Tatsuharu Ohno

Fulminant clonal expansion of large granular lymphocytes: Characterization of their morphology, phenotype, genotype, and function

A 39‐year‐old woman exhibited abrupt malignant transformation of the large granular lymphocytes (LGL) after a chronic course of Tγ‐lymphoproliferative disease (Tγ7‐LPD). The Tγ‐lymphocytes were CD2+, CD3‐, CD8‐, CD16+, Leu7‐, and Leul9+ with morphologic characteristics of LGL. Newly appearing LGL were much larger and had more prominent azurophilic granules. Although fundamentally they had the same phenotype as the LGL in chronic stage, they showed increased la‐like antigen and decreased CD16 antigen expressions. Immunoglobulin (Ig) G‐kappa type monoclonal component was detected in the patients serum. The LGL showed a germ‐line configuration for T‐cell receptor (TCR) beta and gamma chain genes, whereas the clonal chromosomal abnormalities indicated the neoplastic nature of the LGL. The LGL exhibited competent natural killer (NK), interleukin 2 (IL2) activated killer (AK), and antibody‐dependent cell‐mediated cytotoxicity (ADCC) activities. The LGL may have derived from NK cells at their mature stage with prethymic phenotype and may have influenced the homeostasis of the patients humoral immune response.

The Serum Cytokine Profiles of Lymphoma-associated Hemophagocytic Syndrome: A Comparative Analysis of B-Cell and T-Cell/Natural Killer Cell Lymphomas

To elucidate the differences in pathogenesis between lymphoma-associated hemophagocytic syndromes (LAHS) of theT-cell/ natural killer cell (T/NK) and B-cell (B) types,we comparatively analyzed the clinical features and serum cytokine profiles of 33 patients with LAHS registered in the Kyoto University Hematology/Oncology Study Group.The serum cytokine levels of each patient group (B-LAHS versusT/NK-LAHS) were expressed as the ratio of the median to the upper normal values of the respective cytokines and were as follows: 19.05 versus 13.99 for soluble interleukin 2 (IL-2) receptor, 0.67 versus 0.67 for granulocytemacrophage colony-stimulating factor (GM-CSF), 0.64 versus 1.26 for G-CSF, 5.70 versus 3.61 for M-CSF, 1.54 versus 3.39 for interferon γ (IFN-γ), 13.17 versus 1.17 for IL-6, 6.88 versus 1.58 for tumor necrosis factor α (TNF-α), 0.71 versus 0.41 for IL-1, 1.99 versus 0.21 for IL-12, and 105.32 versus 29.65 for IL-10.The serum levels of IL-6,TNF-α, and IL-10 were significantly higher in the B-LAHS group,whereas those of IFN-γ were significantly lower. These differences between the 2 groups may reflect a difference in the pathogenesis. Higher serum levels of IL-6, TNF-α, and IL-10 may be derived at least partly from neoplastic B-cells themselves. In addition, the extremely high serum levels of IL-10 suggest that a compensatory anti-inflammatory process may operate in both groups and give rise to a profound immunosuppressive state and a poor outcome.

Leukemic and meningeal relapse of CD5+ intravascular large B-cell lymphoma with down-modulation of CD20 after rituximab therapy

Although CD20- relapses of B-cell lymphoma following rituximab therapy have increasingly been reported recently, coexistence of both the original and selected clones on relapse in a single patient have not been described. We experienced such a case with rare CD5+ intravascular lymphomatosis (IVL). A 46-year-old woman was admitted because of IVL complicated with cauda equina syndrome and pulmonary infarction. Complete remission was successfully achieved with multidrug chemotherapy in combination with rituximab. However, the disease recurred after 8 months with leukemic progression and meningeal involvement. The phenotype of the abnormal lymphocytes in the peripheral blood was fundamentally the same (CD20+CD5+CD10-CD19+CD23-sIgλ+) as that of the cells in the cerebrospinal fluid (CSF). However, CD20 expression was decreased remarkably compared with that in the CSF and that in the bone marrow before therapy. The targeting of CD20 molecules on the tumor cell surface by rituximab may have provided a selective pressure on lymphoma cells. The escape phenomenon of the lymphoma cells from rituximab was observed by simultaneously comparing the CD20 expression of cells in the peripheral blood and in a site of sanctuary from rituximab, the CSF.

Chronic myeloid leukemia with minor‐bcr breakpoint developed hybrid type of blast crisis

Although a breakpoint in the minor breakpoint cluster region (m‐bcr) of the BCR gene is observed in about two‐thirds of patients with Philadelphia chromosome‐positive acute lymphoblastic leukemia, this type of genomic rearrangement occurs very rarely in chronic myeloid leukemia (CML). We describe here the eighth case of m‐bcr CML, and delineate unique clinical characteristics found in common to the 7 cases reported previously. Monocytosis with a low neutrophil/monocyte ratio resembling chronic myelomonocytic leukemia was the most striking feature of m‐bcr CML. Splenomegaly and basophilia were not conspicuous in chronic phase. A high percentage of immature granulocytes and low neutrophil alkaline phosphatase score were the findings in common with classical CML. Lymphoid and myeloid blast changes have been observed at and shortly after presentation so far. We found a hybrid type of blast crisis in the course of m‐bcr CML.Thus, m‐bcr CML may be a definite subtype of CML, exhibiting distinct clinical characteristics. The presence of fusion product of m‐bcr mRNA in an earlier myeloid cell may involve monocytic lineage in addition to myeloproliferative defects. Am. J. Hematol. 57:320–325, 1998.

MALT lymphoma of the thymus with Sjögren’s syndrome: biphasic changes in serological abnormalities over a 4-year period following thymectomy

Thymic mucosa-associated lymphoid tissue (MALT) lymphoma shows distinct immunological characteristics, such as the expression of the IgA isotype, the frequent presence of immunoglobulin abnormalities, and a strong association with autoimmune disease, especially Sjögren’s syndrome (SjS). We report a case of thymic MALT lymphoma, who exhibited biphasic changes in her clinical characteristics during the 4-year observation period after thymectomy. A 71-year-old woman was admitted because of suspected SjS. A diagnosis of primary thymic MALT lymphoma was made, and SjS was confirmed. Serological abnormalities such as polyclonal hypergammaglobulinemia, IgA M protein, and elevated levels of rheumatoid factor were noted. These abnormalities improved rapidly after the thymectomy, but did not completely disappear. Interestingly, the remaining abnormalities, which can be ascribed to the proliferation of B cells throughout the body under the influence of SjS, have been improving slowly but steadily during the 4-year observation period. It is suspected that the removal of the tumor by thymectomy has more or less normalized the immunological environment and alleviated the SjS disease activity.

The physicochemical properties and the process of pyrogel formation of IgD pyroglobulin.

The extremely rare IgD pyroglobulin caused opalescence, lost its antigenicity and acquired more negative charge when heated for 30 min at 56 degrees C. Exposure to 60 degrees C for 60 min produced a firm gel. The thermoprecipitability was abolished by the treatment with guanidine, urea and sodium dodecyl sulfate, but not by 2-mercaptoethanol or neuraminidase, and required the presence of both heavy and light chains. However, amino acid analysis showed abnormalities only in the heavy chain. We hypothesize that the irreversible heat-induced aggregation of IgD pyroglobulin is the result of a conformational change, triggered by light chain, which increases the molecular hydrophobicity.

Concurrent Autoimmune Neutropenia and Idiopathic Thrombocytopenic Purpura Associated with IgG4-related Diease

IgG4-related disease (IgG4RD) is a multi-organ disorder characterized by an elevated serum IgG4 level and IgG4-positive plasma cell infiltration of the affected organs, accompanied by tissue fibrosis and sclerosis. Although it can affect any organ, to our knowledge, no cases involving concurrent autoimmune neutropenia and thrombocytopenia have been reported. A 62-year-old man visited our hospital and was diagnosed with IgG4RD accompanied by interstitial pneumonitis, lymphadenopathy, and interstitial nephritis. During his clinical course, he developed autoimmune neutropenia and idiopathic thrombocytopenic purpura. Our case, invoving multiple hematological abnormalities, might help deepen our understanding of the pathophysiology of IgG4RD.

Sequential Use of Second-Generation Tyrosine Kinase Inhibitor Treatment and Intensive Chemotherapy Induced Long-Term Complete Molecular Response in Imatinib-Resistant CML Patient Presenting as a Myeloid Blast Crisis

Myeloid blast crisis of chronic myeloid leukemia (CML-MBC) is rarely seen at presentation and has a poor prognosis. There is no standard therapy for CML-MBC. It is often difficult to distinguish CML-MBC from acute myeloid leukemia expressing the Philadelphia chromosome (Ph+ AML). We present a case in which CML-MBC was seen at the initial presentation in a 75-year-old male. He was treated with conventional AML-directed chemotherapy followed by imatinib mesylate monotherapy, which failed to induce response. However, he achieved long-term complete molecular response after combination therapy involving dasatinib, a second-generation tyrosine kinase inhibitor, and conventional chemotherapy.

Adult respiratory distress syndrome complicating hematological diseases

To the Editor: There are reports on patients who suddenly develop respiratory failure in the absence of cardiac failure during treatment for hematological diseases (HRRF) and die unless appropriately treated (1,2). HRRF resembles adult respiratory distress syndrome (ARDS) in terms of pathology, but its pathogenesis remains unclear (3). Between December 1987 and December 1991,522 patients were admitted to the 2nd Department of Internal Medicine, Mie University School of Medicine due to hematological diseases, of whom 22 who developed dyspnea in the absence of cardiac failure and showed an increase in the alveolar arterial carbon dioxide tension difference (AaDO,) and extensive bilateral shadows on chest X-ray films were evaluated for clinical findings, treatment methods, and outcome. Patients with leukostasis or mixed infection in the terminal clinical stage were excluded from the study. HRRF developed in 22 of 522 patients, the incidence being 4.2%. Thirteen patients were male and 9 female. Their ages ranged from 17 to 67 yr (median, 54.5 yr). The underlying disease was blood tumor in all patients, and non-Hodgkin lymphoma (NHL) was the most frequently observed (12 patient s). The clinical symptoms, fever, dry cough, and progressive dyspnea, were observed in all patients. HRRF developed most frequently during induction of remission (13 patients) followed by during remission (4 patients). In all patients, the onset was relatively early after the initiation of treatment; this tendency was marked in NHL. The interval between the final chemotherapy and the onset was 2-60 d (median, 10 d). The interval between the nadir and the onset was 3-24 d (median, 4.5 d), and the disease tended to develop in the leukocyte recovery process from the nadir. Determination of partial blood gas tensions at the onset showed a PO, of 33.2-67.1mmHg (mean, 54.8 mmHg), PCO, of 24.7-53.3 mmHg(niean, 34.3 mmHg), and AaDO, of 29.0-74.5 mmHg (mean, 52.4 mmHg). AaDO, was increased in all patients. The leukocyte count at the onset was 130-24280/~1 (mean 5256/pl). The patient showing a high leukocyte count of 24 280/pl had chronic myelomonocytic leukemia. X-ray examination showed bilateral diffuse shadows. For HRRF, pulse therapy (methylprednisolone 500-1000 mg/d x 3 d + tapering) was performed alone in 3 patients and in combination with administration of anti-cytomegalo high titer gamma globulin (total dose, 15 g) in 6 patients. The two methods were combined with sulfamethoxazole-trimethoprim (ST) mixture (9-12 T/d) administration in 9 patients and administration of ST mixture and an antituberculous drug (INH or STM) in 4 patients. The cure rates in the 4 treatment groups were 100, 83, 100, and 7 5 % , respectively. One patient with multiple myeloma (Pulse therapy + anti-cytomegalo high titer gamma globulin) and 1 with B-CLL (pulse therapy + anti-cytomegalo high titer gamma globulin + ST mixture + antituberculous drug) died of respiratory failure. The cure rate was 91 %. The fact that HRRF developed in the recovery process of bone marrow from the nadir after administration of anti-cancer drugs seems to be important to clarify the pathogenesis of this disease. One case is presented. Respiratory failure that suddenly develops during the course of hematological diseases is considered to be the same pathologic state as ARDS because of common clinical characteristics and high responsiveness to steroids (3). ARDS is characterized by severe dyspnea that develops suddenly, and its pathology is considered to be permeability-enhanced pulmonary edema. As its pathogenesis, studies have shown neutrophils aggregated in the pulmonary capillaries in experimental pulmonary edema produced with phorbol myristate acetate (4), neutrophil accumulation in the lungs by complement activation ( 5 ) , leukocyte aggregation in the lungs in patients with ARDS (6), enhancement of neutrophil adhesion by endotoxin (7), enhancement of the permeability of the pulmonary vessels (8), and increases in thromboxane A, and leukotriene, which increase vascular permeability, due to platelet aggregation by endotoxin (9). In our patients, respiratory failure devel-

Nucleolus-associated J chains in myeloma cells: Clinical significance

Bone marrow aspirates from 20 patients with multiple myeloma (MM), 4 with smoldering multiple myeloma (S‐MM), 1 with idiopathic Bence Jones proteinuria (I‐BJP), and 6 with primary macroglobulinemia (PMG) were examined for nucleolus‐associated J chain. The incidence of nucleolar J chain‐positive (J +) cells among nucleolated cells producing M‐component was measured. This incidence (94.0–100%) in terminal MM was significantly higher than that (0–58.0%) in non‐terminal MM. Judging from a low incidence in the remission phase, chemotherapy might cause a selective elimination of less differentiated myeloma cells with J + nucleoli and might have some effect on J chain synthesis. The incidence of nucleolar J+ cells was very low in S‐MM. The IgM cells in PMG, where J chain is present in a disulfide‐linked form, had no or few J+ nucleoli. No correlation between the incidence of nucleolar J + cells among nucleolated plasma cells and the percentage of nucleolated cells or that of J + cells was found. Large J + nucleoli seemed to be another morphological feature indicating anaplastic myeloma cells. A high incidence of nucleolar J + cells may be one of the indicators for progressive disease.