Skin cancer in organ transplant recipients: Effect of pretransplant end-organ disease

Skin cancer in organ transplant recipients: Effect of pretransplant end-organ disease Clark C. Otley, MD,a,d Wida S. Cherikh, PhD,b Stuart J. Salasche, MD,c,d Maureen A. McBride, PhD,b Leslie J. Christenson, MD,a,d and H. Myron Kauffman, MDb Rochester, Minnesota; Richmond, Virginia; and Tucson, Arizona Background: Solid organ transplant recipients are at increased risk for posttransplant neoplasms. Objective: Our purpose was to determine whether various diseases causing end-organ failure are associated with different degrees of risk of skin cancer development after transplantation. Methods: The Organ Procurement and Transplantation Network/United Network for Organ Sharing Transplant Tumor Registry was searched for the incidence of skin cancer among kidney, liver, and heart transplant recipients in the United States between 1996 and 2001. Multivariate analysis was used to determine the association between disease diagnosis and posttransplant skin cancer. Results: Transplant recipients with specific pretransplant diseases, such as polycystic kidney disease and cholestatic liver disease, were at increased risk for skin cancer. Patients with diabetes mellitus had a lower incidence of skin cancer after kidney transplantation. Limitations: The study had only a brief follow-up period, indirect assessment of photodamage, and possible underreporting. Conclusion: Transplant recipients with a history of certain diseases warrant intensive skin cancer surveillance and strict sun-protective practices. ( J Am Acad Dermatol 2005;53:783-90.)

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ecipients of solid organ transplants receive potent systemic immunosuppression therapy to prevent allograft rejection. As a consequence of long-term immunosuppression, these patients have a considerably increased risk of de

From the Division of Dermatologic Surgery, Mayo Clinic, Rochestera; the United Network for Organ Sharing, Richmondb; the University of Arizona Health Sciences Center, Tucsonc; and the International Transplant Skin Cancer Collaborative.d Funding sources: Supported by a Cutting Edge Research grant from the American Society for Dermatologic Surgery and in part by Health Resources and Services Administration contract 231-00-0115. Conflicts of interest: None identified. The content of this article is the responsibility of the authors alone and does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. Accepted for publication July 23, 2005. Reprints not available from the authors. Correspondence to: Clark C. Otley, MD, Division of Dermatologic Surgery, Mayo Clinic, 200 First St SW, Rochester, MN 55905. Published online September 23, 2005. 0190-9622/$30.00 ª 2005 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2005.07.061

Abbreviations used: CI: CYA: MMF: NMSC: OPTN/UNOS: PRA: RR: TAC:

confidence interval cyclosporine mycophenolate mofetil nonmelanoma skin cancer Organ Procurement and Transplantation Network/United Network for Organ Sharing panel reactive antibody relative risk tacrolimus

novo malignancies, with skin cancer being the most common. Many risk factors for the development of transplant-associated malignancies have been well described. A few studies have investigated the influence of the primary disease that resulted in endorgan failure before transplantation on the incidence of skin cancer. Renal allograft recipients with diabetic nephropathy as a primary cause of end-stage renal failure had a lower incidence of skin cancer, overall cancers, and lymphoma.1-4 Recently, Kasiske et al4 described an increased incidence of nonmelanoma skin cancer (NMSC) in patients who received a transplant for polycystic kidney disease. Patients who had liver failure caused by primary sclerosing 783

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cholangitis or alcoholic liver disease had a higher incidence of skin cancer.5,6 To our knowledge, no studies have systematically analyzed the association of skin cancer with multiple underlying diseases in cardiac, kidney, and liver allograft recipients. The Transplant Tumor Registry of the Organ Procurement and Transplantation Network/United Network for Organ Sharing (OPTN/UNOS) is a national resource for information about malignancies in solid organ transplant recipients. Since 1999, OPTN/UNOS has prospectively collected detailed data on the incidence of de novo solid tumors, posttransplant lymphoproliferative disorder, donorrelated malignancies, and recurrence of preexisting tumors in all solid organ allograft recipients in the United States. Data collection and submission by all US transplant centers on all allograft recipients is mandatory. Data are collected routinely from patients and their medical records by transplant coordinators and physicians as part of the annual transplant evaluation. In the present study, members of the International Transplant Skin Cancer Collaborative and the OPTN/UNOS Transplant Tumor Registry collaborated to investigate comprehensively the association of skin cancer with all underlying disease factors reported to the OPTN/UNOS database among kidney, liver, and cardiac transplant recipients. The objective of the study was to investigate the association between the underlying disease leading to end-stage organ failure and the development of posttransplant skin cancer in kidney, liver, and heart transplant recipients. We hypothesized that the different underlying diseases would be associated with varying degrees of susceptibility or resistance to posttransplant skin cancer.

METHODS Although OPTN/UNOS began collecting comprehensive malignancy data in 1999, type of posttransplant cancer (posttransplant lymphoproliferative disorder, skin cancer, or solid tumor) had been collected since 1994 for thoracic transplants and since 1997 for kidney and liver transplants. Because the lag times between transplantation and the reporting of posttransplant malignancies to the database vary, inclusion of transplants performed between 1996 and 2001 would allow for sufficient time to capture posttransplant tumor data. The OPTN/UNOS Transplant Tumor Registry was queried for data on adult ($18 years of age) primary solid organ transplant recipients; the data were then assessed to determine the incidence of posttransplantation skin cancer (squamous cell carcinoma, basal cell carcinoma, and melanoma) and the underlying disease responsible for transplantation in each

patient. All patients in the United States receiving deceased- and living-donor kidney, deceased-donor whole liver, and deceased-donor heart between Jan 1, 1996 and Dec 31, 2001, were included. Patients had had at least 8 days of follow-up and had received one of the following immunosuppression therapies at discharge: cyclosporine (CYA) and azathioprine, CYA and mycophenolate mofetil (MMF), tacrolimus (TAC) and azathioprine, or TAC and MMF. The study population was limited to recipients who had had no induction therapy or were treated with monoclonal antilymphocyte, polyclonal antilymphocyte, or interleukin 2 receptor antibody. Dosages of induction and maintenance immunosuppressive drugs are not reported to the OPTN/UNOS database and, therefore, are not included in this study. The study was also limited to skin cancer reported no less than 30 days after transplant to be more certain that it was de novo skin cancer. Data on patient follow-up were collected through Aug 22, 2003. Because of the small number of cases of skin cancer found in the study cohort, the multivariate analysis of time to skin cancer for all 3 organs included the following selected characteristics: recipient diagnosis category, type of induction therapy (monoclonal lymphocyte, polyclonal lymphocyte, interleukin 2 receptor antibody, or none), sex, age, race/ethnicity (white non-Hispanic vs other), sun-exposure level (low, medium, high), and year of transplant. Sunexposure level was estimated using the recipient’s state of residency at the time of listing (Table I). In addition, the data for kidney recipients included peak panel reactive antibody (PRA), donor type (living vs deceased donor), and human leukocyte antigen mismatch level. The data for liver and heart recipients included medical urgency status at transplant. The incidence of posttransplant skin cancer for each organ was computed for different recipient and transplant characteristics and compared by using the x2 or Fisher exact test. To determine the association between causative-disease diagnosis for end-organ failure and posttransplant skin cancer, the multivariate Cox proportional hazards regression model was used to model time to first reported skin cancer in the presence of the other characteristics that may influence the development of skin cancer after transplantation. For patients with missing data for certain variables, the median value or most frequent variable was used. The results of the Cox regression are presented as relative risk (RR) of skin cancer development with 95% confidence intervals (CIs) and P values. All statistical analyses were performed using SAS, version 8.02 (SAS Institute, Cary, NC). This study was approved by the Mayo Foundation Institutional Review Board.

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Table I. Estimated level of sun exposure by state Low

Alaska Connecticut Idaho Illinois Indiana Maine Massachusetts Michigan Minnesota Montana New Hampshire New York North Dakota Ohio Oregon Rhode Island South Dakota Vermont Washington Wisconsin

Medium

Colorado Delaware District of Columbia Iowa Kansas Kentucky Maryland Missouri Nebraska New Jersey North Carolina Pennsylvania South Carolina Tennessee Virginia West Virginia Wyoming

High

Alabama Arizona Arkansas California Florida Georgia Hawaii Louisiana Mississippi Nevada New Mexico Oklahoma Puerto Rico Texas Utah Virgin Islands (US)

RESULTS The incidence of posttransplant skin cancer in patients receiving kidney, liver, and heart transplants is summarized by diagnosis category in Table II and by other recipient and transplant characteristics in Table III. The adjusted RRs of skin cancer for different disease diagnoses and other selected risk factors are summarized in Tables IV, V, and VI. Kidney A total of 46,355 adult recipients of primary kidney transplants were included in the final analysis. The median duration of follow-up was 1090 days, and the overall incidence of posttransplant skin cancer was 1.12% (517/46,355). The incidence of skin cancer was significantly different among different diagnosis categories (P \.001); it was the highest in recipients with polycystic kidney disease (2.52%) and lowest in those with diabetes mellitus (0.81%) (Table II). The incidence of skin cancer was significantly higher in recipients who were male, older, white, and had a lower peak PRA level (Table III). The incidence of skin cancer also differed significantly by antibody induction therapy and year of transplant. The incidence of skin cancer was not significantly different by sun-exposure level, donor type, or human leukocyte antigen mismatch level. Table IV shows the adjusted RR of skin cancer for different disease diagnoses and other significant risk factors. Compared with recipients who had glomerular kidney disease, who are believed not to have extra risk except for that associated with

Table II. Incidence of skin cancer by disease diagnosis category in kidney, liver, and heart transplant recipients

Diagnosis category*

Kidney (N = 46,355) Glomerular diseases Tubular and interstitial diseases Diabetes mellitus Hypertensive nephrosclerosis Polycystic kidneys Renovascular and other vascular diseases Other Liver (N = 8,075) Noncholestatic cirrhosis Acute hepatic necrosis Cholestatic liver disease/cirrhosis Malignant neoplasm Other Heart (N = 8,594) Coronary artery disease Cardiomyopathy Valvular heart disease Other

No. of transplant recipients

14,452 2,836

Incidence of cancer, no. (%)

143 (0.99) \.001 46 (1.62)

11,030 7,390

89 (0.81) 70 (0.95)

4,488 2,392

113 (2.52) 25 (1.05)

3,767

31 (0.82)

5,708 663 1,075

54 (0.95) 4 (0.60) 22 (2.05)

224 405

4 (1.79) 3 (0.74)

4,418 3,758 225 193

P value

297 133 11 4

.01

(6.72) \.001 (3.54) (4.89) (2.07)

*Disease responsible for end-organ failure.

immunosuppression, recipients with polycystic kidney disease had a significantly higher risk of skin cancer and recipients with diabetes mellitus had a significantly lower risk. Recipients with tubular and interstitial diseases had a slightly increased risk of posttransplant skin cancer (P = .06). The risk of skin cancer was not significantly increased in patients with hypertensive nephrosclerosis relative to those with glomerular kidney disease. Other patients noted, from the multivariate analysis, to have a higher risk of skin cancer included those older than 34 years, men, and those with white skin. Liver A total of 8075 adult recipients of primary deceased-donor whole-liver transplants were included in the analysis. The median duration of follow-up was 1062 days, and the incidence of posttransplant skin cancer was 1.08% (87/8075).The incidence of skin cancer was significantly different among diagnosis categories (P = .01); it was the highest in recipients with cholestatic liver diseases/cirrhosis (2.05%) and the lowest in those with acute hepatic necrosis (0.60%) (Table II). The incidence of skin cancer was significantly higher in recipients who

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Table III. Incidence of skin cancer by recipient and transplant characteristics in kidney, liver, and heart transplant recipients Kidney (N = 46,355) Characteristic

Sex Women Men Age (y) 18-34 35-55 [55 Race/ethnicity White, non-Hispanic Other Antibody induction therapy Monoclonal Polyclonal IL-2 receptor None Treatment for early acute rejection No Yes Sun-exposure level Low Medium High Transplant year 1996 1997 1998 1999 2000 2001 Peak PRA level (%) 0-9 10-79 801 Donor type Deceased Living HLA mismatch level 0 1-3 4-6 Medical urgency status 1 or 2A 2 or 2B 3 or 4 Medical urgency status 1 or 1A or 1B 2 Total

No. of transplants

Cancer, no. (%)

Liver (N = 8,075) P value

Heart (N = 8,594)

No. of transplants

Cancer, no. (%)

P value

No. of transplants

Cancer, no. (%)

.05

1,961 6,633

45 (2.29) \.001 400 (6.03)

P value

18,570 27,785

132 (0.71) \.001 385 (1.39)

2,934 5,141

23 (0.78) 64 (1.24)

9,468 23,939 12,948

16 (0.17) \.001 225 (0.94) 276 (2.13)

565 5,115 2,395

0 \.001 44 (0.86) 43 (1.80)

707 3,859 4,028

3 (0.42) \.001 135 (3.50) 307 (7.62)

27,725 18,630

491 (1.77) \.001 26 (0.14)

6,232 1,843

85 (1.36) \.001 2 (0.11)

6,894 1,700

434 (6.30) \.001 11 (0.65)

3,831 5,951 10,977 25,596

41 70 92 314

(1.07) (1.18) (0.84) (1.23)

.01

326 188 739 6,822

11 1 7 68

.006

940 1,434 676 5,544

54 82 22 287

(5.74) (5.72) (3.25) (5.18)

.09

42,984 3,371

491 (1.14) 26 (0.77)

.05

6,869 1,206

71 (1.03) 16 (1.33)

.36

7,094 1,500

375 (5.29) 70 (4.67)

.33

15,626 13,913 16,816

195 (1.25) 135 (0.97) 187 (1.11)

.08

2,812 1,789 3,474

42 (1.49) 19 (1.06) 26 (0.75)

.02

2,726 2,668 3,200

135 (4.95) 159 (5.96) 151 (4.72)

.08

1,244 1,060 1,215 1,339 1,569 1,648

26 11 12 14 16 8

(2.09) (1.04) (0.99) (1.05) (1.02) (0.49)

.004

1,340 1,545 1,516 1,295 1,425 1,473

106 119 86 62 41 31

6,360 7,585 7,969 8,176 8,018 8,247

109 114 110 87 61 36

(1.71) \.001 (1.50) (1.38) (1.06) (0.76) (0.44)

(3.37) (0.53) (0.95) (1.00)

(7.91) \.001 (7.70) (5.67) (4.79) (2.88) (2.10)

37,604 7,102 1,649

446 (1.19) 57 (0.80) 14 (0.85)

.01

— — —

— — —

—

— — —

— — —

—

28,655 17,700

331 (1.16) 186 (1.05)

.23

— —

— —

—

— —

— —

—

6,068 21,073 19,214

82 (1.35) 235 (1.12) 200 (1.04)

.13

— — —

— — —

—

— — —

— — —

—

— — —

— — —

—

1,916 4,216 1,943

12 (0.63) 48 (1.14) 27 (1.39)

.58

— — —

— — —

—

— — 46,355

— — 517 (1.12)

—

— — 8,075

— — 87 (1.08)

—

6,144 2,450 8,594

314 (5.11) 131 (5.35) 445 (5.18)

.65

HLA, Human leukocyte antigen; IL, interleukin; PRA, panel reactive antibody.

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Table IV. Selected risk factors for development of posttransplant skin cancer in kidney transplant recipients (N = 46,355)

Table V. Selected risk factors for development of posttransplant skin cancer in liver transplant recipients (N = 8075)

Risk factor

Risk factor

Diagnosis Glomerular diseases (reference) Tubular interstitial diseases Diabetes mellitus Hypertensive nephrosclerosis Polycystic kidneys Renovascular and vascular diseases Other diseases Age (y) 18-34 (reference) 35-55 [55 Sex, women vs men Race/ethnicity, white vs other

RR (95% CI)*

P value

1.00

—

1.38 (0.99-1.93)

.06

0.70 (0.54-0.92) 1.13 (0.85-1.51)

.01 .41

1.65 (1.29-2.12) 1.38 (0.90, 2.12)

\.001 .14

0.97 (0.66-1.44)

.89

1.00 5.04 11.91 0.52 10.90

(3.02-8.40) (7.15-19.85) (0.43-0.64) (7.28-16.30)

— \.001 \.001 \.001 \.001

Table is limited to diagnosis categories and selected significant risk factors. CI, Confidence interval; RR, relative risk. *RR was adjusted for other characteristics described in the ‘‘Methods’’ section.

were 55 years of age or older, had white skin, and lived in states with low sun exposure (Table III). The incidence of skin cancer was also significantly different by antibody induction therapy and year of transplant, but not significantly different by sex, early acute rejection treatment, or medical urgency status at transplant. Table V shows the adjusted RR of skin cancer for different disease diagnoses and other significant risk factors in liver transplant recipients. Because no cases of skin cancer were reported in recipients aged 18 to 34 years, this age category was combined with the 35- to 55-year-old age group in the multivariate analysis (18-55 years), which served as the reference group. After controlling for other risk factors, the risk of skin cancer was significantly higher in recipients with cholestatic liver diseases/ cirrhosis than in those with noncholestatic liver diseases. Recipients with malignant neoplasm had an increased, but not statistically significant, risk of skin cancer (P = .13). Recipients with acute hepatic necrosis or other liver diseases were not at an increased risk for skin cancer compared with those with noncholestatic cirrhosis. In the multivariate analysis, other recipients who had a significantly higher risk of skin cancer included

Diagnosis Noncholestatic cirrhosis (reference) Cholestatic liver disease/cirrhosis Acute hepatic necrosis Malignant neoplasms Other liver disease Age, [55 y vs 18-55 y Sex, women vs men Race/ethnicity, white vs other

RR (95% CI)*

P value

1.00

—

1.80 (1.08-3.00)

.03

0.99 2.23 0.69 2.43 0.54 8.98

(0.35-2.79) (0.80-6.25) (0.21-2.21) (1.59-3.72) (0.33-0.87) (2.19-36.78)

.99 .13 .53 \.001 .01 .002

Table is limited to diagnosis categories and selected significant risk factors. CI, Confidence interval; RR, relative risk. *RR was adjusted for other characteristics described in the ‘‘Methods’’ section.

men, those older than 55 years, and those with white skin. Heart A total of 8594 adult recipients of primary heart transplants were included in the analysis. The median duration of follow-up was 1107 days, and the overall incidence of posttransplant skin cancer was 5.18% (445/8594). The incidence of skin cancer was significantly different among different diagnosis categories (P \ .001) (Table II). The incidence of skin cancer was the highest for patients with coronary artery disease (6.72%). Table III shows that the incidence of skin cancer was significantly higher in heart transplant recipients who were male, were older, and had white skin. The incidence of skin cancer was also different by year of transplant, but not significantly different by antibody induction treatment type, early acute rejection treatment, sun-exposure level, or medical urgency status at transplant. Table VI shows the adjusted RR of skin cancer for different disease diagnoses and other significant risk factors in heart transplant recipients. Although the univariate analysis showed significant differences in the incidence of skin cancer among different disease categories, the multivariate adjusted risks did not confirm differences between recipients with cardiomyopathy, valvular heart disease, or other diseases, as compared with those with coronary artery disease. Variables associated, in the multivariate analysis, with higher incidence of skin cancer included older age, male sex, white skin, and residence in a state with medium versus low sun exposure.

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Table VI. Selected risk factors for development of posttransplant skin cancer in heart transplant recipients (N = 8594) Risk factor

Diagnosis Coronary artery disease (reference) Cardiomyopathy Valvular heart disease Other heart diseases Age (y) 18-34 (reference) 35-55 [55 Sex, women vs men Race/ethnicity, white vs other Sun-exposure level, medium vs low

RR (95% CI)*

P value

1.00

—

0.85 (0.69-1.05) 0.92 (0.50-1.68) 0.87 (0.32-2.37)

.14 .78 .79

1.00 5.64 11.94 0.51 6.79

(1.78-17.88) (3.78-37.77) (0.37-0.69) (3.73-12.39)

1.27 (1.01-1.60)

— .003 \.001 \.001 \.001 .04

Table is limited to diagnosis categories and selected significant risk factors. CI, Confidence interval; RR, relative risk. *RR was adjusted for other characteristics described in the ‘‘Methods’’ section.

DISCUSSION Solid organ transplant recipients have a substantially increased risk of developing posttransplant neoplasms because of prolonged, intense, systemic immunosuppression. Skin cancer is the most common malignancy seen in this setting and can cause substantial morbidity and even mortality. Many constitutional risk factors for the development of skin cancer have been identified and include increased age, longer duration of immunosuppression therapy, increased intensity of immunosuppression therapy, history of increased ultraviolet exposure, human papillomavirus infection, easily burned skin, CD4 lymphocytopenia, male sex, history of actinic keratosis and prior NMSC, blue or hazel eyes, and birth in a hot climate.7,8 Our analysis supports several of these previously documented risk factors, including fair skin, male sex, increased age, and increased time since transplant. We also noted an increased risk of skin cancer in recipients who lived in a state with higher sun exposure, although this was seen only with heart recipients. Finally, we found that a high peak PRA, a measure of lymphocytic reactivity against potential donors, correlated with lower skin cancer risk; it is theorized that a high PRA reflects a stronger immune system and thus a decreased susceptibility to skin cancer. Before the present study, only limited studies had analyzed the effects of disease leading to solid organ transplantation on posttransplant risk of skin cancer.

Four studies showed that patients with diabetic nephropathy as a cause of end-stage renal disease had a lower incidence of posttransplant skin cancer than did kidney transplant recipients with other types of disease.1-4 Primary sclerosing cholangitis or alcoholic liver disease as a cause of liver transplantation has been associated with an increased risk of skin cancer.5,6 Our study aimed to analyze multiple different diseases associated with end-organ failure in cardiac, kidney, and liver transplant patients to determine whether the risk of posttransplant skin cancer was influenced by the primary underlying disease. In the large cohort of renal allograft recipients in the OPTN/UNOS Transplant Tumor Registry, diabetes mellitus was confirmed to be associated with a lower risk of posttransplant NMSC. This finding is consistent with 4 earlier reports.1-4 One possible explanation for the lower incidence is that patients with diabetes have poor immunosuppressive drug absorption as a consequence of diabetic gastroparesis and autonomic neuropathy.9 They also have been reported to have decreased blood levels of CYA,9 TAC,10 and MMF.11 Lower levels of immunosuppression have been well documented to be associated with a lower risk of skin cancer. However, the OPTN/UNOS database does not contain detailed information on patients’ exact dosages or blood levels of immunosuppressants, so it is difficult to prove that their immunosuppressant levels were indeed lower than those of other patients. The decreased incidence of skin cancer in the diabetic patients in our study contrasts with an increased incidence described in diabetic patients in the general population.12,13 No substantial reports of systemic malignancies associated with polycystic kidney disease have been documented.14 Our study showed that patients with polycystic kidney disease were significantly more likely to develop skin cancer than patients with glomerular disease, which was the reference population. Two small single-center studies reported increased incidence of malignancies in transplant recipients who had polycystic disease, but statistical analyses were not reported.15,16 Kasiske et al4 recently reported a significantly increased risk of NMSC in transplant recipients who had polycystic kidney disease. Patients with tubular and interstitial diseases had marginally increased risk of skin cancer, whereas those with hypertensive nephrosclerosis or glomerular disease did not have an increased risk. On the basis of these data, it appears sensible to advise patients with polycystic kidney disease to take special sun-protection precautions. Although patients with diabetes may be less prone to develop skin cancer than kidney transplant recipients with

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other underlying diseases, adherence to sun-protection practices after transplantation remains a sensible strategy, especially in individuals with other established skin cancer risks. In the analysis of the liver transplant recipients, patients with cholestatic liver disease and cirrhosis had an increased risk of skin cancer. Patients who had hepatic neoplasms as an underlying reason for transplantation also had an increased incidence of skin cancer, although the risk was not statistically significant. Patients with other forms of liver disease, including noncholestatic liver disease and acute hepatic necrosis, did not have increased rates of skin cancer. In our analysis, primary sclerosing cholangitis was categorized in the cholestatic liver disease/cirrhosis category. This population of transplant recipients previously has been described as having an increased risk of skin cancer, which is confirmed in our study.5,6 The exact mechanism by which cholestatic or cirrhotic hepatic processes are associated with an increased risk of skin cancer is unknown. Mithoefer, Supran, and Freeman5 hypothesized that immunosuppressive treatment of primary sclerosing cholangitis or an associated inflammatory bowel disease before transplantation may account for a longer duration of immunosuppression in these patients, which is associated with an increased risk of skin cancer. Although all transplant patients should practice sun protection and have skin cancer surveillance, patients with cholestatic and cirrhotic liver disease as causes for liver transplantation may warrant extra encouragement to use strict sun-protective practices. Multivariate analysis showed that, among heart transplant recipients, different underlying diseases leading to transplantation appeared to have comparable risk of skin cancer. However, it is well recognized that cardiac transplant patients, who are generally older and more heavily immunosuppressed than other transplant patients, have the highest risk of skin cancer and, thus, should use strict sun-protective practices. These patients also merit aggressive surveillance. We acknowledge several limitations of our study. The small number of skin cancers in the study cohort reflects that some patients were only followed up for a few years; for most skin cancers, the incidence increases significantly 5 to 7 years after transplantation. Therefore revisiting this database at future intervals would be appropriate. Additionally, because documentation of photodamage is not included in the OPTN/UNOS database, the state of residence at the time of transplantation is used as a surrogate for sun exposure and photodamage. Direct assessment of photodamage would be a more

sensitive means of assessing specific factors that put patients at risk for skin cancer. Our analysis included multiple variables, which makes detection of a statistically significant but clinically insignificant association possible. Of note, our multivariate analysis did account for the potential effects of immunosuppressant medications on skin cancer incidence, but we will report the details of that pathogenically distinct and important analysis separately. Finally, as with all large databases, underreporting is inevitable. Compliance with reporting of overall transplantrelated information to the OPTN/UNOS database, which has a reported error rate of 0.3%, is high17; compliance with submission of cancer-specific data to the OPTN/UNOS Transplant Tumor Registry may be less complete, although the precise rate of submission has not been defined. It is possible, given the low morbidity and mortality associated with most skin cancer, that some skin cancers were not recorded. However, there is no rationale to suggest that patients with one particular underlying disease would be more prone to tumor underreporting. Thus, our analysis, which compares relative incidence of skin cancer development, is likely to be more accurate than absolute incidence data. Furthermore, although complete data-capture is more difficult with a large national database, the shortcomings of imperfect data collection may be ameliorated by the vast number of patients included. A separate analysis of skin cancer incidence, using Medicare claims data and the OPTN database, documented incidences of skin cancer of 2.25% at 1 year, 4.95% at 2 years, and 7.43% at 3 years, a higher incidence than was documented in our study.18 The occurrence of posttransplant skin cancer is a challenge to the quality of life of transplant recipients. Skin cancer is primary among cancers as a cause for morbidity in this immunosuppressed population and may be associated with mortality in extreme cases. Insight derived from multivariate analysis of pretransplant risk factors may help us identify patients at particular risk for skin cancer after transplantation. Aggressive dermatologic intervention, with sun-protective practices, sun avoidance, chemoprophylactic treatments, patient education and self-examination, and regular dermatologic surveillance may lessen the risk of skin cancer in these patients and may improve prognosis for patients in whom skin cancer does develop, if the cancer is identified early.7 REFERENCES 1. Gruber SA, Gillingham K, Sothern RB, Stephanian E, Matas AJ, Dunn DL. De novo cancer in cyclosporine-treated and noncyclosporine-treated adult primary renal allograft recipients. Clin Transplant 1994;8:388-95.

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2. Roeger LS, Sheil AGR, Disney APS, Mathew TH, Amiss N. Risk factors associated with the development of squamous cell carcinomas in immunosuppressed renal transplant recipients. Clin Transplant 1992;6:202-11. 3. Danpanich E, Kasiske BL. Risk factors for cancer in renal transplant recipients. Transplantation 1999;68:1859-64. 4. Kasiske BL, Snyder JJ, Gilbertson DT, Wang C. Cancer after kidney transplantation in the United States. Am J Transplant 2004;4:905-13. 5. Mithoefer AB, Supran S, Freeman RB. Risk factors associated with the development of skin cancer after liver transplantation. Liver Transpl 2002;8:939-44. 6. Saigal S, Norris S, Muiesan P, Rela M, Heaton N, O’Grady J. Evidence of differential risk for posttransplantation malignancy based on pretransplantation cause in patients undergoing liver transplantation. Liver Transpl 2002;8:482-7. 7. Berg D, Otley CC. Skin cancer in organ transplant recipients: epidemiology, pathogenesis, and management. J Am Acad Dermatol 2002;47:1-17. 8. Carroll RP, Ramsay HM, Fryer AA, Hawley CM, Nocol DL, Harden PN. Incidence and prediction of nonmelanoma skin cancer post-renal transplantation: a prospective study in Queensland, Australia. Am J Kidney Dis 2003;41:676-83. 9. Chapman JR, O’Connell PJ, Bovington KJ, Allen RD. Reversal of cyclosporine malabsorption in diabetic recipients of simultaneous pancreas and kidney transplant using a microemulsion formulation. Transplantation 1996;61: 1699-704.

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