Gastric cancer: immunohistochemical classification of molecular subtypes and their association with clinicopathological characteristics

Abstract

Gastric cancer is traditionally divided into intestinal and diffuse histological subtypes, but recent molecular analyses have led to novel classification proposals based on genomic alterations. While the intestinal- and diffuse-type tumours are distinguishable from each other at the molecular level, intestinal-type tumours have more diverse molecular profile. The technology required for comprehensive molecular analysis is expensive and not applicable for routine clinical diagnostics. In this study, we have used immunohistochemistry and in situ hybridisation in molecular classification of gastric adenocarcinomas with an emphasis on the intestinal subtype. A tissue microarray consisting of 244 gastric adenocarcinomas was constructed, and the tumours were divided into four subgroups based on the presence of Epstein-Barr virus, TP53 aberrations and microsatellite instability. The intestinal- and diffuse-type tumours were separately examined. The distribution of EGFR and HER2 gene amplifications was studied in the intestinal-type tumours. Epstein-Barr virus positive intestinal-type tumours were more common in male patients (p = 0.035) and most often found in the gastric corpus (p = 0.011). The majority of the intestinal-type tumours with TP53 aberrations were proximally located (p = 0.010). All tumours with microsatellite instability showed intestinal-type histology (p = 0.017) and were associated with increased overall survival both in the univariate (p = 0.040) and multivariate analysis (p = 0.015). In conclusion, this study shows that gastric adenocarcinomas can be classified into biologically and clinically different subgroups by using a simple method also applicable for clinical diagnostics.

Preservation of Epstein–Barr virus status and mismatch repair protein status along the metastatic course of gastric cancer

“…We therefore analysed EBV and MMR protein status in the primary tumours and corresponding metastases in a large western cohort of resected primary GC. The frequency of EBV‐positive and MMR‐deficient tumours in our cohort is slightly lower compared to GC cohorts in previous publications, where EBV‐positive tumours occurred in a range of between 4 and 14% and MMR‐deficient tumours between 8 and 26% 5,7‐11,16 . We hypothesise that the observed differences of EBV frequency are due mainly to the different patient populations under study, and reflect the known geographical variation in EBV positivity, with both ethnicity and lifestyle as well as environmental risk factors and coinfections as contributing factors 17 .…”

“…These molecular subtypes can be detected using routine immunohistochemistry and in‐situ hybridisation techniques, as demonstrated by previous studies. In particular, identification of EBV‐positive and MSI tumours can be accomplished by using Epstein–Barr‐encoding region (EBER) in‐situ hybridisation and mismatch repair (MMR) protein (MLH1, PMS2, MSH2 and MSH6) immunohistochemistry 8‐10 . The concordance rate of MMR expression profiles by immunohistochemistry and microsatellite instability testing has been shown to be as high as 99% for GC 11 .…”

Vírus Epstein-Barr, Instabilidade De Microssatélite E Expressão De Pd-L1 Nos Adenocarcinomas Gástricos: Aspectos Clínico-Patológicos E Prognósticos.

“…A partir das características fornecidas pelos estudos moleculares, outros marcadores devem ser testados para distinguir os demais subgrupos. Pois embora algumas estratégias sejam sugeridas para aplicação prática, 116,117,121 um refinamento dos painéis de biomarcadores para a estratificação do câncer gástrico ainda é necessário para aproximar os resultados encontrados aos subtipos moleculares de forma mais precisa.…”

Vírus Epstein-Barr, instabilidade de microssatélite e expressão de PD-L1 nos adenocarcinomas gástricos: aspectos clínico-patológicos e prognósticos

“…Em nossa casuística apenas dois casos apresentaram infecção por EBV e MSI simultaneamente, o que sugere que os dois subtipos de CG apresentam vias carcinogênicas distintas. Observações semelhantes foram descritas em estudos anteriores que avaliaram EBV e MSI nos tumores de estômago 112,117. Entretanto, a frequência de gastrectomia subtotal foi significativamente maior entre os CGs com MSI, o que pode não apenas decorrer do acometimento do terço inferior do estômago nestes casos,73,112 mas também devido a idade mais avançada dos pacientes, sendo…”

“…Todos os pacientes foram operados com intenção Assim, a definição dos grupos EBV e MSI alcançadas nesse estudo abrem perspectivas para que novas classificações baseadas no perfil de expressão proteica possam ser propostas.A partir das características fornecidas pelos estudos moleculares, outros marcadores devem ser testados para distinguir os demais subgrupos. Pois embora algumas estratégias sejam sugeridas para aplicação prática,116,117,121 um refinamento dos painéis de biomarcadores para Parecer do projeto "Caracterização da infecção por Helicobacter pylori, vírus Epstein-Barr e perfil gênico-proteico dos adenocarcinomas gástricos" no CEP.…”