We sought to classify endocervical adenocarcinomas (ECAs) based on morphologic features linked to etiology (ie, human papillomavirus [HPV] infection), unlike the World Health Organization 2014 classification. The International Endocervical Adenocarcinoma Criteria and Classification (IECC criteria), described herein, distinguishes between human papillomavirus-associated adenocarcinoma (HPVA), recognized by the presence of luminal mitoses and apoptosis seen at scanning magnification, and no or limited HPVA features (nonhuman papillomavirus-associated adenocarcinoma [NHPVA]). HPVAs were then subcategorized based on cytoplasmic features (mostly to provide continuity with preexisting classification schemes), whereas NHPVAs were subclassified based on established criteria (ie, gastric-type, clear cell, etc.). Complete slide sets from 409 cases were collected from 7 institutions worldwide. Tissue microarrays representing 297 cases were constructed; immunohistochemistry (p16, p53, vimentin, progesterone receptor) and chromogenic in situ hybridization using an RNA-based probe set that recognizes 18 varieties of high-risk HPV were performed to validate IECC diagnoses. The 5 most common IECC diagnoses were usual-type (HPVA) (73% of cohort), gastric-type (NHPVA) (10%), mucinous adenocarcinoma of HPVA type, including intestinal, mucinous not otherwise specified, signet-ring, and invasive stratified mucin-producing carcinoma categories (9%), clear cell carcinoma (NHPVA) (3%) and adenocarcinoma, not otherwise specified (2%). Only 3 endometrioid carcinomas were recognized and all were NHPVA. When excluding cases thought to have suboptimal tissue processing, 90% and 95% of usual-type IECC cases overexpressed p16 and were HPV+, whereas 37% and 3% of NHPVAs were p16+ and HPV+, respectively. The 1 HPV+ gastric-type carcinoma was found to have hybrid HPVA/NHPVA features on secondary review. NHPVA tumors were larger and occurred in significantly older patients, compared with HPVA tumors (P<0.001). The high-risk HPV chromogenic in situ hybridization probe set had superior sensitivity, specificity, and positive and negative predictive values (0.955, 0.968, 0.992, 0.833, respectively) compared with p16 immunohistochemistry (0.872, 0.632, 0.907, 0.545, respectively) to identify HPV-related usual carcinoma and mucinous carcinoma. IECC reliably segregates ECAs into HPVA and NHPVA types using morphology alone. This study confirms that usual-type ECAs are the most common type worldwide and that mucinous carcinomas comprise a mixture of HPVA and NHPVA, with gastric-type carcinoma being the major NHPVA type. Endometrioid and serous carcinomas of the endocervix are extraordinarily rare. Should clinical outcomes and genomic studies continue to support these findings, we recommend replacement of the World Health Organization 2014 criteria with the IECC 2017.
*Department of Pathology, University of Medicine and Pharmacy of Targu Mures, Targu Mures
§Regional Institute of Oncology, Iasi, Romania
†Vancouver General Hospital, Vancouver, BC, Canada
∥Ospedale Sacro Cuore Don Calabria, Negrar, Italy
¶Department of Pathology, Sheba Medical Center, Tel-Hashomer, Ramat Gan, Israel
#Jikei University School of Medicine, Tokyo, Japan
**Hospital de Oncología Mexico City, Mexico City, Mexico
††Massachusetts General Hospital, Boston, MA
‡Memorial Sloan Kettering Cancer Center, New York, NY
Conflicts of Interest and Source of Funding: This study was funded in part through the NIH/NCI Support Grant P30 CA008748 (R.A.S., K.J.P., and M.C.P.). The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article.
Correspondence: Robert A. Soslow, MD, Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065 (e-mail: email@example.com).