Abstract
Melanoma causes significant morbidity in solid organ transplant recipients (SOTRs). Melanomas diagnosed before transplantation can recur with intensive immunosuppression, but outcomes have not been well studied. We evaluated 901 non-Hispanic White SOTRs with a pretransplant melanoma identified using linked transplant and cancer registry data in the United States. Most pretransplant melanomas were invasive (60.7%), and the median time from diagnosis to transplantation was 5.1 years. After transplantation, 41 SOTRs developed a new invasive melanoma, corresponding to 9-fold increased risk compared with the general population (standardized incidence ratio 9.2, 95% confidence interval [CI] 6.6–12). Twenty-two SOTRs died from melanoma after transplantation, corresponding to 52-fold increased risk (standardized mortality ratio 52, 95% CI 33–79). Risk factors for posttransplant melanoma included age at transplantation (adjusted hazard ratio [HR] 2.86, 95% CI 1.24–6.60 for age 55+ vs. <55 years) and maintenance immunosuppression with cyclosporine/azathioprine (adjusted HR 2.53, 95% CI 1.08–5.90). Melanoma mortality was strongly elevated after a posttransplant melanoma diagnosis (HR 35.6, 95% CI 14.0–90.4, adjusted for cyclosporine/azathioprine maintenance therapy and calendar year of transplantation). In conclusion, SOTRs with a pretransplant melanoma are at risk of adverse melanoma-related outcomes after transplantation. These findings support thorough dermatologic evaluation prior to transplantation and frequent posttransplant surveillance.
Background
Melanoma is the most serious common skin cancer owing to its high potential for metastasis. Ultraviolet radiation exposure is the most important risk factor for melanoma and other skin cancers. Notably, melanoma occurs 2–5 times more frequently in solid organ transplant recipients (SOTRs) than in the general population (1). This elevated incidence is likely due, in part, to the immunosuppressive medications used to prevent organ rejection. Moreover, SOTRs are more likely than individuals in the general population to be diagnosed with advanced stage melanoma (2, 3) and to have decreased survival from melanoma (1).
For transplant candidates with a prior history of melanoma, the risk of posttransplant recurrence is a major concern, because of the likelihood of distant metastasis and consequent mortality. Importantly, the immunosuppression associated with transplantation may contribute to poor outcomes in this setting. Consideration of transplant candidacy in a patient with a history of melanoma depends on multiple factors, and data to guide clinical decisions are limited. Small retrospective studies suggest recurrence rates as high as 11–19%, while staging and survival data are lacking (4, 5).
Dermatologists who specialize in the care of SOTRs may serve as a resource to transplantation professionals to help estimate risk of recurrence of a prior melanoma in candidates considered for organ transplantation. After a melanoma diagnosis, a one-year wait time prior to transplantation is recommended for those candidates with stage IA, IB, or IIA melanoma, where the five-year melanoma-specific survival is greater than 90%, and a 1–2-year wait time is recommended for stage IIIA patients (6). The five-year melanoma-specific survival for patients with stage IIB, IIC, or IIIB is greater than 80%, with a plateau observed on the survival curve beyond five years; therefore, a wait time of 2–4 years prior to transplantation is recommended for this group (6).
Additional information regarding risk factors for new melanoma diagnoses after transplantation and mortality from melanoma would be valuable for assessment and planning surveillance of SOTRs with a pretransplant melanoma. In the present study, we used data on SOTRs with a pretransplant melanoma from the Transplant Cancer Match (TCM) Study to estimate the risk of developing a de novo posttransplant melanoma and risk of dying from melanoma (i.e., melanoma mortality) relative to the general population. We also identified risk factors for incident melanoma and for melanoma mortality in this population.
Methods
The TCM Study is a linkage of the United States (US) solid organ transplant registry (Scientific Registry of Transplant Recipients, or SRTR) with multiple US cancer registries (https://transplantmatch.cancer.gov). The study is not considered human subjects research by the National Institutes of Health and was approved, as required, by institutional review boards at participating cancer registries.
For the present study, we included recipients of a first transplant (identified in the SRTR) who resided in the catchment area of 28 participating TCM cancer registries (1990–2019) and were covered for at least one year prior to transplantation by that cancer registry. Together, these cancer registries covered 61% of the US SOTR population for this period. The cancer registries were used to identify diagnoses of cutaneous melanoma (herein, “melanoma). Using the linked transplant registry data, we then identified 936 SOTRs with a pretransplant melanoma diagnosis. The final study cohort was restricted to 901 non-Hispanic White SOTRs with a pretransplant melanoma, because of the small number of SOTRs in other racial/ethnic groups (N=35) and because all posttransplant melanoma diagnoses were observed to arise among non-Hispanic White individuals.
We identified the incidence of posttransplant invasive melanomas in this cohort using the linked cancer registry data; because cancer registries count only new cancer diagnoses and not relapses, these events represent the occurrence of de novo tumors. Similarly, we used information on the underlying cause of death, derived from death certificates and captured by cancer registries from state vital statistics databases and the National Death Index, to identify melanoma deaths (International Classification of Diseases, version 10: codes C430-C439). SOTRs were followed from transplantation until the earliest of death, end of cancer registry coverage, or loss to follow-up by SRTR (median follow-up 3.8 years, interquartile range 1.3–7.0 years). For analyses where posttransplant melanoma was the outcome, SOTRs were additionally censored if they developed a posttransplant melanoma.
We calculated the standardized incidence ratio (SIR) comparing the incidence of invasive melanoma among the included SOTRs to the general population. We similarly calculated the standardized mortality ratio (SMR) comparing melanoma mortality among SOTRs to the general population. Both calculations used expected rates for White individuals from eight Surveillance, Epidemiology, and End Results cancer registries (SEER8, https://seer.cancer.gov/) stratified by sex, age, and calendar year.
We evaluated demographic characteristics, transplant-related factors, and characteristics of the pretransplant melanoma as risk factors for posttransplant invasive melanoma and melanoma mortality in unadjusted Cox proportional hazards models. In addition, we evaluated a diagnosis of posttransplant invasive melanoma as a risk factor for melanoma mortality, treating this as a time-dependent variable in the Cox model. Because of a limited number of events, we used liberal p-value thresholds to identify borderline associations in univariate models (p=0.10 for melanoma incidence, p=0.15 for melanoma mortality). Variables that were significant (p<0.05) or borderline significant were assessed in multivariable models but were kept in the final models only if their p-value in the multivariable model was below 0.05. We tested the proportional hazards assumption for variables in this final group by including an interaction with the log of follow-up time in the regression model.
Results
We evaluated a study cohort of 901 non-Hispanic White SOTRs with a pretransplant diagnosis of melanoma (Table 1). Most of these SOTRs were male (71.3%), and the median age at transplantation was 62 years. Most SOTRs (94.5%) had a single pretransplant melanoma diagnosis, and the majority of pretransplant melanomas were in situ or localized-stage invasive tumors (39.3% and 50.0%, respectively). The median time from melanoma diagnosis to transplantation was 5.1 years (3.9 years for in situ melanoma, 5.8 years for invasive melanoma). Eighty-one percent of the SOTRs received induction immunosuppression and 80.4% received maintenance immunosuppression with tacrolimus and/or mycophenolate.
Table 1.
Characteristics of 901 non-Hispanic White transplant recipients with a pretransplant diagnosis of melanoma
| Characteristic | Number of transplants, % |
|---|---|
|
| |
| Male sex, N (%) | 642 (71.3) |
| Age at transplantation in years, median (interquartile range) | 62 (55–67) |
| Transplanted organ(s), N (%) | |
| Kidney | 512 (56.8) |
| Liver | 205 (22.8) |
| Heart | 83 (9.2) |
| Lung | 62 (6.9) |
| Other/multiple | 39 (4.3) |
| Calendar year of transplantation, N (%) | |
| 1990–1999 | 64 (7.1) |
| 2000–2009 | 393 (36.5) |
| 2010–2019 | 508 (56.4) |
| Number of pretransplant melanoma diagnoses, N (%) | |
| One | 851 (94.5) |
| Two or more | 50 (5.6) |
| Melanoma behavior1 N (%) | |
| In situ | 354 (39.3) |
| Invasive | 547 (60.7) |
| Melanoma stage1, N (%) | |
| In situ | 354 (39.3) |
| Localized | 451 (50.0) |
| Regional/distant | 17 (1.9) |
| Unknown/missing | 79 (8.8) |
| Melanoma site1, N (%) | |
| Head or neck | 215 (23.9) |
| Other sites | 686 (76.1) |
| Years from melanoma diagnosis to transplantation, median (interquartile range) | 5.1 (2.4–9.3) |
| Receipt of induction immunosuppression, N (%) | 730 (81.0) |
| Maintenance immunosuppression regimen2, N (%) | |
| Tacrolimus and/or mycophenolate | 724 (80.4) |
| Cyclosporine and/or azathioprine | 52 (5.8) |
| Other | 125 (13.9) |
Statistics refer to the most recent pretransplant melanoma for individuals with more than one such diagnosis.
“Tacrolimus and/or mycophenolate” refers to receipt of either medication in the absence of cyclosporine or azathioprine. “Cyclosporine and/or azathioprine” refers to receipt of either medication in the absence of tacrolimus or mycophenolate.
Incidence of invasive melanoma after transplantation
During 4,198 person-years of follow-up, 41 of these SOTRs developed a new invasive melanoma after transplantation. Thirty-five of the posttransplant melanomas had a documented stage at diagnosis (30 localized to the dermis and 5 with extension into the dermis or involvement of regional lymph nodes). Posttransplant melanomas occurred throughout follow-up (Figure 1), and this incidence is 9-fold higher than expected in the general population (SIR 9.2, 95% confidence interval [CI] 6.6–12, Table 2). SOTRs with a pretransplant in situ melanoma and SOTRs with a pretransplant invasive melanoma had similarly elevated risk of developing a new posttransplant invasive melanoma (Table 2).
Figure 1.
Kaplan-Meier curves depict the survival probability (i.e., 1 minus the probability of developing the event) for posttransplant invasive melanoma (blue line) and melanoma mortality (red line) among SOTRs with a pretransplant melanoma. Colored regions indicate 95% confidence bands. The numbers below the plot correspond to the number of people under follow-up at each 5-year landmark.
Table 2.
Standardized incidence ratios and standardized mortality ratio analyses for non-Hispanic White solid organ transplant recipients with a pretransplant melanoma
| Incidence of posttransplant invasive melanoma | |||
|---|---|---|---|
|
| |||
| Behavior of pretransplant melanoma | Observed number of posttransplant melanomas | Expected number of posttransplant melanomas | SIR (95%CI) |
| Overall | 41 | 4.5 | 9.2 (6.6–12) |
| In situ | 10 | 1.6 | 6.4 (3.1–12) |
| Invasive | 31 | 2.9 | 11 (7.3–15) |
| Death due to melanoma | |||
|
| |||
| Behavior of pretransplant melanoma | Observed number of melanoma deaths | Expected number of melanoma deaths | SMR (95%CI) |
| Overall | 22 | 0.42 | 52 (33–79) |
| In situ | 7 | 0.15 | 47 (19–96) |
| Invasive | 15 | 0.27 | 55 (31–90) |
Abbreviations: CI confidence interval, SIR standardized incidence ratio, SMR standardized mortality ratio
Unadjusted associations with risk factors for posttransplant invasive melanoma are shown in Table 3. Incidence of posttransplant melanoma was significantly higher among older SOTRs (hazard ratio [HR] 2.96, 95% CI 1.16–7.53 for age 65+ vs. <55 years at transplantation). Based on a p-value cutoff of 0.10 to identify additional associations of borderline significance, incidence was also higher in males than females (HR 2.18, 95% CI 0.97–4.92), in SOTRs with more than one pretransplant melanoma (HR 3.15, 95% CI 0.96–10.3), and in SOTRs who received cyclosporine/azathioprine maintenance in comparison to those who received tacrolimus/mycophenolate (2.14, 0.91–5.04). In multivariable modeling, independent risk factors for posttransplant melanoma included age at transplantation (adjusted HR 2.86, 95% CI 1.24–6.60 for age 55+ vs. <55 years) and maintenance immunosuppression with cyclosporine/azathioprine (adjusted HR 2.53, 95% CI 1.08–5.90). Sex and number of pretransplant melanoma diagnoses were not associated with the incidence of posttransplant melanoma after adjustment for age (Supplemental Table 1). Both age at transplantation and cyclosporine/azathioprine met the proportional hazards assumption in the regression model (not shown).
Table 3.
Unadjusted analyses of risk factors for posttransplant invasive melanoma incidence and melanoma mortality
| Characteristic | Posttransplant invasive melanoma | Melanoma mortality | ||||
|---|---|---|---|---|---|---|
| Melanoma outcomes | HR (95% CI) | p-value | Melanoma deaths | HR (95% CI) | p-value | |
|
| ||||||
| Sex | ||||||
| Female | 7 | 1.00 | 8 | 1.00 | ||
| Male | 34 | 2.18 (0.97–4.92) | 0.06 | 14 | 0.76 (0.32–1.80) | 0.53 |
| Age at transplant, years | ||||||
| <55 | 7 | 1.00 | 7 | 1.00 | ||
| 55–64 | 19 | 2.57 (1.07–6.18) | 0.04 | 8 | 0.89 (0.32–2.45) | 0.82 |
| 65+ | 15 | 2.96 (1.16–7.53) | 0.02 | 7 | 1.00 (0.35–2.88) | 0.99 |
| Transplanted organ | ||||||
| Kidney | 25 | 1.00 | 11 | 1.00 | ||
| Liver | 9 | 0.97 (0.45–2.07) | 0.93 | 5 | 1.26 (0.44–3.64) | 0.66 |
| Heart and/or lung | 5 | 0.65 (0.25–1.71) | 0.39 | 5 | 1.69 (0.59–4.86) | 0.33 |
| Other/multiple | 2 | 1.08 (0.25–4.56) | 0.92 | 1 | 1.13 (0.15–8.79) | 0.90 |
| Calendar year of transplantation | ||||||
| 1990–1999 | 8 | 1.00 | 5 | 1.00 | ||
| 2000–2009 | 17 | 0.58 (0.24–1.40) | 0.23 | 12 | 0.47 (0.17–1.35) | 0.16 |
| 2010–2019 | 16 | 0.83 (0.32–2.16) | 0.71 | 5 | 0.25 (0.07–0.88) | 0.03 |
| Number of pretransplant melanoma diagnoses | ||||||
| One | 38 | 1.00 | 20 | 1.00 | ||
| Two or more | 3 | 3.15 (0.96–10.3) | 0.06 | 2 | 3.37 (0.79–14.4) | 0.10 |
| Pretransplant melanoma stage | ||||||
| In situ | 10 | 1.00 | 7 | 1.00 | ||
| Localized | 26 | 1.55 (0.75–3.24) | 0.24 | 11 | 1.01 (0.39–2.61) | 0.99 |
| Regional/distant | 1 | 2.05 (0.26–16.2) | 0.49 | 1 | 3.27 (0.40–26.6) | 0.27 |
| Unknown/missing | 4 | 1.19 (0.37–3.81) | 0.77 | 3 | 1.44 (0.37–5.57) | 0.60 |
| Pretransplant melanoma site | ||||||
| Head or neck | 11 | 1.36 (0.68–2.71) | 0.39 | 7 | 1.61 (0.65–3.94) | 0.30 |
| Other sites | 30 | 1.00 | 15 | 1.00 | ||
| Years from pretransplant melanoma diagnosis to transplantation | ||||||
| 0–2.49 | 14 | 1.00 | 7 | 1.00 | ||
| 2.50–4.99 | 9 | 0.69 (0.30–1.59) | 0.38 | 9 | 1.40 (0.52–3.75) | 0.51 |
| 5+ | 18 | 0.72 (0.36–1.45) | 0.36 | 6 | 0.46 (0.16–1.38) | 0.17 |
| Receipt of induction immunosuppression | ||||||
| No | 7 | 1.00 | 1 | 1.00 | ||
| Yes | 34 | 1.27 (0.56–2.88) | 0.56 | 21 | 5.17 (0.70–38.4) | 0.11 |
| Maintenance immunosuppression regimen | ||||||
| Tacrolimus and/or mycophenolate | 29 | 1.00 | 14 | 1.00 | ||
| Cyclosporine and/or azathioprine | 7 | 2.14 (0.91–5.04) | 0.08 | 5 | 4.14 (1.49–11.5) | 0.01 |
| Other | 5 | 0.77 (0.30–1.99) | 0.59 | 3 | 1.07 (0.31–3.71) | 0.92 |
| Posttransplant melanoma | ||||||
| No | 14 | 1.00 | ||||
| Yes | 8 | 32.3 (13.1–79.5) | <0.0001 | |||
Significant or borderline significant associations are underlined. P-value thresholds for borderline significance are 0.10 for incidence of posttransplant invasive melanoma and 0.15 for melanoma mortality.
Abbreviations: CI confidence, HR hazard ratio
Melanoma mortality after transplantation
Two-hundred eighty-three SOTRs died during posttransplant follow-up. Cause of death was specified for 262 (92.6%) deceased SOTRs, and 22 deaths (7.8%) were due to melanoma. Among these deaths due to melanoma, the median time from transplantation to death was 3.2 years, 18 of the deaths (82%) occurred within 5 years of transplantation, and all occurred within 10 years (Figure 1). These melanoma deaths correspond to more than 50-fold increased melanoma mortality compared with the general population (SMR 52, 95% CI 33–79, Table 2). SOTRs with a pretransplant in situ melanoma and SOTRs with a pretransplant invasive melanoma had a similar elevated risk of dying from melanoma.
Fourteen of the SOTRs who died from melanoma had only a pretransplant melanoma diagnosis, while the remaining eight SOTRs who died from melanoma also had a posttransplant diagnosis of invasive melanoma (their deaths occurred a median of 1.9 years after the posttransplant melanoma diagnosis). Among the seven SOTRs who had been diagnosed with an in situ pretransplant melanoma and subsequently died of melanoma after transplantation, five of them (71%) were also diagnosed with a posttransplant invasive melanoma. In contrast, among the 15 people who had been diagnosed with an invasive pretransplant melanoma and later died of melanoma after transplantation, only three (20%) also had a posttransplant invasive melanoma (Fisher exact p=0.05).
Unadjusted associations for risk factors for death due to melanoma are shown in Table 3. Diagnosis of a posttransplant melanoma was the strongest risk factor for melanoma mortality (HR 32.3, 95% CI 13.1–79.5). Melanoma mortality was significantly higher in SOTRs who received cyclosporine/azathioprine maintenance in comparison to those who received tacrolimus/mycophenolate (HR 4.14, 95% CI 1.49–11.5), and was significantly lower for SOTRs transplanted in the most recent decade (HR 0.25, 95% CI 0.07–0.88 for 2010–2019 vs. 1990–1999). Based on a p-value cutoff of 0.15 to identify additional associations of borderline significance, mortality was also higher in SOTRs with more than one pretransplant melanoma (HR 3.37, 95% CI 0.79–14.4), those with less than 5 years between diagnosis of the pretransplant melanoma and transplantation (HR 2.57, 95% CI 1.00–6.56), and those who received induction immunosuppression (HR 5.17, 95% CI 0.70–38.4).
In multivariable models (Table 4), melanoma mortality was independently associated with a diagnosis of a posttransplant melanoma and with either calendar year of transplantation (adjusted HR 0.21, 95% CI 0.06–0.77 for 2010–2019 vs. 1990–1999) or maintenance immunosuppression with cyclosporine/azathioprine (adjusted HR 3.23, 95% CI 1.17–8.87). When calendar year of transplantation and maintenance immunosuppressive regimen were included together in the same model, there was a suggestion that both variables remained predictive of melanoma mortality but they lost statistical significance (Table 4).
Table 4.
Multivariable analyses of risk factors for melanoma mortality
| Model/characteristic | Adjusted HR (95% CI) |
|---|---|
|
| |
| Model 1 | |
| Posttransplant melanoma | 29.1 (11.8–71.9) |
| Maintenance immunosuppression with cyclosporine and/or azathioprine1 | 3.23 (1.17–8.87) |
| Model 2 | |
| Posttransplant melanoma | 35.8 (14.2–90.2) |
| Calendar year of transplantation | |
| 1990–1999 | 1.00 |
| 2000–2009 | 0.48 (0.17–1.36) |
| 2010–2019 | 0.21 (0.06–0.77) |
| Model 3 | |
| Posttransplant melanoma | 35.6 (14.0–90.4) |
| Maintenance immunosuppression with | 2.84 (0.85–9.55) |
| cyclosporine and/or azathioprine1 | |
| Calendar year of transplantation | |
| 1990–1999 | 1.00 |
| 2000–2009 | 0.79 (0.22–2.80) |
| 2010–2019 | 0.31 (0.08–1.26) |
Abbreviations: CI confidence interval, HR hazard ratio
“Cyclosporine and/or azathioprine” refers to receipt of either medication in the absence of tacrolimus or mycophenolate.
While posttransplant melanoma and calendar year of transplantation each met the proportional hazards assumption (not shown), maintenance immunosuppression with cyclosporine/azathioprine exhibited significant nonproportionality (p=0.02). Specifically, in a model that included an interaction of cyclosporine/azathioprine with log(follow-up time), cyclosporine/azathioprine exhibited a very strong adverse association with melanoma mortality at one year after transplantation (HR 20.2, 95% CI 4.30–94.8) but this effect was reduced by a factor of 0.23 (95% CI 0.07–0.81) for every doubling of the time since transplantation.
Discussion
In this large population-based study of SOTRs with a pretransplant melanoma, we observed greatly increased risk of developing a de novo posttransplant melanoma (SIR 9.2). Although melanoma was an uncommon cause of death in this population (7.8% of all deaths), mortality from this malignancy was still strongly elevated (SMR 52) compared with the general population. Diagnosis of a posttransplant melanoma was by far the strongest risk factor for melanoma mortality, associated with roughly 30-fold increased mortality in univariate and multivariable analyses. As SOTRs with either a pretransplant in situ or invasive melanoma have an increased risk of developing a new posttransplant invasive melanoma and of dying from melanoma, we believe that dermatologic screening and surveillance posttransplantation should be mandatory for all such patients.
There are limited prior data on outcomes in SOTRs with pretransplant melanoma. Previous studies have often included few cases, which has precluded precise estimation of the risk of recurrence, de novo posttransplant melanoma, or mortality (7). A study from Australia and New Zealand that included 19 SOTRs with a pretransplant melanoma reported that there were only two posttransplant recurrences (11%) (4), while a European study with nine SOTRs with pretransplant melanoma reported no posttransplant recurrences or deaths (8). Brewer et al. examined posttransplant outcomes among 59 SOTRs with pretransplant melanoma (9). They reported no recurrences and two melanoma metastases with a mean follow-up of 10.5 years (9). This study included data from the Israel Penn International Transplant Tumor Registry, for which an earlier report suggested that 6 of 31 SOTRs with pretransplant melanoma died from posttransplant recurrences (5). However, some cases from the earlier report were excluded from Brewer et al. because they were not confirmed by pathology, which partly accounts for the lower risk estimate (9). Finally, a prior study using TCM Study data included 336 SOTRs with a pretransplant melanoma and demonstrated that this group, compared with other SOTRs, had a higher incidence of posttransplant melanoma and melanoma mortality (10). However, the study analyzed a smaller number of SOTRs with pretransplant melanoma than the current study and did not include an analysis of risk factors for posttransplant outcomes.
Our patient population is largely typical of US SOTRs, in that most were male, and the majority (58%) received a kidney transplant (Table 1). Almost all SOTRs with a pretransplant diagnosis of melanoma in our study were non-Hispanic White, and we restricted the cohort to this group. In addition, SOTRs in our patient cohort were older (median age at transplant 62 years) than typical for the transplant population, due to the strong association of age with development of melanoma in the general population. Ninety-five percent of SOTRs had only a single pretransplant melanoma, of which 39% were in situ and almost all the remainder were local stage tumors. The median time from melanoma to transplantation was 5.1 years and was shorter for SOTRs with an in situ melanoma than for those with an invasive melanoma, suggesting that these patients were selected for transplantation after a wait time sufficiently long for clinicians to consider their melanoma at low risk of posttransplant recurrence.
In this patient cohort, the greatly elevated incidence of de novo melanoma after transplantation arises as a result of the strong disposition of individuals who have at least one melanoma to develop another such diagnosis, due to skin type, history of intense ultraviolet radiation exposure, and other factors, as well as from the effects of transplant-related immunosuppression (11–13). Older age at transplantation and male sex were each associated with an increased incidence of posttransplant melanoma. SOTRs with a pretransplant diagnosis of in situ melanoma had a similar increase in risk for posttransplant melanoma as those who had a pretransplant invasive melanoma, reflecting the contribution of the same predisposing factors in both groups.
Twenty-two SOTRs with pretransplant melanoma (2.4%) died from melanoma after transplantation, equating to more than 50-fold increased melanoma mortality compared to the general population. This high mortality is explained by the strongly increased incidence of posttransplant melanoma, the advanced stage of some posttransplant tumors, as well as the impact that immunosuppression has on survival after a melanoma diagnosis (2, 14). Eight of the SOTRs in this study who died from melanoma developed a posttransplant invasive melanoma after transplantation, and the diagnosis of posttransplant melanoma was the single strongest risk factor for melanoma mortality after transplantation.
For all the SOTRS in our cohort, their pretransplant melanoma had been judged by clinicians as having a low probability of recurrence. Nonetheless, approximately two-thirds of the patients in our study who died from melanoma never developed a posttransplant melanoma reported to a cancer registry, so their death is plausibly explained as due to a fatal recurrence of their pretransplant melanoma. A fatal recurrence of the pretransplant melanoma is also suggested by the short time from transplantation to death from melanoma in many instances (median 3.2 years). Of interest, two SOTRs with pretransplant in situ melanoma died of melanoma without a recorded diagnosis of an invasive melanoma posttransplantation. A possible explanation is that their pretransplant melanoma was actually invasive but was misclassified, which can happen with the use of a partial biopsy technique, where a focus of dermal invasive melanoma is not included in the biopsy specimen, or with an excisional biopsy if the area of invasion was outside the plane of section on the examined histopathology slide (15–17). Another explanation could be that the SOTRs had developed an invasive melanoma that was missed by the cancer registry (18).
Maintenance immunosuppression with cyclosporine and/or azathioprine, in comparison to tacrolimus and/or mycophenolate, was associated with greater incidence of posttransplant melanoma and, likely as a result, with higher melanoma mortality. The direct carcinogenic effects of certain immunosuppressive medications are well known (19). Azathioprine in particular, has been shown to promote ultraviolet light-induced DNA damage (20, 21), and azathioprine-induced photosensitivity is ameliorated when this medication is replaced by mycophenolate (22). Of interest, the effect of cyclosporine/azathioprine on melanoma mortality exhibited nonproportionality, i.e., the positive association was strongest early after transplantation. Indeed, all five of the melanoma deaths in SOTRs who received cyclosporine/azathioprine occurred in the first four years after transplantation. This pattern could reflect an especially large short-term effect of these drugs in increasing the early recurrence of pretransplant melanoma.
Importantly, cyclosporine and azathioprine have been largely supplanted by tacrolimus since the early 2000s (23). We saw that melanoma mortality was substantially lower in SOTRs transplanted in 2010 or later, compared with those transplanted before 2000. It is therefore possible that the observed association between cyclosporine/azathioprine and melanoma mortality, rather than arising from the effects of these medications, could instead reflect other changes in transplantation practice over time, such as improved skin cancer screening and earlier detection of posttransplant melanomas. In a multivariable model for melanoma mortality that included both maintenance immunosuppressive regimen and calendar year of transplantation (Table 4), there was a suggestion that these were independent risk factors, but the number of deaths was too small to obtain precise estimates.
Other associations in our study deserve brief comment. Melanoma mortality was higher in SOTRs with less than five years between diagnosis of pretransplant melanoma and transplantation, although this was of borderline significance (p=0.05). This observation might suggest that some patients with pretransplant melanoma, even if their tumor was diagnosed at a localized stage, may require a longer wait time before transplantation. However, we did not have sufficient data to examine wait times in greater detail. We did not see associations between melanoma behavior (in situ versus invasive), location of melanoma, type of transplanted organ, or the use of induction immunosuppression with the incidence of posttransplant melanoma or melanoma mortality.
A strength of this study is our analysis of the largest cohort to date of SOTRs with a pretransplant diagnosis of melanoma, and these individuals were selected from population-based transplant and cancer registries. We systematically examined risk factors for de novo posttransplant melanoma and melanoma mortality and evaluated information on melanoma site and stage, as well as the type of immunosuppression utilized. Cancer registries are responsible for capturing all cancer diagnoses in their coverage region and meet quality standards of the North American Association of Central Cancer Registries, National Cancer Institute, and Centers for Disease Control and Prevention. Melanoma is a tumor that, in the past, was under-ascertained by cancer registries because localized cases diagnosed in physician offices were frequently not reported. However, ascertainment has improved over time due to increasing recognition of this issue and outreach to large medical practices (24). A limitation of our study is that cancer registries do not collect information on recurrence (i.e., relapse) of tumors, so we could not examine this outcome. Instead, we used melanoma mortality as a surrogate for recurrence, since a large proportion of melanoma recurrences after transplantation would likely be fatal. In addition, despite our assessment of a relatively large cohort of patients, the statistical power was limited by the small number of subjects with pretransplant melanoma in some subgroups and the small number of posttransplant events. A final limitation of our study is that we did not have information on American Joint Commission on Cancer tumor stage or Breslow depth, which precluded a more comprehensive evaluation of the severity of melanoma at the time of diagnosis and the impact of staging on melanoma outcomes.
Our findings highlight that SOTRs with pretransplant melanoma are at extremely high risk of de novo melanoma and melanoma mortality after transplantation. Transplant candidates with a history of melanoma should receive a thorough dermatologic evaluation, with a low threshold for biopsy of suspicious lesions, and should receive continual education regarding the importance of sun avoidance and protection. Every effort should be made to obtain medical records pertaining to surgical management of prior melanoma as part of the transplant evaluation.
Recent consensus guidelines indicate a one-year wait time prior to transplantation for transplant candidates with stage IA, IB, or IIA melanoma, a 1–2-year wait time for stage IIIA patients, and 2–4 years is recommended for stage IIB, IIC, or IIIB patients (6). The borderline association that we observed between shorter time intervals and posttransplant melanoma mortality suggests that longer wait times may be warranted. In addition, our results suggest that individuals with more than one prior melanoma diagnosis are at higher risk of posttransplant melanoma mortality and may warrant special attention. The duration of the wait period should be discussed on a case-by-case basis with the patient and the transplantation team. The routine use of sentinel lymph node biopsy should be strongly considered in patients who develop melanoma with greater than 0.8 mm Breslow depth while on the wait list, as a negative biopsy may justify reducing transplantation wait times. Importantly, consideration should also be given to life-threatening comorbidities for patients awaiting a heart, lung, or liver transplant, which provide a countervailing imperative to move to transplantation as expeditiously as possible. Dermatologists who specialize in the care of SOTRs may serve as a resource to estimate the risk of recurrence from pretransplant melanoma in patients being considered for transplantation (25).
Following transplantation, SOTRs who have had a pretransplant melanoma (in situ or invasive) require strict adherence to regular skin cancer screening, timely access to dermatologic care, and ongoing surveillance, preferably by dermatologists in specialty transplant dermatology clinics. Recent guidelines for SOTRs at high risk of skin cancer recommend screening at least every six months (26). Although we did not evaluate skin cancers other than melanoma in our study, it is likely that SOTRs with a pretransplant melanoma are at increased risk for both melanoma and keratinocyte cancers, and so they should be screened at this frequency. SOTRs who are at increased risk for melanoma-associated morbidity may also benefit from a revision of their immunosuppression regimen (27). Given our suggestive findings of adverse associations with cyclosporine/azathioprine, alternative immunosuppression with tacrolimus and/or mycophenolate or use of sirolimus, should be considered, keeping in mind other factors that could affect graft and patient survival. For instance, use of sirolimus as maintenance immunosuppression is associated with a decreased incidence of posttransplant melanoma (28).
In conclusion, we observed greatly increased risk of de novo melanoma and mortality from melanoma among SOTRs with a pretransplant melanoma diagnosis, and the development of a posttransplant invasive melanoma was the strongest risk factor for melanoma mortality. Death due to melanoma was uncommon among SOTRs with a pretransplant melanoma, which reflects the careful selection already practiced by transplant clinicians, but transplant candidacy and wait time need continued careful consideration in accordance with recent guidelines (6). Moreover, the relatively high melanoma morbidity and mortality in SOTRs with a pretransplant melanoma indicates that these patients warrant a multidisciplinary approach to posttransplant melanoma prevention and management, including education of patients regarding the importance of sun protection and frequent dermatologic examinations.
Supplementary Material
Acknowledgements
This research was supported in part by the Intramural Research Program of the National Cancer Institute.
The authors gratefully acknowledge the support and assistance provided by individuals at the Health Resources and Services Administration. We also acknowledge the support and assistance of the following individuals for providing data from the SRTR (Ajay Israni, Jon Snyder) and the following cancer registries: the states of Alabama (Justin George), Alaska (David O’Brien), Arkansas (Lunda Lehing), California (Cyllene Morris), Colorado (Jack Finch), Connecticut (Lou Gonsalves), Florida (Brad Wohler), Georgia (Rana Bayakly), Hawaii (Brenda Hernandez), Idaho (Bożena Morawski), Illinois (Lori Koch), Iowa, Kentucky (Jaclyn McDowell), Louisiana, Michigan (Georgetta Alverson), Montana (Heather Zimmerman), Nebraska (Lifeng Li), Nevada (Ben Claassen), New Jersey (Xiaoling Niu), New Mexico (Angela Meisner), New York (Tabassum Insaf), North Carolina (Chandrika Rao), North Dakota (Yun Zeng), Ohio (Emily Bunt), Oklahoma (Meagan Carter), Oregon (Jeff Soule), Pennsylvania (Jim Rubertone), Puerto Rico (Carlos R. Torres), Rhode Island (Junhie Oh), South Carolina (Deborah Hurley), Texas (Leticia Nogueria), Utah (Jen Doherty), Virginia (Shuhui Wang), and the Seattle-Puget Sound area of Washington (Margaret Madeleine). We also thank David Castenson at Information Management Systems for programming support.
The views expressed in this paper are those of the authors and should not be interpreted to reflect the views or policies of the National Cancer Institute, Health Resources and Services Administration, SRTR, cancer registries, or their contractors.
The SRTR is currently operated under contract number 75R60220C00011 by the Hennepin Healthcare Research Institute, Minneapolis, MN. The following cancer registries are supported by the SEER Program of the National Cancer Institute: California (contracts HHSN261201000036C, HHSN261201000035C, and HHSN261201000034C), Connecticut (HHSN261201800002I), Hawaii (HHSN261201000037C, N01-PC-35137, and N01-PC-35139), Idaho (HHSN261201800006I), Illinois (75N91021D00006), Iowa (HSN261201000032C, N01-PC-35143, HHSN261201800012I), Kentucky (HHSN261201800013I), New Jersey (75N91021D00009), New York (HHSN26120180005I), Seattle-Puget Sound (HHSN261201800004I, N01 PC-2018-00004), and Utah (HHSN261201800016I). The following cancer registries are supported by the National Program of Cancer Registries of the Centers for Disease Control and Prevention: Alaska (agreement NU58DP007163), California (1U58 DP000807-01), Colorado (U58 DP000848-04), Georgia (5U58DP003875-01), Idaho (1NU58DP007160), Illinois (5NU58DP007162-002-00), Kentucky (1NU58DP007144), Michigan (5U58DP003921-03), Nebraska (NU58DP006278), New Jersey (5NU58DP006279-02-00), New Mexico (HHSN261201800014I, Task Order HHSN26100001), New York (5NU58DP007218), North Carolina (U58DP003933), North Dakota (NU58DP006317-05-01), Ohio (NU58DP006284), Oklahoma (NU58DP007125). Oregon (NU58DP007105), Puerto Rico (NU58DP006318), Texas (5U58DP000824-04), and Utah (NU58DP007131). Additional support was provided by the states of California, Colorado, Connecticut, Illinois, Iowa, Montana (5 NU58DP006339-05-00), New Jersey, New York (including the Cancer Surveillance Improvement Initiative), Texas, and Fred Hutchinson Cancer Research Center in Seattle, WA.
Abbreviations
- CI
confidence interval
- HR
hazard ratio
- SEER
Surveillance, Epidemiology, and End Results
- SIR
standardized incidence ratio
- SMR
standardized mortality ratio
- SOTR
solid organ transplant recipient
- SRTR
Scientific Registry of Transplant Recipients
- TCM Study
Transplant Cancer Match Study
- US
United States
Footnotes
Conflict of Interest Statement
The authors have no conflicts of interest to disclose.
Declaration of interests
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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