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.
Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, 91054 Erlangen, Germany.
Hum Pathol. 2018 Oct;80:55-64. doi: 10.1016/j.humpath.2018.05.022. Epub 2018 Jun 6.
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.
全面的分子分析已经确定了膀胱癌（UBC）的不同亚型，这些亚型具有潜在的治疗意义。在这项研究中，我们专注于微乳头状尿路上皮癌（MPUC），这是一种具有侵袭性的、组织形态学定义的罕见变体。除了与传统 UBC 共享的遗传改变外，HER2 基因的改变也被报道具有更高的频率。然而，只有少数 MPUC 队列被分析，其实际影响仍不清楚。我们收集了 94 例 MPUC 病例，并通过免疫组织化学方法检测了 HER2、基底（CD44、CK5、EGFR、p63）和腔面（CD24、FOXA1、GATA3、CK20）标志物，将 MPUC 分配到一个分子亚型。此外，通过显色原位杂交法确定 HER2 扩增状态。使用 Sanger 测序检测 HER2 外显子 4 和 8 的突变。Kruskal-Wallis 检验用于比较 MPUC 成分比例之间的标志物分布。在 91 例分析的 MPUC 中，有 39.6%的病例出现 HER2 2+/3+染色评分，且与 MPUC 成分比例之间无差异分布（P=0.89）。此外，CISH 分析显示，30%的 HER2 扩增肿瘤独立于 MPUC 分数。在 6/90 例可评估的 MPUC 中，检测到一个 p.S310F HER2 突变。大多数 MPUC 中观察到腔面标志物的过表达。我们对最大的 MPUC 队列的研究表明，HER2 过表达和扩增是常见的遗传改变，识别过表达的腔面标志物允许进行亚分类到腔面亚型。这些发现强调了需要对 MPUC 进行组织形态学识别，并分析 HER2 状态和腔面分子亚型，以制定潜在的靶向治疗策略。
