title: Pure versus combined Merkel cell carcinomas: immunohistochemical evaluation of cellular proteins (p53, Bcl-2, and c-kit) reveals significant overexpression of p53 in combined tumors.
abstract: Merkel cell polyomavirus is of oncogenic significance in approximately 80% of Merkel cell carcinomas. Morphological subcategories of the tumor differ in regard to viral status, the rare combined type being uniformly virus negative and the predominant pure type being mainly virus positive. Indications that different biological subsets of the tumor exist led us to explore this diversity. In an Eastern Canadian cohort of cases (75 patients; mean age, 76 years [range, 43-91]; male/female ratio, 43:32; 51 [68%] pure and 24 [34%] combined tumors), we semiquantitatively compared the immunohistochemical expression of 3 cellular proteins (p53, Bcl-2, and c-kit) in pure versus combined groups. Viral status was known in a subset of cases. The significant overexpression of p53 in the combined group (mean [SD], 153.8 [117.8] versus 121.6 [77.9]; P = .01) and the increased epidermal expression of this protein (p53 patches) in the same group lend credence to a primary etiologic role for sun damage in these cases. Expression of Bcl-2 and c-kit did not differ significantly between the 2 morphological groups. A relative increase in c-kit expression was significantly associated with a virus-negative status (median [interquartile range], 100 [60-115] versus 70 [0-100]; P = .03). Emerging data reveal divergent biological pathways in Merkel cell carcinoma, each with a characteristic immunohistochemical profile. Virus-positive tumors (all pure) exhibit high retinoblastoma protein and low p53 expression, whereas virus-negative cases (few pure and all combined) show high p53 and relatively high c-kit expression. The potential biological implications of this dichotomy call for consistent stratification of these tumors in future studies.
authors.affiliation: Department of Pathology, Queen Elizabeth II Health Sciences Center, Capital District Health Authority, Halifax, NS, B3H 1V8, Canada.
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Lai
authors.affiliation: Department of Pathology, Queen Elizabeth II Health Sciences Center, Capital District Health Authority, Halifax, NS, B3H 1V8, Canada; Dalhousie University, Halifax, NS, B3H 1V8, Canada.
authors.forename: Kirsten E
authors.initials: KE
authors.lastname: Fleming
authors.affiliation: Department of Pathology, Queen Elizabeth II Health Sciences Center, Capital District Health Authority, Halifax, NS, B3H 1V8, Canada; Dalhousie University, Halifax, NS, B3H 1V8, Canada.
authors.forename: Thai Yen
authors.initials: TY
authors.lastname: Ly
authors.affiliation: Department of Pathology, Queen Elizabeth II Health Sciences Center, Capital District Health Authority, Halifax, NS, B3H 1V8, Canada; Dalhousie University, Halifax, NS, B3H 1V8, Canada.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Pasternak
authors.affiliation: Dalhousie University, Halifax, NS, B3H 1V8, Canada; Department of Pathology, Saint John Regional Hospital, Horizon Health Network, Saint John, NB, E2L 4L4, Canada.
authors.forename: Marek
authors.initials: M
authors.lastname: Godlewski
authors.affiliation: Dalhousie University, Halifax, NS, B3H 1V8, Canada; Research Methods Unit, Capital District Health Authority, Halifax, NS, B3H 1V7, Canada.
authors.forename: Steve
authors.initials: S
authors.lastname: Doucette
authors.affiliation: Department of Pathology, Queen Elizabeth II Health Sciences Center, Capital District Health Authority, Halifax, NS, B3H 1V8, Canada; Dalhousie University, Halifax, NS, B3H 1V8, Canada. Electronic address: Noreen.walsh@cdha.nshealth.ca.
authors.forename: Noreen M
authors.initials: NM
authors.lastname: Walsh
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis*; D015266:Carcinoma, Merkel Cell / Q000737:chemistry* / Q000473:pathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D018193:Neoplasms, Complex and Mixed / Q000737:chemistry* / Q000473:pathology; D009674:Nova Scotia; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis*; D019009:Proto-Oncogene Proteins c-kit / Q000032:analysis*; D012878:Skin Neoplasms / Q000737:chemistry* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000032:analysis*; D015854:Up-Regulation
chemical_list: C000595707:BCL2 protein, human; D014408:Biomarkers, Tumor; D019253:Proto-Oncogene Proteins c-bcl-2; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D019009:Proto-Oncogene Proteins c-kit
keywords: Bcl-2; CD117 (c-kit); Combined Merkel cell carcinoma; Cutaneous neuroendocrine carcinoma; Merkel cell carcinoma; Pure Merkel cell carcinoma; p53