Skin cancer in organ transplant recipients : histopathological and epidemiological studies

Abstract: Organ transplant recipients (OTRs) have an increased risk of developing a broad spectrum of cancer types, mainly skin cancer. Posttransplantation risk and incidence vary among the three major skin cancer types: cutaneous squamous cell carcinoma (SCC), basal cell carcinoma (BCC), and cutaneous malignant melanoma (melanoma). The etiology is multifactorial but long-term immunosuppression, leading to impaired tumor surveillance and viral defense, is probably the main factor. The overall aim of this thesis is to improve the understanding of the greatly increased risk of skin cancer in this patient group. The investigations were portioned into four parts. Study 1 aimed at gaining a better insight into the link between SCC and the surrounding inflammatory infiltrate. The percentage distributions and cell densities (cells/mm2 tumor section area) in the peritumoral infiltrate of SCCs were therefore compared between OTRs and immunocompetent control patients. In conclusion, the peritumoral infiltrates in OTRs differed in cellular composition, although not in cell densities, which was surprising and implying a more tumor-submissive microenvironment. To further address the aim, data from population-based and nation-wide healthcare registers, mandatory cancer reporting and the Swedish Melanoma Register were evaluated: In Study 2, the risk of posttransplantation cancer was analyzed overall, by anatomical site and by transplanted organ. The Swedish cohort of OTRs, transplanted 1970 – 2008 and including more than 10,000 patients were compared with the general population (SIR = standardized incidence ratio). The relative risk of cancer varied by anatomical site, with the bulk of the excess risk being coupled with an exceptionally high risk of SCC (120-fold). The risk estimates were highest in heart and/or lung (198-fold) and lowest in liver OTRs (32- fold). During follow-up the risk of SCC tripled over 20 years irrespective of graft type, whereas risk of cancer overall, excluding SCC, remained stable. These findings underscore the importance of regular skin screening in OTRs. In Study 3 clinicopathological characteristics of 49 posttransplantation melanomas and mortality in comparison with melanomas from the general population were assessed. Melanomas in OTRs were more advanced at diagnosis with respect to Clark level and clinical stage, but not with respect to millimeter thickness. The risk of melanoma-specific death was 3-fold increased in OTRs compared to the population. Histological reassessment revealed that 73% of all melanomas in OTRs (36 out of 49 cases) were associated with a melanocytic nevus, mainly of the dysplastic/atypical type and the trunk was the most common nevusassociated site (21/ 25, 84%). This fact may be a reason to consider prophylactic excision of truncal nevi among OTRs. Also, only very few cases demonstrated abundant tumorinfiltrating lymphocytes (TILs), indicating that more variables than just millimeter thickness may be associated with prognosis of posttransplantation melanoma. In Study 4 the relative risk of BCC in 4,023 OTRs, transplanted 2004 – 2011, were compared with the general population (SIR = standardized incidence ratio) by using the 2004 established Basal Cell Carcinoma Register. The risk of BCC among OTRs was 6-fold increased and the risk was highest in kidney (7.2-fold) and lowest in liver OTRs (2.6-fold). The risk of BCC increased with time since transplantation and was also increased in patients ≥65 years at transplantation. In comparison to BCC, the SCC incidence was lower and resulted in a SCC to BCC ratio of 1: 1.7, which was considerably less than previously reported and may have depended on length of follow-up time.