Special Section—Fourth Princeton Integrated Pathology Symposium: Gynecologic Pathology, Part II Cervical Adenocarcinomas A Heterogeneous Group of Tumors With Variable Etiologies and Clinical Outcomes Anjelica Hodgson, MD; Kay J. Park, MD  Context.—Cervical adenocarcinomas are a heteroge- neous group of tumors with varying morphologies, etiologies, molecular drivers, and prognoses, comprising approximately 25% of all cervical cancers. Unlike cervical squamous cell carcinoma, adenocarcinomas are not uniformly caused by high-risk human papillomavirus (HPV) infection and, therefore, would not necessarily be prevented by the HPV vaccine. Objective.—To provide a review of endocervical ade- nocarcinoma subtypes and, when appropriate, discuss precursor lesions, etiologies, molecular genetics, and ancillary studies within the context of clinical care. Some historical perspectives will also be provided. Data Sources.—Data sources included published peer- reviewed literature and personal experiences of the senior author. Conclusions.—Endocervical adenocarcinomas are a his- tologically diverse group of tumors with various causes and molecular drivers, not all related to HPV infection. Distinguishing them has important implications for treat- ment and prognosis as well as strategies for prevention. (Arch Pathol Lab Med. 2019;143:34–46; doi: 10.5858/ arpa.2018-0259-RA) C ervical cancer was once one of the most common malignancies to affect women in the United States, but with the advent of Papanicolaou test screening in the mid- 20th century, a sharp decline in the rate of cervical cancer and associated deaths has been noted. Today, cervical cancer ranks as the 14th most common cancer to affect women in the United States and the third most common cancer to affect women worldwide. 1 Most cervical cancers are composed of squamous cell carcinoma caused by human papillomavirus (HPV) infection; however, adenocarcinoma of the cervix appears to be increasing in both true and relative incidence. 2,3 Unlike squamous cell carcinoma, adenocarcinoma of the cervix comprises a heterogeneous group of tumors not universally associated with HPV infection. These tumors demonstrate varying morphologies, etiologies, and prognoses. This review will cover classifica- tion of endocervical adenocarcinomas, associated precursor lesions, pathogenesis, and the latest available data of molecular and immunohistochemical findings. Where ap- plicable, a historical perspective will also be provided. CLASSIFICATION OF ENDOCERVICAL ADENOCARCINOMAS According to the most recent WHO (World Health Organization) Classification of Tumors of Female Reproductive Organs published in 2014, endocervical adenocarcinomas are classified from descriptive morphologic characteristics, primarily cytoplasmic features. 4 This classification suffers from vague definitions and does not reflect our current understanding of endocervical glandular neoplasia. A recent novel classification system based on etiology and biologic behavior was proposed to provide an updated framework for classification of endocervical adenocarcinomas. The International Endocervical Adenocarcinoma Criteria and Classification (IECC) 5 categorizes endocervical adenocarci- nomas by the presence or absence of HPV infection–related features: easily identified apical mitotic figures and apoptotic bodies. HPV-associated adenocarcinomas are further sub- divided by clear definitions centered around cytoplasmic features, while HPV-unassociated adenocarcinomas are subclassified based on established published criteria. 5 It has been suggested by the authors of that study that the IECC, given its etiologically based framework and clear definitions, would replace the current WHO classification should ongoing validation, genomic, and clinical outcome studies support it. The WHO and IECC systems are summarized in Table 1, and each of the known distinct morphologic subtypes is described herein. HPV-ASSOCIATED ADENOCARCINOMAS Usual Type Endocervical Adenocarcinoma According to both the WHO and the IECC systems, usual type endocervical adenocarcinoma (UEA) is the most common subtype, 4,5 accounting for 75% of all invasive Accepted for publication June 8, 2018. From the Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada (Dr Hodgson); and the Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York (Dr Park). The authors have no relevant financial interest in the products or companies described in this article. Presented in part at the 4th Princeton Integrated Pathology Symposium; April 23, 2017; Plainsboro, New Jersey. Corresponding author: Kay J. Park, MD, Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065 (email: ParkK@mskcc.org). 34 Arch Pathol Lab Med—Vol 143, January 2019 Cervical Adenocarcinoma: A Heterogeneous Entity—Hodgson & Park