Cutaneous neuroendocrine (Merkel cell) carcinoma most often arises de novo in the background of a clonally integrated virus, the Merkel cell polyomavirus, and is notable for positive expression of retinoblastoma 1 (RB1) protein and low expression of p53 compared with the rare Merkel cell polyomavirus-negative Merkel cell carcinomas. Combined squamous and Merkel cell tumors are consistently negative for Merkel cell polyomavirus. Little is known about their immunophenotypic or molecular profile. Herein, we studied 10 combined cutaneous squamous cell and neuroendocrine carcinomas for immunohistochemical expression of p53, retinoblastoma 1 protein, neurofilament, p63, and cytokeratin 20 (CK20). We compared mutation profiles of five combined Merkel cell carcinomas and seven 'pure' Merkel cell carcinomas using targeted next-generation sequencing. Combined tumors were from the head, trunk, and leg of Caucasian males and one female aged 52-89. All cases were highly p53- and p63-positive and neurofilament-negative in the squamous component, whereas RB1-negative in both components. Eight out of 10 were p53-positive, 3/10 p63-positive, and 3/10 focally neurofilament-positive in the neuroendocrine component. Six out of 10 were CK20-positive in any part. By next-generation sequencing, combined tumors were highly mutated, with an average of 48 mutations per megabase compared with pure tumors, which showed 1.25 mutations per megabase. RB1 and p53 mutations were identified in all five combined tumors. Combined tumors represent an immunophenotypically and genetically distinct variant of primary cutaneous neuroendocrine carcinomas, notable for a highly mutated genetic profile, significant p53 expression and/or mutation, absent RB1 expression in the context of increased RB1 mutation, and minimal neurofilament expression.
组合性Merkel细胞癌患者为白人男性、一例女性，位于头部、躯干和大腿，年龄52-89岁。所有病例鳞状上皮成分均为p53和p63强阳性和神经丝蛋白阴性，而两种成分Rb1均为阴性。神经内分泌成分8/10例p53阳性、3/10 p63阳性和3/10局灶性神经丝蛋白阳性。6/10显示CK20任一成分均阳性。二代测序显示，与“单纯性” 肿瘤每百万碱基对1.25个突变相比，组合性Merkel细胞癌常常为高频突变，每百万碱基对平均有48个突变。五例组合性Merkel细胞癌均证实有Rb1和p53基因突变。组合性Merkel细胞癌代表的是一种免疫表型和基因改变不同于皮肤原发性神经内分泌癌的独特实体，常常有显著基因突变，如显著p53表达和/或突变、RB1基因突变增加而RB1表达缺失、神经丝蛋白少量表达。