant proportion of epithelial ovarian carcinomas, malignant germ cell tumors are not generally considered heritable, although rare familial cases are reported (Galani, 2005; Stettner, 1999).

These tumors are the most common ovarian malignancies diagnosed during childhood and adolescence, although only 1 percent of all ovarian cancers develop in these age groups. At age 20, however, the incidence of epithelial ovarian carcinoma begins to rise and exceeds that of germ cell tumors (Young, 2003).

Diagnosis

Patient Findings

The signs and symptoms associated with these tumors vary, but in general, most originate from tumor growth and the hormones they produce. Subacute abdominal pain is the presenting symptom in 85 percent of patients and reflects rapid growth of a large, unilateral tumor undergoing capsular distention, hemorrhage, or necrosis. In 10 percent of cases, cyst rupture, torsion, or intraperitoneal hemorrhage leads to an acute abdomen (Gershenson, 2007a). In more advanced disease, ascites may develop and cause abdominal distention. Because of the hormonal changes that frequently accompany these tumors, menses can become heavy or irregular. Although most individuals note one or more of these symptoms, one quarter of individuals are asymptomatic, and a pelvic mass is noted unexpectedly during physical or sonographic examination (Curtin, 1994).

Individuals typically seek care within 1 month of the onset of abdominal complaints, although some note subtle waxing and waning of symptoms for more than a year. Vague pelvic symptoms are common during adolescence due to initiation of ovulation and menstrual cramping. As a result, early symptoms may be missed. Moreover, girls may be silent about changes to their normal pattern, fearful of their significance. Most young women with these tumors are nulligravidas with normal periods, but as discussed later, dysgenetic gonads is a known risk factor for development of these tumors (Brown, 2014b). Therefore, adolescents who present with pelvic masses and delayed menarche should be evaluated for gonadal dysgenesis (Chap. 16).

Distinguishing physical findings are typically lacking in individuals with malignant germ cell tumors. A palpable mass on pelvic examination is the most common. In children and adolescents, however, completing a comprehensive pelvic or transvaginal sonographic examination can be difficult and can lead to diagnostic delay. Accordingly, premenarchal patients may require examination under anesthesia to adequately assess a suspected adnexal tumor. The remainder of the physical examination searches for signs of ascites, pleural effusion, and organomegaly.

Laboratory Testing

In patients with a suspected malignant germ cell tumor, serum human chorionic gonadotropin (hCG) and alpha-fetoprotein (AFP) tumor markers, complete blood count, and liver function tests are drawn before treatment. Alternatively, the appropriate tumor markers may be ordered in the operating room if the diagnosis was not previously suspected (Table 36-1). Preoperative karyotyping of young women with primary amenorrhea and a suspected germ cell tumor can clarify whether both ovaries should be removed, as in the case of individuals with gonadal dysgenesis (Hoepffner, 2005).

Imaging

Early symptoms can be misinterpreted as those of pregnancy, and acute pain may be confused with appendicitis. Finding an adnexal mass is the first diagnostic step. In most cases, sonography can adequately display those qualities that typically characterize benign and malignant ovarian masses (Chap. 9). Functional ovarian cysts are vastly more common in young women. Once these hypoechoic smooth-walled cysts are identified by sonography, they may be observed. Mature cystic teratomas (dermoid cysts) usually display characteristic features when imaged with sonography or computed tomography (CT) (Chap. 9). In contrast, the appearance of malignant germ cell tumors differs, and a multilobulated complex ovarian mass is typical (Fig. 36-2). Moreover, prominent blood flow in the fibrovascular septa may be seen using color flow Doppler sonography and suggests the likelihood of malignancy (Kim, 1995). Additional preoperative CT or magnetic resonance (MR) imaging may be indicated based on clinical suspicion. Chest radiography is warranted upon diagnosis to search for tumor metastases in the lungs or mediastinum.

Diagnostic Procedures

Surgical resection is generally required for definitive tissue diagnosis, staging, and treatment. The surgeon should request a frozen section analysis to confirm the diagnosis, but discrepancies between frozen section interpretations and the final paraffin histology are commonplace (Kusamura, 2000). In addition, specific immunostaining is often required to resolve equivocal cases (Cheng, 2004; Ramalingam, 2004; Ulbright, 2005). In contrast, a sonographically or CT-guided percutaneous biopsy has a very limited role in the management of select patients with an ovarian mass suspicious for malignancy.

Role of the Generalist

Most patients will initially be seen by a generalist gynecologist. Initial symptoms may point to the more common functional ovarian cyst. Persistent symptoms or an enlarging pelvic mass, however, should prompt sonographic evaluation. If a complex ovarian mass with solid features is noted in this young age group, then measurement of serum hCG and AFP levels and referral to a gynecologic oncologist for primary surgical management should ensue.

If a specialist is unavailable or the diagnosis is not anticipated beforehand, intraoperative decision making is crucial to adequately treat the patient without compromising future fertility. Peritoneal washings are obtained and set aside before proceeding with dissection of any suspicious adnexal mass. These can be discarded later if malignancy is excluded. Initially, the decision to perform cystectomy or oophorectomy depends on the clinical circumstances (Chap. 9). In general, the entire adnexa should be removed once a malignant ovarian germ cell tumor is diagnosed. A generalist gynecologist should request intraoperative assistance with staging from a gynecologic oncologist or refer the patient postoperatively if a specialist is not immediately available. At minimum, the abdomen should be explored. Palpation of the omentum and upper abdomen and inspection of the pelvis—especially the contralateral ovary—is easy to perform and document.

Pathology

Classification

The modified World Health Organization (WHO) classification of ovarian germ cell tumors is presented in Table 36-2. These tumors are composed of several histologically different tumor types derived from primordial germ cells of the embryonic gonad. There are two major categories: primitive malignant germ cell tumors (dysgerminomas) and teratomas, almost all of which are accounted for by mature cystic teratomas (dermoid cysts).

Histogenesis

Primitive germ cells migrate from the wall of the yolk sac to the gonadal ridge (Fig. 18-1). As a result, most germ cell tumors arise in the gonad. Rarely, these tumors may develop primarily in extragonadal sites such as the central nervous system, mediastinum, or retroperitoneum (Hsu, 2002).

Ovarian germ cell tumors have a variable pattern of differentiation (Fig. 36-3). Dysgerminomas are primitive neoplasms that do not have the potential for further differentiation. Embryonal carcinomas are composed of multipotential cells that are capable of further differentiation. This lesion is the precursor of several other types of extraembryonic (yolk sac tumor, choriocarcinoma) or embryonic (teratoma) germ cell tumors. The process of differentiation is dynamic, and the resulting neoplasms may be composed of different elements that show various stages of development (Teilum, 1965).

Dysgerminoma

Because their incidence has declined by approximately 30 percent over the past few decades, dysgerminomas currently account for only approximately one third of all malignant ovarian germ cell tumors (Chan, 2008; Smith, 2006). Dysgerminomas are the most common ovarian malignancy detected during pregnancy. This is believed to be an age-related coincidence, however, and not due to some particular characteristic of gestation.

Five percent of dysgerminomas are discovered in phenotypic females with karyotypically abnormal gonads, specifically, with the presence of a normal or abnormal Y-chromosome (Morimura, 1998). Commonly, this group includes those with Turner syndrome mosaicism (45,X/46,XY) and with Swyer syndrome (46,XY, pure gonadal dysgenesis) (Chap. 16). The dysgenetic gonads of these individuals often contain gonadoblastomas, which are benign germ cell neoplasms. These tumors may regress or alternatively may undergo malignant transformation, most commonly to dysgerminoma. Because approximately 40 percent of gonadoblastomas in these individuals undergo malignant transformation, both ovaries should be removed (Brown, 2014b; Hoepffner, 2005; Pena-Alonso, 2005).

Dysgerminomas are the only germ cell malignancy with a significant rate of bilateral ovarian involvement—15 to 20 percent. Half of patients with bilateral lesions will have grossly obvious disease, whereas cancer in the remainder will only be detected microscopically. Five percent of women have elevated serum hCG levels due to intermingled syncytiotrophoblast. Similarly, serum lactate dehydrogenase (LDH) and the isoenzymes LDH-1 and LDH-2 may also be useful in monitoring individuals for disease recurrence (Pressley, 1992; Schwartz, 1988).

Dysgerminomas have a variable gross appearance, but in general are solid, pink to tan to cream-colored lobulated masses (Fig. 36-4). Microscopically, there is a monotonous proliferation of large, rounded, polyhedral clear cells that are rich in cytoplasmic glycogen and contain uniform central nuclei with one or a few prominent nucleoli. The tumor cells closely resemble the primordial germ cells of the embryo and are histologically identical to seminoma of the testis.

The standard treatment of dysgerminoma usually involves fertility-sparing surgery with unilateral salpingo-oophorectomy (USO). In some extenuating circumstances, ovarian cystectomy may be considered (Vicus, 2010). Surgical staging is generally extrapolated from epithelial ovarian cancer, but lymphadenectomy is particularly important (Chap. 35). Of the malignant germ cell tumors, dysgerminoma has the highest rate of nodal metastases, approximately 25 to 30 percent (Kumar, 2008). Although staging deviations do not adversely affect survival, comprehensive staging allows a safe observation strategy for stage IA tumors (Billmire, 2004; Palenzuela, 2008).

Preservation of the contralateral ovary leads to “recurrent” dysgerminoma in 5 to 10 percent of retained gonads during the next 2 years. This finding in many cases is thought to reflect the high rate of clinically occult disease in the remaining ovary rather than true recurrence. Indeed, at least 75 percent of recurrences develop within the first year of diagnosis (Vicus, 2010). Other common recurrence sites are within the peritoneal cavity or retroperitoneal lymph nodes. Despite this significant incidence of recurrent disease, a conservative surgical approach does not adversely affect long-term survival because of this cancer’s sensitivity to chemotherapy (Liu, 2013).

Dysgerminomas have the best prognosis of all malignant ovarian germ cell tumor variants. Two thirds are stage I at diagnosis, and the 5-year disease-specific survival rate approximates 99 percent (Table 36-3). Even those with advanced disease have high survival rates following chemotherapy. For example, those with stage II-IV disease have a greater than 98-percent survival rate with platinum-based agents (Chan, 2008).

Yolk Sac Tumors

These tumors account for 10 to 20 percent of all malignant ovarian germ cell tumors. These lesions were previously called endodermal sinus tumors, but the terminology has been revised. One third of individuals are premenarchal at the time of initial presentation. Involvement of both gonads is rare, and the other ovary is usually involved with metastatic disease only when there are other metastases in the peritoneal cavity.

Grossly, these tumors form solid masses that are more yellow and friable than dysgerminomas. They are often focally necrotic and hemorrhagic, with cystic degeneration and rupture. The microscopic appearance of yolk sac tumors is often diverse. The most common appearance, the reticular pattern, reflects extraembryonic differentiation, with the formation of a network of irregular anastomosing spaces that are lined by primitive epithelial cells. Schiller-Duval bodies are pathognomonic when present (Fig. 36-5). These characteristically have a single papilla, which is lined by tumor cells and contains a central vessel. Alpha-fetoprotein is commonly produced. As a result, yolk sac tumors usually contain cells that stain immunohistochemically for AFP, and serum levels can serve as a reliable tumor marker in posttreatment surveillance.

Yolk sac tumors are the deadliest malignant ovarian germ cell tumor type. As a result, all patients are treated with chemotherapy regardless of stage. Fortunately, more than half present with stage I disease, corresponding to a 5-year disease-specific survival rate of approximately 93 percent (Chan, 2008). Disadvantageously, yolk sac tumors have a greater propensity for rapid growth, peritoneal spread, and distant hematogenous dissemination to the lungs. Accordingly, individuals with stage II-IV disease have a 5-year survival rate ranging from 64 to 91 percent. Of tumor recurrences, most will occur within the first year, and treatment is usually ineffective (Cicin, 2009).

Other Primitive Germ Cell Tumors

The rarest subtypes of nondysgerminomatous tumors are typically mixed with other more common variants and usually are not found in pure form.

Embryonal Carcinoma

Patients diagnosed with embryonal carcinoma are characteristically younger, with a mean age of 14 years, than those having other types of germ cell tumors. Epithelial cells resembling those of the embryonic disc form these primitive tumors. The solid disorganized sheets of large anaplastic cells, glandlike spaces, and papillary structures are distinctive and allow easy identification of these rare tumors (Ulbright, 2005). Although dysgerminomas are the most common germ cell tumor resulting from malignant transformation of gonadoblastomas in individuals with dysgenetic gonads, occasionally embryonal “testicular” tumors may also originate (LaPolla, 1990). Embryonal carcinomas typically produce hCG, and 75 percent also secrete AFP.

Polyembryoma

These rare tumors characteristically contain many embryolike bodies. Each has a small central “germ disc” positioned between two cavities, one mimicking an amnionic cavity and the other a yolk sac. Syncytiotrophoblast giant cells are frequent, but elements other than the embryoid bodies should constitute less than 10 percent of the tumor for the “polyembryoma” designation to be used. Conceptually, these tumors may be viewed as a bridge between the primitive (dysgerminoma) and differentiated (teratoma) germ cell tumor types. For this reason, polyembryomas are often considered to be the most immature of all teratomas (Ulbright, 2005). Serum AFP or hCG levels or both may be elevated in these individuals due to the yolk sac and syncytial components, respectively (Takemori, 1998).

Choriocarcinoma

Primary ovarian choriocarcinoma arising from a germ cell appears similar to gestational choriocarcinoma with ovarian metastases, which is discussed in Chapter 37. The distinction is important because nongestational tumors have a poorer prognosis (Corakci, 2005). The detection of other germ cell components indicates nongestational choriocarcinoma, whereas a concomitant or proximate pregnancy suggests a gestational form (Ulbright, 2005). Clinical manifestations are common and result from high hCG levels produced by these rare tumors. These elevated levels may induce sexual precocity in prepubertal girls or heavy, irregular bleeding in reproductive-aged women (Oliva, 1993).

Mixed Germ Cell Tumors

Ovarian germ cell tumors have a mixed pattern of cellular differentiation in 25 to 30 percent of cases, although the incidence of these tumors has also declined by approximately 30 percent over the past few decades (Smith, 2006). Dysgerminoma is the most common component and is typically seen with yolk sac tumor or immature teratoma or both. The frequency of bilateral ovarian involvement depends on the presence or absence of a dysgerminoma component and increases when it is present. However, treatment and prognosis are determined by the nondysgerminomatous component (Low, 2000). For this reason, elevated serum hCG and particularly AFP levels in a woman with a presumed pure dysgerminoma should prompt a search for other germ cell components by a more extensive histologic evaluation (Aoki, 2003).

Immature Teratomas

Due to a 60-percent increased incidence during the past few decades, immature teratomas are now the most common variant and account for 40 to 50 percent of all malignant ovarian germ cell tumors (Chan, 2008; Smith, 2006). They are composed of tissues derived from the three germ layers: ectoderm, mesoderm, and endoderm. The presence of immature or embryonal structures, however, distinguishes these tumors from the much more common and benign mature cystic teratoma (dermoid cyst). Bilateral ovarian involvement is rare, but 10 percent have a mature teratoma in the contralateral ovary. Tumor markers are often not elevated unless the immature teratoma is mingled with other germ cell tumor types. Alpha-fetoprotein, cancer antigen 125 (CA125), CA19-9, and carcinoembryonic antigen (CEA) may be helpful in some cases (Li, 2002).

With gross external inspection, these tumors are large, rounded or lobulated, soft or firm masses. They frequently perforate the ovarian capsule and invade locally. The most frequent site of dissemination is the peritoneum and much less commonly the retroperitoneal lymph nodes. With local invasion, surrounding adhesions commonly form and are thought to explain the lower rates of torsion with this tumor compared with that of its benign mature counterpart (Cass, 2001). On cut surface, the interior is typically solid with intermittent cystic areas, but occasionally the reverse is seen, with solid nodules present only in the cyst wall (Fig. 36-6). Solid parts may correspond to the immature elements, cartilage, bone, or a combination of these. Cystic areas are filled with hair and with serous fluid, mucinous fluid, or sebum.

Microscopic examination reveals a disorderly mixture of tissues. Of the immature elements, neuroectodermal tissues almost always predominate and are arranged as primitive tubules and sheets of small, round, malignant cells that may be associated with glia formation. The diagnosis is usually difficult to confirm during frozen section analysis, and most tumors are confirmed only on final pathologic review (Pavlakis, 2009). Tumors are graded 1 to 3 primarily by the amount of immature neural tissue they contain. O’Connor and Norris (1994) analyzed 244 immature teratomas and noted significant inconsistencies in grade assignment by different observers. For this reason, they proposed changing the system to two grades: low (previous grades 1 and 2) and high (previous grade 3). This practice, however, has not been universally accepted.

In general, survival is predicted most accurately by stage and by histologic grade of the tumor. For example, almost three quarters of immature teratomas are stage I at diagnosis and have a 5-year survival rate of 98 percent (Chan, 2008). Those with stage IA grade 1 immature teratomas have an excellent prognosis and do not require adjuvant chemotherapy (Bonazzi, 1994; Marina, 1999). Patients with stage II-IV disease have a 5-year survival rate ranging from 73 to 88 percent (Chan, 2008).

Unilateral salpingo-oophorectomy is the standard care for these and other malignant germ cell tumors in reproductive-aged women. Beiner and colleagues (2004), however, treated eight women with early-stage immature teratoma with ovarian cystectomy and adjuvant chemotherapy and noted no recurrences.

Immature teratomas may be associated with mature tissue implants studding the peritoneum that do not increase the stage of the tumor or diminish the prospect of survival. However, these implants of mature teratomatous elements, even though benign, are resistant to chemotherapy and can enlarge during or after chemotherapy. Termed the growing teratoma syndrome, these implants require second-look surgery and resection to exclude recurrent malignancy (Zagame, 2006).

Malignant Transformation of Mature Cystic Teratomas (Dermoid Cysts)

These rare tumors are the only germ cell variants that typically develop in postmenopausal women. Malignant areas are usually found as small nodules in the cyst wall or a polypoid mass within the lumen after removal of the entire mature cystic teratoma (Pins, 1996). Squamous cell carcinoma is most common and is found in approximately 1 percent of mature cystic teratomas (Fig. 36-7). Platinum-based chemotherapy with or without pelvic radiation is most often used for adjuvant treatment of early-stage disease (Dos Santos, 2007). However, regardless of treatment received, patients with advanced disease do poorly (Gainford, 2010).

Other uncommon types of malignant features may include basal-cell carcinomas, sebaceous tumors, malignant melanomas, adenocarcinomas, sarcomas, and neuroectodermal tumors. Moreover, endocrine-type neoplasms such as struma ovarii (teratoma composed mainly of thyroid tissue) and carcinoid may also be found within mature cystic teratomas.

Treatment

Surgery

A vertical abdominal incision is traditionally recommended if ovarian malignancy is suspected. However, increasingly, investigators with advanced endoscopic skills have noted laparoscopy to be a safe and effective alternative for women with smaller ovarian masses and apparent stage I disease (Shim, 2013).

If present, ascites is evacuated and sent for cytologic evaluation. Otherwise, washings of the pelvis and paracolic gutters are collected for analysis prior to manipulation of the intraperitoneal contents. The entire peritoneal cavity is systematically inspected. The ovaries are assessed for size, tumor involvement, capsular rupture, external excrescences, and adherence to surrounding structures.

Fertility-sparing USO is performed in all reproductive-aged women diagnosed with malignant ovarian germ cell tumors, as this conservative approach in general does not adversely affect survival (Chan, 2008; Lee, 2009). Following USO, blind biopsy or wedge resection of a normal-appearing contralateral ovary is not recommended. For those who have completed childbearing, hysterectomy with bilateral salpingo-oophorectomy (BSO) is appropriate (Brown, 2014b). In either case, following removal of the affected ovary, surgical staging by laparotomy or laparoscopy proceeds as previously described for epithelial ovarian cancer (Chap. 35) (Gershenson, 2007a). Because of tumor dissemination patterns, lymphadenectomy is most important for dysgerminomas, whereas staging peritoneal and omental biopsies are particularly valuable for yolk sac tumors and immature teratomas (Kleppe, 2014).

Cytoreductive surgery is recommended for advanced-stage malignant ovarian germ cell tumors if it can be accomplished with minimal residual disease (Bafna, 2001; Nawa, 2001; Suita, 2002). The same general principles for debulking are applied as described for epithelial ovarian cancer. Because of the exquisite chemosensitivity of most malignant germ cell tumors, however, neoadjuvant chemotherapy is a reasonable option for patients thought to be unresectable (Talukdar, 2014).

Many women will be referred to an oncologist after USO for a tumor that was clinically confined to the excised ovary. For such patients, if initial surgical staging was incomplete, options may include a second surgery to complete primary staging, regular surveillance, or adjuvant chemotherapy. Unfortunately, few data support a preferred approach. Because of its minimally invasive qualities, laparoscopy is a particularly attractive option for delayed surgical staging following primary excision and has been shown to accurately detect those women who require chemotherapy (Leblanc, 2004). Surgical staging following primary excision, however, is less important for scenarios in which chemotherapy will be administered regardless of surgical findings such as clinical stage I yolk sac tumors and high-grade clinical stage I immature teratomas (Stier, 1996). In such patients, reassurance of no abnormalities by CT imaging is often sufficient prior to proceeding with adjuvant chemotherapy (Gershenson, 2007a).

Surveillance

Patients with malignant ovarian germ cell tumors are followed by careful clinical, radiologic, and serologic surveillance every 3 months for the first 2 years after therapy completion (Dark, 1997). Ninety percent of recurrences develop within this time frame (Messing, 1992). Second-look surgery at the completion of therapy is not necessary in women with completely resected disease or in those individuals with advanced tumor that does not contain teratoma. However, incompletely resected immature teratoma is the one circumstance among all types of ovarian cancer in which patients clearly benefit from second-look surgery and excision of chemorefractory tumor (Culine, 1996; Rezk, 2005; Williams, 1994).

Chemotherapy

Stage IA dysgerminomas and stage IA grade 1 immature teratomas do not require additional chemotherapy. More advanced disease and all other histologic types of malignant ovarian germ cell tumors have historically been treated with combination chemotherapy after surgery (Suita, 2002; Tewari, 2000). However, there is a strong trend toward exploring the feasibility of surgery followed by close surveillance in pediatric and adolescent girls (Billmire, 2014). Because chemotherapy remains effective when used at the time of relapse, some investigators are attempting to identify additional low-risk, early-stage subgroups that may be observed postoperatively and thereby avoid treatment-related toxicity (Bonazzi, 1994; Cushing, 1999; Dark, 1997). However, before this strategy can be incorporated into general practice, additional large studies are needed.

The standard regimen is a 5-day course of bleomycin, etoposide, and cisplatin (BEP) given every 3 weeks (Gershenson, 1990; Williams, 1987). Modified 3-day BEP combinations are also safe and effective (Chen, 2014; Dimopoulos, 2004). Carboplatin and etoposide, given in three cycles, has shown promise as an alternative for selected patients (Williams, 2004). For women with incompletely resected disease, at least four courses of BEP are usually recommended (Williams, 1991).

Radiation

Chemotherapy has replaced radiation as the preferred adjuvant treatment for all types of malignant ovarian germ cell tumors. This transition was prompted primarily by the exquisite sensitivity of these tumors to either modality, but higher likelihood of retained ovarian function using chemotherapy (Solheim, 2015). Patients treated with radiotherapy are also much more likely to develop a second cancer within 10 years (Solheim, 2014). Occasional situations may still exist in which radiotherapy is considered, such as palliation of a germ cell tumor that has demonstrated resistance to chemotherapy.

Relapse

At least four courses of BEP chemotherapy is the preferred treatment for recurrent ovarian germ cell tumors in women initially managed with surgery alone. Patients who achieved a sustained clinical remission of greater than 6 months after completing BEP or another platinum-based chemotherapy regimen may be treated again with BEP. Because their tumors are generally more responsive, these “platinum-sensitive” patients have a much better prognosis. However, women who do not achieve remission with BEP chemotherapy or relapse within a few months (fewer than 6) are considered “platinum-resistant,” and treatment options are limited. Chemorefractory cases with dysgerminoma or immature teratoma appear to have a better outcome than other subtypes, and surgical salvage aimed at achieving no residual disease may benefit some patients (Li, 2007). Another option for this group is vincristine, dactinomycin, and cyclophosphamide (VAC) (Gershenson, 1985). Other potentially active drugs include paclitaxel, gemcitabine, and oxaliplatin (Hinton, 2002; Kollmannsberger, 2006).

Second-look procedures with surgical debulking have a limited role because of the inherent chemosensitivity of these recurrent tumors. Chemorefractory immature teratomas are notable exceptions (Munkarah, 1994). Growth or persistence of a tumor after chemotherapy does not necessarily imply progression of malignancy, but these masses should still be resected (Geisler, 1994).

Prognosis

Malignant ovarian germ cell tumors have an excellent overall prognosis (see Table 36-3) (Solheim, 2013, 2014). Moreover, the number of cases with distant and unstaged disease has dramatically declined, suggesting that germ cell tumors are being diagnosed earlier. In addition, the survival rates have significantly improved for all subtypes, especially with the demonstrated efficacy of cisplatin-based combination therapy (Smith, 2006). Histologic cell type, elevated serum marker levels, surgical stage, and the amount of residual disease at initial surgery are the major variables affecting prognosis (Murugaesu, 2006; Smith, 2006). Typically, pure dysgerminomas recur within 2 years and are highly treatable (Vicus, 2010). However, for nondysgerminomatous tumors, outcome after relapse is poor, and fewer than 10 percent of patients achieve long-term survival (Murugaesu, 2006).

Most women treated with fertility-sparing surgery, with or without chemotherapy, will resume normal menses and are able to conceive and bear children (Gershenson, 2007b; Zanetta, 2001). In addition, none of the reported studies has noted an increased rate of birth defects or spontaneous abortion in those treated with chemotherapy (Brewer, 1999; Low, 2000; Tangir, 2003; Zanetta, 2001).

Management During Pregnancy

Persistent adnexal masses are detected in 1 to 2 percent of all pregnancies. These neoplasms are usually seen during routine obstetric sonographic examination, but occasionally a dramatically elevated maternal serum alpha-fetoprotein (MSAFP) level is the presenting sign of a malignant germ cell tumor (Horbelt, 1994; Montz, 1989). Mature cystic teratomas (dermoid cysts) make up one third of tumors resected during pregnancy. In contrast, dysgerminomas account for only 1 to 2 percent of such neoplasms but still are the most common ovarian malignancy during pregnancy. Development of other germ cell tumors is rare (Shimizu, 2003).

Initial surgical management including surgical staging is the same as for the nonpregnant woman (Horbelt, 1994; Zhao, 2006). Fortunately, very few patients have advanced disease necessitating radical dissection for cytoreduction. The decision to administer chemotherapy during pregnancy is controversial. Malignant ovarian germ cell tumors have the propensity to grow rapidly, and delaying treatment until after delivery is potentially hazardous. Treatment with BEP appears to be safe during pregnancy, but some reports have speculated that fetal complications are possible (Elit, 1999; Horbelt, 1994). For this reason, some advocate postponing treatment until the puerperium (Shimizu, 2003). Unfortunately, there are no results from large studies to resolve this dilemma. Although BEP administration may be delayed until the puerperium for completely resected dysgerminomas, patients with nondysgerminomatous tumors (mainly yolk sac tumors and immature teratomas) and incompletely resected disease warrant strong consideration of chemotherapy during pregnancy.

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.

Epidemiology

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).

Diagnosis

Patient Findings

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.

Laboratory Testing

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).

Imaging

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).

Diagnostic Procedures

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).

Role of the Generalist

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.

Pathology

Classification

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).

Histologic Grading

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).

Granulosa Cell Tumors

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 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).

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).

Thecoma-Fibroma Group

Thecomas

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-Fibrosarcomas

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

Sertoli 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).

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).

Steroid Cell Tumors

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.

Gynandroblastomas

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).

Treatment

Surgery

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).

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.

Surveillance

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.

Chemotherapy

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).

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.

Radiation

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).

Relapse

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).

Prognosis

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.