Histologic effects of medroxyprogesterone acetate on endometrioid endometrial adenocarcinoma: a Gynecologic Oncology Group study

Abstract

Progestins have been used in the treatment of recurrent endometrial adenocarcinoma for almost 50 yr. 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. The Gynecologic Oncology Group initiated a study of 75 women with endometrioid endometrial adenocarcinoma, 59 of whom received the progestin, medroxyprogesterone acetate for 21 to 24 d immediately before hysterectomy and had available slides. Initial biopsies and hysterectomies were hematoxylin and eosin-stained and immunostained for estrogen receptor (ER) and progesterone receptor (PR), progesterone receptor-β (PRB), Bcl-2, Ki-67, and cleaved caspase-3 (Casp3). A histologic response was defined subjectively, following which specific histologic measurements and semiquantitative scores of immunohistologic variables of initial biopsies were compared with posttreatment slides. Only 1 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 nonresponders 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 downregulated following progestin therapy, as were Ki-67 and Bcl-2. However, ER and Casp3 did not change significantly. Tumors that displayed a histologic response had significantly lower pretreatment levels of Ki-67. Mean Ki-67 and Bcl-2 decreases following medroxyprogesterone acetate were greater in histologic responders than nonresponders, 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. Three weeks of medroxyprogesterone acetate therapy induces partial histologic responses in most endometrioid adenocarcinomas. Previously suggested features of histologic response do not capture the entire spectrum of changes seen. Downregulation of ER, PR, PRB, Ki-67, and Bcl-2 occurs without a significant change in Casp3. These alterations suggest that progestins act by differentiation of neoplastic cells with diminished proliferation rather than tumor cell death. As stromal decidualization was confined to areas surrounding benign glands, a paracrine effect may be involved in complete response to progestins.

Figures

Fig 1

(A) FIGO grade 1 endometrioid adenocarcinoma (#684), pre-treatment (all photomicrographs have been taken at the same magnification). (B) Post-treatment (#684), partial histologic response includes loss of nuclear stratification, occasional luminal secretion and acquisition of abundant eosinophilic cytoplasm.

Fig 1

(A) FIGO grade 1 endometrioid adenocarcinoma (#684), pre-treatment (all photomicrographs have been taken at the same magnification). (B) Post-treatment (#684), partial histologic response includes loss of nuclear stratification, occasional luminal secretion and acquisition of abundant eosinophilic cytoplasm.

Fig 2

(A) FIGO grade 1 endometrioid adenocarcinoma (#960), pre-treatment. (B) Post-treatment (#960), partial histologic response includes both acquisition of abundant eosinophilic cytoplasm and squamous differentiation.

Fig 2

(A) FIGO grade 1 endometrioid adenocarcinoma (#960), pre-treatment. (B) Post-treatment (#960), partial histologic response includes both acquisition of abundant eosinophilic cytoplasm and squamous differentiation.

Fig 3

(A) FIGO grade 1 endometrioid adenocarcinoma (#733), pre-treatment. (B) Post-treatment (#733), no histologic response is identified, with persistence of nuclear stratification and no change in cell cytoplasm.

Fig 3

(A) FIGO grade 1 endometrioid adenocarcinoma (#733), pre-treatment. (B) Post-treatment (#733), no histologic response is identified, with persistence of nuclear stratification and no change in cell cytoplasm.

Fig 4

(A) FIGO grade 2 endometrioid adenocarcinoma (#957), post-treatment, with cytoplasmic vacuolization and luminal secretion. The stroma is composed of small cells with scant cytoplasm. (B) Benign appearing endometrium adjacent to the tumor (#957), post treatment. There is extensive pre-decidual change of the stroma.

Fig 4

(A) FIGO grade 2 endometrioid adenocarcinoma (#957), post-treatment, with cytoplasmic vacuolization and luminal secretion. The stroma is composed of small cells with scant cytoplasm. (B) Benign appearing endometrium adjacent to the tumor (#957), post treatment. There is extensive pre-decidual change of the stroma.