Cumulative UV Exposure or a Modified SCINEXA™-Skin Aging Score Do Not Play a Substantial Role in Predicting the Risk of Developing Keratinocyte Cancers after Solid Organ Transplantation-A Case Control Study

Abstract

The risk of keratinocyte cancer is determined by intrinsic and extrinsic factors, which also influence skin aging. Few studies have linked skin aging and UV exposure with the incidence of non-melanoma skin cancer (NMSC). We evaluated signs of actinic skin damage and aging, individual UV burden, and melanocortin-1 receptor (MC1R) variants. A total of 194 organ transplant recipients (OTR) who suffered from NMSC were compared to 194 tumor-free controls matched for gender, age, type of transplanted organ, post-transplantation (TX) period, and immunosuppressive therapy. Compared with the cases, the controls scored higher in all skin aging scores and there were no differences in UV burden except for intentional whole-body UV exposure for specific UV scenarios and periods of life in favor of cases. The number of NMSCs correlated with all types of skin aging scores, the extent of intentional sun exposure, older age, longer post-TX period, shorter interval from TX to first NMSC, and specific MC1R risk groups. Multivariable models revealed a 7.5-fold risk of developing NMSC in individuals with actinic keratosis; 4.1- or 3.6-fold in those with green or blue eyes, respectively; and a 1.9-fold increased risk in the MC1R medium- + high-risk group. In the absence of skin aging contributing to NMSC development, certain MC1R risk types may identify OTR at risk for high tumor burden.

Keywords: MC1R; UV burden; immunosuppression; keratinocyte cancer; skin aging; solid organ transplant recipients.

Figure 1

Anatomical localization of NMSC subtypes.

Figure 2

Signs of skin aging and skin aging scores. Significant p values are indicated by asterisks: * p < 0.05, ** p < 0.01, *** p < 0.001. (A) Signs of skin aging in cases and controls; (B) skin aging scores (mean ± standard deviation) in cases and controls; (C) in age groups ≥60 (n = 310) and <60 (n = 78) years at time of evaluation; (D) in males (n = 298) and females (n = 90); (E) correlated with smoking history: smokers (n = 243) and non-smokers (n = 145); (F) in cases with ≥5 NMSCs (n = 87) and cases with 1–4 NMSCs (n = 107); (G) in cases with ≥10 NMSCs (n = 44) and cases with 1–9 NMSCs (n = 150).

Figure 2

Signs of skin aging and skin aging scores. Significant p values are indicated by asterisks: * p < 0.05, ** p < 0.01, *** p < 0.001. (A) Signs of skin aging in cases and controls; (B) skin aging scores (mean ± standard deviation) in cases and controls; (C) in age groups ≥60 (n = 310) and <60 (n = 78) years at time of evaluation; (D) in males (n = 298) and females (n = 90); (E) correlated with smoking history: smokers (n = 243) and non-smokers (n = 145); (F) in cases with ≥5 NMSCs (n = 87) and cases with 1–4 NMSCs (n = 107); (G) in cases with ≥10 NMSCs (n = 44) and cases with 1–9 NMSCs (n = 150).

Figure 3

Correlations between UV exposure, localization, and number of NMSCs. NMSC types are shown as colored circles and the percentage of NMSCs as colored wedges, with the intensity of the colors corresponding to the percentage of the total number of each tumor. Significant p values are indicated by asterisks, *: p < 0.05, **: p < 0.01, ***: p < 0.001.

Figure 4

Distribution of MC1R risk groups in different cases/controls scenarios: (A) correlated with skin aging scores; significant p values (p < 0.05) calculated by Chi-square test are displayed in bold; n.a.: not available, ISA: intrinsic skin aging, ESA: extrinsic skin aging, TSA: total skin aging; (B) in the entire study population, *: p = 0.03; (C) in cases with ≥5 NMSC (n = 87) and cases with 1–4 NMSC (n = 107), **: p = 0.004; (D) in cases with ≥10 NMSC (n = 44) and cases with 1–9 NMSC (n = 150), **: p = 0.01; (E) in cases with ≥5 NMSC (n = 87) and matched controls (n = 87), **: p = 0.008; (F) in cases with ≥10 NMSC (n = 44) and matched controls (n = 44), **: p = 0.019; (G) in cases with ≥5 NMSC and FST II (n = 48) and matched controls and FST II (n = 34), **: p = 0.008; (H) in cases with ≥10 NMSC and FSTIII (n = 15) and cases with 1–9 NMSC and FSTIII (n = 68), **: p = 0.008.

Figure 5

Multivariate logistic regression analysis for factors contributing to the risk of NMSC development. The x-axis represents the odds ratios (diamonds) and 95% confidence intervals (solid horizontal lines). The dashed vertical line indicates an OR value of 1 (no effect). Factors identified in multivariable models and significantly associated with NMSC development included blue eyes (OR: 3.6; 95% CI: 2.02–6.28; p < 0.001), green eyes (OR: 4.1; 95% CI: 1.88–8.81; p < 0.001), MC1R medium- + high-risk variants (OR: 1.9; 95% CI: 1.13–3.08; p = 0.015), and AKs (OR: 7.5; 95% CI: 4.08–13.68; p < 0.001).