| 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
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 ,,, . 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 ,,, 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  . 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 ,,, . 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  .
The most common malignancies affect the skin and lips and comprise 37% of all neoplasms in the CTTR ,, . They occur on sun exposed areas, mainly of the head and neck and upper extremities ,,, , especially in light-skinned individuals with blue eyes and blonde or red hair  . 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 ,,,, . 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  .
Skin cancers in transplant patients show several unusual features compared with similar lesions in the general population ,,,,,, . 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  and malignant melanoma five times more commonly than expected  . 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  . 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 ,, . 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  .
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 ,, . 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 ,, .
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 ,, . As many lesions straddle the borderland between infection and neoplasia the term post-transplant lymphoproliferative disorder (PTLD) is frequently used ,, .
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 ,, . 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 ,, . Another remarkable finding is the frequency of either macroscopic or microscopic allograft involvement which occurs in 23% of patients with NHL ,, . 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 ,, .
Kaposi's sarcoma (KS) is most common in transplant patients who are Arab, Black, Italian, Jewish or Greek  . It occurred in 1.6% of 820 Italian renal transplant recipients  . Kaposi's sarcoma is the most common malignancy in renal transplant recipients in Saudi Arabia, comprising 76% of all tumors  .
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 ,,, . 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  . 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  . 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  .
Most renal carcinomas in renal allograft recipients arise in their own diseased kidneys although 9% occur in the allografts ,,, . Unlike most other cancers, which arise as complications of immunosuppressive therapy, many renal carcinomas are related to the underlying kidney disease necessitating transplantation  . 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  . 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  . 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  . 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 ,,, . Females outnumber males by 2.5:1 in contrast with most other post-transplant cancers where males outnumber females by more than 2:1 ,, . One-third of patients have in-situ lesions  . 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  .
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 ,,, . Most hepatobiliary tumors are hepatomas and a substantial number of patients have a preceding history of hepatitis B infection  . 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 ,,, . The major types in descending order are fibrous histiocytoma, leiomyosarcoma, fibrosarcoma, rhabdomyosarcoma, hemangiosarcoma, and mesothelioma  .
Post-transplant neoplasms probably arise from a complex interplay of many factors ,,,,,,,, . 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 ,,,,,,,,, . EpsteinBarr virus is strongly implicated in causing NHL, ,,,,, smooth muscle tumors  and, possibly Hodgkin's disease ,, ; various strains of papilloma-virus in causing carcinomas of the skin, vulva, perineum, uterine cervix, and anus ,,,, ; hepatitis B or hepatitis C virus in causing hepatomas ,,, and a new strain of herpes virus appears to play a key role in the development of KS  .
Some immunosuppressive agents may directly damage DNA and cause neoplasms ,, . 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 ,, . 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 ,, . For example, several studies have linked various HLA groups either to increased susceptibility or resistance to the development of skin cancers  .
| Acknowledgment|| |
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.
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Department of Surgery, University of Cincinnati Medical Center, P.O. Box 670558, Cincinnati, OH 45267-0558