Physical Address
304 North Cardinal St.
Dorchester Center, MA 02124
Sex cord stromal tumors of the ovary
Clinical case
A 58-year-old G2P2 female presents with a 10 cm complex adnexal mass and postmenopausal bleeding. CT imaging also demonstrates a 4 cm perihepatic tumor implant ( Fig. 2.1 ). Image-guided biopsy of this implant demonstrates an adult granulosa cell tumor (AGCT), and preoperative inhibin A was elevated at 22 pg/mL and inhibin B was elevated at 751 pg/mL. How do you treat this patient?
Epidemiology
Incidence/mortality
The sex cords and stromal compartments collectively comprise the mesenchymal support structures and sites of local and systemic hormone production for both the male and female gonad. Pure sex cord tumors include those arising from granulosa cells and Sertoli cells, as well as the rarer entity sex cord tumor with annular tubules which occur in the setting of Peutz–Jeghers syndrome (PJS) in up to 30% of cases. Pure stromal malignancies of the ovary are generally rare and include fibrosarcomas and malignant steroid cell tumors. Mixed Sertoli–Leydig cell tumors (SLCTs) are uncommon, and although they may be associated with androgenic excess, the majority of such tumors described in large historical series exhibited benign behavior. The World Health Organization classification of sex cord/stromal tumor is shown in Table 2.1 . The incidence rate of sex cord/stromal ovarian cancers in the United States has been estimated to be approximately 0.5 per 100,000 using large cancer registries, but this may be an underestimate due to misclassification of early stage disease as nonmalignant. For example, the category “Granulosa cell tumor, adult type” carries a nonmalignant behavior code in the International Classification of Diseases for Oncology (ICD-O) and thus is excluded from many cancer registry analyses. In support of this observation are longitudinal multinational population data from Scandinavia showing that between the years 1953 and 2012, the incidence rate of ovarian granulosa cell tumors alone was between 0.6 and 0.8 per 100,000, a higher rate than has been reported for all sex cord/stromal ovarian cancers in the United States.
Table 2.1
WHO classification of sex cord/stromal tumors of the ovary.
| Sex cord/stromal tumors |
|---|
| Pure stromal tumors |
|
| Pure sex cord tumors |
|
| Mixed sex cord/stromal tumors |
|
The median age for diagnosis of AGCT of the ovary is around 45–50 years with most diagnoses occurring in the fourth of fifth decade of life. The juvenile-type of granulosa cell tumor (JGCT) of the ovary is histologically distinct from AGCT of the ovary and arises most often during the prepubertal years. Including both benign and malignant entities, SLCTs tend to arise in the third decade of life but there is wide variance in the reported age of onset. A review of patients in the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database showed women diagnosed with SLCTs were younger than those diagnosed with granulosa cell tumors (median age 32 vs 51). Staging of sex cord/stromal tumors of the ovary uses the same FIGO system employed in the management of more common epithelial malignancies of the ovary. In general, sex cord/stromal tumors are more likely to be stage I at the time of diagnosis (75%–90%) than are the more common epithelial subtype of ovarian cancers. Largely due to the combination of a favorable stage distribution at diagnosis and indolent behavior, 10-year survival rates for SLCT and AGCT of the ovary are generally excellent for completely resected disease. Stage at diagnosis is the clinical factor that has most consistently been linked to recurrence risk and outcomes across sex cord/stromal tumor subtypes. Additionally, poorly differentiated SLCTs or those with heterologous elements are more likely to recur and exhibit malignant behavior following initial surgical resection. Some evidence also suggests that the presence of a retiform pattern may also portend a higher risk of SLCT recurrence. Among AGCT of the ovary, several factors including mitotic rate, cellular atypia, and tumor size, patient body mass index at the time of diagnosis have been variably associated with recurrence risk and survival outcomes.
Etiology/risk factors
There are no known environmental risk factors for the development of sex cord/stromal tumors. For example, a population-based cohort study in Scandinavia examined the risk of granulosa cell tumor across time and occupation between the years 1953 and 2012. The stability of granulosa cell tumor incidence over the observation period of this study suggests that the usage of hormonal contraceptives, postmenopausal hormone replacement therapy, or fertility treatments do not substantially influence patterns of risk for this disease, since the use of these interventions changed dramatically throughout the 60-year observation period of this study. In the United States, both Sertoli–Leydig and granulosa cell tumors occur more frequently in Black women compared to White women or Asian/Pacific Islanders.
Genetic evidence indicates that germline mutations may account for a subset of sex cord/stromal tumors. Hotspot somatic missense mutations in the RNase IIIb domain of the gene coding for the microRNA processing enzyme DICER1 are found in approximately 60% of SLCTs, with a smaller subset of affected individuals also carrying truncating germline DICER1 mutations. Evidence from public exome sequencing datasets indicate that at least 1 in 10,000 individuals likely carry such a germline DICER1 mutation, representing a Mendelian syndrome associated with an increased risk of SLCT as well as a spectrum of other malignancies including pediatric pleuropulmonary blastoma. The association between sex cord tumor with annular tubules and PJS was known from the time this tumor type was first described in 1970. Germline pathogenic mutations in the STK11 gene, the causative lesion of PJS, account for approximately one-third of all cases of sex cord tumor with annular tubules. In contrast, STK11 mutations are rare in sporadic sex cord tumor with annular tubules.
Pathology
Adult granulosa cell tumor
Gross
The majority of AGCT are unilateral. The tumor size can vary from microscopic to extremely large (mean 10.0 cm). The tumors can be either entirely solid, solid and cystic or less commonly entirely cystic. The cyst contents may be serous or more typically hemorrhagic and rupture may result in hemoperitoneum. The cut surface of the solid component is usually yellow white in appearance.
Microscopic features
AGCT can demonstrate a variety of patterns including diffuse, microfollicular, macrofollicular, insular (discrete nests), trabecular/corded, gyriform, pseudopapillary, and watered-silk. The diffuse pattern is most common and is composed of fascicles of spindle cells ( Fig. 2.2 ). The Call-Exner body ( Fig. 2.3 ) characterized by the presence of tumor cells around a central space containing eosinophilic secretions, degenerating nuclei or hyaline material, resulting in the microfollicular pattern is the histologic hallmark of these tumors. The background stroma can be either fibromatous or thecomatous and in some cases can largely overrun the granulosa cell component, making it difficult to recognize ( Fig. 2.4 ). The nuclei of AGCT are oval and monotonous with fine chromatin and indistinct nucleoli. The coffee bean appearance secondary to the presence of nuclear grooves ( Fig. 2.5 ) is characteristic. Mitotic activity is variable but is low in most cases (< 4/10 hpfs). Of the various pathologic parameters no single one is predictive of adverse outcome for stage IA patients. Pathologic parameters such as tumor size, nuclear atypia, and the predominant histologic pattern of the tumor have not been shown to consistently predict behavior in patients with Stage 1A disease. There is some controversy about the mitotic index in that some authors report worse outcome with mitoses anywhere from > 4 to > 10/10 hpfs, while others have not found mitotic index to be predictive of behavior.
Ancillary testing
AGCT and all other sex cord tumors described in this chapter are usually positive for SF-1, inhibin ( Fig. 2.6 ), and calretinin. Reticulin stain usually highlights loss of reticulin fibers around individual tumor cells.
Differential diagnosis
Due to the numerous histologic patterns of AGCT the differential diagnosis is quite vast and depends on the dominant pattern. Diffuse AGCT can be misinterpreted as cellular fibroma or endometrial stromal sarcoma. Loss of reticulin fibers around individual tumor cells in AGCT can help distinguish it from cellular fibroma. Endometrial stromal sarcomas have short spindle cells with typical spiral arteriole-like vascular pattern, lack of nuclear grooves and CD10 positivity, while they are negative for inhibin, calretinin and SF-1.
Endometrioid adenocarcinoma, particularly when they have sex cord-like pattern, can closely mimic the microfollicular pattern of AGCT. Areas of conventional pattern of endometrioid carcinoma with squamous and or mucinous differentiation are usually present and should facilitate this diagnosis. Furthermore, an adenofibromatous component and endometriosis will further support this diagnosis. Endometrioid carcinomas are positive for EMA and PAX-8 while negative for inhibin/calretinin/SF-1.
The nested appearance of the insular pattern of AGCT can resemble carcinoid tumor. The latter tumor has salt and pepper chromatin, lacks nuclear grooves and is positive for neuroendocrine markers synaptophysin and chromogranin. Markers of sex cord differentiation such as SF-1, inhibin and calretinin are negative. FOXL2 immunostain is positive in majority of sex cord/stromal tumors and can be used as an additional marker to distinguish sex cord/stromal tumors from epithelial tumors and other mimics, though this stain is not routinely available in most laboratories.
Lastly, the macrofollicular pattern of AGCT can mimic a follicular cyst. If the cyst is larger than 10 cm, has loss of theca cells and shows nuclear grooving and organization of tumor cells, a diagnosis of AGCT would be favored.
Molecular alterations
FOXL2 belongs to the family of forkhead/winged-helix transcription factors and has been shown to play an important role in the formation of follicles in the adult ovary. The majority of AGCT harbor a missense mutation c.402C-G (p.C134W) in the Forkhead box L2 ( FOXL2) gene. This mutation is absent in most sex cord tumors as well as epithelial tumors and is fairly sensitive and specific for AGCT. Rarely thecomas and JGCT have been reported to have the FOXL2 mutation. Molecular testing for FOXL2 is not typically performed in routine practice but may be helpful in challenging cases such as fibromatous AGCT.
Juvenile granulosa cell tumor
Gross
JGCT are typically unilateral and present with disease confined to the ovary. These tumors can range from small to very large (mean, 12 cm). Similar to AGCT, the cut surface of the tumor can be purely solid, solid and cystic, or only cystic.
Microscopic findings
Histologically JGCT are composed of granulosa cells that can either have a diffuse or nodular pattern. Necrosis and hemorrhage may be present. Follicle-like spaces filled with basophilic or eosinophilic material are a key histologic feature in the diagnosis of JGCT ( Fig. 2.7 ). A subset of cases may have a pseudopapillary pattern. The tumor cells often have abundant pale pink or clear cytoplasm and the nuclei are small, round or oval. Nuclear grooves are rare or absent. Tumors with brisk mitotic activity and bizarre atypia ( Fig. 2.7 ) are seen in about 10% of cases, but these findings do not appear to have an impact on prognosis. Small foci of JGCT can sometimes be admixed with AGCT or Sertoli cell tumors and these cases are classified based on the dominant histotype.
Ancillary testing
JGCT are positive for the usual sex cord markers such as inhibin, calretinin, CD56 and SF-1. A small subset may be positive for FOXL2 immunostain but its use in routine diagnosis is limited.
Differential diagnosis
Differentiating JGCT from AGCT can be difficult particularly when the latter tumor shows prominent luteinization. Young age at presentation, nodular pattern, follicle-like spaces, and lack of nuclear grooves would favor JGCT.
Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) can closely mimic JGCT as both tumors are characterized by the presence of follicle-like spaces. SCCOHT is composed of small cells with minimal cytoplasm as well as rhabdoid morphology (large cell variant), and are negative for sex cord markers. Clinically, unlike JGCT, SCCOHT presents with advanced stage disease and a subset of patients have accompanying hypercalcemia. Recently studies have shown that most SCCOHT have either somatic or germline mutations in the SMARCA4 gene, and lack SMARCA4 (BRG1) expression by immunohistochemistry. This latter finding is virtually diagnostic of SCCOHT and facilitates the correct diagnosis.
Molecular alterations
The molecular mechanisms of JGCT are not that well studied. Trisomy12 is the most frequent cytogenetic abnormality identified and is present in most cases tested so far. FOXL2 mutations rarely occur in JGCT. Recent studies have shown that JCGT have activating alterations in AKT1 and GNAS that may contribute to the pathogenesis of these tumors.
You're Reading a Preview
Become a Clinical Tree membership for Full access and enjoy Unlimited articles
If you are a member. Log in here