Elsemieke I. Plasmeijer

β-Papillomavirus Infection and Skin Cancer

The development of highly sensitive PCR techniques and multiplex bead-based Luminex platforms has accelerated the search for a specific role of human papilloma viruses in the development of squamous cell carcinoma. Human papillomaviruses are most likely indirectly involved in this process by facilitating UV-related carcinogenesis via preventing UV-induced apoptosis or impairing DNA repair, but other mechanisms are also possible.

Persistence of Betapapillomavirus Infections as a Risk Factor for Actinic Keratoses, Precursor to Cutaneous Squamous Cell Carcinoma

Human papillomaviruses from the beta genus (betaPV) are a possible cause of cutaneous squamous cell carcinoma (SCC). We assessed the extent to which betaPV infections persisted long-term in a subtropical Australian community and whether betaPV persistence is positively associated with actinic keratoses, precursor for SCC. Eyebrow hairs were collected from 171 participants of the community-based Nambour Skin Cancer Study in 1996 and 2003. Hair samples were tested for the presence of DNA from 25 different betaPV types and assessed in relation to actinic keratosis presence in 2007. In 1996, a total of 413 betaPV infections were found in 73% of participants, increasing to 490 infections among 85% in 2003. Of the total betaPV infections detected, 211 (30%) were found to persist. Age was significantly associated with betaPV persistence: those ages >60 years had 1.5-fold (95% confidence interval, 1.1-1.9) increased risk of type-specific viral persistence than those ages <40 years. After accounting for actinic keratoses at baseline, persistence of betaPV DNA resulted in a 1.4-fold (95% confidence interval, 1.0-1.9) increase in risk of having actinic keratoses on the face in 2007. In conclusion, persistent betaPV infections in this population were associated with an increased occurrence of actinic keratosis. Additional studies are needed to determine the possible association of betaPV persistence with SCC.

Betapapillomavirus infection profiles in tissue sets from cutaneous squamous cell-carcinoma patients

Human papillomaviruses from the genus beta (betaPV) are a possible cause of cutaneous squamous cell carcinoma (SCC). We compared the betaPV infections in SCC and in sets of cutaneous tissues collected from a series of individual SCC patients to determine concordance and to assess the adequacy of eyebrow hairs as noninvasive markers of betaPV infection. Biopsies of SCC tumors, perilesional tissue, normal skin from the mirror image of nonfacial SCC and plucked eyebrow hairs were collected from 21 patients with incident SCC living in Queensland, Australia. These were tested for the presence of DNA from 25 different betaPV types. Overall prevalence of betaPV was high in every sample type, ranging from 81% to 95%. The median number of types was significantly higher in the SCC tumour (6), perilesional skin (5) and eyebrow hairs (5) than in normal skin (2). Comparing SCC tissue with other sample types within patients showed 63 overlapping infections with eyebrow hairs (71%; 95% CI: 60–80); 56 with perilesional skin samples (63%; 95% CI: 52–73) and 23 with normal skin samples (26%; 95% CI: 17–36). The sensitivity of eyebrow hair testing for detection of betaPV in the tumor was 82% (95% CI: 57–96) with concordance defined as 50% of betaPV types in common and 29% (95% CI: 10–56) for 100% concordance. These findings support the concept that perilesional skin represents an area of field change involving betaPV preceding SCC development and indicate that eyebrow hairs can serve to some degree as an easily collected marker of tumor betaPV status in epidemiological studies.

The Presence of Betapapillomavirus Antibodies around Transplantation Predicts the Development of Keratinocyte Carcinoma in Organ Transplant Recipients: A Cohort Study

Organ transplant recipients (OTRs) have an increased risk of developing keratinocyte carcinomas (KCs). The aim of this study was to correlate infection with human papillomaviruses (HPVs) belonging to the beta genus (Beta-papillomavirus (Beta-PV)) at transplantation with later development of KCs. In a cohort study, sera collected between 1 year before and 1 year after transplantation of OTRs transplanted between 1990 and 2006 were tested for antibody responses against the L1 capsid antigen of Beta-PV and other HPV genera (Gamma-, Mu-, Nu-, and Alpha-PV) using multiplex serology. The OTRs were followed for a maximum of 22 years. Cox regression models with KC, squamous cell carcinoma (SCC), and basal cell carcinoma (BCC) as outcome variables were used. Out of 445 OTRs, 60 had developed KC: 14 developed only SCC, 24 only BCC, and 22 both types of KC. The time-dependent hazard ratio (HR) to develop either or both types of KC, adjusted for age, sex, and transplanted organ, in tested Beta-PV-seropositive OTR around the time of transplantation compared with Beta-PV-seronegative OTR was 2.9 (95% confidence interval (CI) 1.3-6.4). The HR for SCC was 2.9 (95% CI 0.99-8.5) and for BCC it was 3.1 (95% CI 1.2-8.0). There was also an association between Mu-PV seropositivity and KC, but there were no significant associations between other HPV genera tested and KC. A positive seroresponse for Beta-PV around transplantation significantly predicted the development of KC in OTRs up to 22 years later, providing additional evidence that infection with Beta-PV has a role in KC carcinogenesis.

The association between cutaneous squamous cell carcinoma and betapapillomavirus seropositivity: a cohort study

Background: It is currently unclear whether betapapillomaviruses (betaPV) play a role in the etiology of cutaneous squamous cell carcinoma (SCC). We investigated the association between betaPV antibodies and subsequent SCC in a population-based cohort study. Methods: Serum samples were collected in 1992 and/or 1996 from 1,311 participants of the community-based Nambour Skin Cancer Study. These were tested for the presence of L1 antibodies against 21 different betaPV types. Histologically diagnosed SCCs were ascertained through three full-body skin examinations and linkage with the local pathology laboratories. We used age- and sex-adjusted Cox proportional hazards models to analyze the relationship between betaPV antibodies and SCC occurrence from 1992 until 2007. Results: SCC was newly diagnosed in 150 people. No associations were found between the presence of any betaPV L1 antibodies and the occurrence of SCC (HR = 1.0), and stratification by sex, skin color, and sunburn propensity did not affect these results. However, among people who were less than 50 years old in 1992, the presence of betaPV antibodies was associated with a two-fold increased risk of SCC. There was no significant association between antibodies to any individual betaPV type examined and the later development of SCC. Conclusions: Whether betaPV infection of the skin, and indirectly betaPV antibodies, are involved in the oncogenic process in the general population remains unclear, and this longitudinal study provides only limited support. Impact: This study emphasizes the need for additional longitudinal studies of HPV (human papilloma virus) and SCC, to avoid the possibility of reverse causality in case–control studies. Cancer Epidemiol Biomarkers Prev; 20(6); 1171–7. ©2011 AACR.

Pain Identifies Squamous Cell Carcinoma in Organ Transplant Recipients: The SCOPE-ITSCC PAIN Study

Organ transplant recipients (OTR) are at high risk for cutaneous squamous cell carcinomas (SCC). We aimed to define clinically meaningful patient‐reported warning signals predicting the presence of invasive SCC. Patient‐reported signs and symptoms of 812 consecutively biopsied skin lesions from 410 OTR were determined by questionnaire and physical examination and related to the subsequent biopsy‐proven diagnoses. Receiver‐operating characteristic (ROC) curve analyses were used as a measure of distinction between the predictive values of patient‐reported warning signals and the occurrence of SCC. Pain was an independent predictive patient‐reported warning signal for a biopsy‐proven invasive SCC. The odds ratio from the fully adjusted model predicting SCC was 4.4 (95% confidence interval: 2.4–8.2). Higher scores on the visual analog scale (VAS) for pain were associated with a greater likelihood for the presence of SCC compared to none or mild pain. The for scores on the VAS from 1 to 3, 4 to 6 and 7 to 10 were 4.9 (2.2–10.5), 2.3 (0.96–5.5) and 16.5 (3.6–75.8), respectively. Pain is the most powerful patient‐reported warning signal for invasive cutaneous SCC in OTR. Empowerment of patients by education could accelerate diagnosis and treatment of cutaneous SCC.

Lack of association between the presence and persistence of betapapillomavirus DNA in eyebrow hairs and betapapillomavirus L1 antibodies in serum

Betapapillomavirus (betaPV) DNA and seroresponses are highly prevalent in the general population and both are frequently used as infection markers in epidemiological studies to elucidate an association with cutaneous squamous cell carcinoma (SCC). Little is known about the natural history of betaPV infection and the aspects of infection that drive antibody responses. To investigate the relationship between these markers, this study assessed whether the presence or persistence of betaPV DNA in eyebrow hairs and L1 antibodies of the same betaPV type co-occurred more frequently than would be expected by chance in both a cross-sectional assessment and a longitudinal study. betaPV DNA in plucked eyebrow hairs and L1 antibodies in serum were measured in 416 participants of the Australian community-based Nambour Skin Cancer Study in 1996. Similar data were available for a subset of 148 participants in 2003. Observed co-occurrence of betaPV DNA and antibodies was compared with expected values based on prevalence. A case-wise concordance index was used to calculate the overall concordance of betaPV DNA and antibodies of the same type. No significant associations were found between the presence or persistence of betaPV DNA and antibody responses. The age and sex of the host did not influence the association, and nor did SCC status or a history of sunburns. It was concluded that betaPV antibody responses in adults are not primarily driven by betaPV infection as measured in eyebrow hairs. Other factors, such as viral load, may play a more pivotal role in the induction of detectable seroresponses.

Skin Cancer Arising in Scars: A Systematic Review

BACKGROUND Despite numerous case reports, epidemiologic evidence regarding true rate of skin cancer in scars of any etiology is sparse. METHODS Systematic literature review of all published epidemiologic studies on skin cancer in scar tissue from surgery, ulcers, or burns using citation databases and manual review. RESULTS There were no epidemiologic data to quantify risk of skin cancer in surgical scars or chronic ulcers. Two eligible cohort studies were identified, from Denmark and Sweden, in which skin cancers in 16, 903 and 37,095 burn patients, respectively, were ascertained through cancer registry follow‐up. Each reported standardized incidence ratios (SIRs) for skin cancer types on any site that were uniformly less than unity compared with the general population. Only the Danish cohort assessed skin cancers specifically on past burn injury sites and found a burn‐site‐specific SIR of 1.2 (95% confidence interval (CI)=0.4–2.7) for squamous cell carcinoma (SCC), 0.7 (95% CI=0.4–1.1) for basal cell carcinoma, and 0.3 (95% CI=0.0–1.2) for melanoma. CONCLUSIONS Available epidemiologic data suggest that burn patients are not at higher risk of skin cancers in general, although a modest excess of SCC in burn scars cannot be excluded, nor can excess risk with longer follow‐up. Risk of skin cancer in scars other than burn scars has not been investigated epidemiologically. Renovo, Ltd., UK provided funding for this study. A. Green has been a consultant for Renovo Ltd.

Transmission of betapapillomaviruses between domestic partners in an Australian community.

BACKGROUND Betapapillomaviruses may be associated with the development of cutaneous squamous cell carcinoma but little is known about their transmission. One suggestion is that they are transmitted through close skin contact. OBJECTIVES To test this hypothesis we assessed whether co-habiting opposite-sex couples were more or less likely to share betaPV types than each member of the couple and an age-matched, opposite-sex control. STUDY DESIGN Betapapillomavirus was measured in eyebrow hairs of 57 couples and 114 age- and sex-matched controls. We compared the proportion of partners who shared at least one betaPV type with the proportion of control partnerships sharing a betaPV type. We further subdivided those who shared at least one type into those who shared only one and those who shared more than one. We tested the significance of differences in these proportions using Chi-squared tests. A case-wise concordance index was used to calculate the overall concordance of the partners and the control pairings. RESULTS At least one betaPV type was shared by 39% of the co-habiting couples and 26% of the control pairs (p=0.10). When restricted to all people with at least one virus infection (26 couples) 74% of the partners and 46% of the control pairs shared at least one type (p=0.02). The case-wise concordance index for partners was 0.28 (95% CI 0.21-0.35) and for the matched control pairs 0.16 (95% CI 0.12-0.20) (p<0.001). CONCLUSIONS Our results support the hypothesis that skin-to-skin contact is the primary means of betapapillomavirus transmission.

Risk Factors and Clinical Outcomes in Patients with IBD with Melanoma

Background: Patients with inflammatory bowel disease (IBD) are at increased risk to develop malignant melanoma and this risk may increase with use of anti-tumor necrosis factor (TNF) therapy. Impaired survival of immunosuppressed melanoma patients is reported in transplant and rheumatology patients. This study aims to (1) identify risk factors for melanoma development in patients with IBD, (2) compare clinical characteristics of melanoma in patients with IBD to the general population, and (3) assess the influence of immunosuppressive medication on survival. Methods: We retrospectively searched the Dutch Pathology Database to identify all Dutch patients with IBD with cutaneous melanoma between January 1991 and December 2011. We then performed 2 case–control studies. To identify risk factors for melanoma development in IBD, we compared patients with IBD with melanoma to the general IBD population. To compare outcome and survival after melanoma diagnosis, we compared cases with non-IBD melanoma patients. Results: We included 304 patients with IBD with melanoma, 1800 IBD controls, and 8177 melanoma controls. IBD cases had more extensive IBD (ulcerative colitis: pancolitis: cases 44.5% versus IBD controls without melanoma 28.1%; P < 0.01; Crohns disease: ileal and colonic disease: cases 57.9% versus controls 48.9%; P = 0.02). Despite a lower Nodes (N)-stage in patients with IBD (N1+ 8.3% versus 18.2%; P < 0.01) with comparable Tumor (T) and Metastasis (M) stages, survival was similar between groups, regardless of immunosuppressive or anti-TNF therapy. Conclusions: This study showed that IBD extent is a risk factor for melanoma development. Despite the lower N-stage in patients with IBD, we could not confirm impaired survival after melanoma in patients with IBD, regardless of anti-TNF and/or thiopurine use.