International Endocervical Adenocarcinoma Criteria and Classification (IECC): A New Pathogenetic Classification for Invasive Adenocarcinomas of the Endocervix

Abstract

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.

Figure 1

HPV-associated adenocarcinomas (HPVA): Usual-type (A), mucinous (B), invasive adenocarcinoma with features reminiscent of stratified mucin-producing intraepithelial lesion (iSMILE) (C), villoglandular (D)

Figure 2

HPV-unassociated adenocarcinomas (NHPVA): Gastric-type (A), clear cell (B), endometrioid (C), serous (D)

Figure 3

HPV-positivity in a usual type adenocarcinoma using the ACD RNAscope® Probe HPV HR18. This recognizes 18 types of high-risk HPV

Figure 4

Usual-type adenocarcinoma with both p16 and HPV positivity: H&E (A), p16 (B), HPV (C)

Figure 5

Usual-type adenocarcinomas with either p16 or HPV positivity: H&E (A), patchy p16 (B), positive HPV (C), H&E (D), block-like p16 (E), negative HPV (F)

Figure 6

Unusual gastric-type adenocarcinomas: H&E (A), block-like p16; note presence of goblet cells (B); negative HPV (C); H&E (D); block-like p16 (E); positive HPV (F). The latter case, represented in figures D–F, was reclassified as usual-type adenocarcinoma with a gastric-like appearance on H&E

Figure 7

Endometrioid adenocarcinoma. This rare case (A) was negative for HPV (B), as expected.

Figure 8

IECC Classification 2017 1: HPV associated adenocarcinomas encompass those with and without intracytoplasmic or stromal mucin. Examples with mucinous differentiation may contain glands, goblet cells, signet ring cells or solid nests of tumor cells with intracytoplasmic mucin (i.e. iSMILE). Further work is needed to determine whether these histological variants are biologically and clinically distinctive. The designation “usual-type” HPV-associated endocervical adenocarcinoma can be used for mucin-poor tumors, whereas the designation “mucinous” HPV-associated endocervical adenocarcinoma can be used for cases with obvious intracytoplasmic mucin. 2: Gastric-type adenocarcinoma may contain goblet cells 3: It is uncertain whether true serous carcinomas arise in the endocervix. Together with the HPV-unassociated NOS category (0.8–1.6%), miscellaneous tumors represent at most 2% of all endocervical adenocarcinomas.