A clinicopathological study of 20 patients with T/natural killer (NK)-cell lymphoma-associated hemophagocytic syndrome with special reference to nasal and nasal-type NK/T-cell lymphoma.

We describe the clinicopathological features of 20 patients with T/natural killer (NK)-cell lymphoma-associated hemophagocytic syndrome (T/NK-LAHS). These patients were categorized into 2 groups according to the onset of hemophagocytic syndrome (HPS). Group 1 developed HPS during the clinical course, typically at the terminal phase of the disease. This group consisted of 7 patients with extranodal lymphoma arising in the nasal cavity, paranasal cavity, tonsils, or skin at presentation. In 5 of these patients, the preferred diagnosis was nasal and nasal-type NK/T-cell lymphoma, whereas the disease diagnoses in the remaining 2 patients were peripheral T-cell lymphoma of unspecified type and angioimmunoblastic T-cell lymphoma, respectively. Group 2 consisted of 13 patients whose disease corresponded to so-called malignant histiocytosis-like lymphoma, which is characterized by HPS at the initial presentation and the infiltration of the liver, spleen, and/or bone marrow without tumor formation. Nine of these 13 cases were found to have common histopathological features: CD56+, Epstein-Barr virus positivity, cytotoxic molecules, and nasal-type NK/T-cell lymphoma. The very poor prognosis of T/NK-LAHS may be partly explained by the finding that nasal and nasal-type NK/T-cell lymphoma, which is resistant to standard chemotherapy, made up the highest percentage (70%) of the cases.

A clinical analysis of 52 adult patients with hemophagocytic syndrome: the prognostic significance of the underlying diseases.

We retrospectively analyzed 52 adult patients with hemophagocytic syndrome (HPS). The underlying diseases were heterogeneous, including malignant lymphoma (lymphoma-associated hemophagocytic syndrome [LAHS]) in 26 patients, systemic lupus erythematosus in 3 patients, viral infections in 7 patients, and bacteria] or fungal infections in 6 patients. More than 83% of patients received prednisolone as an initial treatment. Multiple-agent chemotherapies (cyclophosphamide, doxorubicin, and vincristine) were administered to 96% of LAHS patients after a histopathological diagnosis of lymphoma. HPSs were controllable and remissions were achieved except for those patients with LAHS, fulminant Epstein-Barr virus-associated HPS, and an immunosuppressive state. Twenty-one (81%) of the LAHS patients had uncontrollable HPS and died of multiple organ failure and disseminated intravascular coagulation. The median survival time of LAHS patients was 83 days. In contrast, 3 (12%) of the other HPS patients died of multiple organ failure within 44 days.The clinical manifestations and the laboratory findings of LAHS and the other HPSs were too variable to establish the prognosis based only on the findings at the onset of HPS. The prognostic factors of adult HPS were found to be the underlying diseases, notably malignant lymphoma and infections, accompanied by the immunosuppressive state.

[Lymphoma-associated hemophagocytic syndrome in Japan].

This report describes characteristics of lymphoma-associated hemophagocytic syndrome (LAHS) in 142 patients throughout Japan who were enrolled in a questionnaire survey. The 68 patients with B-cell LAHS (B-LAHS) were older on average than the 64 who had T-cell or natural killer-cell LAHS (T/NK-LAHS) (median ages at diagnosis: 63.5 versus 49 years). However, the clinical signs of cytopenia, coagulopathy, and liver dysfunction were generally less severe in the former group than in the latter. Furthermore, the prognosis was better for the B-LAHS group than the T/NK-LAHS group (median survival: 242 days versus 69 days). The Epstein-Barr virus genome was detected by EBERs in situ hybridization in 3 of 24 B-LAHS patients examined, and in 19 of 23 T/NK-LAHS patients. Based on observed clinical manifestations, T/NK-LAHS was subdivided into 2 types: LAHS that developed in patients with nasal or nasal-type NK/T-cell lymphoma during their clinical course; and LAHS as the initial presentation in T/NK-cell lymphoma patients with hepatosplenomegaly and without lymphadenopathy. In B-LAHS, hemophagocytic syndrome was the major initial symptom, and patients had hepatosplenomegaly without lymphadenopathy. Also, 10 of 20 B-LAHS patients demonstrated intravascular lymphomatosis. Based on the findings of this survey, we proposed a set of new diagnostic criteria for LAHS.

Crescentic glomerulonephritis accompanied by myeloperoxidase-antineutrophil cytoplasmic antibodies in a patient having myelodysplastic syndrome with trisomy 7.

A 63-year-old woman developed rapidly progressive glomerulonephritis syndrome with serum myeloperoxidase-anti-neutrophil cytoplasmic antibodies (MPO-ANCA). A renal biopsy showed diffuse crescentic glomerulonephritis. Immunofluorescence and electron microscopic studies showed no significant deposits in the glomeruli. The morphological findings were consistent with pauci-immune type crescentic glomerulonephritis. In addition, the patient had erythropoietin-resistant anemia and subsequent pancytopenia. Bone marrow was normocellular without an excess of blasts. However, multinuclear erythroblasts, hypersegmented neutrophils, and megakaryocytes without platelet formation were observed. Chromosome analysis of the bone marrow showed 47,XX,+7. This is the first case of MPO-ANCA-related crescentic glomerulonephritis in a patient with myelodysplastic syndromes (MDS). A possible relationship between MPO-ANCA and MDS is discussed.

BCL6 rearrangement in a patient with mantle cell lymphoma.

We describe a patient with mantle cell lymphoma (MCL) associated with BCL6 gene rearrangement. MCL is a distinct subtype of non-Hodgkin's lymphoma characterized by CD5+, CD10-, CD20+, t(11;14)(q13;q32) and PRAD1/cyclin D1 overexpression. Although rearrangement of the BCL6 gene is the most frequent genetic change among diffuse lymphomas and some follicular lymphomas this is the first report of a patient with MCL associated with BCL6 rearrangement.

11q23 aberration is an additional chromosomal change in de novo acute leukemia after treatment with etoposide and mitoxantrone.

We report on 2 patients with acute leukemia who had an 11q23 chromosomal aberration as an additional change after treatment with etoposide and mitoxantrone, agents that affect topoisomerase II (Topo II). One patient with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (L2) received chemotherapy, including 1,000 mg of etoposide and 75 mg of mitoxantrone. She relapsed 10 months later. Analysis at time of relapse showed a chromosomal aberration of del(11)(q23) as an additional cytogenetic change. The other patient was diagnosed with acute monoblastic leukemia (M5a) and received two autologous peripheral blood stem-cell transplantations. Her cumulative doses of etoposide and mitoxantrone were 6,000 mg and 42 mg, respectively. She also relapsed, and analysis at that time revealed del(11)(q23) as an additional chromosomal aberration. The mixed lineage leukemia/myeloid-lymphoid leukemia (MLL) gene was not rearranged in either case, making these cases distinct from previously described therapy-related leukemias caused by Topo II inhibitors. Based on these two cases, it may be that Topo II inhibitors can cause clonal evolution affecting chromosome band 11q23.

Development of secondary leukemia associated with (1;7)(q10;p10) in a patient with Crow-Fukase syndrome.

A 42-year-old woman with Crow-Fukase syndrome developed acute myeloid leukemia (M6: FAB classification) following treatment with alkylating agents (a total of 2,500 mg of melphalan and 9,800 mg of cyclophosphamide). Chromosome analysis of the bone marrow showed 49,XX,der(1;7)(q10;p10), +8, +19, +21 in therapy-related myelodysplastic syndrome with additional chromosomes 8, and 12 and two additional chromosomes 21 in acute leukemia. Because of the risk of therapy-related leukemia, alkylating agents should be used with caution in the treatment of Crow-Fukase syndrome.

[Response-oriented salvage chemotherapy with mitoxantrone, etoposide and enocitabine for previously treated acute myeloid leukemia. Tohoku Leukemia Study Group].

Twenty-two patients with previously treated acute myeloid leukemia (AML) received salvage chemotherapy with mitoxantrone, 5 mg/m2/d on days 1 to 3, etoposide, 70 mg/m2/d on days 1 to 5, and enocitabine, 170 mg/m2/d on days 1 to 7 (BHAC-ME). Additional mitoxantrone, etoposide (both for up to 2 days) and enocitabine (for up to 7 days) were given if the bone marrow obtained on day 8 was not severely hypoplastic. Mitoxantrone and etoposide had been previously administered in 14 and 15 patients, respectively. Seven patients had primary resistance; 14 patients had first relapse (4 early and 10 late): and 2 patients had second relapse. Overall, seven patients (31%) achieved a complete remission; 7/14 with first relapse, and 0/8 with primary resistance or second relapse. Four patients, 3 with primary resistance and 1 with first relapse, died of infectious complication in aplasia. First relapse patients who had been previously treated both with mitoxantrone and etoposide, had a lower CR rate than the other first relapse patients [2/8 (25%) vs 5/6 (86%)], although patient characteristics such as duration of first CR, initial karyotype, and performance status, were similar between the two groups. We conclude that response-oriented BHAC-ME regimen is still active in first relapse AML patients unless they have received both mitoxantrone and etoposide previously.

Bone and brain involvement in a case of diffuse large B cell lymphoma associated with t(2;3)(p12;q27).

We report a 57-year-old male with non-Hodgkin's lymphoma (NHL) associated with t(2;3)(p12;q27). The patient showed bone lesions at presentation and brain involvement at relapse in addition to systemic lymph node swelling. Histological diagnosis was malignant lymphoma, diffuse, large cell, immunoblastic, plasmacytoid. Chromosome analysis revealed t(2;3) which is a variant type of t(3;14)(q27;q32). Fluorescence in situ hybridization (FISH) analysis disclosed splits of signals of BCL-6 gene. Among the cases reported in the literature, the common feature of t(2;3)(p11 or p12;q27) was diffuse, large cell lymphoma of B cell, kappa phenotype and four patients immunosuppressive state before lymphoma.

Successful hematopoietic reconstitution with granulocyte colony-stimulating factor in a patient with hypoplastic acute myelogenous leukemia.

We describe a 68-year-old Japanese male with hypoplastic acute myelogenous leukemia (AML) who achieved complete hematological reconstitution following granulocyte colony-stimulating factor (G-CSF) administration. The patient had pancytopenia and the bone marrow was hypocellular with 19 to 36% peroxidase-positive blasts without morphological abnormalities suggestive of myelodysplasia. After receiving G-CSF as a supportive therapy for pneumonia, the blood count became normal and the bone marrow was normocellular with less than 5% of blasts. Without subsequent chemotherapy, he relapsed as a form of overt leukemia and died of pneumonia. Chemotherapy may be necessary to maintain remission in hypoplastic AML after hematopoietic reconstitution by G-CSF.

Extramedullary megakaryoblastic tumors following an indolent phase of myelofibrosis.

A 59-year-old man developed multiple subcutaneous and bone tumors after 2 years' duration of indolent myelofibrosis. These tumors exhibited a diffuse proliferation of pleomorphic blast cells. The skeletal x-rays showed disseminated osteolysis and osteosclerosis. Blast cells obtained from the pleural effusion did not react with myeloperoxidase, sudan black B or non-specific esterase. Genotypic analysis of DNA samples at autopsy did not demonstrate rearrangements of T-cell receptor beta-chain or immunoglobulin heavy-chain genes. Frozen-section immunohistochemical studies revealed that the neoplastic cells were derived from megakaryocytic lineage. The present case represents a novel and unusual subtype of megakaryocytic neoplasm.

Virus-associated hemophagocytic syndrome due to measles accompanied by acute respiratory failure.

An 18-year-old male who was admitted to hospital due to fever, skin rashes, cough, and malaise showed laboratory examination findings of leukopenia, thrombocytopenia, mild liver dysfunction, and hypoxia. Bone marrow aspiration revealed 2% histiocytes with hemophagocytosis. Chest X-ray showed bilateral diffuse interstitial pneumonia. The titer of anti-measles virus antibody was < 1:4, and that at convalescence stage was 1:64. He was diagnosed as having hemophagocytic syndrome and acute respiratory failure due to measles, and was treated with methylprednisolone pulse therapy. He promptly recovered from thrombocytopenia and acute respiratory distress. Steroid pulse therapy may be effective in these conditions due to measles.

Syndrome of inappropriate secretion of antidiuretic hormone in patients with lymphoma-associated hemophagocytic syndrome.

We report three lymphoma patients in whom the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) was observed during the course of lymphoma-associated hemophagocytic syndrome (LAHS). The clinical course was devoid of any known mechanism for SIADH which could be attributable to lymphoma or antineoplastic treatment. Alternatively, high serum levels of interleukin-1 beta and tumor necrosis factor-alpha, which stimulate the secretion of antidiuretic hormone, may have contributed to the development of SIADH in our patients, who were receiving glucocorticoids. In conclusion, LAHS patients should be considered to be at high risk for SIADH.

Risk factors for hepatosplenic abscesses in patients with acute leukemia receiving empiric azole treatment.

The authors retrospectively evaluated 63 febrile neutropenic episodes in 33 consecutive patients with leukemia who received empiric azole treatment for refractory or relapsing fever that occurred despite broad-spectrum antibiotics. In 8 patients (24%), hepatosplenic abscesses (HSA) developed. To identify the risk factors for the development of HSA, the authors compared various characteristics of febrile episodes in those with and without HSA. The risk factors included relapsed status of leukemia (P = 0.04) and Candida colonization of surveillance cultures from the throat (P = 0.03) and stool (P = 0.03). However, the duration of neutropenia, gastrointestinal symptoms, types of chemotherapy, and leukemia subtypes were not correlated with the development of HSA. Based on these results, the authors identified the high risk group for the development for HSA as patients with relapsed leukemia with fungal colonization of gastrointestinal tract during neutropenia despite empiric antifungal treatment with azoles.

Autoreactive T cell-dependent polyclonal hypergammaglobulinemia in mantle cell lymphoma.

We investigated the mechanism of polyclonal B cell differentiation in mantle cell lymphoma (MCL) using peripheral blood mononuclear cells (PBMC) from a patient with MCL in leukemic stage presenting polyclonal hypergammaglobulinemia. Patient T cells not only responded to autologous non-T cells but induced polyclonal production of IgG in vitro. Flow cytometric analysis of PBMC showed the increased conversion of CD4+ T cells from the naive to the memory state. We propose the possible mechanism that autoreactive T cells may be involved in polyclonal B cell differentiation in this monoclonal B cell disorder.

[Acute monoblastic leukemia (M5a) with dysmegakaryocytopoiesis associated with t(16;21) (p11;q22)].

We report a 24-year-old woman who had acute monoblastic leukemia associated with t(16;21) (p11;q22). She was referred to our hospital in April 1992 because of high fever and hemorrhagic diathesis. Physical examination on admission showed no hepatosplenomegaly. The hemoglobin was 5.1g/dl, platelet count 1.7 x 10(4)/microliters, the white blood cell count 18,700/microliters. Bone marrow aspirate showed that 86% of nucleated cells were monoblasts which were positive for peroxidase and alpha-naphtyl butyrate esterase. She was diagnosed as having M5a. Dysmegakaryopoiesis, such as micromegakaryocytes and megakaryocytes with multiple small separated nuclei, was seen in the bone marrow. Chromosomal analysis revealed t(16;21). Complete remission was achieved after two courses of BHAC-DMP therapy, but dysmegakaryopoietic features remained. She relapsed in September 1992. Review of the literature and this patient indicate that acute nonlymphocytic leukemia with t(16;21) is associated with multilineage leukemic differentiation.