Current Issues in Gynecologic Pathology

In this issue of Archives of Pathology & Laboratory Medicine, several reviews on various topics in gynecologic pathology are presented, ranging from the spectrum of endocervical adenocarcinomas to ovarian germ cell tumors. Additional reviews discussing these topics will also be presented in the April 2014 issue of the ARCHIVES. Together, the reviews in the March and April issues provide an update on the morphologic features, differential diagnosis, alternate approaches to classification, value of immunohistochemical markers, and potential novel targets for therapy. Endometrial carcinoma is a common gynecologic cancer. Although a vast majority of endometrial carcinomas develop in perimenopausal and postmenopausal women, a very small proportion do develop in women younger than 40 years. Even among younger women, many of the tumors are associated with estrogen excess. Nonetheless, young age at presentation should raise the possibility of DNA mismatch repair abnormalities and Lynch syndrome. A review by Karuna Garg, MD, and Robert Soslow, MD, addresses the association of endometrial carcinomas occurring prior to age 40 years with Lynch syndrome, and how to confirm this with proper use of immunohistochemical stains for DNA mismatch repair proteins (MLH1, PMS2, MSH2, and MSH6). Recognition of Lynch syndrome–associated adenocarcinomas is important for management of these young women; the risk for recurrence and progression requires careful monitoring when conservative therapy is selected. Among the adenocarcinomas that develop in the older age group, the serous papillary carcinomas are particularly aggressive, and identification of novel targets for therapy could potentially result in substantial improvement in survival and quality of life. Encouraged by the results of trastuzumab therapy in management of HER2-positive breast cancers, several recent studies have evaluated HER2 expression and/or amplification in endometrial carcinomas. Natalia Buza, MD, Dana Roque, MD, and Alessandro Santin, MD, address the potential of HER2 as a target for therapy in endometrial carcinomas. It is important to note that conclusions of various studies have been variable in their enthusiasm for routine assessment of HER2 in endometrial cancers and its value as a target for therapy. These differences, at least in part, emanate from inclusion of various subtypes of endometrial carcinoma in some studies, whereas others have focused on the serous subtype. Furthermore, most of these studies have basically used variable cutoffs for positivity. It is important to have a largescale, multi-institutional study to look at what should be considered a positive HER2 result immunohistochemically for serous endometrial carcinomas—what level of intensity in what percentage of tumor cells, as well as what ratio of HER2:CEP17 should be required for amplification. Is an equivocal category by immunohistochemistry or fluorescent in situ hybridization even necessary for endometrial carcinomas? The ultimate result should show a positive response to therapy. We also have to agree on what level of therapeutic response is sufficient to treat hundreds of women with this expensive therapeutic option. Francisco Nogales, MD, PhD, Isabel Dulcey, MD, and Ovidiu Preda, MD, PhD, have contributed a superb update on ovarian germ cell tumors. This most useful and wellillustrated review addresses pathogenesis, differential diagnosis, and value of immunohistochemical stains, and it includes a recently described condition of autoimmune encephalitis against N-methyl-D-aspartate receptor that has been noted as the most common autoimmune disorder associated with ovarian teratomas. Also related to ovarian teratomas, gliomatosis peritonei and its possible pathogenetic mechanisms are discussed. Two additional reviews in this special section will appear in the April 2014 issue. Joana Loureiro, MD, and Esther Oliva, MD, have contributed an exceptional review of the variety of glandular lesions of the cervix that will remind pathologists of the wide range of glandular alterations other than neoplastic squamous lesions that occur in the cervix. In my consultation practice, it is not uncommon for a cervical sample to be sent with a question about the changes in the squamous epithelium, whereas the coexisting endocervical glandular alterations that are often equally as important from a clinical standpoint are overlooked. The review illustrates the common and uncommon glandular lesions to remind us of their morphologic characteristics so that they can be recognized, even if the presenting symptoms leading to sampling of the cervix were due to pathology in the squamous epithelium. During the past several decades, the classification of endometrial hyperplasias has gone through several changes, all based purely on morphology. Significant interobserver differences in interpretation have persisted, however, when the current classifications of hyperplasia and atypical hyperplasia (simple and complex) are used. The review prepared by Richard Owings, MD and Charles M. Quick, MD, focuses on Dr Mutter’s concept of endometrial intraepithelial neoplasia (EIN). The review addresses the molecular alterations, defines diagnostic criteria, and explains Accepted for publication October 31, 2013. From the Department of Pathology, Yale University School of Medicine, New Haven, Connecticut. doi: 10.5858/arpa.2013-0664-ED Reprints: Fattaneh A. Tavassoli, MD, Department of Pathology, Yale University School of Medicine, Lauder Hall 222, 310 Cedar St, New Haven, CT 06510 (e-mail: fattaneh.tavassoli@yale.edu).