ong-term survival after organ transplantation is increasing. As a result, many physicians may encounter patients who have long-term complications of transplantation. Adequate graft function requires lifelong immunosuppressive treatment, and the resultant modification of the immune system is associated with an increased risk of various cancers, particularly those involving viruses. Skin cancers are the most common malignant conditions in transplant recipients 1-4 (Table 1) and account for substantial morbidity and mortality in such patients. In this review, we discuss the most common forms of skin cancer in transplant recipients. Squamous-cell and basal-cell carcinomas account for more than 90 percent of all skin cancers in transplant recipients. 1,3,5,6 The incidence of these carcinomas increases with the duration of immunosuppressive therapy, ultimately affecting 50 percent or more of white transplant recipients. 1,5,7 For example, the cumulative incidence of skin cancer in transplant recipients in Queensland, Australia, increases from 7 percent after 1 year of immunosuppressive therapy 5 to 82 percent after 20 years. 8 Among Dutch transplant recipients, the incidence of skin cancer at one year is 0.2 percent and the long-term incidence is 41 percent. 5 Squamous-cell carcinoma is the most common skin cancer in transplant recipients, occurring 65 to 250 times as frequently as in the general population. 6,7,9 The incidence of basal-cell carcinomas is reportedly increased by a factor of 10 in transplant recipients. 7 The risk appears to increase linearly for basal-cell carcinomas and exponentially for squamous-cell carcinomas 1 ; thus, the ratio of squamous-cell to basal-cell carcinomas in patients without transplants (1:4) is reversed in transplant recipients. 1,5,10 The relative risk of squamous-cell carcinoma after transplantation is higher for men than for women, except for cancers of the lip. 9 Curiously, skin cancers appear to be extremely rare in Japanese patients with transplants. 11 The mean interval between transplantation and diagnosis of a tumor is eight years for patients who received transplants at approximately 40 years of age, 10 but is only about three years for those who received transplants after the age of 60. 1 The severity of these tumors is linked to their number. Approximately 30 to 50 percent of patients with squamous-cell carcinomas also have basal-cell carcinomas. 5,10 According to a Scandinavian study, 25 percent of patients with a first squamous-cell carcinoma will have a second lesion within 13 months, and 50 percent will have a second lesion within 3.5 years. 9 Liddington et al. reported a mean interval of 15 months between detection of the first and second cancers, and 11 months between the second and third. 12 Carcinomas are usually associated with multiple warts and premalignant keratoses, and are often associated with Bowen's disease (an intraepidermal carcinoma of the skin or mucous membranes that may progress to invasive carcinoma) and keratoacanthomas (Fig. 1A). The appearance ...

BACKGROUND: Transplant recipients in whom cutaneous squamous-cell carcinomas develop are at high risk for multiple subsequent skin cancers. Whether sirolimus is useful in the prevention of secondary skin cancer has not been assessed. METHODS: In this multicenter trial, we randomly assigned transplant recipients who were taking calcineurin inhibitors and had at least one cutaneous squamouscell carcinoma either to receive sirolimus as a substitute for calcineurin inhibitors (in 64 patients) or to maintain their initial treatment (in 56). The primary end point was survival free of squamous-cell carcinoma at 2 years. Secondary end points included the time until the onset of new squamous-cell carcinomas, occurrence of other skin tumors, graft function, and problems with sirolimus. RESULTS: Survival free of cutaneous squamous-cell carcinoma was significantly longer in the sirolimus group than in the calcineurin-inhibitor group. Overall, new squamous-cell carcinomas developed in 14 patients (22%) in the sirolimus group (6 after withdrawal of sirolimus) and in 22 (39%) in the calcineurin-inhibitor group (median time until onset, 15 vs. 7 months; P=0.02), with a relative risk in the sirolimus group of 0.56 (95% confidence interval, 0.32 to 0.98). There were 60 serious adverse events in the sirolimus group, as compared with 14 such events in the calcineurin-inhibitor group (average, 0.938 vs. 0.250). There were twice as many serious adverse events in patients who had been converted to sirolimus with rapid protocols as in those with progressive protocols. In the sirolimus group, 23% of patients discontinued the drug because of adverse events. Graft function remained stable in the two study groups. CONCLUSIONS: Switching from calcineurin inhibitors to sirolimus had an antitumoral effect among kidney-transplant recipients with previous squamous-cell carcinoma. These observations may have implications concerning immunosuppressive treatment of patients with cutaneous squamous-cell carcinomas. (Funded by Hospices Civils de Lyon and others; TUMORAPA ClinicalTrials.gov number, NCT00133887.).

Skin cancers are the most frequent malignancies in organ transplant recipients (OTR), with 95% being nonmelanoma skin cancers (NMSC), especially squamous (SCC) and basal cell carcinomas. Most OTR with a first SCC subsequently develop multiple NMSC within 5 years, highlighting the concept of 'field cancerization' , and are also at high risk for noncutaneous cancers. In order to reduce the tumor burden in these patients, their management requires an interdisciplinary approach including revision of immunosuppression, new dermatological treatments and adequate education about photoprotection in specialized dermatology clinics for OTR. Whereas surgery remains the gold-standard therapy for NMSC, noninvasive methods have shown promising results to treat superficial keratoses and subclinical lesions on large body areas. Although the threshold of skin cancer necessitating revision of immunosuppression is debated, this measure should be envisaged at the occurrence of the first SCC, or in case of multiple non-SCC NMSC. While the role of immunosuppressants in the occurrence of NMSC is widely recognized, the best immunosuppressive strategies remain to be defined. Presently, randomized prospective studies assess the burden of new skin tumors, as well as graft and patient survival, in patients with one or several NMSC after the introduction of mTOR (mammalian target of rapamycin) inhibitors.

Nonmelanoma skin cancer (NMSC) is the most common malignancy occurring in white populations. It is currently becoming an important challenge in terms of public health management as the increasing incidence rates will probably have a tremendous impact on healthcare costs. Possible factors driving this rise in NMSC numbers are increases in both acute and prolonged UV exposure together with increasing numbers of older people in the population. A better understanding of NMSC epidemiology in Europe is essential if an evidence-based European-wide public health policy is to be developed. It is obvious this can only be achieved by recording and analysing comparative epidemiological data. Finally, by improving the skin examination training for physicians, developing guidelines and exchanging best practices, a high level of healthcare could be provided for NMSC.

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Although the proportion of HTR developing new tumors is greater as compared with KTR, the mean number of tumors per patient is higher in KTR. This could be due to a longer immunosuppression in patients younger at transplantation.

Human papillomaviruses (betaPV) from the beta genus cannot be classified according to their oncogenicity due to a paucity of information. This study evaluates the association between betaPV infection and cutaneous squamous cell carcinoma in conjunction with measures of UV exposure and susceptibility. We performed casecontrol studies in the Netherlands, Italy, and Australia, countries with profoundly different UV exposures. The presence of 25 betaPV types in eyebrow hair follicles was determined using a highly sensitive HPV DNA genotyping assay, and antibodies for the 15 most prevalent betaPV types in a total of 689 squamous cell carcinoma cases and 845 controls were detected using multiplex serology. Multivariate logistic regression models were used for case-control comparisons and interaction analyses. BetaPV DNA was detected in eyebrow hairs of more than 90% of all participants. The presence of betaPV DNA was associated with an increased risk of squamous cell carcinoma in the Netherlands (OR ¼ 2.8; 95% CI 1.3-5.8) and Italy (OR ¼ 1.7; 95% CI 0.79-3.6), but not in Australia (OR ¼ 0.91; 95% CI 0.53-1.6). Seropositivity for betaPV in controls ranged between 52% and 67%. A positive antibody response against 4 or more betaPV types was associated with squamous cell carcinoma in Australia (OR ¼ 2.2; 95% CI 1.4-3.3), the Netherlands (OR ¼ 2.0; 95% CI 1.2-3.4) and fair-skinned Italians (OR ¼ 1.6, 95% CI 0.94-2.7). The association between UV susceptibility and squamous cell carcinoma was stronger in betaPV-seropositive people. These combined data support the hypothesis that betaPV may play a role in the development of cutaneous squamous cell carcinoma. Cancer Res; 70(23); 9777-86. Ó2010 AACR.