[CANCER RESEARCH 41, 4253-4261, November 1981] 0008-5472/81 /0041-OOOOS02.00 Clinical Spectrum of Lymphoproliferative Disorders in Renal Transplant Recipients and Evidence for the Role of Epstein-Barr Virus1 Douglas W. Manto,2 Glauco Frizzerà , David T. Purtilo, ' Kiyoshi Sakamoto, John L. Sullivan, Ari K. Saemundsen, George Klein, Richard L. Simmons, and John S. NajarÃ-an Departments of Surgery [D. W. H.. R. L. S., J. S. N.¡and Laboratory Medicine and Pathology ¡G.F.], University of Minnesota Health Sciences Center, Minneapolis, Minnesota 55455: Department of Pathology and Laboratory Medicine, University of Nebraska Medical Center. Omaha, Nebraska 68105 [D. T. P., K. S.]: Department of Pediatrics, University of Massachusetts Medical Center. Worcester, Massachusetts 01605 [J. L. S.I: and Department of Tumor Biology, Karolinska InstitutetS 104 01 Stockholm 60, Sweden [A. K. S., G. K.¡ Abstract Six renal transplant recipients with abnormal lymphoprolif- erative disorders were studied in an attempt to define their clinical features and the role of Epstein-Barr virus (EBV) in their pathogenesis. Patients were either teenage (three) or in the sixth decade (three). The younger patients presented an aver age of 3 months after transplantation with fever, sore throat, and lymphadenopathy; had been markedly immunosup- pressed; frequently had preceding or concomitant cytomega- lovirus infections; and two of three had a rapidly fatal course. The older patients presented an average of 5 years after transplantation while on maintenance ¡mmunosuppressive drugs; in two of three cases with an oropharyngeal tumor; and had a more indolent, but frequently fatal, clinical course. The most frequent sites of biopsy-proven involvement in these patients were lymph nodes (three), the oropharynx (three), liver (three), bone marrow (three), transplanted kidney (three), colon (two), and central nervous system (two). EBV-specific antibody titers including anti-viral capsid anti gen IgG, anti-viral capsid antigen IgM, anti-early antigen, and anti-Epstein-Barr nuclear antigen were serially measured in all patients. Four patients demonstrated serological evidence of a primary (one) or reactivation (three) EBV infection. No patient had significant changes in anti-early antigen or anti-Epstein- Barr nuclear antigen titers. All three patients tested for oropha ryngeal shedding of EBV were positive. A touch imprint of one tumor was stained for the presence of Epstein-Barr nuclear antigen, and a majority of cells were positive. EBV complemen tary RNA/DNA filter hybridization and/or viral DNA/DNA reas- sociation analysis performed on tumor biopsy specimens in five patients demonstrated multiple EBV genome equivalents per cell in all eight specimens tested. Clinical, pathological, serological, and molecular hybridiza tion studies provide substantial evidence that EBV was the cause of these lymphoproliferative disorders occurring after renal transplantation. Impaired host defenses allow the EBV- transformed B-lymphocytes to escape normal control mecha nisms. This impairment is variable and influenced by many factors resulting in the observed spectrum of disease. Cyto- genetic changes, however, may also be important. Introduction Immunodeficiency, whether genetically determined or iatro- genically induced, in some instances predisposes to the de velopment of de novo cancers. The reported incidence of cancer arising in individuals with genetically determined im munodeficiency diseases and in immunosuppressed renal al- lograft recipients is 4% and 6%, respectively (30,41 ), markedly greater than that expected in the general population matched for age. The most frequent neoplasms in the former group are those of the lymphoreticular system, and in the latter, non- melanotic skin and lip cancers followed by ML.4 More than 20% of posttransplant cancers are ML and 65% have been classified previously as PCS. The risk of a transplant recipient developing ML or RCS is increased 40 and 350 times, respec tively (14). Unusual characteristics of RCS are reported to include a 49% incidence of CNS involvement (compared to less than 2% in the nontransplanted patient), which in 82% is limited to the CNS (30, 38), and evidence that they may be polyclonal (10, 13). Hodgkin's disease, the most common form of malignant lymphoma in the general population in any age group, is rare in the transplanted patient (3). Many theories of causation have been invoked, including impaired immune surveillance mechanisms (21), chronic anti- genie stimulation (9), reactivation of latent oncogenic herpes- viruses (24), and direct oncogenic effects of ¡mmunosuppres sive drugs (30), but none have been proven. One of the more attractive theories is that reactivation of oncogenic herpesvi- ruses, in particular the EBV, is responsible. EBV, an infectious and oncogenic virus, transforms B-lymphocytes inducing a polyclonal proliferation in vitro (35) and in vivo (34); causes IM in humans (11) and a fatal lymphoproliferative disorder in cotton-top marmosets (7, 25); and has been linked to BL (19), NPC (20), and the lymphoproliferative disorders occurring in patients with XLP (31, 32). In renal transplant recipients, oro pharyngeal shedding of EBV occurs in 47 to 87% (5, 42), compared to 17% in normal seropositive individuals (4). In addition, significant rises in antibodies to EBV are common after transplantation (6). Clinical illness due to EBV in these patients, however, has been rarely described (6, 23). The 6 renal transplant patients presented in this report represent a pathobiological as well as clinical spectrum of abnormal lymphoproliferation. These disorders are shown to ' Supported in part by USPHS Grants AM 13083. CA 19527, and CA 23561 ; NIH Grant 1CP 33316; and a grant from the Swedish Cancer Society. 2 To whom requests for reprints should be addressed, at the University of Minnesota, Department of Surgery. Box 171, Mayo Memorial Building, 420 Delaware Street, S. E., Minneapolis, Minn. 55455. 3 Recipient of a Fogarty Senior International Fellowship. Received November 20, 1980; accepted March 13, 1981. ' The abbreviations used are: ML, malignant lymphoma; RCS, reticulum cell sarcoma; CNS, central nervous system; EBV, Epstein-Barr virus; IM, infectious mononucleosis; BL, African Burkitt's lymphoma; NPC, nasopharyngeal carci noma; XLP, X-linked lymphoproliferative syndrome; ALG, antilymphocyte globu lin; VCA, viral capsid antigen; EA, early antigen; EBNA, Epstein-Barr nuclear antigen; cRNA. complementary RNA; vDNA, viral DNA; PTD, posttransplant day; CMV, cytomegalovirus; HSV, herpes simplex virus; i.e., intracranial(ly). NOVEMBER 1981 4253 on April 21, 2017. © 1981 American Association for Cancer Research. cancerres.aacrjournals.org Downloaded from