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An 18-year-old man was admitted to our hospital because of 39 degrees C fever for over one month, marked hepatosplenomegaly, and pancytopenia. Malignant histiocytosis, malignant lymphoma, or hemophagocytic syndrome were ruled out by bone marrow aspiration and liver biopsy. A diagnosis of chronic EB virus infection was made according to his characteristic clinical features, abnormally high titiers of anti-EBV antibodies (VCA-IgG x 2560, EA-IgG x 1280), and the detection of EBV genome in the peripheral blood mononuclear cells by polymerase chain reaction. He also manifested granular lymphocyte proliferative disorder (GLPD). The phenotype of the proliferating granular lymphocytes was CD2 (+), CD3 (-), CD56 (+), and IL-2R beta (+), showing the NK lineage of these cells. Chromosomal abnormality of the cells cultured for a short time with IL-2 and a monoclonal junctional DNA structure of EB virus terminal repeat analyzed by the Southern blotting provided definitive evidence for the monoclonal expansion of the granular lymphocytes. These findings indicate a causative role of EV virus in NK-GLPD or NK-leukemia.

The 9-year-old boy was admitted to Shizuoka Children's Hospital because of cervical lymphoadenopathy. Complete blood count showed normal RBC and platelet counts. WBC was 2700/microliters with no tumor cells. Bone marrow aspirate showed normocellularity with 34% tumor cells. Lymph node biopsy from his right neck was performed and the patient was diagnosed as non-Hodgkin's lymphoma (lymphoblastic type). Surface marker analysis disclosed that the tumor cells were positive for CD5, CD7, CD19, CD38, CD71, and Ia antigen. Chromosomal analysis of the cervical lymph node revealed 46, XY, t(7;14) (p15;q32). Molecular investigation with appropriate probe showed germ-line configurations of IgH gene, TcR beta gene, and TcR gamma gene, and one rearranged band of TcR delta gene. Monoclonality of tumor cells was demonstrated from chromosomal analysis and molecular study. CD7 and CD19 are not lineage specific antigens because CD7 is expressed on immature AML cells and CD19 is expressed on T ALL cells or AML cells. Moreover, TcR delta rearrangement is considered to occur at early phase of hematolymphoid cells. Based on these data, tumor cells of this patient is considered to originate from immature lymphoid cell, so-called lymphoid stem cell.

We have treated two pediatric patients with refractory ANLL and four with relapsed high-risk ALL with Adriamycin continuous Ara-C i.v. Four out of six patients were able to enter complete remission after first or second course of the treatment. All of them developed severe bone marrow suppression, and various degree of oral mucositis, liver dysfunction and gastrointestinal toxicity, and two patients died from side effects. Recently this combination chemotherapy is becoming a best regimen for the treatment of untreated ANLL. Although our cases are small in number, this combination therapy also seems to be effective for refractory ANLL and relapsed high-risk ALL. It is needless to say that we have to pay more attention when we use this regimen.

Recent recombinant DNA techniques have made possible the production of gene probes and the search for genetic damage in neoplastic cells, and now occupy one of the central place in cancer research. More recently, detection of immunoglobulin and T cell receptor gene rearrangements has been shown to be a powerful procedure for identifying monoclonality and the cellular lineage of lymphoid cells even when conventional studies give an ambiguous diagnosis. Such genetic markers are not only useful for differential diagnosis and classification, but serves also as a sensitive unique clonal marker to detect early cancer relapse. In a similar manner, chromosomal translocations associated with specific disease types can be detected with DNA probes in southern blot analysis without the use of conventional cytogenetics. These methods have wider application and will play an increasing role in the clinical use in the near future.