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Malignancy
HORIZONS IN ORGAN TRANSPLANTATION
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MALIGNANCY Israel Penn, MD
Worldwide more than 300,000 solid organ transplants have been performed. Many survivors are no longer followed at the transplant center at which they received their allografts. Therefore, nontransplant surgeons may be called upon to deal with various complications that occur in these patients. One of these problems is an increased incidence of certain malignancies.3, 10, 13-18, 21, 22 In this article we describe the more common cancers and their clinical features and management. Until December 1993 the Cincinnati Transplant Tumor Registry (CTTR) accumulated data on 7796 cancers that arose in 7316 organ transplant recipients, including 6251 who received a kidney transplant, 598 heart, 269 liver, 122 bone marrow, 36 pancreas, 22 combined heart and lung, 14 lung, and 4 upper-abdominal organ "cluster" transplants. INCIDENCE OF MALIGNANCIES
The prevalence in several large series of renal allograft recipients ranged from 4% to 18%, with an average of 6%.18 In cardiac allograft recipients, the figures were similar, with a range of 3% to 9% and an average of 6%. However, these data underestimate the problem, as patients with short survival times or short lengths of follow-up were included. AGE AND GENDER OF PATIENTS
The tumors occurred in a relatively young group of patients, whose average age at the time of transplantation was 42 years (range, 3 months to 80 years). Forty-three percent were younger than 40 years at the time of transplantation. The average age of the patients at the time of diagnosis of their neoplasms was Supported in part by a grant from the Department of Veterans Affairs.
From the Department of Surgery, University of Cincinnati Medical Center; and the Cincinnati Veterans Affairs Medical Center, Cincinnati, Ohio
SURGICAL CLINICS OF NORTH AMERICA VOLUME 74.· NUMBER 5 • OCTOBER 1994
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47 years. Sixty-six percent of patients were male and 34% female, in keeping with the 2:1 ratio of male to female patients who undergo renal transplantation.18 INTERVAL BETWEEN TRANSPLANTATION AND CANCER
Some cancers appeared at fairly distinct intervals after transplantationP-18 In the general population, an interval of 5 to 20 years or even more elapses between exposure to many carcinogens and the development of overt tumors. In
contrast, many neoplasms appeared a relatively short time after transplantation. Kaposi's sarcoma (KS) was first to appear at an average of 21 (range, 1 to 225.5) months after transplantation. Lymphomas appeared at an average of 32 (range, 1 to 254) months after transplantation. Other neoplasms (excluding carcinomas of the vulva and perineum) appeared at an average of 69 (range, 1 to 298.5) months following transplantation. Carcinomas of the vulva and perineum appeared at the longest interval after transplantation, at an average of 112 (1.5 to 285.5) m,onths. If all cancers are considered, the average time of their appearance was 61 (range, 1 to 298.5) months. The incidence of neoplasia increased with the length of follow-up after transplantation. An Australasian study of 5879 patients showed that the probability of developing cancer following renal transplantation from cadaver donors 20 years after operation was 54% for skin cancers, 21% for nonskin cancers, and 63% for any type of malignancy.21 These exceptional figures must be interpreted with caution, as most tumors were skin cancers (which are very common in Australia) and the number of 20-year survivors was small. Nevertheless, they emphasize the need to follow transplant patients indefinitely. VARIETIES OF DE NOVO MALIGNANCY
The malignancies that are frequently observed in the general population (carcinomas of the lung, breast, prostate, colon, and invasive uterine cervical carcinomas) showed no increase or even a decrease. l 4, 18 Only two types of cancer frequently seen in the general population were encountered in significant numbers in transplant patients. Excluding lip cancers, the percentage of nonmelanoma skin tumors (32%) was very similar to that observed in the general population (30% of all tumors), but the incidence of squamous cell carcinomas (SCCs) was markedly increased. Another tumor, which comprises 3% of all tumors in the general population, is in situ carcinoma of the uterine cervix, which also made up 3% of neoplasms in transplant patients. If nonritelanoma skin cancers and in situ carcinomas of the cervix were excluded, as they are from most cancer statistics, we then observed a variety of tumors in transplant patients which occurred infrequently in the general population: lymphomas, 23% versus 5%; lip cancers, 7% versus 0.3%; KS, 5.6% versus a negligible incidence; carcinomas of the kidney, 4.8% versus 2%; carcinomas of the vulva and perineum, 3.6% versus 0.6%; hepatobiliary tumors, 2.4% versus 1%; and sarcomas (excluding KS), 1.6% versus 0.5%.14.15.17.18 Cancers of the Skin and Lips
These were the most common, comprising 2897 of the 7796 cancers (37%) (Table 1). Their incidence freuqently varied with the amount of sunlight expo-
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Table 1. DE NOVO CANCERS IN ORGAN ALLOGRAFT RECIPIENTS Type of Neoplasm
No. of Tumors·
Cancers of the skin and lips Lymphomas Carcinomas of the lung Carcinomas of the uterus (cervix 273; body 42; unspecified 4) Kaposi's sarcoma Carcinomas of the colon and rectum Carcinomas of the kidney (host kidney 231 ; allograft kidney 24; unspecified 10) Carcinomas of the breast Carcinomas of the head and neck (excluding thyroid, parathyroid, and eye) Carcinomas of the vulva, perineum, penis, scrotum Carcinomas of the urinary bladder Metastatic carcinoma (primary site unknown) Leukemias Hepatobiliary carcinomas Carcinomas of the prostate gland Carcinomas of the thyroid gland Cancers of the stomach Sarcomas (excluding Kaposi's sarcoma) Testicular carcinomas Ovarian cancers Miscellaneous tumors Total
2897 1276 428 319 311 280 265 246 223 200 175 172 149 135 112 99 91 90 69 57 202 7796
-There were 7316 patients, of whom 446 (6%) had two or more distinct tumor types involving different organ systems. Of these, 32 patients each had three separate types of cancer and one had four.
sure. 'S, 18,21 In areas with limited exposure, there was a four- to seven-fold increase, but in localities with copious sunlight there was an almost 21-fold rise over the already high incidence seen in the local population. Almost all the increase was in SCCs (see below). However, exposure to sunlight is not the only factor involved. A surprisingly high incidence of SCCs was reported from areas of low sunlight in Canada, Sweden, and Scotland and may be related to malignant change in papillomavirus-induced cutaneous warts, under the influence of immunosuppression, sunlight, and possibly other factors. " 3, 5, 15 The incidence of cutaneous tumors increases with the length of follow-up after transplantation, as demonstrated by an Australasian study of 5879 recipients of cadaveric renal allografts who showed a linear increase in the incidence of skin cancer, reaching 54% at 20 years after transplantation?' In transplant patients skin cancers show several unusual features compared with their counterparts in the general population. 's, 17, 18 Basal cell carcinomas (BCCs) outnumber SCCs in the general population by 5 to 1, but the opposite is true in transplant recipients, in whom SCCs outnumbered BCCs by 1.8 to 1. In the population at large, nonmelanoma skin cancers occur mainly in people in their 60s and 70s, whereas affected transplant patients' average ages are 30 years younger." The incidence of multiple skin neoplasms (present in at least 42%) is remarkably high and is comparable to that seen only in people in the general population living in areas of abundant sunshine. Several patients each had more than 100 skin cancers. Malignant melanomas comprised 5.2% of cutaneous neoplasms, in contrast to an incidence of 2.7% in the general population of the United States.
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Most skin cancers were of low-grade malignancy, but a significant percentage of SCCs behaved much more aggressively than their counterparts in the general population.'5, 17, 18 Lymph node metastases occurred in 167 patients (5.8%), 126 of whom had SCCs, 28 malignant melanomas, 12 Merkel's cell tumors, and 1 BCC. One hundred and forty-three (4.9%) patients died of their skin cancers, 89 of SCCs, 46 of malignant melanomas, 6 of Merkel's cell tumors, and 2 of BCCs. The behavior of skin tumors in transplant patients contrasts markedly with that seen in the general population, in whom they cause only 1% to 2% of all cancer deaths, the great majority of which are from malignant melanoma. Non-Hodgkin's Lymphomas Of a total of 1276 lymphomas in the CTIR (Table I), only 34 (2.7%) were cases of Hodgkin's disease, whereas it comprises 12% of lymphomas in the general population.14, 17, 18 Similarly, myeloma comprised only 48 cases (3.8%), compared with a 21% incidence among lymphomas in the general population. The bulk of the post-transplant lymphomas (1194) were non-Hodgkin's lymphomas (NHLs), which made up 93.6% of the lymphomas, compared with only 67% in the general population,17, 18 The high incidence found in the CTIR was confirmed by two epidemiologic studies which showed that the incidence of NHLs was increased 28-fold to 49-fold above that seen in age-matched controls.lO Morphologically, most NHLs were classified as immunoblastic sarcomas, reticulum cell sarcomas, microgliomas, or large celllymphomas.14, 17, 18 Because there is an ill-defined zone between inflammatory lymphoproliferations and neoplastic growths of lymphocytes, some pathologists prefer to use the rather vague term "post-transplant lymphoproliferative disorder" (PTLD)P Of NHLs studied immunologically, 87% arose from B lymphocytes, 12.6% were of T-cell origin, and 0.4% were of null cell origin. Fifty-two percent involved multiple organs or sites, whereas 48% were confined to a single organ or site. Post-transplant NHLs differed from their counterparts in the general population in several ways?' 12, 14, 16-18,23 Whereas extranodal involvement occurs in 24% to 48% of NHL patients in the community at large, it was present in 69% of NHLs in transplant patients. In the general population, about 1% of NHLs affect the brain parenchyma, whereas in organ transplant patients 24% involved the central nervous system (CNS), usually the brain, in which the lesions were frequently multicentric in distribution. Spinal cord involvement was rare. (These figures exclude 10 patients with meningeal involvement only and 7 patients whose cerebrospinal fluid showed lymphomatous cells without apparent CNS lesions.) Another notable feature was that in at least 56% of patients with CNS involvement the lesions were confined to the brain, whereas in the general population cerebral lymphomas are frequently associated with involvement of other organs. A striking finding was the frequency of either macroscopic or microscopic involvement of the allograft by lymphoma. '4, 17, 18 In 1168 patients studied, this was present in 271 recipients (23%)-142 renal, 68 hepatic, 21 cardiac, 21 pulmonary (several in recipients of heart-lung transplants), 8 pancreatic, 8 bone marrow, and 3 with abdominal organ clusters. In some individuals with renal, cardiac, or hepatic allografts, the lymphomatous infiltrate was misdiagnosed as rejection when biopsies done because of allograft dysfunction were studied microscopically. The genome of Epstein-Barr virus has been isolated from many NHLs in organ allograft recipients. It is believed to cause a spectrum of lesions ranging from benign polyclonal Bcell hyperplasia on the one hand to frank monoclonal B-cell lymphomas on the other.7,12
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The outcomes were studied in 729 patients with NHLs. Of these, 137 patients (19%) had no treatment, and the tumor was discovered at autopsy in 70 of them (51%). No treatment data are available in 32 patients (4%). Treatment was given to 560 patients (77%) and of these 227 (41%) had complete remissions. In 48 of these recipients (21%) the only treatment used was reduction or cessation of immunosuppressive therapy. Kaposi's Sarcoma
The frequent occurrence of KS in transplant recipients (Table 1) is in marked contrast to its incidence in the general population of the United States (before the acquired immunodeficiency syndrome [AIDS] epidemic started), in which it comprised only 0.02% to 0.07% of all neoplasms.'" 15, 17,18 The high incidence of KS in this worldwide collection of patients is comparable to that seen in tropical Africa, where it occurs with greatest frequency, making up 3% to 9% of all neoplasms. It is remarkable that the number of transplant patients with KS (311) in the CTTR exceeds those with carcinomas of the colorectum (280) or breast (246) (Table 1). Apart from individuals with AIDS, who frequently have KS, there is probably no other series in which the number of cases of KS exceeds either of these two common tumors, except possibly in tropical Africa where KS occurs frequently and colon cancer is rare. Very few transplant patients with KS have tested positive for the human immunodeficiency virus. An epidemiologic study showed a 400- to 500-fold increase in incidence of KS in renal transplant recipients compared with controls of the same ethnic origin. KS affected males more than females in a 3:1 ratio, a figure far less than the 9:1 to 15:1 ratio seen with KS in the general population.14, 15, 17, 18 KS was most common in transplant patients who were Arabic, Jewish, black, or of Mediterranean ancestry. Sixty percent had nonvisceral KS confined to the skin, conjunctiva, or oropharyngolaryngeal mucosa, and 40% had visceral disease, which involved mainly the gastrointestinal tract, lungs, and lymph nodes but also affected other organs. Of 188 patients with nonvisceral disease, the lesions were confined to the skin in 184 patients (98%) and to the mouth or oropharynx in 4 (2%). The 123 patients with visceral disease had no skin involvement in 29 instances (24%), but 4 of them (3%) had oral involvement, which provided an easily accessible site for biopsy and diagnosis of the disease. Of those with nonvisceral disease, 89 (47%) had complete remissions following treatment. Interestingly, 29 (33%) of these remissions occurred when the only treatment was a drastic reduction of immunosuppressive therapy. In patients with visceral disease, only 24 of 123 patients (20%) had complete remissions. However, 13 of the 24 remissions (54%) occurred in response to reduction or cessation of immunosuppressive therapy only. Occasional patients, in whom immunosuppessive therapy was later resumed, developed recurrences of KS. Sixty-six percent of the patients with visceral KS died. Of the deaths, 54 of the 74 patients (73%) died of the malignancy per se. Renal Carcinomas
There were 265 patients with carcinomas of the kidney (Table 1). This figure excludes 234 patients who had lymphomatous involvement of the native or allograft kidneys and 3 patients who had renal sarcomas (2 involving the allograft and 1 a native kidney)."5, 18 Of the tumors, 197 (74%) were described as renal cell carcinomas, hypernephromas, clear cell carcinomas, or adenocarcinomas; 33
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(12%) as transitional cell carcinomas or urothelial carcinomas; and 35 (13%) as miscellaneous carcinomas. A notable feature was that in at least 25 patients (9%) renal failure had been caused by analgesic abuse, which is known to cause carcinomas of the renal pelvis, ureter, or bladder.'s, 18 Although an underlying renal disease may have caused carcinomas of the kidney in some renal allograft recipients, there is no apparent explanation of why renal carcinomas occurred in 15 cardiac and 3 hepatic allograft recipients. Another unusual feature was that 66 of the 265 patients (25%) had incidentally discovered renal malignancies, mostly renal cell carcinomas. These were discovered at nephrectomy for hypertension or other reasons, during work-up for other disorders, during operation for some other disease, or at autopsy examination.
Carcinomas of the Vulva and Perineum
The increased incidence of carcinomas of the vulva, perineum, scrotum, penis, perianal skin, or anus in the CTIR (Table 1)13,14,17,18 is in keeping with an epidemiologic study showing that the incidence in renal transplant recipients was increased 100-fold compared with controls. 3 Females outnumbered males by 2.5:1, in contrast to most other post-transplant cancers, in which males outnumbered females by more than 2:l. One third of patients had in situ lesionsY A disturbing feature is that patients with invasive lesions were much younger (average age, 42 years) than their counterparts in the general population, whose average age is usually between 50 and 70 years. Approximately one third of transplant patients gave a history of condyloma acuminatum (genital warts), which must be regarded as a premalignant lesion. In women multicentric lesions were quite frequent, involving several sites in the vulva, perianal area, or anus, and sometimes the cervix and/ or vagina as wellY, 14, 17. 18 Although many patients with cancers of the vulva and perineum responded well to local or extensive excisions of their lesions, some succumbed to metastases despite abdominoperineal resections or radical vulvectomies.
Carcinomas of the Uterus
Carcinomas of the cervix occurred in 11% of women with post-transplant cancers (Table 1).14,,7,,8 At least 72% of patients had in situ lesions. As mentioned above, the CTIR data show no difference in the incidence of in situ uterine cervical carcinoma from that seen in the general population. This is surprising in view of two epidemiologic studies that showed a 14- to 16-fold increased incidence in transplant patients. '9, 22 This suggests that many cases are being missed. In order to avoid this error, every postadolescent female organ transplant recipient should have regular pelvic examinations and cervical smears.
Hepatobiliary Tumors
Two epidemiologic studies showed a 20- to 38-fold increased incidence over controls. 1O,18 Most cases in the CTIR (Table 1) were hepatomas, and a substantial number of patients gave a preceding history of hepatitis B infection.14, 17, 18, 20 The role of hepatitis C virus in causing these tumors has not yet been determined.
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Sarcomas (Excluding Kaposi's Sarcoma)
The majority involved the soft tissues or visceral organs, whereas cartilage or bone involvement was uncommonP' 18 Of the 90 sarcomas, the major types were fibrous histiocytoma (18 cases), leiomyosarcoma (12), fibrosarcoma (11), rhabdomyosarcoma (8), hemangiosarcoma (7), mesothelioma (6), synovial sarcoma (4), and miscellaneous sarcomas (24). TUMORS IN RENAL VERSUS NON RENAL RECIPIENTS
Significant differences occur in tumor incidence in renal and nonrenal recipients (Table 2).'6-'8 The striking incidence of lymphomas (47% versus 11%) in nonrenal recipients is most likely related to the intensity of the immunosuppression given to the former group. Severe rejection of a renal transplant can be handled by placing the patient back on dialysis and discontinuing immunosuppressive therapy, whereas severe rejection of a cardiac, pulmonary, or hepatic allograft results in death of the patient unless the immunosuppressive therapy is substantially increased, except in rare instances when one is fortunate enough to obtain a new organ with which to replace the failing allograft. Many renal recipients have been followed for 10 to 25 years after transplantation, whereas the minority of nonrenal recipients have been followed for that long. This may account for the higher incidence of late-appearing malignancies of the skin, uterine cervix, vulva, and perineum in the renal recipients. The higher incidence of carcinomas of the kidney in renal recipients may reflect the influence of analgesic nephropathy and acquired cystic disease of the kidney in predisposing to renal neoplasms. 's POSSIBLE CAUSES OF POST-TRANSPLANT TUMORS
The neoplasms probably arise from a complex interplay of multiple factors that are discussed in detail elsewhere.'4, 16-18 Severely depressed immunity may impair the body's ability to eliminate malignant cells induced by various carcinogens. '8 Chronic antigenic stimulation by the foreign antigens of transplanted organs, by repeated infections, or by transfusions of blood or blood products may overstimulate a partially depressed immune system and lead to NHLs.'8 Alternately, defective feedback mechanisms may fail to control the extent of
Table 2. COMMON CANCERS IN RENAL VERSUS NONRENAL RECIPIENTS Renal (6709 tumors)" Skin cancers Lymphomas Kaposi's sarcoma Carcinomas of the cervix Renal tumors Carcinoma of the vulval perineum *In 6251 patients. tin 1065 patients.
Percent
Nonrenal (1087 tumors)t
2635 763 282 263
39 11 4
262 513 29
4
10
247
4
193
3
18 7
Percent 24 47 3
<1 2 <1
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immune reactions and lead to unrestrained lymphoid proliferation and lymphomas. Furthermore, once this loss of regulation occurs, the defensive ability of the immune system is weakened, and other nonlymphoid malignancies may appear. 18 The activation of oncogenic viruses in some immunosuppressed patients is highly likely.14, 18 Epstein-Barr virus (EBV) is strongly implicated in causing NHLs in primary immunodeficiency diseases, organ transplant recipients, and AIDS patients7, 12,14,18; certain papillomaviruses in causing carcinomas of the lip, vulva, perineum, uterine cervix, and anus14. 18, 22; and viruses (as yet unidentified) are believed to playa key role in the development of Kaposi's sarcoma. 14, 18 Some immunosuppressive agents such as azathioprine, cyclophosphamide, and cyclosporine may directly damage DNA and cause neoplasms. 18 Immunosuppressive agents may enhance the effects of other carcinogens, such as sunlight in causing carcinomas of the skin or papillomavirus in causing carcinomas of the uterine cervix. 18 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. 18 For example, several studies have linked various HLA groups either to increased susceptibility or resistance to the development of KS. However, a CTTR study of HLA-A and HLA-B typing in 135 patients and HLA-DR typing in 67 recipients with KS showed no significant differences when the patients' ethnic backgrounds were taken into consideration. Fifty-six percent of the patients were Italian, Greek, Jewish, or Arab. 4 TREATMENT OF POST-TRANSPLANT MALIGNANCIES
When treating cancers in organ allograft recipients, one must bear in mind that they frequently demonstrate more aggressive behavior than do similar tumors in nontransplant patients.2 Early tumors are curable with local treatment provided that their growth has not given them adequate vascular access. Once this has been obtained, the host's depressed immune system is believed to permit greater than normal survival of tumor cells in the bloodstream.2 The result is more rapid malignant dissemination and demise of the host than would be expected in a setting of immunocompetence. In managing patients with premalignant skin lesions or early cancers, a useful treatment is a 6-week course of topical 5-fluorouracil cream applied twice daily.18 This destroys many premalignant lesions and even superficial carcinomas. This treatment is rapidly being superseded by topical use of 0.05% tretinoin cream (a retinoid). This is effective in treating warts and keratoses in organ allograft recipients and perhaps may inhibit cutaneous carcinogenesis.s Treatment of skin cancers includes surgical excision, cryosurgery, chemosurgery, or radiation therapy.18 In situ carcinomas of the uterine cervix respond well to simple hysterectomy, cervical conization, or cryotherapy.18 Localized lymphomas may be successfully excised or treated with radiation therapy. A significant proportion of more extensive lesions have regressed partially or completely following reduction or cessation of immunosuppressive therapy.18,23 In particular, in recipients with widespread or extensive lymphomas or with potentially life-threatening lymphomas, all immunosuppression should be stopped except for a minimal dose of prednisone, 5 to 10 mg/ day, until all evidence of lymphoma has disappeared. Allograft rejection may not occur or may occur slowly in chronic fashion, as many of these patients have been very heavily immunosuppressed and a long time may be needed for immunocompe-
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tence to be restored. Once the lymphoma has regressed, immunosuppressive therapy should be resumed in a small dose and then gradually increased to maintenance levels. Often lymphomas respond to multimodality therapy, which may include excision, radiation therapy, reduction of immunosuppression, acyclovir or ganciclovir administration to control an associated EBV infection, and treatment with interferon-a. IS Chemotherapy is reserved for patients who do not respond to these measures. It is not well tolerated in these very heavily immunosuppressed patients, as chemotherapy itself is immunosuppressive. The lymphoma may vanish following chemotherapy, but the patient may die of an uncontrollable infection. Localized KS responds well to excision, radiation therapy, or intralesional injections of chemotherapeutic agents such as bleomycin.ls More extensive lesions may respond to reduction or cessation of immunosuppressive therapy (see above). Approximately 50% of renal allograft recipients who responded to this treatment lost their allograft function. Interferon-a is another useful treatment in some patients with widespread KS. KS responds well also to chemotherapy using agents such as vincristine, vinblastine, or bleomycin. The patients who have had complete regressions of KS frequently have required various combinations of the above treatments. Malignancies other than those mentioned above should be treated by standard surgical, radiation, or chemotherapeutic modalities. ls Although some patients with NHLs and KS have responded to reduction or cessation of immunosuppressive therapy, disappointingly, such treatment has rarely caused regression of epithelial tumors. IS Nevertheless, we may decrease the level of immunosuppressive therapy in patients with highly malignant, extensive, or advanced neoplasms in the hope that the immune system may recover from its suppressed state and aid in their destruction. However, as indicated above, such treatment carries the risk of allograft rejection. Renal allograft recipients may return to dialysis therapy, but cardiac, hepatic, or pulmonary allograft recipients may die of this complication. In patients requiring cytotoxic therapy of widespread cancers, we must remember that most agents depress the bone marrow. IS It is therefore prudent to stop or reduce azathioprine dosage during such treatment to avoid severe bone marrow depression. Because most cytotoxic drugs have immunosuppressive side effects, satisfactory allograft function may persist for prolonged periods. Treatment with prednisone may be continued, as it is an important component of many cancer chemotherapy protocols. When using cytotoxic therapy in renal transplant recipients or in recipients of other organs who have impaired renal function, one should avoid, if possible, the use of nephrotoxic agents, such as cisplatin. SUMMARY
Although cancer is a complication of transplantation, one must emphasize that the great majority of organ allograft recipients do not develop this problem. The risk of developing a de novo malignancy is generally not a contraindication to transplantation. Many patients who develop de novo malignancies have readily treatable in situ carcinomas of the cervix, low-grade skin tumors, and in situ carcinomas of the vulva and perineum. However, with the limited experience gained thus far, nonrenal allograft recipients appear to be more prone to develop potentially life-threatening tumors, mainly lymphomas. Their occurrence may be
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related to the more intense immunosuppressive therapy that the surgeon is forced to give to some patients compared with renal allograft recipients. In these patients efforts to preserve a rejecting kidney may be abandoned in favor of dialysis and cessation of immunosuppressive therapy. A second transplantation can be performed at a later date when the patient has recovered from the effects of heavy immunosuppression. When large numbers of nonrenal allograft recipients have been followed for prolonged periods, it is likely that the pattern of malignancies described in renal allograft recipients will be seen in them as well. 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.
References 1. Barr BBB, Benton EC, McLaren K, et al: Human papilloma virus infection and skin cancer in renal allograft recipients. Lancet 1:124, 1989 2. Barrett WL, First MR, Aron BS, et al: Clinical course of malignancies in renal transplant recipients. Cancer 72:2186, 1993 3. Blohme I, Brynger H: Malignant disease in renal transplant patients. Transplantation 39:23,1985 4. Brunson ME, Balakrishnan K, Penn I: HLA and Kaposi's sarcoma in solid organ transplantation. Hum Immuno129:56, 1990 5. Euvrard S, Verschoore M, Touraine JL, et al: Topical retinoids for warts and keratoses in transplant recipients [letter to editor]. Lancet 340:48, 1992 6. Gupta AK, Cardella CJ, Haberman HF: Cutaneous malignant neoplasms in patients with renal transplants. Arch DermatolI22:1288, 1986 7. Hanto DW, Birkenbach M, Frizzera G, et al: Confirmation of the heterogeneity of posttransplant Epstein-Barr virus-associated B cell proliferations by immunoglobulin gene rearrangement analyses. Transplantation 47:458,1989 8. Harwood AR, Osoba D, Hofstader SL, et al: Kaposi's sarcoma in recipients of renal transplants. Am J Med 67:759, 1979 9. Hemmens VJ, Moore DE: Photochemical sensitization by azathioprine and its metabolites: II. Azathioprine and nitroimidazole metabolites. Photochem Photobiol 43:3:257, 1986 10. Kinlen LJ: Incidence of cancer in rheumatoid arthritis and other disorders after immunosuppressive treatment. Am J Med 78(SuppllA):44, 1985 11. Mullen DL, Silberberg SG, Penn I, et al: Squamous cell carcinoma of the skin and lip in renal homograft recipients. Cancer 37:729, 1976 12. Nalesnik MA, Makowka L, Starzl TE: The diagnosis and treatment of posttransplant lymphoproliferative disorders. Curr Probl Surg 25:371,1988 13. Penn I: Cancers of the anogenital region in renal transplant recipients: Analysis of 65 cases. Cancer 58:611,1986 14. Penn I: Immunosuppression and opportunistic tumors: Do viruses playa role? In Dammaco F (ed): Advances in Tumor Immunology and Allergic Disorders. Immuno Incontri, vol 6. Milan, Edi Ermes, 1992, p 139 15. Penn I: Posttransplant kidney cancers and skin cancers (including Kaposi's sarcoma). In Schmahl D, Penn I(eds): Cancer in Organ Transplant Recipients. Berlin, SpringerVerlag, 1991, p 46 16. Penn I: The changing patterns of posttransplant malignancies. Transplant Proc 23:1101, 1991 17. Penn I: Tumors after renal and cardiac transplantation. Hematol Oncol Clin North Am 7:431,1993
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18. Penn I: Why do immunosuppressed patients develop cancer? In Pimentel E (ed): CRC Crit Rev Oncogenesis 1:27, 1989 19. Porreco R, Penn I, Droegemueller W, et al: Gynecologic malignancies in immunosuppressed organ homograft recipients. Obstet Gynecol45:359, 1975 20. Schroter GPJ, Weil R III, Penn I, et al: Hepatocellular carcinoma associated with chronic hepatitis B virus infection after kidney transplantation [letter to editor]. Lancet 2:381, 1982 21. Sheil AGR, Disney APS, Mathew TH, et al: Cancer development in c!idaveric donor remll allograft recipients treated with azathioprine (AZA) or cyc1osporine (CYA) or AZA/CYA. Transplant Proc 23:1111,1991 22. Sillman F, Stanek A, Sedlis A, et al: The relationship between human papillomavirus and lower genital intraepithelial neoplasia in immunosuppressed women. Am J Obstet GynecoI150:300, 1984 23. Starzl TE, Nalesnik MA, Porter KA, et al: Reversibility of lymphomas and lymphoproliferative lesions developing under cyc1osporine-steroid therapy. Lancet 1:583, 1984
Address reprint requests to Israel Penn, MD University of Cincinnati Medical Center Department of Surgery 231 Bethesda Avenue Cincinnati, OH 45267-0558
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MALIGNANCY Israel Penn, MD
Worldwide more than 300,000 solid organ transplants have been performed. Many survivors are no longer followed at the transplant center at which they received their allografts. Therefore, nontransplant surgeons may be called upon to deal with various complications that occur in these patients. One of these problems is an increased incidence of certain malignancies.3, 10, 13-18, 21, 22 In this article we describe the more common cancers and their clinical features and management. Until December 1993 the Cincinnati Transplant Tumor Registry (CTTR) accumulated data on 7796 cancers that arose in 7316 organ transplant recipients, including 6251 who received a kidney transplant, 598 heart, 269 liver, 122 bone marrow, 36 pancreas, 22 combined heart and lung, 14 lung, and 4 upper-abdominal organ "cluster" transplants. INCIDENCE OF MALIGNANCIES
The prevalence in several large series of renal allograft recipients ranged from 4% to 18%, with an average of 6%.18 In cardiac allograft recipients, the figures were similar, with a range of 3% to 9% and an average of 6%. However, these data underestimate the problem, as patients with short survival times or short lengths of follow-up were included. AGE AND GENDER OF PATIENTS
The tumors occurred in a relatively young group of patients, whose average age at the time of transplantation was 42 years (range, 3 months to 80 years). Forty-three percent were younger than 40 years at the time of transplantation. The average age of the patients at the time of diagnosis of their neoplasms was Supported in part by a grant from the Department of Veterans Affairs.
From the Department of Surgery, University of Cincinnati Medical Center; and the Cincinnati Veterans Affairs Medical Center, Cincinnati, Ohio
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47 years. Sixty-six percent of patients were male and 34% female, in keeping with the 2:1 ratio of male to female patients who undergo renal transplantation.18 INTERVAL BETWEEN TRANSPLANTATION AND CANCER
Some cancers appeared at fairly distinct intervals after transplantationP-18 In the general population, an interval of 5 to 20 years or even more elapses between exposure to many carcinogens and the development of overt tumors. In
contrast, many neoplasms appeared a relatively short time after transplantation. Kaposi's sarcoma (KS) was first to appear at an average of 21 (range, 1 to 225.5) months after transplantation. Lymphomas appeared at an average of 32 (range, 1 to 254) months after transplantation. Other neoplasms (excluding carcinomas of the vulva and perineum) appeared at an average of 69 (range, 1 to 298.5) months following transplantation. Carcinomas of the vulva and perineum appeared at the longest interval after transplantation, at an average of 112 (1.5 to 285.5) m,onths. If all cancers are considered, the average time of their appearance was 61 (range, 1 to 298.5) months. The incidence of neoplasia increased with the length of follow-up after transplantation. An Australasian study of 5879 patients showed that the probability of developing cancer following renal transplantation from cadaver donors 20 years after operation was 54% for skin cancers, 21% for nonskin cancers, and 63% for any type of malignancy.21 These exceptional figures must be interpreted with caution, as most tumors were skin cancers (which are very common in Australia) and the number of 20-year survivors was small. Nevertheless, they emphasize the need to follow transplant patients indefinitely. VARIETIES OF DE NOVO MALIGNANCY
The malignancies that are frequently observed in the general population (carcinomas of the lung, breast, prostate, colon, and invasive uterine cervical carcinomas) showed no increase or even a decrease. l 4, 18 Only two types of cancer frequently seen in the general population were encountered in significant numbers in transplant patients. Excluding lip cancers, the percentage of nonmelanoma skin tumors (32%) was very similar to that observed in the general population (30% of all tumors), but the incidence of squamous cell carcinomas (SCCs) was markedly increased. Another tumor, which comprises 3% of all tumors in the general population, is in situ carcinoma of the uterine cervix, which also made up 3% of neoplasms in transplant patients. If nonritelanoma skin cancers and in situ carcinomas of the cervix were excluded, as they are from most cancer statistics, we then observed a variety of tumors in transplant patients which occurred infrequently in the general population: lymphomas, 23% versus 5%; lip cancers, 7% versus 0.3%; KS, 5.6% versus a negligible incidence; carcinomas of the kidney, 4.8% versus 2%; carcinomas of the vulva and perineum, 3.6% versus 0.6%; hepatobiliary tumors, 2.4% versus 1%; and sarcomas (excluding KS), 1.6% versus 0.5%.14.15.17.18 Cancers of the Skin and Lips
These were the most common, comprising 2897 of the 7796 cancers (37%) (Table 1). Their incidence freuqently varied with the amount of sunlight expo-
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Table 1. DE NOVO CANCERS IN ORGAN ALLOGRAFT RECIPIENTS Type of Neoplasm
No. of Tumors·
Cancers of the skin and lips Lymphomas Carcinomas of the lung Carcinomas of the uterus (cervix 273; body 42; unspecified 4) Kaposi's sarcoma Carcinomas of the colon and rectum Carcinomas of the kidney (host kidney 231 ; allograft kidney 24; unspecified 10) Carcinomas of the breast Carcinomas of the head and neck (excluding thyroid, parathyroid, and eye) Carcinomas of the vulva, perineum, penis, scrotum Carcinomas of the urinary bladder Metastatic carcinoma (primary site unknown) Leukemias Hepatobiliary carcinomas Carcinomas of the prostate gland Carcinomas of the thyroid gland Cancers of the stomach Sarcomas (excluding Kaposi's sarcoma) Testicular carcinomas Ovarian cancers Miscellaneous tumors Total
2897 1276 428 319 311 280 265 246 223 200 175 172 149 135 112 99 91 90 69 57 202 7796
-There were 7316 patients, of whom 446 (6%) had two or more distinct tumor types involving different organ systems. Of these, 32 patients each had three separate types of cancer and one had four.
sure. 'S, 18,21 In areas with limited exposure, there was a four- to seven-fold increase, but in localities with copious sunlight there was an almost 21-fold rise over the already high incidence seen in the local population. Almost all the increase was in SCCs (see below). However, exposure to sunlight is not the only factor involved. A surprisingly high incidence of SCCs was reported from areas of low sunlight in Canada, Sweden, and Scotland and may be related to malignant change in papillomavirus-induced cutaneous warts, under the influence of immunosuppression, sunlight, and possibly other factors. " 3, 5, 15 The incidence of cutaneous tumors increases with the length of follow-up after transplantation, as demonstrated by an Australasian study of 5879 recipients of cadaveric renal allografts who showed a linear increase in the incidence of skin cancer, reaching 54% at 20 years after transplantation?' In transplant patients skin cancers show several unusual features compared with their counterparts in the general population. 's, 17, 18 Basal cell carcinomas (BCCs) outnumber SCCs in the general population by 5 to 1, but the opposite is true in transplant recipients, in whom SCCs outnumbered BCCs by 1.8 to 1. In the population at large, nonmelanoma skin cancers occur mainly in people in their 60s and 70s, whereas affected transplant patients' average ages are 30 years younger." The incidence of multiple skin neoplasms (present in at least 42%) is remarkably high and is comparable to that seen only in people in the general population living in areas of abundant sunshine. Several patients each had more than 100 skin cancers. Malignant melanomas comprised 5.2% of cutaneous neoplasms, in contrast to an incidence of 2.7% in the general population of the United States.
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Most skin cancers were of low-grade malignancy, but a significant percentage of SCCs behaved much more aggressively than their counterparts in the general population.'5, 17, 18 Lymph node metastases occurred in 167 patients (5.8%), 126 of whom had SCCs, 28 malignant melanomas, 12 Merkel's cell tumors, and 1 BCC. One hundred and forty-three (4.9%) patients died of their skin cancers, 89 of SCCs, 46 of malignant melanomas, 6 of Merkel's cell tumors, and 2 of BCCs. The behavior of skin tumors in transplant patients contrasts markedly with that seen in the general population, in whom they cause only 1% to 2% of all cancer deaths, the great majority of which are from malignant melanoma. Non-Hodgkin's Lymphomas Of a total of 1276 lymphomas in the CTIR (Table I), only 34 (2.7%) were cases of Hodgkin's disease, whereas it comprises 12% of lymphomas in the general population.14, 17, 18 Similarly, myeloma comprised only 48 cases (3.8%), compared with a 21% incidence among lymphomas in the general population. The bulk of the post-transplant lymphomas (1194) were non-Hodgkin's lymphomas (NHLs), which made up 93.6% of the lymphomas, compared with only 67% in the general population,17, 18 The high incidence found in the CTIR was confirmed by two epidemiologic studies which showed that the incidence of NHLs was increased 28-fold to 49-fold above that seen in age-matched controls.lO Morphologically, most NHLs were classified as immunoblastic sarcomas, reticulum cell sarcomas, microgliomas, or large celllymphomas.14, 17, 18 Because there is an ill-defined zone between inflammatory lymphoproliferations and neoplastic growths of lymphocytes, some pathologists prefer to use the rather vague term "post-transplant lymphoproliferative disorder" (PTLD)P Of NHLs studied immunologically, 87% arose from B lymphocytes, 12.6% were of T-cell origin, and 0.4% were of null cell origin. Fifty-two percent involved multiple organs or sites, whereas 48% were confined to a single organ or site. Post-transplant NHLs differed from their counterparts in the general population in several ways?' 12, 14, 16-18,23 Whereas extranodal involvement occurs in 24% to 48% of NHL patients in the community at large, it was present in 69% of NHLs in transplant patients. In the general population, about 1% of NHLs affect the brain parenchyma, whereas in organ transplant patients 24% involved the central nervous system (CNS), usually the brain, in which the lesions were frequently multicentric in distribution. Spinal cord involvement was rare. (These figures exclude 10 patients with meningeal involvement only and 7 patients whose cerebrospinal fluid showed lymphomatous cells without apparent CNS lesions.) Another notable feature was that in at least 56% of patients with CNS involvement the lesions were confined to the brain, whereas in the general population cerebral lymphomas are frequently associated with involvement of other organs. A striking finding was the frequency of either macroscopic or microscopic involvement of the allograft by lymphoma. '4, 17, 18 In 1168 patients studied, this was present in 271 recipients (23%)-142 renal, 68 hepatic, 21 cardiac, 21 pulmonary (several in recipients of heart-lung transplants), 8 pancreatic, 8 bone marrow, and 3 with abdominal organ clusters. In some individuals with renal, cardiac, or hepatic allografts, the lymphomatous infiltrate was misdiagnosed as rejection when biopsies done because of allograft dysfunction were studied microscopically. The genome of Epstein-Barr virus has been isolated from many NHLs in organ allograft recipients. It is believed to cause a spectrum of lesions ranging from benign polyclonal Bcell hyperplasia on the one hand to frank monoclonal B-cell lymphomas on the other.7,12
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The outcomes were studied in 729 patients with NHLs. Of these, 137 patients (19%) had no treatment, and the tumor was discovered at autopsy in 70 of them (51%). No treatment data are available in 32 patients (4%). Treatment was given to 560 patients (77%) and of these 227 (41%) had complete remissions. In 48 of these recipients (21%) the only treatment used was reduction or cessation of immunosuppressive therapy. Kaposi's Sarcoma
The frequent occurrence of KS in transplant recipients (Table 1) is in marked contrast to its incidence in the general population of the United States (before the acquired immunodeficiency syndrome [AIDS] epidemic started), in which it comprised only 0.02% to 0.07% of all neoplasms.'" 15, 17,18 The high incidence of KS in this worldwide collection of patients is comparable to that seen in tropical Africa, where it occurs with greatest frequency, making up 3% to 9% of all neoplasms. It is remarkable that the number of transplant patients with KS (311) in the CTTR exceeds those with carcinomas of the colorectum (280) or breast (246) (Table 1). Apart from individuals with AIDS, who frequently have KS, there is probably no other series in which the number of cases of KS exceeds either of these two common tumors, except possibly in tropical Africa where KS occurs frequently and colon cancer is rare. Very few transplant patients with KS have tested positive for the human immunodeficiency virus. An epidemiologic study showed a 400- to 500-fold increase in incidence of KS in renal transplant recipients compared with controls of the same ethnic origin. KS affected males more than females in a 3:1 ratio, a figure far less than the 9:1 to 15:1 ratio seen with KS in the general population.14, 15, 17, 18 KS was most common in transplant patients who were Arabic, Jewish, black, or of Mediterranean ancestry. Sixty percent had nonvisceral KS confined to the skin, conjunctiva, or oropharyngolaryngeal mucosa, and 40% had visceral disease, which involved mainly the gastrointestinal tract, lungs, and lymph nodes but also affected other organs. Of 188 patients with nonvisceral disease, the lesions were confined to the skin in 184 patients (98%) and to the mouth or oropharynx in 4 (2%). The 123 patients with visceral disease had no skin involvement in 29 instances (24%), but 4 of them (3%) had oral involvement, which provided an easily accessible site for biopsy and diagnosis of the disease. Of those with nonvisceral disease, 89 (47%) had complete remissions following treatment. Interestingly, 29 (33%) of these remissions occurred when the only treatment was a drastic reduction of immunosuppressive therapy. In patients with visceral disease, only 24 of 123 patients (20%) had complete remissions. However, 13 of the 24 remissions (54%) occurred in response to reduction or cessation of immunosuppressive therapy only. Occasional patients, in whom immunosuppessive therapy was later resumed, developed recurrences of KS. Sixty-six percent of the patients with visceral KS died. Of the deaths, 54 of the 74 patients (73%) died of the malignancy per se. Renal Carcinomas
There were 265 patients with carcinomas of the kidney (Table 1). This figure excludes 234 patients who had lymphomatous involvement of the native or allograft kidneys and 3 patients who had renal sarcomas (2 involving the allograft and 1 a native kidney)."5, 18 Of the tumors, 197 (74%) were described as renal cell carcinomas, hypernephromas, clear cell carcinomas, or adenocarcinomas; 33
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(12%) as transitional cell carcinomas or urothelial carcinomas; and 35 (13%) as miscellaneous carcinomas. A notable feature was that in at least 25 patients (9%) renal failure had been caused by analgesic abuse, which is known to cause carcinomas of the renal pelvis, ureter, or bladder.'s, 18 Although an underlying renal disease may have caused carcinomas of the kidney in some renal allograft recipients, there is no apparent explanation of why renal carcinomas occurred in 15 cardiac and 3 hepatic allograft recipients. Another unusual feature was that 66 of the 265 patients (25%) had incidentally discovered renal malignancies, mostly renal cell carcinomas. These were discovered at nephrectomy for hypertension or other reasons, during work-up for other disorders, during operation for some other disease, or at autopsy examination.
Carcinomas of the Vulva and Perineum
The increased incidence of carcinomas of the vulva, perineum, scrotum, penis, perianal skin, or anus in the CTIR (Table 1)13,14,17,18 is in keeping with an epidemiologic study showing that the incidence in renal transplant recipients was increased 100-fold compared with controls. 3 Females outnumbered males by 2.5:1, in contrast to most other post-transplant cancers, in which males outnumbered females by more than 2:l. One third of patients had in situ lesionsY A disturbing feature is that patients with invasive lesions were much younger (average age, 42 years) than their counterparts in the general population, whose average age is usually between 50 and 70 years. Approximately one third of transplant patients gave a history of condyloma acuminatum (genital warts), which must be regarded as a premalignant lesion. In women multicentric lesions were quite frequent, involving several sites in the vulva, perianal area, or anus, and sometimes the cervix and/ or vagina as wellY, 14, 17. 18 Although many patients with cancers of the vulva and perineum responded well to local or extensive excisions of their lesions, some succumbed to metastases despite abdominoperineal resections or radical vulvectomies.
Carcinomas of the Uterus
Carcinomas of the cervix occurred in 11% of women with post-transplant cancers (Table 1).14,,7,,8 At least 72% of patients had in situ lesions. As mentioned above, the CTIR data show no difference in the incidence of in situ uterine cervical carcinoma from that seen in the general population. This is surprising in view of two epidemiologic studies that showed a 14- to 16-fold increased incidence in transplant patients. '9, 22 This suggests that many cases are being missed. In order to avoid this error, every postadolescent female organ transplant recipient should have regular pelvic examinations and cervical smears.
Hepatobiliary Tumors
Two epidemiologic studies showed a 20- to 38-fold increased incidence over controls. 1O,18 Most cases in the CTIR (Table 1) were hepatomas, and a substantial number of patients gave a preceding history of hepatitis B infection.14, 17, 18, 20 The role of hepatitis C virus in causing these tumors has not yet been determined.
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Sarcomas (Excluding Kaposi's Sarcoma)
The majority involved the soft tissues or visceral organs, whereas cartilage or bone involvement was uncommonP' 18 Of the 90 sarcomas, the major types were fibrous histiocytoma (18 cases), leiomyosarcoma (12), fibrosarcoma (11), rhabdomyosarcoma (8), hemangiosarcoma (7), mesothelioma (6), synovial sarcoma (4), and miscellaneous sarcomas (24). TUMORS IN RENAL VERSUS NON RENAL RECIPIENTS
Significant differences occur in tumor incidence in renal and nonrenal recipients (Table 2).'6-'8 The striking incidence of lymphomas (47% versus 11%) in nonrenal recipients is most likely related to the intensity of the immunosuppression given to the former group. Severe rejection of a renal transplant can be handled by placing the patient back on dialysis and discontinuing immunosuppressive therapy, whereas severe rejection of a cardiac, pulmonary, or hepatic allograft results in death of the patient unless the immunosuppressive therapy is substantially increased, except in rare instances when one is fortunate enough to obtain a new organ with which to replace the failing allograft. Many renal recipients have been followed for 10 to 25 years after transplantation, whereas the minority of nonrenal recipients have been followed for that long. This may account for the higher incidence of late-appearing malignancies of the skin, uterine cervix, vulva, and perineum in the renal recipients. The higher incidence of carcinomas of the kidney in renal recipients may reflect the influence of analgesic nephropathy and acquired cystic disease of the kidney in predisposing to renal neoplasms. 's POSSIBLE CAUSES OF POST-TRANSPLANT TUMORS
The neoplasms probably arise from a complex interplay of multiple factors that are discussed in detail elsewhere.'4, 16-18 Severely depressed immunity may impair the body's ability to eliminate malignant cells induced by various carcinogens. '8 Chronic antigenic stimulation by the foreign antigens of transplanted organs, by repeated infections, or by transfusions of blood or blood products may overstimulate a partially depressed immune system and lead to NHLs.'8 Alternately, defective feedback mechanisms may fail to control the extent of
Table 2. COMMON CANCERS IN RENAL VERSUS NONRENAL RECIPIENTS Renal (6709 tumors)" Skin cancers Lymphomas Kaposi's sarcoma Carcinomas of the cervix Renal tumors Carcinoma of the vulval perineum *In 6251 patients. tin 1065 patients.
Percent
Nonrenal (1087 tumors)t
2635 763 282 263
39 11 4
262 513 29
4
10
247
4
193
3
18 7
Percent 24 47 3
<1 2 <1
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immune reactions and lead to unrestrained lymphoid proliferation and lymphomas. Furthermore, once this loss of regulation occurs, the defensive ability of the immune system is weakened, and other nonlymphoid malignancies may appear. 18 The activation of oncogenic viruses in some immunosuppressed patients is highly likely.14, 18 Epstein-Barr virus (EBV) is strongly implicated in causing NHLs in primary immunodeficiency diseases, organ transplant recipients, and AIDS patients7, 12,14,18; certain papillomaviruses in causing carcinomas of the lip, vulva, perineum, uterine cervix, and anus14. 18, 22; and viruses (as yet unidentified) are believed to playa key role in the development of Kaposi's sarcoma. 14, 18 Some immunosuppressive agents such as azathioprine, cyclophosphamide, and cyclosporine may directly damage DNA and cause neoplasms. 18 Immunosuppressive agents may enhance the effects of other carcinogens, such as sunlight in causing carcinomas of the skin or papillomavirus in causing carcinomas of the uterine cervix. 18 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. 18 For example, several studies have linked various HLA groups either to increased susceptibility or resistance to the development of KS. However, a CTTR study of HLA-A and HLA-B typing in 135 patients and HLA-DR typing in 67 recipients with KS showed no significant differences when the patients' ethnic backgrounds were taken into consideration. Fifty-six percent of the patients were Italian, Greek, Jewish, or Arab. 4 TREATMENT OF POST-TRANSPLANT MALIGNANCIES
When treating cancers in organ allograft recipients, one must bear in mind that they frequently demonstrate more aggressive behavior than do similar tumors in nontransplant patients.2 Early tumors are curable with local treatment provided that their growth has not given them adequate vascular access. Once this has been obtained, the host's depressed immune system is believed to permit greater than normal survival of tumor cells in the bloodstream.2 The result is more rapid malignant dissemination and demise of the host than would be expected in a setting of immunocompetence. In managing patients with premalignant skin lesions or early cancers, a useful treatment is a 6-week course of topical 5-fluorouracil cream applied twice daily.18 This destroys many premalignant lesions and even superficial carcinomas. This treatment is rapidly being superseded by topical use of 0.05% tretinoin cream (a retinoid). This is effective in treating warts and keratoses in organ allograft recipients and perhaps may inhibit cutaneous carcinogenesis.s Treatment of skin cancers includes surgical excision, cryosurgery, chemosurgery, or radiation therapy.18 In situ carcinomas of the uterine cervix respond well to simple hysterectomy, cervical conization, or cryotherapy.18 Localized lymphomas may be successfully excised or treated with radiation therapy. A significant proportion of more extensive lesions have regressed partially or completely following reduction or cessation of immunosuppressive therapy.18,23 In particular, in recipients with widespread or extensive lymphomas or with potentially life-threatening lymphomas, all immunosuppression should be stopped except for a minimal dose of prednisone, 5 to 10 mg/ day, until all evidence of lymphoma has disappeared. Allograft rejection may not occur or may occur slowly in chronic fashion, as many of these patients have been very heavily immunosuppressed and a long time may be needed for immunocompe-
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tence to be restored. Once the lymphoma has regressed, immunosuppressive therapy should be resumed in a small dose and then gradually increased to maintenance levels. Often lymphomas respond to multimodality therapy, which may include excision, radiation therapy, reduction of immunosuppression, acyclovir or ganciclovir administration to control an associated EBV infection, and treatment with interferon-a. IS Chemotherapy is reserved for patients who do not respond to these measures. It is not well tolerated in these very heavily immunosuppressed patients, as chemotherapy itself is immunosuppressive. The lymphoma may vanish following chemotherapy, but the patient may die of an uncontrollable infection. Localized KS responds well to excision, radiation therapy, or intralesional injections of chemotherapeutic agents such as bleomycin.ls More extensive lesions may respond to reduction or cessation of immunosuppressive therapy (see above). Approximately 50% of renal allograft recipients who responded to this treatment lost their allograft function. Interferon-a is another useful treatment in some patients with widespread KS. KS responds well also to chemotherapy using agents such as vincristine, vinblastine, or bleomycin. The patients who have had complete regressions of KS frequently have required various combinations of the above treatments. Malignancies other than those mentioned above should be treated by standard surgical, radiation, or chemotherapeutic modalities. ls Although some patients with NHLs and KS have responded to reduction or cessation of immunosuppressive therapy, disappointingly, such treatment has rarely caused regression of epithelial tumors. IS Nevertheless, we may decrease the level of immunosuppressive therapy in patients with highly malignant, extensive, or advanced neoplasms in the hope that the immune system may recover from its suppressed state and aid in their destruction. However, as indicated above, such treatment carries the risk of allograft rejection. Renal allograft recipients may return to dialysis therapy, but cardiac, hepatic, or pulmonary allograft recipients may die of this complication. In patients requiring cytotoxic therapy of widespread cancers, we must remember that most agents depress the bone marrow. IS It is therefore prudent to stop or reduce azathioprine dosage during such treatment to avoid severe bone marrow depression. Because most cytotoxic drugs have immunosuppressive side effects, satisfactory allograft function may persist for prolonged periods. Treatment with prednisone may be continued, as it is an important component of many cancer chemotherapy protocols. When using cytotoxic therapy in renal transplant recipients or in recipients of other organs who have impaired renal function, one should avoid, if possible, the use of nephrotoxic agents, such as cisplatin. SUMMARY
Although cancer is a complication of transplantation, one must emphasize that the great majority of organ allograft recipients do not develop this problem. The risk of developing a de novo malignancy is generally not a contraindication to transplantation. Many patients who develop de novo malignancies have readily treatable in situ carcinomas of the cervix, low-grade skin tumors, and in situ carcinomas of the vulva and perineum. However, with the limited experience gained thus far, nonrenal allograft recipients appear to be more prone to develop potentially life-threatening tumors, mainly lymphomas. Their occurrence may be
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related to the more intense immunosuppressive therapy that the surgeon is forced to give to some patients compared with renal allograft recipients. In these patients efforts to preserve a rejecting kidney may be abandoned in favor of dialysis and cessation of immunosuppressive therapy. A second transplantation can be performed at a later date when the patient has recovered from the effects of heavy immunosuppression. When large numbers of nonrenal allograft recipients have been followed for prolonged periods, it is likely that the pattern of malignancies described in renal allograft recipients will be seen in them as well. 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.
References 1. Barr BBB, Benton EC, McLaren K, et al: Human papilloma virus infection and skin cancer in renal allograft recipients. Lancet 1:124, 1989 2. Barrett WL, First MR, Aron BS, et al: Clinical course of malignancies in renal transplant recipients. Cancer 72:2186, 1993 3. Blohme I, Brynger H: Malignant disease in renal transplant patients. Transplantation 39:23,1985 4. Brunson ME, Balakrishnan K, Penn I: HLA and Kaposi's sarcoma in solid organ transplantation. Hum Immuno129:56, 1990 5. Euvrard S, Verschoore M, Touraine JL, et al: Topical retinoids for warts and keratoses in transplant recipients [letter to editor]. Lancet 340:48, 1992 6. Gupta AK, Cardella CJ, Haberman HF: Cutaneous malignant neoplasms in patients with renal transplants. Arch DermatolI22:1288, 1986 7. Hanto DW, Birkenbach M, Frizzera G, et al: Confirmation of the heterogeneity of posttransplant Epstein-Barr virus-associated B cell proliferations by immunoglobulin gene rearrangement analyses. Transplantation 47:458,1989 8. Harwood AR, Osoba D, Hofstader SL, et al: Kaposi's sarcoma in recipients of renal transplants. Am J Med 67:759, 1979 9. Hemmens VJ, Moore DE: Photochemical sensitization by azathioprine and its metabolites: II. Azathioprine and nitroimidazole metabolites. Photochem Photobiol 43:3:257, 1986 10. Kinlen LJ: Incidence of cancer in rheumatoid arthritis and other disorders after immunosuppressive treatment. Am J Med 78(SuppllA):44, 1985 11. Mullen DL, Silberberg SG, Penn I, et al: Squamous cell carcinoma of the skin and lip in renal homograft recipients. Cancer 37:729, 1976 12. Nalesnik MA, Makowka L, Starzl TE: The diagnosis and treatment of posttransplant lymphoproliferative disorders. Curr Probl Surg 25:371,1988 13. Penn I: Cancers of the anogenital region in renal transplant recipients: Analysis of 65 cases. Cancer 58:611,1986 14. Penn I: Immunosuppression and opportunistic tumors: Do viruses playa role? In Dammaco F (ed): Advances in Tumor Immunology and Allergic Disorders. Immuno Incontri, vol 6. Milan, Edi Ermes, 1992, p 139 15. Penn I: Posttransplant kidney cancers and skin cancers (including Kaposi's sarcoma). In Schmahl D, Penn I(eds): Cancer in Organ Transplant Recipients. Berlin, SpringerVerlag, 1991, p 46 16. Penn I: The changing patterns of posttransplant malignancies. Transplant Proc 23:1101, 1991 17. Penn I: Tumors after renal and cardiac transplantation. Hematol Oncol Clin North Am 7:431,1993
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18. Penn I: Why do immunosuppressed patients develop cancer? In Pimentel E (ed): CRC Crit Rev Oncogenesis 1:27, 1989 19. Porreco R, Penn I, Droegemueller W, et al: Gynecologic malignancies in immunosuppressed organ homograft recipients. Obstet Gynecol45:359, 1975 20. Schroter GPJ, Weil R III, Penn I, et al: Hepatocellular carcinoma associated with chronic hepatitis B virus infection after kidney transplantation [letter to editor]. Lancet 2:381, 1982 21. Sheil AGR, Disney APS, Mathew TH, et al: Cancer development in c!idaveric donor remll allograft recipients treated with azathioprine (AZA) or cyc1osporine (CYA) or AZA/CYA. Transplant Proc 23:1111,1991 22. Sillman F, Stanek A, Sedlis A, et al: The relationship between human papillomavirus and lower genital intraepithelial neoplasia in immunosuppressed women. Am J Obstet GynecoI150:300, 1984 23. Starzl TE, Nalesnik MA, Porter KA, et al: Reversibility of lymphomas and lymphoproliferative lesions developing under cyc1osporine-steroid therapy. Lancet 1:583, 1984
Address reprint requests to Israel Penn, MD University of Cincinnati Medical Center Department of Surgery 231 Bethesda Avenue Cincinnati, OH 45267-0558