Abstract：
Merkel cell carcinoma (MCC) is an aggressive skin cancer frequently caused by genomic integration of the Merkel cell polyomavirus (MCPyV). MCPyV-negative cases often present as combined MCCs, which represent a distinctive subset of tumors characterized by association of an MCC with a second tumor component, mostly squamous cell carcinoma. Up to now, only exceptional cases of combined MCC with neuroblastic differentiation have been reported. Herein we describe two additional combined MCCs with neuroblastic differentiation and provide comprehensive morphologic, immunohistochemical, transcriptomic, genetic and epigenetic characterization of these tumors, which both arose in elderly men and appeared as an isolated inguinal adenopathy. Microscopic examination revealed biphasic tumors combining a poorly differentiated high-grade carcinoma with a poorly differentiated neuroblastic component lacking signs of proliferation. Immunohistochemical investigation revealed keratin 20 and MCPyV T antigen (TA) in the MCC parts, while neuroblastic differentiation was confirmed in the other component in both cases. A clonal relation of the two components can be deduced from 20 and 14 shared acquired point mutations detected by whole exome analysis in both combined tumors, respectively. Spatial transcriptomics demonstrated a lower expression of stem cell marker genes such as SOX2 and MCM2 in the neuroblastic component. Interestingly, although the neuroblastic part lacked TA expression, the same genomic MCPyV integration and the same large T-truncating mutations were observed in both tumor parts. Given that neuronal transdifferentiation upon TA repression has been reported for MCC cell lines, the most likely scenario for the two combined MCC/neuroblastic tumors is that neuroblastic transdifferentiation resulted from loss of TA expression in a subset of MCC cells. Indeed, DNA methylation profiling suggests an MCC-typical cellular origin for the combined MCC/neuroblastomas. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
摘要：
默克尔细胞癌（MCC）是一种侵袭性皮肤癌，通常由默克尔细胞多瘤病毒（MCPyV）的基因组整合引起。MCPyV阴性病例通常表现为合并的MCC，它们代表了一个独特的肿瘤子集，其特征是MCC与第二个肿瘤成分相关联，主要是鳞状细胞癌.到目前为止,仅报道了MCC合并成神经细胞分化的特殊病例。在这里，我们描述了两个额外的联合MCC与神经母细胞分化，并提供了全面的形态学，免疫组织化学，转录组，这些肿瘤的遗传和表观遗传特征，两者都出现在老年男性中，并表现为孤立的腹股沟腺病。显微镜检查显示，双相肿瘤结合了低分化的高级别癌和低分化的神经母细胞成分，缺乏增殖迹象。免疫组织化学研究显示MCC部分中的角蛋白20和MCPyVT抗原（TA），而在两种情况下，其他成分均证实了神经母细胞分化。两种成分的克隆关系可以从通过全外显子组分析在两种组合肿瘤中检测到的20和14个共享的获得性点突变中推导出来。分别。空间转录组学表明，干细胞标记基因如SOX2和MCM2在神经母细胞成分中的表达较低。有趣的是,虽然神经母细胞部分缺乏TA表达，在两个肿瘤部位观察到相同的基因组MCPyV整合和相同的大T截短突变.鉴于已经报道了MCC细胞系在TA抑制后的神经元转分化，两种合并的MCC/神经母细胞性肿瘤最可能的情况是神经母细胞性转分化是由MCC细胞亚群中TA表达缺失引起的。的确,DNA甲基化分析提示MCC/神经母细胞瘤的MCC-典型细胞起源。©2024作者（S）。由JohnWiley＆SonsLtd代表英国和爱尔兰病理学会出版的病理学杂志。
