Skin cancer in relation to tobacco use and organ transplantation

Abstract

Background: Skin cancer incidence in fair-skinned populations has increased more rapidly than any other cancer form during the past several decades. The possible impact of common exposures in the population, such as tobacco use and overweight/obesity, is not established. The risk of cutaneous squamous cell carcinoma (CSCC) in organ transplant recipients (OTR) is substantially increased, although the underlying mechanism is not known. From previous studies of multi-drug regimens it has been suggested that risk of post-transplant CSCC is conferred by an overall immunosuppressive burden rather than by specific drugs.

Aims and methods: The first aim of this thesis was to evaluate the impact of tobacco use and body mass index (BMI) on the risk of CSCC and cutaneous malignant melanoma (CMM), melanoma in situ (MIS), and intraocular malignant melanoma (IMM). To accomplish this aim we analyzed a large retrospective cohort of Swedish male construction workers (n≈340 000) with prospectively collected exposure information and virtually complete follow-up. The second aim was to separate the effects on post-transplant CSCC occurrence of immunosuppressive level, infections, immunosuppressive drug use, and other potential risk factors. For this purpose we designed a case-control study, nested in the population-based cohort of OTRs (n≈6 000), and collected detailed exposure information from patient medical records by use of a standardized questionnaire.

Results: Current smokers were associated with a 30-50% risk reduction of CMM, MIS and IMM, compared to never tobacco users. Risk of CMM and MIS decreased with increasing smoking duration and quantity. Similarly, exclusive users of cigarettes, pipe and snuff were at reduced risks of CMM and MIS. Tobacco smoking was, however, unrelated to risk of CSCC. Snuff use was associated with a 40% decreased risk of CSCC, compared to non-tobacco users. A BMI ≥25 kg/m2 was associated with a 1.3-fold increased risk of CMM, compared to a BMI<25 kg/m2, but there was no effect on risk of MIS, IMM or CSCC. Azathioprine (Aza) treatment was found to considerably increase the risk of CSCC during all time periods analyzed post-transplantation. Additionally, a high accumulated dose of corticosteroids (Cs) after longer treatment durations conferred an increased risk of CSCC, compared to a very low accumulated dose of Cs. Cyclosporine treatment was unrelated to risk of CSCC. There were no significant associations between number or type of post-transplant infections and CSCC. HLA type and mismatch, number of transplantations and rejections, type of organ, as well as donor characteristics were not associated with risk of CSCC in OTRs.

Conclusions: In our study, tobacco use was associated with a decreased risk of CMM and MIS, but unrelated to risk of CSCC. Likewise, we found a relation between overweight/obesity and an increased risk of CMM, but not of CSCC, MIS or IMM. These findings need further research in order to understand the underlying mechanisms. Post-transplant CSCC development seems not to be a result of immunosuppressive burden, instead we found important differences in risk conferred by specific immunosuppressive drugs. Other transplant-related factors were not associated with CSCC risk in our study. Future studies are required to further separate the direct carcinogenic, and the indirect immunosuppressive, effects of immunosuppressive drugs on risk of CSCC in OTRs and in other patient groups.