Epstein-Barr Virus in a Malignant Lymphoproliferative Disorder of B-Cells Occurring after Thymic Epithelial Transplantation for Combined Immunodeficiency1

A fatal disseminated polyclonal malignant lymphoproliferative disorder of B-cells (immunoblastic sarcoma) developed shortly after a second thymic epithelial peritoneal implant in a 5-yr-old girl with combined immunodeficiency. The immuno deficiency was characterized by low T-cell numbers and func tion, very low levels of thymic hormone, dysgammaglobulinemia, and an inability to mount a primary antibody or cellmediated response to new antigens. At necropsy, the thymus fulfilled morphological criteria for thymic dysplasia. Epstein-Barr virus (EBV) antigen and DNA were identified in neoplastic infiltrates in the lymph nodes and thymus by ¡mmunofluorescence for the EBV nuclear antigen and by EBV-specific complementary RNA/DNA hybridization. No antibodies to nuclear antigen, early antigen, or viral capsid antigen of EBV were identified in the serum. The concurrence of these events suggests that the thymic epithelial implant itself may have been instrumental in the pathogenesis of this neoplasm. It is proposed that the thymus may have provided factors which indirectly potentiated the proliferation of EBV-infected B-cells, possibly by induction of nonspecific T-helper cells and perhaps through other thymic humoral factors. It is suggested that some forms of immunoblastic sarcoma, even when polyclonal, and especially those which arise in immunocompromised hosts, may, in some instances, represent an opportunistic form of EBV-induced B-cell neoplasia. Fatal B-cell lymphoproliferative disorders complicating trans plantation of cultured thymic epithelium in CID5 have been described recently (3). The authors suggested that EBV may have been responsible for the induction of the neoplasm in a manner similar to that proposed in XLP (25). Studies to test this postulate were not performed. This report documents the presence of EBV in neoplastic cells of a malignant B-cell lymphoproliferative disorder (immu1This is Publication 81-004 of the McGill University-Montreal Children s Hospital Research Institute. 2 Supported by the Nathan Steinberg Family Foundation. To whom requests for reprints should be addressed. 3 Supported by Grant MA 5518 from the Medical Research Council of Canada and a grant from the National Cancer Institute of Canada. 'Supported by Grant CA-19014 from the National Cancer Institute of the U. S. A. 5 The abbreviations used are: CID, combined immunodeficiency; EBV, EpsteinBarr virus; XLP, X-linked lymphoproliferative syndrome; ERFC, E rosette-forming cells; EBNA. Epstein-Barr virus nuclear antigen; EA, early antigen; VCA. viral capsid antigen. Received November 20, 1980; accepted April 21, 1981. noblastic sarcoma) in a patient with CID following implantation of cultured thymic epithelium. Because of the close temporal relationship between thymic epithelial implantation and the clinical emergence of the neoplasm, the possible pathogenetic role of the thymic epithelium as a contributing factor in B-cell neoplasia is discussed. Materials and Methods Case Report. Immunologies! studies were performed on C. C., a white female, at the age of 2 years, because of persistent Hemophilus influenza pneumonia and hyper-lgA dysgammaglobulinemia. She was born at term to a mildly preeclamptic Para 1 Gravida 1 mother. There was no family history of immunodeficiency, and consanguinity was denied. Previous hospital admissions, beginning at 3 months of age, were for failure to thrive, gastroenteritis, anemia, persistent thrush, conjunctivitis, and bronchopneumonia. She had received 4 immuniza tions with diphtheria-pertussis-tetanus (DPT) and one of rubeola-rubella. At the time of these studies, no abnormalities were noted on physical examination. Immunoglobulins (mg/dl) were: IgG (1950); IgM (55); IgA (1620); and IgD (20). IgE was 20 ID/ml. The IgA was polyclonal on ¡mmunoelectrophoresis. Antibody titers were; rubella, 1: 256; diphtheria, 1:320; tetanus, nil; anti B, nil (Blood Group A, Rh positive). (The diphtheria titer subsequently became undetectable.) Classical and alternative pathway hemolytic complement were normal. Delayed skin tests to Monilia and dermatophytin were positive, and the Schick skin test indicated immunity. ERFC were 20%, and cells bearing surface membrane immunoglobulin were 14%. There was virtually no mitogen response to phytohemagglutinin, concanavalin A, pokeweed mitogen, and allogeneic cells. Thymic hormone (measured by M. Dardenne, Paris, France) was 1:8 (very low for age). Incubation of lymphocytes with thymosin fraction V (provided by A. Goldstein, Wash ington, D. C.) effected a 7% augmentation of ERFC. Lymphocyte adenosine deaminase and nucleoside phosphorylase were present in normal to elevated levels. Typhoid immunization elicited no antibody response; sensitization to dinitrochlorobenzene was negative. HLA typing of blood lymphocytes revealed A2, A28, B18, and BW54. Subsequent admissions were for 3 episodes of pneumococcal septi cemia with different serotypes, recurrent otitis, pneumonia, staphylococcal infections, intractable diarrhea, and severe, prolonged varicella. Cultured thymic epithelium was given i.p. at 3 years, 10 months and at 4 years, 9 months of age. One day following the first thymic implantation, the percentage of B-cells increased to 48% with all heavy chain classes represented. This subsequently declined, while the per centage of ERFC doubled. Prior to the second thymic epithelial graft, the percentage of B-cells was again elevated to 35%, and the serum IgA was 6000 mg/dl. Immediately following the graft, the percentage of ERFC again increased, and there was a small increase in the response to phytohemagglutinin and concanavalin A (Table 1). Three weeks following the second graft, the patient became febrile, devel oped generalized progressive lymphadenopathy, hepatosplenomegaly.