Zaino Richard J, Brady William E, Todd William, Leslie Kimberly, Fischer Edgar G, Horowitz Neil S, Mannel Robert S, Walker Joan L, Ivanovic Marina, Duska Linda R
Division of Anatomic Pathology (R.J.Z., W.T.), Hershey Medical Center, Pennsylvania State University, Hershey, Pennysylvania Gynecologic Oncology Group Statistical and Data Center (W.E.B.), Buffalo, New York University of Iowa Med Center (K.L., M.I.), Iowa City, Iowa University of New Mexico (E.G.F.), Albuquerque, New Mexico Dana-Farber Partners Cancer Care Center, Brigham and Women's Hospital (an Affiliate of Fox Chase Cancer Center) (N.S.H.) Massachusetts General Hospital (L.R.D.), Dana-Farber Partners Cancer Care Center, (an Affiliate of Fox Chase Cancer Center), Boston, Massachusetts University of Oklahoma (R.S.M., J.L.W.), Oklahoma City, Oklahoma.
Int J Gynecol Pathol. 2014 Nov;33(6):543-53. doi: 10.1097/PGP.0000000000000177.
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.
孕激素已用于复发性子宫内膜腺癌的治疗近50年。一些子宫内膜癌对激素治疗有反应，但其作用机制仍不完全清楚。我们希望确定孕激素诱导子宫内膜样癌组织学反应的疗效，并探讨其对生长和细胞死亡的组织学及免疫组化指标的影响。妇科肿瘤学组启动了一项针对75例子宫内膜样子宫内膜腺癌女性的研究，其中59例在子宫切除术前立即接受了21至24天的孕激素醋酸甲羟孕酮治疗，且有可用的切片。初始活检和子宫切除术标本进行苏木精-伊红染色以及雌激素受体（ER）、孕激素受体（PR）、孕激素受体-β（PRB）、Bcl-2、Ki-67和裂解的半胱天冬酶-3（Casp3）的免疫染色。组织学反应采用主观定义，随后将初始活检的特定组织学测量和免疫组织学变量的半定量评分与治疗后切片进行比较。仅观察到1例完全组织学反应，但37例肿瘤（63%）有部分组织学反应。特定的组织学变化包括：核分级降低、有丝分裂象数量减少、核仁减少、平均腺细胞密度降低，以及获得更丰富的嗜酸性细胞质、鳞状化生和分泌。治疗后显示主观定义的组织学反应的肿瘤最初与未显示反应的肿瘤仅在初始核分级和有丝分裂指数方面存在差异。治疗后反应者与无反应者的癌组织特定组织学特征在统计学上的显著差异仅在于获得淡嗜酸性细胞质和管腔分泌。超过90%的肿瘤最初为ER阳性，76%为PR阳性。ER或PR的初始存在与主观组织学反应无关。孕激素治疗后PR和PRB显著下调，Ki-67和Bcl-2也显著下调。然而，ER和Casp3没有显著变化。显示组织学反应的肿瘤Ki-67的预处理水平显著较低。醋酸甲羟孕酮治疗后，组织学反应者的平均Ki-67和Bcl-2降低幅度大于无反应者，但ER、PR、PRB和Casp3的降低幅度并非如此。肿瘤及其间质中的组织学反应在数量和质量上与相邻良性子宫内膜不同，在良性子宫内膜中，蜕膜样变伴随着管腔分泌和腺体分泌耗竭。三周的醋酸甲羟孕酮治疗可在大多数子宫内膜样腺癌中诱导部分组织学反应。先前提出的组织学反应特征并未涵盖所见变化的整个范围。ER、PR、PRB、Ki-67和Bcl-2下调，而Casp3无显著变化。这些改变表明孕激素通过使肿瘤细胞分化并减少增殖而非肿瘤细胞死亡发挥作用。由于间质蜕膜样变局限于良性腺体周围区域，旁分泌效应可能参与了对孕激素的完全反应。
