Morphological and molecular characteristics of HER2 amplified urothelial bladder cancer.

J Tschui,V Genitsch,U Baumgartner,D Rotzer,E Vassella,N Bandi,A Fleischmann,G N Thalmann,R Seiler

doi:10.1007/s00428-015-1729-4

Abstract

Several (pre-) clinical trials are currently investigating the benefit of HER2-targeted therapy in urothelial bladder cancer (UBC). Patients with HER2 amplified UBC could potentially profit from these therapies. However, little is known about histomorphology, HER2 protein expression patterns and occurrence of alterations in the HER2 gene in their tumors. Among 150 metastasizing primary UBC, 13 HER2 amplified tumors were identified. Their histopathological features were compared with 13 matched, non-amplified UBC. HER2 protein expression was determined by immunohistochemistry. The 26 tumors were screened for mutations in exons 19 and 20 of the HER2 gene. UBC with HER2 amplification presented with a broad variety of histological variants (median 2 vs. 1), frequently featured micropapillary tumor components (77 % vs. 8 %) and demonstrated a high amount of tumor associated inflammation. Immunohistochemically, 10 of 13 (77 %) HER2 amplified tumors were strongly HER2 protein positive. Three tumors (23 %) were scored as HER2 negative. One of the HER2 amplified tumors harbored a D769N mutation in exon 19 of the HER2 gene; all other tested tumors were wild type. In conclusion, HER2 amplified UBC feature specific morphological characteristics. They frequently express the HER2 protein diffusely and are, therefore, promising candidates for HER2 targeted therapies. The detection of mutations at the HER2 locus might add new aspects to molecular testing of UBC.

Highlights

The human epidermal growth factor receptor 2 (HER2/neu, erbB2) constitutes, together with HER1 (EGFR, erbB1), HER3, and HER4, the type I group of 20 families of receptor tyrosine kinases
Recent works have evaluated HER2 status in urothelial bladder cancer (UBC) in order to assess the therapeutic potential of this target, demonstrating significant protein overexpression or gene amplification in approximately 10 % of the tumors [11,12,13,14,15]
One tumor (8 %) featured a purely sarcomatoid growth pattern (100 %, Fig. 2b) with accompanying urothelial carcinoma in situ and one (8 %) had micropapillary components (40 % of the otherwise conventional UBC), which accounted for 3 % of the total tumor mass in this group

Summary

Introduction

The human epidermal growth factor receptor 2 (HER2/neu, erbB2) constitutes, together with HER1 (EGFR, erbB1), HER3 (erbB3), and HER4 (erbB4), the type I group of 20 families of receptor tyrosine kinases. The orphan HER2 without known ligand acts as co-receptor for heterodimer formations with the other EGFR family members [2] These receptor heterodimers are drivers of cellular proliferation [3], inhibit apoptosis [4], and promote angiogenesis [5]. Detected in a subset of breast cancer [7], amplification of the HER2 gene is the primary mechanism for protein overexpression [8]. Recent works have evaluated HER2 status in urothelial bladder cancer (UBC) in order to assess the therapeutic potential of this target, demonstrating significant protein overexpression (score 2+ or 3+) or gene amplification in approximately 10 % of the tumors [11,12,13,14,15].

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Results

Conclusion