Human Papillomaviruses Associated with Epidermodysplasia Verruciformis in Non-Melanoma Skin Cancers: Guilty or Innocent?

Abstract

Non-melanoma skin cancers (NMSC), namely basal cell carcinomas (BCC) and squamous cell carcinomas (SCC), represent the most common form of malignancy in fairskinned populations. Solar ultraviolet radiation (UVR), immunosuppression, and genetic constitution of the host are well-known risk factors for the development of NMSC. Epidermodysplasia verruciformis (EV), a rare genetic disease associated with a high risk of skin cancer, provided the first clue to a possible role of viruses in human skin carcinogenesis (Jablonska et al, 1972). Due to mutations in either of the related EVER1 and EVER2 genes, EV patients are abnormally susceptible to a specific group of related human papillomavirus genotypes (known as EV HPV) and to the oncogenic potential of some of these viruses (Orth, 1987;Ramoz et al, 2002). EV HPV cause widespread, inapparent infections in the general population (Antonsson et al, 2003). In EV patients, however, infection leads to persistent wartlike and macular skin lesions, and premalignant lesions and SCC develop on sun-exposed areas of the skin in about half of the patients. EV SCC harbor high copy numbers of episomal HPV genomes (HPV5 or occasionally HPV8, 14, 17, 20, or 47) and abundant transcripts of the E6 and E7 genes. Phenocopies of EV are exceptionally observed in immunosuppressed patients. EV is thus a rare experiment of nature that provides a model for studying the interaction among potentially oncogenic HPV genotypes, UVR, immunity, and genetic factors (Orth, 1987).EV HPV DNA sequences have only rarely been detected in cutaneous premalignant tumors and NMSC in non-EV patients by Southern blot hybridization, which is sensitive enough to detect one HPV genome per cell. Using highly sensitive PCR approaches, however, HPV DNA sequences were detected in 25%-65% of NMSC in immunocompetent individuals and in up to 90% of SCC in organ transplant recipients (OTR), a population at a greatly increased risk of developing SCC. Similar HPV detection rates were found for actinic keratoses (AK), the precursor lesion of SCC (reviewed in Forslund et al, 2004). These data led researchers to consider a role for HPV, especially EV HPV types, in the development of NMSC (Orth, 2004).Available epidemiological and seroepidemiological data provide some support to an association between the presence of EV HPV DNA in normal skin or eyebrow hairs or the seroreactivity to some EV HPV and an increased risk of AK and SCC (reviewed in Purdie et al, 2005;Weissenborn et al, 2005). The link between EV HPV and the development of NMSC in immunocompetent and immunosuppressed individuals, however, remains unclear (reviewed in Orth, 2004). EV HPV and non-EV cutaneous HPV types represent impressively diverse, ubiquitous viruses, which are highly prevalent in the normal skin of healthy adults (Antonsson et al, 2003). A great diversity of cutaneous HPV types, most frequently EV HPV or putative novel EV HPV-related types, is detected in AK and NMSC, and mixed infections are frequently observed in tumors of OTR patients. Furthermore, ...

Infecção pelo papilomavírus humano: etiopatogenia, biologia molecular e manifestações clínicas

“…Patients with EV are highly predisposed to infection by a specific group of HPVs and at a high risk of developing cutaneous malignant tumors, resulting from the oncogenic effects of the viruses. 29 The skin lesions appear early in childhood and are polymorphic. They are indistinguishable from flat warts when present on the face and neck, and scaly hypo or hyper-pigmented erythematous macules, similar to versicolor, when present on the trunk and limbs.…”

The EVER Proteins as a Natural Barrier against Papillomaviruses: a New Insight into the Pathogenesis of Human Papillomavirus Infections

“…Among the beta-HPVs, HPV5 and HPV8 are classified as high-risk genotypes since they are associated with skin carcinomas occurring in EV patients (151,152). It is worth stressing that beta-HPVs have been detected in trace amounts in a large proportion of nonmelanoma skin carcinomas (NMSCs) of non-EV patients, particularly those carcinomas that develop in immunocompromised individuals (57,153,165,171,202). Moreover, it has been suggested that these viruses may contribute to skin tumors in immunocompetent individuals (75), and a possible role of beta-HPV in skin carcinogenesis constitutes a hot research topic (35,76,153).…”

Prevalence and associated factors of betapapillomavirus infections in individuals without cutaneous squamous cell carcinoma

“…The first evidence that cutaneous HPV types might play a role in the pathogenesis of cutaneous squamous cell carcinoma (SCC) was based on the detection of specific HPV types, predominantly HPV5 and HPV8 and rarely HPV types 14, 17, 20 or 47, in over 90 % of SCCs in epidermodysplasia verruciformis (EV) patients (Orth, 2005;Pfister, 2003). EV patients suffer a genetic defect that confers high susceptibility to specific HPV types that induce characteristic, macular skin lesions disseminated over the body that frequently progress to SCC.…”