Are Immunohistochemical Markers Useful in Phenotypic Gastric Cancer Classification?

Abstract

To identify useful markers for prognostic and therapeutic purposes, The Cancer Genome Atlas (TCGA) provided a molecular classification of gastric cancers (GCs). Previous studies have used immunohistochemistry (IHC) and chromogenic in situ hybridization (CISH) to define immunophenotypic surrogate markers of the molecular alterations. Some critical issues concerning the correct definition of immunophenotypic groups have emerged in these studies that employed tissue microarrays (TMAs). We performed an immunophenotypic classification by evaluating MLH1, p53, HER2, E-cadherin, and Epstein-Barr virus (EBV) on the whole section of the surgical GC samples compared to most of the studies conducted on TMAs. We also investigated the immunohistochemical expression of PD-L1, a known therapeutic target. We identified the following immunophenotypic groups: EBV (2.9%); mismatch repair deficient (MMR-D) (7.2%); overexpressed p53 and/or HER2+ (61.4%); aberrant E-cadherin (11.4%); and normal pattern (17.1%). The use of surgical samples emphasized that some immunohistochemical markers were not useful for properly classifying the GC specimens. We can state that EBV (significantly correlated to PD-L1 expression) and MMR-D GCs are well-defined groups, mutually exclusive, and easily assessable with IHC and CISH, and could be candidates for immunotherapy with PD-1/PD-L1 inhibitors. As regards p53, our findings suggest that IHC assessment may be responsible for a misclassification of GC groups. Immunohistochemical evaluation of E-cadherin needs to be standardized, particularly in terms of the heterogeneous cytoplasmic/membranous staining pattern. Whether to consider the normal-pattern group as a separate category remains to be clarified. Because GC specimens with known therapeutic targets account for only 40%, we suggest reviewing the immunophenotypic classification to find new therapeutic targets, such as PD-L1, MLH1, and HER2.

Histological and mutational profile of diffuse gastric cancer: current knowledge and future challenges

“…based on IHC and ISH, was used to evaluate MLH1, p53, HER2, E-cadherin, and EBV in whole sections from surgical GC specimens [44]. Another similar approach was used to apply the IHC/ISH molecular algorithm to a cohort of GC patients from Chile [46].…”

“…Given the complexity and high cost of the experimental approaches needed to stratify GC according to TCGA and ACRG classifications, several studies proposed less costly approaches to reach similar endpoints (Fig. 2 ) [ 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 ].…”

“…In 2019, 894 consecutive GC Korean patients were used to validate previous classifications, with IHC‐ and PCR‐based approaches and confirming the association between molecular subtypes and patients’ overall survival [ 43 ]. More recently, in 2020, an immunophenotypic classification, based on IHC and ISH, was used to evaluate MLH1, p53, HER2, E‐cadherin and EBV in whole sections from surgical GC specimens [ 44 ]. Another similar approach was used to apply the IHC/ISH molecular algorithm to a cohort of GC patients from Chile [ 46 ].…”

Prognostic importance of molecular-like classification in gastroesophageal junction tumors (Izmir Oncology Group [IZOG] study)

“…However, in rare studies, a fifth group has been defined as in our study. In the study of Di Pinto et al, it was stated that all immunomarkers were negative in this group, which was defined as "normal pattern" [25]. In our study, a fifth subgroup was determined, different from the TCGA classification.…”

Aldehyde dehydrogenase 1 (ALDH1) expression in serrated colonic polyps

“…Immunohistochemical prognostic markers are promising direction for a search. These markers would make it possible to assess the risk of cancer growth in polyp's biopsy samples [4][5]. Among modern and still insufficiently studied markers -aldehyde dehydrogenase 1 (ALDH1).…”