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.

The International Endocervical Adenocarcinoma Criteria and Classification was developed to separate endocervical adenocarcinomas (ECAs) into 2 main categories on the basis of morphology such as human papilloma virus–associated (HPVA) and non-human papilloma virus–associated adenocarcinomas. We aimed to improve the diagnostic accuracy of International Endocervical Adenocarcinoma Criteria and Classification by performing a comprehensive immunohistochemical evaluation and constructing objective immunohistochemical-based algorithms for the classification of these tumors. Tissue microarrays were constructed from 297 of 409 cases used to develop the original classification. Immunostains included p16, p53, estrogen receptor (ER), progesterone receptor, androgen receptor, Vimentin, CK7, CK20, HER2, HIK1083, MUC6, CA-IX, SATB2, HNF-1beta, napsin A, PAX8, CDX2, GATA3, p63, p40, and TTF-1. High-risk human papilloma virus (HR-HPV) was detected by in situ hybridization (ISH) using probes against E6 and E7 mRNA expressed in 18 different virus types. Vimentin, ER, and progesterone receptor were expressed in a significant minority of ECAs, mostly HPVAs, limiting their use in differential diagnosis of endometrioid carcinoma when unaccompanied by HPV-ISH or p16. HR-HPV ISH had superior sensitivity, specificity, and negative and positive predictive values compared with p16, as published previously. HNF-1beta did not have the anticipated discriminatory power for clear cell carcinoma, nor did MUC6 or CA-IX for gastric-type carcinoma. HNF-1beta and napsin A were variably expressed in clear cell carcinoma, with HNF-1beta demonstrating less specificity, as it was ubiquitously expressed in gastric-type carcinoma and in the majority of HPV-associated mucinous (predominantly intestinal-type and invasive ECA resembling stratified mucin-producing intraepithelial lesion [iSMILE]) and usual-type carcinomas. HIK1083 was expressed in nearly half of gastric-type carcinomas, but not in the vast majority of other subtypes. GATA3 was positive in 10% of usual-type adenocarcinomas and in single examples of other subtypes. Rare gastric-type and HPVA mucinous carcinomas displayed HER2 overexpression. Androgen receptor was positive in 6% of usual-type adenocarcinomas. Aberrant p53 expression was found in only 3.6% of usual-type HPVA carcinomas, but it was more prevalent in mucinous (intestinal type and iSMILE) HPVAs and non-human papilloma virus–associates (particularly in gastric-type carcinoma, >50% of cases). The following diagnostic classification algorithms were developed with the above data. Carcinomas without overt cytoplasmic mucin (endometrioid, usual-type endocervical, clear cell, and mesonephric carcinomas) can be subclassified using HR-HPV ISH, ER, and GATA3, whereas carcinomas with easily appreciated cytoplasmic mucin (endometrioid carcinoma with mucinous features, HPVA mucinous, and gastric-type carcinomas) can be subclassified with HR-HPV ISH and ER.

The current World Health Organization (WHO) classification for endocervical adenocarcinoma (EA) is based on descriptive morphologic characteristics; however, it does not fully reflect our current knowledge of the diverse pathogenesis of cervical glandular neoplasia. A novel classification system, the International Endocervical Adenocarcinoma Criteria and Classification (IECC), which incorporates etiology and biological behavior into the morphologic scheme, has been recently proposed. We aimed to validate the IECC by assessing its interobserver reproducibility in comparison to the WHO system. A cohort of 75 EAs was reviewed independently by 7 gynecologic pathologists and categorized following IECC and WHO criteria based on hematoxylin and eosin material alone and after immunohistochemistry results for p16, PR, p53, Napsin-A, vimentin, CDX2, and GATA3 were provided. Human papillomavirus (HPV) in situ hybridization and polymerase chain reaction results were compared with consensus diagnoses. IECC was superior to WHO in terms of interobserver agreement with κ=0.46 versus 0.3, respectively, on hematoxylin and eosin review and κ=0.51 versus 0.33, respectively, with immunohistochemistry. Under the IECC, 73 (97%) of EAs had majority agreement (≥4 reviewers in agreement) whereas 42 (56%) had perfect agreement (7/7 reviewers in agreement). Conversely, WHO showed majority agreement in 56 (75%) and perfect agreement in only 7 (10%) EAs. Reproducibility was poor in HPV-related WHO types (usual κ=0.36, mucinous not otherwise specified κ=0.13, intestinal κ=0.31, villoglandular κ=0.21) and good in major HPV-unrelated categories (gastric type κ=0.63, clear cell κ=0.81, mesonephric κ=0.5). Classification as per the IECC had excellent correlation with HPV status (by RNA in situ hybridization or polymerase chain reaction). We have shown that the IECC has superior interobserver agreement compared with the WHO classification system, and that distinction between HPV-related and HPV-unrelated EA can be made with good reproducibility and excellent prediction of HPV status. WHO morphologic variants of HPV-related EA are poorly reproducible. Conversely, agreement is high among important high-risk HPV-unrelated subtypes. Thus, our results further support replacing the current WHO classification with the IECC.

Cervical clear cell carcinoma (CCC) is a rare human papillomavirus–independent adenocarcinoma. While recent studies have focused on gastric-type endocervical adenocarcinoma (GTA), little is known about CCC. A total of 58 (CCCs) were collected from 14 international institutions and retrospectively analyzed using univariable and multivariable methods and compared with 36 gastric-type adenocarcinomas and 173 human papillomavirus–associated (HPVA) endocervical adenocarcinoma (ECA) regarding overall survival (OS) and recurrence-free survival (RFS). Most cases were FIGO stage I (72.4%), with Silva C pattern of invasion (77.6%), and the majority were treated with radical surgery (84.5%) and adjuvant therapy (55.2%). Lymphovascular invasion was present in 31%, while lymph node metastasis was seen in 24.1%; 10.3% were associated with abdominopelvic metastases at the time of diagnosis; 32.8% had recurrences, and 19% died of disease. We did not find statistically significant differences in OS and RFS between CCC and GTA at 5 and 10 years (P=0.313 and 0.508, respectively), but there were significant differences in both OS and RFS between CCC and HPVA ECA (P=0.003 and 0.032, respectively). Also, OS and RFS in stage I clear cell and GTA were similar (P=0.632 and 0.692, respectively). Multivariate analysis showed that OS is influenced by the presence of recurrence (P=0.009), while RFS is influenced by the FIGO stage (P=0.025). Cervical CCC has poorer outcomes than HPVA ECA and similar outcomes to human papillomavirus–independent GTA. Oncologic treatment significantly influences RFS in univariate analysis but is not an independent prognostic factor in multivariate analysis suggesting that alternative therapies should be investigated.