Malignancies complicating organ transplantation

Malignancies Complicating Organ Transplantation M.R. First and V.R. Peddi

S

INCE the initial reports in the late 1960s1 of lymphomas arising de novo in renal transplant recipients,1 evidence has accumulated that organ transplantation, and the prolonged or intense immunosuppression associated with it, are complicated by the development of an unusual assortment of malignancies.2 At the Cincinnati Transplant Tumor Registry (CTTR), data from transplant centers throughout the world have been collected by Dr I. Penn for over 25 years. Currently, data are available on 9324 tumors in 8757 transplant recipients (Table 1). Malignancies in transplant recipients have a very different pattern from that seen in the Table 1. De Novo Tumors in Organ Transplant Recipients Reported to the Cincinnati Transplant Tumor Registry Type of neoplasm

Number of tumors*

Cancer of skin and lips Lymphomas Carcinoma of lung Kaposi sarcoma Carcinoma of the uterus (cervix 313, body 54, unspecified 3) Carcinoma of the colon and rectum Carcinoma of the kidney (native kidney 278, allograft 31, unspecified 13) Carcinoma of the breast Carcinoma of the head and neck (excluding thyroid, parathyroid, and eye) Carcinoma of the vulva, perineum, penis, and scrotum Carcinoma of the urinary bladder Metastatic carcinoma with primary site unknown Leukemias Carcinoma of the prostate gland Hepatobiliary carcinomas Sarcomas (excluding Kaposi sarcoma) Carcinoma of the thyroid gland Carcinoma of the stomach Testicular carcinoma Carcinoma of the pancreas Ovarian cancers Miscellaneous tumors Total

3393 (36.3%) 1595 (17.1%) 521 (5.5%) 380 (4.1%) 370 (4.0%) 324 (3.5%) 322 (3.5%) 294 (3.1%) 267 (2.9%)

230 (2.5%) 205 (2.2%) 203 (2.2%) 173 (1.9%) 163 (1.7%) 158 (1.7%) 117 (1.2%) 114 (1.2%) 110 (1.2%) 74 (0.8%) 73 (0.8%) 63 (0.7%) 175 (1.9%) 9324 (100%)

*There were 8757 patients of whom 528 (6%) developed two or more distinct tumor types involving different organ systems; of these, 3 patients had three distinct types of cancer, and 1 patient had four different types (Dr I. Penn, personal communication).

general population. Cancers that have a higher incidence in immunosuppressed transplant recipients than the general population (expressed as percentages of the overall cancer occurrence) are lymphomas (24% vs 5%), lip cancers (6% vs 0.2%), Kaposi sarcoma (6% vs less than 0.1%), vulvar and perineal cancers (3.5% vs 0.4%), hepatobiliary cancers (2.4% vs 1.5%), and sarcomas excluding Kaposi (1.8% vs 0.5%).4 The frequency of cancers common in the general population such as carcinomas of the lung, prostate, breast, and colon and invasive carcinomas of the uterine cervix is not increased among transplant recipients.2 Most patients who develop malignancies after transplantation have received multiple immunosuppressive drugs, and no single agent can be implicated. Prolonged suppression of the immune system impairs the ability of the body to cope with cancers caused by carcinogens such as sunlight or oncogenic viruses.5 Infections with potentially oncogenic viruses are common in immunosuppressed patients. These include Epstein–Barr-virus-related B-cell lymphoproliferative disease, human papilloma virus causing carcinoma of the cervix, vulva, perineum, and other skin areas, and hepatitis B virus (HBV)-related and hepatitis C virus (HCV)-related hepatocellular carcinoma.5 Kaposi sarcoma (KS) also appears to be viral in origin, and herpesvirus-like DNA sequences have been identified in tissue samples from patients with acquired immunodeficiency syndrome (AIDS) associated KS, homosexual men with KS who are seronegative for the human immunodeficiency virus (HIV) infection, and in patients with the classic form of KS, which occurs on the lower extremities, most often in elderly men of Mediterranean, Middle Eastern, or Eastern European ethnic origin.6 The tumors in transplant recipients occur in a relatively young population whose average age at the time of transplantation is 41 years.2 The mean time to the diagnosis of malignancies from the time of transplantation is 61 months.2,4 Certain tumors have been shown to appear at fairly distinct time intervals after transplantation, with From the Division of Nephrology and Hypertension, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA. Address reprint requests to Dr M. Roy First, Section of Transplantation, Division of Nephrology and Hypertension, PO Box 670585, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0585.

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Transplantation Proceedings, 30, 2768–2770 (1998)

MALIGNANCIES COMPLICATING ORGAN TX

Kaposi sarcoma presenting at an average of 20 months, lymphomas at an average of 33 months, miscellaneous other tumors at an average of 67 months, and carcinomas of the vulva and perineum at an average of 107 months.4 POSTTRANSPLANT LYMPHOPROLIFERATIVE DISORDERS

As malignancies of the skin are discussed in detail in a separate section of the conference, it is sufficient to say here that cancers of the lip and skin are the most common and comprise 36.3% of the malignancies reported to the CTTR (Table 1). These are followed by lymphomas, the second most common of the malignancies reported (Table 1). The bulk of the posttransplantation lymphomas are the nonHodgkin lymphomas (NHLs) (posttransplant lymphoproliferative disorder, or PTLD), which comprise 93% of the lymphomas as compared with 65% in the general population.2 Of those NHLs studied immunologically, 86% are of B-cell origin, 14% are of T-cell origin, and less than 1% are of null-cell origin.4 Fifty-one percent of the NHLs reported to the CTTR involve multiple organs or sites.4,7 Posttransplant NHLs differ from those encountered in the general population in several respects. Extranodal involvement occurs in 70% of transplant recipients with NHL, whereas it occurs in 24% to 48% of NHL patients in the community.4,7 The most common extranodal sites are the central nervous system (CNS) (27%), liver (23%), lungs (22%), kidney (21%), intestines (20%), and spleen (13%).7 NHL affects the brain in 1% of the general population, whereas in transplant recipients CNS involvement occurs in 27%, and the lesions are usually multicentric in distribution.4,7 Spinal cord involvement is rare.4,7 Unlike in the general population, in approximately 61% of the transplant patients with CNS lymphoma, the lesions are confined to the brain.7 Macroscopic or microscopic involvement of the allograft occurs in 20% of patients with NHL.2,4,7 The use of immunosuppression in organ transplantation increases the risk of lymphoma formation. The major risk factors are the duration of immunosuppression, the dosage of immunosuppression, and the number of immunosuppressant drugs used (together or sequentially).2,8 When patients treated with cyclosporine-based regimens are compared with regimens based on azathioprine or cyclophosphamide, lymphomas make up 26% of neoplasms in the cyclosporine group and 11% in the azathioprine or cyclophosphamide group.2,4 Moreover, lymphomas in the cyclosporine-treated patients occur earlier than those in azathioprine- or cyclophosphamide-treated patients (15 vs 48 months).4 The incidence of PTLD with a tacrolimus-based regimen appears to be comparable to PTLD occurring with cyclosporine-based regimens.9 In patients treated with OKT3, lymphomas occur at a disproportionately high incidence and account for 64% of all tumors,4 in contrast to an overall proportion of 17.1% (Table 1). The OKT3-related lymphomas occur early after transplantation, at an average of 7 months.4 It is the use of multiple immunosuppressive agents used either simultaneously or sequentially, however,

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which seriously impairs lymphocyte function and may lead to the development of lymphoma.7 The genome of Epstein– Barr virus (EBV) has been isolated from many nonHodgkin lymphomas in transplant recipients. EBV, either as a primary or reactivation infection, replicates in the oropharyngeal epithelial cells and transforms B lymphocytes. It is then believed to cause a variety of lesions ranging from benign polyclonal B-cell hyperplasia to frank monoclonal B-cell lymphomas.10 The clinical symptoms of PLTD are variable, and a high index of suspicion is required for accurate diagnosis. PTLD presents in the lymph nodes but also extranodally in a significant number of patients. It frequently occurs in the gastrointestinal tract. This disorder may present with graft dysfunction and has also been identified as a source of ureteric obstruction.11 Two basic clinical patterns are seen, with some overlap. The first, occurring in the early (usually ,90 days) posttransplant period, usually manifests with widespread lesions in an EBV-susceptible patient. The second pattern occurs in patients who have received longterm immunosuppression and may present several years after transplantation, with lesions confined to a single organ.12 Treatment of PTLD consists of partial or complete withdrawal of immunosuppression. Such treatment carries the risk of allograft rejection and return of the renal allograft recipient to dialysis. Treatment with prednisone may be continued, however, as it is an important component of many cancer chemotherapy protocols. If EBV infection is suspected, treatment with acyclovir is initiated pending documentation of EBV infection. Other treatment options include interferon-a therapy to enhance the immune attack on lymphoma cells, surgical excision or local radiotherapy to localized tumors, and, in advanced cases, chemotherapy.7 The potential strategies that may decrease the incidence of PTLD include: (1) use of the lowest possible doses of immunosuppression required to maintain stable allograft function; (2) avoidance of prolonged courses of antilymphocyte preparations; (3) use of lower doses of antilymphocyte agents such as OKT3 2.5 mg/d instead of 5 mg/d whenever appropriate; (4) reduction of the doses of concomitant immunosuppression during treatment with antilymphocyte antibody preparations; and (5) use of antiviral agents such as acyclovir or ganciclovir during periods of intense immunosuppression. KAPOSI SARCOMA

Kaposi sarcoma (KS) occurs at a much greater incidence (400- to 500-fold) in transplant recipients compared with the general population.5,13 This condition is more common in transplant patients who are of Jewish, Arabic, subSaharan African, or Mediterranean ancestry.5 In allograft recipients with KS reported to the CTTR, the average age at presentation was 43 years (range 4.5 to 67 years); the male:female ratio was nearly 3:1; KS was uncommon in the pediatric transplant recipients, who comprised only 3% of the patients with KS; and KS was observed mainly in renal

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allograft recipients, with a much lower incidence in recipients of other solid organs, and rarely in bone marrow allograft recipients.13 The majority of patients (92%) tested negative for HIV.13 The average time of appearance of KS was 21 months (range 1 to 225.5 months) after transplantation.13 However, 46% of KS appeared within 1 year after transplantation.13 KS has complicated the use of virtually all immunosuppressive agents, including the more recently introduced agents tacrolimus and mycophenolate mofetil.13 Sixty-one percent of the cases of KS reported to the CTTR had nonvisceral involvement confined to the skin, conjunctiva, or oropharyngeal mucosa, and 39% had visceral involvement affecting mainly the gastrointestinal tract and lungs, but other organs were also affected.5 Kaposi’s sarcoma should be suspected whenever a transplant recipient presents with reddish-blue macules or papules in the skin or oropharyngeal mucosa or with apparently infected granulomas that fail to heal. If the diagnosis is confirmed, a comprehensive work-up is needed to exclude visceral involvement.5,13 In addition, one must consider reduction or cessation of immunosuppressive therapy, as such treatment alone was shown to be responsible for the complete remission of 31% of nonvisceral and 52% of visceral KS cases reported to CTTR.5 The prognosis of patients with visceral involvement is much worse than those with nonvisceral disease: 46% of patients with visceral involvement died from the disease, whereas fatalities rarely occurred in patients with nonvisceral disease.5 Posttransplant KS differs from the disease seen in patients with AIDS in that visceral involvement is far less common and fatalities from KS are less frequent in the former group.13 In addition, the immunosuppression in transplant recipients can be reduced or totally stopped, with the possibility of subsequent regression of the KS lesions, whereas, in AIDS, persistence of the immunodeficiency is a major feature.13 CONCLUSIONS

Although the overall risk of the development of cancer in transplant recipients is small, it is vitally important to follow all patients indefinitely. The natural history of tumors

FIRST AND PEDDI

associated with immunosuppression used for transplantation may be more aggressive than in patients without immunosuppression.14 Preventive measures are undertaken to reduce the incidence of posttransplant malignancies. All postadolescent female patients require regular pelvic examinations and cervical smears to diagnose cervical and vulvar lesions at an early stage. Use of barrier methods of contraception may prevent the development of condylomata acuminatum. Early eradication of this condition may prevent the development of carcinomas of the vulva, perineum, and uterine cervix. Administration of hepatitis B vaccine to dialysis and transplant recipients may prevent the development of hepatitis B infection and the associated complication of hepatocellular carcinoma. Avoidance of excessive sun exposure by wearing protective clothing and use of sunscreen applications may prevent skin tumors. Because cancers in transplant recipients are often mistaken for other disorders, a high index of suspicion is required. Any untoward symptom should be thoroughly investigated, and any suspicious areas biopsied, if accessible.5 REFERENCES 1. Penn I, Hammond W, Brettschneider L, et al: Transplant Proc 1:106, 1969 2. Penn I: N Engl J Med 323:1767, 1990 3. Penn I: personal communication 4. Penn I: Transplant Proc 23:1101, 1991 5. Penn I: In Jacobson HR, Striker GF, Klahr S (eds): The Principles and Practice of Nephrology. Philadelphia: Mosby; 1995, p 833 6. Moore PS, Chang Y: N Engl J Med 332:1182, 1995 7. Penn I: Clin Transplantation 6:214, 1992 8. Legendre C, Kreis H: Clin Transplant 6:220, 1992 9. Nalesnik MA, Demetris AJ, Fung JJ, et al: Transplant Proc 23:1108, 1991 10. Hanto DW: Clin Transplant 6:227, 1992 11. Renoult E, Aymard B, Gregoire MJ, et al: Am J Kidney Dis 26:84, 1995 12. Alfrey EJ, Friedman AL, Grossman RA, et al: Clin Transplant 6:246, 1992 13. Penn I: Transplantation 64:669, 1997 14. Barrett WL, First MR, Aron BS, et al: Cancer 72:2186, 1993