Viral DNA detection and RAS mutations in actinic keratosis and nonmelanoma skin cancers

Background Actinic keratosis (AK) is a well‐established precancerous skin lesion that has the potential to progress to squamous cell carcinoma (SCC). Basal cell carcinoma (BCC) is a locally aggressive slowly growing tumour that rarely metastasizes. A number of viruses have been proposed to play a role in the development of nonmelanoma skin cancers (NMSC), but the most plausible evidence to date suggests that cutaneous human papillomavirus (HPV) is the key instigating factor. Objectives To evaluate the prevalence of HPV, cytomegalovirus (CMV), herpes simplex virus (HSV) and Epstein–Barr virus (EBV) and investigate their relationship with the presence of RAS gene mutations in cutaneous lesions obtained from nonimmunosuppressed patients. Methods HPV, CMV, HSV and EBV detection was performed using polymerase chain reaction (PCR) in skin biopsies (26 AK, 12 SCC and 15 BCC samples) that were collected from immunocompetent patients. The RAS mutation incidence was also investigated in all cutaneous lesions by use of PCR/restriction fragment length polymorphism and direct DNA sequencing. Results Seventeen out of 53 (32%) skin lesions were found to be positive for HPV DNA. The highest incidences of HPV infection were five of 15 (33%) in BCC and four of 12 (33%) in SCC specimens. The HPV incidence was eight of 26 (31%) in AK and eight of 53 (15%) in normal skin tissue. Twelve out of 53 (23%) skin lesions were CMV‐positive. The highest incidence of CMV infection was six of 15 (40%), observed in BCC specimens. The CMV incidence was two of 26 (8%) in AK and four of 12 (33%) in SCC. No normal skin biopsy was found to be positive for CMV. All cutaneous samples were negative for HSV and EBV DNA, as assessed by our PCR‐based assays. Only three samples, one AK (4%), one BCC (6%) and one SCC (8%), were found to carry a G>T transversion at the second position of HRAS codon 12. Both HRAS mutant SCC and BCC biopsies were HPV‐ and CMV‐positive, as well. Conclusions HPV DNA is detected in NMSC, AK and normal skin biopsies. Our results also indicate that CMV is involved in NMSC at higher levels than in premalignant lesions, whereas the virus was not detected in normal skin biopsies. HSV and EBV do not appear to be involved in the pathogenesis of cutaneous lesions. Moreover, we suggest that the HRAS codon 12 mutation is not a very common event in AK or NMSC. Finally, both viral infection and HRAS activation appear to represent independent factors in the aetiology of NMSC, samples of which were obtained from immunocompetent patients.     

A broad spectrum of human papillomavirus types is present in the skin of Australian patients with non-melanoma skin cancers and solar keratosis

BACKGROUND: Human papillomavirus (HPV) may play a role in the pathogenesis of non-melanoma skin cancer (NMSC) in epidermodysplasia verruciformis (EV) patients, but in the general population no specific HPV types have been associated with these lesions. Objectives To examine the spectrum of HPV types present in the skin and tumours of Australian patients with NMSC or solar keratosis (SK). METHODS: Biopsies from tumours, and cotton swab samples of perilesional skin and buttock skin from each of 59 Australian patients with basal cell carcinoma (BCC), squamous cell carcinoma (SCC) or SK were tested for HPV DNA by polymerase chain reaction (PCR) using HPV consensus (FAP) primers and by type-specific primers for HPV 38 and candidate HPV 92. The identification of HPV type from consensus PCR was performed by sequencing and comparison with GenBank. RESULTS: In total, 49 of 59 (83%) patients harboured HPV DNA, which was detected in 28 of 64 (44%) biopsies, 48 of 64 (75%; P < 0.001) perilesional swabs and 36 of 59 (61%; P = 0.04) buttock swabs. Forty-five different HPV types/putative types were detected: 15 were previously characterized HPV types, 17 were earlier described putative types and 13 were new putative types. In addition, six subtypes and four variants of HPV sequences were identified. HPV types within the B1 group (EV HPV types) were found in 26 of 64 (40%) lesions, 44 of 64 (69%) perilesional swabs and 35 of 59 (59%) buttock swabs. HPV 38 was detected in 23 of 59 (39%) patients, and was found in seven of 16 (43%) SKs, but was less common in SCCs [three of 23 (13%); P = 0.037] and BCCs [four of 25 (16%); P = 0.056]. Candidate HPV 92 was found in seven of 59 (12%) patients. CONCLUSIONS: A broad spectrum of HPV types, the majority from the B1 group, was found in skin of Australian patients with skin tumours. HPV 38 was found significantly more often in SK than in SCC. However, the role of cutaneous HPV infection in the pathogenesis of NMSC remains elusive.     

HPV und Neoplasien der Haut

Human papillomaviruses (HPV) induce benign and malignant tumors of skin and mucosa. Non-melanoma skin cancer (NMSC) is the most frequent malignancy in fair-skinned populations, particularly frequent in countries with high sun exposure and in immunosuppressed patients. The high prevalence of Beta-HPV in skin tumors renewed interest in a possible etiologic role of HPV. In contrast to cervical cancer, the presence of HPV is probably not mandatory for maintenance of the malignant phenotype of skin cancer cells, since only low copy numbers of HPV DNA persist in skin cancers. Higher viral loads in actinic keratoses are compatible with a carcinogenic role of cutaneous HPV in early phases of NMSC development. There is some evidence from case-control studies for an increased risk of cutaneous squamous cell carcinoma related to beta-HPV infection. HPV8 is clearly carcinogenic in transgenic mice. At the molecular level, oncogenic activities of beta-HPV have been attributed to effective inhibition of apoptosis and interference with DNA repair pathways by viral E6 proteins. In addition E7 proteins deregulate the cell cycle and enhance invasive growth.     

Human papillomavirus infection in Netherton's syndrome

BACKGROUND: Netherton's syndrome (NS) is a hereditary disorder with dermatological signs (e.g. ichthyosis) and a complex immunological dysfunction. In immunodeficient individuals human papillomavirus (HPV) types are associated with carcinomas on non-mucosal sites. OBJECTIVES: To study the presence of HPV infection in different skin lesions of three male NS patients and to investigate a possible association between HPV and malignancies in NS. METHODS: Patient 1 had extraordinary widespread multiple skin carcinomas on sunlight-exposed areas, as well as common viral warts. Patient 2 showed disseminated viral plane warts that resolved spontaneously, and patient 3 was free of skin lesions suspicious for HPV infection; only pseudoepitheliomatous wart-like lesions as a symptom of ichthyosis were apparent. We performed nested polymerase chain reaction analysis of DNA from benign and malignant skin lesions and HPV-8 serology in these three patients. RESULTS: Antibodies to HPV-8 were not detectable in our patients; however, seven of 22 (31%) biopsies of the three NS patients were positive for HPV DNA. Epidermodysplasia verruciformis (EV) -associated HPV types and normal cutaneous types (HPV-2, HPV-28) were detected. Interestingly, only the patient with cutaneous carcinomas harboured, preferentially in malignant lesions, EV-HPV types (HPV-19, 23, 38 and HPV-RTRX9, closely related to EV-HPVs), whereas plane warts of patient 2 were positive for HPV-28. The pseudoepitheliomatous skin lesions were HPV-DNA negative in all investigated probes. CONCLUSIONS: These data in NS patients further confirm an association of EV-HPVs with non-melanoma skin cancer (NMSC) and suggest a possible carcinogenic role similar to that assumed for NMSC in transplant recipients. A complex immunological disorder facilitating EV-HPV infection, negative HPV serology and photochemotherapy may all have contributed to the unusual occurrence of multiple cancers in one of our NS patients.     

Human papillomavirus status in extragenital nonmelanoma skin cancers

About 5% of all cancers worldwide can be attributed to human papillomaviruses (HPVs); namely, six sites are strongly associated with HPV infections: cervix, penis, vulva, vagina, anus, and oropharynx. Nonmelanoma skin cancers (NMSC), basal cell carcinoma (BCC), and squamous cell carcinoma (SCC) are the most common malignancies in Caucasians. In fact, there is an intense connection between sunlight exposure, fair skin, HPV, and development of NMSC. We have conducted a pilot study that included tissue samples from 26 carcinoma patients, of which there were 13 BCC and 13 SCC. HPV detection and typing was done with DNA amplification and sequencing, respectively. In total, 23.1% of SCC samples (3/13) and 7.7% of BCC samples (1/13) were positive for HPV DNA. The importance of understanding all aspects of NMSC carcinogenesis may be to reveal novel therapeutic options or preventive measures for HPV containing NMSC patients.     

Prevalence of human polyomaviruses in common and rare types of non‐Merkel cell carcinoma skin cancer

Background Little is known about the association of human polyomaviruses (HPyVs) other than Merkel cell polyomavirus (MCPyV) with nonmelanoma skin cancer. Objectives To evaluate the presence of HPyV6, HPyV7, trichodysplasia spinulosa‐associated polyomavirus (TSV), also called HPyV8, and the recently discovered HPyV9 in basal cell carcinoma (BCC), actinic keratosis (AK), squamous cell carcinoma in situ (SCCis), squamous cell carcinoma (SCC), keratoacanthoma (KA), microcystic adnexal carcinoma (MAC) and atypical fibroxanthoma (AFX). Methods Archival paraffin‐embedded samples (n = 193: 41 BCC, 31 AK, 8 SCCis, 52 SCC, 42 KA, 5 MAC and 14 AFX) were analysed for the presence of the respective HPyV by polymerase chain reaction (PCR). HPyV DNA loads (HPyV DNA copies per β‐globin gene copy) were determined in all HPyV‐positive samples by quantitative real‐time PCR. Immunohistochemical analysis of MCPyV large T‐antigen (LTA) expression was performed using the monoclonal antibody CM2B4. Results MCPyV DNA was found in 29% of BCC, 19% of AK, 25% of SCCis, 27% of SCC, 29% of KA, 0% of MAC and 29% of AFX. MCPyV DNA loads never exceeded 0·3 MCPyV DNA copies per β‐globin gene copy (median 0·004). In the immunohistochemical analysis of MCPyV LTA expression, all evaluated samples (32 MCPyV DNA‐positive samples) were LTA negative. HPyV6 DNA was found in 7% of BCC, 3% of AK, 12% of SCCis, 4% of SCC, 5% of KA, and 0% of MAC and AFX. HPyV6 DNA loads never exceeded 0·7 HPyV6 DNA copies per β‐globin gene copy (median 0·015). None of the 193 samples was positive for HPyV7, TSV or HPyV9 DNA. Conclusions Our findings argue against a pathogenic role for MCPyV, HPyV6, HPyV7, TSV and HPyV9 in the analysed types of non‐Merkel cell carcinoma skin cancer.     

Human papillomavirus in cutaneous squamous cell carcinoma and cervix of a patient with psoriasis and extensive ultraviolet radiation exposure

"High-risk" human papillomaviruses (HPVs) are associated with intraepithelial neoplasia and cancer of the uterine cervix. HPV has also been found in nonmelanoma skin cancer (NMSC), especially in squamous cell carcinomas (SCCs) of immunosuppressed patients. Recently, lesions of psoriasis have been shown to harbor HPV, and patients with psoriasis often have a history of extensive therapy with ultraviolet radiation (UVR). UVR is the major known risk factor in the occurrence of NMSC, in which HPV may be a cofactor for SCC. We report an otherwise healthy, nonimmunosuppressed patient with psoriasis who had a history of extensive exposure to UVR and experienced multiple SCCs on UV-exposed body sites. By the polymerase chain reaction method, we detected HPV in 5 of 9 SCCs. Automated sequencing showed HPV types 12 and 17. Only 1 of 3 normal skin specimens was HPV positive (HPV type 17). This positive specimen was from UV-exposed skin; one of the two HPV-negative, normal skin specimens was located on a body site not exposed to sun. In addition, HPV type 62 was found in a brush specimen of the uterine cervix. This case report suggests an association between psoriasis, HPV infection, and UVR exposure, in onset of SCC.     

High beta-HPV DNA loads and strong seroreactivity are present in epidermodysplasia verruciformis

Epidermodysplasia verruciformis (EV) is a rare disease, characterized by cutaneous warts and associated with a strong predisposition to beta-genus human papillomavirus (HPV). Earlier studies reported high copy numbers of HPV-DNA in nearly all skin tumors from EV patients, but neither HPV replication status in non-lesional skin nor anti-HPV seroreactivity in these patients have been reported yet. We therefore performed a comprehensive viral load analysis for the more common beta-HPV types on skin samples and plucked eyebrow hairs from four EV patients treated at our dermatology department. The results clearly demonstrate that they carry a multiplicity (up to eighteen types) of beta-HPV genotypes in both skin sites. Worthy of note, a high intrapatient concordance for specific types between hair bulbs and skin biopsies was observed and the same beta-PV profile was maintained over time. Viral load analysis revealed a load range between less than one HPV-DNA copy per 100 cells to more than 400 HPV-DNA copies per cell in both eyebrow hairs and skin proliferative lesions. Evaluation of seroreactivity to beta-HPV types in the four EV patients revealed that antibodies against the 16 beta-HPV were significantly more prevalent and showed higher titers than in the controls.     

Patient‐reported health outcomes in patients with non‐melanoma skin cancer and actinic keratosis: results from a large‐scale observational study analysing effects of diagnoses and disease progression

Background

Non‐melanoma skin cancer (NMSC) and actinic keratosis (AK) are very common among fair‐skinned individuals. A disease continuum from AK to squamous cell carcinoma (SCC) has been frequently postulated. AK and NMSC may influence quality of life (QL) of patients, and it can be suspected that disease progression entails a QL reduction. The purpose of this study was to document QL in patients with NMSC and AK using the health‐outcome questionnaire EQ‐5D‐5L.

Methods

The study was designed as a non‐interventional, prospective, cross‐sectional study. Patients with AK, SCC, basal cell carcinoma (BCC) or multiple diagnoses were enrolled in this study in 29 dermatological centres across Germany. Patients were asked to complete the EQ‐5D‐5L (compromising EQ Index and EQ VAS), and the dermatologists provided diagnosis, disease history and treatment data.

Results

A total of 1184 patients were enrolled and diagnosed as follows: 73% AK, 49% BCC and 17% SCC. 66% had a single diagnosis, 28% two different diagnoses and 6% three different diagnoses. QL was strongly associated with patients’ diagnosis. Patients with a single AK diagnosis had significantly higher mean EQ VAS (78) than patients with BCC (74), SCC (72), and BCC plus SCC (69), P < 0.050. When the effects of disease progression were calculated, patients with AK plus SCC reported significantly less mean EQ VAS (71) than patients with a single AK diagnosis (78), P < 0.011.

Conclusions

While rarely being imminently life‐threatening, NMSC and AK have an impact on QL as quantified by the EQ‐5D‐5L. This impact is associated with diagnosis (AK vs. NMSC) and clinical progression (AK vs. AK plus SCC). Both lead to a clear decline in QL. This shows that disease progression is perceived and judged as detrimental by patients and that AK and NMSC should be diligently treated to preserve and restore QL.     

Seropositivity for human papillomavirus and incidence of subsequent squamous cell and basal cell carcinomas of the skin in patients with a previous nonmelanoma skin cancer

Background Infection with human papillomaviruses (HPVs) is a risk factor for several epithelial cancers, but its relationship with keratinocyte tumours has not yet been established. Objective In this prospective study we investigated the possible role of different HPVs in the incidence of a subsequent nonmelanoma skin cancer (NMSC). Methods One hundred and fifty‐three patients with squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) enrolled in a previous case–control study were re‐contacted, and a follow‐up visit was offered. Demographic and clinical data, date of first NMSC presentation, Fitzpatrick skin type and history of NMSC during the follow‐up period were ascertained. Recurrences and new second cancers were considered together as ‘outcomes’ in time‐to‐event analyses and in Cox proportional hazard models. Results Clinical data were obtained in 107 patients. HPV seropositivity at baseline was strongly associated with the risk of developing a second SCC after 5 years for a number of beta and gamma HPV types. For example, HPV‐24‐seropositive patients with an SCC at baseline had a 4‐fold increased risk of developing a subsequent SCC (hazard ratio 4·35, 95% confidence interval 1·2–15·6, P = 0·024). No association between serological status for any HPV type tested and an increased risk of BCC was found. Conclusions We observed a consistent pattern of a positive association between seropositivity for beta and gamma HPV types and the risk of a subsequent SCC in patients with a previous SCC. Our data corroborate the results of previous case–control studies and may spur further prospective studies on the causal role of HPVs in NMSC.     

Differences in tumor microvessel density between squamous cell carcinomas and basal cell carcinomas may relate to their different biologic behavior

Tumor microvessel density (TMVD) has been recognized as an important indicator for the metastatic risk in certain tumors. The purpose of this study was to analyse whether there is an association of TMVD in epithelial neoplasms of the skin with their clinical behavior. Paraffin sections of keratoacanthomas (KA, n=10), squamous cell carcinomas (SCC, n=9), nodular (nod-BCC, n=13), and sclerosing (scl-BCC, n=12) basal cell carcinomas were immunohistochemically stained for factor-VIII-related antigen and TMVD was determined. In all SCC, KA and nod-BCC, TMVD significantly exceeded perilesional skin microvessel density (PSMVD) (SCC:TMVD/PSMVD = 20.54:11.25, p < 0.0001; KA:TMVD/PSMVD = 20.90:12.17, p < 0.0001; nod-BCC:TMVD/PSMVD = 16.77:13.34, p=0.03). In contrast, no significant difference between TMVD and PSMVD was found in scl-BCC (15.44:12.86, p=0.22). TMVD was significantly higher in SCC and KA compared to nod-BCC (p=0.036 and 0.006, respectively). Our data demonstrate that SCC and KA are highly vascularized tumors. The fact that TMVD does not differ significantly between SCC and KA (p=0.80) suggests that MVD is not an indicator for the metastatic risk or aggressive growth behavior of epithelial skin tumors. The finding that MVD in both nod- and scl-BCC is significantly lower than in SCC and KA, might at least in part explain the slow growth of BCC.     

Raptor、Rictor和磷酸化Akt在日光性角化病、Bowen病及鳞状细胞癌中的表达

目的:检测Raptor、Rictor和磷酸化Akt(p-Akt)在日光性角化病、Bowen病和鳞状细胞癌中的表达。方法:采用免疫组化法检测Raptor、Rictor及p-Akt(Ser473)在20例正常皮肤、20例日光性角化病、20例Bowen病及40例鳞状细胞癌中的表达。结果:Raptor在鳞状细胞癌、Bowen病和日光性角化病中的阳性表达率分别为87.50%、70.00%和60.00%,均高于正常皮肤的25.00%(均P0.05);其中低分化鳞状细胞癌中Raptor的阳性表达率为100%,高于高分化鳞状细胞癌的阳性表达率75%(P0.05)。Rictor在鳞状细胞癌、Bowen病和日光性角化病中的阳性表达率分别为80.00%、70.00%及55.00%,均高于正常皮肤阳性表达率的20%(均P0.05);p-Akt(Ser473)在鳞状细胞癌、Bowen病和日光性角化病中的阳性表达率分别为77.50%、65.00%及50.00%,而正常皮肤阳性表达率为0。鳞状细胞癌、Bowen病和日光性角化病中Rictor的阳性表达水平和p-Akt(Ser473)的阳性表达水平均呈正相关(均P0.05)。结论:Raptor、Rictor和p-Akt(Ser473)的高表达可能与日光性角化病、Bowen病和鳞状细胞癌的发生发展有关。     

Detección del virus del papiloma humano en muestras de cáncer cutáneo no melanoma y piel sana perilesional en pacientes trasplantados renales y pacientes inmunocompetentes

BackgroundThe influence of human papillomavirus (HPV) on the development of nonmelanoma skin cancer (NMSC) is a topic of debate. HPV types from the beta genus (HPV-β) have been most frequently associated with the development of skin cancer.ObjectivesTo analyze the prevalence and range of HPV types in NMSC lesions and healthy perilesional skin in immunodepressed and immunocompetent patients and to evaluate the influence of various clinical factors on the prevalence of HPV in skin cancer.MethodsNested polymerase chain reaction and sequencing were used to detect HPV in 120 NMSC samples obtained by biopsy from 30 kidney transplant recipients and 30 immunocompetent patients. In all cases, a sample was taken from the tumor site and the surrounding healthy skin. Potential confounders were assessed and the data analyzed by multivariate logistic regression.ResultsHPV DNA was detected in 44 (73.3%) of the 60 samples from immunodepressed patients and in 32 (53.3%) of the 60 samples from immunocompetent patients (adjusted odds ratio, 3.4; 95% CI, 1.2-9.6). In both groups of patients, HPV was more common in healthy perilesional skin than in lesional skin. HPV-β was the most common type isolated.ConclusionWe found a wide range of HPV types (mostly HPV-β) in the skin of kidney transplant recipients and immunocompetent patients with skin cancer.     

p53 immunoreactivity in non-melanoma skin cancer from immunosuppressed and immunocompetent individuals: a comparative study of 246 tumours

p53 immunoreactivity was examined in 132 cutaneous non-melanoma tumours from renal transplant recipients and in 114 histologically matched specimens from immunocompetent individuals. Skin lesions examined included 52 viral warts, 50 clysplastic keratoses, 51 intraepidermal carcinomas (IEC), 50 invasive squamous cell carcinomas (SCC) and 43 basal cell carcinomas (BCC). Overall, 51% (51/101) pre-malignant skin lesions and 45% (42/93) non-melanoma skin cancers (NMSC) showed p53 immunoreactivity, with extensive (> 50% cells positive) p53 staining in 27% (27/101) of pre-malignant and 20% (19/93) of malignant lesions. 17% (9/52) viral warts showed p53 immunoreactivity, but this was limited to focal or basal p53 staining. p53 immunoreactivity in all tumours was less in transplant than in non-transplant patients and this reached statistical significance for SCCs (p = 0.03).     

Topical imiquimod therapy for basal and squamous cell carcinomas: a clinical experience

Basal cell carcinomas (BCCs) and cutaneous squamous cell carcinomas (SCCs) are the most common malignancies in humans. Together, they constitute approximately 95% of nonmelanoma skin cancers (NMSCs). Surgical excision remains the mainstay of therapy of low-risk NMSC, though Mohs micrographic surgery is the gold standard for high-risk NMSC. Both methods produce high cure rates, but they may not be appropriate treatments for elderly patients who are either not surgical candidates or refuse to undergo surgery for their skin cancers. Imiquimod cream 5% is a topical immune response modifier that targets the toll-like receptors 7 and 8 and up-regulates inflammatory pathways targeting diseased tissue. This noninvasive topical therapy may be more appropriate for some patients. Herein, we describe our 5-month clinical experience in mostly elderly subjects with BCC (n=21) or SCC (n= 19) who were not candidates for surgical excision and were treated with topical imiquimod. Most subjects had a history of skin cancer, and the median age of the subjects was 78 years and 79 years in the BCC and SCC groups, respectively. After biopsy alone or biopsy followed by curettage, subjects received imiquimod cream 5% once daily 5 times weekly for 6 weeks. Twenty-three BCC lesions and 22 SCC lesions were included in the analysis. Most of the 45 lesions treated were located on the head and most were in high-risk areas. Approximately 3 months after imiquimod therapy, repeat biopsies showed that only 3 (2 BCCs and 1 SCC) lesion sites had residual tumor. After a median follow-up of 26 months, there was only one additional SCC recurrence. We also present a selection of representative case studies. Imiquimod cream 5% as adjunctive therapy to curettage was safe and well-tolerated in this mostly elderly population. The improved residual tumor and recurrence rates compared with historical rates for electrodesiccation and curettage (ED&C) alone suggest that adjunctive imiquimod therapy may be an appropriate treatment option for patients who desire or require less invasive treatment for NMSCs.     

Awareness of, knowledge of and attitudes to nonmelanoma skin cancer (NMSC) and actinic keratosis (AK) among physicians

BACKGROUND: Nonmelanoma skin cancer (NMSC) is the most common type of cancer that affects the Caucasian population. Approximately 80% of NMSCs are basal cell carcinoma (BCC) and 20% are squamous cell carcinoma (SCC). Actinic keratosis (AK) is a precancerous lesion that may develop into SCC. METHODS: A market research survey was conducted in which dermatologists and primary care physicians (PCPs) were randomly selected from seven countries (USA, Australia, UK, Italy, France, Germany and Spain). Their knowledge of nonmelanoma skin cancer and their current clinical practice were assessed. RESULTS: In total, 2100 physicians took part in the survey. They had practised medicine for between 1 and 30 years and saw at least 30 patients in a typical week. The majority of dermatologists (97%) were familiar with BCC and AK, and treated each condition with a minimum of referrals. PCPs were more familiar with BCC (90%) than with AK (74%). Of the PCPs that were aware of BCC, only 31% treated the condition, and of those aware of AK, 40% treated the condition. Surgery was the most common choice of treatment for BCC. The most popular treatment choice for AK lesions was cryotherapy. Eighty to 100% of physicians reported that they discussed skin cancer prevention with their patients. A much lower number of physicians (ranging from 5 to 37%) provided educational material to patients. Overall, PCPs in the two countries that have a high incidence of NMSC (USA and Australia) were more familiar with BCC and AK and more likely to treat each condition than PCPs in Europe. All physicians rated BCC as a more serious condition than AK. Facial lesions were considered more serious than lesions on the head or trunk for both conditions. CONCLUSIONS: As the burden of disease and the number of patients seeking treatment for NMSC increase, dermatologists are well placed to lead educational initiatives for PCPs and provide educational material for patients. This would increase awareness of AK and BCC and could improve early diagnosis.     

Trends in incidence of nonmelanoma skin cancers in Alberta,Canada, 1988–2007

Background Nonmelanoma skin cancer (NMSC) is the most common malignancy affecting caucasian populations and has been seeing global increases in incidence for decades. Objectives The objective of this study was to determine trends in incidence of NMSC in Alberta, Canada from 1988 to 2007. Methods A retrospective analysis of patients from Alberta diagnosed with NMSC from 1988 to 2007 inclusive was conducted with data retrieved from the Alberta Cancer Registry (ACR). Sex‐, age‐ and anatomical location‐specific incidence rates and trends were examined. Results From 1988 to 2007, there were 66 192 basal cell carcinomas, 19 959 invasive squamous cell carcinomas (SCC) and 12 494 in situ SCC. ACR coding for the 2007 data was not completed at the time of this study; hence, data from this year were not included in the trend analyses. Incidence of NMSC in women has been stable since 2000 [annual percentage change (APC) 0·08, P = 0·88] and has declined in men since 2001 (APC −1·28, P = 0·026). BCC incidence has been stable since 2000 (APC −0·80, P = 0·09). In situ and invasive SCC also showed a trend towards stabilization in 2000 (APC 0·36, P = 0·77) and 1995 (APC 0·01, P = 0·98), respectively. NMSC primarily affects the elderly and is rarely seen in individuals before the age of 40 years. Although the head and neck region was the location most often involved with NMSC (71·1%), it revealed a stabilizing trend, whereas most other anatomical regions demonstrated an increasing NMSC incidence rate. Conclusions NMSC incidence in Alberta has stabilized in women and declined in men. As 95–99% of NMSC occurs in patients aged 40 years or older, and with its increased frequency in traditionally clothed areas, the authors recommend regular complete skin examinations starting at 40 years of age.     

Expression of RPE65, a putative receptor for plasma retinol-binding protein, in nonmelanocytic skin tumours

BACKGROUND: In a recent report we described RPE65, a protein originally characterized in retinal pigment epithelium, to be expressed in normal human epidermis. RPE65 is suspected to be involved in cellular uptake of retinol which is transported in the bloodstream complexed with plasma retinol-binding protein. OBJECTIVES: To evaluate protein and mRNA expression of RPE65 in actinic keratosis (AK), squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) compared with normal skin. METHODS: RPE65 mRNA expression in skin tumours relative to normal skin of the respective donor was studied by real-time polymerase chain reaction in AK (n = 15), invasive SCC (n = 30) and BCC (n = 18). A peptide-specific anti-RPE65 antibody was used for immunohistochemical staining of formalin-fixed and paraffin-embedded tissue sections of the respective tumours. RESULTS: RPE65 mRNA expression was reduced in AK. A highly significant reduction of RPE65 mRNA was observed in invasive SCC relative to normal skin of the respective donors. Immunohistochemistry revealed a continuous staining of basal and suprabasal keratinocytes in normal human epidermis. RPE65 in AK shown by immunohistochemical staining was reduced and quite irregular, whereas invasive SCC revealed no staining of tumour cells with the anti-RPE65 antibody. RPE65 mRNA values were elevated, whereas immunohistochemical staining for RPE65 protein was heterogeneous in BCC. CONCLUSIONS: These results suggest progressive downregulation of RPE65 from AK to invasive SCC.     

Increased risk of skin cancer associated with the presence of epidermodysplasia verruciformis human papillomavirus types in normal skin

BACKGROUND: Human papillomaviruses (HPVs) are found in normal skin and in benign and malignant skin conditions. Epidermodysplasia verruciformis (EV) HPV types are those most plausibly linked to the development of squamous cell carcinomas of the skin. OBJECTIVES: To assess the risk of nonmelanoma skin cancer (NMSC) associated with the presence of EV HPV in normal skin in immunocompetent (IC) individuals and renal transplant recipients (RTRs). METHODS: Using a degenerate and nested polymerase chain reaction technique, HPV DNA was sought in 124 normal skin samples from sun-exposed and nonsun-exposed sites, from 39 IC individuals and 38 RTRs, both with and without NMSC. Data were analysed using the Mantel-Haenszel test and by logistic regression analysis. RESULTS: HPV DNA was detected in 58/67 (87%) and 20/57 (35%) samples from renal transplant and IC patients, respectively. There was no difference in either the prevalence or spectrum of HPV types found in sun-exposed and nonsun-exposed normal skin. However, there was significant association between NMSC and the presence of EV HPV DNA. Multivariate analysis provided an odds ratio of 6.41 (95% confidence interval 1.79-22.9) for the association of EV HPV DNA in normal skin (irrespective of site) and NMSC status, even after stratifying for patient group and adjusting for the clustering effect of multiple sampling. Conversely, there was no association between skin cancer status and the presence of cutaneous or mucosal HPV types in either sun-exposed or nonsun-exposed skin. CONCLUSIONS: HPV DNA is widespread in normal adult skin, particularly in transplant patients. In our study, the presence of EV but not cutaneous HPV DNA in normal skin was significantly associated with NMSC status and may prove to be of predictive value for skin cancer risk. These data provide reason to focus on EV HPV types as causal agents in skin cancer.