Abstract
Background: Human papillomavirus (HPV) has long been proposed as a cofactor in the pathogenesis of cutaneous squamous cell carcinoma (cSCC). More recently, the striking clinico-pathological features of cSCCs that complicate treatment of metastatic melanoma with inhibitors targeting BRAF mutations (BRAFi) has prompted speculation concerning a pathogenic role for oncogenic viruses. Here, we investigate HPV and human polyomaviruses (HPyV) and correlate with clinical, histologic, and genetic features in BRAFi-associated cSCC.Materials and Methods: Patients receiving BRAFi treatment were recruited at Barts Health NHS Trust. HPV DNA was detected in microdissected frozen samples using reverse line probe technology and degenerate and nested PCR. HPV immunohistochemistry was performed in a subset of samples. Quantitative PCR was performed to determine the presence and viral load of HPyVs with affinity for the skin (HPyV6, HPyV7, HPyV9, MCPyV, and TSPyV). These data were correlated with previous genetic mutational analysis of H, K and NRAS, NOTCH1/2, TP53, CDKN2A, CARD11, CREBBP, TGFBR1/2. Chromosomal aberrations were profiled using single nucleotide polymorphism (SNP) arrays.Results: Forty-five skin lesions from seven patients treated with single agent vemurafenib in 2012–2013 were analyzed: 12 cSCC, 19 viral warts (VW), 2 actinic keratosis (AK), 5 verrucous keratosis/other squamoproliferative (VK/SP) lesions, one melanocytic lesion and 6 normal skin samples. Significant histologic features of viral infection were seen in 10/12 (83%) cSCC. HPV DNA was detected in 18/19 (95%) VW/SP, 9/12 (75%) cSCC, 4/5 (80%) SP, and 3/6 (50%) normal skin samples and in 1/12 cases assessed by immunohistochemistry. HPyV was co-detected in 22/30 (73%) of samples, usually at low viral load, with MCPyV and HPyV7 the most common. SNP arrays confirmed low levels of chromosomal abnormality and there was no significant correlation between HPV or HPyV detection and individual gene mutations or overall mutational burden.Conclusion: Despite supportive clinicopathologic evidence, the role for HPV and HPyV infection in the pathogenesis of BRAFi-induced squamoproliferative lesions remains uncertain. Synergistic oncogenic mechanisms are plausible although speculative. Nonetheless, with the prospect of a significant increase in the adjuvant use of these drugs, further research is justified and may provide insight into the pathogenesis of other BRAFi-associated malignancies.
Highlights
Human papillomaviruses (HPV), those of the beta genus, have long been proposed as cofactors with ultraviolet radiation in the pathogenesis of cutaneous squamous cell carcinoma, especially those associated with the rare genodermatosis, epidermodysplasia verruciformis and with immune suppression (Wang et al, 2014; Howley and Pfister, 2015; Quint et al, 2015; Harwood et al, 2017)
In this study we have examined HPV and human polyomaviruses (HPyV) status in a series of benign and malignant BRAF inhibitors (BRAFi)-associated skin lesions and correlated these data with key clinical, histologic and genetic parameters in order to further investigate the contribution of these viruses to the pathogenesis of BRAFi-induced skin tumors
A high proportion of BRAFi-cutaneous squamous cell carcinoma (cSCC) had histologic viral wart-like features on histology, consistent with virus-driven processes, and the majority were positive for beta-PV, HPyV7 and Merkel cell polyomavirus (MCPyV), which were co-detected in 73% of lesions tested
Summary
Human papillomaviruses (HPV), those of the beta genus (beta-PV), have long been proposed as cofactors with ultraviolet radiation in the pathogenesis of cutaneous squamous cell carcinoma (cSCC), especially those associated with the rare genodermatosis, epidermodysplasia verruciformis and with immune suppression (Wang et al, 2014; Howley and Pfister, 2015; Quint et al, 2015; Harwood et al, 2017). The clinical and histologic features of cSCCs and other squamoproliferative lesions that complicate treatment for metastatic melanoma with oral small molecule BRAF inhibitors (BRAFi) have raised the possibility of significant viral involvement in their pathogenesis (Boussemart et al, 2013). Both HPV and HPyV have been investigated, but studies have to date provided conflicting evidence for their role. Human papillomavirus (HPV) has long been proposed as a cofactor in the pathogenesis of cutaneous squamous cell carcinoma (cSCC). We investigate HPV and human polyomaviruses (HPyV) and correlate with clinical, histologic, and genetic features in BRAFi-associated cSCC
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