Commentaries 689
Human papillomavirus and cutaneous squamous cell carcinoma: does ethnicity matter? DOI: 10.1111/bjd.13318 ORIGINAL ARTICLE, p 779 Human papillomavirus (HPV) has been recognized as a causative agent in some epithelial malignancies, represented by cervical squamous cell carcinoma (SCC).1 Accumulated evidence supports the theory that persistent HPV infection contributes to the development of cervical SCCs and preceding precancerous lesions,2 whereas the role of HPV in the pathogenesis of cutaneous SCCs remains elusive. Indeed, the prevalence and types of HPV detected in cutaneous SCCs have not been consistent in previous studies. HPVs are categorized into mucosal, cutaneous and epidermodysplasia verruciformis (EV) subtypes. The mucosal-type HPVs are further categorized into low- and high-risk subgroups. The high-risk HPVs contain two important oncogenes, E6 and E7, which silence the tumour-suppressive p53 and Rb proteins to give rise to cervical SCCs.3 These HPV subsets are frequently detectable in anogenital cutaneous SCCs and precancerous lesions as bowenoid papulosis, supporting their roles in carcinogenesis. In contrast, to what extent other types of HPV are involved in cutaneous SCC development is still unclear. Harwood et al.4 detected EV-type HPV in 27% of cutaneous SCCs in immunocompetent individuals. Interestingly, most EV-type HPV-positive SCCs also showed positive reactivity for cutaneous or mucosal-type HPVs, an observation contradicting the dogma that double HPV infection cannot happen in healthy subjects, and implying that cutaneous SCCs may not be linked to a specific HPV subtype. Perhaps, each HPV subtype may equally promote carcinogenesis. Alternatively, HPVs could be just an innocent bystander in cutaneous SCCs. In this issue of BJD, Shimizu et al.5 examined the frequency of HPV infection in Japanese patients with cutaneous SCCs. Unexpectedly, only two of 38 cases with anogenital SCCs were found to be HPV positive. Polymerase chain reaction analyses detected mucosal high-risk-type HPVs in lesions. No HPV was detected in any of the other cases. The current finding is dramatically distinct from previous observations.4,6,7 This discrepancy may be attributed to the difference in adopted methodologies or the limitation of the size of the cohort. Intriguingly, low HPV frequency in cutaneous SCCs has also been reported in Japanese patients by Hama et al.,8 demonstrating mucosal high-risk-type HPVs in two of 22 cutaneous SCCs, while Loeb et al.7 reported a higher prevalence of HPV (66% positive in tumoral lesions) in cutaneous SCCs in white patients. These data may imply that ethnic background or skin type affect HPV positivity in cutaneous SCC.
© 2014 British Association of Dermatologists
However, there are still many unknowns to be resolved. Are there any racial differences in skin barrier functions resulting in distinctive HPV infection rates? Does lifestyle or surrounding environment predispose an individual to HPV transmission? Recent studies reported high prevalence of HPV in photodamaged skin and actinic keratoses.4,6 The difference in ethnicity-dependent ultraviolet resistance may partially define HPV infectivity in each race, with resultant diverse HPV detection rates in cutaneous SCCs. The study by Shimizu et al. urges us to re-evaluate the relationship between HPV and cutaneous SCC carcinogenesis in the context of host difference. Of course, further investigation is indispensable to decode this enigma fully.
Conflicts of interest None declared. 1
Department of Dermatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajiicho, Hirokoji, Kawaramachi, Kamigyo-Ku, Kyoto 602-8566, Japan 2 Department of Dermatology, Keio University School of Medicine, Tokyo, Japan E-mail: [email protected]
J. ASAI1 M. OHYAMA2
References 1 Walboomers JM, Jacobs MV, Manos MM et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 1999; 189:12–19. 2 Nobbenhuis MA, Walboomers JM, Helmerhorst TJ et al. Relation of human papillomavirus status to cervical lesions and consequences for cervical-cancer screening: a prospective study. Lancet 1999; 354:20–5. 3 Goodwin EC, DiMaio D. Repression of human papillomavirus oncogenes in HeLa cervical carcinoma cells causes the orderly reactivation of dormant tumor suppressor pathways. Proc Natl Acad Sci USA 2000; 97:12513–18. 4 Harwood CA, Surentheran T, McGregor JM et al. Human papillomavirus infection and non-melanoma skin cancer in immunosuppressed and immunocompetent individuals. J Med Virol 2000; 61:289–97. 5 Shimizu A, Kato M, Takeuchi Y et al. Detection of human papillomavirus (HPV) in patients with squamous cell carcinoma and the clinical characteristics of HPV-positive cases. Br J Dermatol 2014; 171:779–85. 6 Weissenborn SJ, Nindl I, Purdie K et al. Human papillomavirus-DNA loads in actinic keratoses exceed those in non-melanoma skin cancers. J Invest Dermatol 2005; 125:93–7. 7 Loeb KR, Asgari MM, Hawes SE et al. Analysis of Tp53 codon 72 polymorphisms, Tp53 mutations, and HPV infection in cutaneous squamous cell carcinomas. PLoS ONE 2012; 7:e34422. 8 Hama N, Ohtsuka T, Yamazaki S. Detection of mucosal human papilloma virus DNA in bowenoid papulosis, Bowen’s disease and squamous cell carcinoma of the skin. J Dermatol 2006; 33:331–7.
British Journal of Dermatology (2014) 171, pp687–695
Human papillomavirus and cutaneous squamous cell carcinoma: does ethnicity matter? DOI: 10.1111/bjd.13318 ORIGINAL ARTICLE, p 779 Human papillomavirus (HPV) has been recognized as a causative agent in some epithelial malignancies, represented by cervical squamous cell carcinoma (SCC).1 Accumulated evidence supports the theory that persistent HPV infection contributes to the development of cervical SCCs and preceding precancerous lesions,2 whereas the role of HPV in the pathogenesis of cutaneous SCCs remains elusive. Indeed, the prevalence and types of HPV detected in cutaneous SCCs have not been consistent in previous studies. HPVs are categorized into mucosal, cutaneous and epidermodysplasia verruciformis (EV) subtypes. The mucosal-type HPVs are further categorized into low- and high-risk subgroups. The high-risk HPVs contain two important oncogenes, E6 and E7, which silence the tumour-suppressive p53 and Rb proteins to give rise to cervical SCCs.3 These HPV subsets are frequently detectable in anogenital cutaneous SCCs and precancerous lesions as bowenoid papulosis, supporting their roles in carcinogenesis. In contrast, to what extent other types of HPV are involved in cutaneous SCC development is still unclear. Harwood et al.4 detected EV-type HPV in 27% of cutaneous SCCs in immunocompetent individuals. Interestingly, most EV-type HPV-positive SCCs also showed positive reactivity for cutaneous or mucosal-type HPVs, an observation contradicting the dogma that double HPV infection cannot happen in healthy subjects, and implying that cutaneous SCCs may not be linked to a specific HPV subtype. Perhaps, each HPV subtype may equally promote carcinogenesis. Alternatively, HPVs could be just an innocent bystander in cutaneous SCCs. In this issue of BJD, Shimizu et al.5 examined the frequency of HPV infection in Japanese patients with cutaneous SCCs. Unexpectedly, only two of 38 cases with anogenital SCCs were found to be HPV positive. Polymerase chain reaction analyses detected mucosal high-risk-type HPVs in lesions. No HPV was detected in any of the other cases. The current finding is dramatically distinct from previous observations.4,6,7 This discrepancy may be attributed to the difference in adopted methodologies or the limitation of the size of the cohort. Intriguingly, low HPV frequency in cutaneous SCCs has also been reported in Japanese patients by Hama et al.,8 demonstrating mucosal high-risk-type HPVs in two of 22 cutaneous SCCs, while Loeb et al.7 reported a higher prevalence of HPV (66% positive in tumoral lesions) in cutaneous SCCs in white patients. These data may imply that ethnic background or skin type affect HPV positivity in cutaneous SCC.
© 2014 British Association of Dermatologists
However, there are still many unknowns to be resolved. Are there any racial differences in skin barrier functions resulting in distinctive HPV infection rates? Does lifestyle or surrounding environment predispose an individual to HPV transmission? Recent studies reported high prevalence of HPV in photodamaged skin and actinic keratoses.4,6 The difference in ethnicity-dependent ultraviolet resistance may partially define HPV infectivity in each race, with resultant diverse HPV detection rates in cutaneous SCCs. The study by Shimizu et al. urges us to re-evaluate the relationship between HPV and cutaneous SCC carcinogenesis in the context of host difference. Of course, further investigation is indispensable to decode this enigma fully.
Conflicts of interest None declared. 1
Department of Dermatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajiicho, Hirokoji, Kawaramachi, Kamigyo-Ku, Kyoto 602-8566, Japan 2 Department of Dermatology, Keio University School of Medicine, Tokyo, Japan E-mail: [email protected]
J. ASAI1 M. OHYAMA2
References 1 Walboomers JM, Jacobs MV, Manos MM et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 1999; 189:12–19. 2 Nobbenhuis MA, Walboomers JM, Helmerhorst TJ et al. Relation of human papillomavirus status to cervical lesions and consequences for cervical-cancer screening: a prospective study. Lancet 1999; 354:20–5. 3 Goodwin EC, DiMaio D. Repression of human papillomavirus oncogenes in HeLa cervical carcinoma cells causes the orderly reactivation of dormant tumor suppressor pathways. Proc Natl Acad Sci USA 2000; 97:12513–18. 4 Harwood CA, Surentheran T, McGregor JM et al. Human papillomavirus infection and non-melanoma skin cancer in immunosuppressed and immunocompetent individuals. J Med Virol 2000; 61:289–97. 5 Shimizu A, Kato M, Takeuchi Y et al. Detection of human papillomavirus (HPV) in patients with squamous cell carcinoma and the clinical characteristics of HPV-positive cases. Br J Dermatol 2014; 171:779–85. 6 Weissenborn SJ, Nindl I, Purdie K et al. Human papillomavirus-DNA loads in actinic keratoses exceed those in non-melanoma skin cancers. J Invest Dermatol 2005; 125:93–7. 7 Loeb KR, Asgari MM, Hawes SE et al. Analysis of Tp53 codon 72 polymorphisms, Tp53 mutations, and HPV infection in cutaneous squamous cell carcinomas. PLoS ONE 2012; 7:e34422. 8 Hama N, Ohtsuka T, Yamazaki S. Detection of mucosal human papilloma virus DNA in bowenoid papulosis, Bowen’s disease and squamous cell carcinoma of the skin. J Dermatol 2006; 33:331–7.
British Journal of Dermatology (2014) 171, pp687–695
