Different immunohistochemical sex cord-stromal markers have been previously studied in various types of ovarian sex cord-stromal tumors; however, the sensitivity for sex cord-stromal lineage may vary between markers, and some markers may not be as sensitive in some types of sex cord-stromal tumors compared with other tumors in this spectrum of neoplasms. The goals of this study were to determine which immunohistochemical markers are the most sensitive and immunohistochemically robust for sex cord-stromal lineage within a given type of ovarian sex cord-stromal tumor, and to establish whether there are substantial differences of expression of these markers between different types of sex cord-stromal tumors. Immunohistochemical stains for markers which have known variable specificity for sex cord-stromal lineage [inhibin, calretinin, MART-1/melan-A, CD99, steroidogenic factor 1 (SF-1, adrenal 4-binding protein), and WT1], were performed in 127 cases of 5 different types of ovarian sex cord-stromal tumors: adult granulosa cell tumor (n=32), Sertoli cell tumor (n=27), Sertoli-Leydig cell tumor (n=18), steroid cell tumor (n=25), and fibroma/fibrothecoma (n=25). All cases in each type of sex cord-stromal tumor expressed SF-1. Inhibin and calretinin were expressed in all groups of tumors but with a lesser frequency (56% to 100% and 36% to 100% of cases, respectively). All types of tumors except steroid cell tumor expressed WT1. Fibroma/fibrothecoma was the only type of tumor that did not express CD99. The only tumor groups that showed expression of MART-1 were Sertoli-Leydig cell tumor (restricted to the Leydig cell component) and steroid cell tumor (94% and 96% of cases, respectively). The type of sex cord-stromal tumor that was least frequently positive for several of the different markers studied was fibroma/fibrothecoma. Among all tumor groups combined, inhibin and WT1 were the 2 markers showing the most diffuse expression. Likewise, the single marker showing the most optimal combination of diffuse and strong staining (immunohistochemical composite score: possible range, 1 to 12) varied between tumors: adult granulosa cell tumor-inhibin (score 10.0); Sertoli cell tumor-WT1 (score 10.8); Sertoli-Leydig cell tumor (Sertoli cell component)-WT1 (score 10.4); steroid cell tumor-inhibin (score 11.2); and fibroma/fibrothecoma-WT1 (score 8.9). We conclude that most immunohistochemical sex cord-stromal markers have sufficient sensitivity for sex cord-stromal lineage. Although each of the different types of sex cord-stromal tumors has a slightly unique immunoprofile in terms of frequency and extent of expression, these differences are relatively minor for most types of tumors with certain exceptions (eg, WT1 is not diagnostically useful in steroid cell tumor; CD99 is not diagnostically useful in fibroma/fibrothecoma; the only sex cord-stromal tumor for which MART-1 is diagnostically useful is steroid cell tumor; inhibin and calretinin are less diagnostically useful in fibroma/fibrothecoma than in the other types of tumors, but expression in fibrothecoma was higher than in fibroma). SF-1 is the most sensitive sex cord-stromal marker among the most common types of sex cord-stromal tumors. Given the findings relating to sensitivity and extent of expression in this study, and known specificity in the literature, the most informative sex cord-stromal markers to be used for the distinction from nonsex cord-stromal tumors are inhibin, calretinin, SF-1, and WT1 (the exact number of markers to be used should be based on the degree of difficulty of the case and level of experience of the pathologist); however, the utility of immunohistochemistry for the diagnosis of fibroma/fibrothecoma is somewhat limited.

Introduction: The prevalence of cervical Human Papillomavirus (HPV) infection varies greatly worldwide and data regarding HPV prevalence and genotypes in China are limited.

Immunohistochemistry can be an important part of the diagnosis of Sertoli cell tumor of the ovary, including distinction from non-sex cord-stromal tumors such as the sertoliform variant of endometrioid carcinoma and carcinoid. Several good markers for this differential diagnosis have been identified, particularly inhibin, Wilms tumor 1 gene product (WT1), epithelial membrane antigen, and chromogranin; however, many available markers have limitations to some degree. Steroidogenic factor 1 (SF-1; adrenal 4-binding protein; Ad4BP) is a nuclear transcription factor involved in gonadal and adrenal development. In the testes, SF-1 is expressed in Sertoli cells. Immunohistochemical expression of this marker in ovarian sex cord-stromal tumors, including utility for differential diagnosis, has not been rigorously evaluated. As an extension of our previous immunohistochemical studies of ovarian Sertoli cell tumor, expression of SF-1 and comparison with WT1 and inhibin were assessed in 111 primary ovarian tumors: 27 Sertoli cell tumors, 60 endometrioid tumors (including borderline tumors, conventional well-differentiated carcinomas, and sertoliform variants of carcinoma), and 24 carcinoids. SF-1 was expressed in 100% of Sertoli cell tumors but not in endometrioid tumors or carcinoid. WT1 was expressed in 100% of Sertoli cell tumors and 17% of endometrioid tumors; all carcinoids were negative. Inhibin was expressed in 96% of Sertoli cell tumors and 2% of endometrioid tumors (4% of conventional well-differentiated carcinomas); all carcinoids were negative. The extent of expression of all 3 markers was similar in Sertoli cell tumor but greatest for WT1: 63%, 96%, and 78% of cases showed expression of SF-1, WT1, and inhibin, respectively, in more than 50% of tumor cells. Immunohistochemical composite scores combining both extent and intensity of staining in positive cases were calculated for Sertoli cell tumor (possible range: 1-12). Combined extent/intensity of immunostaining was similar for all 3 markers, but WT1 showed the most robust immunoreactivity in positive cases (mean immunohistochemical composite scores for SF-1, WT1, and inhibin: 6.1, 10.8, and 7.8, respectively). We conclude that for the differential diagnosis with endometrioid tumors and carcinoid of the ovary, SF-1 is a sensitive and specific immunohistochemical marker for Sertoli cell tumor and that SF-1 is diagnostically comparable with other good sex cord-stromal markers.

The clinicopathologic features of 472 ovarian epithelial clear cell neoplasms (4 adenofibromas [AFs], 41 atypical proliferative [borderline] tumors [APTs], and 427 carcinomas [CAs]) were studied in order to elucidate the morphologic steps involved in the pathogenesis of these tumors and determine whether clear cell CA is a type I or type II tumor in the dualistic model of ovarian carcinogenesis. Thirty-three percent of the CAs had an adenofibromatous background [CA(AF+)], and 67% did not [CA(AF-)]. Endometriosis was found in all types of tumors, but tumors arising in endometriotic cysts were more frequent with CA(AF-)s (p<0.0001). The subset of women with CA(AF-)s with endometriosis were younger (p<0.0001), their tumors were more frequently cystic (pI) and were higher grade compared to CA(AF+)s or CA(AF-) with endometriosis (p-values, <0.0001 to 0.0071). All AFs and APTs were stage I compared to 79% of CA(AF+)s. An increase in mean tumor size correlated with each respective tumor category from AF (6.8 cm) to CA(AF+) [12.9 cm]. Notable nuclear atypia was absent in all AFs but was focally present in 27% of APTs and in the adenofibromatous background of 24% of the CA(AF+)s. An increase in the proportion of carcinoma in the CA(AF+)s correlated with an increase in grade and advanced stage. In summary, ovarian clear cell CA appears to develop along two pathways, both of which are related to endometriosis. We speculate that, in one, epithelial atypia arises in an endometriotic cyst and then evolves into clear cell CA, and, in the other, non-cystic endometriosis induces a fibromatous reaction resulting in the formation of AF, which then develops into APT and subsequently a clear cell CA. The absence of endometriosis or adenofibromatous components in CC(AF-)s may be due to overgrowth and obliteration by the invasive carcinoma. Finally, the findings in this study support the view that both types of clear cell CA [CC(AF+) and CC(AF-)] are more closely related to type I tumors.