Improved detection reveals active ß-papillomavirus infection in skin lesions from kidney transplant recipients.

The aim of this study was to determine whether detection of ß-HPV gene products, as defined in epidermodysplasia verruciformis skin cancer, could also be observed in lesions from kidney transplant recipients alongside the viral DNA. A total of 111 samples, corresponding to 79 skin lesions abscised from 17 kidney transplant recipients, have been analyzed. The initial PCR analysis demonstrated that ß-HPV-DNA was highly present in our tumor series (85%). Using a combination of antibodies raised against the E4 and L1 proteins of the ß-genotypes, we were able to visualize productive infection in 4 out of 19 actinic keratoses, and in the pathological borders of 1 out of 14 squamous cell carcinomas and 1 out of 31 basal cell carcinomas. Increased expression of the cellular proliferation marker minichromosome maintenance protein 7 (MCM7), that extended into the upper epithelial layers, was a common feature of all the E4-positive areas, indicating that cells were driven into the cell cycle in areas of productive viral infections. Although the present study does not directly demonstrate a causal role of these viruses, the detection of E4 and L1 positivity in actinic keratosis and the adjacent pathological epithelium of skin cancer, clearly shows that ß-HPV are actively replicating in the intraepidermal precursor lesions of kidney transplant recipients and can therefore cooperate with other carcinogenic agents, such as UVB, favoring skin cancer promotion.

Dietary immunosuppressants do not enhance UV-induced skin carcinogenesis, and reveal discordance between p53-mutant early clones and carcinomas.

Immunosuppressive drugs are thought to cause the dramatically increased risk of carcinomas in sun-exposed skin of organ transplant recipients. These drugs differ in local effects on skin. We investigated whether this local impact is predictive of skin cancer risk and may thus provide guidance on minimizing the risk. Immunosuppressants (azathioprine, cyclosporine, tacrolimus, mycophenolate mofetil, and rapamycin) were assessed on altering the UV induction of apoptosis in human skin models and of p53 mutant cell clones (putative tumor precursors) and ensuing skin carcinomas (with mutant p53) in the skin of hairless mice. Rapamycin was found to increase apoptosis (three-fold), whereas cyclosporine decreased apoptosis (three-fold). Correspondingly, a 1.5- to five-fold reduction (P = 0.07) or a two- to three-fold increase (P < 0.001) was found in cell clusters overexpressing mutant p53 in chronically UV-exposed skin of mice that had been fed rapamycin or cyclosporine, respectively. Deep sequencing showed, however, that the allelic frequency (∼5%) of the hotspot mutations in p53 (codons 270 and 275) remained unaffected. The majority of cells with mutated p53 seemed not to overexpress the mutated protein. Unexpectedly, none of the immunosuppressants admixed in high dosages to the diet accelerated tumor development, and cyclosporine even delayed tumor onset by approximately 15% (P < 0.01). Thus, in contrast to earlier findings, the frequency of p53-mutant cells was not predictive of the incidence of skin carcinoma. Moreover, the lack of any accelerative effect on tumor development suggests that immunosuppressive medication is not the sole cause of the dramatic increase in skin cancer risk in organ transplant recipients.

Subsequent squamous- and basal-cell carcinomas in kidney-transplant recipients after the first skin cancer: cumulative incidence and risk factors.

BACKGROUND: The risk of skin cancer is highly increased in kidney-transplant recipients (KTR), but the risk of subsequent skin cancers is less well studied. The aim of this study was to estimate the cumulative incidence of subsequent squamous- and basal-cell carcinomas (BCCs) and to analyze potential risk factors. METHODS: All histologically confirmed skin cancers between 1966 and 2006 were included in the study and counted. Cumulative incidences of subsequent squamous- and BCCs were calculated using Kaplan-Meier survival analyses. For the analyses of risk factors, we used Cox proportional hazard analyses. RESULTS: A total of 239 (13%) of 1906 KTR developed skin cancer of whom 222 were diagnosed in our hospital. Altogether 167 (75%) of these 222 patients developed multiple skin cancers. The cumulative incidence of a second skin cancer increased from 32%, 1 year, to 59%, 3 years, and 72%, 5 years after the first skin cancer. KTR who started with squamous-cell carcinoma (SCC) mainly developed SCC and recipients who started with BCC mainly developed BCC as second skin cancer. Immunosuppression with azathioprine in combination with prednisone was associated with a significantly increased risk of subsequent SCCs but not with subsequent BCCs. CONCLUSION: Skin cancer multiplicity is common in KTR. Patients with a first skin cancer are at increased risk for more skin cancers and need to be carefully checked for subsequent skin cancers.