Histologic Effects of Medroxyprogesterone Acetate on Endometrioid Endometrial Adenocarcinoma

Abstract

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 ...

Downregulation of FOXO1 mRNA levels predicts treatment failure in patients with endometrial pathology conservatively managed with progestin-containing intrauterine devices

“…Of the 10 patients that were included in the study, most demonstrated a significant reduction in PR protein expression post-IUD insertion as compared to pre-insertion (Figure 2A–C). Levels of the progesterone receptor isoform B (PRB) were also markedly decreased in post-treatment biopsies (Figure 2A–C), consistent with a previous report demonstrating downregulation in response to progestin-based therapy [20]. Pearson correlation analysis demonstrated that post-IUD insertion expression of ER significantly correlated with PRB (Figure 2D), in line with the reported relationship between hormone receptors in endometrial tumors [29].…”

“…In general, PR and PRB levels decrease in response to progestin-IUD therapy, as has been previously demonstrated in the non-therapeutic study of the histologic impact of medroxyprogesterone acetate in patients scheduled for hysterectomy for endometrial cancer (GOG 211) [20]. The mechanism underlying short term hormone receptor down-regulation in response to ligand has been well documented: ligand causes receptor phosphorylation – the necessary precursor for transcriptional activation – while at the same time serving as a signal for receptor ubiquitination and destruction in the proteasome.…”

“…Based on the GOG 211 study [20], we originally hypothesized that we would observe a significant loss in hormone receptor expression in response to therapy. However, we unexpectedly found that, in patients who progressed on therapy, the magnitude of the decrease in hormone receptor levels in post-treatment biopsies was significantly blunted.…”

“…However, Upson et al reported that PRB over-expression confers a decreased risk of stable disease or progression by 90% in patients with atypical hyperplasia [22], while Gunderson et al reported that ER and PR expression did not predict for treatment response to progesterone therapy [15]. In GOG211 which examined ER, PR, and Bcl-2, lower pre-treatment levels of the proliferative indicator Ki-67 were the only pre-treatment predictor of histologic response [20]. Towards identifying a biomarker for response, we also screened patients who progressed to cancer for mutations in genes commonly altered in endometrial cancer [2] but did not detect mutations in p53, KRAS, PTEN, or PI3 kinase (data not shown).…”

The Epigenetic Landscape in the Treatment of Gynecologic Malignancies

“…The authors reported a 64% par al response rate and one complete response among 59 women. 28 Interes ngly, GOG-0211 illustrated a downregula on of progesterone receptor a er exposure to medroxyprogesterone. In preclinical models, progesterone receptor downregula on is thought to result from promoter CpG hypermethyla on and gene silencing.…”