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

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.

Urothelial cancer harbours EGFR and HER2 amplifications and exon 20 insertions

“…We assessed the morphology of EGFR exon20ins and ERBB2 exon20ins cases for shared histological features, akin to ERBB2 base substitutions and micropapillary UC . An inverted growth pattern was observed in some cases where cystectomy specimens were assayed, but due to the quality and size of specimens from metastatic sites, definitive assessment of the frequency of this histological finding was not possible.…”

“…The mutual exclusivity with other drivers in UC, as well as the trend towards younger age in the exon 20 insertion population, suggests these patients form a distinct clinico‐pathological class, which may also have an association with histological features. A cardinal example of this is micropapillary UC, which is associated with alteration of HER2 as well as a poor prognosis . To that end, we assessed the histology of these cases.…”

Progressive plasmacytoid variant bladder cancer with retroperitoneal dissemination: An autopsy case report

“…12 Approximately 10% of patients with UC were positive for HER2. 13 Moreover, approximately 40% of patients with the micropapillary variant, another variant of UC, present with HER2 positivity, 14 which is associated with poor outcome. 15 In a previous study, 80% of patients with PUC were positive for HER2.…”

Histologic Variants of Urothelial Carcinoma: Morphology, Molecular Features and Clinical Implications

“…HER2/ERBB2 overexpression and amplification is found at a higher rate in MP compared to conventional UC [31,32]. In breast cancer, amplification or overexpression of HER2 is found in aggressive subtypes, including micropapillary.…”

“…Despite the fact that HER2 amplification is associated with worse cancerspecific survival, it may also provide an opportunity for ERBB2-targeted therapy [33,34]. The majority of MP cancers are of urothelial-like or luminal subtype, which is confirmed by the expression of FOXA1, a biomarker of luminal phenotype [18,31]. A subset of luminal MP bladder cancers defined as being p53-like are the most aggressive variant of the disease, as they are associated with chemo-resistance to cisplatin-based neoadjuvant chemotherapy [29].…”