Differential Activation of the Mammalian Target of Rapamycin (mTOR) Pathway in Poromas and Porocarcinomas
Camille T Elkins, Obiajulu H Iwenofu, Thomas Olencki, Sara B Peters. Ohio State University Medical Center, Columbus, OH
Background: Adnexal carcinomas are rare and treatment options are limited. Recent studies have identified a PIK3CA (c.1633 G>A) mutation in a subset of metastasizing porocarcinomas and have proposed a role for phosphatidiylinositol 3-kinase (PI3K) pathway inhibitors as treatment for these tumors. The mammalian target of rapamycin (mTOR), a serine/threonine kinase, represents a key mitogenic output of PI3K pathyway activation and is an additional potential therapeutic target. Using antibodies to PI3K, p-mTOR, p70S6K (an intermediate molecule) and pS6rp (an mTOR surrogate marker), we sought to determine the role of the PI3K/mTOR pathway in 6 poromas and 7 porocarcinomas.
Design: An electronic database search for cases of poroma and porocarcinoma yielded 6 and 7 cases, respectively. Slides were reviewed and sections were stained with previously optimized antibodies to PI3K, p-mTOR, p70S6K and pS6rp. Staining was evaluated by two pathologists. Moderate to intense staining in ≥30% of tumor cells was interpreted as positive. Sections with only faint staining were interpreted as background/negative.
Results: Differential staining was observed between the two groups. The poroma group was negative for PI3K, mTOR, and pS6rp staining. Only weak, focal staining was observed with PI3K (interpreted as negative). Porocarcinomas were positive for p-mTOR and pS6rp, and 4/7 were positive for PI3K. Though a threshold of 30% or tumor cells was used for positivity, several of the porocarcinomas showed diffuse positive staining. Notably, p70S6 demonstrated uniform strong and diffuse positive nuclear staining in both categories.
Conclusions: Immunohistochemically, porocarcinomas show increased expression of p-mTOR and pS6rp compared to poromas. Four of seven porocarcinomas showed reactivity for PI3K; these results support the previously published finding of PIK3CA mutations in half of the porocarcinomas in one study. However, the downstream activation of mTOR and its surrogate marker pS6rp in porocarcinomas (including those without increased PI3K expression) is promising and supports further investigation of the use of mTOR inhibitors for these rare adnexal carcinomas. The nuclear expression of p70S6K in both poromas and porocarcinomas may suggest an alternate mechanism of mTOR pathway activation.
Wednesday, March 6, 2013 9:30 AM
Poster Session V # 64, Wednesday Morning