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Merkel Cell Polyomavirus and HPV-17 Associated With Cutaneous Squamous Cell Carcinoma Arising in a Patient With Melanoma Treated With the BRAF Inhibitor Dabrafenib

Gerald S. Falchook, MD, MS; Peter Rady, MD, PhD; Sharon Hymes, MD; Harrison P. Nguyen; Stephen K. Tyring, MD, PhD; Victor G. Prieto, MD, PhD; David S. Hong, MD; Razelle Kurzrock, MD
JAMA Dermatol. 2013;149(3):322-326. doi:10.1001/jamadermatol.2013.2023.
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Importance  Approximately 10% to 25% of patients treated with BRAF inhibitors develop cutaneous squamous cell carcinoma (SCC), but the mechanism responsible has not yet been determined. We report what we believe to be the first case in which Merkel cell polyomavirus (MCPyV) and human papillomavirus subtype 17 (HPV-17) were associated with cutaneous SCC that developed during treatment with the BRAF inhibitor dabrafenib.

Observations  A 62-year-old woman with V600E BRAF -mutant metastatic melanoma enrolled in a phase 1 trial of dabrafenib, a selective inhibitor of V600-mutant BRAF kinase. During the first 6 weeks of treatment, the patient developed multiple skin lesions, including a 6-mm crusted papule on the left eyebrow, which was resected and, on pathology examination, revealed SCC. The DNA extracted from paraffin-embedded tissue was amplified by polymerase chain reaction for detection of MCPyV and epidermodysplasia verruciformis HPV (EV-HPV) types. Analysis of the cloned and sequenced polymerase chain reaction products revealed the presence of MCPyV and HPV-17 DNA. Other EV-HPV subtypes were not detected.

Conclusions and Relevance  To our knowledge, this is the first report demonstrating the coexistence of MCPyV and HPV-17 in cutaneous SCC. Because both viruses have oncogenic potential, their role in the development of BRAF inhibitor–related SCC merits further investigation.

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Grahic Jump Location

Figure 1. Left eyebrow squamous cell carcinoma before resection.

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Figure 2. Invasive squamous cell carcinoma, moderately differentiated, 3.3 mm thick. A, Marked cytologic atypia at the interface between the tumor and the dermis (hematoxylin-eosin, original magnification ×20). B, Notice the presence of large nuclei, prominent nucleoli, and mitotic figures (original magnification ×40).

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Grahic Jump Location

Figure 3. Detection of epidermodysplasia verruciformis–human papillomavirus (EV-HPV) DNA, β-globin reference gene DNA, and Merkel cell polyomavirus (MCPyV) DNA by polymerase chain reaction (PCR) in skin squamous cell carcinoma (SCC) from a patient with melanoma treated with a BRAF inhibitor. A, EV-HPV detection. Putative EV-HPV PCR products can be seen in the lanes for SCC and the viral-positive control (PC). B, β-Globin detection. β-Globin PCR fragments can be seen in the lanes for SCC, actinic keratosis (AK), the viral-negative control (NC), and the viral PC. C, Merkel cell polyomavirus detection. The PCR products can be seen in the lanes for the PC, SCC, and AK. A and B, The NC was HPV-negative DNA extracted from peripheral blood mononuclear cells (PBMCs) (Promega Co), and the PC was EV-HPV DNA. C, The NC was MCPyV-negative DNA extracted from PBMCs, and the PC was MCPyV-positive DNA (plasmid with MCPyV DNA insert derived from the small T viral gene). bp Indicates base pair; M, ΦX174RF DNA marker (Promega Co); and R, reagent control.

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