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Saudi Journal of Kidney Diseases and Transplantation
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EDITORIAL Table of Contents   
Year : 1996  |  Volume : 7  |  Issue : 1  |  Page : 1-5
Malignancy in Renal Transplant Recipients


Department of Surgery, University of Cincinnati Medical Center, Cincinnati, Ohio, USA

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   Abstract 

Immunosuppressed organ allograft recipients have a 3-4 fold increased risk of developing cancer, but the chance of developing certain malignancies is increased several hundredfold. With the exception of skin cancers, most of the common neoplasms seen in the general population are not increased in incidence in organ allograft recipients. Instead, there is a higher frequency of relatively rare tumors including lymphomas, Kaposi's sarcoma, other sarcomas, vulvar and perineal carcinomas, renal and hepatobiliary carcinomas. Tumors appear after a relatively short time post-transplantation. The earliest is Kaposi's sarcoma, which appears after an average of 22 months post-transplantation, and the latest are vulvar and perineal carcinomas, which present after an average of 113 months post-transplantation. Unusual features of lymphomas are: (a) high incidence of non-Hodgkin's lymphomas; (b) high frequency of Epstein-Barr virus-related lesions; (c) frequent involvement of extra-nodal sites; (d) marked predilection for the brain; and (e) frequent allograft involvement. Skin cancers also present unusual features: (a) remarkably high frequency of Kaposi's sarcoma; (b) reversal of the ratio of basal to squamous cell carcinomas seen in the general population; (c) young age of the patients; and (d) high incidence of multiple tumors, which occur in 43% of patients. Vulvar and perineal cancers occur at a much younger age than in the general population. Probably, multiple factors play a role in the etiology of the cancers. Immunodeficiency per se and infection with oncogenic viruses may be major influences. Other factors possibly playing a role include direct damage to DNA by various immunosuppressive agents; possibly synergistic effects of these treatments with carcinogens; and genetic factors influencing susceptibility or resistance to development of malignancy.

Keywords: Transplantation, Cancer, Immunosuppression, Lymphomas, Kaposi′s sarcoma.

How to cite this article:
Penn I. Malignancy in Renal Transplant Recipients. Saudi J Kidney Dis Transpl 1996;7:1-5

How to cite this URL:
Penn I. Malignancy in Renal Transplant Recipients. Saudi J Kidney Dis Transpl [serial online] 1996 [cited 2019 Nov 21];7:1-5. Available from: http://www.sjkdt.org/text.asp?1996/7/1/1/39530
Successful renal transplantation has a number of complications, among which is an increased incidence of malignancy. Overall there is a 3-4 fold increase compared with age-matched controls in the general population [1],[2],[3],[4] . Apart from skin cancers (mostly squamous cell carcinomas­ SCCs), which show a 4-21 fold increased incidence, neoplasms that are frequently encountered in the general population (carcinomas of the lung, breast, prostate, colon and invasive uterine cervical carci­nomas) show no increase, but a variety of mostly uncommon tumors are encountered. Epidemiologic studies show an increase of 28-49 fold of non-Hodgkin's lymphomas (NHL), 29 fold of lip carcinomas, 400-500 fold of Kaposi's sarcoma (KS), 100 fold of vulvar and anal carcinomas, 20-38 fold of hepatocellular carcinomas, 14-16 fold of in­situ uterine cervical carcinomas, and a small increase in sarcomas (excluding KS) and renal carcinomas [1],[2],[3],[4] among renal transplant recipients when compared to the general population. A large part of this editorial is based on material collected by the Cincinnati Transplant Tumor Registry (CTTR), a worldwide tumor database, that has information on 8191 organ allograft recipients who developed 8,724 de novo cancers. The great majority (6821) were kidney allograft recipients who had a total of 7,319 tumors.

The incidence of cancer increases with length of follow-up post-transplantation. An Australasian study of 6596 patients shows that the percent probability of developing cancer following renal transplantation from cadaver donors 24 years post-operatively is 66% for skin cancers, 27% for non-skin cancers and 72% for any type of neoplasm [5] . These exceptional figures must be interpreted with caution as most tumors are skin cancers (which are very common in Australia) and the number of 24 year survivors is small. Nevertheless, they emphasize the need to follow transplant patients indefinitely.

Cancers occur at a relatively short time post-transplantation with KS appearing at an average of 22 months post-transplant­ation, lymphomas at an average of 33 months, and vulvar and perineal carcinomas appearing at the longest time post-trans­plantation, at an average of 113 months [1],[2],[3],[4] . If all tumors are considered the average time of their appearance is 61 months. Neoplasms that occur in organ allograft recipients frequently demonstrate a more aggressive nature than do similar tumors in the non-transplant population [6] .

The most common malignancies affect the skin and lips and comprise 37% of all neoplasms in the CTTR [1],[2],[3] . They occur on sun exposed areas, mainly of the head and neck and upper extremities [1],[2],[3],[7] , especially in light-skinned individuals with blue eyes and blonde or red hair [7] . Exposure to sunshine is not the only etiologic factor. A surprisingly high incidence of SCCs is recorded from areas of low sun­light in some northern countries and may be related to malignant change in papilloma virus-induced warts, under the influence of immunosuppression, sunlight, HLA-antigens and other factors [1],[2],[3],[7],[8] . The incidence of cutaneous tumors increases with length of follow-up after transplantation, as demon­strated by a Dutch study showing a 10% incidence of non-melanoma skin cancer at 10 years post-transplantation, rising to 40% after 20 years [9] .

Skin cancers in transplant patients show several unusual features compared with similar lesions in the general population [1],[2],[3],[6],[7],[8],[9] . Whereas basal cell carcinomas (BCCs) outnumber SCCs in the general population by 5 to 1, in transplant recipients BCCs are out numbered by SCCs by 1 to 1.8. Squamous cell carcinoma is estimated to occur at a frequency between 40 and 250 times higher than in general population, BCC ten times higher [9] and malignant melanoma five times more commonly than expected [7] . In the general population, SCCs occur mostly in people in their 60's and 70's, but the average age of transplant patients is 30 years younger [10] . In addition, the incidence of multiple skin cancers in the CTTR is remarkably high (43%) and, despite being a world-wide collection, is similar to that seen only in areas of copious sunlight [1],[2],[3] . Some patients each have skin cancers involving more than 100 sites. In some patients, there is an apparently widespread skin abnormality with areas of unstable epithelium containing multifocal pre-malignant and malignant lesions [7] .

In the general population, most lymph node metastases and deaths from skin cancer are caused by melanomas. In contrast, SCCs are much more aggressive in transplant patients than in the general population and account for the bulk of lymph node metastases and death from skin cancer [1],[2],[3] . Thus, 5.8% of patients with skin cancers in the CTTR have lymph node metastases. Of these, 75% are from SCCs and only 17% from melanomas. Similarly 5.1% of patients die of skin cancer, with 61% of deaths being from SCC and only 34% from melanomas [1],[2],[3] .

Among the post-transplant lymphomas Hodgkin's disease and plasmacytoma/myeloma are much less common than in the general population and most tumors (94%) are NHL [1],[2],[3] . As many lesions straddle the borderland between infection and neoplasia the term post-transplant lymphoproliferative disorder (PTLD) is frequently used [11],[12],[13] .

The bulk of NHL arise from B-lympho­cytes but CTTR data indicate that 13% arise from T-lymphocytes, while rare cases are of null cell origin [1],[2],[3] . Post-transplant NHL differ from their counterparts in the general population in several respects. Whereas extra-nodal involvement occurs in from 24-­48% of patients in the community at large, it is present in 69% of post-transplant NHL. Surprisingly, one of the most common extra-nodal sites is the central nervous system which is involved in 22% of cases [1],[2],[3] . Another remarkable finding is the frequency of either macroscopic or micro­scopic allograft involvement which occurs in 23% of patients with NHL [1],[2],[3] . In some patients, the infiltrate is mistaken for rejection when allograft biopsies are studied microscopically. It is disappointing that 18% of patients with NHL die without treatment, either because the diagnosis is missed, or is made too late to save them. Following treatment, complete remissions are obtained in 41% of patients [1],[2],[3] .

Kaposi's sarcoma (KS) is most common in transplant patients who are Arab, Black, Italian, Jewish or Greek [4] . It occurred in 1.6% of 820 Italian renal transplant recipi­ents [14] . Kaposi's sarcoma is the most common malignancy in renal transplant recipients in Saudi Arabia, comprising 76% of all tumors [15] .

A clinician should suspect KS whenever a transplant patient, particularly one belonging to the ethnic groups described above, presents with reddish blue macules or plaques in the skin or oropharyngeal mucosa, or apparently infected granulomas that fail to heal [1],[2],[3],[4] . If the diagnosis is confirmed, a thorough workup including CT scans of the chest and abdomen and upper and lower gastro­intestinal endoscopy, is needed to exclude any internal visceral involvement.

Non-visceral KS occurs in 60% of patients and is confined to the skin, or oropharyngeal mucosa and 40% have visceral disease, affecting mainly the gastrointestinal tract, lungs, and lymph nodes, but other organs are also affected [4] . In patients with non-­visceral disease the lesions are confined to the skin in 98% and the mouth or oropharynx in 2%. Patients with visceral lesions have no skin involvement in 27%, but 3% of them have oral involvement which provides an accessible site for biopsy and diagnosis [4] . The outlook of patients with non-visceral disease is much more favorable than those with visceral disease, as 53% of the former group have complete remissions following treatment compared with only 27% in the latter [4] .

Most renal carcinomas in renal allograft recipients arise in their own diseased kidneys although 9% occur in the allografts [1],[2],[3],[16] . Unlike most other cancers, which arise as complications of immunosuppressive therapy, many renal carcinomas are related to the underlying kidney disease necessitating transplantation [16] . One example is carci­noma of the renal pelvis which accounts for 14% of renal neoplasms in the CTTR compared with 5-10% in the general population. The increase is almost certainly due to the high incidence of analgesic nephropathy among renal allograft recipients, which occurs in 10% of CTTR patients with carcinomas of their native kidneys [16] . This disorder is known to cause carcinomas in various parts of the urinary tract. This is borne out in the CTTR series in which 68% of patients with analgesic-related renal carcinomas have similar malignancies elsewhere in the urinary tract [16] . Another predisposing cause of neoplasms is acquired cystic disease of the native kidneys, which, in dialysis patients, is complicated by an increased incidence of renal carcinomas [17] . The exact incidence of such carci­nomas in renal transplant recipients is not known.

A group of carcinomas arise in the vulva in females, the penis or scrotum in males, and in the perineum, perianal skin or anus in either sex. Female patients sometimes have multifocal lesions with involvement not only of the vulva and perineum but also the vagina and/or uterine cervix [1],[2],[3],[18] . Females outnumber males by 2.5:1 in contrast with most other post-transplant cancers where males outnumber females by more than 2:1 [1],[2],[3] . One-third of patients have in-situ lesions [18] . A worrying finding is that patients with invasive lesions are much younger (average age 42 years) than their counterparts in the general population, whose average age is usually between 50 and 70 years. Prior to the development of the malignancy, approxi­mately one third of transplant patients have condyloma acuminata ("genital warts"), caused by human papilloma virus [18] .

It is likely that many in-situ carcinomas of the uterine cervix are missed because they are asymptomatic. Therefore, all post­adolescent female renal allograft recipients should have regular pelvic examinations and cervical smears to detect these lesions, and also carcinomas of the vulvar and anal areas [1],[2],[3],[18] . Most hepatobiliary tumors are hepatomas and a substantial number of patients have a preceding history of hepatitis B infection [19] . A few recipients with a history of hepatitis C infection are now being encountered. Most sarcomas (other than Kaposi's sarcoma) involve the soft tissues or visceral organs whereas cartilage or bone involvement is uncommon [1],[2],[3],[4] . The major types in descending order are fibrous histiocytoma, leiomyosarcoma, fibrosarcoma, rhabdomyosarcoma, hemangio­sarcoma, and mesothelioma [4] .

Post-transplant neoplasms probably arise from a complex interplay of many factors [1],[2],[3],[4],[7],[8],[11],[12],[13] . Severely depressed immunity may impair the body's ability to eliminate malignant cells induced by various carci­nogens. Chronic antigenic stimulation by the foreign antigens of transplanted organs, by repeated infections, or transfusions of blood or blood products may overstimulate a partially depressed immune system and lead to NHL. Alternatively, defective feedback mechanisms may fail to control the extent of immune reactions and lead to unrestrained lyrnphoid proliferation and lymphomas. Furthermore, once this loss of regulation occurs, the defensive ability of the immune system is weakened and other non-lymphoid malignancies may appear.

Activation of oncogenic viruses probably plays an important role in the development of some tumors [1],[2],[3],[4],[8],[11],[12],[13],[18],[19] . EpsteinBarr virus is strongly implicated in causing NHL, [1],[2],[3],[11],[12],[13] smooth muscle tumors [20] and, possibly Hodgkin's disease [1],[2],[3] ; various strains of papilloma-virus in causing carcinomas of the skin, vulva, perineum, uterine cervix, and anus [1],[2],[3],[8],[18] ; hepatitis B or hepatitis C virus in causing hepatomas [1],[2],[3],[19] and a new strain of herpes virus appears to play a key role in the development of KS [21] .

Some immunosuppressive agents may directly damage DNA and cause neoplasms [1],[2],[3] . Immunosuppressive agents may enhance the effects of other carcinogens, such as sunlight in causing carcinomas of the skin, or papilloma virus in causing carcinomas of the uterine cervix or vulva [1],[2],[3] . Genetic factors may affect suscepti­bility to malignancy by affecting carcinogen metabolism, level of interferon secretion, response to virus infections, or regulation of the immune response by the major histo­compatibility system [1],[2],[3] . For example, several studies have linked various HLA groups either to increased susceptibility or resistance to the development of skin cancers [22] .


   Acknowledgment Top


The author wishes to thank numerous colleagues, working in transplant centers throughout the world, who have generously contributed data concerning their patients to the Cincinnati Transplant Tumor Registry.

 
   References Top

1.Penn I. Why do immunosuppressed patients develop cancer? In: Pimentel E, (ed). CRC Critical Reviews In Onco­genesis. Boca Raton: CRC 1989;1:27-52.  Back to cited text no. 1    
2.Penn I. Depressed immunity and the development of cancer. Cencer Detect Prev 1994;18:241-52.  Back to cited text no. 2    
3.Penn I. Malignancy after immuno­suppressive therapy: how can the risk be reduced? Clin Immunotherap 1995;4:207-18.  Back to cited text no. 3    
4.Penn I. Sarcomas in organ allograft reci­pients. Transplantation 1995;60:1485-91.  Back to cited text no. 4    
5.Sheil AG, Disney AP, 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.  Back to cited text no. 5    
6.Barrett WL, First MR, Aron BS, Penn I. Clinical course of malignancies in renal transplant recipients. Cancer 1993;72:2186-9.  Back to cited text no. 6    
7.Sheil AG. Skin cancer in renal transplant recipients. Transplant Sci 1994;4:42-5.  Back to cited text no. 7    
8.Barr BB, Benton EC, McLaren K, et al. Human papilloma virus infection and skin cancer in renal allograft recipients. Lancet 1989;1:124-9.  Back to cited text no. 8    
9.Hartevelt MM, Bavinck JN, Kootte AM, Vermeer BJ, Vandenbroucke JP. Incidence of skin cancer after renal transplantation in the Netherlands. Transplantation 1990;49(3):506-9.  Back to cited text no. 9    
10.Mullen DL, Silverberg SG, Penn I, Hammond WS. Squamous cell carcinoma of the skin and lip in renal homograft recipients. Cancer 1976;37:729-34.  Back to cited text no. 10    
11.Nalesnik MA, Locker J, Jaffe R, et al. Experience with post transplant lymphoproliferative disorders in solid organ transplant recipients. Clin Transplant 1992;6:249-52.  Back to cited text no. 11    
12.Nalesnik MA, Starzl TE. Epstein-Barr virus, infectious mononucleosis, and posttransplant lymphoproliferative disorders. Transplant Sci 1994;4:61-79.  Back to cited text no. 12    
13.Hanto DW. Classification of Epstein-Barr virus associated post transplant lymphoproliferative disease: implications for understanding their patho genesis and developing rational treatment strategies. Ann Rev Med 1995;46:381-94.  Back to cited text no. 13    
14.Montagnino G, Bencini PL, Tarantino A, Caputo R, Ponticelli C. Clinical features and course of Kaposi's sarcoma in kidney transplant patients: report of 13 cases. Am J Nephrol 1994;14:121-6.  Back to cited text no. 14    
15.al-Sulaiman MH, al-Khader AA. Kaposi's sarcoma in renal transplant recipients. Transplant Sci 1994;4:46-60.  Back to cited text no. 15    
16.Penn I. Primary kidney tumors before and after renal transplantation. Transplantation 1995;59:480-5.  Back to cited text no. 16    
17.Ishikawa I. Acquired cysts and neoplasms of the kidneys in renal allograft recipients. In: Berlyne GM, ed. The kidney today. Selected topics in renal science. Basel, Karger: Contrib Nephrol 1992;100:254-68.  Back to cited text no. 17    
18.Penn I. Cancers of the anogenital region in renal transplant recipients. Analysis of 65 cases. Cancer 1986;58:611-6.  Back to cited text no. 18    
19.Schroter GP, Weil R 3rd, Penn I, Speers WC, Waddell WR. Hepatocellular carcinoma associated with chronic hepatitis B virus infection after kidney transplantation (Letter). Lancet 1982;2:381-2.  Back to cited text no. 19    
20.Lee ES, Locker J, Nalesnik M, et al. The association of Epstein-Barr virus with smooth-muscle tumors occurring after organ transplantation. N Engl J Med 1995;332:19-25.  Back to cited text no. 20    
21.Moore PS, Chang Y. Detection of herpes virus-like DNA sequences in Kaposi's sarcoma in patients with and without HIV infection. N Engl J Med 1995;332:1181-5.  Back to cited text no. 21    
22.Bouwes Bavinck JN, Vermeer BJ, van der Woude FJ, et al. Relation between skin cancer and HLA antigens in renal transplant recipients. N Engl J Med 1991;325:843-8.  Back to cited text no. 22    

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Correspondence Address:
Israel Penn
Department of Surgery, University of Cincinnati Medical Center, P.O. Box 670558, Cincinnati, OH 45267-0558
USA
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PMID: 18417907

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