High levels of ultraviolet B exposure increase the risk of non-melanoma skin cancer in psoralen and ultraviolet A-treated patients

Sunlight and psoralen and ultraviolet A (PUVA) are risk factors for the development of squamous cell carcinoma (SCC) and, to a lesser extent, basal cell carcinoma (BCC). Ultraviolet B (UVB) therapy, used for the treatment of psoriasis, might also increase the risk of these tumors. We studied the relation of skin cancer incidence to UVB use among 1380 adult subjects enrolled in a long-term safety trial of PUVA therapy. We used negative binomial regression models to quantify the association between UVB and the development of non-melanoma skin cancer (NMSC), controlling for known confounders. High UVB exposure (> or =300 treatments vs <300 treatments) was associated with a modest but significant increase in SCC (adjusted incidence rate ratio (IRR)=1.37, 95% confidence interval (CI)=1.03-1.83) and BCC (adjusted IRR=1.45, 95% CI=1.07-1.96) risk. Among patients with <100 PUVA treatments, high UVB exposure was significantly associated with the development of SCC (adjusted IRR=2.75, 95% CI=1.11-6.84) and BCC (adjusted IRR=3.00, 95% CI=1.30-6.91) on body sites typically exposed to UVB therapy but not on chronically sun-exposed sites typically covered during therapy. For adults with high UVB exposure levels, UVB confers a modest increase in NMSC risk, much less than that observed with PUVA. Therefore, UVB remains a relatively low-risk treatment for psoriasis.     

Iatrogenic skin cancer: induction by psoralen/ultraviolet A and immunosuppression of organ transplant recipients

Photochemotherapy (psoralen/UVA (PUVA)) is an efficient therapeutic tool for a wide range of skin diseases. Concern, however, exists regarding the long-term carcinogenic effects of this treatment modality and, as a consequence, is being used less frequently. PUVA remains an important treatment in our therapeutic armamentarium but must be used with caution in those patients with risk factors and cumulative dose exposure must be limited. PUVA-induced cancers show features in common with skin cancers induced by immunosuppressed organ transplant recipients. Tumours in the latter group of individuals are, however, much more aggressive and difficult to manage.     

The persistent risk of genital tumors among men treated with psoralen plus ultraviolet A (PUVA) for psoriasis

BACKGROUND: In the general population, squamous cell carcinomas (SCCs) of the male genitalia are rare. Ten years ago, we documented a significant dose-dependent increase in the risk of malignant genital neoplasms among men treated with psoralen plus ultraviolet A (PUVA). Since that time, fewer cohort patients have used PUVA, and genital protection among PUVA users is likely to be frequent. OBJECTIVE: Our aim was to determine the incidence and risk factors for genital neoplasms since 1989 and risk factors for these neoplasms among patients treated with PUVA. METHODS: We conducted a prospective cohort study of 892 men first treated with PUVA in 1975-1976. RESULTS: Twenty-four men (2.7%) had 51 genital neoplasms, including 10 patients with a first tumor after May 1, 1989 (the ending date for our 1990 report). Since May 1, 1989, the incidence of invasive penile and scrotal SCCs was elevated 52.6-fold (95% confidence interval, 19.3-114.6) compared with that expected for the general white population. Multivariate models revealed the highest genital tumor risk among men with high-dose exposure to both PUVA and topical tar/ultraviolet B, with an incidence rate ratio of 4.5 (95% confidence interval, 1.3-16.1) compared with the low-dose exposure group. CONCLUSION: Although use of PUVA has decreased and genital shielding in our cohort has increased, the dose-dependent increase in the risk of genital tumors in men treated with PUVA has persisted. Particularly high risks occur among those with high-dose exposures to both PUVA and topical tar/ultraviolet B.     

CD30+ large cell transformation of mycosis fungoides after psoralen plus ultraviolet A photochemotherapy

Psoralen plus ultraviolet A (PUVA) photochemotherapy is widely used for the therapy of mycosis fungoides (MF). Clinical progression of MF is often associated with an increase in the size of tumour cells known as transformation. We report two patients with CD30+ large cell transformation that appeared after low-dose PUVA therapy for MF. Clinical data, histopathology, immunohistopathology and T-cell receptor gene rearrangement were studied. Nodules consisted of atypical large cells that expressed CD30. Monoclonal rearrangement of T-cell receptors was observed in one case. Low-dose PUVA therapy may be associated with CD30+ large cell transformation in patients with MF.     

Burn injuries and skin cancer: a population-based cohort study

Development of malignant tumours in chronic burn wounds or scars is extremely rare, but a frequently reported complication. Most of these tumours are squamous cell carcinoma and, more occasionally, basal cell carcinoma and malignant melanoma are reported. The interval between the initial burn and the diagnosis of the tumour is usually long; 20-30 years or more. A large number of case reports and small series of selected patients have been published. Only one epidemiological study has been performed recently, but it could not confirm any increased risk. We conducted a historical cohort study to assess the risk of cancer in Swedish patients with burn injuries. Using the national Inpatient Registry we identified 37,095 patients who had been hospitalized for burn injuries. This cohort was linked with the Swedish Cancer Registry for a virtually complete follow-up with regard to cancer. The mean follow-up time was 16.4 years (range >0-39). The risk of developing any form of cancer was slightly increased: standardized incidence ratio (SIR) 1.11 (95% confidence interval (CI) 1.06-1.16) based on 2227 patients with cancer. However, squamous cell carcinoma: SIR 0.88 (95% CI 0.70-1.09) and malignant melanoma: SIR 0.88 (95% CI 0.68-1.12) did not occur more often than expected. Also, in a subgroup of 12,783 patients who were followed for 20-39 years, no increased risk of skin cancer could be detected. This study does not support any casual association between burn injuries and a later risk of skin cancer.     

MICA gene polymorphism is not associated with an increased risk for skin cancer

The MICA gene encodes for major histocompatibility complex class I chain-related proteins (MIC), which belong to a recently identified new family of nonclassical major histocompatibility complex molecules. The general structure of the MICA molecule resembles that of major histocompatibility complex class I molecules. MIC molecules are considered to be stress-induced antigens that are recognized by cytotoxic T cells and natural killer cells, which play an important role in the surveillance of transformed infected and damaged cells. Associations of major histocompatibility complex class I molecules with skin cancer have been described before. To evaluate the possible association of MICA gene polymorphism with the risk for nonmelanoma skin cancer we evaluated 153 cases with squamous cell carcinoma, 261 cases with basal cell carcinoma, 111 controls with malignant melanoma, and 247 controls without a history of skin cancer. Five distinct MICA alleles A4, A5, A6, A9, and A5.1 were studied. As the MICA 5.1 variant gene contains a four-nucleotide insertion that causes a stop codon in the trans membrane region, the resulting truncated MICA molecule does not reside on the cellular membrane. In the case of individuals who are homozygous for MICA 5.1 this results in cells that are naked for the MICA molecule. We therefore specifically addressed the possible association between MICA 5.1 homozygosity and skin cancer, as these individuals are expected to be at the highest risk for skin cancer if the MICA gene plays a role in skin carcinogenesis. Viral proteins may serve as antigens for recognition of skin cancer by the immune system. Human papillomavirus is the most likely candidate virus to be involved in the carcinogenesis of cutaneous squamous cell carcinoma. Hence, we also assessed the association between MICA polymorphism and squamous cell carcinoma in human-papillomavirus-positive and human-papillomavirus-negative individuals as identified by the presence of human papillomavirus DNA in hairs plucked from their eyebrows. Our analyses did not reveal any significant differences regarding the MICA allele frequencies between cases and controls. Also homozygotes and heterozygotes for the MICA 5.1 variant gene were not at an increased risk for skin cancer compared to individuals without this variant gene and infection with human papillomavirus did not materially influence these findings. The same group of cases and controls was large enough to show an association between melanocortin 1 receptor gene polymorphism and skin cancer and to reasonably exclude an association between p53 codon 72 polymorphism and skin cancer. Therefore, we conclude that an association between MICA gene polymorphism and nonmelanoma skin cancer is not likely.     

Psoriasis is associated with increased risk of bullous pemphigoid: A nationwide population‐based cohort study in Taiwan

Psoriasis may coexist with bullous pemphigoid (BP); however, no cohort studies have investigated the relationship between psoriasis and the risk of BP. This study aims to investigate the relationship between psoriasis and the risk of BP in Taiwan. This cohort study consists of 109 777 psoriatic patients and 109 777 matched non‐exposed controls. Psoriatic patients diagnosed between 2002 and 2012 were identified from the Taiwan National Health Insurance Research Database. The age‐, sex‐ and index date‐matched non‐exposed group was selected from the same database. The relationship between psoriasis and the risk of BP was investigated using Cox proportional hazards analyses. Psoriasis was significantly associated with an increased risk of BP (hazard ratio, 3.05; 95% confidence interval, 2.10–4.43; P < 0.001). The mean interval between the diagnoses of psoriasis and BP was 2.86 years, with the highest occurrence in the first year after psoriasis diagnosis, and gradually decreasing with each year of observation. Psoriatic patients with BP were significantly younger than BP patients in the non‐exposed group (71.6 ± 13.9 vs 76.6 ± 7.7 years, respectively; P = 0.030). A higher proportion of patients with coexisting psoriasis and BP received phototherapy (20%). In conclusion, psoriasis was independently associated with a 3.05‐fold increased risk of BP, and psoriatic patients with BP were younger, with over one‐third of BP cases diagnosed in the first year after incident psoriasis. Therefore, clinicians treating patients with psoriasis may be aware of the possibility of the development of BP.     

A comparative study of different treatment frequencies of psoralen and ultraviolet A in psoriatic patients with darker skin types (randomized-controlled study)

BACKGROUND: Photochemotherapy psoralen and ultraviolet A (PUVA) is a viable option for treatment of psoriasis. However, concerns about its side effects have raised the need to change current PUVA protocols. The aim of this study is to determine whether reducing the treatment frequency of PUVA to twice/week instead of three times/week would affect the efficacy of PUVA therapy. PATIENTS AND METHODS: The study included 20 psoriatic patients, randomized into two groups, 10 patients in each group. The first group received two weekly sessions, the second group received three. The study lasted until complete clearance or for 12 weeks (endpoint). Psoriasis area and severity index (PASI) score was done prior to therapy, at mid therapy and at end of therapy (PASI final). RESULTS: No significant different in PASI final and in the percentage of reduction of PASI score between both groups (P value >0.05) was found. However, a significant difference in the total number of sessions and the total cumulative UVA doses between both groups was found (P value <0.001). CONCLUSION: Our study suggests reducing PUVA frequency and the cumulative UVA dose does not compromise the efficacy of PUVA, but it may improve its benefit/risk ratio. RESTRICTIONS: Few number of cases.     

The risk and risk factors of a second non-melanoma skin cancer: a study in a Mediterranean population

BACKGROUND: Non-melanoma skin cancer (NMSC) patients often develop second primary skin tumours. Studies assessing the risk and risk factors on the appearance of a second NMSC are scarce, especially in European countries. OBJECTIVES: To assess the 5-year risk of a second NMSC in a Mediterranean population, and to find patient characteristics predicting second tumours. METHODS: NMSC patients at our institution were studied retrospectively. In situ tumours, recurrences, follow-up shorter than 2 months and mucosal lesions were excluded. Data analysed included age, gender, anatomical site, histological subtype, number of tumours and months of follow-up. Disease-free interval was defined as time from histological documentation of the first NMSC to the date of the last follow-up or to the date of histological documentation of the second NMSC. Survival analysis was conducted with the life-table analysis. Cox's proportional hazards regression model was used to assess risk factors. RESULTS: The study group comprised 535 cases. Of these, 120 patients presented a second NMSC (22.4%). Hazard rates remained high in all yearly intervals. Multivariate analysis showed older age, multiple tumours and male sex as significant prognostic factors. When the second NMSC was diagnosed in the first year of follow-up, a trend to a high risk of further NMSCs was observed. CONCLUSIONS: The risk of a second NMSC is similar to other studies, although in the lower range. Prognostic factors are also similar to other studies. Yearly hazard rates not falling suggests that long-term follow-up is needed. Prospective studies including whole-body examination could define the exact risk of a second NMSC.     

The time-course of psoralen ultraviolet A (PUVA) erythema.

The time-course for the development of ultraviolet A-induced erythema in psoralen-sensitized skin differs from that caused by ultraviolet B or ultraviolet A but objective data are not available. During psoralen ultraviolet A therapy, the minimal phototoxic dose is determined 72 h after exposure, when psoralen ultraviolet A erythema is assumed to be maximal. This measurement is of fundamental importance in optimizing the therapeutic regimen. We examined a detailed time-course for development of psoralen ultraviolet A erythema in 16 subjects. The erythemal responses to ultraviolet B, ultraviolet A and psoralen ultraviolet A were assessed visually and using a reflectance device. Ultraviolet B erythema was maximal 24 h after exposure compared with subsequent time-points. Psoralen ultraviolet A erythema was evident at 24 h, with reduction in the median ultraviolet A minimal erythema dose from 14 to 5 J per cm2 in the presence of psoralen (p < 0.01; n = 9). Peak psoralen ultraviolet A erythema, assessed by minimal phototoxic dose, did not occur until 96 h or later in 75% of subjects. Using individual dose- response curves, we determined that only 67% of mean maximum psoralen ultraviolet A erythemal intensity had developed by 72 h. Furthermore, at the time of maximal erythema, the slope of the psoralen ultraviolet A dose-response curve was approximately 2-fold shallower than that for ultraviolet B-induced erythema. If assessment of psoralen ultraviolet A erythemal sensitivity had been made at 96 h instead of the conventional 72 h time-point, peak erythemal responses would not have been missed in any of the subjects. Based on these findings, it seems appropriate to consider whether psoralen ultraviolet A minimal phototoxic dose measurements should be performed 96 h after exposure.