Histologic Alterations in Endometrial Hyperplasia and Well-differentiated Carcinoma Treated With Progestins

Abstract

The treatment of complex atypical hyperplasia (CAH) and well-differentiated endometrioid carcinoma (WDC) by progestin therapy has been shown to be a safe alternative to hysterectomy. Accurate assessment for regressive changes induced by the progestins is critical to successful treatment. However, there are few studies detailing the histopathologic changes associated with progestin therapy. A total of 44 patients with CAH or WDC, treated with oral progestins or a progesterone or levonorgestrel-releasing intrauterine device, were followed by endometrial biopsy and/or curettage at 3 to 6 month intervals for a maximum of 25 months. The pretreatment and posttreatment endometrial samples were evaluated for response to treatment and for the histologic features of gland-to-stroma ratio, architectural abnormalities [back-to-back glands and confluency (cribriform and/or papillary patterns)], glandular cellularity, mitotic activity, cytologic atypia, and cytoplasmic changes. Histologic changes seen in progestin-treated endometria included a decreased gland-to-stroma ratio, decreased glandular cellularity, decreased to absent mitotic activity, loss of cytologic atypia, and a variety of cytoplasmic changes including mucinous, secretory, squamous, and eosinophilic metaplasia. Architectural changes tended to resolve later in the course of treatment. Some architectural abnormalities, specifically cribriform and papillary patterns, were induced by progestins mimicking progression. Twelve (67%) of 18 women with CAH had complete resolution, 2 (11%) regressed to complex hyperplasia without atypia, and 4 (22%) demonstrated persistent disease over a median follow-up period of 11 months. Eleven (42%) of 26 women with WDC had complete resolution and 15 (58%) had persistent disease over a median follow-up period of 12 months. Three instances of disease progression occurred, presumably only after discontinuing progestin treatment. Only persistent architectural abnormalities and/or cytologic atypia in the 7 to 9-month biopsies were predictive of treatment failure, with a trend for cytologic atypia to be the most powerful predictor. These findings indicate that progestin therapy should be continued for no less than 6 months to accurately assess treatment response. A modified classification for progestin-treated lesions of the endometrium is proposed.

Novel Hydroxysteroid (17β) Dehydrogenase 1 Inhibitors Reverse Estrogen-Induced Endometrial Hyperplasia in Transgenic Mice

“…8 The correlation between serum E2 levels and the risk of endometrial cancer is controversial 44 -46 and increased intratissular E2 concentrations are considered a more definite risk factor. 44,46 Progestins antagonize estrogen-mediated cell proliferation in the endometrium 47,48 and are, therefore, widely included in hormone replacement therapy to decrease the risk of endometrial hyperplasia and cancer. 49,50 The endocrinology of the mouse endometrium closely resembles that of humans.…”

Antiproliferative Effect of Metformin on the Endometrium - a Clinical Trial

“…It is well recognized that high dose progesterone can be used for treatment of patients with atypical endometrial hyperplasia and well differentiated endometrial carcinoma who desire preserve fertility or those who are poor candidate for hysterectomy (Mutter et al, 2002a;2002b;Mutter et al, 2007;Nevadunsky et al, 2013) .Treatment of the hyperplastic or neoplastic endometrium with high dose progesterone causes inactive or atrophic glands in a decidualized stroma in association with reverse of architecheral abnormality and nuclear atypia. In a cohort study conducted by Wheeler et al in 44 patients who had atypical hyperplasia or low grade endometrial carcinoma, they concluded that persisting of architectural abnormalities and nuclear atypia more than 6 months of therapy strongly indicates for treatment failure (Wheeler et al, 2007).…”

Endometrial intraepithelial neoplasia with secretory differentiation: diagnostic features and underlying mechanisms

“…First, progestins inhibit glandular proliferation and induce apoptosis, resulting in decreased glandular cellularity and nuclear changes, including reduction in nuclear size and loss of 'atypia'. 2,6,13,14 Despite these absolute changes that may occur over the course of time with therapy, contrast between lesion and background cytology is generally maintained throughout and thus more informative than fixed definitions of cytological atypia. We made the diagnosis of EIN only when the cytology of crowded glands exceeding 1 mm in size, although secretory, differed from the cytological changes found in the background.…”