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Cutaneous Human Papillomaviruses Found in Sun-Exposed Skin: Beta-papillomavirus Species 2 Predominates in Squamous Cell Carcinoma

  1. Ola Forslund1,
  2. Thomas Iftner6,
  3. Kristin Andersson1,
  4. Bernt Lindelöf3,
  5. Eva Hradil2,
  6. Peter Nordin4,
  7. Bo Stenquist5,
  8. Reinhard Kirnbauer8,
  9. Joakim Dillner1,
  10. Ethel-Michele de Villiers4 and
  11. Viraskin Study Groupa
  1. 1Department of Medical Microbiology, Malmö University Hospital, Lund University, Malmö
  2. 2Department of Dermatology, Malmö University Hospital, Malmö
  3. 3Department of Dermatology, Karolinska University Hospital, Stockholm
  4. 4Dermatology Clinic, Läkarhuset
  5. 5Department of Dermatology, Sahlgrenska University Hospital, Gothenburg, Sweden
  6. 6Medical Virology, Section of Experimental Virology, University Hospital of Tübingen, Germany
  7. 7Division of Tumourvirus Characterization, Deutsches Krebsforschungszentrum Heidelberg, Germany
  8. 8Laboratory of Viral Oncology, Division of Immunology, Allergy and Infectious Diseases, Medical University Vienna, Austria
  1. Reprints or correspondence: Ola Forslund, Medical Microbiology, Entrance 78, UMAS, SE-20502 Malmö, Sweden (Ola.Forslund{at}med.lu.se).

  1. Presented in part: 23rd International Papillomavirus Conference, Prague, Czech Republic, 6 September 2006 [abstract PS 28-6].

 
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Abstract

Background. A spectrum of cutaneous human papillomaviruses (HPVs) is detectable in nonmelanoma skin cancers, as well as in healthy skin, but the significance that the presence of these types of HPV DNA has for the pathogenesis of skin cancer remains unclear.

Methods. We studied 349 nonimmunosuppressed patients with skin lesions (82 with squamous cell carcinomas, 126 with basal cell carcinomas, 49 with actinic keratoses, and 92 with benign lesions). After superficial skin had been removed by tape, paired biopsy samples—from the lesion and from healthy skin from the same patient—were tested for HPV DNA. Risk factors for HPV DNA were analyzed in multivariate models.

Results. Overall, 12% of healthy skin samples were positive for HPV DNA, compared with 26% of benign lesions, 22% of actinic keratoses, 18% of basal cell carcinomas, and 26% of squamous cell carcinomas. HPV DNA was associated with sites extensively exposed to the sun, both for the lesions (odds ratio [OR], 4.45 [95% confidence interval {CI}, 2.44–8.11]) and for the healthy skin samples (OR, 3.65 [95% CI 1.79–7.44]). HPV types of Betapapillomavirus species 2 predominate in squamous cell carcinomas (OR, 4.40 [95% CI, 1.92–10.06]), whereas HPV types of Beta-papillomavirus species 1 are primarily found in benign lesions (OR, 3.47 [95% CI, 1.72–6.99]).

Conclusions. Cutaneous HPV types are primarily detected at sites extensively exposed to the sun. HPV types of Beta-papillomavirus species 2, but not of species 1, are associated with squamous cell carcinoma.

Nonmelanoma skin cancers (NMSCs) are the most prevalent malignancies among white populations [1], with increasing prevalence in many European countries [2]. UV radiation is the major etiological factor in skin cancer [3], and genomes of the cutaneous human papillomaviruses (HPVs) are commonly detected in the tumors [4]. However, cutaneous HPV is also common in healthy human skin [5–12], and the pathological significance of these viruses is unclear.

Among genital HPV types, different genera and HPV types have clearly various carcinogenic potential [13]. Specific cutaneous HPV types have been associated with squamous cell carcinoma (SCC) of the skin of individuals with the rare hereditary disease Epidermodysplasia verruciformis (EV) [14], but such association has not been reported for SCC in the general population.

The cutaneous HPVs are classified into different genera, of which the genus Beta-papillomavirus contains 23 different fully characterized HPV types (previously designated “EV” types), the genus Gamma-papilloma-virus contains 7 fully characterized HPV types (HPV 4, 48, 50, 60, 65, 88, and 95), the genus Mu-papillomavirus contains 2 HPV types (HPV 1 and 63), and the genus Nu-papillomavirus contains HPV 41 [15]. The genus Beta-papillomavirus is further divided into 5 distinct species containing related HPV types (Beta-1, containing HPV 5, 8, 12, 14, 19, 20, 21, 24, 25, 36, 47, and 93; Beta-2, containing HPV 9, 15, 17, 22, 23, 37, 38, and 80; Beta-3, containing HPV 49, 75, and 76; Beta-4, containing HPV92; and Beta-5, containing HPV 96) [15].

The possibility exists that viruses shed from infected skin might be trapped on the surface of skin tumors, resulting in HPV-positive tumor samples, although the viral DNA is not present in the tumor itself. Indeed, simple stripping of the skin surface by tape greatly reduces the proportion of tumors that test positive for HPV DNA [16]. If HPV infection is of direct etiological relevance, the virus should presumably be present not only on top of the tumor but also within the tumor. No case-control study using tape-stripped lesions has thus far been reported that would allow assessment of risk factors for HPV DNA inside the lesions. To obtain consistent evidence regarding risk factors for HPV infection in benign and malignant tapestripped lesions, we performed a hospital-based case-control study in which 3 independent laboratories identified the presence of HPV DNA by cloning and sequencing of polymerase chain reaction (PCR)-generated amplicons.

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Patients, Materials, and Methods

Patients

The present study was designed as a hospital-based case-control study of NMSCs and premalignant and benign skin lesions. The study base was defined as patients seeking medical care at participating dermatology clinics, where surgical removal of a skin lesion was medically indicated and the patients gave informed consent to participate. In total, 365 patients were enrolled; 16 of them subsequently were excluded on the basis of a follow-up review of the study file. The exclusion criteria were decided by the entire study group and without prior knowledge of any HPV DNA results. Restriction of the study to immunocompetent patients accounted for 3 of the 16 patients excluded, and restriction to nongenital lesions accounted for 1 of the 16 patients excluded; 5 patients were excluded because they had disease that did not meet case definitions (3 had melanomas, 1 had fungal infection, and 1 had 2 different tumors that belonged to different case groups); and 7 patients were excluded because their tumors had inadvertently not been tape-stripped before a biopsy was performed.

The remaining 349 immunocompetent patients had attended dermatology clinics in either Sweden (Stockholm, 148 patients; Gothenburg, 91 patients; and Malmö, 102 patients) or Austria (8 patients). Cases of SCC (n = 82; mean age, 80 years [range, 50–94 years]) and of basal cell carcinoma (BCC) (n = 126; mean age, 75 years [range, 34–93 years]) were confirmed histologically. There were 49 patients with actinic keratoses (AKs) (mean age, 74 years [range, 53–95 years]) and 92 with benign lesions (mean age, 71 years [range, 29–94 years]) consisting of seborrhoeic keratoses (SKs) (n = 48; mean age, 75 years [range, 48–89 years]) and other benign lesions (n = 44; mean age, 70 years [range, 29–94 years]) (benign epidermal dysplasia, 1 case; unspecified benign lesion, 1 case; benign squamous papilloma, 1 case; epidermoid cyst, 1 case; fibroma, 2 cases; inflammatory lesion, 1 case; keratoacanthoma, 7 cases; neurofibroma, 1 case; nevus, 7 cases; no tumor/healthy skin, 3 cases; pilaracanthoma, 1 case; scar tissue, 6 cases; skin tag, 1 case; verruca, 1 case; verruca seborrhoica, 4 cases; verruca vulgaris, 1 case; trichoepithelioma, 1 case; and acrotrichoma, 1 case); in the benignlesion group we also included 1 case each of cornu cutaneum, squamous atypia, and squamous dysplasia.

The study adhered to the Declaration of Helsinki and was approved by the Ethical Review Committees of Karolinska Institute and of Lund University (Sweden) and of Medical University Vienna (Austria).

Collection of Samples and Data

Each patient donated both a biopsy sample from the lesion and a control biopsy sample from healthy skin, the latter of which typically was collected 10–15 cm from the lesion, at sites such as the neck, the shoulder, the back, or proximally to the ear. Before 2-mm punch-biopsy samples were taken, the skin was anesthetized (without ethanol cleaning ) and stripped with tape (article 1527-1, Transpore; 3M Health Care) that was attached 5 times, and a new piece of tape was attached for another 5 times [16]. The remaining tumor was excised and sent for histopathological diagnosis. In most cases, AKs, SKs, and other benign lesions were diagnosed only clinically. Patients were interviewed by use of a standardized questionnaire inquiring about skin type (I–IV, according to the Fitzpatrick classification [17]), history of sunburns, hair color, history of profession, eye color, smoking habits, history of skin cancer, and family history of skin cancer. The level of sun exposure at the site of biopsy was classified, by a single dermatologist (B.L.), as being in 1 of 3 categories based on anatomical site: extensive (i.e., head and neck, dorsal side of the hands), moderate (i.e., trunk and extremities), or low (i.e., buttocks and genital area). For 18% (63/349) of the patients, the paired biopsy samples were taken from sites with different sun-exposure classification.

Analysis of HPV DNA

Adequacy of sample. DNA was extracted from all samples by a simple phenol-free method, in a single laboratory [18]. The adequacy of the sample was tested by PCR amplification of the human β-globin gene [16]. If the result was negative (3.7% [26/698] of the samples), the β-globin PCR was repeated after ethanol precipitation; if the sample remained negative (0.5% [4/698] of the samples), the DNA was column purified (QIAmp Min Elute Media Kit; Qiagene) and retested, resulting in all samples being β-globin positive.

Testing. For maximum reliability and sensitivity of analysis, in the effort to detect as many infections as possible, 3 different experienced laboratories applied their routinely used HPV-detection method. The data were pooled for maximum sensitivity, and all positive samples were verified by cloning and sequencing, for maximum specificity.

In the 3 laboratories, aliquots of each sample were tested for the presence of HPV DNA by use of PCR amplification with degenerate primers described as being able to amplify all known and new putative HPV types. Laboratory 1 used both a singleround PCR with FAP primers [18] and single tube-nested “hanging droplet” FAP PCR [19], whereas laboratory 3 used single tube-nested “hanging droplet” FAP PCR only [19]; laboratory 2 used a single-round FAP-PCR [18], a 2-step version of the nested FAP-PCR [19], a single-round PCR with CP primers, and a nested CP-PCR [20] with modified PCR conditions [21]. PCR amplicons were cloned and sequenced. A least 10 clones per sample were sequenced by laboratory 2, and 3 clones per sample were sequenced by laboratories 1 and 3.

A sample was scored as being positive for HPV DNA if (1) the sequences adequately aligned (i.e., harbored the conserved regions defining HPV) to known HPV sequences in the GenBank database when Blast searches were performed (http://www.ncbi.nlm.nih.gov/BLAST/) and (2) the identical HPV type/putative type was detected in at least 2 of the 3 laboratories; by these criteria, 31% (219/698) of the samples were positive for any HPV type, and 17% (120/698) of them were positive for identical HPV type(s).

An isolate was classified as being a known HPV type if its sequence homology to the known HPV type was >90% and as being a putative type if such similarity was <90%. For categorization of the new putative types into genera and species of the family Papillomaviridae, phylogenetic trees were constructed by use of ClustalW, in BioEdit [22], and Molecular Evolutionary Genetics Analysis (MEGA), version 2.1 [23].

The necessary precautions to avoid contamination between samples were observed during all levels of sample handling, and, in each batch of HPV tests, water samples without DNA were included as negative controls.

Statistical Analysis

Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by use of multivariate logistic regression models in LogXact (version 6; Cytel Software Corporation). Results for which the 95% CI excluded unity were considered to be significant.

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Results

A total of 42 different HPV types/putative types were identified, of which 37 were classified as belonging to the genus Betapapillomavirus, 3 to the genus Gamma-papillomavirus, and 2 to the genus Alpha-papillomavirus, harboring mainly the genital HPV types (table 1). The most frequently detected types were HPV20 (18 samples) and HPV21 (11 samples) in genus Beta-papillomavirus species 1 and HPV38 (10 samples) in genus Beta-papillomavirus species 2 (table 1). Overall, 12.0% of healthy skin samples were positive for HPV DNA, compared with 26.1% of benign lesions, 22.5% of AKs, 17.5% of BCCs, and 25.6% of SCCs (table 2).

Table 1
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Table 1

Frequency of 42 human papillomavirus (HPV) types/putative types in lesions and in healthy skin biopsy samples.

Table 2
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Table 2

Risk factors for cutaneous human papillomavirus (HPV).

In multivariate models, the presence of HPV DNA was associated with skin sites classified as having been extensively exposed to the sun (OR 4.28 [95% CI, 2.67–6.85]) (table 2). This applied to both the site of the lesion (OR, 4.45 [95% CI, 2.44–8.11]) and the site of the healthy skin sample (OR, 3.65 [95% CI, 1.79–7.44]), after adjustment for age, sex, skin type, sunburns, and eye color. SCCs and benign lesions were more commonly positive for HPV DNA than were healthy skin samples (OR, 2.13 [95% CI, 1.13–4.03] for SCCs; OR, 3.12 [95% CI, 1.69–5.75] for benign lesions) (table 2). HPV types of genus Beta-papillomavirus species 2 were more common in SCCs than in healthy skin samples (OR, 4.40 [95% CI, 1.92–10.06]), whereas HPV types of genus Beta-papillomavirus species 1 were more common in benign lesions than in healthy skin samples (OR, 3.47 [95% CI, 1.72–6.99]) (table 3).

Table 3
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Table 3

Diagnosis associated with human papillomavirus (HPV) of Beta-papillomavirus species 1 or 2.

Pairwise comparisons of lesions and healthy skin samples from the same patients found that HPV types, in particular of genus Beta-papillomavirus species 1, were more frequently detected in benign lesions than in the matched healthy skin samples (OR, 18.5 [95% CI, 3.1-∞]) (table 4). There was a tendency for HPV types of genus Beta-papillomavirus species 2 to associate with SCC and AK (table 4). Identical HPV types in the lesion and the healthy skin sample from the same patient were identified in only 2.3% (8/349) of the patients.

Table 4
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Table 4

Pairwise comparisons of human papillomavirus (HPV) DNA in lesions and in healthy skin biopsy samples.

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Discussion

The present study indicates that extensive sun exposure at the site of biopsy is the strongest risk factor for cutaneous HPV infection. Previous studies of the association between UV exposure and HPV had reported variable results, from finding no association [12] to increased prevalence of HPV on the forehead and other exposed sites than at sites that were less exposed to the sun [6, 24]. A possible explanation for the present study's finding of a strong association between HPV and UV exposure may lie in the fact that this is the first casecontrol study of cutaneous HPV that has used “stripping” to reduce surface contamination of HPV. Also, in the present study the paired biopsy samples from each patient were taken from the same region of the body, which enhanced the possibility to detect whether a local HPV infection was specifically associated with skin lesions. This regional matching did not impair the ability to detect association with UV exposure, because, for a substantial proportion of the patients, the paired biopsy samples were taken from sites with different sun-exposure classifications. In addition, minimum misclassification was assured by the requirement that, for a sample to be scored as being positive for HPV DNA, the same HPV type had to be detected by at least 2 of the 3 laboratories.

The increased prevalence of HPV at sun-exposed skin sites may result from amplification of the viral genome via UV light, as has been reported for bovine papillomavirus (BPV) DNA in BPV-transformed cells [25]. Furthermore, in vitro studies have demonstrated increased viral promoter activity after UV irradiation, for a number of cutaneous HPV types [26, 27], as well as decreased apoptosis after UV treatment of host cells containing single cutaneous HPV types [28]. Such decreased apoptosis might lead to the accumulation of UV-induced mutations—for example, p53 mutations, which have been found in >90% of SCCs [29].

It has been established that UV exposure can cause reactivation of herpes simplex virus [30] and that local UV-immunosuppressive effects appear to be involved in such reactivation [31]. Our preferential finding of HPV DNA in sun-exposed skin sites might also be related to local UV-immunosuppressive effects [32], which may have promoted somewhat increased copy numbers of HPV. It is also tempting to speculate that the high risk of SCC among renal transplant patients [33] might be due to increased activity of HPV at sun-exposed sites, in combination with local UV immunosuppression and immunosuppressive therapy.

However, our finding of a strong association between HPV and UV exposure, the major risk factor for SCC, raises the possibility that the association between HPV and SCC could be attributable to confounding via UV exposure. Because both the extent of UV exposure and HPV infection are difficult to determine, significant effects remaining after adjustment might be caused by residual confounding. Another possibility is that a carcinogenic effect of UV exposure is in part mediated via its effect on HPV: if HPV and UV exposure act on the same causal pathway, the inclusion of UV exposure in the model could risk removal of an etiological association. Interestingly, a recent serological study found a tendency for UV exposure to be a risk factor for SCC primarily in HPV-seropositive subjects [34].

Contrary to the results of a previous study of NMSCs [35], the present study detected only a single case of genital highrisk HPV (HPV16), which was present in an SCC from the perianal region, suggesting that genital HPV types are rare in skin disorders, which were the subject of the present study. The earlier study had used nonstripped skin samples, which might cause an increased rate of detection of genital HPV types if superficially trapped on lesions [35].

In the present study, no cutaneous high-risk HPV type could be identified. However, the group of phylogenetically related HPV types of genus Beta-papillomavirus species 2 was more associated with SCC than with healthy skin, in all patients (OR, 4.40 [95% CI, 1.92–10.06]), and a similar, albeit not significant, point estimate of association was observed for SCC samples compared with matched healthy skin samples from the same patient (OR, 5.84 [95% CI, 0.91–80.79]). Other studies have not stripped the skin surface before sampling, which may explain the differences in results [12, 35–37]; for example, HPV38, of genus Beta-papillomavirus species 2, has been reported to be much more prevalent in NMSCs (50%) than in healthy skin samples (10%) [38]; however, when biopsy samples from stripped skin were analyzed by highly sensitive type-specific PCR, HPV38 was found in only 3% of NMSCs and in 1% of healthy skin samples [39].

Overall, the present study's finding of a strong association between HPV and sun exposure, in combination with the fact that the point estimate of the association between genus Beta-papillomavirus species 2 and SCC was reduced after adjustment for sun exposure, implies that this association must be interpreted with caution. Much larger studies with strong epidemiological study designs, such as prospective cohort studies, would be necessary to allow inferences as to any possible causal role. However, the results of the present study suggest that a specific group of cutaneous HPV types (i.e., Beta-2) are an important risk factor in the etiology of SCC; in vitro studies are necessary to validate this observation.

The increased prevalence, among the benign lesions (most of which were SKs), of HPV of genus Beta-papillomavirus species 1 might be due to morphological features resulting in less efficient tape-stripping of superficially occurring HPV. The data of the present study are in line with those of a previous study that reported that HPV20 of genus Beta-papillomavirus species 1 was the predominating type in both SKs and healthy skin samples [40].

Quantitative real-time PCR, performed for a limited number of HPV types (i.e., HPV38, 92, 93, and 96) in the present study, found only very low viral copy numbers (range, 1 copy/50 cells-1 copy/70,000 cells) [39, 41]. Low copy numbers of HPV DNA in AKs and malignant skin lesions is a consistent finding in other studies also [24, 42]. The present study has not explored the issue of whether the presence of low amounts of HPV DNA is attributable to remaining superficial HPV or implies that HPV DNA is not required for maintenance of the malignant phenotype. The latter possibility is supported by the fact that HPV DNA is not detectable after in vitro passages of cutaneous SCCs, which suggests that HPV DNA is not required for maintenance of the malignant phenotype in every carcinoma cell [43, 44].

In conclusion, we find that reproducibly detectable cutaneous HPV is strongly associated with extensive sun exposure at the biopsy site and that different species of genus Beta-papillomaviruses tend to have different associations with malignant versus benign skin lesions. Therefore, it will be essential to consider both sun exposure and HPV species in future epidemiological studies of the etiology of SCC.

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Viraskin Study Group

Members of the Viraskin Study Group are as follows: Katharina Slupetzky (Laboratory of Viral Oncology, Division of Immunology, Allergy and Infectious Diseases, Medical University of Vienna, Vienna, Austria), Angelika Iftner (Medical Virology, Section Experimental Virology, University Hospital of Tübingen, Tübingen, Germany), Sonja Stephan and Corinna Whitley (Division of Tumourvirus Characterization, Deutsches Krebsforschungszentrum, Heidelberg, Germany), and Christina Gerrouda (Department of Medical Microbiology, Malmö University Hospital, Lund University, Malmö, Sweden).

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Acknowledgments

We thank Anna Kristoffersson for laboratory assistance and Pontus Naucler for statistical-analysis assistance.

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Footnotes

  • ↵a Study group members are listed after the text.

  • Potential conflicts of interest: none reported.

  • Financial support: European Commission (grant “Viraskin” QLK2-CT-2002-01500); Swedish Research Council; Swedish Cancer Society.

  • Received February 1, 2007.
  • Accepted April 3, 2007.
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  1. J Infect Dis. (2007) 196 (6): 876-883. doi: 10.1086/521031
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