Gastric cancer molecular classification based on immunohistochemistry and in situ hybridization: Analysis in western patients after curative-intent surgery

BACKGROUND: Gastric cancer (GC) is a highly heterogeneous disease, and the identification of molecular subtyping of gastric adenocarcinoma emerged as a promising option to define therapeutic strategies and prognostic subgroups. However, the costs and technical complexity of molecular methodologies remains an obstacle to its adoption, and their clinical significance by other approaches needs further evidence. AIM: To evaluate the clinicopathological characteristics and long-term survival of GC based on the subgroups of molecular classification by immunohistochemistry (IHC) and in situ hybridization (ISH). METHODS: We retrospectively evaluated all patients who underwent D2-gastrectomy between 2009 and 2016 in a Western cohort of GC patients treated with curative intent. Microsatellite instability (MSI) status, E-cadherin, and p53 expression were analyzed by IHC, and Epstein-Barr virus (EBV) by ISH. Tissue microarrays were constructed for analysis. Clinicopathological characteristics and survival of GC were evaluated according to subtypes defined by The Cancer Genome Atlas (TCGA) Research Network Group and Asian Cancer Research Group (ACRG) classification systems. RESULTS: A total of 287 GC patients were included. Based on IHC and ISH analysis, five profiles were defined as follows: E-cadherin aberrant (9.1%), MSI (20.9%), p53 aberrant (36.6%), EBV positivity (10.5%), and p53 normal (31%), which corresponded to tumors that showed no alteration in another profile. A flowchart according to the TCGA and ACRG classifications were used to define the subtypes, where clinical and pathological characteristics associated with GC subtypes were evidenced. Proximal location (P < 0.001), total gastrectomy (P = 0.001), and intense inflammatory infiltrate (P < 0.001) were characteristics related to EBV subtype. MSI subtype was predominantly associated with advanced age (P = 0.017) and the presence of comorbidities (P = 0.011). While Laurén diffuse type (P < 0.001) and advanced stage (P = 0.029) were related to genomically stable (GS) subtype. GS tumors and microsatellite stable/epithelial to mesenchymal transition phenotype subtype had worse disease-free survival (DFS) and overall survival (OS) than other subtypes. Conversely, MSI subtype of GC had better survival in both classifications. Type of gastrectomy, pT and the TCGA subtypes were independent factors associated to DFS and OS. CONCLUSION: The IHC/ISH analysis was able to distinguish immunophenotypic groups of GC with distinct characteristics and prognosis, resembling the subtypes of the molecular classifications. Accordingly, this method of classification may represent a viable option for use in a clinical setting.