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Hum Pathol. 2018 Oct;80:55-64. doi: 10.1016/j.humpath.2018.05.022. Epub 2018 Jun 6.

Micropapillary urothelial carcinoma: evaluation of HER2 status and immunohistochemical characterization of the molecular subtype.

Author information

1
Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, 91054 Erlangen, Germany; Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin Institute for Medical Systems Biology, 13125 Berlin, Germany.
2
Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, 91054 Erlangen, Germany. Electronic address: veronika.weyerer@uk-erlangen.de.
3
Department of Pathology, Hôpital Tenon, Assistance Publique-Hôpitaux de Paris, UPMC Paris VI, 75020 Paris, France.
4
Centre de Pathologie Amiens Picardie, 80000 Amiens, France.
5
Institute of Pathology, RWTH Aachen University, 52074 Aachen, Germany.
6
Institute of Pathology, University of Bern, 3008 Bern, Switzerland.
7
Institute of Pathology, University Hospital Carl Gustav Carus, 01307 Dresden, Germany.
8
Institute of Pathology, University Hospital Bonn, 53127 Bonn, Germany.
9
STRATIFYER Molecular Pathology GmbH, 50935 Cologne and Institute of Pathology at The St Elisabeth Hospital Köln-Hohenlind, 50935 Cologne, Germany.
10
Department of Pathology and Laboratory Medicine and Urology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
11
Department of Urology and Pediatric Urology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, 91054 Erlangen, Germany.
12
Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, 91054 Erlangen, Germany.

Abstract

Comprehensive molecular analyses of urothelial bladder cancer (UBC) have defined distinct subtypes with potential therapeutic implications. In this study, we focused on micropapillary urothelial carcinoma (MPUC), an aggressive, histomorphologically defined rare variant. Apart from genetic alterations shared with conventional UBC, alterations of the HER2 gene have been reported in higher frequencies. However, only small cohorts of MPUCs have been analyzed, and the real impact is still unclear. We collected a cohort of 94 MPUCs and immunohistochemically tested HER2, basal (CD44, CK5, EGFR, p63) and luminal (CD24, FOXA1, GATA3, CK20) markers to allocate MPUC to a molecular subtype. Additionally, HER2 amplification status was assigned by chromogenic in situ hybridization. Sanger sequencing of exon 4 and 8 was used to test for HER2 mutations. Kruskal-Wallis test was calculated to compare marker distribution between proportions of the MPUC component. HER2 2+/3+ staining scores were identified in 39.6% of 91 analyzed MPUCs and were not differentially distributed among the proportion of the MPUC component (P = .89). Additionally, CISH analysis revealed 30% of HER2-amplified tumors independently of the MPUC fraction. In 6/90 evaluable MPUCs, a p.S310F HER2 mutation was detected. Overexpression of luminal markers was observed in the majority of MPUC. Our investigations of the largest cohort of analyzed MPUC demonstrate that HER2 overexpression and amplifications are common genetic alterations and identification of overexpressed luminal markers allows subclassification to the luminal subtype. These findings highlight the need of histomorphological recognition of MPUC and analysis of HER2 status and the luminal molecular subtype for potential targeted therapeutic strategies.

KEYWORDS:

HER2; Micropapillary variant; Molecular subtype; Targeted therapy; Urothelial bladder cancer

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