Purpose Progestins have been used in the treatment of recurrent endometrial adenocarcinoma for almost 50 years. Some endometrial carcinomas respond to hormonal therapy, but the mechanism of action remains incompletely known. We wished to determine the efficacy of progestins to induce a histologic response in endometrioid carcinomas and explore its effects on histologic and immunohistochemical measures of growth and cell death. Methods The Gynecologic Oncology Group initiated a study of 75 women with endometrioid endometrial adenocarcinoma, 59 of whom received the progestin, medroxyprogesterone acetate (MPA) for 21-24 days immediately prior to hysterectomy and had available slides. Initial biopsies and hysterectomies were H&E stained and immunostained for estrogen receptor (ER) and progesterone receptor (PR), progesterone receptor Beta (PRB), Bcl-2, Ki-67, and cleaved caspase-3 (Casp3). A histologic response was defined subjectively, following which specific histologic measurements and semi-quantitative scores of immunohistologic variables of initial biopsies were compared to post-treatment slides. Results Only one complete histologic response was seen, but 37 tumors (63%) had a partial histologic response. Specific histologic changes included the following: a decrease in the nuclear grade, the number of mitotic figures, nucleoli, and mean gland cellularity, and acquisition of more abundant eosinophilic cytoplasm, squamous metaplasia, and secretion. The tumors that displayed a subjectively defined histologic response following treatment differed initially from those that did not only with respect to initial nuclear grade and the mitotic index. Statistically significant differences in the specific histologic features in carcinomas of responders versus non-responders following treatment were found only with respect to acquisition of pale eosinophilic cytoplasm and luminal secretion. More than 90% of tumors were initially ER positive and 76% were PR positive. The initial presence of ER or PR was not related to subjective histologic response. PR and PRB were significantly down-regulated following progestin therapy, as were Ki-67 and Bcl-2. However, ER ad Casp3 did not change significantly. Tumors that displayed a histologic response had significantly lower pre-treatment levels of Ki-67. Mean Ki-67 and Bcl-2 decreases following MPA were greater in histologic responders than non-responders, but not decreases in ER, PR, PRB and Casp3. The histologic response in the tumors and their stroma differed quantitatively and qualitatively from that of the adjacent benign endometrium, where decidual change accompanied luminal secretion and secretory exhaustion of glands. Conclusion Three weeks of MPA therapy induces partial histologic responses in most endometrioid adenocarcinomas. Previously suggested features of histologic response do not capture the entire spectrum of changes seen. Down regulation of ER, PR, PRB, Ki-67 and Bcl-2 occurs without a significant change in Casp3. These alterations suggest that progestins act ...
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