Renal transplantation (RT) is the most effective treatment for end-stage renal disease (ESRD). However, posttransplant malignancy is the leading cause of death and allograft loss, reducing the recipient’s lifespan and requiring heightened surveillance (1–3). Skin cancer, commonly categorized as non-melanoma skin cancer (NMSC) and melanoma according to tumor incidence, recurrence, metastasis, and aggressiveness (4, 5), represents a major threat to RT recipients. NMSC, primarily squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), is the most frequent posttransplant malignancy, with a total incidence of 7.5%, which is up to 100-fold greater than that in the general population (6–11). Melanoma has a posttransplant incidence 1.5–2.5 times greater than that during dialysis (12–15) and is associated with high mortality and metastasis, comprising only 4% of cutaneous malignancies, but accounting for 80% of skin cancer deaths in the general population (16, 17).

Several studies have been conducted on posttransplant skin cancer (PTSC). Ponticelli et al. reviewed PTSC regarding its histopathological classification, characteristics, and treatment (18). In the general population, SCC is the second most common cancer in Caucasians, outnumbered by BCC at a 4:1 ratio (19). However, in transplant recipients, this ratio is reversed; the incidence of SCC is higher, followed by BCC (16, 17). This may reflect different pathogenic mechanisms underlying the development of these tumors in kidney transplant recipients. Ascha et al. highlighted the risk factors for melanoma and reported a greater risk of melanoma in American RT recipients than in the general population (20). Immunosuppressive therapy, skin color, and viral infection are widely recognized risk factors for skin cancer (17). Immunosuppressive agents are known to accelerate melanoma development in transplant recipients (21), whereas NSMC is closely related to sun exposure [especially ultraviolet (UV) radiation] (6, 22). Genetic factor as a fundamental cause of oncogenic activity should not be ignored. Laing et al. revealed that methylene tetrahydrofolate reductase (MTHFR) polymorphism plays a critical role in the elevated rate of SCC in renal transplant recipients (23, 24). Nevertheless, research in this field has mainly focused on the prevalence and risk factors for skin cancer after RT, but has not explored further aspects. Other studies were limited to one kind of skin cancer, NMSC or melanoma, and lack comprehensive comparison of different kinds of skin cancer.

Hence, we conducted a retrospective population-based cohort study using data from the Organ Procurement and Transplantation Network (OPTN) that includes three pathological types of PTSC. The study aimed to compare the outcomes of recipients and grafts and to identify risk factors for PTSC. We explore the impact of risk factors on PTSC development and outcomes. Our findings will improve our understanding of PTSC and could aid in the development of strategies to prevent or treat skin cancers in RT recipients.

From January 2000 to December 2014, 241,627 patients received renal transplant registration in the United Network for Organ Sharing (UNOS). A total of 199,564 RT recipients met the inclusion criteria, of whom 7,334 (3.68%), 6,093 (3.05%), and 936 (0.47%) were diagnosed with SCC, BCC, and melanoma after RT, respectively.

Compared with the cancer-free group, cancer groups were older (56.01–57.33 vs. 48.95 years), were more male (69.7%–74.1% vs. 59.8%), had a higher proportion of Caucasians (92.3%–95.5% vs. 51.6%), had lower creatinine at discharge (2.30 vs. 2.82 mg/dl), had more pretransplant malignancy history (12.7%–13.7% vs. 4.5%), and had more polycystic kidney disease (PKD)-induced ESRD (16.6%–19.9% vs. 8.6%), but fewer had diabetes (17.3%–24% vs. 24.5%)- or hypertension (13.6%–15.1% vs. 22.5%)-induced ESRD, had more blood type A (42.9%–45.5% vs. 37.1%) and type B (8%–10.3% vs. 13%) but less type O (41.6%–42.2% vs. 45.1%), had a shorter waiting time (1.42–1.52 vs. 1.93 years) and dialysis duration (1.91–2.09 vs. 3.13 years), had less diabetes history (24.3%–31.3% vs. 31.3%), had less viral infection history including hepatitis B virus (HBV; 1%–1.6% vs. 1.8%), cytomegalovirus (CMV; 4.7%–5.2% vs. 5.5%), and human immunodeficiency virus (HIV; 0%–0.2% vs. 0.4%), had a higher proportion of college degrees (53%–55.6% vs. 42.8%), and had more private insurance (49.4%–55.6% vs. 38.7%). Regarding donors, cancer groups exhibited lower Kidney Donor Profile Index scores (KDPI; 0.39–0.41 vs. 0.41), were older (41.72–41.93 vs. 39.25, years), were not male (48.8%–50.1% vs. 52.4%), had a significantly higher proportion of Caucasians (86.9%–90.2% vs. 68.6%), had less obesity (22.8%–23.6% vs. 24.2%), had less deceased donors (46.5%–50.9% vs. 61.2%), had more donor skin cancer history (0.5%–0.7% vs. 0.3%), and had less human leukocyte antigen (HLA) mismatch (66.8%–73.3% vs. 76.9%). With regard to immunosuppressant therapy at discharge, cancer groups used less T-cell-depleting antibodies (29.6%–31.4% vs. 28.3%) and mTOR inhibitors (5.2%–6.1% vs. 7.7%), but more tacrolimus (72.7%–74.9% vs. 71.8%) and mycophenolic acid (MPA; 84.3%–84.9% vs.81.9%) ( Table 1 ).

Melanoma patients were the oldest (57.33 [11.42] years), were mostly male (74.1%), were the most obese (31.4%), had the most pretransplant malignancy (13.7%) and skin cancer (6.9%) histories, had a history of diabetes (31.3%), had the lowest KDPI (0.39 [0.27]), had the lowest HLA mismatch (66.8%), and had the lowest acute rejection incidence rate (0.7%). Among NSMC, there were no significant differences between baseline SCC and BCC rates ( Table 1 ).

The skin color of the patients was associated with the incidence of skin cancer. The proportion of Caucasian patients with skin cancer was 40% higher than that in cancer-free patients. Interestingly, in the donor cohort, the proportion of Caucasians in the skin cancer group was 20% higher than that in the cancer-free group ( Table 1 ). To clarify the significant proportion difference in donor ethnicity, we analyzed the proportion of recipient ethnicity who received Caucasians’ donor kidney. Compared to the cancer-free group, there is an obviously higher proportion of Caucasians who received kidney from a Caucasian donor (95.8%–97.1% vs. 65.7%), while a lower proportion of Blacks received kidney from a Caucasian donor in the skin cancer group (0.6%–1.5% vs. 20.6%). Furthermore, in both living donors and deceased donors, Caucasian recipients in skin cancer groups are more likely to receive a Caucasian donor kidney than those in the cancer-free group (living donor, 51.4%–57.2% vs. 34.5%; deceased donor, 40.0%–45.3% vs. 31.1%) ( Supplementary Table 1 ). Regarding proportion of cancer type in ethnic groups, the most common type of PTSC in Blacks is SCC (81.3%). Pretransplant malignancy was also a risk factor for skin cancer incidence after transplantation. The incidence rate of skin cancer history in the cancer group was 5% higher than that in the cancer-free group and nearly 10% higher in terms of total malignancy history ( Table 1 ).

It is important to acknowledge the PTSC from three disease dimensions of incidence, onset momentum, and prognosis (mortality). We found not only that the risk factors for three dimensions of PTSC were different, but also that the effects of some cofounders on PTSC incidence, onset momentum, and mortality were opposite. Patients with hypertension, diabetes-induced ESRD, deceased donor, or T-cell-depleting agents have a significantly lower incidence risk of PTSC but a poorer prognosis if diagnosed with PTSC. On the contrary, PKD-induced ESRD or mTOR inhibitor use will raise the patient’s PTSC risk but exhibit relatively better outcome. Regarding outcomes, PTSC, particularly BCC, exhibited better outcomes, while patients with melanoma showed comparable PS and better GS compared with cancer-free cancer RT recipients.

Skin carcinogenesis following RT is associated with several factors, including immunosuppressive therapy, UV exposure, light skin color, genetic and epigenetic factors, viral infection, and psychogenic factors (20, 25–27). Laing et al. depicted that SCC was featured by aberrant methylation of DNA, which appears related to polymorphisms of MTHFR (28). An international survey indicated that the incidence rates of skin cancer were observed to increase with age in all of the studied countries including the USA (29). Skin cancer is more common in light-skinned Caucasians than in persons with skin of color and is often associated with greater morbidity and mortality, but is related to a slower onset momentum because skin color would minimize the likelihood of early detection of these tumors (30). Patients with pretransplant malignancies are prone to PTSC, which was also reported in another study using UNOS data. Patients with a history of malignancies had a hazard ratio of 1.77 to develop first posttransplant malignancy and 1.23-fold risk of mortality (31). A population-based study assessed the incidence of NMSC in American men, and it was twice that in women. Clearly, sex-related hormonal differences may play key roles in UV-induced skin inflammation and cancer development (32, 33). Considering that graft kidneys are unlikely to affect the patient’s skin and Caucasian candidates are more likely to be paired with Caucasian donors in living donor donations, whether Caucasian donors are a risk factor need to be determined by further studies. Generally, lower socioeconomic status is associated with decreased sun protection practices (34–36), but recipients with private insurance in our study, which usually means greater socioeconomic status, displayed an elevated risk of PTSC, which may be explained by the fact that most private insurance owners are Caucasian. Meanwhile, Caucasians or private insurance owners have a relatively lower risk of mortality, resulting from timely therapy with a shorter delay between diagnosis and definitive surgery (37, 38). Previous studies showed that PKD is an independent risk factor for NMSC development after RT, but the mechanisms linking PKD and NMSC are unclear. T-cell-depleting agents increasing the risk of cancers, such as melanoma, have already been proven (39, 40). The maintenance regimen often includes a calcineurin inhibitor (tacrolimus or cyclosporin), an antiproliferative agent (MPA or azathioprine), and steroids, all which are known to increase the risk of cutaneous malignancies. Our analysis corroborates results from current literature (41). Ascha et al. reported that sirolimus was a risk factor for melanoma after RT; however, another prospective clinical study suggested that mTOR inhibitors could have a preventive effect on PTSC genesis (42). We found that patients who used mTOR inhibitors at discharge, an immunosuppressant well known for its antioncogenic effects (43, 44), had a significantly decreased risk of PTSC. Interestingly, obesity is associated with a decreased risk of developing non-melanoma skin cancers. On one hand, obese individuals may likely spend less time outdoors with less chronic sun exposure (45). On the other hand, the “obesity paradox” has revealed that obesity may potentially attenuate the magnitude of inflammation (46). The protective effect of metformin, an antidiabetic drug associated with decreased cancer risk, on skin cancer in patients with diabetes has been proven in a cohort study in Taiwan (47, 48). Nevertheless, diabetes negatively impacts the recipients’ health and results in a worse prognosis. Several plausible hypotheses have been proposed for the observed association between ABO blood groups and skin cancer risk. Celi´c et al. demonstrated that the AB blood group was significantly associated with the occurrence of NMSCs (49), whereas Xie et al. revealed an association between the non-O blood group and a decreased risk of each type of skin cancer (50). One study found that patients with deceased donor had a significantly lower risk of PTSC incidence compared with those who did not. In our study, recipients of kidney from a deceased donor had a 1.38 greater hazard of mortality compared with living donor recipients. This is partially discordant with prior studies, with patients from deceased donors experiencing greater incidence of cancer and mortality (3, 51).

Skin cancer is the most commonly diagnosed cancer in the United States, in both RT recipients and the general population (4, 52, 53), threatens RT recipients’ lifespan and quality (11, 16, 22), and is regarded as a contraindication to transplantation (54). Partially congruent with previous studies, we observed higher morbidity but moderate skin cancer mortality in RT recipients. Compared with cancer-free patients after transplantation, posttransplant NMSC patients exhibited better survival, even melanoma, which usually results in early metastasis and is highly aggressive, also presented comparable survival in this study. This may be explained by the following reasons: (1) Tumor patients may have an inactive (immune escape) immune system to favor tumor progression but a better immune tolerance, which would be beneficial in terms of reducing transplant kidney rejection (55). It could also explain the fact that PTSC patients show lower proportion of HLA mismatch, lower creatinine at discharge, lower rate of delay graft function, and acute rejection. (2) RT patients are more proactive and regular in the early stages after RT, resulting in early treatment. Considering that skin cancer rarely impacts the kidney or allograft, and recipients with PTSC were more likely to undergo closer medical follow-up and thorough surveillance strategies, these recipients exhibited better GS features than cancer-free patients. (3) Given the time of skin cancer diagnosis in our study was more than 5 years after transplantation, most PTSC patients experience immunosuppression, and reducing it would not significantly impair their immune balance. However, skin cancer, especially melanoma, remains a common cause of death in patients with PTSC. Several studies found that melanoma and NMSC after transplantation are common causes of substantial mortality (26, 56). Combined with evidence from our study, the mean time to developing PTSC after RT was approximately 10 years and PTSC incidence increased gradually. The epidemiological features and tendency of PTSC provide important perspectives on prevention and evaluation of PTSC over the long-term and allow clinicians to take subsequent active steps to achieve the expected benefit during the early follow-up period.

Notably, this study may provide a basis for PTSC screening and treatment, especially for risk stratification and the development of individualized strategies. Considering that PTSC does not obviously impact PS and GS, which was demonstrated in our study, routine screening for PTSC may not be necessary for all recipients, but individualized screening among high-risk individuals particularly in the early follow-up period, especially cancer history, may be a more suitable and cost-effective approach.

Our research is a comprehensive observation that enrolled a large sample size spanning 15 years of registry and 7–10 years of follow-up period nationwide. However, several limitations exist in this study. First, despite the relatively large sample size, we lack information regarding cancer risk after transplant failure and are limited to avoiding loss to follow-up, which might result in underestimation of PTSC mortality in RT recipients. Secondly, information regarding sun exposure, such as occupational or recreational pastimes and sun protective habits, was unavailable. Thirdly, granular patient information of the data, particularly as it relates to immunosuppressive scheme during follow-up, and skin cancer details such as grade, stage, and therapies are insufficiently detailed in the UNOS registry. Finally, we could not assess certain risk factors for melanoma because they were not captured in the UNOS database.

Older age, male, Caucasian recipients, having pretransplant malignancy, PKD-induced ESRD, retransplantation, private health insurance, use of T-cell depletion, tacrolimus, and MPA are risk factors of PTSC incidence. Obesity, B blood group, hypertension- or diabetes-induced ESRD, diabetes history, deceased donor, and mTOR inhibitor use decreased the risk of PTSC incidence. Despite PTSC being a major cause of recipient death, its impact on both PS and GS remains limited. Given the differences in individual risks for PTSC and overall prognosis, a personalized approach to screening may be an appropriate strategy to address the complex issues encountered by RT recipients.

Publicly available datasets were analyzed in this study. This data can be found here: https://optn.transplant.hrsa.gov/data/request-data/.

Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

XH, WL, JD, and QY designed the study. XH and WL conducted the statistical analysis and wrote the manuscript. All authors contributed to the critical revision of the manuscript for intellectual content and revised the manuscript. All authors read and approved the final manuscript.

We gratefully acknowledge research support of the OPTN/UNOS data and Dr. Nahel Elias of the Center for Transplantation Sciences and Division of Transplant Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA, for providing guidance in data analysis.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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