Disseminated intravascular coagulation (DIC) is associated with organ failure and it is often fatal condition. The main underlying diseases are infection, hematological malignancy and solid cancer. DIC is subclassified into overt DIC and non-overt DIC. The International Society on Thrombosis and Haemostasis (ISTH) and the Japanese Association for Acute Medicine (JAAM) published the diagnostic criteria for DIC after several recent clinical trials. These diagnostic criteria are modified versions of the Japanese Ministry of Health, Labor and Welfare (JMHLW) criteria. The JAAM diagnostic criteria demonstrated excellent sensitivity for mortality but low specificity. The mechanisms of onset of DIC vary based on the underlying diseases, and depend on tissue factor, cytokines, etc. Early diagnosis and early treatment for DIC are important, and the use of hemostatic molecular markers is necessary to successfully make an early and rapid diagnosis. The mortality of DIC might be improved by the administration of recombinant activated protein C or recombinant thrombomodulin. Further investigation to improve the mortality of DIC is required, including new methods for diagnosing and treating the disease. [J Clin Exp Hematopathol 51(2) : 67-76, 2011]

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Toll like receptor (TLR), one of the key functions of innate immune system, can recognize not only exogenous pathogen-associated molecular patterns, namely PAMPs, but also endogenous molecules created upon tissue injury, sterile inflammation and degeneration. Endogenous TLR ligands are called as damage-associated molecular patters (DAMPs), including endogenous molecules released by activated and necrotic cells, and extracellular matrix molecules. DAMPs are also known as alarmins. TLR research has brought about new insights in the rheumatic diseases. Previous reports suggest that TLRs and the signal pathways intensively contribute to the pathogenesis of rheumatoid arthritis (RA) and other arthritic conditions with interaction of various TLR ligands. Accumulated knowledge of TLR system is summarized to overlook TLRs and the signaling pathway in arthritis conditions, with special reference to RA. [J Clin Exp Hematopathol 51(2) : 77-92, 2011]

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Primary central nervous system lymphoma (PCNSL) is one of the most aggressive malignant lymphomas with a median survival of less than 20~40 months. Interest in signal transducer and activator of transcription 3 (Stat3) has increased during the past decade because Stat3 activation was found to contribute to tumor progression by inducing angiogenesis, immunosuppression, and metastasis. We previously demonstrated a significant correlation between Stat3 activation in tumor cells and infiltrating anti-inflammatory (M2) macrophages. Here, we focused on the phenotypes of infiltrating macrophages/microglial cells and Stat3 activation in PCNSL cells. The correlation of Stat3 activation or density of M2 macrophage infiltration with patient prognosis was also evaluated. We performed immunostaining for CD68, CD163, CD204, and pStat3 using paraffin-embedded PCNSL specimens obtained from 43 patients. CD163 and CD204 served as markers of the M2 phenotype. Dense infiltration of CD68⁺ macrophages was found in all samples. High numbers of CD163⁺ and CD204⁺ M2 macrophages/microglial cells were observed in 29 and 25 cases, respectively. Stat3 activation in lymphoma cells was enhanced in the patients who showed denser infiltration of CD163⁺ macrophages/microglial cells in tumor tissues. In vitro co-culture experiment to investigate cell-cell interactions between macrophages and lymphoma cells found that Stat3 in lymphoma cells was strongly activated by co-culture with macrophages. Numbers of CD68⁺, CD163⁺, and CD204⁺ tumor-associated macrophages/microglial cells (TAMs) and Stat3 activation in lymphoma cells were not correlated with prognosis. However, because Stat3 involvement in tumor development was demonstrated in several malignant tumors, our present finding that cell-cell interactions of M2 macrophage/microglial cells with lymphoma cells induced Stat3 activation may provide novel insights into PCNSL pathogenesis. [J Clin Exp Hematopathol 51(2) : 93-99, 2011]

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Disseminated intravascular coagulation (DIC) is a clinical entity with high mortality and is characterized by multiple organ failure caused by activation of systemic intravascular coagulation. Although a standard treatment for DIC has not been established owing to the absence of randomized controlled trials, recent reports have indicated that recombinant human soluble thrombomodulin (rTM) is effective against DIC. To elucidate the clinical characteristics and outcomes of DIC, we retrospectively analyzed 35 DIC patients treated with rTM at our institution over a 2-year period (infectious disease: 21 cases; hematological disease: 14 cases). Diagnosis of DIC was based on the diagnostic criteria for DIC of the Japanese Ministry of Health and Welfare. In addition to the treatment of underlying diseases, we administered rTM for 6 consecutive days. Twenty-one (60.0%) of the DIC patients attained resolution of DIC at 7 days after administration (infectious disease: 61.9%; hematological disease: 57.1%). Furthermore, 7 of the remaining 14 DIC patients (who did not attain resolution at 7 days) attained resolution at an average of 12.1 days. Consequently, 28 (80.0%) of the 35 patients were alive with resolution of DIC after a 28-day observation period (infectious disease: 76.2%; hematological disease: 85.7%). Among them, for 7 (70%) of the 10 DIC patients with severe life-threatening bleeding symptoms without hemorrhagic shock, treatment with heparin was contraindicated; these patients were successfully treated with rTM without the progression of hemorrhage. In the majority of DIC patients, rTM administration may be an effective, safe, and feasible therapeutic modality producing a good outcome. [J Clin Exp Hematopathol 51(2) : 101-107, 2011]

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The prognosis of adult Burkitt lymphoma (BL) has improved in western countries since the introduction of high-dose methotrexate (HD-MTX)-containing chemotherapy. Here we analyzed nine consecutive Japanese patients diagnosed with BL at our institution. All except for the three elderly (> 70 years) patients were treated with a regimen including 13 g/m² HD-MTX in total, divided into 3 cycles. The median follow-up period was 56 months (range 38-118). All the nine patients achieved complete remission and have not shown any disease progression, including the three elderly patients who received reduced doses or alternative treatments. These observations suggest that chemotherapy including 13 g/m² HD-MTX in total is tolerable and effective in Japanese adult BL patients aged < 70 and that BL is curable even if developed in those who are > 70 years. [J Clin Exp Hematopathol 51(2) : 109-114, 2011]

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Fournier's syndrome is the fulminant necrotizing fasciitis of the external genitalia. The occurrence of Fournier's syndrome in patients with hematologic malignancies has been reported. Here we report a case of an intravascular lymphoma complicated with Fournier's syndrome due to multidrug-resistant Pseudomonas aeruginosa (MDRP). A 71-year-old Japanese man received intensive chemotherapy for recurring intravascular lymphoma. Blood culture revealed MDRP, and physical examination led to the diagnosis of Fournier's syndrome. Aggressive treatment that comprised granulocyte transfusion, granulocyte stimulating factor, endotoxin filtration, appropriate antibiotic coverage, and aggressive surgical therapy was administered, and this lead to the successful recovery from sepsis and Fournier's syndrome. [J Clin Exp Hematopathol 51(2) : 115-118, 2011]

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A 74-year-old man was admitted to hospital because of persistent fever, diarrhea, and abdominal pain. CT scanning showed extensive wall thickening of the colon. He was transferred to our hospital because he further developed ascites and paraaortic lymph node swelling. On presentation, he was extremely emaciated with superficial lymph node swelling, ascitic signs, and leg edema. Histological image of a biopsied mesenteric lymph node demonstrated diffuse infiltration of large abnormal T cells. Surface antigen analysis of abnormal cells in the ascites revealed positivity for CD3, CD8, CD56, and weak positivity for CD103. Polymerase chain reaction analysis showed monoclonal rearrangement of the T cell receptor (TCR) gene. The subtype of TCR was αβ. A diagnosis of enteropathy-associated T cell lymphoma (EATL) type II was made. The lymphoma involved the bone marrow. The patient also had severe hemolytic anemia with a positive Coomb's test result. An additional diagnosis for autoimmune hemolytic anemia (AIHA) was made, which was resistant to methylprednisolone therapy. We first treated him with only vincristine in addition to the steroid to avoid acute tumor lysis syndrome ; however, he died of septic shock that occurred soon after vincristine administration. To the best of our knowledge, this may be the first reported case of EATL complicated by AIHA. [J Clin Exp Hematopathol 51(2) : 119-123, 2011]

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In 2000, a 48-year-old woman developed a left orbital mass with lacrimal gland involvement and then, in 2003, a right orbital mass with lacrimal gland involvement, both of which were diagnosed as extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). She underwent 30 Gy external beam radiation to bilateral orbital lesions. The lymphoma cells in both lesions did not share the same clonality, as shown by amplification by polymerase chain reaction of the immunoglobulin heavy chain gene. Immunoglobulin light chain analysis by immunohistochemistry and messenger RNA in situ hybridization showed λ chain monotype in the left orbital lesion but κ chain monotype in the right orbital lesion. She developed recurrent left orbital mass with high uptake on fluorodeoxyglucose positron emission tomography fused with computed tomography in 2010, and excisional biopsy disclosed the formation of follicles and infiltration with immunoglobulin G4 (IgG4)-positive plasma cells mainly in interfollicular areas. The immunoglobulin light chain analysis showed the λ chain and κ chain bitype. With the immunohistopathological diagnosis of IgG4-related disease, the serum IgG4 level was found to show elevation at 376 mg/dL, and the patient chose observation. This is the first reported case of development of IgG4-related disease after bilataral orbital MALT lymphoma with external beam radiotherapy. [J Clin Exp Hematopathol 51(2) : 125-133, 2011]

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A 30-year-old man was referred to our hospital with leukocytosis and fecal occult blood. His white blood cell count was 30.2 × 10⁹/L with 79% small- to medium-sized lymphocytes. Surface antigen analysis revealed that these lymphocytes were positive for CD19, CD20, CD10, and CD23, but negative for CD5. The lymphocytes infiltrated the bone marrow. On endoscopic examination of the duodenum and jejunum, many small polypoid lesions were observed. A histologic picture of a biopsied lesion showed diffuse infiltration of small- to medium-sized lymphocytes in the submucosal region. On immunohistochemistry, these lymphocytes were positive for CD20, BCL2, and CD10 (weakly). Polymerase chain reaction analysis of cells from peripheral blood, bone marrow, and intestinal lesion showed a fusion product of BCL2 and immunoglobulin heavy chain (IGH) genes. The fused BCL2/IGH gene was also demonstrated by fluorescence in situ hybridization in the same cell sources. Computed tomography scanning showed marked wall thickening throughout the small intestine and enlarged mesenteric lymph nodes. A diagnosis of follicular lymphoma with massive intestinal involvement in a leukemic state was made. After 6 courses of rituximab-combined CHOP chemotherapy, complete remission was obtained. [J Clin Exp Hematopathol 51(2) : 135-140, 2011]

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Deletion of the long arm of chromosome 20 (del 20q) has been observed in patients with myelodysplastic syndrome (MDS) or myeloid malignancies. We experienced an MDS female case of del 20q accompanied by clusters of plasmacytic cells in bone marrow. Her bone marrow cells showed morphological abnormalities in three lineages and the chromosomal abnormality of 46, XX, del (20) (q11.2q13.3). Although the percentage of plasma cells was low in free cells, such cells showed nuclear abnormalities. In bone marrow clots, we also observed clusters of anti-CD38 and anti-CD138 antibody-positive cells. According to the FAB or WHO classification, the diagnosis was unclear. Therefore, we were obliged to term this case as MDS with plasma cell dysplasia. This patient was considered to be a rare case of MDS related to abnormalities in myeloid and B-lymphoid cells. [J Clin Exp Hematopathol 51(2) : 141-145, 2011]

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