Immunoexpression of inhibin (alpha) subunit, inhibin/activin (beta A) subunit and CD99 in ovarian tumors

Archives of Pathology & Laboratory Medicine, Apr 2000 by Choi, Yoon-La, Kim, Hy-Sook, Ahn, Geunghwan

Objective.-Anti-inhibin alpha and inhibin/activin beta A subunit and anti-CD99 monoclonal antibodies (mAbs) have recently been demonstrated to be able to label ovarian granufosa cells; thus, they may be of value in the diagnosis of granulosa cell tumors. The present study aimed to determine what combination of these mAbs may be useful for the differential diagnosis of sex cord-stromal tumors of ovary.

Design.-Immunohistochemical analyses with anti-inhibin alpha and inhibin/activin beta A subunit antibody and antiCD99 mAb were performed on 42 ovarian tumors, including sex cord-stromal tumors (29), ovarian epithelial cancers (10), and Krukenberg tumors (3).

Results.-All sex cord-stromal tumors were positive for inhibin a subunit, and 17 cases (58.6%) of sex cord-stromal tumors were immunoreactive for inhibin/activin PiA subunit. Epithelial tumors and Krukenberg tumors were all negative for inhibin/activin beta A subunit except mucinous carcinoma, which showed strong cytoplasmic immuno

reactivity. All sex cord-stromal tumors except one granulosa cell tumor showed membranous staining for CD99. A case of serous carcinoma and a case of mucinous carcinoma were positive for CD99, and the remaining epithelial tumors and Krukenberg tumor were all negative for CD99.

Conclusions.-The results of immunohistochemical analysis, together with literature review, suggest that inhibin alpha subunit may be a useful diagnostic marker for sex cordstromal tumor of the ovary. In addition, anti-CD99 antibody may be useful for the differential diagnosis between ovarian tumors. Inhibin/activin beta A subunit has a limited usefulness in the differential diagnosis of ovarian tumor because of its wider immunoreactivity for both sex cord-stromal tumors and mucinous carcinomas. The differential diagnosis of sex cord-stromal tumors of the ovary would be better made with a combined use of both anti-inhibin ot subunit and anti-CD99 mAbs.

(Arch Pathol Lab Med. 2000;124:563-569)

Ovarian cancer is the fourth most common cancer and the leading cause of death from gynecologic malignancy.1 Despite considerable efforts to elucidate the exact mechanisms by which growth and proliferation of both normal and malignant ovarian cells are regulated in the human ovary little is known. The most common type of malignancy in the ovary is serous cystadenocarcinoma (43%), whereas sex card-stromal tumors (SCSTs) are relatively uncommon, accounting for only T% of all malignant neoplasms.1 Sex cords-stromal tumors can be distinguished for the most part from ovarian epithelial tumors and metastatic malignancies either by characteristic histologic patterns or by immunophenotypic analysis using antibody against intermediate filament.2 Sex cord-stromal cells, however, have a rather nonspecific immunohistochemical profile. Thus, differentiation of SCSTs from other types of ovarian tumors such as endometrioid carcinomas, ovarian small cell carcinomas, and soft tissue sarcomas may be difficult.3 Recently, novel markers have been reported as being produced by sex card-stromal cells and their corresponding tumors.4,5 Subsequent studies have also demonstrated the utility of serum inhibin measurements as a marker of recurrent disease in patients with SCSTs.6

The inhibin/activin is a disulfide-linked glycoprotein dimes belonging to the transforming growth factor beta peptide family. The inhibins are alpha:beta heterodimers, whereas the activins are beta:beta dimers. Two unique but homologous beta subunits, beta A and beta B, are shared between these growth factors. The inhibins and activins were initially described as gonadal peptides that either inhibited as stimulated the production of pituitary follicle-stimulating hormone (FSH). The major gonadal sites of inhibin synthesis are the Sertoli cells in males and the granulosa cells in females.4,5 A role for inhibin in the regulation of tumor growth has recently been suggested because of its suppressive effect on the development of both gonadal SCSTs and adrenocortical tumors in mice deficient for the alpha-subunit of inhibin.7 Elevated levels of inhibin and its subunits have been detected in patients with a variety of gonadal stromal tumors, most commonly granulosa cell tumors.

Immunohistochemical studies demonstrated that inhibin detection is a sensitive marker for the sex cord-stromal differentiation.8 Detection of inhibin/activin subunit, however, has also been reported in some ovarian epithelial and germ cell tumor.8-10 The expression of the inhibin/ activin subunit in epithelial tumor of ovary has mainly been studied in the field of endocrinology in view of the tumorigenesis. The previous study of inhibin/activin in ovarian cancer cell line suggests that the lack of inhibin combined with the overproduction of activin lead to uncontrolled gonadal cell proliferation and eventual tumor formation.11 The unbalanced expression of inhibin and actuvin subunits in ovarian surface epithelium may represent an early event that leads to epithelial proliferation.9 However, data from many independent experiments regarding the expression of inhibin/activin in epithelial tumor of ovary showed considerable discrepancies.8-10,12-17