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 mesenchymal 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 microenvironment (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 ( < 0.001). Patients with the EBVa type were younger ( < 0.001) and had higher PD-L1 and CD8 expression ( < 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 ( < 0.001).

Conclusion: Different SM classifications have different clinicopathological features and expression patterns, which indicate the probable clinical treatment strategies for these subtypes.