Molecular subtyping of gastric cancer with respect to the growth pattern of lymph-node metastases.

Abstract

Gastric cancer is the third leading cause of cancer-related death. Recently, innovative diagnostic and prognostic molecular subtypes have been proposed. We revealed that extranodal extension (ENE) of lymph-node metastases independently influences survival. Therefore, the aim of the present study was to evaluate novel molecular subtyping with regard to the growth pattern of lymph-node metastases. A total of 189 gastric carcinomas with lymph-node metastases were analyzed. The expression of p53, SOX2, SOX9, and the mismatch-repair gene products MLH1, PMS2, MSH2, and MSH6 were analyzed by immunohistochemistry. To determine the correlation with EBV infection, in situ hybridization for EBV-encoded small RNA (EBER) was applied. ENE was present in 36% of patients. EBV-positive carcinoma was evident in 5.8%, and p53 aberrant (chromosomal instable) tumors in 22.2%, a gastric cancer with deficient mismatch-repair status in 9%, and MSS/p53neg/EBVneg tumors were seen in 63% of patients. There was no significant correlation between the presence or absence of ENE and the molecular subtypes. However, a significant association between molecular subgroups and the Lauren classification, the oncogene SOX2, and tumor grading was detected. The present findings suggest that alterations in gastric cancer leading to ENE are not associated with alterations underpinning the molecular subgroups. Nonetheless, molecular subtyping on the basis of IHC and ISH is feasible and might become clinical routine. Thus, further studies are needed to clarify the mechanisms of extranodal extension in gastric cancer.