Ann Thorac Surg 2003;75:367-371
© 2003 The Society of Thoracic Surgeons
Original article: general thoracic
Bronchogenic carcinoma after solid organ transplantation
Marc de Perrot, MDa,
Dennis A. Wigle, MDa,
Andrew F. Pierre, MDa,
Ming S. Tsao, MDa,
Thomas K. Waddell, MDa,
Thomas R.J. Todd, MDa,
Shaf H. Keshavjee, MDa*
a Division of Thoracic Surgery, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada
Accepted for publication August 29, 2002.
* Address reprint requests to Dr Keshavjee, Division of Thoracic Surgery, Toronto General Hospital, E10-224, 200 Elizabeth St, Toronto, Ontario M5G 2C4, Canada.
e-mail: shaf.keshavjee{at}uhn.on.ca
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Abstract
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BACKGROUND: This study assesses the risk of bronchogenic carcinoma after solid organ transplantation. Although the overall incidence of malignancy is increased after solid organ transplantation, the risk of bronchogenic carcinoma in the transplant population has not been systematically studied.
METHODS: Among a cohort of 3,374 patients transplanted in our institution between 1985 and 2000 (1,735 kidney recipients, 930 liver, 313 heart, and 396 lung recipients), 9 patients (0.3%) had a bronchogenic carcinoma develop. Lung carcinoma occurred in 3 kidney recipients, 3 liver recipients, 2 heart recipients, and 1 lung recipient.
RESULTS: Time to diagnosis after the transplant procedure ranged from 9 to 126 months (mean, 63 months). Aside from the lung transplant candidate, all recipients had a smoking history. Seven patients underwent thoracotomy and 6 had a complete resection. Tumors were classified as stage IA (n = 1), IB (n = 2), IIB (n = 2), IIIA (n = 2), IIIB (n = 1), and IV (n = 1). Genotyping demonstrated that the carcinoma arising in the lung transplant recipient originated from the donor and may have been transmitted at the time of transplantation. Two patients were alive without recurrence 21 and 42 months after the operation.
CONCLUSIONS: The risk of bronchogenic carcinoma is low and occurs mainly in recipients with a smoking history. However, bronchogenic carcinoma can also be transmitted from donor lungs at the time of transplantation. Hence careful examination of chest roentgenograms, and computed tomographic chest scan if available, as well as meticulous assessment of the lung, and biopsy of any suspicious lesions, are important to limit the risk of lung cancer transmission, especially with the liberalization of donor criteria.
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Introduction
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The risk of malignancy after solid organ transplantation is a well-recognized event in long-term immunosuppressed transplant recipients. The overall incidence of carcinoma is increased by up to 100-fold and the incidence of non-Hodgkin’s lymphoma by 40-fold [1]. However, the incidence may vary with the type of allograft because of differences in induction therapy and immunosuppressive regimens [2–5].
The incidence of bronchogenic carcinoma after solid organ transplantation remains controversial. Although some authors have reported an incidence similar to the overall population, others have found an unexpectedly high incidence in the heart transplant population [3, 6, 7]. In order to determine the risk of bronchogenic carcinoma after solid organ transplantation, we retrieved the data of all patients who had bronchogenic carcinoma develop after kidney, liver, heart, and lung transplantation in our institution over the past 15 years; we also reviewed the literature on this relatively rare condition.
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Material and methods
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Patient data
Among a cohort of 1,735 kidney recipients, 930 liver, 313 heart, and 396 lung recipients transplanted at the Toronto General Hospital between January 1985 and December 2000, 9 recipients had a bronchogenic carcinoma develop (0.3%). Three bronchogenic carcinomas occurred after kidney transplantation (0.2%), three after liver transplantation (0.3%), two after heart transplantation (0.6%), and one after lung transplantation (0.3%).
Clinical follow-up
After discharge from the hospital, all recipients were followed at the Toronto General Hospital in the outpatient clinic with regular visits every 1 to 3 months during the first 2 years and then at least once or twice per year according to the patient’s clinical status and location. All transplanted patients were entered in a multiorgan transplant database, which was regularly updated with outcome and cause of death.
Genotyping
Genotyping was performed to determine the origin of the tumor in the lung transplant recipient using the polymerase chain reaction based Promega short tandem repeat system. Genomic DNA was purified from either lung tissue or whole blood using standard phenol-chloroform extraction protocols. A total of eight loci were examined for genetic analysis, including D18S51, D21S11, TH01, D3S1358, FGA, TPOX, D8S1179, and vWA. Peak heights for each allele were derived from lane scans to obtain the percentage contribution of each allele to the indicated locus. Using the derived recipient blood and normal donor lung profiles, the percentage of DNA contribution for the lung tumor and normal lung samples was calculated for each locus.
Histology
Formalin fixed, paraffin embedded tissue sections (5 µm) were mounted on positive charged microscope slides. Tissue sections where then incubated for 12 hours at 60°C, deparaffinized in xylene and rehydrated through decreasing concentrations of ethanol. Sections were stained with hematoxylin and eosin and viewed by light microscopy.
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Results
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There were 7 males and 2 females with a mean age of 56 years (range, 50 to 67 years) at the time of transplantation. Four patients were treated with cyclosporine, azathioprine, and prednisone, 4 with cyclosporine and prednisone, and 1 with only cyclosporine. Except for the lung transplant recipient, all other patients had a smoking history (Table 1).
Two patients presented with concomitant malignant disease. One patient had a previous laryngeal carcinoma treated by radiotherapy 10 years before undergoing liver transplantation, but did not develop recurrence with an immunosuppression regimen. Time to diagnosis of bronchogenic carcinoma after the transplant procedure ranged from 9 to 126 months (mean, 63 months). The length of time between the last chest roentgenogram and the diagnosis of bronchogenic carcinoma ranged between 3 and 96 months (mean, 25 months). Seven patients underwent thoracotomy and 6 had a complete resection. Tumors were classified as stage IA (n = 1), IB (n = 2), IIB (n = 2), IIIA (n = 2), IIIB (n = 1), and IV (n = 1). Adjuvant radiotherapy was administered in 1 patient after operation because of metastatic hilar lymph nodes. Two patients had radiotherapy as their primary treatment because of advanced stage carcinoma. Two patients are alive without disease 21 and 42 months after operation (Table 2).
The lung transplant recipient underwent a lobectomy 9 months after the transplantation procedure for a stage IB bronchioloalveolar carcinoma, but died of a fulminant Pseudomonas aeruginosa sepsis 6 days after operation. Retrospectively, the lesion was detectable on a postoperative computed tomographic chest scan performed 6 weeks after the transplantation procedure, which was interpreted as lung consolidation. The lung donor was a 60-year-old female with no smoking history who died from a subarachnoid hemorrhage. Genotyping of the lung tumor, normal donor lung tissue, and recipient blood demonstrated that the tumor originated from the donor (Fig 1).
Calculation of the genetic contribution from each indicated that approximately 70% of the tumor cells were from the donor, with the remaining contribution from recipient inflammatory cells infiltrating the lung tissue and the tumor (Fig 2).
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Fig 1. Genotyping of normal donor lung tissue, the tumor, and recipient blood was performed to determine the origin of the lung tumor in the lung transplant recipient. (Recipient contribution is in black and donor contribution is in gray). A total of 8 different DNA loci were examined, of which 3 (A–C) are represented here. Calculation of the genetic contribution of the tumor demonstrated that approximately 70% of the tumor cells were from the donor (D). The remaining cells were from the recipient and included mainly inflammatory cells, which were also present in the normal donor lung tissue.
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Fig 2. Tissue section from the bronchoalveolar carcinoma originating in the lung transplant recipient (hematoxylin & eosin, x400). Genotyping indicated that approximately 70% of the tumor cells were from the donor, whereas the remaining contribution was from the recipient and included mainly inflammatory cells that infiltrated the normal donor lung tissue and the tumor.
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Comment
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The Cincinnati Transplant Tumor Registry has reported 397 carcinomas of the lung among a total of 7,248 tumors occurring in the transplanted population [3]. However, few studies have provided information on smoking history, type of transplantation, histology, stage of disease, and outcome of recipients with bronchogenic carcinoma. A majority of these reports were published over the past 10 years as summarized in Table 3.
[6–20].
In our experience the rate of bronchogenic carcinoma in the transplant population was relatively low and ranged between 0.2% and 0.6% with no significant difference between the type of organ transplanted. Similar findings have been observed in other series and suggest that the incidence of bronchogenic carcinoma in the transplant population is not increased when compared with that in the overall population after adjusting for age, smoking history, and gender [21–23]. However, some authors have recently observed an unexpectedly high proportion of bronchogenic carcinoma in the heart transplant population with a rate of up to 4.1% in one series [6, 7, 14, 15]. This finding could be explained by a higher incidence of smoking history in patients undergoing heart transplantation. In our review of the literature we observed overall that 93% of the recipients with bronchogenic carcinoma also had a smoking history, and 88% of these recipients were men whose mean age was usually between 50 and 60 years (Table 3). Hence an immunosuppression regimen does not seem to have precipitated lung cancer in patients that otherwise were not at risk.
The low effect of an immunosuppression regimen on the development of bronchogenic carcinoma in the absence of risk factors is highlighted in the lung transplant population. Indeed, if an immunosuppression regimen had a direct impact on the development of lung cancer, the incidence of lung cancer after single lung transplantation should be similar in both the transplanted and the native lung. However, whereas bronchogenic carcinoma in newly transplanted lungs is extremely rare [20], several authors have reported bronchogenic carcinoma occurring in the recipient’s native lung after single lung transplantation [18–20]. Similarly, in our experience we have performed more than 400 lung transplants since 1983, and we have observed only 1 patient with lung cancer in the transplanted lung. The tumor was determined to have originated from donor lung tissue and may have been transmitted at the time of transplantation because it was retrospectively detectable on the first postoperative computed tomographic chest scan performed 6 weeks after operation.
Bronchogenic carcinoma has been occasionally transmitted with the kidney graft in the early era of transplantation when the risk of cancer transmission was not appreciated and donors with widespread malignancies were used [24, 25]. Currently the transmission of bronchogenic carcinoma with a cadaveric or living-related donor may still occur when the primary tumor remains undetected [26, 27]. Hence, careful preoperative examination of the chest roentgenograms, and computed tomographic chest scan if available, as well as meticulous examination of the lung and biopsy of any suspicious lesions are of prime importance to limit the risk of lung cancer transmission. These recommendations are of particular importance with the liberalization of donor criteria to donors older than 55 years who also have a smoking history greater than 20 pack-years [28].
Among the 77 patients reported in Table 3, almost two thirds were diagnosed at an advanced stage and only 11 (8 at stage IA or IB) were alive without disease after a mean follow-up of 30 months (range, 15 to 54 months). This observation reflects the rapid evolution of malignant tumors in immunosuppressed patients. Hence, considering the poor prognosis of bronchogenic carcinoma under immunosuppressive drug therapy, computed tomography of the chest before solid organ transplantation is recommended for all patients with a smoking history [6, 7, 19]. A high index of suspicion also should be maintained during follow-up after transplantation. Indeed, we and others have observed that bronchogenic carcinoma can often be missed or misdiagnosed as an infectious process in patients with heart or lung transplantation, and appropriate therapy may occasionally be delayed by several months [18, 19].
In conclusion, bronchogenic carcinoma occurs mainly in recipients with a smoking history, and a careful search for bronchogenic carcinoma in this group of recipients may help to improve the outcome of this rare but aggressive condition. Careful assessment of the donor lungs before retrieval is important to avoid donor transmission of lung cancer.
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Acknowledgments
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The authors would like to thank Terry Owen and Helix Biotech (Vancouver, British Columbia, Canada) for assistance with analysis and interpretation of the genotyping results.
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References
|
|---|
- Penn I. Depressed immunity and the development of cancer. Clin Exp Immunol 1981;46:459-474.[Medline]
- Nalesnik M.A., Makowka L., Starzl T.E. The diagnosis and treatment of posttransplant lymphoproliferative disorders. Curr Probl Surg 1988;25:371-472.
- Penn I. Incidence and treatment of neoplasia after transplantation. J Heart Lung Transplant 1993;12:S328-336.[Medline]
- Melosky B., Karim M., Chui A., et al. Lymphoproliferative disorders after renal transplantation in patients receiving triple and quadruple immunosuppression. J Am Soc Nephrol 1992;2:S290-294.
- Swinnen L.J., Costanzo-Nordin M.R., Fisher S.G., et al. Increased incidence of lymphoproliferative disorders after immunosuppression with the monoclonal antibody OKT3 in cardiac transplant recipients. N Engl J Med 1990;323:1723-1728.[Abstract]
- Goldstein D.J., Austin J.H.M., Zuech N., et al. Carcinoma of the lung after heart transplantation. Transplantation 1996;62:772-775.[Medline]
- Curtil A., Robin J., Tronc F., Ninet J., Boissonnat P., Champsaur G. Malignant neoplasms following cardiac transplantation. Eur J Cardiothorac Surg 1997;12:101-106.[Abstract]
- Penn I., Starzl T.E. Malignant tumors arising de novo in immunosuppressed organ transplant recipients. Transplantation 1972;14:407-417.[Medline]
- Fishman N.H., Belzer F.O. Resection of de novo lung cancer after renal transplantation. Transplantation 1975;20:268-269.[Medline]
- Forslund T., Hortling L., Timonen T., Laasonen L. Two different primary lung malignancies after a successful kidney transplantation. Acta Radiol Oncol 1984;23:411-413.[Medline]
- Couetil J.P., McGoldrick J.P., Wallwork J. Malignant tumors after heart transplantation. J Heart Transplant 1990;9:622-626.[Medline]
- Fleming R.H., Jennison S.H., Naunheim K.S. Primary bronchogenic carcinoma in the heart transplant recipient. Ann Thorac Surg 1994;57:1300-1301.[Abstract]
- Kehinde E.O., Petermann A., Morgan J.D., et al. Triple therapy and incidence of de novo cancer in renal transplant recipients. Br J Surg 1994;81:985-986.[Medline]
- Pham S.M., Kormos R.L., Landreneau R.J., et al. Solid tumors after heart transplantation: lethality of lung cancer. Ann Thorac Surg 1995;60:1623-1626.[Abstract/Free Full Text]
- Delcambre F., Pruvot F.R., Ramon P., et al. Primary bronchogenic carcinoma in transplant recipients. Transplant Proc 1996;28:2884-2885.[Medline]
- Frezza E.E., Fung J.J., Van Thiel D.H. Non-lymphoid cancer after liver transplantation. Hepatogastroenterol 1997;44:1172-1181.
- Johnson W.M., Baldursson O., Gross T.J. Double jeopardy: lung cancer after cardiac transplantation. Chest 1998;113:1720-1723.[Abstract/Free Full Text]
- Choi Y.H., Leung A.N., Miro S., Poirier C., Hunt S., Theodore J. Primary bronchogenic carcinoma after heart or lung transplantation: radiologic and clinical findings. J Thorac Imaging 2000;15:36-40.[Medline]
- Arcasoy S.M., Hersh C., Christie J.D., et al. Bronchogenic carcinoma complicating lung transplantation. J Heart Lung Transplant 2001;20:1044-1053.[Medline]
- De Soyza A.G., Dark J.H., Parums D.V., Curtis A., Corris P.A. Donor-acquired small cell lung cancer following pulmonary transplantation. Chest 2001;120:1030-1031.[Abstract/Free Full Text]
- Blohme I., Brynger H. Malignant disease in renal transplant patients. Transplantation 1985;39:23-25.[Medline]
- Kim M.S., Kim S.I., Kim Y.S., Oh C.K., Park K. De novo cancer in transplant recipients. Transplant Proc 1996;28:1651-1652.[Medline]
- Kelly D.M., Emre S., Guy S.R., Miller C.M., Schwartz M.E., Sheiner P.A. Liver transplant recipients are not at increased risk for nonlymphoid solid organ tumors. Cancer 1998;83:1237-1243.[Medline]
- Penn I. Transmission of cancer from organ donors. Ann Transplant 1997;2:7-12.[Medline]
- Wilson R.E., Hager E.B., Hampers C.L., Corson J.M., Merrill J.P., Murray J.E. Immunologic rejection of human cancer transplanted with a renal allograft. N Engl J Med 1968;278:479-483.
- Winter T.C., Keller P.R., Lee F.T., Jr, Pozniak M.A. Donor-derived malignancy: transmission of small cell lung cancer via renal transplantation. J Ultrasound Med 2001;20:559-562.[Medline]
- Kauffman H.M., McBride M.A., Delmonico F.L. First report of the United Network for Organ Sharing Transplant Tumor Registry: donors with a history of cancer. Transplantation 2000;70:1747-1751.[Medline]
- Bhorade S.M., Vigneswaran W., McCabe M.A., Garrity E.R. Liberalization of donor criteria may expand the donor pool without adverse consequence in lung transplantation. J Heart Lung Transplant 2000;19:1199-1204.[Medline]
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Top
Abstract
Introduction
