Intratumoral and intertumoral heterogeneity of HER2 immunohistochemical expression in gastric cancer.

BACKGROUND

Given the high heterogeneity of tumor tissue in gastric cancer (GC), inaccurate detection of tumor biomarkers will inevitably hamper a precise diagnosis and selection of patients for targeted therapies. Human epidermal growth factor receptor 2 (HER2) has been widely accepted as an underlying treatment biomarker of GC. The objective of this study is to investigate the heterogeneity (both intratumoral and intertumoral) of HER2 expression in GC, and the relationship between heterogeneity and the clinicopathological features.

METHODS

A total of 618 patients with primary gastric adenocarcinoma were recruited, and two formalin-fixed paraffin-embedded (FFPE) tumor-containing blocks of each patient were selected for HER2 immunohistochemical (IHC) assay. Clinicopathological characteristics were recorded, and intratumoral and intertumoral heterogeneity of HER2 IHC expression was determined.

RESULTS

The results indicated that the dual-block assays significantly increased the HER2 overexpression (IHC 2+ and 3+) rate compared with the single paraffin block detection. Approximately 50 % of the cases showed intratumoral HER2 heterogeneity within a single tissue section, and 30.10 % of cases showed intertumoral heterogeneity between a patient's two blocks. Furthermore, intertumoral heterogeneity was associated with tumors of small size (P = 0.029) and distal location (P = 0.032) characters, while the intratumoral heterogeneity was correlated with poorly differentiated carcinomas. Laurén's diffuse type showed a notably higher intratumoral heterogeneity rate, and the mixed type exhibited higher intertumoral HER2 discordance between the dual-block cohorts (P < 0.001). Besides, HER2 heterogenous overexpression was not associated with age, gender, type of resection, lymphatic or venous invasion, perineural invasion or pTNM (P > 0.05) for both cohorts.

CONCLUSION

The research findings in this paper indicate that the intratumoral and intertumoral heterogeneity of HER2 overexpression is common in GC patients, and these variations are associated with certain clinicopathological features. We highly recommend multi-block HER2 assessment for accurate diagnosis of GC.