Merkel cell polyomavirus and HPV-17 associated with cutaneous squamous cell carcinoma arising in a patient with melanoma treated with the BRAF inhibitor dabrafenib

Abstract

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.

Figure 1

Left eyebrow squamous cell carcinoma before resection

Figure 2

Invasive squamous cell carcinoma, moderately differentiated, 3.3 mm in thickness (A) Marked cytologic atypia at the interface between the tumor and the dermis (×20) (B) Notice the presence of large nuclei, prominent nucleoli and mitotic figures (×40)

Figure 2

Invasive squamous cell carcinoma, moderately differentiated, 3.3 mm in thickness (A) Marked cytologic atypia at the interface between the tumor and the dermis (×20) (B) Notice the presence of large nuclei, prominent nucleoli and mitotic figures (×40)

Figure 3

Detection of EV-HPV- and β-globin reference gene-DNA and MCPyV DNA by PCR in skin squamous cell carcinoma from a melanoma patient treated with a BRAF inhibitor. (A) EV-HPV detection. Putative EV-HPV PCR products can be seen in lanes SCC and PC. (B) β-globin detection. β-globin PCR fragments can be seen in lanes SCC, AK, NC, and PC. (C) MCPyV detection. PCR products can be seen in lanes SCC, AK, and PC.

Figure 3

Detection of EV-HPV- and β-globin reference gene-DNA and MCPyV DNA by PCR in skin squamous cell carcinoma from a melanoma patient treated with a BRAF inhibitor. (A) EV-HPV detection. Putative EV-HPV PCR products can be seen in lanes SCC and PC. (B) β-globin detection. β-globin PCR fragments can be seen in lanes SCC, AK, NC, and PC. (C) MCPyV detection. PCR products can be seen in lanes SCC, AK, and PC.

Figure 3

Detection of EV-HPV- and β-globin reference gene-DNA and MCPyV DNA by PCR in skin squamous cell carcinoma from a melanoma patient treated with a BRAF inhibitor. (A) EV-HPV detection. Putative EV-HPV PCR products can be seen in lanes SCC and PC. (B) β-globin detection. β-globin PCR fragments can be seen in lanes SCC, AK, NC, and PC. (C) MCPyV detection. PCR products can be seen in lanes SCC, AK, and PC.

Figure 3

Detection of EV-HPV- and β-globin reference gene-DNA and MCPyV DNA by PCR in skin squamous cell carcinoma from a melanoma patient treated with a BRAF inhibitor. (A) EV-HPV detection. Putative EV-HPV PCR products can be seen in lanes SCC and PC. (B) β-globin detection. β-globin PCR fragments can be seen in lanes SCC, AK, NC, and PC. (C) MCPyV detection. PCR products can be seen in lanes SCC, AK, and PC.