Introduction

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 &[Prime]not otherwise specified (NOS)&[Prime] urothelial carcinoma. MPUC has been previously shown to be associated with ERBB2 amplification and HER2 protein overexpression. However, the status and distribution of these findings within MP and NOS components of MPUC have not been addressed. Therefore, we evaluated the ERBB2/HER2 expression in MP and NOS components by FISH and IHC.

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. _x000D_ _x000D_ 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&[prime] survival outcome (p=1.00, 0.75 respectively)._x000D_

Conclusions

The majority of MPUC is associated with ERBB2 amplification and HER2 overexpression. In MPUC, ERBB2 amplification and HER2 overexpression were preferentially but not exclusively identified in MP component compared to NOS component. Our findings provide evidence for intratumoral heterogeneity of ERBB2 amplification and HER2 expression in MPUC.

Funding

Ruth L. Kirschstein National Research Service Award T32CA082088