[CD5-positive diffuse large B-cell lymphoma with gastrointestinal infiltration presenting with protein-losing enteropathy].

Protein-losing enteropathy is rarely associated with malignant lymphoma. This report describes the case of a 67-year-old man with diffuse large B-cell lymphoma (DLBCL) and concomitant protein-losing enteropathy who was admitted to our hospital for evaluation of watery diarrhea, edema, and abdominal fullness. On admission, the patient reported a history of weight gain. Subsequent examination showed ascites, hepatosplenomegaly, and hypoalbuminemia. Notably, 99mTc-labeled human serum albumin scintigraphy revealed protein loss from the intestine, and the patient was diagnosed with protein-losing enteropathy. Endoscopy revealed erosive and edematous hyperplasia of the gastric-colonic mucosa, and histopathological evaluation of a biopsy specimen showed proliferation of CD20+ and CD5+ tumor cells. Thus, the diagnosis of DLBCL was histopathologically confirmed. Lymphomatous infiltration of the bone marrow was observed; however, no lymphadenopathy was detected. Based on these findings, the patient was diagnosed with protein-losing enteropathy associated with gastrointestinal infiltration of CD5+ DLBCL. Hypoalbuminemia and diarrhea improved following the initiation of R-CHOP regimen. The DLBCL showed a favorable response to treatment, and gastrointestinal lesions and hepatosplenomegaly improved, along with the resolution of protein-losing enteropathy.

Virus-infected peripheral blood plasmablasts in a patient with severe fever with thrombocytopenia syndrome.

Severe fever with thrombocytopenia syndrome (SFTS) is a tick-borne viral hemorrhagic disease with a high fatality rate. It is caused by the SFTS virus and is endemic in East Asian countries such as China, South Korea, and Japan. Previous studies have shown that plasmablasts appear transiently in peripheral blood during the acute phase of SFTS, but do not specify the characteristics of these plasmablasts. In this report, we describe the features of peripheral blood plasmablasts in a patient with SFTS. Immunohistochemical and immunofluorescence staining detected a small number of atypical lymphocytes expressing the SFTS virus antigen among peripheral leukocytes in a blood sample. The phenotype of the virus-infected cells was CD27+, CD38+, MUM1+, and CD138+, which is consistent with that of plasmablasts. This novel study demonstrates that plasmablasts in the peripheral blood of patients with SFTS are targets of the SFTS virus.

[Acute thrombocytopenia after obinutuzumab administration in a patient with relapsed follicular lymphoma].

A 64-year-old woman was admitted to our hospital because of relapsed follicular lymphoma. Obinutuzumab (OBZ) and bendamustine (GB) therapy was administered for her lymphoma, and thrombocytopenia requiring platelet transfusion was observed after the first course. Although the dose of bendamustine had been reduced, her thrombocytopenia was observed again after the second course. Complete remission of her lymphoma was achieved after 4 courses of GB therapy, and the patient was switched to OBZ maintenance therapy. Nevertheless, thrombocytopenia was observed again during the maintenance therapy with OBZ alone. Observing the platelet count that changed over time after OBZ administration in detail, the platelet count started to decrease 1 hour after the end of OBZ administration, decreased to half after 6 hours, reached the lowest value 4 days after administration, and gradually recovered from 10 days after administration. Although OBZ administration-associated thrombocytopenia is a relatively common complication, acute thrombocytopenia up to 24 hours after administration is rare. However, as in this case, thrombocytopenia may progress in an extremely short time after administration, and it is necessary for clinicians to pay attention to OBZ treatment.

Transient Appearance of Plasmablasts in the Peripheral Blood of Japanese Patients With Severe Fever With Thrombocytopenia Syndrome.

Atypical lymphocytes in the peripheral blood in patients with severe fever with thrombocytopenia syndrome (SFTS) have not been well examined. In this study, we analyzed counts and characteristics of atypical lymphocytes in 7 patients with SFTS. Atypical lymphocytes resembled plasma cells morphologically and appeared in the peripheral blood of all patients 4-8 days after onset of disease. Among these lymphocytes flow cytometry showed a CD19+CD38+CD138-/+ phenotype, and immunohistochemical staining revealed a CD79a+CD38+CD138-/+CD27+ phenotype. From our observations, atypical lymphocytes transiently that appeared in the peripheral blood during the acute phase of SFTS were considered to be plasmablasts.

[Successful treatment with rituximab for type III cryoglobulinemia].

A 71-year-old man with rheumatoid arthritis was referred to our hospital with complaints of face and leg edema and was admitted for management of acute renal failure. Type III cryoglobulinemia was diagnosed based on histopathological findings of a kidney biopsy which revealed cryoglobulinemic nephropathy. Immunofixation showed no serum M-proteins. Steroid pulse and apheresis were initiated but the proteinuria did not improve. Rituximab was administered four times weekly as a second-line treatment, eliminating the proteinuria, after which the steroid dose was gradually tapered until discontinuation. No recurrence of proteinuria was observed more than 1 year after termination of rituximab therapy. This suggests that rituximab exerts a long-term effect. Although this patient developed candidiasis during rituximab therapy, the therapy could be continued as the antifungal agents prevented exacerbation of the infection. Rituximab can be used for the treatment of steroid-refractory cryoglobulinemia. However, clinicians should remain aware of possible infections associated with immunosuppression.

The first identification and retrospective study of Severe Fever with Thrombocytopenia Syndrome in Japan.

BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS) is caused by SFTS virus (SFTSV), a novel bunyavirus reported to be endemic in central and northeastern China. This article describes the first identified patient with SFTS and a retrospective study on SFTS in Japan. METHODS: Virologic and pathologic examinations were performed on the patient's samples. Laboratory diagnosis of SFTS was made by isolation/genome amplification and/or the detection of anti-SFTSV immunoglobulin G antibody in sera. Physicians were alerted to the initial diagnosis and asked whether they had previously treated patients with symptoms similar to those of SFTS. RESULTS: A female patient who died in 2012 received a diagnosis of SFTS. Ten additional patients with SFTS were then retrospectively identified. All patients were aged ≥50 years and lived in western Japan. Six cases were fatal. The ratio of males to females was 8:3. SFTSV was isolated from 8 patients. Phylogenetic analyses indicated that all of the Japanese SFTSV isolates formed a genotype independent to those from China. Most patients showed symptoms due to hemorrhage, possibly because of disseminated intravascular coagulation and/or hemophagocytosis. CONCLUSIONS: SFTS has been endemic to Japan, and SFTSV has been circulating naturally within the country.

[Latent malignant lymphoma diagnosed at autopsy in a patient with cold agglutinin disease coexisting thrombotic thrombocytopenic purpura].

An 89-year-old woman presented to our hospital with hemolytic anemia and a high titer of cold agglutinins. Red cell agglutination was observed on a blood smear. Agglutination visibly decreased after warming the blood; therefore, the patient was diagnosed with cold agglutinin disease (CAD). Bone marrow aspiration revealed no infiltration of malignant cells. Computed tomography indicated moderate splenomegaly. The patient had neither an infection nor autoimmune disease. Initial steroid therapy was ineffective and hemolysis worsened. Meanwhile, thrombocytopenia, delirium, fever, and schistocytes in the blood were observed. The progression of hemolysis was attributed not only to CAD but also to coexisting thrombotic thrombocytopenic purpura (TTP) because of the decreased ADAMTS 13 level. Autopsy revealed mild paraaortic lymphadenopathy and splenomegaly. Microscopic examination revealed lymphoma cell infiltration in the spleen, liver, bone marrow, and paraaortic lymph nodes. These observations suggested that TTP and CAD were both secondary complications. This case highlights the importance of an autopsy for the detection of latent lymphoma, which can be difficult to diagnose before the patient's death. Careful examination to exclude lymphomas is important in patients with CAD at the time of diagnosis.

[Acute leukemia of ambiguous lineage with monosomy 7 and Philadelphia chromosome].

A 67-year-old female was admitted with a diagnosis of acute leukemia. Immature blasts did not show cytoplasmic granules and were POX(-), ES(-), and PAS(+). Flow cytometry of leukemic cells demonstrated positivity for CD7, CD10, CD19, CD13, CD34, HLA-DR, and coexpression of CD7 and CD34, CD10 and HLA-DR, and CD19 and CD13. Cytogenetic analysis demonstrated -7 and t(9;22)(q34;q11.2), and genomic studies demonstrated minor BCR/ABL chimeric mRNA and rearrangements of IgH and TCR. These findings indicated the clonal proliferation of leukemic blasts that expressed a mixed phenotype. Acute leukemia of ambiguous lineage was diagnosed, although the significance of the specificity of lineage markers remains unclear. The differential diagnosis included CML and B-ALL. The patient was treated according to Ph+ALL. However, the hematological response was poor, with persistent residual blasts and severe pancytopenia. The subsequent administration of imatinib mesylate led to a complication of heart failure, and the patient died on the 19th hospital day.

[Neurological disturbance of the lower extremities by an extramedullary hematopoietic mass complicated with primary myelofibrosis].

A 59-year-old man with primary myelofibrosis developed motor and sensory neurological disturbance of the legs. Magnetic resonance imaging (MRI) demonstrated a mass lesion of the thoracic vertebra at Th4-6, and in the thoracic vertebral canal at Th4-9, which compressed the spinal cord. Needle biopsy of the mass lesion demonstrated extramedullary hematopoiesis. Initial treatment with bolus methylprednisolone was ineffective and, after subsequent radiation therapy, the mass lesion disappeared and the neurological symptoms ameliorated; however, regrowth of the extramedullary lesion was observed one month later. Surgical resection of the extramedullary lesion, laminectomy, and subsequent radiation were performed. The clinical course after the final treatment was good with no neurological symptoms, although the follow-up period is still short.

Massive ascites associated with all-trans retinoic acid treatment in therapy-related acute promyelocytic leukemia.

A 77-year-old man who developed pancytopenia was administered granulocyte colony-stimulating factor (G-CSF) by another doctor, and referred to us for the evaluation of pancytopenia. He had hepatocellular carcinoma and was treated with transcatheter arterial chemoembolization (TACE) containg epirubicin (total dose: 300 mg over the last two years). Bone marrow aspiration smear demonstrated hypercellular marrow with promyelocytes. Cytogenetic analysis demonstrated del(7), t(15;17)(q22;q12), and a fluorescence in-situ hybridization (FISH) study demonstrated chimeric fusion genes of PML-RAR-alpha. He was diagnosed with therapy-related acute promyelocytic leukemia (APL), and treated with all trans-retinoic acid (ATRA). He showed the progressive accumulation of ascites with liver damage, without pulmonary symptoms of ATRA differentiation syndrome. After 60 days of ATRA treatment, complete hematological and cytogenetic responses were achieved. However, the patient died of septic circulatory failure.

A case of acute promyelocytic leukemia showing transient thrombocytosis caused by increased interleukin-6 and thrombopoietin after treatment with all-trans retinoic acid and chemotherapy.

A patient with acute promyelocytic leukemia(APL)treated with all-trans retinoic acid(ATRA)and chemotherapy for remission induction developed marked thrombocytosis after bone marrow recovery. Thrombocytosis also occurred after post remission chemotherapies, although the degree of thrombocytosis gradually decreased. During thrombocytosis, plasma levels of interleukin-6(IL-6)were elevated while those of thrombopoietin(TPO)were not elevated. However, the plasma level of TPO was markedly elevated at the nadir after post remission chemotherapy. These findings suggest that in APL patients, thrombocytosis after treatment with ATRA and or chemotherapy may be caused by increased plasma levels of both of IL-6 and TPO.

Transient severe pancytopenia due to elevated tumor necrosis factor-alpha in overwhelming infection.

A 66-year-old woman complained of fever, sore throat, and neck pain due to pharyngitis and painful lymph node swelling. CBC revealed severe pancytopenia and markedly hypocellular marrow. The administration of antibiotics and granulocyte-colony stimulating factor (G-CSF) successfully ameliorated the inflammatory lesions, and hematopoiesis recovered. Causes for pancytopnenia was unlikely to be virus infection or drugs, and aplastic anemia was also unlikely since only the plasma levels of tumor necrosis factor-alpha (TNF-alpha) was markedly elevated, erythropoietin (EPO) was slightly elevated, interferon-gamma (IFN-gamma) was normal, and flow cytometric analysis for paroxysmal nocturnal hemoglobinuria (PNH)-type cells was negative. These results suggested that the cause of impaired hematopoiesis in the present patient might have been due to elevated TNF-alpha in overwhelming infection, although the pathogen was not identified.

[Multiple myeloma with variant type translocation, t(8;22)(q24;q11.2)].

A 68-year-old female complained of anemia and bone pain. Monoclonal increase of plasma IgA, lambda-type was observed, and immature plasma cells were detected in the bone marrow. These plasma cells showed intermediate differentiation on CD38 gating flow cytometry. Chromosomal analysis demonstrated complex abnormalities including repeats and translocation, t(8;22)(q24;q11.2) by G-banding, and breakpoint down stream of 3'c-MYC on fluorescence in situ hybridization. Multiple myeloma with variant type translocation was diagnosed. Treatment with continuous infusion of dexamethasone and oral administration of thalidomide effectively decreased IgA, plasma cells and chromosomal abnormality, facilitating complete remission.

Angioimmunoblastic T cell lymphoma associated with reversible myelofibrosis.

A 56-year-old man complained of fever, anemia, thrombocytopenia and lymph node swelling. Biopsy of the lymph node demonstrated angioimmunoblastic T cell lymphoma (AITL) with the loss of normal architecture, proliferation of neoplastic T cells, small vessels mixed with eosinophils and plasma cells. Aspiration of bone marrow was dry tap, and biopsy demonstrated myelofibrosis with increased proliferation of reticulin fiber. Markedly elevated plasma levels of transforming growth factor beta1 (TGF-beta1) and soluble interleukin-2 receptor (sIL-2R) were observed, and that of platelet growth factor (PDGF) AB was slightly elevated. After chemotherapy, remission of lymphoma was achieved. The aspiration of bone marrow became possible, and the level of TGF-beta1 and PDGF AB showed normalization; thus, myelofibrosis was reversible.

Autografting followed by a reduced-intensity conditioning unrelated donor cord blood transplantation for a patient with refractory multiple myeloma: successful engraftment with minimal toxicity.

We report on a 59-yr-old man with recurrent multiple myeloma. To reduce treatment-related mortality, while retaining the cytoreductive effects of high-dose chemotherapy, as well as graft vs. myeloma effect, we used a reduced-intensity conditioning umbilical cord blood (CB) transplantation following high-dose chemotherapy with autologous stem cell transplantation support. This patient was engrafted rapidly and extramedullary toxicities were acceptable. Although he had local recurrence in the right calf on day +130 after the CB transplantation, the tumor was successfully treated with radiation therapy, and he is alive and well at present (day +480).

Two cases of acute myeloblastic leukemia evolving from aplastic anemia.

Two cases of acute myeloblastic leukemia (AML) evolving from aplastic anemia are presented. The first case was diagnosed 18 years ago, and treatment with bolus methylprednisolone, prednisolone, and androgens resulted in partial hematological response. Severe pancytopenia recurred, and AML M0 by French-American-British classification developed. The second case was diagnosed 7 years ago. The patient had HLA DRB1*1501, and treatment with granulocyte colony-stimulating factor (G-CSF), cyclosporine, and methenolone resulted in complete hematological response. Thrombocytopenia recurred and did not respond to cyclosporine and methenolone or to later treatment with antithymocyte globulin, and AML M1 developed. Cytogenetic studies demonstrated 7q- in the first patient and +8 in the second patient. No mutations of N-ras or p53 were observed in either patient. These patients were treated with cytosine arabinoside, aclacinomycin, and G-CSF (CAG) chemotherapy, and the number of leukemic cells decreased substantially. However, pancytopenia after CAG chemotherapy persisted, and the first patient died of pneumonia and the second patient of cerebral hemorrhage.

Propylthiouracil (PTU)-induced vasculitis associated with antineutrophil antibody against myeloperoxidase (MPO-ANCA).

A 54-year-old woman had been administered propylthiouracil (PTU) for Graves' disease for 4 years. Recently, she complained of hemoptysis due to pulmonary alveolar hemorrhage causing anemia, and also had microhematuria. Antineutrophil cytoplasmic antibody against myeloperoxidase (MPO-ANCA) was positive, and she was diagnosed with PTU-induced vasculitis. Cessation of PTU and the administration of corticosteroids ameliorated these manifestations.

Therapy-related erythroleukemia caused by the administration of UFT and mitomycin C in a patient with colon cancer.

A 54-year-old man with colon cancer underwent hemicolectomy. He received postoperative adjuvant chemotherapy with UFT (tegafur/uracil at a 1 : 4 molar ratio) and mitomycin C (MMC) for 3 years. Three years and 4 months after the start of chemotherapy, pancytopenia was noted. Bone marrow aspiration smear demonstrated an increased number of immature erythroblasts, including megaloblasts and myeloblasts. Chromosomal analysis demonstrated structural and numerical abnormalities of 5, 7, 15, and 17. Therapy-related erythroleukemia, acute myeloid leukemia (AML), M6, was diagnosed. The disease progressed after 5 months, and the patient was received chemotherapy with cytosine arabinoside, aclacinomycin, and granulocyte colony-stimulating factor (CAG), and showed a partial hematological response. Careful monitoring for the generation of therapy-related leukemia is needed when UFT and MMC are used for postoperative adjuvant chemotherapy for colorectal cancer.

[Thoracic aortic aneurysm with chronic disseminated intravascular coagulation treated successfully with orally administered camostat mesilate, warfarin and aspirin].

We describe a case of thoracic aortic aneurysm complicated by chronic disseminated intravascular coagulation (DIC). Initially the DIC was controlled successfully by administration of gabexate mesilate and dalteparin. However, because these drugs were given intravenously, the patient could not be discharged. Subsequently, the DIC was treated successfully by changing to orally administered camostat mesilate, warfarin and aspirin, which allowed the patient to leave hospital.