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Query: UMLS:C0023418 (leukemia)
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Hemophagocytic lymphohistiocytosis (HLH) is a rare, often fatal, disease of early infancy. The diagnosis of HLH is frequently delayed or made at autopsy because no genetic or biologic marker has been identified. To improve the classification and treatment of HLH, the Histiocyte Society has established an 'International Registry for HLH'. Data collected included family history, clinical and laboratory features at the onset of illness, and treatment outcome. Stringent diagnostic criteria (ie fever, splenomegaly, cytopenia, hypertriglyceridemia, and/or hypofibrinogenemia, and hemophagocytosis without evidence of malignancy) were used for patient selection. One hundred and twenty-two patients (61 males, 61 females) were enrolled from 17 centers in 11 countries. The rate of parental consanguinity was 24%. A positive family history was reported in 49% of cases including two pairs of affected male twins. The median age at disease onset was 2.9 months, with no difference between familial and sporadic cases. Age at onset was similar in affected sibs from 10 of 14 families, but in four up to 3-year differences were observed. Hemophagocytosis was present at diagnosis in 75%. An associated infection (usually by common viral pathogens) was reported in 50 of the 122 (41%) cases, of which 25 had familial disease. Natural killer activity was impaired in 36 of 37 patients studied. Chromosome analysis was normal in all tested patients. A decreased frequency of HLA-B7 and B8 alleles and increased frequency of HLA-B21 and DQ3 were observed. The estimated 5-year survival (SE) was 21% (18.7) for all patients. It was 66% (37.8) for patients who received allogeneic bone marrow transplant and 10.1% (9.6) for patients treated with chemotherapy alone (P=0.0001). None of the previously proposed prognostic indicators (age, associated infection, cerebrospinal fluid pleocytosis, family history) correlated with treatment outcome.
Leukemia 1996 Feb
PMID:Hemophagocytic lymphohistiocytosis. Report of 122 children from the International Registry. FHL Study Group of the Histiocyte Society. 863 26

Hemophagocytic syndrome is a proliferative disorder of an activated monocyte-macrophage system and is characterized by fever, hepato-splenomegaly and pancytopenia. The serum level of interferon-gamma in the syndrome is increased but its origin is unknown. Here we describe a case of NK cell leukemia with hemophagocytic syndrome with elevated serum level of interferon-gamma. The levels of various cytokines were monitored during the course and statistic analysis was performed. To identify the clonal component, the NK cell fraction was sorted from the mononuclear layer and was subjected to Southern blot hybridization with a probe for EB virus tandem repeats. The fraction was also stimulated with interleukin-2 and the level of interferon-gamma in the conditioned medium was measured. Levels of M-CSF and interferon-gamma were significantly correlated with the degree of clinical manifestations and laboratory data. Southern blot hybridization revealed monoclonality of an NK cell fraction. The fraction also released interferon-gamma. Since macrophage can be activated through cytokines, the hemophagocytosis might have been triggered by factor(s) released from the abnormal NK cell clone at least in this case.
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PMID:Hemophagocytosis as a para-neoplastic syndrome in NK cell leukemia. 885 71

Hemophagocytic syndrome (HPS) is a clinicopathologic syndrome that can reveal a non-Hodgkin's lymphoma. The pathologic features of lymphoma associated with HPS remain ill defined. We studied 11 lymphomas associated with HPS on initial bone marrow biopsies, consecutively diagnosed during a 6-year period in a Western institution. There were seven diffuse large B-cell lymphomas (DLBCLs), three T-cell lymphomas (one peripheral T-cell lymphoma unspecified, two hepatosplenic gammadelta T-cell lymphomas [HS gammadeltaTLs]), and one aggressive NK-cell lymphoma/leukemia (NKL). These lymphomas shared common clinicopathologic features with a systemic presentation, a poor outcome (nine patients died within 2 years), and a mild interstitial lymphoid infiltrate of the bone marrow at presentation in nine patients. This equivocal lymphoma infiltrate was blending with normal hematopoietic cells, and CD20 and CD3 immunolabelings were essential for its detection. A high number of reactive T (CD3+) cells, most often with a predominant cytotoxic (CD8+ TiA1+) phenotype, was present in all DLBCLs. By in situ hybridization, Epstein-Barr virus was detected in neoplastic cells of three cases (one DLBCL, one HS gammadeltaTL, and one NKL), which also showed serum viral DNA. Polymerase chain reaction studies disclosed HHV6 DNA sequences in tumor tissues of two DLBCLs, whereas HHV8 DNA was not detected. Because tumor mass indicative of lymphoma was not striking in most patients, bone marrow biopsy appears to be of great value for the diagnosis of an HPS-associated lymphoma, which may be, in Western patients, of B- as well as T- or NK-cell type. Immunostaining for CD3 and CD20 is essential to identify the common subtle lymphoma involvement. Together with a better understanding of the pathogenic processes, an early diagnosis may improve the prognosis of HPS-associated lymphoma.
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PMID:Bone marrow involvement in lymphomas with hemophagocytic syndrome at presentation: a clinicopathologic study of 11 patients in a Western institution. 1142 Apr 57

Natural killer cell leukemia (NK leukemia) is an aggressive form of lymphoproliferative disease of granular lymphocytes, and frequently complicates fulminant hemophagocytic lymphohistiocytosis. NK leukemia cells usually possess a single episomal form of Epstein-Barr virus (EBV), and therefore originate from a single EBV-infected NK cell. The NK leukemia cells lack endogenous Bcl-2 expression and are sensitive to apoptotic cell death. However, they constitutively produce interferon-gamma and maintain their survival in an autocrine fashion. The interferon-gamma released from NK leukemia cells may trigger the occurrence of hemophagocytic lymphohistiocytosis through activating macrophages/histiocytes. In the primary infection of EBV, T cells infected with the episomal form of EBV sometimes produce a high amount of interferon-gamma that may lead to the occurrence of hemophagocytic lymphohistiocytosis. Thus, it is important to determine the role of EBV in the increased production of interferon-gamma that occurs in EBV-infected T and NK cells to clarify the developmental mechanism of NK leukemia and its paraneoplastic hemophagocytic lymphohistiocytosis.
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PMID:Epstein-Barr virus-infected natural killer cell leukemia. 1142 29

Epstein-Barr virus (EBV) is the major triggering factor producing hemophagocytic syndrome or hemophagocytic lymphohistiocytosis (HLH). In this review, diagnostic problems, clinical and histopathological features, and treatment strategies of EBV-HLH have been described. In patients with EBV-HLH, the EBV-infected T cells or natural killer (NK) cells are mostly mono- or oligo-clonally proliferating, where hypercytokinemia plays a major role and causes hemophagocytosis, cellular damage and dysfunction of various organs. Although the majority of EBV-HLH cases develop in apparently immunocompetent children and adolescents, it also occurs in association with infectious mononucleosis, chronic active EBV infection, familial HLH, X-linked lymphoproliferative disease, lymphoproliferative disease like peripheral T-cell lymphoma and NK cell leukemia. In terms of treatment, special therapeutic measures are required to control the cytokine storm generated by EBV and to suppress proliferating EBV-genome-containing cells, because the clinical courses are often fulminant and result in a poor outcome.
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PMID:Clinical features and treatment strategies of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis. 1246 66

Epstein-Barr virus (EBV) is a ubiquitous virus that infects the majority of the world population by adulthood. The major target for infection is the B lymphocyte, and acute infection causes vigorous EBV-specific killer T-cell responses exemplified clinically by acute infectious mononucleosis (IM). EBV infection usually persists latently life-long without eliciting any clinical symptoms. Rarely, active EBV infection is prolonged, with abnormal expansions of EBV-infected T or NK cells, conditions collectively defined here as EBV-associated T/NK lymphoproliferative diseases. Hemophagocytic lymphohistiocytosis (HLH), chronic active EBV infection (CAEBV), NK lymphoma/leukemia, and T-cell lymphoma are entities included in this category. Hypersensitivity to mosquito bite (HMB) represents a unique syndrome characterized by expansion of EBV-infected NK cells in the peripheral circulation and within the inflammatory skin lesions induced by mosquito bites. Target cell specificity, defects in host immune responses, and strain differences of EBV may account for ectopic EBV infections and for the unique clinical presentations characteristic of each illness.
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PMID:Epstein-Barr virus-associated T-/natural killer cell lymphoproliferative diseases. 1270 89

We report a rare case of a cute lymphoblasticleukemia (ALL) who developed dyspnea, neurological disturbance with illusions, pancytopenia, phagocytosis and coagulation disturbances following bacterial tonsillitis. The values of soluble interleukin-2 receptor (sIL-2R), IL-6 and IL-8 were also elevated. Her clinicolaboratory findings were similar to hemophagocytic lymphohistiocytosis (HLH), which is a cytokine disease induced by activated T cells and macrophages. Atypical HLH following bacterial tonsillitis should be kept in mind in leukemia patients.
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PMID:Atypical hemophagocytic lymphohistiocytosis following bacterial tonsillitis in acute lymphoblastic leukemia. 1291 81

About 30% of cases of the autosomal recessive immunodeficiency disorder hemophagocytic lymphohistiocytosis are believed to be caused by inactivating mutations of the perforin gene. We expressed perforin in rat basophil leukemia cells to define the basis of perforin dysfunction associated with two mutations, R225W and G429E, inherited by a compound heterozygote patient. Whereas RBL cells expressing wild-type perforin (67 kD) efficiently killed Jurkat target cells to which they were conjugated, the substitution to tryptophan at position 225 resulted in expression of a truncated ( approximately 45 kD) form of the protein, complete loss of cytotoxicity, and failure to traffic to rat basophil leukemia secretory granules. By contrast, G429E perforin was correctly processed, stored, and released, but the rat basophil leukemia cells possessed reduced cytotoxicity. The defective function of G429E perforin mapped downstream of exocytosis and was due to its reduced ability to bind lipid membranes in a calcium-dependent manner. This study elucidates the cellular basis for perforin dysfunctions in hemophagocytic lymphohistiocytosis and provides the means for studying structure-function relationships for lymphocyte perforin.
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PMID:The functional basis for hemophagocytic lymphohistiocytosis in a patient with co-inherited missense mutations in the perforin (PFN1) gene. 1536 97

Up to 60% of cases of the autosomal recessive immunodeficiency hemophagocytic lymphohistiocytosis (HLH) are associated with mutations in the perforin (PRF1) gene. In this study, we expressed wild-type and mutated perforin in rat basophil leukemia cells to study the effect on lytic function of the substitutions A91V and N252S (commonly considered to be neutral polymorphisms) and 22 perforin missense substitutions first identified in HLH patients. Surprisingly, we found that A91V perforin was expressed at reduced levels compared with wild-type perforin, resulting in partial loss of lytic capacity. In contrast, expression and function of N252S-substituted perforin were normal. Most HLH-associated mutations resulted in protein degradation (probably due to misfolding) and complete loss of perforin activity, the exception being R232H, which retained approximately 30% wild-type activity. Several other mutated proteins (H222Q, C73R, F157V, and D313V) had no detectable lytic activity but were expressed at normal levels, suggesting that their functional defect might map downstream at the level of the target cell membrane. One further perforin substitution identified in an HLH patient (V183G) was normally expressed and displayed normal lysis. This report represents the first systematic functional analysis of HLH-associated missense mutations and the 2 most common perforin polymorphisms.
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PMID:A functional analysis of the putative polymorphisms A91V and N252S and 22 missense perforin mutations associated with familial hemophagocytic lymphohistiocytosis. 1575 97

Epstein-Barr virus (EBV)-associated T/NK-cell lymphoproliferative disease (LPD) has been linked to several different disorders. Its prognosis is generally poor and a treatment strategy has yet to be established. There are reports, however, that hematopoietic stem cell transplantation (HSCT) can cure this disease. To clarify the current situation regarding allogeneic hematopoietic stem cell transplantation (allo-HSCT) for EBV-associated T/NK-LPD, a nationwide survey was performed in Japan. Data for 74 patients were collected. There were 42 cases of chronic active EBV infection (CAEBV), 10 cases of EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH), and 22 cases of EBV-associated lymphoma/leukemia (EBV-lymphoma/leukemia). Of those with CAEBV, 54% had the EBV-infected T-cell type and 59% with EBV-lymphoma/leukemia had the EBV-infected NK-cell type. Most patients with EBV-HLH and EBV-lymphoma/leukemia received allo-HSCT within 1 year after onset compared to only 14% of patients with CAEBV. The event-free survival (EFS) rate following allo-HSCT was 0.561 +/- 0.086 for CAEBV, 0.614 +/- 0.186 for EBV-HLH, and 0.309 +/- 0.107 for EBV-lymphoma/leukemia. The EFS of allo-HSCT with conventional conditioning was 0.488 +/- 0.074 and with reduced-intensity conditioning was 0.563 +/- 0.124. Thus, in a substantial number of cases, EBV-associated T/NK-LPD can be cured by either allogeneic conventional stem cell transplantation or reduced-intensity stem cell transplantation.
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PMID:Allogeneic hematopoietic stem cell transplantation for Epstein-Barr virus-associated T/natural killer-cell lymphoproliferative disease in Japan. 1862 84


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