Key Points
Question
What is the frequency of and what are the risk factors for nonmelanoma skin cancer in Australian heart and lung transplant recipients?
Findings
In a cohort analysis of 94 Australian patients who underwent heart and/or lung transplant, the probability of developing nonmelanoma skin cancer was 67% at 10 years posttransplantation. Risk factors for nonmelanoma skin cancer included older age at transplantation and history of pretransplant skin cancer; a Fitzpatrick skin type of III to VI was associated with a reduced risk.
Meaning
There may be a high frequency of nonmelanoma skin cancer in heart and lung transplant recipients in Australia.
Abstract
Importance
There is limited research examining the incidence of nonmelanoma skin cancer (NMSC) in heart and lung transplant recipients in Australia.
Objective
To determine the frequency of and risk factors for NMSC in a cohort of Australian heart and lung transplant recipients.
Design, Setting, and Participants
A retrospective cohort study was conducted at an Australian tertiary center where heart and lung transplants are performed between March 21 and December 14, 2016. A consecutive sample of 94 patients who underwent heart and/or lung transplant presenting for outpatient dermatologic review were evaluated. Data analysis was conducted between April 18 and October 30, 2017.
Exposures
Risk factors examined for association with posttransplantation NMSC included age at the time of transplantation, sex, skin phenotype, UV radiation exposure, history of allograft rejection, history of smoking, history of skin cancer prior to transplant, and transplant type.
Main Outcomes and Measures
The primary outcome measure was the occurrence of posttransplantation NMSC. The probabilities of developing NMSC in general, and squamous cell carcinoma and basal cell carcinoma specifically, were separately summarized based on Kaplan-Meier analysis. Association of risk factors with development of NMSC was examined using univariable and multivariable Cox proportional hazards regression analysis.
Results
Of the 94 study participants, 58 (62%) were men; median age at transplantation was 51.9 years (range, 15.1-69.7 years). There were 801 posttransplantation skin cancers in 57 (61%) of the patients who underwent heart and/or lung transplant. The probabilities for NMSC were 41% (95% CI, 31%-53%) at 5 years and 67% (95% CI, 55%-78%) at 10 years; for basal cell carcinoma, 27% (95% CI, 18%-38%) at 5 years and 53% (95% CI, 40%-67%) at 10 years; and for squamous cell carcinoma, 33% (95% CI, 24%-45%) at 5 years and 62% (95% CI, 50%-74%) at 10 years. On multivariable analysis, older age at transplantation was associated with the development of NMSC (hazard ratio [HR], 1.07/1 year; 95% CI, 1.04-1.10; P < .001) and history of pretransplant skin cancer was associated with development of basal cell carcinoma (HR, 4.56; 95% CI, 1.67-12.42; P = .003). A Fitzpatrick skin type III to VI was associated with a decreased risk of NMSC (HR, 0.42; 95% CI, 0.24-0.74; P = .003). Sex, transplanted organ, UV radiation exposure, and history of allograft rejection were not associated with an increased risk of skin cancer.
Conclusions and Relevance
In this study of Australian heart and lung transplant recipients, there was a probable high frequency of NMSC. Routine dermatologic surveillance at frequent intervals is advised for similar populations.
This cohort study examines the risk factors for and frequency of nonmelanoma skin cancer in Australian recipients of heart and/or lung transplant recipients over 10 years.
Introduction
Skin cancer is a major cause of morbidity and mortality in solid organ transplant recipients (SOTRs) undergoing immunosuppression.1,2,3 Most research in this area has focused on transplantation of solid organs other than heart and lung, including liver, kidney, and pancreas. In this study, we aimed to investigate the frequency of nonmelanoma skin cancer (NMSC) in a cohort of Australian heart and lung transplant recipients (HLTRs) at our institution. We also determined the association of potential risk factors with the development of NMSC in this cohort.
Methods
Inclusion criteria were heart and/or lung transplantation in patients 18 years or older at the time of evaluation who were able to provide written informed consent. A control population was not used. Participants were recruited during routine attendance for outpatient dermatologic review at St Vincent’s Hospital Sydney, Darlinghurst, New South Wales, Australia, between March 21 and December 14, 2016. Data analysis was conducted between April 18 and October 30, 2017.
Baseline demographic features were obtained from participants’ medical records. A questionnaire was administered to all participants regarding risk factors for skin cancer. Skin cancers recorded included histologically confirmed Bowen disease (squamous cell carcinoma in situ), squamous cell carcinoma (SCC), and basal cell carcinoma (BCC). The study was approved by the St Vincent’s Hospital Sydney Human Research Ethics Committee. Participants did not receive financial compensation.
The probabilities of developing NMSC, SCC, and BCC were separately summarized based on Kaplan-Meier analysis. The outcome of interest in analysis was the time from transplantation to development of the first posttransplantation skin cancer or the date of the study visit for each participant.
Risk factors examined for association with posttransplantation skin cancer included age at the time of transplantation, sex, skin phenotype grouped into Fitzpatrick skin types I to II and III to VI, degree of lifetime UV radiation exposure, history of allograft rejection, defined as International Society for Heart and Lung Transplantation grade A2 or greater for lung transplant recipients and grade 2R or greater for heart transplant recipients,4,5 history of smoking, history of skin cancer prior to transplant, and transplant type.
Statistical Analysis
Association of these risk factors with development of NMSC, SCC, or BCC was examined using univariable and multivariable Cox proportional hazards regression analysis. In probability and risk factor analyses, SCC includes Bowen disease and NMSC includes BCC, SCC, and Bowen disease. With 2-tailed, unpaired testing, P values <.05 were considered significant. Analysis was conducted using R, version 3.5.1 (R Foundation).
Results
Patient Demographics
Of the 94 participants, 58 (62%) were men and 36 (38%) were women. The median age at transplantation was 51.9 years (range, 15.1-69.7 years) and the median time from transplantation to the initial study visit, as a surrogate measure of duration of immunosuppression, was 8.4 years (range, 0.4-27 years). Forty-nine participants (52%) had received a bilateral lung transplant, 3 (3%) received a single lung transplant, 41 (44%) received a heart transplant, and 1 (1%) received a combined heart and lung transplant.
Skin Cancer Frequency
There was a total of 801 histologically confirmed posttransplantation skin cancers in 57 of the 94 participants (61%). The probabilities for developing NMSC, BCC, and SCC at 5 and 10 years posttransplantation are reported in Table 1. The probabilities for NMSC were 41% (95% CI, 31%-53%) at 5 years and 67% (95% CI, 55%-78%) at 10 years; for BCC, 27% (95% CI, 18%-38%) at 5 years and 53% (95% CI, 40%-67%) at 10 years; and for SCC, 33% (95% CI, 24%-45%) at 5 years and 62% (95% CI, 50%-74%) at 10 years. Lung transplant recipients had the highest 10-year risk of developing NMSC, although there was no statistically significant difference in skin cancer risk between heart and lung transplant recipients (Figure).
Table 1. Probability of Developing NMSC in Heart and Lung Transplant Recipients.
| Allograft | Years Posttransplant | Probability of Skin Cancer, % (95% CI) | ||
|---|---|---|---|---|
| BCC | SCC | NMSC | ||
| Heart and/or lung | 2 | 12 (7-21) | 14 (8-26) | 19 (12-29) |
| 5 | 27 (18-38) | 33 (24-45) | 41 (31-53) | |
| 10 | 53 (40-67) | 62 (50-74) | 67 (55-78) | |
| Heart | 2 | 17 (9-33) | 17 (9-33) | 22 (12-38) |
| 5 | 36 (23-54) | 33 (21-50) | 42 (29-59) | |
| 10 | 50 (33-69) | 62 (45-78) | 61 (45-78) | |
| Lung | 2 | 9 (3-21) | 10 (4-23) | 17 (9-31) |
| 5 | 17 (9-34) | 34 (22-52) | 41 (27-57) | |
| 10 | 56 (38-76) | 62 (45-80) | 73 (56-87) | |
Abbreviations: BCC, basal cell carcinoma; NMSC, nonmelanoma skin cancer; SCC, squamous cell carcinoma.
Figure. Probability of Developing Nonmelanoma Skin Cancer (NMSC) After Heart and Lung Transplantation.
Lung transplant recipients had the highest 10-year risk of developing NMSC, although there was no statistically significant difference compared with heart transplant recipients.
Risk Factors
The associations of risk factors with skin cancer development were examined using univariable Cox proportional hazards regression analysis (Table 2). Older age at transplantation (hazard ratio [HR], 1.06/1 year; 1.03-1.08; P < .001), history of pretransplant skin cancer (HR, 4.32; 95% CI, 1.77-10.50; P = .001), and history of smoking (HR, 2.52; 95% CI, 1.40-4.53; P = .002) were associated with an increased risk of any posttransplantation NMSC. These 3 factors continued to be significantly associated with an increased risk for BCC (age at transplantation: HR, 1.05; 95% CI, 1.02-1.09; P = .001; pretransplant skin cancer: HR, 8.08; 95% CI, 3.07-21.2; P < .001; and history of smoking: HR, 3.39; 95% CI, 1.66-6.93; P = .001) but only older age at transplantation (HR, 1.06; 95% CI, 1.04-1.09; P < .001) and history of smoking (HR, 2.58; 95% CI, 1.40-4.78; P = .003) were associated with an increased risk for SCC. Participants with Fitzpatrick skin type III to VI had a significantly reduced risk of SCC (HR, 0.57; 95% CI, 0.33-1.00; P = .048), but not NMSC or BCC.
Table 2. Univariable Analysis of Risk Factors for NMSC in Heart and Lung Transplant Recipients.
| Risk Factor | NMSC | SCC | BCC | |||
|---|---|---|---|---|---|---|
| HR (95% CI) | P Value | HR (95% CI) | P Value | HR (95% CI) | P Value | |
| Older age at transplantation (per 1 y) | 1.06 (1.03-1.08) | <.001a | 1.06 (1.04-1.09) | <.001a | 1.05 (1.02-1.09) | .001a |
| Female | 0.75 (0.43-1.31) | .32 | 0.70 (0.39-1.27) | .24 | 0.73 (0.37-1.41) | .34 |
| Lung transplantation | 1.14 (0.67-1.94) | .62 | 1.10 (0.63-1.92) | .74 | 0.89 (0.47-1.67) | .71 |
| Fitzpatrick skin type III-VI | 0.60 (0.35-1.02) | .06 | 0.57 (0.33-1.00) | .048a | 0.55 (0.29-1.02) | .06 |
| UVR exposure | ||||||
| Low | 1 [Reference] | 1 [Reference] | 1 [Reference] | |||
| High | 1.35 (0.60-3.06) | .47 | 1.62 (0.70-3.71) | .26 | 1.10 (0.42-2.88) | .84 |
| Medium | 1.45 (0.69-3.02) | .33 | 1.71 (0.80-3.64) | .16 | 1.21 (0.53-2.80) | .65 |
| Allograft rejection | 0.85 (0.49-1.48) | .56 | 0.95 (0.54-1.68) | .87 | 0.95 (0.50-1.78) | .87 |
| History of pretransplant skin cancer | 4.32 (1.77-10.50) | .001a | 1.75 (0.54-5.73) | .35 | 8.08 (3.07-21.2) | <.001a |
| History of smoking | 2.52 (1.40-4.53) | .002a | 2.58 (1.40-4.78) | .003a | 3.39 (1.66-6.93) | .001a |
Abbreviations: BCC, basal cell carcinoma; HR, hazard ratio; NMSC, nonmelanoma skin cancer; SCC, squamous cell carcinoma; UVR, UV radiation.
Reached statistical significance.
In a multivariable Cox model, age at transplantation continued to be associated with any NMSC (HR, 1.07/1 year; 95% CI, 1.04-1.10; P < .001), SCC (HR, 1.08/1 year; 95% CI, 1.05-1.11; P < .001), and BCC (HR, 1.06/1 year; 95% CI, 1.02-1.09; P = .001). History of pretransplant skin cancer was associated with risk of BCC (HR, 4.56; 95% CI, 1.67-12.42; P = .003), but not any NMSC or SCC, and history of smoking was not associated with risk of skin cancer on multivariable analysis. A Fitzpatrick skin type of III to VI, compared with Fitzpatrick skin type I to II, was associated with a decreased risk of any NMSC (HR, 0.42; 95% CI, 0.24-0.74; P = .003), SCC (HR, 0.38; 95% CI, 0.21-0.68; P = .001), and BCC (HR, 0.49; 95% CI, 0.25-0.96; P = .04).
Discussion
This study aimed to determine the frequency of NMSC in Australian HLTRs. Our results show probabilities of 41% and 67% for developing NMSC in HLTRs after 5 and 10 years, respectively. Lung transplant recipients had a 73% risk of developing NMSC at 10 years posttransplantation. Although direct comparisons are problematic owing to varying study methods and the lack of a control population in this study, these frequencies are greater than those reported in the literature for other SOTRs. It has been reported that approximately 45% of SOTRs in Australian studies develop a skin cancer within 10 years after transplantation, which is a higher figure compared with the 10% to 15% frequency reported in European patients.1 The highest reported frequency of NMSC in SOTRs was in a cohort of renal transplant recipients in Queensland, Australia, with a cumulative incidence for developing NMSC of 52% after 10 years and 82% after 20 years.6 The frequencies of NMSC observed in this study are also greater than those reported specifically in heart and lung transplant recipients; in a study involving North American lung transplant recipients, the cumulative incidence for any skin cancer was 31% and 47% at 5 and 10 years posttransplantation, respectively.7 Frequencies of skin cancer previously reported in European and North American heart transplant recipients have varied between 6% and 20% at 5 years, 21% and 43% at 7 to 10 years, and 46% and 57% at 15 years posttransplantation.8,9,10,11,12,13,14 The high frequency of NMSC in the present study’s cohort may be due to the higher immunosuppressive drug burden in HLTRs1,3,7 and the study location, with Australia having the highest frequency of NMSC in the world.15
Our study results showed no statistically significant difference in the frequency of NMSC between heart and lung transplant recipients, in contrast to a previous study that found a higher frequency of skin cancer in lung transplant recipients compared with heart transplant recipients within the same institution (P = .04).7
The ratio of SCC to BCC was 2.8:1, which is consistent with prior studies in SOTRs that showed an SCC-to-BCC ratio of approximately 3:1, an approximate reversal of the ratio of 1:4 found in the general population.2,3
Limitations
The study has limitations. Participants were recruited via the outpatient clinic, which may have introduced selection bias. The degree of lifetime UV radiation exposure is difficult to quantify and in this study was represented as a sun score, which has not been validated and may explain why UV radiation exposure was not found to be a significant risk factor for NMSC.
Conclusions
The results of this study reveal a probable high frequency of NMSC in HLTRs. Risk factors associated with the development of NMSC on multivariable analysis included older age at transplantation and history of pretransplant skin cancer. A Fitzpatrick skin type of III to VI was associated with a decreased risk of NMSC. Routine dermatologic surveillance in HLTRs in Australia at frequent intervals is advised.
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