{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T11:08:31Z","timestamp":1785409711827,"version":"3.56.0"},"reference-count":59,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T00:00:00Z","timestamp":1782691200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100018712","name":"Iuliu Ha\u021bieganu University of Medicine and Pharmacy","doi-asserted-by":"publisher","award":["internal grant number 32153\/7\/ 16.12.2024"],"award-info":[{"award-number":["internal grant number 32153\/7\/ 16.12.2024"]}],"id":[{"id":"10.13039\/501100018712","id-type":"DOI","asserted-by":"publisher"}]},{"award":["internal grant number 32153\/7\/ 16.12.2024"],"award-info":[{"award-number":["internal grant number 32153\/7\/ 16.12.2024"]}],"id":[{"id":"https:\/\/ror.org\/051h0cw83","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diagnostics"],"abstract":"<jats:p>Background: Cutaneous squamous cell carcinoma (cSCC) is commonly regarded as a sporadic malignancy primarily driven by ultraviolet exposure. However, the occurrence of multiple, aggressive tumors at a relatively young age suggests the presence of underlying genetic susceptibility. The role of germline variants affecting extracellular matrix organization, pigmentation pathways, and tumor metabolism in aggressive cSCC remains incompletely understood. Case Presentation: We describe a 53-year-old patient with a long-standing history of multiple aggressive cutaneous squamous cell carcinomas involving the scalp and facial regions, characterized by recurrent and multifocal disease. A comprehensive diagnostic approach was undertaken, including histopathological examination, fluorescence confocal microscopy, high-frequency cutaneous ultrasound, and genetic analysis using whole-exome sequencing (WES). Results: Histopathology confirmed high-risk features consistent with aggressive cSCC. Cutaneous ultrasound and fluorescence confocal microscopy provided complementary, non-invasive insights into tumor depth, architecture, and invasive patterns. Whole-exome sequencing identified a heterozygous truncating variant in COL6A3 (NM_004369.4:c.5645C&gt;A, p.Ser1882Ter), classified as likely pathogenic according to ACMG criteria. Additionally, two heterozygous variants of uncertain significance were detected in TYR (NM_000372.5:c.1569C&gt;A, p.Ser523Arg) and FH (NM_000143.4:c.1237-5_1237-4insTCTCCCTCCCTC). Although individually inconclusive, the combined germline genetic background may have contributed to the patient\u2019s aggressive and multifocal cutaneous phenotype. Discussion: This case report supports a potential role of extracellular matrix remodeling, pigmentation-related susceptibility, and metabolic dysregulation in cutaneous carcinogenesis and tumor aggressiveness. This case illustrates how integrating WES with advanced non-invasive imaging techniques can enhance the understanding of biologically aggressive cSCC. Conclusions: This report highlights a unique case of multifocal aggressive cSCC characterized by a distinct germline genetic profile identified by WES and multimodal imaging assessment. Comprehensive molecular and imaging evaluation may be beneficial in selected patients with atypical or aggressive cutaneous squamous cell carcinoma, with implications for personalized surveillance and management.<\/jats:p>","DOI":"10.3390\/diagnostics16132032","type":"journal-article","created":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T15:27:37Z","timestamp":1782746857000},"page":"2032","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Multimodal Analysis of Aggressive Multifocal Cutaneous Squamous Cell Carcinoma Associated with a Germline COL6A3 Truncating Variant: A Case Report"],"prefix":"10.3390","volume":"16","author":[{"given":"Mircea","family":"Negrutiu","sequence":"first","affiliation":[{"name":"Department of Dermatology, \u201cIuliu Ha\u021bieganu\u201d University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan Cristian","family":"Vesa","sequence":"additional","affiliation":[{"name":"Department of Functional Sciences, Discipline of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, \u201cIuliu Ha\u021bieganu\u201d University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bogdan","family":"Florea","sequence":"additional","affiliation":[{"name":"Clinical Hospital of Infectious Diseases, 400000 Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana","family":"Miclea","sequence":"additional","affiliation":[{"name":"Mother and Child Department, \u201cIuliu Ha\u021bieganu\u201d University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania"},{"name":"Medical Genetics Department, Clinical Emergency Hospital for Children, 400001 Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Razvan","family":"Bucur","sequence":"additional","affiliation":[{"name":"Sanconfind Hospital, 107425 Poiana C\u00e2mpina, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrian","family":"Baican","sequence":"additional","affiliation":[{"name":"Department of Dermatology, \u201cIuliu Ha\u021bieganu\u201d University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6735-5146","authenticated-orcid":false,"given":"Monica","family":"Foc\u0219an","sequence":"additional","affiliation":[{"name":"Nanobiophotonics and Laser Microspectroscopy Center, Interdisciplinary Research Institute on Bio-Nano-Sciences, Babes-Bolyai University, 400271 Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0968-4026","authenticated-orcid":false,"given":"Sorina","family":"Danescu","sequence":"additional","affiliation":[{"name":"Department of Dermatology, \u201cIuliu Ha\u021bieganu\u201d University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.hoc.2018.08.001","article-title":"Cutaneous Squamous Cell Carcinoma","volume":"33","author":"Waldman","year":"2019","journal-title":"Hematol. 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