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Ann Thorac Surg 1995;60:1623-1626
© 1995 The Society of Thoracic Surgeons

Original Articles: Cardiovascular

Solid Tumors After Heart Transplantation: Lethality of Lung Cancer

Si M. Pham, MD, Robert L. Kormos, MD, Rodney J. Landreneau, MD, Akihiko Kawai, MD, Ivan Gonzalez-Cancel, MD, Robert L. Hardesty, MD, Brack G. Hattler, MD, PhD, Bartley P. Griffith, MD

Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania


   Abstract
Top
 Footnotes
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 References
 
Background. Prolonged nonspecific immunosuppression after solid-organ transplantation is associated with an increased risk of certain cancers. This study examined the development of solid-organ tumors after cardiac transplantation.

Methods. Thirty-eight solid tumors were identified in 36 (5.9%) of 608 cardiac transplant recipients who survived more than 30 days. Two patients had two types of skin tumors (basal cell and squamous cell). The tumors included the following types: skin (15), lung (10), breast (1), bladder (2), larynx (2), liver (1), parotid (1), testicle (1), uterus (2), melanoma (2), and Merkel's cell (1). Four immunosuppression regimens based on cyclosporin A or FK 506 were used during this period.

Results. There was no association between the incidence of solid tumors and the use of lympholytic therapy. After the diagnosis of tumor was made, the actuarial 2-year survival rates of recipients with skin, lung, and other solid tumors were 71%, 22%, and 23%, respectively. Eight of 10 patients with lung cancer were in stage IIIA or higher at the time of diagnosis.

Conclusion. Skin and lung tumors are the most frequent solid tumors in heart transplant recipients. Skin tumors (except Merkel's cell carcinoma and melanoma) usually have a benign course, whereas lung and other tumors developing in cardiac transplant recipients carry a poor prognosis. Advanced disease stage at the time of diagnosis is responsible for the dismal outcome of recipients in whom solid tumors develop. Close postoperative tumor surveillance after cardiac transplantation is warranted.


   Introduction
Top
 Footnotes
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 References
 
Prolonged nonspecific immunosuppression after solid-organ transplantation is associated with an increased risk of certain cancers. The risk of de novo malignant tumors in transplant recipients ranges from 4% to 18% (mean risk, 6%) and is at least 100 times higher than that in a matched general population [1]. Because of the large number of renal transplant recipients with long-term follow-up, most of the published data on posttransplantation malignancies have involved these recipients, with skin tumors and lymphoma being the primary malignancies reported [2]. Posttransplantation lymphoproliferative disease after cardiac transplantation has been widely reported [3–5]. However, there is a paucity of information regarding the development of solid-organ tumors after cardiac transplantation.

For editorial comment, see page 1559.


   Material and Methods
Top
 Footnotes
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 References
 
Between January 1980 and June 1993, 648 patients underwent cardiac transplantation at the University Health Center of Pittsburgh. Six hundred eight patients (94%) who survived for more than 30 days after transplantation constituted the population for this study. Neoplastic conditions developed in 93 of these 608 patients. Posttransplantation lymphoproliferative disease developed in 55 patients, solid tumors in 36, and chronic myeloid leukemia and multiple myeloma in 1 patient each. Five hundred seventeen patients remain free from malignancy at their most recent follow-up, averaging 4.3 ± 2.8 years after transplantation. This report focuses on the 36 patients in whom solid tumors developed during this period. All patients were followed until death or until June 1993. Details of recipient and donor selection, donor organ preservation, surgical technique, and postoperative management have been reported previously [6–8].

Immunosuppression protocols, which were based on cyclosporin A or FK 506, are depicted in Table 1Go. Details of the immunosuppression management have been published elsewhere [7–9]. Briefly, azathioprine was administered intravenously at a dose of 4 mg/kg intraoperatively and then maintained at 2 mg/kg daily as long as the white blood cell count was greater than 3,500/µL. A continuous infusion of cyclosporine (1.5 to 3.0 mg • kg-1 • day-1) was initiated 4 to 6 hours postoperatively, and conversion to an oral dose began on postoperative day (POD) 1. Whole-blood trough cyclosporine levels (whole blood TDx; Abbott, Abbott Park, IL) were maintained at 700 to 1,200 ng/mL. A continuous intravenous infusion of FK 506 (0.05 to 0.10 mg • kg-1 • day-1) was begun 4 to 6 hours postoperatively. Oral administration of FK 506 (0.30 mg • kg-1 • day-1 in two divided doses) was started on POD 1, and the dosage was titrated to keep the 12-hour trough serum level (by enzyme-linked immunosorbent assay technique [10]) between 0.5 and 2.0 ng/mL. Methylprednisolone (1,000 mg intravenously) was administered just before reperfusion of the transplanted heart and was continued at a dosage of 3 mg • kg-1 • day-1 on POD 1. The steroid dosage was tapered to 0.3 mg • kg-1 • day-1 by POD 7, and the patient was gradually weaned from steroids 1 year to 2 years after transplantation. Prophylactic OKT3 (Orthoclone; Ortho Pharmaceutical Corp, Raritan, NJ) was given as part of a randomized trial [8] from 1987 to 1990 at a dose of 5 mg/d intravenously beginning on POD 2 or 3 and continued for 14 days. Prophylactic rabbit antithymocyte globulin, which was manufactured in our surgical laboratories by Dr Charles P. Bieber according to the method of Davis and associates [11], was given intramuscularly at a dosage of 1.5 mg • kg-1 • day-1 for 5 days starting on POD 1. Either rabbit antithymocyte globulin or OKT3 was also used as a rescue therapy for cellular rejection that was refractory to pulse steroid therapy.


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  		Table 1. . Demographics of Cardiac Recipients With and Without Solid Tumorsa
 
Posttransplantation Surveillance
Transvenous endomyocardial biopsy, radionuclide left ventriculography, and cardiac catheterization were performed as previously described [7–9]. Standard chest roentgenograms were performed at 6-month intervals during follow-up. No other surveillance was routinely performed beyond the usual monitoring of the biochemical and hematologic effects of the immunosuppression regimen.

Statistical Analysis
Continuous variables were expressed as the mean ± the standard deviation and analyzed using the t test or Mann-Whitney test. The {chi}2 test was used for discrete variables. Time-related events, such as survival and freedom from tumor, were analyzed by Cutler-Ederes (life-table) method using BMDP statistical software (Berkeley, CA). Differences in survival curves were analyzed using Mantel-Cox and Breslow statistics. Significance was defined as a p value of less than 0.05.


   Results
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 Footnotes
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 References
 
After a mean follow-up of 4.6 ± 2.6 years, solid tumors (excluding lymphoma and hematologic malignancy) had developed in thirty-six of the 608 cardiac transplant recipients who survived more than 30 days. The mean age of these 36 patients was significantly greater than that of those remaining free from tumors (51.4 ± 8.9 years versus 43.1 ± 16.4 years; p < 0.05), but there was no difference between these two groups in average follow-up (4.9 ± 2.3 years versus 4.3 ± 2.8 years) (see Table 1Go).

Among the recipients who had cyclosporine-based immunosuppression, there was no significant difference ({chi}2 test) in the incidence of solid tumors between those who received lympholytic prophylaxis (rabbit antithymocyte globulin or OKT3) and those who did not (9.7% versus 6.1%). No patient in the FK 506 group has yet had development of a solid tumor. This probably reflects the relatively short follow-up in this group of patients, as FK 506 was only recently introduced (in 1989) into our immunosuppression protocol (see Table 1Go).

There were 38 solid tumors in the 36 patients. Two of these recipients had both a squamous and a basal cell skin cancer. The various solid tumors encountered are noted in Table 2Go. The average time from transplantation to tumor detection was 41.6 ± 20.5 months, 26.7 ± 17.9 months, and 45.2 ± 28.9 months for skin, lung, and other tumors, respectively. Recipients in whom bronchogenic carcinomas developed had a median survival of 27 days after the diagnosis of tumor was made. Those with skin and other tumors had a median survival of 27.7 months and 8.8 months, respectively. The actuarial freedom from solid tumor among our entire cardiac transplant group at 1 year, 5 years, and 10 years was 100%, 93.4%, and 88.4%, respectively (Fig 1Go). The actuarial 2-year survival rates of recipients after a diagnosis of skin, lung, and other solid tumors was made were 71%, 22%, and 23%, respectively (Fig 2Go).


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  		Table 2. . Types of Solid Tumors in Cardiac Recipients
 


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  		Fig 1. . Actuarial freedom from solid tumors after cardiac transplantation.

 


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  		Fig 2. . Actuarial probability of survival of cardiac transplant recipients after diagnosis of solid tumor.

 
Table 3Go depicts the characteristics of lung tumors developing in cardiac transplant recipients. Of the 10 patients with lung cancers, 8 were in stage IIIA or higher at the time of diagnosis. The most striking finding was that the median survival after the diagnosis of lung tumor was 27 days. All recipients who were in stage IIIA or higher at the time of diagnosis died within 14 months (mean time, 3.3 ± 4.9 months). Of the 2 patients with stage I disease, 1 had local recurrence 1 year after a curative resection and died of myocardial infarction 2.2 years after the development of lung tumor, and 1 is still alive 3 years after a curative resection.


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  		Table 3. . Summary of Data on Cardiac Transplant Recipients With Lung Tumors
 

   Comment
Top
 Footnotes
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
References
 
In this study, we focused on the problem of solid tumors that develop de novo after cardiac transplantation. After a mean follow-up of 4.6 years, 36 (5.9%) of 608 cardiac transplant recipients who survived more than 30 days after transplantation had development of solid tumors. In general, solid tumors occurred in older recipients (mean age, 51.4 ± 8.9 years at the time of diagnosis versus 43.1 ± 16.4 years for those without tumors). The average time from transplantation to diagnosis of tumor was 26.7 months for lung tumors, 41.6 months for skin tumors, and 45.2 months for other tumors. Under the cyclosporine-based immunosuppression, there was no correlation between the use of lympholytic agents (OKT3 or rabbit antithymocyte globulin) and the development of tumors. The actuarial risk of developing a solid tumor is proportional to the length of follow-up: 6.6% at 5 years and 11.6% at 10 years (see Fig 1Go). Others have also found an increase in the risk of developing tumors with time. Krikorian and colleagues [12] reported that the actuarial probability of developing any type of malignancy (solid tumors and lymphomas) was 2.7% and 25.6% at 1 year and five years, respectively.

Skin Tumors
As in previous reports [13, 14], our current study demonstrates that skin tumor is the most common tumor in cardiac transplant recipients (47% of all tumors). In contrast to the report by Lanza and associates [15] from South Africa in which 33% of malignant tumors developing after cardiac and renal transplantations were Kaposi's sarcoma, we did not observe any Kaposi's sarcoma in our patients. This may be due to the differences in geographic location and patient population, as in the general population, Kaposi's sarcoma represents 0.06% and 9% of all malignant neoplasms in the United States and in Central Africa (before the acquired immunodeficiency syndrome epidemic), respectively [16]. Except for patients with melanoma and Merkel's cell carcinoma, none of our patients died as a direct result of skin tumors. Because skin cancer is common after heart transplantation and because exposure to sunlight is an important risk factor for skin cancers [17], cardiac transplant recipients, especially those at high risk for skin cancers (light-skinned people with blue eyes and blond or red hair), should be advised to minimize exposure to sunlight. In addition, the need of long-term use of azathioprine in cardiac transplant recipients should be reconsidered because metabolites of this drug (methylnitrothioimidazole and related imidazole compounds) are known to sensitize the skin to sunlight [18].

Lung Tumors
Lung tumors were the second most common solid tumor in this series, accounting for 26% of all solid tumors. The prevalence is 1.6% (10/608 patients), 25-fold higher than that of the general population (64/100,000) [19]. Our results are similar to those of the Cincinnati Transplant Tumor Registry [14] in which lung tumor is also the second most prevalent solid tumor (10% of all tumors). In contrast to that registry, our series has a lower prevalence of lung cancer in cardiac recipients (1.6% versus 6.4%). This difference may be due to the difference in patient demographics and the duration of follow-up. The most striking feature is the fact that of the 10 patients with lung cancer, 8 had advanced disease (stage IIIA or higher) at the time of diagnosis, even though these patients were followed up very closely (chest roentgenograms every 6 months). The advanced disease stage is mainly responsible for the dismal prognosis for these patients whose median survival after diagnosis was 27 days. This is in contrast with a median survival of 11 months and 6 months, respectively, for regionally advanced and metastatic lung cancer in the general population [19]. Our experience as reported here and that of others [20] have indicated that long-term survival can be achieved in patients with stage I lung tumors who undergo curative resection. These findings support aggressive surgical intervention for lung tumors that are detected at early stages in cardiac transplant recipients.

Skin tumors (except Merkel's cell carcinoma and melanoma) have a benign course, whereas lung and other solid tumors developing in cardiac transplant recipients carry a poor prognosis. Advanced disease stage at the time of diagnosis is responsible for the dismal outcome in recipients with lung cancer. Avoidance of excessive exposure to sunlight, cessation of smoking, and close surveillance for solid tumors are recommended for cardiac transplant recipients.


   Footnotes
Top
 Footnotes
Abstract
 Introduction
 Material and Methods
 Results
 Comment
 References
 
Presented at the Poster Session at the Thirtieth Annual Meeting of The Society of Thoracic Surgeons, New Orleans, LA, Jan 31–Feb 2, 1994.

Address reprint requests to Dr Pham, Division of Cardiothoracic Surgery, University of Pittsburgh School of Medicine, Suite C-700, Presbyterian University Hospital, 200 Lothrop St, Pittsburgh, PA 15213.


   References
Top
 Footnotes
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 References
 

  1. Penn I. Incidence and treatment of neoplasia after transplantation. J Heart Lung Transplant 1993;12:s328–36.
  2. MacLeod AM, Catto GD. Cancer after transplantation. Br Med J 1988;297:4–5.
  3. Armitage JM, Kormos RL, Stuart RS, et al. Posttransplant lymphoproliferative disease in thoracic organ transplant patients: ten years of cyclosporine-based immunosuppression. J Heart Lung Transplant 1991;10:877–86.[Medline]
  4. Randhawa PS, Yousem SA, Paradis IL, et al. The clinical spectrum, pathology, and clonal analysis of Epstein-Barr virus-associated lymphoproliferative disorders in heart-lung transplant recipients. Am J Clin Pathol 1989;92:177–85.[Medline]
  5. Swinnen LJ, Costanzo-Nordin M, Fisher SG, et al. Increased incidence of lymphoproliferative disorder after immunosuppression with the monoclonal antibody OKT3 in cardiac transplant recipients. N Engl J Med 1990;323:1723–8.[Abstract]
  6. Griffith BP, Hardesty RL, Bahnson HT. Powerful but limited immunosuppression for cardiac transplantation with cyclosporine and low-dose steroid. J Thorac Cardiovasc Surg 1984;87:35–42.[Abstract]
  7. Griffith BP, Hardesty RL, Deeb GM, et al. Cardiac transplantation with cyclosporin A and prednisone. Ann Surg 1982;196:324–9.[Medline]
  8. Kormos RL, Armitage JM, Dummer JS, et al. Optimal perioperative immunosuppression in cardiac transplantation using rabbit antithymocyte globulin. Transplantation 1990;49:306–11.[Medline]
  9. Armitage JM, Kormos RL, Morita S, et al. Clinical trial of FK 506 immunosuppression in adult cardiac transplantation. Ann Thorac Surg 1992;54:205–11.[Abstract]
  10. Tamura K, Kobayashi M, Hashimoto K, et al. A highly sensitive method to assay FK 506 levels in plasma. Transplant Proc 1987;19(Suppl 6):23–9.[Medline]
  11. Davis RC, Cooperband SR, Mannick JA. Preparation and in vitro assay of effective and ineffective antithymocyte sera. Surgery 1969;66:58–64.[Medline]
  12. Krikorian JG, Anderson JL, Bieber CP, et al. Malignant neoplasms following cardiac transplantation. JAMA 1978;240:639–43.[Abstract]
  13. Bieber CP, Hunt SA, Schwinn DA, et al. Complications in long-term survivors of cardiac transplantation. Transplant Proc 1981;13:207–11.[Medline]
  14. Penn I. Tumors after renal and cardiac transplantation. Hematol Oncol Clin North Am 1993;7:431–45.[Medline]
  15. Lanza RP, Cooper DKC, Cassidy MJD, et al. Malignant neoplasm occurring after cardiac transplantation. JAMA 1983;249:1746–8.[Abstract]
  16. Rothman S. Remark on sex, age, and racial distribution of Kaposi's sarcoma and possible pathologic factors. Acta Unio Int Contra Cancrum 1962;18:326–30.
  17. Penn I. Why do immunosuppressed patients develop cancer? Crit Rev Oncogenesis 1989;1:27–52.[Medline]
  18. Hemmens VJ, Moore DE. Photochemical sensitization by azathioprine and its metabolites. II. Azathioprine and nitroimidazole metabolites. Photochem Photobiol 1986;43:257–62.[Medline]
  19. Mountain CF. A new international staging system for lung cancer. Chest 1986;86(Suppl):225S–33S.
  20. Fleming RH, Jennison SH, Naunheim KS. Primary bronchogenic carcinoma in the heart transplant recipient. Ann Thorac Surg 1994;57:1300–1.[Abstract]

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