Heterogeneous amplification of ERBB2 in primary lesions is responsible for the discordant ERBB2 status of primary and metastatic lesions in gastric carcinoma

Abstract

Aims: To determine the extent of HER2 homogeneity/heterogeneity in primary versus metastatic gastric carcinoma ( GC). Materials and results: The human epidermal growth factor receptor 2 ( HER2) status in primary and metastatic lesions was evaluated by immunohistochemistry ( IHC) and fluorescence in-situ hybridization ( FISH). Four separate cohorts consisting of primary GC alone or primary GC paired with metastatic lesions were examined. In the FISH analysis of 325 primary GCs, eight cases ( 2.5%) showed amplification with a heterogeneous pattern, whereas 27 cases ( 8.3%) showed amplification with a homogeneous pattern, and in this cohort the discordant: concordant FISH ratio based on examination of three different areas in each primary lesion was 0.30: 1. FISH testing using 250 paired primary and metastatic lesions revealed seven cases (2.8%) with discordant amplification. In metastatic disease positive conversion occurred in six cases (2.4%), whereas negative conversion happened in one case (0.4%). The discordant: concordant ratio of primary versus secondary lesions was 0.23: 1. When the seven discordant cases were re-evaluated using whole sections of primary GCs, six showed a heterogeneous pattern of amplification. Conclusions: These findings suggest that the discordant HER2 amplification observed in metastatic lesions is explained substantially by heterogeneity within primary tumours.