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Human papillomavirus (HPV) is ubiquitous in skin and has been associated with nonmelanoma skin cancer. Iannacone et al. investigate the role of HPV in basal cell carcinoma (BCC) by assessing the presence of HPV antibodies, HPV DNA in tumors, and the relationship between these two markers and BCC. In contrast to SCC, there is no association between HPV and BCC.
Ultraviolet (UV) radiation is the most important risk factor for non-melanoma skin cancers (NMSC). However, in the last decade, evidence has implicated human papillomavirus (HPV) as a possible risk factor in their development. Ascertaining the role of cutaneous HPV infection in NMSC is important, especially as certain genera of HPV are believed to augment UV radiation-induced DNA damage (Arron et al., 2011).
HPV is a DNA virus that replicates exclusively in keratinocytes and relies on the differentiation of keratinocytes to complete its life cycle (Aldabagh et al., 2012). There are over 180 types of HPV, which have specific tropism for cutaneous or mucosal epithelium, and belong to one of five genera- alpha, beta, gamma, mu or nu. The association between high-risk alpha-HPV and cervical cancer and the mechanism for viral transformation have been well established, but associations reported between HPV and NMSC are inconsistent.
In this issue, Iannacone et al. address the question of whether HPV is associated with development of basal cell carcinoma (BCC). They evaluated circulating antiviral antibodies and lesional HPV DNA, and determine that there is no association between this virus and BCC.
Several groups have reported the presence of HPV DNA in lesional tissue and antibody seropositivity to cutaneous HPV, especially beta-types, in patients with squamous cell carcinoma (SCC) (Aldabagh et al., 2012; Bouwes Bavinck et al., 2010). Both HPV carriage and SCC, but not BCC, are increased in immunosuppressed individuals, suggesting an etiologic role for this virus in SCC. At present, there are only a few studies and some conflicting on the role of HPV in BCC.
No study to date has found a significant association between seropositivity to any genus-beta type and BCC (Andersson et al., 2008; Feltkamp et al., 2003; Karagas et al., 2010); two studies failed to show an association with genus-alpha seropositivity as well (Andersson et al., 2012; Andersson et al., 2008). One report found that patients with BCC had lower seroprevalence than controls with benign skin diagnoses, which was postulated to be due to the inability of patients with BCC to mount an adequate HPV antibody response (Andersson et al., 2008). To date only two studies have reported findings on the association between BCC and seroreactivity to cutaneous HPV in genera other than the beta-genus (Andersson et al., 2012; Andersson et al., 2008).
In this issue, Iannacone et al. investigate the association between BCC and HPV in a US population, using a clinic-based case-control study of 224 immunocompetent patients with BCC and 300 controls. They report the seroprevalence of antibodies to cutaneous papillomaviridae from all five genera of HPV and the presence of lesional viral DNA in a subset of tumors. However, there was no analysis of viral DNA from tissue in control subjects for comparison. Serum antibodies investigated by Iannacone et al. include those against cutaneous alpha types 2, 3, 7, 10, 27, 57, and 77; beta types 5, 8, 9, 15, 17, 20, 23, 24, 36, 38, 49, 75, 76, 92, 96 and 107; gamma types 4, 48, 50, 65, 88, 95, 101, and 103; mu type 1 and nu type 41. The authors detected viral DNA in lesional tissue from of beta types 5, 8, 9, 12, 14, 15, 17, 19, 20, 21, 22, 23, 24, 25, 36, 37, 38, 47, 49, 75, 76, 80, 92, 93 and 96, gamma types 4, 65, 95, 60, 48, 50, 88, 101, 103, 108, 109, 112, 116, 119, 121, 123, alpha types 2, 3, 10, 27, 57, mu type 1. These broad and comprehensive assays have been used previously and are a key strength of this study.
They found that BCC was associated with antibodies to genus-gamma, but there were no type specific associations for this genus. In patients with epidermodysplasia verruciformis, beta-HPV 5 and 8 are high-risk types for SCC, which makes these particular types of interest for SCC in the general population. In contrast to SCC, no HPV types have been consistently observed to predominate in BCC (Andersson et al., 2012; Feltkamp et al., 2003) suggesting that the presence of serum antibodies to HPV in patients with BCC may be incidental. Indeed, patients without a history of NMSC can also be seropositive to cutaneous HPV (Casabonne et al., 2007).
Beta-genus DNA has been detected in BCC tumors in immunocompetent individuals in varying amounts (Andersson et al., 2008; Forslund et al., 2004). Iannacone et al. found that 50% of BCC tumors were positive for genus-beta HPV DNA and only 8.4% of tumors were genus-gamma DNA positive. The authors further explored the concordance between serum antibodies to genus alpha, beta and gamma HPV and viral DNA within BCC tumor tissue. Only a few previous studies have compared lesional HPV DNA and serology (Andersson et al., 2012; Andersson et al., 2008), with the majority comparing HPV DNA from plucked eyebrow hairs as opposed to tumor tissue (Aldabagh et al., 2012; Bouwes Bavinck et al., 2010). There was greater seroprevalence associated with HPV DNA positive tumors in genus-beta, greater seropositivity regardless of tumor HPV-DNA status in genus-alpha, and, surprisingly greater seropositivity with HPV DNA negative tumors in genus-gamma. However, the small sample size (n=17) of patients with genus-gamma DNA-positive BCCs makes it difficult to draw conclusions in this group. The authors note that since there is no information at present on the functionality of genus-gamma HPV types, there is no clear explanation for the observed inverse relationship between seropositivity and HPV DNA-negative tumors in their study.
In agreement with previous groups (Andersson et al., 2008), the study by Iannacone et al confirms the inaccuracy of serology as a predictor of lesional viral DNA with less than 37% of HPV DNA positive tumors testing seropositive for the same HPV type. The difficulty in interpreting serology is probably due to the fact that the natural history of cutaneous HPV infection and its antibody response is not yet well understood.
Hypotheses for lesion-antibody discordance include the possibility that the detected serum antibodies arose from past viral infections or infections at different sites (Andersson et al., 2008). It is possible that some HPV types may avoid detection by the host's immune system, or that the body does not mount an immune response to localized viral carriage in the epidermis. Comparing studies of associations between cutaneous HPV and BCC is a challenge, as the discrepancy in results may be attributed to the differences in the HPV genera and types investigated.
Exposure to UV radiation is believed to play a synergistic role with cutaneous HPV infection in the development of NMSC (Bouwes Bavinck et al., 2010). Cutaneous HPV types are predominantly found in sites extensively exposed to sun, in both lesions and healthy skin samples (Forslund et al., 2007). Some in vitro and in vivo studies have shown that E6 and E7 proteins from certain genus-beta HPV types can inhibit UV-induced cell cycle check points and DNA repair, inactivate p53 and lead to immortalization of cells (Aldabagh et al., 2012; Arron et al., 2011). These may be the mechanisms involved in SCC, in which genus-beta HPV is often found, but the evidence is lacking for BCC. Instead, BCCs seem to be largely explained by dysregulation of the Hedgehog pathway, with the possibility of cutaneous HPV being merely a superficial environmental contaminant of lesion specimens. Indeed, stripping the skin with tape prior to performing a biopsy commonly demonstrates HPV DNA in the superficial layers, but not necessarily throughout tumors (Forslund et al., 2004).
The significance of lesional HPV DNA and seropositivity to cutaneous HPV in patients with NMSC remains unclear, despite dozens of studies on the subject. Iannacone et al's study is the first to focus on BCC rather than SCC or NMSC overall, and suggests that HPV is not involved in BCC carcinogenesis. This stands in contrast to previous association of HPV and SCC. Why HPV may play a role in a neoplasm of squamous keratinocytes and not basal keratinocytes is unclear. Given the intimate association of the HPV life cycle with keratinocyte maturation, a reasonable hypothesis is that the biologic mechanisms favoring HPV proliferation also drive infected keratinocytes towards squamous, rather than basal cell carcinoma.
Given the inconsistent associations reported between HPV and BCC, even in well-designed large case-control studies such as Iannacone et al's, it is not clear how additional epidemiologic studies can elucidate this issue. Future research should be aimed at understanding the natural history of cutaneous HPV, including the antibody response to infection and the mechanism by which HPV transforms keratinocytes. In addition, future studies should extend analysis beyond the presence of viral DNA in tissue to assess viral gene or protein expression. Finally, researchers need to address the alternate hypothesis that HPV carriage on the skin is merely a reflection of local immune surveillance and not a specific oncoviral etiologic agent for NMSC.
STA is supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through UCSF-CTSI Grant Number KL2 TR000143.
JYT is supported by the Damon Runyon Clinical Investigator Award.