Intratumoral heterogeneity of ERBB2/HER2 expression in micropapillary urothelial carcinoma.

Abstract

383 Background: Micropapillary urothelial carcinoma (MPUC) is a rare but an aggressive variant of urothelial carcinoma. Histologically, most of these tumors are associated with variable amounts of “not otherwise specified (NOS)” urothelial carcinoma. MPUC has been shown to be associated with ERBB2/HER2 amplification and protein overexpression. However, the status and distribution of these findings within the different components of tumors containing both MP and NOS urothelial carcinoma have not been addressed. Methods: We identified 44 cases of MPUC that had tissue available for FISH and IHC at our institute, of which an NOS component sufficient for both FISH and IHC was identified in 37 cases. We followed the updated ASCO/CAP Guidelines for breast cancer and as such amplification was defined by a HER2/CEP17 ratio of ≥ 2.0 or > 6 copies of the gene and HER2 overexpression was considered with IHC scores of 2+ and 3+. Results: In urothelial tumors with both MP and NOS components (n = 37), ERBB2 amplification in MP and NOS components was present in 25 and 16 cases respectively. ERBB2 amplification was significantly higher in the MP component compared to NOS component within the same tumor (67.57% vs. 43.24%, p = 0.049). HER2 overexpression in MP and NOS components was present in 25 and 13 cases respectively. HER2 overexpression was significantly higher in the MP component compared to NOS component within the same tumor (67.56% vs. 35.13%, p = 0.012). In addition, ERBB2 amplification strongly correlated with HER2 overexpression in both MP (rho = 0.65, p < 0.001) and NOS (rho = 0.74, p < 0.001) components. In this cohort (n = 44), tumor stage and lymph node status were significant predictors for overall survival (p = 0.01, < 0.001 respectively). However, ERBB2 amplification and HER2 overexpression in MP component were not associated with patients’ survival outcome (p = 1.00, 0.75 respectively). Conclusions: In MPUC, ERBB2 amplification and HER2 overexpression were preferentially but not exclusively identified in MP component compared to NOS component within the same tumor. Our findings provide evidence for intratumoral heterogeneity of ERBB2 amplification and HER2 expression in MPUC.