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

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.