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Ann Thorac Surg 1995;60:1559-1560
© 1995 The Society of Thoracic Surgeons
Department of Surgery, University of Cincinnati Medical Center, and Cincinnati Veterans Affairs Medical Center, Cincinnati, Ohio
Most information about tumors that arise de novo after transplantation is gleaned from studies of renal allograft recipients. Overall there is threefold to fourfold increased incidence of cancer compared with age-matched controls in the general population [1, 2]. Apart from skin cancers (mostly squamous cell carcinomas [SCCs]), which show fourfold to 21-fold increased incidence, frequently encountered neoplasms in the general population (carcinomas of the lung, breast, prostate, and colon and invasive uterine cervical carcinomas) show no increase, but a variety of mostly uncommon tumors are seen.
Epidemiologic studies show increases of 28-fold to 49-fold of non-Hodgkin's lymphomas, 29-fold of lip carcinomas, 400-fold to 500-fold of Kaposi's sarcoma (KS), 100-fold of vulvar and anal carcinomas, 20-fold to 38-fold of hepatocellular carcinomas, 14-fold to 16-fold of in situ uterine cervical carcinomas, and small increases in sarcomas (excluding KS) and renal carcinomas. Up until May 1995 a worldwide tumor database, the Cincinnati Transplant Tumor Registry (CTTR), had information on 8,191 organ allograft recipients in whom 8,724 types of de novo cancer developed. The great majority (6,821) were kidney allograft recipients, but there were also 830 cardiothoracic (CT) recipients (772 cardiac, 29 lung, and 29 combined heart-lung) who had a total of 859 tumors [2]. Marked differences in the pattern of malignancies were apparent when CT and renal recipients were compared. The most significant finding was a disproportionately high incidence of lymphomas in CT recipients, comprising 39% of all malignancies versus 12% in renal recipients. (A similar high incidence of lymphomas was also seen in recipients of other extrarenal organs, in whom they comprised 55% of malignancies.) The difference was even more marked in pediatric compared with adult cardiac allograft recipients: lymphomas comprised 84% of tumors in pediatric patients compared with 37% in adults. Other differences between renal and CT recipients were in the proportions of skin cancers (39% versus 28% of all tumors), carcinomas of the cervix (4% versus 0.8%), and carcinomas of the vulva and perineum (2.9% versus 0.7%). Several factors probably account for these differences [2, 3]. In CT and other extrarenal organ recipients intense immunosuppressive therapy is frequently necessary to save lives by reversing rejection, whereas with severe rejection of kidney allografts physicians are likely to discontinue immunosuppressive therapy and return patients to dialysis. A complication of intense immunosuppression is a disproportionate increase in the incidence of malignancies that occur in the early months after transplantation, namely lymphomas.
Another factor is the length of follow-up after transplantation [2, 3]. Many renal transplant recipients have been followed up for a decade or even two decades or more, whereas most CT recipients were treated in the last 8 to 10 years. As skin cancers, cervical carcinomas and carcinomas of the vulva and anus occur late after transplantation; this may explain the different patterns of tumors in renal versus CT recipients. The relatively small number of CT patients compared with the large number of renal transplant recipients also may have contributed to the different patterns of cancers [3].
In this issue of The Annals are reports from two major cardiac transplant centers detailing their experience with solid malignancies among 633 [4] and 608 patients [5] who survived more than a month after transplantation. Both studies excluded patients with lymphomas as they had been discussed in previous reports. Nevertheless, these were the most common tumor in both studies, affecting 39 (6%) and 55 (9%) of patients, respectively.
In both studies a striking finding was the prominence of lung cancers, which comprised 7 of 21 tumors (33%) in one study and 10 of 23 tumors (43%) in the second (excluding basal cell and SCC skin cancers, as was done in the first study). These findings are in keeping with CTTR data, which showed that lung cancers made up 68 of 291 tumors (23%) (if lymphomas and skin and lip cancers were excluded). Unlike the bulk of de novo tumors, which probably arise as complications of immunosuppression and various viral infections, lung cancers are most likely related to a history of smoking in the affected patients. A major indication for cardiac transplantation is ischemic cardiomyopathy, which is often related to smoking. Furthermore, in both studies a substantial number of patients had other smoking-related malignancies (carcinomas of the bladder, larynx, and tongue). Of the other malignancies in the two studies several may have been transplant-related (skin cancers, KS, and a fibriohistiosarcoma), others may have been related to hormonal changes in older patients (carcinomas of breast, prostate, and uterus), and some may have occurred by chance.
A disturbing feature of Pham and associates' study [5] is that despite chest radiography every 6 months 8 of 10 patients with lung cancer had advanced disease at the time of diagnosis. It suggests that more sensitive methods need to be developed for detecting lung cancers in allograft recipients with a history of smoking. The advanced stage of the disease at the time of diagnosis is consistent with the suggestion that once vascular access by tumor cells has been obtained, the host's immune system allows far greater than normal survival in the bloodstream [6]. The result is more rapid tumor dissemination and demise of the patient than would be expected in the setting of immunocompetence.
A note of caution is necessary about the behavior of SCCs. Although the tumors reported by Pham and associates [5] had a benign course, many observers have noted that some behave aggressively in organ allograft recipients [1–3, 7]. In more than 3,000 patients with skin cancers in the CTTR, 5.8% had lymph node metastases, of which 75% were from SCCs, and 5.1% died of skin cancers, of whom 60% died of SCCs [2–4].
There is an ill-defined group of tumors that may be either early de novo cancers or preexisting malignancies that were not recognized before transplantation but became apparent a short time later. Thus 3% of de novo nonlymphomatous tumors in the CTTR were diagnosed within the first 4 months after transplantation, including several prostatic and lung carcinomas in cardiac allograft recipients. In Goldstein and associates' study [4] 6 tumors (29%) were diagnosed within 6 months after transplantation. With the exception of 1 case of KS, which can occur within months after transplantation, it is likely that the other tumors (including 3 lung cancers) were present before transplantation, but were not recognized during pretransplantation evaluation [4]. We perform extensive pretransplantation evaluation for occult malignancies in renal transplant candidates more than 40 years of age including examination of the skin, chest radiography, mammography in women, serum prostate specific antigen levels, rectal examination, urinanalysis and radiography of the bladder, occult blood examination of stool, and colonoscopy or barium enema examination. Candidates for CT transplantation should undergo similar workups provided that their cardiopulmonary condition permits these to be done. A patient with an untreated major malignancy is not a candidate for CT transplantation.
How may the incidence of solid tumors in CT transplant recipients be reduced [7]? The level of immunosuppressive therapy should be kept as low as is compatible with good allograft function. Because sunlight exposure is important in skin cancer development, patients must be educated regarding skin protection. As viral infections are related to the development of many posttransplantation malignancies, attempts should be made to prevent these infections. Epstein-Barr virus plays a role in many lymphomas and some leiomyosarcomas. A newly recognized herpesvirus has been linked to the development of KS in patients with acquired immunodeficiency syndrome. Other herpesviruses possibly may play a minor role in the development of carcinomas of the uterine cervix, vulva, lip, and skin. Whether antiviral prophylaxis with agents such as ganciclovir or acyclovir will affect the incidence of posttransplantation malignancies is open to debate. Hepatocellular cancer, related to hepatitis B infection, may be prevented by administration of hepatitis B vaccine to those candidates at high risk for development of this infection. As papilloma virus infections (suspected as causes of carcinomas of the cervix, vulva, and perineum) are sexually transmitted, patients should be advised regarding barrier methods of contraception using condoms. All postadolescent female patients should undergo regular pelvic examinations and cervical smears. All premalignant lesions, such as condyloma acuminatum or uterine cervical dysplasia, should be treated early to try to prevent progression to cancer.
As the incidence of cancer increases with the length of follow-up [2–4, 7] it is important that patients be seen at regular intervals to treat premalignant lesions or investigate untoward symptoms. Repeated surveillance is particularly important in known high-risk groups such as heavy smokers.
Acknowledgments
Supported in part by a grant from the Department of Veterans Affairs.
Footnotes
Address reprint requests to Dr Penn, Department of Surgery, University of Cincinnati Medical Center, PO Box 670558, Cincinnati, OH 45267-0558.
References
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  M. Rinaldi, C. Pellegrini, A. M. D'Armini, M. Aiello, M. Negri, E. Arbustini, G. Ippoliti, and M. Vigano Neoplastic disease after heart transplantation: single center experience Eur. J. Cardiothorac. Surg., May 1, 2001; 19(5): 696 - 701. [Abstract] [Full Text] [PDF]
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