{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T07:19:52Z","timestamp":1787728792368,"version":"build-2784847793"},"reference-count":38,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2024,1,18]],"date-time":"2024-01-18T00:00:00Z","timestamp":1705536000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Combined Merkel cell carcinoma (MCC) and squamous cell carcinoma (SCC) have classically been regarded as more aggressive than conventional, pure, Merkel cell polyomavirus (MCPyV)-positive MCC. It is still unknown whether combined MCC and SCC are more aggressive than pure, MCPyV-negative MCC, and the origin of both the SCC and MCC elements of these combined tumors has not been elucidated. The main objective of this systematic review was to assess whether combined MCC and SCC tumors are associated with a worse prognosis than pure MCC; the secondary goals were the characterization of the clinical and histopathological features of these combined neoplasms. A total of 38 studies, including 152 patients, were selected for review. In total, 76% of the cases were MCPyV-negative, whereas 4% were MCPyV-positive. The most frequent histopathological pattern was that of an SCC in situ combined with a dermal MCC (36%), followed by both an in situ and invasive SCC combined with a dermal MCC (20%). Forty-seven percent of all cases fitted in the morphology of the so-called \u201ccollision tumors\u201d. Three combined MCC cases that would fit in the morphological category of collision tumors presented both squamous and neuroendocrine elements in their respective nodal metastases. The mean overall survival was 36 months, comparable to that of pure, MCPyV-negative MCC. This review found similarly aggressive behavior for combined MCC and SCC and pure, MCPyV-negative MCC. Preliminary data strongly suggest that all MCPyV-negative MCC tumors, whether combined or pure, are part of a common spectrum.<\/jats:p>","DOI":"10.3390\/cancers16020411","type":"journal-article","created":{"date-parts":[[2024,1,18]],"date-time":"2024-01-18T03:50:56Z","timestamp":1705549856000},"page":"411","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Combined Merkel Cell Carcinoma and Squamous Cell Carcinoma: A Systematic Review"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4528-4946","authenticated-orcid":false,"given":"Elisa","family":"R\u00edos-Vi\u00f1uela","sequence":"first","affiliation":[{"name":"Escuela de Doctorado, Universidad Cat\u00f3lica de Valencia San Vicente M\u00e1rtir, 46001 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8478-6455","authenticated-orcid":false,"given":"Fatima","family":"Mayo-Mart\u00ednez","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Fundaci\u00f3n Instituto Valenciano de Oncolog\u00eda, 46009 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3433-8707","authenticated-orcid":false,"given":"Eduardo","family":"Nagore","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Fundaci\u00f3n Instituto Valenciano de Oncolog\u00eda, 46009 Valencia, Spain"},{"name":"School of Medicine, Universidad Cat\u00f3lica de Valencia San Vicente M\u00e1rtir, 46001 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Millan-Esteban","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Fundaci\u00f3n Instituto Valenciano de Oncolog\u00eda, 46009 Valencia, Spain"},{"name":"School of Medicine, Universidad Cat\u00f3lica de Valencia San Vicente M\u00e1rtir, 46001 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celia","family":"Requena","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Fundaci\u00f3n Instituto Valenciano de Oncolog\u00eda, 46009 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Onofre","family":"Sanmart\u00edn","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Fundaci\u00f3n Instituto Valenciano de Oncolog\u00eda, 46009 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatriz","family":"Llombart","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Fundaci\u00f3n Instituto Valenciano de Oncolog\u00eda, 46009 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,1,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1001\/archderm.1972.01620040075020","article-title":"Trabecular Carcinoma of the Skin","volume":"105","author":"Toker","year":"1972","journal-title":"Arch. Dermatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1425","DOI":"10.1111\/jdv.16158","article-title":"Merkel Cell Carcinoma Update: The Case for Two Tumours","volume":"34","author":"Nirenberg","year":"2020","journal-title":"J. Eur. Acad. Dermatol. Venereol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1016\/j.jid.2021.07.175","article-title":"Merkel Cell Polyomavirus\u2013Negative Merkel Cell Carcinoma Originating from In Situ Squamous Cell Carcinoma: A Keratinocytic Tumor with Neuroendocrine Differentiation","volume":"142","author":"Kervarrec","year":"2021","journal-title":"J. Investig. Dermatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1096","DOI":"10.1126\/science.1152586","article-title":"Clonal Integration of a Polyomavirus in Human Merkel Cell Carcinoma","volume":"319","author":"Feng","year":"2008","journal-title":"Science"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1038\/s41379-019-0288-7","article-title":"Morphologic and Immunophenotypical Features Distinguishing Merkel Cell Polyomavirus-Positive and Negative Merkel Cell Carcinoma","volume":"32","author":"Kervarrec","year":"2019","journal-title":"Mod. Pathol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/j.jid.2016.08.015","article-title":"Shared Oncogenic Pathways Implicated in Both Virus-Positive and UV-Induced Merkel Cell Carcinomas","volume":"137","author":"Derdak","year":"2017","journal-title":"J. Investig. Dermatol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1016\/j.jid.2016.10.028","article-title":"Polyomavirus-Negative Merkel Cell Carcinoma: A More Aggressive Subtype Based on Analysis of 282 Cases Using Multimodal Tumor Virus Detection","volume":"137","author":"Moshiri","year":"2017","journal-title":"J. Investig. Dermatol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Houben, R., Celikdemir, B., Kervarrec, T., and Schrama, D. (2023). Merkel Cell Polyomavirus: Infection, Genome, Transcripts and Its Role in Development of Merkel Cell Carcinoma. Cancers, 15.","DOI":"10.3390\/cancers15020444"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1111\/his.12091","article-title":"Merkel Cell Carcinoma with Divergent Differentiation: Histopathological and Immunohistochemical Study of 15 Cases with PCR Analysis for Merkel Cell Polyomavirus","volume":"62","author":"Martin","year":"2013","journal-title":"Histopathology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1038\/modpathol.2015.60","article-title":"Cutaneous Squamous and Neuroendocrine Carcinoma: Genetically and Immunohistochemically Different from Merkel Cell Carcinoma","volume":"28","author":"Pulitzer","year":"2015","journal-title":"Mod. Pathol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Mendoza, M.-D., Santonja, C., Gonzalez-Vela, C., Concha, A., Iglesias Pena, N., Andr\u00e9s-Esteban, E.-M., Vaque, J.P., Cereceda, L., Pajares, R., and Kutzner, H. (2020). The Presence of Merkel Cell Carcinoma Polyomavirus Is Associated with a Distinct Phenotype in Neoplastic Merkel Cell Carcinoma Cells and Their Tissue Microenvironment. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0232517"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1991","DOI":"10.1111\/jdv.18256","article-title":"Clinicopathological Features, MCPyV Status and Outcomes of Merkel Cell Carcinoma in Solid-Organ Transplant Recipients: A Retrospective, Multicentre Cohort Study","volume":"36","author":"Llombart","year":"2022","journal-title":"J. Eur. Acad. Dermatol. Venereol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"938","DOI":"10.1093\/jnci\/djp139","article-title":"Clinical Factors Associated with Merkel Cell Polyomavirus Infection in Merkel Cell Carcinoma","volume":"101","author":"Sihto","year":"2009","journal-title":"JNCI J. Natl. Cancer Inst."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Naseri, S., Steiniche, T., Georgsen, J.B., Thomsen, R., Ladekarl, M., Heje, M., Damsgaard, T.E., and B\u00f8nnelykke-Behrndtz, M.L. (2020). Tumor Ulceration, Reduced Infiltration of CD8-Lymphocytes, High Neutrophil-to-CD8-Lymphocyte Ratio and Absence of MC Virus Are Negative Prognostic Markers for Patients with Merkel Cell Carcinoma. Cancers, 12.","DOI":"10.3390\/cancers12040888"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1007\/s10654-019-00576-5","article-title":"A 24-Step Guide on How to Design, Conduct, and Successfully Publish a Systematic Review and Meta-Analysis in Medical Research","volume":"35","author":"Muka","year":"2020","journal-title":"Eur. J. Epidemiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1146\/annurev-psych-010418-102803","article-title":"How to Do a Systematic Review: A Best Practice Guide for Conducting and Reporting Narrative Reviews, Meta-Analyses, and Meta-Syntheses","volume":"70","author":"Siddaway","year":"2019","journal-title":"Annu. Rev. Psychol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1097\/CCO.0000000000000608","article-title":"Immunobiology of Merkel Cell Carcinoma","volume":"32","author":"Samimi","year":"2020","journal-title":"Curr. Opin. Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Garc\u00eda-Mesa, Y., Mart\u00edn-Sanz, R., Garc\u00eda-Piqueras, J., Cobo, R., Mu\u00f1oz-Bravo, S., Garc\u00eda-Su\u00e1rez, O., Mart\u00edn-Biedma, B., Vega, J.A., and Feito, J. (2022). Merkel Cell Carcinoma Display PIEZO2 Immunoreactivity. J. Pers. Med., 12.","DOI":"10.3390\/jpm12060894"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.humpath.2023.03.004","article-title":"Merkel Cell Carcinoma: An Update","volume":"140","author":"DeCoste","year":"2023","journal-title":"Hum. Pathol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e2249674","DOI":"10.1001\/jamanetworkopen.2022.49674","article-title":"Genomic Alterations and Tumor Mutation Burden in Merkel Cell Carcinoma","volume":"6","author":"Brazel","year":"2023","journal-title":"JAMA Netw. Open"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1111\/1346-8138.12808","article-title":"Histogenesis of Pure and Combined Merkel Cell Carcinomas: An Immunohistochemical Study of 14 Cases","volume":"42","author":"Narisawa","year":"2015","journal-title":"J. Dermatol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"632","DOI":"10.1016\/j.humpath.2010.09.011","article-title":"Association of Merkel Cell Polyomavirus Infection with Morphologic Differences in Merkel Cell Carcinoma","volume":"42","author":"Kuwamoto","year":"2011","journal-title":"Hum. Pathol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1038\/s41379-021-00928-1","article-title":"Genomic Evidence Suggests That Cutaneous Neuroendocrine Carcinomas Can Arise from Squamous Dysplastic Precursors","volume":"35","author":"Harms","year":"2022","journal-title":"Mod. Pathol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1007\/s00428-018-2342-0","article-title":"Detection of the Merkel Cell Polyomavirus in the Neuroendocrine Component of Combined Merkel Cell Carcinoma","volume":"472","author":"Kervarrec","year":"2018","journal-title":"Virchows Arch."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.humpath.2022.07.021","article-title":"Morphological Patterns of Metastases from Combined Merkel Cell Carcinomas: Study of an Eastern Canadian Cohort of Cases","volume":"129","author":"Gruchy","year":"2022","journal-title":"Hum. Pathol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.humpath.2021.08.003","article-title":"Relationship between P63 and P53 Expression in Merkel Cell Carcinoma and Corresponding Abnormalities in TP63 and TP53: A Study and a Proposal","volume":"117","author":"DeCoste","year":"2021","journal-title":"Hum. Pathol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2494","DOI":"10.1158\/1078-0432.CCR-20-0864","article-title":"Virus-Positive Merkel Cell Carcinoma Is an Independent Prognostic Group with Distinct Predictive Biomarkers","volume":"27","author":"Harms","year":"2021","journal-title":"Clin. Cancer Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"968","DOI":"10.1016\/j.jaad.2015.08.041","article-title":"Clinical and Dermoscopic Features of Combined Cutaneous Squamous Cell Carcinoma (SCC)\/Neuroendocrine [Merkel Cell] Carcinoma (MCC)","volume":"73","author":"Louis","year":"2015","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1829","DOI":"10.1038\/s41379-022-01151-2","article-title":"RB1-Deficient Squamous Cell Carcinoma: The Proposed Source of Combined Merkel Cell Carcinoma","volume":"35","author":"DeCoste","year":"2022","journal-title":"Mod. Pathol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1111\/cup.14360","article-title":"Combined Merkel Cell Carcinoma and Cutaneous Squamous Cell Carcinoma with Lymph Node Metastases: Report of Two Cases","volume":"50","author":"Traves","year":"2023","journal-title":"J. Cutan. Pathol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1097\/DAD.0000000000001548","article-title":"Morphologic Diversity of Merkel Cell Carcinoma","volume":"42","author":"Ogawa","year":"2020","journal-title":"Am. J. Dermatopathol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"680","DOI":"10.1053\/hupa.2001.25904","article-title":"Primary Neuroendocrine (Merkel Cell) Carcinoma of the Skin: Morphologic Diversity and Implications Thereof","volume":"32","author":"Walsh","year":"2001","journal-title":"Hum. Pathol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1097\/DAD.0b013e31823b9b4e","article-title":"Detection of Merkel Cell Polyomavirus and Human Papillomaviruses in Merkel Cell Carcinoma Combined with Squamous Cell Carcinoma in Immunocompetent European Patients","volume":"34","author":"Mitteldorf","year":"2012","journal-title":"Am. J. Dermatopathol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1016\/j.anndiagpath.2008.07.001","article-title":"Merkel Cell Carcinoma with Eccrine Differentiation: A Clinicopathologic Study of 7 Cases","volume":"12","year":"2008","journal-title":"Ann. Diagn. Pathol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1097\/DAD.0000000000000927","article-title":"Lymph Node Metastasis With Both Components of Combined Cutaneous Squamous Cell Carcinoma\/Merkel Cell (Neuroendocrine) Carcinoma","volume":"40","author":"Navarrete","year":"2018","journal-title":"Am. J. Dermatopathol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e61","DOI":"10.1097\/DAD.0000000000001318","article-title":"Concurrent Metastatic Merkel Cell Carcinoma and Cutaneous Squamous Cell Carcinoma in the Same Lymph Node","volume":"41","author":"Suaiti","year":"2019","journal-title":"Am. J. Dermatopathol."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Liu, C.-Y., Kang, N.-W., Takeuchi, K., and Chuang, S.-S. (2023). Combined Merkel Cell Carcinoma with Nodal Presentation: Report of a Case Diagnosed with Excisional but Not Incisional Biopsy and Literature Review. Diagnostics, 13.","DOI":"10.3390\/diagnostics13030449"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.humpath.2017.10.014","article-title":"Genetic Profiles of Different Subsets of Merkel Cell Carcinoma Show Links between Combined and Pure MCPyV-Negative Tumors","volume":"71","author":"Carter","year":"2018","journal-title":"Hum. Pathol."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/16\/2\/411\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T13:49:29Z","timestamp":1760104169000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/16\/2\/411"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1,18]]},"references-count":38,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2024,1]]}},"alternative-id":["cancers16020411"],"URL":"https:\/\/doi.org\/10.3390\/cancers16020411","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,1,18]]}}}