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An 8-year-old maternally related relative of three boys who had developed agammaglobulinemia associated with Epstein-Barr virus (EBV)-induced infectious mononucleosis was studied for X-linked lymphoproliferative syndrome (XLP) in 1979. At that time, he demonstrated no striking immunologic aberrations and was seronegative for EBV. Subsequently, immunologic abnormalities including failure to switch from IgM to IgG antibody synthesis after secondary immunization with bacteriophage phi X174 were detected. In 1983, he experienced episodic intracerebral hemorrhages, with the second being fatal. At autopsy, necrotizing vasculitis and aneurysms involving arteries of the central nervous system were observed. Studies of blood obtained immediately before and after death failed to show antibodies to EBV. However, EBV genome was demonstrated in tissues obtained at autopsy by DNA hybridization studies. Fatal lymphoid vasculitis in this patient is unique among boys with XLP in the registry. These findings probably extend the phenotypic expressions of XLP.

Nineteen children who presented with fever, hepato-splenomegaly, bone marrow and/or hepatic failure, and biopsy evidence of histiocytic proliferations were evaluated for lymphocyte dysfunction and evidence of prior viral infection. Seventeen of the children had erythrophagocytosis consistent with the previously described virus-associated hemophagocytosis syndrome (VAHS) or Familial erythrophagocytic lymphohistiocytosis (FEL). The other two had benign histiocytic proliferations in the central nervous system (CNS) with liver and bone marrow dysfunction. There were two sibling pairs and six patients with known disorders of immune deficiency. The remaining nine cases appeared to be sporadic and idiopathic. Epstein-Barr Virus (EBV) was identified in patients by serologic or DNA hybridization studies (15), EBV and cytomegalovirus (CMV) (1), adenovirus plus EBV and CMV (1), or adenovirus and EBV (1). Herpes zoster was associated with reactivation of symptoms in one patient. Immunologic impairment was evidenced by lymphopenia in 10 of 19 patients. More extensive evaluations could be done at diagnosis on only some of the children because the histiocytic proliferative syndrome was not recognized or because there were insufficient numbers of lymphocytes in samples obtained. For those who could be evaluated, the following immune deficiencies were found: decreased lymphocyte proliferation to mitogens (4 of 9), absent or markedly decreased natural killer function (5 of 5), and decreased cytotoxic lymphocyte reactivity to allogenic EBV-infected target cells (3 of 3). A new finding reported here is a higher than expected prevalence of HLA types A30, B8, and A1/B8 among the patients tested.

Oncogenes of retroviruses are directly related to cancers in animals; however, finding relevant associations with human cancer has been difficult. Studies reported here were designed to assess the extent of protooncogene transcription in human leukemias as compared to normal cells. Low-stringency hybridization of viral oncogene DNAs to cell messenger RNAs was done to determine whether evolutionarily divergent oncogene sequences were increased in leukemic cells. Several oncogenes hybridized at low levels to normal messenger RNAs. Some oncogene transcripts in fresh leukemic cells of 28 patients were present at higher levels than in normal cells. The oncogenes abl, erb, myc, and ras were expressed in all normals tested and a majority of the leukemic cells. However, fes, fps, and src probes hybridized rarely to transcripts in normal cells although more frequently to messenger RNA from leukemic cells. No oncogenes were expressed in specific patterns by cell types. It is concluded that transformation of human hematopoietic cells involves more than one oncogene and may include sequences unrelated to retroviruses.

The management of children's tumors has changed significantly in the past several years. New techniques and combined surgical, chemotherapeutic, and radiation approaches are responsible for improved survival in most instances. Cooperation of the surgeon with the specialists in separate disciplines is imperative to continued advancements in neoplastic disease of childhood.

A 12-year-old white female with recurrent Burkitt's lymphoma had a spontaneous remission associated with a localized herpes zoster infection. The remission lasted nearly 2 months before the tumor recurred in the central nervous system. LDH isoenzyme determinations done on an earlier ovarian tumor and serum at time of bone marrow relapse showed different predominant LDH isoenzyme patterns. These data might be interpreted as showing that different malignant cell clones were responsible for ovarian and bone marrow relapses. Studies to elucidate the mechanism of spontaneous remission at the time of zoster infection demonstrated serum factor(s) which stimulated normal B lymphocytes.

We describe the development of Epstein-Barr-virus (EBV)-related lymphoproliferative disease (LPD) in the recipient of a histocompatible bone marrow transplant (BMT). Although this rare complication is more common in recipients of mismatched bone marrow, several distinguishing features of our case may have contributed to the development of LPD in the recipient of a matched bone marrow transplant. The patient had received marrow from a sibling with Trisomy 21, a syndrome associated with variable cellular and humoral immune defects. Our patient also was infected with cytomegalovirus and was treated with immunosuppressant therapy for graft versus host disease. Although development of LPD in transplant recipients is a multifactorial process, either acquired or congenital immunosuppression/dysregulation is a common prerequisite for the process. Our case suggests that subtle immune defects in individuals with Down syndrome may contribute to the immunosuppressed setting in which EBV-related LPD can develop.

Bovine leukemia virus (BLV) is the causative agent of enzootic bovine lymphosarcoma. Much speculation continues to be directed at the role of BLV in human leukemia. To test this hypothesis rigorously, a case-control study of childhood acute lymphoblastic leukemia and non-Hodgkin's lymphoma was conducted between December 1983 and February 1986. Cases (less than or equal to 16 years at diagnosis) derived from patients diagnosed at the primary institutions and affiliated hospitals were matched (age, sex, and race) with regional population controls. DNA samples from bone marrow or peripheral blood from 157 cases (131 acute lymphoblastic leukemia, 26 non-Hodgkin's lymphoma) and peripheral blood from 136 controls were analyzed by Southern blot technique, under highly stringent conditions, using cloned BLV DNA as a probe. None of the 157 case or 136 control DNA samples hybridized with the probe. The high statistical power and specificity of this study provide the best evidence to date that genomic integration of BLV is not a factor in childhood acute lymphoblastic leukemia/non-Hodgkin's lymphoma.

A case of therapy-related myelodysplasia followed by acute nonlymphocytic leukemia in a 5-year-old child successfully treated for diffuse Langerhans cell histiocytosis is described. A syndrome of severe cell-mediated immune deficiency and persistent Epstein-Barr virus (EBV) infection coincided with the evolution of myelodysplasia. Specific abnormalities of chromosomes number 7 and 3 were associated with the onset of myelodysplasia and acute nonlymphocytic leukemia and are believed to be linked to the patient's immune dysfunction and compromised ability to contain viral infection.

Castleman's disease is a morphologically and clinically heterogeneous lymphoproliferative disorder. Both a localized benign variant and an aggressive form with systemic manifestations have been described. To investigate the differences between these variants of Castleman's disease, the authors analyzed lymph node DNA from 4 patients with the localized type and 4 with the systemic type of Castleman's disease for immunoglobulin and T-cell receptor gene rearrangements. The role of Epstein-Barr virus (EBV) and cytomegalovirus (CMV) was also studied by viral genomic DNA probes. They detected clonal rearrangements in 3 of the 4 patients with the systemic variant of Castleman's; no patients with localized disease had rearrangements. Copies of EBV genome were also detected in 2 of the 3 patients with clonal rearrangements. These results suggest that systemic Castleman's disease is a disorder distinct from the classical localized variant in that it may evolve into a clonal lymphoproliferation.