Case 3 -

Endometrioid Carcinoma Resembling Sex Cord-Stromal Tumor Jaime Prat Professor and Chairman of Pathology Hospital de la Santa Creu i Sant Pau Autonomous University of Barcelona, Spain

Clinical History: A 73-year old woman had vaginal bleeding for 6 months. On pelvic examination she was found to have a left adnexal tumor. Twenty-six years prior to admission she underwent a right salpingo-oophorectomy for an unknown reason. She also had a mastectomy for carcinoma 9 years previously. An endometrial biopsy done a few weeks before admission was reported as "proliferative" endometrium. At laparotomy, the left ovary was replaced by a grayish-white, multinodular tumor, 8.5 cm (285 g) in diameter. A total abdominal hysterectomy with left salpingo-oophorectomy was done. On section, the ovarian tumor was solid. It exhibited a central star-shaped fibrous component surrounded by confluent nodules of fleshy grayish-yellow tissue. Case 3 - Figure 1 Click to view with ImageScope Click to view with a Web-Based Viewer Diagnosis: Endometrioid Carcinoma Resembling Sex Cord-Stromal Tumor Gross Features: Solid multinodular tumor, 8.5 cm (285 g) Central fibrous component Peripheral nodules of grayish-yellow firm tissue Absence of hemorrhage or necrosis Microscopic Features: Small hollow tubules simulating those of well differentiated Sertoli cell tumor Larger glands with luminal mucin typical of endometrioid carcinoma Luteinization of the stroma resembling Leydig cell component Pale, oval and angular nuclei many of which are grooved (Sertoli-like) Round hyperchromatic nuclei with numerous mitoses (endometrioid carcinoma) Thin cords resembling sex cords Absence of squamous differentiation Negative a -Inhibin ( only positive in luteinized stromal cells) Follow-up: No adjuvant treatment was given. The patient was well and without evidence of disease at 4 years Discussion Endometrioid carcinomas may have several patterns that differ from those of the typical adenocarcinoma of the endometrium. Among these are patterns resembling those of sex cord-stromal tumors, characterized by the presence of small hollow tubular glands, solid tubular structures, thin ribbons of epithelial cells, small cavities containing eosinophilic material and simulating Call-Exner bodies, and diffuse sheets and dicrete nests of relatively uniform cells with scant cytoplasm. The hollow and solid tubular structures may resemble those seen in well-differentiated Sertoli or Sertoli-Leydig cell tumors, and the thin ribbons of epithelial cells may simulate the sex cord-like formations of Sertoli-Leydig cell tumors of intermediate differentiation. In addition, endometrioid carcinomas, in common with a wide variety of tumors may contain luteinized cells in their stroma, which can be mistaken for the Leydig cells of a Sertoli-Leydig cell tumor. A number of clinical and pathologic differences between endometrioid carcinomas and Sertoli-Leydig cell tumors however help to establish the diagnosis. The former generally occur at an older age than the latter, which are detected at an average age of 25 years. Sertoli-Leydig cell tumors are androgenic in approximately half the cases whereas endometrioid carcinomas are usually non-functioning. It should be emphasized however that the presence of lutein cells within an endometrioid carcinoma may be associated with steroid hormone production and resultant endocrine manifestations. Other features that are more compatible with the diagnosis of an endometrioid carcinoma are bilaterality and high stage, both of which are exceptional in cases of Sertoli-Leydig cell tumor. Usually, however, both types of tumor are Stage I and unilateral and the diagnosis rests on correct evaluation of the microscopic findings. In our experience the sex cord-stromal tumor with which an endometrioid carcinoma is most often confused is the Sertoli-Leydig cell tumor. However, the presence of Call-Exner-like bodies, and diffuse and insular patterns in an endometrioid carcinoma sometimes suggest the diagnosis of a granulosa cell tumor. Since endometrioid carcinomas may vary greatly in their appearance from one area to another, thorough sampling is important in the evaluation of any tumor with an unusual pattern in which the diagnosis of an endometrioid carcinoma is a possibility. The most convincing evidence is the presence of foci of typical endometrioid carcinoma, the glands of which are usually larger and more irregular in shape than the tubules of a sex cord-stromal tumor and are usually lined by less well differentiated epithelium. The presence of significant amounts of intraluminal mucin also strongly favours the diagnosis of endometrioid carcinoma as does the finding of squamous differentiation, which has not been encountered in sex cord-stromal tumors. Squamous change in endometrioid tumors is not always overt but may be abortive in the form of spindle-shaped cells growing in more or less rounded aggregates; the presence of such foci should suggest the diagnosis of an endometrioid neoplasm. Finally, the occurrence of adenofibromatous foci is an additional helpful clue in many endometrioid carcinomas. With regard to differentiation from a granulosa cell tumor high power examination of the nuclei of an endometrioid carcinoma does not show the pale, grooved appearance characteristic of granulosa cells. With the exception of vimentin, the expression of intermediate filaments in sex cord-stromal tumors is quite variable, and this variability does not facilitate the diagnosis. Recently, three immunohistochemical markers have been reported to be expressed by sex cord-stromal cells and their corresponding tumors: Alpha-inhibin, CD99, and Müllerian inhibiting substance. Inhibin is a gonadal polypeptide hormone which inhibits FSH secretion by the anterior pituitary gland. It is a glycoprotein made up by two subunits; an alpha-subunit and one of the two closely related beta-subunits (beta-A and beta-B). Complete inhibin is produced by granulosa cells, theca cells and Sertoli cells. In contrast, Leydig cells express exclusively the alpha-subunit of inhibin. Both inhibin and MIS are members of the transforming growth factor beta (TGF beta) gene family. Alpha-inhibin has proved to be a good marker for granulosa cell tumors, Sertoli-Leydig cell tumors and steroid cell tumors of the ovary. Most studies have confirmed negative alpha-inhibin staining in the neoplastic components of ovarian epithelial-stromal tumors. Interestingly, alpha-inhibin is also expressed by the luteinized non-neoplastic stromal cells that frequently surround clusters of neoplastic epithelial cells in so-called ovarian tumors with functioning stroma. In fact, the production of inhibin by the stromal cells explains why inhibin serum levels are sometimes elevated in patients with ovarian cancer. In ovarian tumors with functioning stroma, tumor cells do not react for alpha-inhibin whereas the activated stroma is strongly immunoreactive. Contrariwise, in sex-cord stromal tumors alpha-inhibin immunoreactivity is seen both in the trabecular and stromal component of the neoplasm. Recently, Arora et al have demonstrated positive alpha-inhibin and activin immunostaining in six ovarian granulosa cell tumors. In this study, eight of nine epithelial-stromal tumors of the ovary expressed activin exclusively. Interestingly, alpha-inhibin was also expressed in a single case of an ovarian clear cell adenocarcinoma. The cell surface antigen defined by the cluster of differentiation (CD)99 is a transmembrane glycoprotein coded by the MIC-2 gene that has been mapped to both chromosomes X and Y. The MIC-2 gene is ubiquitously expressed by a great variety of human tissues, varying from virtually undetectable expression in some tissues to significant overexpression in lymphocytes, Ewing's sarcoma, and peripheral neuroectodermic tumor. CD99 has been reported to be positive both in normal granulosa and Sertoli cells as well as in 69% of ovarian granulosa cell tumors and 67% of Sertoli-Leydig cell tumors. However, CD99 is also positive in a variety of tumors of different origins, which may represent a problem for its practical use in tumor differential diagnosis. The Müllerian inhibiting substance (MIS) is a homodimeric glycoprotein secreted by Sertoli cells of fetal and adult testes and granulosa cells of the postnatal ovary. The primary function of MIS is the regression of the Müllerian ducts during male fetal development. Müllerian inhibiting substance (MIS) can be demonstrated by immunohistochemistry in fetal Sertoli cells and also in the granulosa and theca cells of the ovarian follicle. Even more, MIS serum levels have been found to be elevated in patients with sex-cord stromal tumors. As illustrated by the case under discussion, one of the most difficult problems in differential diagnosis in gynecologic tumor pathology is the distinction between sex cord-stromal tumors and endometrioid carcinomas that exhibit a sex cord-like architectural pattern of growth. All three markers (MIS, alpha-inhibin and CD99) are expressed by all sex cord stromal tumors but not by endometrioid carcinomas resembling sex cord-stromal tumors. Of the three antibodies, alpha-inhibin is the most reliable, showing the most specific staining. References: Roth LM, Liban E, Czernobilsky B. 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