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

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Original Articles: Cardiovascular

Solid Tumors After Heart Transplantation: Lethality of Lung Cancer

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 1. 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.

Statistical Analysis
Continuous variables were expressed as the mean ± the standard deviation and analyzed using the t test or Mann-Whitney test. The 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

Top 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 1).

Among the recipients who had cyclosporine-based immunosuppression, there was no significant difference (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 1).

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 2. 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 1). 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 2).

View larger version (11K): [in this window] [in a new window]   Fig 1. . Actuarial freedom from solid tumors after cardiac transplantation.

View larger version (15K): [in this window] [in a new window]   Fig 2. . Actuarial probability of survival of cardiac transplant recipients after diagnosis of solid tumor.

	Comment

Top Footnotes Abstract Introduction Material and Methods Results Comment References

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.[Free Full Text]
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]
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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/Free Full Text]
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]
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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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This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Si M. Pham Robert L. Kormos Rodney J. Landreneau Akihiko Kawai Ivan Gonzalez-Cancel Robert L. Hardesty Brack G. Hattler Bartley P. Griffith Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Pham, S. M. Articles by Griffith, B. P. Search for Related Content PubMed PubMed Citation Articles by Pham, S. M. Articles by Griffith, B. P. Related Collections Related Article