Key Points
Question
What is the incidence and timing of presentation of malignant melanoma in the cardiothoracic transplant population?
Findings
In this single-center study of cardiothoracic transplant patients, the incidence of malignant melanoma was 0.4% with a median time to presentation of 2.5 years.
Meaning
The cardiothoracic transplant population has an incidence of melanoma similar to that of the renal transplant population but with a distinct time to presentation, warranting further studies and distinctive guidelines for dermatologic follow-up.
Abstract
Importance
The immunosuppression vital to maintaining transplanted organs comes with an increased incidence of cutaneous neoplasms. Understanding the genesis of malignant melanoma (MM) in transplant subpopulations is necessary for adequate disease surveillance.
Objective
To determine the incidence and timing of presentation of MM in the cardiothoracic (heart and/or lung) transplant (CTT) population.
Design, Setting, and Participants
This was a retrospective cohort study of 1164 patients who underwent a CTT from 2001 through 2016 with a median follow-up time of 4.3 years. The study was performed at a single academic, tertiary referral center. The retrospective database was used to identify 1164 patients who underwent a CTT at Duke University Hospital from 2001 to 2016. Ten patients were excluded from the study owing to a history of MM, resulting in 1154 patients in the study. Five patients who developed MM after CTT were identified.
Exposures
Exposures included tacrolimus, prednisone, and mycophenolate mofetil.
Main Outcomes and Measures
The primary outcome measurement was the MM incidence. Secondary outcomes included time to diagnosis and survival.
Results
Five of 1154 patients who underwent a CTT (0.4%) developed biopsy-proven MM at a median follow-up time of 4.3 years after transplantation at a median age of 64.5 years (range, 31.0-74.0 years). Of the 1154 patients, 923 (80%) were men. Their mean (SD) age range was 63.8 years (27.2-68.2 years). Four patients (80%) presented with stage I disease while 1 (20%) presented with stage IV disease at a median time of 2.5 years (range, 0.1-5.3 years) after transplant compared with a median time of 6.2 years (range, 0.9-8.7 years) in Duke University’s renal transplant population at a median follow-up time of 6.6 years. Two patients died after transplant, 1 owing to complications of the transplant and 1 owing to metastatic MM.
Conclusions and Relevance
Representing one of the largest reported studies of patients with CTT developing MM, our findings suggest that the CTT population experiences an incidence of MM similar to that of other solid organ transplant recipients and with a median of 2.5 years from transplant to melanoma diagnosis. While the small scale of our study prevents far-reaching conclusions, further study is warranted to better understand the incidence, timing, and clinical ramifications of melanomagenesis in the CTT population.
This cohort study examines the incidence and timing of presentation of malignant melanoma in the cardiothoracic (heart and/or lung) transplant population.
Introduction
Transplant recipients have a reported 2- to 5-fold increased risk of malignant melanoma (MM) as a consequence of immunosuppression.1,2 Melanoma in the transplant population has been shown to be more aggressive than in the nontransplant population.2 Matched for Breslow thickness and Clark level, MM has been associated with worse outcomes in the transplant population.3 Cardiothoracic transplantation (CTT), which has a propensity for higher rates of organ rejection, may require high levels of immunosuppression to maintain graft function.4 Accordingly, patients with CTT have been shown to be particularly susceptible to the cutaneous complications of immunosuppression.4 More than 100 000 cardiothoracic (heart and/or lung) transplants have occurred in the United States since 1988, with United Network for Organ Sharing reporting a 20% increase from 2012 to 2016.5 Specific MM risk factors include age greater than 50 years or less than 18 years at transplant, white race, and a pretransplant history of MM.6,7,8
Treatment options for patients with melanoma have greatly expanded with the introduction of immune checkpoint inhibitors (ICIs) and BRAF-targeted therapies.9,10 Prior to introduction of ICIs, the 5-year survival for stage IV melanoma ranged from 10% to 30%11,12 ; however, transplant recipients may have few viable treatment options because transplantation is generally considered at least a relative contraindication. Taken together, the increased incidence and aggressiveness of MM in the CTT population, coupled with limited treatment options for advanced disease, highlight the importance of early detection. The aim of this study was to describe the incidence and timing of clinical presentation of MM in a large CTT population at a major academic medical center.
Methods
We performed an institutional review board–approved, retrospective study of cardiothoracic and renal transplant patients. We used the Duke Enterprise Data Unified Content Explorer (DEDUCE) to identify all adult patients (>18 years) who underwent a transplant at Duke University Hospital between January 1, 2001, and December 31, 2016. That cohort was further refined by narrowing it to include only patients with a diagnosis of MM. Patients diagnosed as having MM prior to transplantation were excluded from the study. Data regarding type and date of transplant and melanoma characteristics, including stage and location, were recorded. A Fisher exact test was used to compare the incidence of MM in the CTT with that of the renal transplant (RT) population. A log-rank test was used to compare the time from transplant to MM diagnosis in the CTT group with that of the RT group.
Results
From 2001 to 2016, 1164 patients underwent a heart and/or lung transplant. Fifteen patients with a diagnosis of MM were identified, with 10 of those being excluded owing to a diagnosis of MM prior to transplant. All 10 of those patients had been successfully treated with wide local excision prior to transplant with none of them developing a new primary or recurrent lesion at a median follow-up time of 4.3 years (range, 1.2-7.3 years). Five of the 1154 patients (0.4%) undergoing CTT developed biopsy-proven MM after transplantation, which was not significantly different than the 6 of 1714 (0.35%) in Duke’s RT population who developed posttransplant MM at a median follow-up time of 6.6 years (P = .74) (Table 1). Eighty percent (923) were men. Their median age (range) was 56.3 years (42.7-69.1 years). Four men and 1 woman were diagnosed as having MM following CTT. Four patients (80%) presented with stage I disease while the other patient (20%) presented with stage IV disease. The 4 patients with stage I disease were successfully treated via wide local excision. The patient presenting with metastatic disease experienced rapid progression and eventually died without systemic treatment within 4 weeks of diagnosis. That patient’s melanoma was BRAF negative, and he was deemed ineligible for immunotherapy given his transplant status. None of the patients had a family history of MM. The median time from CTT to diagnosis was 2.6 years (range, 0.2-5.4 years), which was significantly different from the median of 6.2 years in Duke’s RT population (P = .048) (Table 2). The median age at MM diagnosis was 64.6 years (range, 31.0-74.0 years). The 4 patients presenting with stage 1 MM had primary locations on the neck, forearm, chest, and forehead. The single patient who presented with stage IV MMpresented with visceral disease involving multiple organs. During the 4.3-year median follow-up time, 2 patients died after transplant, 1 owing to complications of the transplant and 1 owing to metastatic MM. All patients received more than 5 mg of tacrolimus daily, 4 (80%) took at least 5 mg of prednisone daily, and 3 (60%) received mycophenolate mofetil daily prior to their MM diagnosis. Voriconazole was used briefly in 1 patient, and 3 patients had sun-damaged skin clinically documented by dermatologists. None of the patients had a documented history of dysplastic nevi.
Table 1. Patient Demographics for CTT Population Developing Melanoma.
| Sex | Organ Transplanted | Age at CTT, y | Melanoma Stage | Tacrolimus Dose, mg/d | Time to Melanoma, y |
|---|---|---|---|---|---|
| M | Heart | 62.4 | I | 6.0 | 0.1 |
| M | Lung | 66.1 | IV | 5.0 | 2.5 |
| M | Heart | 63.8 | I | 7.0 | 0.8 |
| F | Heart | 27.2 | I | 8.0 | 4.2 |
| M | Lung | 68.2 | I | 5.5 | 5.4 |
Abbreviation: CTT, cardiothoracic (heart and/or lung) transplant.
Table 2. CTT and RT Population Demographic Characteristics and Follow-up Times.
| Population | Age at Transplant, Median (Range), y | Male Sex, No. (%) | White Race, No. (%) | Patients, Total No. | Follow-up Time, Median (Range), y |
|---|---|---|---|---|---|
| CTT | 63.8 (27.2-68.2) | 923 (80.0) | 1065 (92.3) | 1154 | 4.3 (1.2-7.3) |
| RT | 56.3 (42.7-69.1) | 1286 (75.0) | 1457 (85.0) | 1714 | 6.6 (2.2-11.0) |
Abbreviations: CTT, cardiothoracic (heart and/or lung) transplant; RT, renal transplant.
Discussion
Solid organ transplantation confers an elevated risk of MM, which is often more aggressive than in the nontransplant population. However, transplantation is usually deemed a contraindication to the use of effective ICI. Without effective systemic therapy options, early diagnosis and wide excision remains the best hope for a cure. To properly monitor for the development of MM, an understanding of incidence and presentation of MM in the CTT population is necessary.
The CTT cohort is maintained on a higher level of immunosuppressive medication than other transplant patients.13 This regimen often includes cyclosporine, calcineurin inhibitors, and azathioprine, which have been shown to increase the risk of cutaneous neoplasms.13,14 As such, the CTT group has been considered to be particularly prone to the development of MM and other nonmelanoma skin cancers. The frequency of post-CTT MM in our study was 0.4%, similar to both the published incidence and our institution’s frequency in the RT population. This frequency is similar to previously reported figures regarding the incidence of MM in the transplant population at 2- to 5-fold more common than in the general population. In addition, the cardiothoracic cohort presented at a median time of 2.5 years from transplantation, which is less than half of the latency period (6.1 years) observed in RT patients at the same center.
Limitations
The major limitation of this study is its small sample size and the limited power of our statistical analysis on this cohort. Its single-centered retrospective nature introduces bias about outcomes and key variables. Records of sun-damaged skin were not available for all patients and may have affected the incidence of melanoma. A larger, multicenter study would provide more reliable estimates of the true incidence of MM in the CTT population and help to establish the potential need for practice-changing guidelines to improve the surveillance and management of this unique group of patients.
Conclusions
In one of the largest known single-center studies of CTT patients, the frequency of MM was 0.4% with a median time to diagnosis of 2.5 years compared with 0.35% and 6.2 years in the RT group. While it has been reported that the CTT population has a higher frequency of MM compared with the RT population, our study did not support this claim. These study results, while limited, owing to small sample size, suggest the need for specialized recommendations regarding dermatologic surveillance in the CTT population.
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