Primary diffuse large B-cell lymphoma of the bone marrow complicated with autoimmune hemolytic anemia and erythroid hypoplasia

A 75-year-old woman was admitted for general fatigue. Diagnostic investigations showed no lymphadenopathy or hepatosplenomegaly. Laboratory examinations revealed severe anemia and an undetectable level of haptoglobin in the peripheral blood. A direct Coombs test was positive. Bone marrow examination showed abnormal, large, CD20-positive lymphocytes and erythroid hypoplasia. Accordingly, a diagnosis of primary diffuse large B-cell lymphoma (DLBCL) of the bone marrow with autoimmune hemolytic anemia (AIHA) and erythroid hypoplasia was made. The patient was treated with prednisolone and 3 courses of rituximab, followed by 6 courses of R-CHOP. AIHA and erythroid hypoplasia subsided after prednisolone and 3 courses of rituximab. Treatment with 6 courses of R-CHOP resulted in complete remission. Isolated bone marrow disease as a presenting feature of DLBCL is very rare. Although malignant lymphomas are often associated with immunologic disorders, this is the first report of diffuse large B-cell lymphoma with isolated bone marrow disease and simultaneous autoimmune hemolytic anemia and erythroid hypoplasia. This case provides valuable information concerning the pathophysiology of an immunologic anomaly with malignant lymphoma.     

Lymphoproliferative disease of granular T lymphocytes presenting as aplastic anemia

Lymphoproliferative disease of granular T lymphocyte (T-LDGL), also known as T-cell large granular lymphocyte leukemia, is a clonal disorder of cytotoxic T lymphocytes that is clinically manifested as chronic neutropenia and anemia. Association with autoimmune disorders is common. In 9 patients, T-LDGL is reported as presenting as aplastic anemia. The clinical characteristics were similar to acquired aplastic anemia. Morphologic evidence of increased granular lymphocytes in the peripheral blood and an excess of CD3(+)/CD8(+)/CD57(+) cells in the bone marrow were found in most cases. Cyclophosphamide was ineffective, but noncytotoxic immunosuppressive agents generally produced a good response. After a median follow-up of 49 months, 5 patients had died from the disease or related complications. Median survival was 40 months. Aplastic anemia can be a presenting manifestation of T-LDGL, and T-LDGL should be considered in the differential diagnosis of acquired aplastic anemia.     

Occurrence of lymphoplasmacytic lymphoma 6?years after amelioration of primary cold agglutinin disease by rituximab therapy

Cold agglutinin disease (CAD) is a rare autoimmune hemolytic anemia, classified into primary and secondary types. Secondary CAD accompanies infection or malignant disease, most often lymphoma, whereas primary CAD frequently represents a lymphoproliferative bone marrow disorder characterized by clonal expansion of B cells. Here, I describe a case of lymphoplasmacytic lymphoma (LPL) developed 6?years after amelioration of primary CAD by rituximab monotherapy. A 54-year-old Japanese woman was diagnosed with primary CAD characterized by a small fraction of B lymphocytes and kappa laterality in the peripheral blood. M-protein was not detected by immuno-electrophoresis. The patient achieved remission following two courses of rituximab monotherapy. The level of IgM was specifically decreased, although levels of IgG and IgA were slightly increased. Six years after rituximab monotherapy, she developed LPL without CAD recurrence. Flow cytometry performed on bone marrow specimens revealed that lymphoma cells were positive for CD19 and CD20 with kappa laterality. The lymphoma may have transformed from clonal B lymphocytes at presentation of CAD. Rituximab monotherapy induced remission of CAD by specific decrease of IgM level, but did not eliminate the clonal B lymphocytes that may have progressed to LPL. This experience may provide clues toward the understanding of the pathophysiology of primary CAD with clonal lymphoproliferative disease of the bone marrow.     

CD5- CD11c+ CD23- small lymphocytic lymphoma evolving from aplastic anemia

A 91-year-old woman was hospitalized with acute respiratory distress syndrome due to pneumonia in June 1997. Since she had pancytopenia and a bone marrow aspirate indicated hypocellularity with no increase in myeloblasts, dysplasia or abnormal chromosomes, aplastic anemia (AA) was diagnosed. Pulse therapy with methylprednisolone and antibiotics proved successful, and blood cell numbers stabilized. In June 2001, she was readmitted to our hospital with persistent low grade fever and leukopenia. A bone marrow aspirate from the sternum and iliac bone biopsy revealed compact proliferation of small lymphocytes, and the surface marker CD5- CD10- CD11c+ CD19+ CD20+ CD23- was detected through immune staining and flowcytometry. CD30+, CD34+and CD56+cells were scarce. Tests for surface immunoglobulins, IgG, IgA, IgM and IgD, were negative. No nodal or extranodal lesions were evident. Since Southern blot analysis of bone marrow cells indicated rearrangement of the immunoglobulin heavy chain and abnormal chromosomes were evident, small lymphocytic lymphoma (SLL) was diagnosed. Four intravenous infusions of rituximab (375mg/m2) were administered without critical adverse effects. Tests conducted four weeks later revealed saturation of CD20+ antigens of lymphoma cells and chromosomal abnormalities and rearrangement of the immunoglobulin heavy chain were still apparent. Though complete remission of the pancytopenia was not achieved, serum concentrations of lactate dehydrogenase and soluble interleukin-2 receptor decreased, and the numbers of platelets and erythrocytes increased. There was also an improvement in systemic condition. This was a rare case of SLL having the surface marker of CD5- CD10- CD11c+ CD19+ CD20+ CD23-, which had evolved from AA and infiltrated bone marrow.     

Massive plasmocytosis due to methimazole-induced bone marrow toxicity.

Pancytopenia is a rare complication of the thionamide therapy reported secondary to aplastic anemia, the bone marrow being invariably hypocellular. We present a case of a 16-year-old female with Graves' disease who presented with massive bone marrow plasmocytosis mimicking multiple myeloma. The patient had already been on methimazole for a month when she was admitted to the Pediatric Unit with the diagnosis of sepsis. CBC revealed pancytopenia. Bone marrow aspirations showed hypocellular-normocellular bone marrow, 98% of plasma cells. At that time, MMI was discontinued and the patient was started on broad-spectrum antibiotics, dexamethasone, and G-CSF. Bone marrow aspiration day +4 still showed hypo-normocellular marrow, with remaining 6% plasma cells. Myeloma screen was negative; ANC >1,000 at day +7, platelets >50,000 at day +24. Twenty-four months after patient's discharge, her clinical condition, CBC, and bone marrow remained normal. To our knowledge this is the first report of pancytopenia due to MMI, where the usual hypoplasia found is replaced by massive plasmocytosis.     

Methimazole-induced aplastic anemia caused by hypocellular bone marrow with plasmacytosis.

Aplastic anemia is a rare but severe complication of methimazole (MMI) treatment for Graves' disease. We present a case of a 53-year-old Japanese female who had been treated with 30 mg/d of MMI for 30 days for Graves' disease and was subsequently admitted to the Japan Self Defense Forces (JSDF) Central Hospital with a mild sore throat and high-grade fever that began the previous day. The patient had a reduced white blood cell count (WBC) count of 0.9 x 10(3) per microliter with severe granulocytopenia and increased lymphocytes, a platelet count of 49 x 10(3) per microliter, and hemoglobin of 10.6 g/dL. Bone marrow (BM) aspirates showed hypocellular bone marrow with plasmacytosis. Because of poor recovery of her peripheral blood values after withdrawal of MMI, she was given transfusions of platelets and erythrocytes thereafter. This is the second report of plasmacytosis in bone marrow of MMI-induced aplastic anemia, and suggests that immunogenic mechanisms may cause this rare complication.     

Aplastic anemia which terminated in hypoplastic leukemia 10 years after diagnosis

A 57-year-old woman was admitted to our hospital because of further examination of anemia in November, 1978. She was diagnosed as having aplastic anemia, which was not associated with any atypical findings. Treatment with oxymetholone had been effective. However, she developed pancytopenia in January, 1988. A bone marrow aspiration revealed a hypocellular marrow with 75.6% blasts. Following two courses with low dose cytosine arabinoside and vitamin D3, the leukemia improved although she needs red cell transfusions at intervals of one to two months because of persistent pancytopenia. We present a patient with aplastic anemia who developed a hypoplastic leukemia at the tenth year of the disease.     

Granular lymphocyte proliferative disorder with penis cancer

A case of granular lymphocyte proliferative disorder with squamous cell carcinoma of penis is described. A 77-year-old Japanese male was admitted to our hospital in March, 1989 because of ulceration of penis and lymphocytosis. He had hepatomegaly and lymphadenopathy but not splenomegaly on physical examination. The WBC count was 10800/microliters with 83% of granular lymphocytes. Thrombocytopenia (32000/microliters) and mild anemia were also demonstrated. Bone marrow aspirate showed hypercellular marrow with 84% of granular lymphocytes. Proliferative granular lymphocytes were CD2+ CD3+ CD4- CD8- CDw29+ and exhibited ADCC activity but not NK activity. On March 15, amputation of penis was performed. But his lymphocytosis didn't change and thrombocytopenia increased. Thus we considered his granular lymphocytosis was neoplastic rather than reactive. Our case seemed to be rare and was compared with previous reports.     

Leukemic phase of intermediate non-Hodgkin's lymphoma with cells showing different matured stages in invaded various organs.

A 56-year-old male was admitted to our hospital with lymphocytosis (16.4 x 10(9)/l; 79% lymphocytes including 50% small lymphocytes), generalized lymphadenopathy, massive splenomegaly, and heavily infiltrated bone marrow. Immunophenotype analysis of the neoplastic cells in the bone marrow revealed that they were B cells (CD20 + CD19 + Ia1 + sIgM+) positive for CD10. By contrast, the cells in the lymph node were CD20 + CD19 + Ia1 + sIgM+ but negative for CD10. The patient was tentatively diagnosed as having lymphosarcoma cell lymphoma, however, the final diagnosis was leukemic phase of intermediate lymphocytic lymphoma. We concluded that CD10+ neoplastic cells in the bone marrow and peripheral blood had differentiated to CD10- cells.     

De novo CD5-positive diffuse large B-cell lymphoma associated with autoimmune hemolytic anemia presenting as erythroid hypoplasia

A 54-year-old woman was admitted due to high-grade fever, cervical lymphadenopathy and general malaise in May 2003. On examination, severe anemia was noted, direct Coombs and cold hemagglutinin tests were positive and the haptoglobin level was low in the peripheral blood. However, a bone marrow examination revealed marked erythroid hypoplasia. A diagnosis was made of co-existing combined type autoimmune hemolytic anemia (AIHA) and erythroid hypoplasia. A pathologic diagnosis of de novo CD5-positive diffuse large B-cell lymphoma (de novo CD5+ DLBCL) was made based on a cervical lymph node biopsy. The patient was treated with CHOP accompanied by rituximab (R-CHOP), resulting in complete remission after 3 courses of chemotherapy. The AIHA and erythroid hypoplasia subsided after 2 courses of R-CHOP. The sera obtained during erythroid hypoplasia significantly inhibited the growth of erythroid progenitor cells (erythroid colony-forming units, CFU-E) from her bone marrow collected after recovery. We report here a patient with de novo CD5+ DLBCL associated with both AIHA and erythroid hypoplasia, suggesting that the lymphoma triggered an abnormal immunity which generated some humoral inhibitors against erythropoiesis.     

Induction of Complete Remission of Hypoplastic Leukemia with Antithymocyte Globulin

A 13-year-old boy was admitted to a local hospital because of pancytopenia. A bone marrow aspiration and biopsy revealed severely hypocellular marrow with no obvious leukemic cells. The diagnosis was severe aplastic anemia, and the patient was treated with antithymocyte globulin and cyclosporin A. A trilineage response was obtained, and the patient became transfusion-independent within 2 weeks. Two months later, the peripheral blood count normalized with an increased bone marrow cellularity. However, the patient was readmitted 5 months later for recurrence of the pancytopenia. A bone marrow aspiration revealed hypocellular marrow with morphologically blastoid cells. A surface marker study revealed the presence of a single clone that was positive for CD7, CD33, CD34, and HLA-DR. A diagnosis of hypoplastic leukemia was made on the basis of morphology and the surface marker studies. Retrospectively, the laboratory findings were the same as those seen at the onset of the disease. The patient did not respond to combination chemotherapy consisting of vincristine, prednisolone, cyclophosphamide, L-asparaginase, and doxorubicin, but administration of etoposide resulted in complete remission. An in vitro study revealed that >95% of the leukemic cells of this patient could be lysed after an incubation with antithymocyte globulin and human AB serum or baby rabbit serum. These findings suggest the efficacy of antithymocyte globulin in treating certain hypoplastic leukemias.     

T-cell receptor gammadelta-large granular lymphocytic leukemia associated with an aberrant phenotype and TCR-Vbeta20 clonality

Large granular lymphocytic (LGL) leukemia is a rare heterogenous disorder of mature lymphocytes with a characteristic morphology, multiple autoimmune disorders and indolent clinical course. Most cases exhibit a T-cell phenotype of CD3, CD8 and CD57 positivity, while the minority exhibit a CD2, CD56, and CD16 positive NK-cell phenotype. We report a case of a 71-year-old female suffering from a TCRgammadelta positive T-cell leukemia with a morphology compatible to LGL leukemia. She referred to the hospital for investigation of mild anemia, lymphocytosis, neutropenia and hyperglobulinemia. Peripheral blood and bone marrow were occupied by mature large granular lymphocytes with abundant azurophilic granules. The immunophenotype was CD3+, CD2+, CD5+, CD7+, CD4-, CD8-, CD16-, CD56-, CD57- and the Vbeta repertoire analysis showed clonal reactivity with Vbeta20 mAb. The patient was diagnosed as having T-LGL and was treated with G-CSF. So far, she experiences an indolent clinical course. To our knowledge, this is a rare case of TCRgammadelta positive T-LGL leukemia with the aberrant immunophenotype of CD3+, CD4-, CD8-, CD16-, CD56-, CD57-.     

Prolonged Bone Marrow Failure With Monosomy 7 After Engraftment Failure Following Bone Marrow Transplantation

A patient with acute myelogenous leukemia developed prolonged bone marrow failure along with the monosomy 7 chromosome abnormality. The patient had undergone bone marrow transplantation with CD34+ selection following induction failure. However, she then suffered engraftment failure and long-term pancytopenia. Her white blood cell count gradually increased with supportive therapy including granulocyte colony-stimulating factor (G-CSF), and chromosomal analysis of bone marrow cells revealed an abnormal karyotype. Thirty months after the bone marrow transplantation we observed monosomy 7 together with the existing chromosomal abnormality in the patient's bone marrow cells. It has been reported that some patients with idiopathic and posthepatitis aplastic anemia develop clonal disorders such as myelodysplastic syndrome/acute myelogenous leukemia with monosomy 7. The findings in our case suggest that the appearance of monosomy 7 in patients with aplastic anemia may be caused by prolonged low-level hematopoiesis, with or without G-CSF stimulation.     

再生障碍性贫血雄激素受体与T细胞亚群的变化

目的:检测慢性再生障碍性贫血(CAA)患者骨髓单个核细胞(MNC)雄激素受体(AR)以及骨髓中T细胞亚群水平,探讨AR在CAA免疫病理机制中的作用。方法:①免疫细胞化学SP法检测CAA患者骨髓MNC内AR的表达水平;②流式细胞术检测CAA骨髓中T细胞亚群(CD3 CD4 细胞、CD3 CD8 细胞)的含量。结果:①CAA患者骨髓MNC中AR阳性水平[(35．18±8．78)个／200个MNC]显著低于对照组[(48．46±9．82)个／200个MNC];不同性别间AR的含量差异无统计学意义。②CAA患者骨髓中的CD3 CD8 细胞含量为(28．54±7．57)％,显著高于对照组。③CAA患者骨髓中的AR阳性水平与骨髓中的CD3 CD8 细胞呈负相关(r=-0．576,P<0．01);而与CD3 CD4 细胞含量未见明显的直线相关关系。结论:CAA患者骨髓AR的表达减少,从而使雄激素刺激造血的作用减弱。患者AR的表达与CD3 CD8 细胞含量呈明显负相关,表明AR的异常可能在一定程度上参与了CAA发病机制中的细胞免疫。     

Congenital stomatocytosis associated with aplastic anemia

A seven year-old boy with hereditary stomatocytosis complicated with aplastic anemia was reported. He was admitted to our hospital because of pale and general fatigue. On physical examination, he had severe anemia, petechiae, but no hepatosplenomegaly. Peripheral blood cell count revealed pancytopenia; RBC 103 X 10(4)/microliters, Hb 3.5 g/dl, Ret 21%, WBC 1,200/microliters, Pl 1.3 X 10(4)/microliters, and bone marrow revealed markedly hypocellular marrow. Red cell morphology demonstrated stomatocytosis. Red cell life span (51Cr T1/2) was 12 days, Coombs' test and Ham's test were negative. Indirect bilirubin was 1.1 mg/dl and marked decrease of haptoglobin was found. Family studies showed that his father and sister had stomatocytosis on peripheral blood examination, but no anemia. The patient had severe anemia because of complicated aplastic anemia. Congenital stomatocytosis with aplastic anemia is extremely rare. The authors are interested in a possible relationship between hereditary stomatocytosis and aplastic anemia although the precise mechanism remains to be elucidated.     

Multiple lymphoid nodules in bone marrow have the same clonality as underlying myelodysplastic syndrome recognized with fluorescent in situ hybridization technique

Benign nodular lymphoid lesions are not rare in the bone marrow of patients with myelodysplastic syndrome (MDS). Herein, we report a case of MDS with clonal lymphoid aggregates in the bone marrow but without evidence of systemic lymphoma. The case of a 71-year-old man was evaluated for cytopenia. His bone marrow was initially hypocellular, with 10% blasts and a few small lymphoid aggregates. The diagnosis of refractory anemia with excess blasts was made. The disease progressed gradually, and he received erythropoietin and granulocyte colony-stimulating factor for a short time. Forty-two months later, acute leukemia (M1) developed, with 60% to 70% blasts in the bone marrow. The bone marrow also showed large aggregates of lymphocytes. Immunohistochemical study of these cells in the nodular lesions showed 50% CD3+ and 50% CD20+. Cytogenetic and molecular genetic studies revealed monosomy 7 and T- and B-cell clonal gene rearrangement. Fluorescent in situ hybridization study with centromere-specific probes of a bone marrow specimen showed monosomy 7 in both nodular lymphoid lesions and surrounding bone marrow cells, indicating that both processes originated from the same abnormal pluripotential progenitor. Am. J. Hematol. 59:252–257, 1998. © 1998 Wiley-Liss, Inc.     

Epstein-Barr virus-associated lymphoproliferative disorder developed after anti-thymocyte globulin therapy in a patient with bone marrow failure associated with T-cell large granular lymphocytic leukemia

A 75-year-old man was referred to our hospital for marked neutropenia and anemia. Bone marrow examination showed marked hypoplasia with 45.2% infiltration of CD3+, CD8+, CD16+ and CD57+ granular lymphocytes. Monoclonal rearrangement of T-cell receptor gene was observed by Southern blot analysis. Taking these findings together, T-cell large granular lymphocyte leukemia (T-LGL) with bone marrow failure was diagnosed. The patient was treated with immunosuppressive therapy (IST) consisting of anti-thymocyte globulin and cyclosporine. Although pancytopenia subsided after IST, fever and lymphoadenopathy developed on the 29th day after IST. The presence of Epstein-Barr virus (EBV) in peripheral blood was confirmed using real time PCR (3.5×10(6) copies/10(6)WBC). Although gancyclovir and foscarnet were started, rapidly progressive hepatomegaly and liver dysfunction developed. The patient died on the 42nd day after IST. Autopsy specimen showed infiltration of abnormal CD20-positive large lymphocytes in the portal area of the liver, white pulp of the spleen, kidneys and adrenal glands. The nuclear EBV-encoded RNA (EBER) stain was positive in the abnormal large lymphocytes and a diagnosis of EBV-associated B-cell lymphoproliferative disorder (EBV-LPD) was made. We should regard the potential risk of EBV-LPD after immunosuppressive therapy for patients with bone marrow failure caused by T-LGL.     

Bone marrow-restricted involvement of T-cell granular lymphocyte leukemia

A 66-year-old female was referred to our hospital with bone pain and progressive pancytopenia with granular lymphocyte infiltration only in the bone marrow (BM). Flow cytometric and histological analyses revealed that these cells were positive for CD3, TCRalphabeta, granzyme B, and the diagnosis of T-cell granular lymphocyte leukemia (T-GLL) with myelofibrosis was made. These BM granular lymphocytes were greatly ruffled and showed the CD3/CD20 double positive phenotype, which was not detected in the peripheral blood. The patient was treated with a single course of fludarabine followed by a favorable clinical course for 3 months. Many of the BM lymphocytes displayed almost normal appearance after treatment, however, the number of lymphocytes in the BM did not decrease and these were still CD3/CD20 double positive. This is an overlap case of T-GLL and peripheral T-cell lymphoma, unspecified (PTCLu).     

Mycobacterium genavense infection in a patient with long-standing chronic lymphocytic leukaemia

We describe the first case of disseminated infection with Mycobacterium genavense in an HIV-seronegative patient with a chronic haematological disorder. Our patient, an 80-year-old woman, had been under long-term treatment with chlorambucil (partially in combination with prednisone) for B-cell chronic lymphocytic leukaemia (B-CLL). When she developed general fatigue and progressive anaemia, as well as progressive lymphadenopathy and splenomegaly, bone marrow biopsy revealed granulomas with acid-fast bacilli, and cultures of both bone marrow and blood grew M. genavense. The patient's CD4+ cell count was approximately 100 microL(-1). Treatment with clarithromycin, ethambutol and rifabutin resulted in improvement of anaemia and general health as well as in regression of lymphadenopathy and splenomegaly.     

Ruptured Klebsiella pneumoniae liver abscess after high-dose cyclophosphamide for severe aplastic anemia

A 19-year-old woman with severe aplastic anemia who had previously failed antithymocyte globulin/cyclosporine A received high-dose cyclophosphamide without bone marrow rescue. On day +14, she complained of right upper quadrant abdominal pain and fever. A CT scan of the abdomen showed multiple liver abscesses with rupture and Klebsiella pneumoniae was isolated from blood. In spite of aggressive antibiotic therapy, she rapidly deteriorated and died of overwhelming sepsis. To our knowledge, our patient is the first case of fatal ruptured liver abscess after high-dose cyclophosphamide in a patient with severe aplastic anemia.