Painful skin lesions and squamous cell carcinoma predict overall mortality risk in organ transplant recipients: a cohort study.

BACKGROUND: Organ transplant recipients (OTRs) have a highly increased risk of cutaneous squamous cell carcinomas (SCCs). Sensation of pain in cutaneous tumours is a powerful patient-reported warning signal for invasive SCCs in OTRs. OBJECTIVES: To investigate the impact of painful vs. painless skin lesions and SCC vs. other skin lesions on the overall mortality risk in OTRs. METHODS: We followed 410 OTRs from 10 different centres across Europe and North America between 2008 and 2015. These patients had been enrolled in an earlier study to define clinically meaningful patient-reported warning signals predicting the presence of SCC, and had been included if they had a lesion requiring histological diagnosis. Cumulative incidences of overall mortality were calculated using Kaplan-Meier survival analysis, and risk factors were analysed with Cox proportional hazard analysis. RESULTS: There was an increased overall mortality risk in OTRs who reported painful vs. painless skin lesions, with a hazard ratio (HR) of 1·6 [95% confidence interval (CI) 0·97-2·7], adjusted for age, sex and other relevant factors. There was also an increased overall mortality risk in OTRs diagnosed with SCC compared with other skin lesions, with an adjusted HR of 1·7 (95% CI 1·0-2·8). Mortality due to internal malignancies and systemic infections appeared to prevail in OTRs with SCC. CONCLUSIONS: We suggest that OTRs have an increased overall mortality risk if they develop painful skin lesions or are diagnosed with cutaneous SCC.

PTCH1 gene haplotype association with basal cell carcinoma after transplantation.

BACKGROUND: Basal cell carcinoma (BCC) is 10 times more frequent in organ transplant recipients (OTRs) than in the general population. Factors in OTRs conferring increased susceptibility to BCC include ultraviolet radiation exposure, immunosuppression, viral infections such as human papillomavirus, phototype and genetic predisposition. The PTCH1 gene is a negative regulator of the hedgehog pathway, that provides mitogenic signals to basal cells in skin. PTCH1 gene mutations cause naevoid BCC syndrome, and contribute to the development of sporadic BCC and other types of cancers. Associations have been reported between PTCH1 polymorphisms and BCC susceptibility in nontransplanted individuals. OBJECTIVES: To search for novel common polymorphisms in the proximal 5' regulatory region upstream of PTCH1 gene exon 1B, and to investigate the possible association of PTCH1 polymorphisms and haplotypes with BCC risk after organ transplantation. METHODS: Three PTCH1 single nucleotide polymorphisms (rs2297086, rs2066836 and rs357564) were analysed by restriction fragment length polymorphism analysis in 161 northern Italian OTRs (56 BCC cases and 105 controls). Two regions of the PTCH1 gene promoter were screened by heteroduplex analysis in 30 cases and 30 controls. RESULTS: Single locus analysis showed no significant association. Haplotype T(1686)-T(3944) appeared to confer a significantly higher risk for BCC development (odds ratio 2.98, 95% confidence interval 2.55-3.48; P = 0.001). Two novel rare polymorphisms were identified at positions 176 and 179 of the 5'UTR. Two novel alleles of the -4 (CGG)(n) microsatellite were identified. No association of this microsatellite with BCC was observed. CONCLUSIONS: Haplotypes containing T(1686)-T(3944) alleles were shown to be associated with an increased BCC risk in our study population. These data appear to be of great interest for further investigations in a larger group of transplant individuals. Our results do not support the hypothesis that common polymorphisms in the proximal 5' regulatory region of the PTCH1 gene could represent an important risk factor for BCC after organ transplantation.

Risk of nonmelanoma skin cancer in Italian organ transplant recipients. A registry-based study.

BACKGROUND: Organ transplant recipients are at an increased risk of nonmelanoma skin cancer. Few data concern heart transplantation and populations from southern Europe. METHODS: A total of 1,329 patients who received their first kidney (1,062 subjects) or heart allograft (267 subjects) were included in a partly retrospective cohort study to evaluate the risk of skin cancer. The incidence rate per 1,000 person-years and the cumulative incidence were computed. Standardized morbidity ratio was estimated by comparison with Italian cancer registry data. To analyze the role of potential prognostic factors, Cox's regression method was used. RESULTS: The overall incidence rate of nonmelanoma skin cancer was 10.0 cases per 1,000 posttransplant person-years (95% confidence interval 8.2-11.7). This estimate was far higher than expected in the general population. The overall risk of developing skin cancer increased from a cumulative incidence of 5.8% after 5 posttransplant years to an incidence of 10.8% after 10 years of graft survival. In a Cox proportional hazard risk model, the most important factors that appeared to favor the development of skin cancer were age at transplantation and sex. After adjustment for age at transplantation and sex, no definite increased risk was documented among heart as compared with kindney transplant recipients. CONCLUSIONS: Our study confirms the increased risk of nonmelanoma skin cancer among organ transplant recipients in a southern European population.

Skin cancer in heart transplant recipients: risk factor analysis and relevance of immunosuppressive therapy.

BACKGROUND: The frequency of skin tumors of all types and specifically of squamous cell carcinoma (SCC) is increased in heart transplantation (HT), but the predisposing risk factors are controversial. METHODS AND RESULTS: We studied 300 patients (age 49+/-15 years, 258 men, mean follow-up 4.6 years, follow-up range 1 month to 12 years) who were receiving standard double (cyclosporin plus azathioprine) or triple (cyclosporin plus azathioprine plus prednisone) therapy. The first-year rejection score was calculated for endomyocardial biopsy samples (International Society for Heart and Lung Transplantation grade 0=0, 1A=1, 1B=2, 2=3, 3A=4, 3B=5, and 4=6) and used as an indirect marker of the level of immunosuppression. Multivariate analysis (Cox regression) included age at HT, sex, skin type, first-year rejection score, presence of warts and solar keratosis, lifetime sunlight exposure, and first-year cumulative dose of steroids. The incidence of skin tumors of all types increased from 15% after 5 years to 35% after 10 years after HT according to life-table analysis. Age at HT of >50 years (P:=0.03, RR=5.3), skin type II (P:=0.05, RR=2.6), rejection score of 19 (P:=0.003, RR=5.7), solar keratosis (P:=0.001, RR=6.9), and lifetime sunlight exposure of >30 000 hours (P:=0.0003, RR=7.6) were risk factors for SCC. CONCLUSIONS: Older age at HT, light skin type, solar keratosis, greater sunlight exposure, and high rejection score in the first year were independently associated with an increased risk of SCC. The progressive increase in cancer frequency during follow-up and the association with high rejection scores suggest that both the length and level of immunosuppression may be relevant. Because cumulative immunosuppressive load is cumbersome to calculate, a high rejection score in the first year may provide a useful predictor for patients at risk.

Skin cancer in heart transplant recipients: frequency and risk factor analysis.

BACKGROUND: The frequency of skin cancer is increased among organ transplant recipients, but the predisposing risk factors are controversial. It is also unclear whether heart transplant patients face an increased risk compared to recipients of other organs, e.g. kidney transplants. METHODS: We performed univariate and multivariate analysis of risk factors for skin cancer in 252 heart transplants and in a control series of 228 kidney transplants followed up at a single center. An extensive dermatologic examination was carried out; baseline features, type of immunosuppression, number of 3A rejection episodes, extent of sunlight exposure and skin type were recorded. Multivariate analysis (Cox regression) included: age at transplantation, sex, skin type (Fitzpatrick's criteria), presence of solar keratosis, presence of warts, type of organ, sunlight exposure. RESULTS: During follow up skin cancer was more common among heart transplants (40, 16 %) than in kidney transplants (16, 7%, p = 0.004). The cumulative incidence of skin cancer by life table analysis increased from 16% after 5 years to 33% after 10 years in heart transplant patients and from 6% to 17% in kidney transplants (p 10000 hours (relative risk = 2.8), but not organ type were significant risk factors. CONCLUSION: Age at transplant, skin type and sunlight exposure, but not type of organ and type of immunosuppressive regimen, are associated with increased risk of skin cancer in heart transplantation.