Clear Cell Carcinomas of the Mullerian System: Does the Pathogenesis Vary Depending on Their Nuclear Grade and Their Association with Endometriosis? An Immunohistochemical Analysis

Clear cell carcinomas (CCC) of the mullerian system are considered high grade tumors, but morphologically, the cells of CCC show both low and high grade features. The aims of the current study were to categorize CCC into low and high nuclear grade types, correlate their association with endometriosis, and then observe possible variations in pathogenesis based on their expression of p53 and Ki-67. We studied 41 pure mullerian CCCs and designated each as either a high (HNG) or low (LNG) nuclear grade tumor. Morphologically, 17 (41%) CCCs were LNG and 24 (59%) were HNG. Nine (38%) HNG and 2 (12%) LNG tumors showed positive immunostaining with p53. Endometriosis was associated with 8 (47%) LNG tumors and 8 (33%) HNG CCCs. Of the 11 cases with p53 alteration, 4 (1 LNG and 3 HNG) were associated with endometriosis. Conclusions: HNG CCCs, irrespective of their association with endometriosis, have alterations of p53. In general, LNG ovarian and endometrial CCCs, irrespective of their association with endometriosis/adenomyosis, are less likely to show p53 alteration. It appears that mullerian CCCs may have variable pathogenesis depending on their nuclear grade and association with endometriosis. A larger study is needed to validate these findings. 1. Introduction While the pathogenesis of mullerian serous and endometrioid carcinomas has been linked to p53 and PTEN mutations, respectively, the pathogenesis of clear cell carcinoma remains largely speculative. Clear cell carcinoma (CCC) was initially termed “mesonephroid tumor” in 1939 [1] and, since 1973, has been strictly defined by the WHO as a tumor characterized by clear cells growing in solid/tubular or glandular patterns and sometimes as hobnail cells [2]. CCCs of the mullerian system are largely found in the endometrium and ovary, but primary peritoneal clear cell carcinoma has also been reported. CCCs also arise in the uterine cervix and vagina of women of all ages including children [3, 4]. It is known that many clear cell carcinomas arise in endometriosis. Recent studies have speculated that ovarian clear cell carcinoma may develop along two pathways, both of which are related to endometriosis [5]. In one pathway, the epithelial atypia arises within an endometriotic cyst and then progresses to carcinoma. In the noncystic pathway, endometriosis induces fibromatosis resulting in the formation of an adenofibroma. In this second pathway, adenofibromas progress to atypical adenofibroma and subsequently to CCC. CCCs of the uterus have been reported to arise from adenomyosis [6]. Studies have shown that cystic