New substituted molecular classifications of advanced gastric adenocarcinoma:characteristics and probable treatment strategies

Background:Gastric adenocarcinoma(GA)is a heterogeneous tumor,and the accurate classification of GA is important.Previous classifications are based on molecular analysis and have not focused on GA with the primitive enterocyte phenotype(GAPEP),a unique subtype with a poor prognosis and frequent liver metastases.New substituted molecular(SM)classifications based on immunohistochemistry(IHC)are needed.Methods:According to the IHC staining results,we divided 582 cases into six types:mismatch repair deficient(dMMR),Epstein-Barr virus associated(EBVa),the primitive enterocyte phenotype(PEP),the epithelial mes-enchymal transition(EMT)phenotype,not otherwise specified/P53 mutated(NOS/P53m)and not otherwise specified/P53 wild-type(NOS/P53w).We analyzed the clinicopathological features,the immune microenviron-ment(PD-L1,CD8)and expression of HER2 and VEGFR2 of those types.Results:There were 31(5.3%)cases of the dMMR type,13(2.2%)cases of the EBVa type,44(7.6%)cases of the PEP type,122(21.0%)cases of the EMT type,127(21.8%)cases of the NOS/P53m type and 245(42.1%)cases of the NOS/P53w type.Patients with the dMMR type had the best survival(P<0.001).Patients with the EBVa type were younger(P<0.001)and had higher PD-L1 and CD8 expression(P<0.001)than other patients.Patients with the EMT type exhibited poor differentiation and a higher rate of abdominal metastasis.Patients with the NOS/P53m and PEP types had the worst survival rates and the highest PD-L1/HER2/VEGFR2 expression levels among all patients(P<0.001).Conclusion:Different SM classifications have different clinicopathological features and expression patterns,which indicate the probable clinical treatment strategies for these subtypes.