title: Cutaneous squamous and neuroendocrine carcinoma: genetically and immunohistochemically different from Merkel cell carcinoma.
abstract: 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.
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Melissa P
authors.initials: MP
authors.lastname: Pulitzer
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: A Rose
authors.initials: AR
authors.lastname: Brannon
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Berger
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Louis
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Sasinya N
authors.initials: SN
authors.lastname: Scott
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Achim A
authors.initials: AA
authors.lastname: Jungbluth
authors.affiliation: Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Coit
authors.affiliation: Dermatology Branch, National Cancer Institute, National Institute of Health, Washington, DC, USA.
authors.forename: Isaac
authors.initials: I
authors.lastname: Brownell
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Klaus J
authors.initials: KJ
authors.lastname: Busam
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics; D015266:Carcinoma, Merkel Cell / Q000737:chemistry* / Q000208:ethnology / Q000235:genetics* / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000737:chemistry* / Q000208:ethnology / Q000235:genetics* / Q000473:pathology; D004252:DNA Mutational Analysis; D005260:Female; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007150:Immunohistochemistry; D053554:Keratin-20 / Q000032:analysis; D008297:Male; D008875:Middle Aged; D009154:Mutation; D018193:Neoplasms, Complex and Mixed / Q000737:chemistry* / Q000208:ethnology / Q000235:genetics* / Q000473:pathology; D016900:Neurofilament Proteins / Q000032:analysis; D010641:Phenotype; D011237:Predictive Value of Tests; D016160:Retinoblastoma Protein / Q000032:analysis / Q000235:genetics; D012878:Skin Neoplasms / Q000737:chemistry* / Q000208:ethnology / Q000235:genetics* / Q000473:pathology; D014157:Transcription Factors / Q000032:analysis; D016159:Tumor Suppressor Protein p53 / Q000032:analysis / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000032:analysis; D044465:White People / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; C507499:KRT20 protein, human; D053554:Keratin-20; D016900:Neurofilament Proteins; D016160:Retinoblastoma Protein; C495901:TP53 protein, human; C115051:TP63 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins