Outcome of patients with micropapillary urothelial carcinoma following radical cystectomy: ERBB2 (HER2) amplification identifies patients with poor outcome

Abstract

Micropapillary urothelial carcinoma exhibits amplification of the human epidermal growth factor receptor, ERBB2(HER2), and overexpression of the ERBB2 protein product. The clinical significance of this has yet to be established. The objective of this study was to examine ERBB2 amplification and protein expression in micropapillary urothelial carcinoma and stage-matched typical urothelial carcinoma treated by radical cystectomy to assess the frequency of amplification and protein expression, and to determine the association with cancer-specific survival. Pathologic material and data from patients undergoing cystectomy at Mayo Clinic between 1980 and 2008 were reviewed. ERBB2 amplification by fluorescence in situ hybridization (FISH) and protein expression by immunohistochemistry were assessed. Univariate and multivariate Cox proportional hazards regression models were used to evaluate for associations of ERBB2 amplification and protein expression with survival. ERBB2 amplification was identified in 9 (15%) of 61 micropapillary carcinomas compared with 9 (9%) of 100 urothelial carcinomas. In patients with micropapillary carcinoma, ERBB2 amplification was associated with a nearly threefold increased risk of cancer death. ERBB2 amplification (hazard ratio 4.3; P ¼ 0.0008) remained associated with an increased risk of death from bladder cancer among patients with micropapillary urothelial carcinoma on multivariate analysis. The association of cancer-specific survival and ERBB2 amplification was not seen in patients with urothelial carcinoma. ERBB2 immunohistochemistry correlated with ERBB2 amplification but there was no association of ERBB2 protein expression and survival. ERBB2 amplification is more frequent in micropapillary urothelial carcinoma than typical urothelial carcinoma, and patients with micropapillary carcinoma who have ERBB2 amplification have worse cancer-specific survival than those who do not. Identification of ERBB2 amplification in micropapillary carcinoma could provide important prognostic information and possibly provide a role for ERBB2 targeted therapy.

The 2016 WHO Classification of Tumours of the Urinary System and Male Genital Organs—Part B: Prostate and Bladder Tumours

“…At the molecular level, overexpression or amplification of ERBB2 is more common in this variant than in conventional urothelial carcinoma (Fig. 5a) [89][90][91].…”

Her-2 Oncoprotein Expression in Urothelial Carcinoma

“…38,39,40 What proportion of micropapillary urothelial carcinoma express HER-2 is not well established, perhaps three-quarters of them, the range varying widely in different studies. 37,33 Another feature exhibited by these tumours is a significantly higher morphologic heterogeneity reflected by a higher number of subtype components per tumour. For molecular targeted therapy, pathologists will have to identify HER-2 overexpressing tumours in near future.…”

“…33 HER-2/Neu overexpression can also be used to distinguish reactive atypia from carcinoma in situ. 34 Flat urothelial lesions like urothelial dysplasia, flat urothelial hyperplasia, reactive urothelial atypia of unknown significance and urothelial carcinoma in situ are at times difficult to distinguish.…”

Histopathological Evaluation of Patients with Bladder Urothelial Carcinoma Diagnosed in Our Clinic

“…Because of this heterogeneity, there are difficulties in target treatment, but new treatment possibilities are also investigated in some cases. In recent studies, the overexpression of Human Epidermal Receptor Protein-2 was detected in conventional UC and micropapillary variants, and it was reported that they could be candidates for target treatment (30).…”