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Annals of Surgical Oncology 9:785-788 (2002)
© 2002 Society of Surgical Oncology

ORIGINAL ARTICLES

Malignancy After Renal Transplantation: Incidence and Role of Type of Immunosuppression

Francine Tremblay, MD, Myriam Fernandes, RN, Fadi Habbab, BSc, Michael D. deB. Edwardes, PhD, Rolf Loertscher, MD and Sarkis Meterissian, MD

From the Divisions of General Surgery (FT, FH, SM), Transplantation (MF, RL), and Clinical Epidemiology (MDE), McGill University Health Center, Montreal, Quebec.

Correspondence: Address correspondence and reprint requests to: S. Meterissian, MD, 687 Pine Ave. W., Suite S10.22, Montreal, Quebec, H3A 1A1; Fax: 514-843-1503; E-mail: sarkis.meterissian{at}muhc.mcgill.ca


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Cancer, particularly skin cancer and lymphoma, is a complication of posttransplantation immunosuppression. We investigated the characteristics of cancers in our renal transplant population, the role of type of immunosuppression on cancer incidence, and whether newer, more potent immunosuppressive agents produce cancers sooner after transplantation.

Methods: The charts of patients who developed cancer after renal transplantation between 1958 and 2000 were reviewed. Statistical analyses were performed with the mid-P version of Fisher’s exact test for 2 x 2 tables for incidence comparison of cancer and with Student’s t-test for differences between mean times to cancer.

Results: Between 1958 and 2000, 924 transplantations in 760 patients were performed. We found a cancer incidence of 12.2%. The most frequent cancers were skin and genitourinary. The overall mortality was 54%. We found an increased incidence of cancer in the group of patients in the cyclosporine era and for patients >=45 years at transplantation. Cancer did not develop sooner in the cyclosporine group.

Conclusions: The distribution of types of cancer was similar to that reported in the literature. The mortality rate was high. The incidence of cancer was higher in the cyclosporine era in patients >=45 years at transplantation.

Key Words: Cancers • Renal transplants • Cyclosporine • Immunosuppression


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The development of cancer is a well-known complication of immunosuppression. In the renal transplant population, cancer of the lip and skin and lymphoma are the most frequent neoplasms, with a reported incidence of 40% to 53% and 16%, respectively.1 The incidence of other malignancies is also increased compared with the general population.2–4 Cancer is associated with significant consequences for the transplant patient. A necessary change in immunosuppression may increase the risk of rejection. With the use of more potent immunosuppressive agents, the success rate of renal transplantation has increased, but so has the rate of some complications, including the development of cancers. The purpose of this study was 3-fold: (1) to define the characteristics of the cancers in our renal transplant population, (2) to determine the role of type of immunosuppression on cancer incidence, and (3) to determine whether newer, more potent immunosuppressive agents produce cancers sooner after transplantation.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients
We reviewed all the outpatient and hospital charts of patients who had a functioning renal transplant followed by a diagnosis of cancer between May 1958 and December 1999 at the Royal Victoria Hospital (Montreal, Quebec, Canada). Data gathered included sex, date of transplantation, age at transplantation, number of transplantations, type of immunosuppression, date of diagnosis of cancer, type of cancer, number of primary tumors, time between transplantation and diagnosis of the first cancer, outcome of the patient, time between date of transplantation and death, and duration of follow-up for each patient until December 31, 2000.

Patients with a diagnosis of cancer less than a month after transplantation were excluded because the tumor was most likely present before the transplantation. Because of the retrospective nature of the study, there were some missing data. The date of diagnosis of cancer was missing in 7 patients, and the pathology report was missing in 13 patients, mainly because they had been treated at another institution for their cancers. The majority of missing pathology reports were for skin and lung tumors. There were also no available data regarding other risk factors, such as family history of cancer or sun exposure.

Immunosuppression
There were two main periods of immunosuppressive regimens. The first period of immunosuppression was from May 1958 to January 1986. Only azathioprine and prednisone were used. The second period of immunosuppression was from January 1986 to December 2000. Antithymocyte globulin was introduced for induction with azathioprine and prednisone, and cyclosporine or tacrolimus was added to maintenance therapy.

Statistics
The statistical analyses were performed by using the mid-P version of Fisher’s exact test for 2 x 2 tables for incidence comparison of cancer and Student’s t-test for differences between mean times to cancer.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Cancer Incidence
Nine hundred twenty-four renal transplantations in 760 patients were performed between May 1958 and December 2000. There were 265 women and 495 men. We found 93 patients, or 12.2% of all transplant patients, with a posttransplantation diagnosis of cancer. There were 28 women (11% of all women with transplants) and 65 men or (13% of all men women with transplants). The mean age at transplantation of the patients with cancer was 43 years (range, 15–69 years). If these cancer patients are stratified according to the type of immunosuppression received, the mean age at transplantation for the precyclosporine group was 36 years, and for the cyclosporine group, 51 years.

A total of 111 primary tumors occurred in these 93 patients, of whom 15 (16%) had multiple tumors. Two patients had synchronous tumors, and 13 had metachronous tumors. The mean age at diagnosis of cancer was 51.5 years in the whole group of cancer patients, 47.6 years in the precyclosporine group, and 55.4 years in the cyclosporine group. The distribution of the cancers is shown in Table 1. The most frequent tumors were skin and lip (42.3%), followed by genitourinary (15.3%), gastrointestinal (12.6%), and lung (10.8%).


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  		TABLE 1. Distribution of cancers
 
Survival Analysis
The outcome of the 93 patients was as follows: 46% were still alive, 41% died of cancer, 11% died of other causes, and 2% died of unknown causes. We followed up the 35 patients with skin cancers: 60% were still alive, 26% died of cancer, and 14% died of other causes. Of those who died of cancer, two died of a second primary tumor (one lung cancer and one colon cancer), one patient died of a metastatic melanoma, and six patients died of a very aggressive squamous cell carcinoma (Table 2).


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  		TABLE 2. Status of the 35 patients with skin cancer
 
We also analyzed the outcome of the 58 patients with nonskin cancers: 50% died of cancer, 9% died of other causes, and in 3% the cause of death was unknown. The mean survival of the group was low, at 1.7 years (Table 3). The outcome of the grafts was as follows: 35% of the patients were alive with functioning grafts, 40% died with functioning grafts, and 15% returned to dialysis (the status of 10% of patients was unknown). Despite decreasing the immunosuppression at diagnosis of cancer, very few patients lost their graft (Table 4).


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  		TABLE 3. Status of the 58 patients with non-skin cancer
 

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  		TABLE 4. Status of patients as of December 31, 2000
 
Effect of Immunosuppression
To determine the effect of the type of immunosuppression on cancer incidence, we analyzed the two eras separately. There were 469 grafts during the first period of immunosuppression, and 49 patients developed cancers. There were 455 grafts during the second period of immunosuppression, and 44 patients developed cancers.

The mean follow-up for the whole group, defined by the time from graft to death or to December 2000, was 13.4 years. The patients were separated into two groups according to the type of immunosuppression they received. In the precyclosporine group, the follow-up was 18.6 years, and in the cyclosporine group it was 7.6 years. The follow-up was much shorter in the cyclosporine group, and this should influence the incidence of cancer, because the exposure to immunosuppression is a known risk factor for cancer development.5,6 Because of this difference in follow-up, we analyzed the incidence in two equivalent time periods. For the first group, from 1969 to 1983 (a 14-year period), there were 260 transplants with 15 cancers, for an incidence of 5.8%. For the second group, from 1986 to 2000 (also a 14-year period), there were 421 transplants with 43 cancers, for an incidence of 10.2%. This increase in incidence was statistically significant (P = .04 by Fisher’s mid-P exact text). Because increasing age is a risk factor for cancer, we restricted the analysis to patients of the same age group. We looked at patients <45 years old and at patients 45 years and older at transplantation. For patients <45 years old, there were, in the precyclosporine era, 198 transplants (mean age, 30 years) with 11 cancers, for an incidence of 5.6%. In the cyclosporine era, there were 180 transplants (mean age, 34 years) with 11 cancers, for an incidence of 6.1%. The difference between groups was not significant (P = .85). In the patients 45 years and older, in the precyclosporine era there were 75 transplants (mean age, 50 years) with 4 cancers, for an incidence of 5.3%. In the cyclosporine era, there were 223 transplants (mean age, 56 years) with 32 cancers, for an incidence of 14.3%; the difference between groups was significant (P = .03).

To determine whether cancers occurred earlier after transplantation with more aggressive immunosuppression, we analyzed the time from transplantation to diagnosis of cancer. In the precyclosporine group it was 5.4 years (±2.4 years), and in the cyclosporine group it was 4.9 years (±3.5 years). This difference was not statistically significant (P = .7; Student’s t-test; two-sided P value).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The cancer incidence rate for each tumor category was similar to those reported in the literature, except for lymphoma.1 The 2.7% incidence rate (or 5.2% of patients with nonskin tumors) is much lower than the 11% to 16% of other series.7–9 This may be due to a less aggressive use of immunosuppression in our institution. It is well known that the incidence of lymphoma is higher in liver and heart transplant recipients and that this is probably related to a more intensive immunosuppression.3

The prognosis of patients with nonskin cancer was poor: half died of cancer, and the overall survival was <2 years. This is similar to the survival reported by Sheil et al.4 The prognosis of patients with skin cancer was a little better. The mortality from skin cancer was 26%, and the mean survival was 4 years. If the two patients with skin cancer who died of another primary cancer are removed from the group, the mortality rate is still high, at 20%. This is worse than the 5.4% mortality rate reported by the Cincinnati Transplant Tumor Registry.10 There is no explanation for the high incidence of aggressive squamous cell tumors in this series, except that this is a small number of patients. On the basis of these results, we are planning a more regular screening program for skin tumors in our renal transplant population.

We have no standard protocol for the management of immunosuppression after a diagnosis of cancer, but usually azathioprine is discontinued because of its effect on DNA synthesis. With this decrease in immunosuppression, only 15% of the patients returned to dialysis. Of the patients who died, nearly 90% (37 of 42) had a functioning graft despite an alteration of their immunosuppression regimen.

The increased incidence of cancer in the cyclosporine group was statistically significant (10.2% vs. 5.8%). After having controlled for age, the difference in incidence of cancer between the precyclosporine and the cyclosporine groups was significant only for patients 45 years and older at transplantation. This is an important finding because in the cyclosporine era, transplantation is offered to older patients, and we must be aware of the increased incidence of cancers. This increased incidence of cancer must be weighed against improved graft survival. It is possible that the intensity of immunosuppression also plays an important role in the incidence of cancers.9 The delay before diagnosis of cancer in the cyclosporine group was shorter than in the precyclosporine group, but this was not statistically significant. We conclude that with the high incidence of cancer in the renal transplants, these patients should undergo regular screening for malignancy. Some clinical practice guidelines were developed recently by the American Society of Nephrology for the surveillance of these patients,1 and we recommend their adoption.


   Footnotes
 
Presented at the Society of Surgical Oncology Meeting, Washington, DC, March 2001.

There is a particular distribution of cancers in the renal transplant population. The mortality rate is high, and the type of immunosuppression used may have an influence on cancer incidence.

Received for publication June 25, 2001. Accepted for publication June 4, 2002.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Kasiske BL, Vazquez MA, Harmon WE, et al. Recommendation for the outpatient surveillance of renal transplant recipients. J Am Soc Nephrol 2000; 11: S1–86.[Abstract/Free Full Text]
  2. Birkeland SA, Storm HH, Lamm LU, et al. Cancer risk after renal transplantation in the Nordic countries, 1964–1986. Int J Cancer 1995; 60: 183–9.[Medline]
  3. Sheil AGR, Disney APS, Mathew TH, Livingston BER, Keogh AM. Lymphoma incidence, cyclosporine, and the evolution and major impact of malignancy following organ transplantation. Transplant Proc 1997; 29: 825–7.[CrossRef][Medline]
  4. Sheil AGR, Disney APS, Mathew TH, Amiss N. De novo malignancy emerges as a major cause of morbidity and late failure in renal transplantation. Transplant Proc 1993; 25: 1383–4.[Medline]
  5. Danpanich E, Kasiske BL. Risk factors for cancer in renal transplant recipients. Transplantation 1999; 68: 1859–64.[CrossRef][Medline]
  6. London NJ, Famery SM, Will EJ, Davison AM, Lodge JPA. Risk of neoplasia in renal transplant patients. Lancet 1995; 346: 403–6.[CrossRef][Medline]
  7. Behrend M, Kolditz M, Kliem V, et al. Malignancies in patients under long-term immunosuppression after kidney transplantation. Transplant Proc 1997; 29: 834–5.[CrossRef][Medline]
  8. Sheil AGR. Malignancy in organ transplantation recipients. Transplant Proc 1996; 28: 1162.[Medline]
  9. Penn I. Cancers in cyclosporine-treated vs azathioprine-treated patients. Transplant Proc 1996; 28: 876–8.[Medline]
  10. Penn I. The changing pattern of posttransplant malignancies. Transplant Proc 1991; 23: 1101–3.[Medline]



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