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.