Diagnostic Algorithmic Proposal Based on Comprehensive Immunohistochemical Evaluation of 297 Invasive Endocervical Adenocarcinomas

Abstract

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.

Expanded study on the risk of lymphovascular space invasion and lymph node metastasis of endocervical adenocarcinoma using Pattern Classification: a single-centre analysis of 213 cases

“…Diagnostic criteria for ADC histological types were established as per the 2014 WHO classification 2 and the International Endocervical Adenocarcinoma Criteria and Classification (IECC) system. 3,13 For this study, 201 cases of U-EAC and 12 cases of GAC were included; the remaining 11 cases of other histological types of ADCs (clear cell carcinoma, 7 cases; mesonephric carcinoma, 1 case; serous carcinoma, 1 case; endometrioid carcinoma, 2 cases) were excluded. This study was approved by the Institutional Ethics Board at Xijing Hospital.…”

Gastric‐type mucinous carcinoma of the cervix and its precursors – historical overview

“…GAS is characterised as negative for p16 INK4a , oestrogen receptor, and progesterone receptor, and positive for p53 (mutant pattern), hepatocyte nuclear factor‐1β, carbonic anhydrase type IX, PAX8, and a variety of gastric markers . An algorithmic approach to the diagnosis of GAS with a panel of antibodies has been proposed . Asaka et al .…”

“…47,51,53,54 An algorithmic approach to the diagnosis of GAS with a panel of antibodies has been proposed. 55 Asaka et al recently demonstrated the diagnostic utility of Trefoil factor family 2 protein, which is a novel sensitive and specific gastric marker. 56 It should be kept in mind that p16 INK4a can be positive, and diffuse positive staining does not necessarily implicate high-risk HPV in pathogenesis, and does not exclude GAS.…”

Immunohistochemical expression of HIK1083 and MUC6 in endometrial carcinomas

“…For example, Park et al reported that only 9% of their gastric‐type EA cohort showed diffuse positivity for HIK1083, and Carleton et al showed that whereas MUC6 expression was seen in 81% of their gastric‐type EAs, diffuse staining was present in only 35% of positive cases . In addition, p53 may also show a mutation‐type pattern (strong, diffuse expression or complete lack of expression) in up to 50% of the cases . Oestrogen and progesterone receptor staining is most commonly negative .…”

“…13 In addition, p53 may also show a mutation-type pattern (strong, diffuse expression or complete lack of expression) in up to 50% of the cases. 13,17 Oestrogen and progesterone receptor staining is most commonly negative. 13 Also of note is that gastric-type EAs have been reported to express napsin A and hepatocyte nuclear factor 1b, which are markers typically associated with the diagnosis of clear cell carcinoma.…”