Chemoimmunotherapy for hemophagocytic lymphohistiocytosis: long-term results of the HLH-94 treatment protocol

Hemophagocytic lymphohistiocytosis (HLH) used to have a dismal prognosis. We report the final results of HLH-94, the largest prospective diagnostic/therapeutic HLH study so far. The treatment includes immunosuppressive and cytotoxic therapy aiming at clinical remission, followed by HSCT in patients with familial, persistent, or recurrent disease. Altogether, 249 patients fulfilled inclusion criteria and started HLH-94 therapy (July 1994-December 2003); 227 (91%) were followed-up for ≥ 5 years. At 6.2 years median follow-up, estimated 5-year probability of survival was 54% ± 6%. Seventy-two patients (29%) died before HSCT, 64 within 1 year, 97% of whom had active disease. In 124 patients who underwent HSCT, 5-year survival was 66 ± 8%; tendency to increased survival (P = .064) in patients with nonactive disease at HSCT. Patients with familial disease had a 5-year survival of 50% ± 13%; none survived without HSCT. Patients deceased during the first 2 months more often had jaundice, edema, and elevated creatinine. Forty-nine patients (20%) were alive without signs of HLH activity and off-therapy > 1-year without HSCT; they presented at older age (P < .001), were more often female (P = .011), and less often had CNS disease (P < .001) or hepatomegaly (P = .007). To conclude, HLH-94 chemoimmunotherapy has considerably improved outcome in HLH. Collaborative efforts are needed to further reduce early mortality, HSCT-related mortality, and neurologic late effects.     

Successful engraftment of haploidentical stem cell transplant for familial haemophagocytic lymphohistiocytosis using both bone marrow and peripheral blood stem cells

Familial haemophagocytic lymphohistiocytosis (HLH) is a disease with a very poor prognosis unless patients receive a bone marrow transplant. It is often difficult to find an HLA-matched donor and haploidentical familial donors may be considered. The main complication of this type of transplant is graft rejection. We describe a patient with familial HLH who received a haploidentical transplant using both mobilized peripheral blood and bone marrow stem cells in an attempt to overcome graft rejection by increasing the stem cell dose. The peripheral blood stem cell inoculum was CD34 enriched using a Cellpro column and T-cell depleted by Campath-1M, the patient received conditioning for a matched sibling donor transplant with the addition of Campath 1G. There was rapid and full engraftment and the patient remains disease free at 5 months. This technique may be applicable for other fatal inborn errors in the absence of an HLA-matched donor.     

Hemophagocytic lymphohistiocytosis: Recent progress in the pathogenesis,diagnosis and treatment

Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome that develops as a primary (familial/hereditary) or secondary (non-familial/hereditary) disease characterized in the majority of the cases by hereditary or acquired impaired cytotoxic T-cell (CTL) and natural killer responses. The molecular mechanisms underlying impaired immune homeostasis have been clarified, particularly for primary diseases. Familial HLH (familial hemophagocytic lymphohistiocytosis type 2-5, Chediak-Higashi syndrome, Griscelli syndrome type 2, Hermansky-Pudlak syndrome type 2) develops due to a defect in lytic granule exocytosis, impairment of (signaling lymphocytic activation molecule)-associated protein, which plays a key role in CTL activity [e.g., X-linked lymphoproliferative syndrome (XLP) 1], or impairment of X-linked inhibitor of apoptosis, a potent regulator of lymphocyte homeostasis (e.g., XLP2). The development of primary HLH is often triggered by infections, but not in all. Secondary HLH develops in association with infection, autoimmune diseases/rheumatological conditions and malignancy. The molecular mechanisms involved in secondary HLH cases remain unknown and the pathophysiology is not the same as primary HLH. For either primary or secondary HLH cases, immunosuppressive therapy should be given to control the hypercytokinemia with steroids, cyclosporine A, or intravenous immune globulin, and if primary HLH is diagnosed, immunochemotherapy with a regimen containing etoposide or anti-thymocyte globulin should be started. Thereafter, allogeneic hematopoietic stem-cell transplantation is recommended for primary HLH or secondary refractory disease (especially EBV-HLH).     

Clinical presentation of Crohn's disease. association between familial disease, smoking, disease phenotype, extraintestinal manifestations and need for surgery

BACKGROUND/AIMS: Recent molecular data suggest that genetic factors may underlie the disease heterogeneity observed in Crohn's disease (CD). It was also suggested that familial inflammatory bowel disease (IBD) is a homogenous subgroup, phenotypically different from sporadic disease. Our aim was to determine the clinical presentation in a large CD population. METHODOLOGY: 564 CD patients (m/f: 278/286, age: 37.4 (SD 12.7) yrs, duration: 8.4 (7.1) yrs) were included. Disease phenotype was determined according to Vienna classification. Familial disease, extraintestinal manifestations (EIM), need for surgery and smoking habits were also analyzed. RESULTS: Familial IBD was present in 73 (12.9%) patients. Age at onset and presence of EIMs was associated with familial disease. Penetrating (44.6% vs. <10 yrs: 29.1%, P<0.0001) and ileocolonic disease (54.4% vs. 42.8%, P=0.03) were more common in patients with a disease duration of > or =10 yrs. In a logistic regression model female gender, colonic/ileocolonic location, smoking and familial IBD were independent risk factors for EIMs, while ileal and non-inflammatory disease increased the risk for resections. Smoking was also associated with frequent relapses. CONCLUSIONS: Familial IBD was associated with the presence of EIMs, while ileal involvement and noninflammatory behavior independently increased the risk for surgery. Since penetrating and extensive disease was more frequent in patients with longer disease duration our data support a possible change in location and behavior during the course of disease.     

Haemophagocytic lymphohistiocytosis and Epstein–Barr virus: a complex relationship with diverse origins,expression and outcomes

Epstein–Barr virus (EBV) is a ubiquitous herpesvirus with rare but severe potential for lymphoproliferative complications. EBV is associated with a variety of presentations of haemophagocytic lymphohistiocytosis (HLH). HLH is a life-threatening hyperinflammatory syndrome that can occur in patients with genetic defects associated with dysregulation of the immune response (familial HLH) or arise in patients with underlying infection or malignancy (non-familial or secondary HLH). EBV can both serve as the incidental trigger of familial HLH or as the driving factor in patients with selective inherited vulnerability (e.g. X-linked lymphoproliferative disease). Alternatively, acute infection can idiosyncratically cause non-neoplastic HLH in patients without inherited predisposition (i.e. secondary HLH), while EBV-associated T/natural killer (NK)-cell lymphoproliferative disorders and lymphomas can cause neoplasia-associated HLH. The present review will discern between EBV-associated familial and non-familial HLH and highlight diagnostic and therapeutic considerations. Non-familial EBV-associated HLH is a major diagnostic dilemma, as it represents a diverse spectrum of disease ranging from highly curable (non-neoplastic EBV-HLH) to indolent but incurable (chronic active EBV) to acutely fatal (systemic EBV-positive T-cell lymphoma of childhood). Increased clinical awareness and understanding of this rare and potentially devastating subset of EBV-related complications is desperately needed to improve survival for patients with neoplasia-associated HLH.     

Hemophagocytic lymphohistiocytosis: An update on pathogenesis,diagnosis, and therapy

Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening state of immune hyperactivation that arises in the setting of genetic mutations and infectious, inflammatory, or neoplastic triggers. Sustained, aberrant activation of cytotoxic CD8⁺ T cells and resultant inflammatory cytokine release are core pathogenic mechanisms. Key clinical features include high persistent fever, hepatosplenomegaly, blood cytopenia, elevated aminotransferase and ferritin levels, and coagulopathy. HLH is likely under-recognized, and mortality remains high, especially in adults; thus, prompt diagnosis and treatment are essential. Familial forms of HLH are currently treated with chemotherapy as a bridge to hematopoietic stem cell transplantation. HLH occurring in rheumatic disease (macrophage activation syndrome) is treated with glucocorticoids, IL-1 blockade, or cyclosporine A. In other forms of HLH, addressing the underlying trigger is essential. There remains a pressing need for more sensitive, context-specific diagnostic tools. Safer, more effective therapies will arise with improved understanding of the cellular and molecular mechanisms of HLH.     

Elevated serum ferritin is not specific for hemophagocytic lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) is a rare, potentially fatal, syndrome of excessive and ineffective activation of the immune system. The majority of the reported data on HLH is from pediatric patients and lacks specificity. This makes HLH diagnosis challenging especially in adults where HLH is triggered by many conditions and can resemble many disease entities. Elevated ferritin is one of the diagnostic criteria for HLH. We determined the conditions associated with elevated ferritin at our medical center to assess how specific ferritin is for predicting HLH. We retrospectively reviewed all ferritin results >10,000 μg/L in pediatric and adult patients. The most common condition associated with elevated ferritin was hematologic malignancy in adults (25.7%) and HLH in pediatric patients (48.9%). HLH was diagnosed in 14.2% of adults and 48.9% of children with ferritin >10,000 µg/L. Hyperferritinemia occurs in a variety of conditions and is not specific for adult or pediatric HLH. Common causes of elevated ferritin should be considered before entertaining the possibility of HLH, especially in adult patients.     

Clinical characteristics,prognostic factors,and outcomes of adult patients with hemophagocytic lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) is a rare clinical syndrome characterized by the activation of the mononuclear phagocytic system. The diagnosis of HLH in adults is challenging not only because the majority of the reported data are from pediatric patients, but also because HLH occurs in many disease entities. This study reports the clinical and laboratory findings and prognostic factors of adult HLH in a large cohort managed at a single medical center from 2003 to 2014. Seventy‐three patients met the HLH‐2004 diagnostic criteria. The median age was 51 years (range, 18–82 years); 41 (56.2%) were male. Patients manifested fever, cytopenias, and elevated ferritin in >85% of cases. Likely causes of HLH were as follows: 30 (41.1%) infections, 21 (28.8%) malignancies, 5 (6.8%) attributed to autoimmune disorders, 1 (1.4%) primary immunodeficiency, 2 (2.7%) post solid organ transplantation, and 13 (17.8%) idiopathic. The median overall survival was 7.67 months. Patients with malignancy‐associated HLH had a markedly worse survival compared with patients with non–malignancy‐associated HLH (median overall survival 1.13 vs. 46.53 months, respectively; P < 0.0001). In a multivariable analysis, malignancy (hazard ratio = 12.22; 95% CI: 2.53–59.02; P = 0.002) correlated with poor survival. Ferritin >50,000 µg/L correlated with 30‐day mortality. Survival after a diagnosis of HLH is dismal, especially among those with malignancy‐associated HLH. The development of a registry for adults with HLH would improve our understanding of this syndrome, validate diagnostic criteria, and help develop effective treatment strategies. Am. J. Hematol. 90:220–224, 2015. © 2014 Wiley Periodicals, Inc.     

Mutations of the hemophagocytic lymphohistiocytosis-associated gene UNC13D in a patient with systemic juvenile idiopathic arthritis

The clinical syndromes of hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are both characterized by dysregulated inflammation with prolonged fever, hepatosplenomegaly, coagulopathy, hematologic cytopenias, and evidence of hemophagocytosis in the bone marrow or liver. While HLH is either inherited or acquired, children with severe rheumatic diseases, most notably systemic juvenile idiopathic arthritis, are at risk for MAS. The phenotypic similarity between HLH and MAS raises the possibility that they share common pathogenetic mechanisms. Familial forms of HLH have been attributed to mutations in the genes encoding perforin (PRF1) and Munc13-4 (UNC13D), among others, and are characterized by defective cytotoxic lymphocyte function. While some patients with systemic JIA have decreased levels of perforin protein expression and natural killer (NK) cell function, mutations of HLH-associated genes in patients with systemic JIA have not been reported. We report the case of an 8-year-old girl with systemic JIA without MAS who was found to have compound heterozygous mutations of UNC13D and reduced NK cell cytotoxic function. This case broadens the range of clinical phenotypes attributable to UNC13D mutations and offers new insights into the etiology and pathogenesis of systemic JIA.     

Subtyping of natural killer cell cytotoxicity deficiencies in haemophagocytic lymphohistocytosis provides therapeutic guidance

The familial form of haemophagocytic lymphohistiocytosis (HLH) is a fatal disease, with allogeneic stem cell transplantation (SCT) being the only curative treatment. In contrast, patients with secondary (infection-associated) HLH usually do not require SCT. Since it often is difficult to distinguish primary and secondary HLH, we wanted to identify a tool that provides guidance on whether SCT is required. The clinical outcome of 65 HLH patients was analysed in relation to the recently reported four types of defects in natural killer (NK)-cell cytotoxicity in HLH. None (0%) of the 36 patients with NK-cell deficiency type 3 attained a sustained (1-year) remission after stopping therapy without receiving SCT, in contrast to 45% (13/29) non-type 3 patients (P < 0.001). Most type 3 patients (22/36) underwent SCT (14/22, 64% are alive), whereas 11 of 14 that did not receive SCT died, and the three others had received HLH-therapy during the last year of follow-up. Of 54 patients analysed for perforin expression and/or mutation, the five with perforin deficiency were all type 3 patients. The data suggests that HLH patients with NK-cell deficiency type 3 will probably require SCT to survive. Thus, NK-cell deficiency classification may provide valuable guidance in judging whether an HLH-patient needs SCT.     

Mutations of the hemophagocytic lymphohistiocytosis–associated gene UNC13D in a patient with systemic juvenile idiopathic arthritis

The clinical syndromes of hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are both characterized by dysregulated inflammation with prolonged fever, hepatosplenomegaly, coagulopathy, hematologic cytopenias, and evidence of hemophagocytosis in the bone marrow or liver. While HLH is either inherited or acquired, children with severe rheumatic diseases, most notably systemic juvenile idiopathic arthritis, are at risk for MAS. The phenotypic similarity between HLH and MAS raises the possibility that they share common pathogenetic mechanisms. Familial forms of HLH have been attributed to mutations in the genes encoding perforin (PRF1) and Munc13‐4 (UNC13D), among others, and are characterized by defective cytotoxic lymphocyte function. While some patients with systemic JIA have decreased levels of perforin protein expression and natural killer (NK) cell function, mutations of HLH‐associated genes in patients with systemic JIA have not been reported. We report the case of an 8‐year‐old girl with systemic JIA without MAS who was found to have compound heterozygous mutations of UNC13D and reduced NK cell cytotoxic function. This case broadens the range of clinical phenotypes attributable to UNC13D mutations and offers new insights into the etiology and pathogenesis of systemic JIA.     

Familial resemblance of asthma severity in the EGEA* study.

Familial resemblance of asthma is well known but epidemiological research focused on familial resemblance of asthma severity is scanty. We studied whether asthma and asthma severity in first-degree relatives of cases with asthma were related to asthma severity of the index case. The analysis was based upon the examination of 944 subjects (348 cases, 239 relatives with asthma, and 357 subjects without asthma) and upon the information on 3467 first- degree relatives of probands. The risks of asthma in relatives of adult and pediatric cases were significantly higher than in relatives of subjects without asthma (OR 3.4 [95% CI 2.5-4.7] and 4.5 [2.6- 8.1], respectively). Proportions of asthma in relatives were not related to the asthma severity of cases for the three severity criteria studied (clinical score, FEV(1) % predicted, and inhaled corticosteroid use). Using both regression models and intraclass correlation coefficients, there was a significant familial resemblance for the clinical severity score (ICC = 0.23 and 0.23) and for FEV(1) (ICC = 0.19 and 0.25) among families of pediatric and adult probands, respectively. In conclusion, asthma occurrence in relatives may be independent of the severity of the cases with asthma, but results suggest familial resemblance in the severity of asthma when it occurs.     

Comprehensive analyses and characterization of haemophagocytic lymphohistiocytosis in Vietnamese children

Haemophagocytic lymphohistiocytosis (HLH) is a fatal haematological disorder with diverse aetiology. This prospective study was undertaken to characterize HLH cases in Vietnamese children. Clinical and laboratory data, genetic analyses and outcome of the HLH patients were analysed. A total of 33 patients were enrolled from March 2007 to December 2008, with a median age of 3 years. Mutations of the SH2D1A ( SAP ) and PRF1 genes were detected in one patient, respectively. The virus association was high, up to 63·6% (21/33), including Epstein–Barr virus (19/33), cytomegalovirus (2/33) and dengue virus (2/33). Five patients had malignant lymphoma and two had autoimmune diseases. Twenty-eight patients were treated according to the HLH-2004 protocol. The first response rate was 64·3% (18/28), with an early death rate of 35·7% (10/28). High levels of interferon-γ, interleukin-10, MIG and interferon-inducible protein-10 (IP-10) were associated with early mortality ( P  <   0·05). Reactivation among the responders was high (9/18) and the uneventful resolution was low (3/18) after a median follow-up of 35 weeks. In conclusion, the majority of HLH cases are associated with virus infections in Vietnamese children. Familial HLH is rare. The frequent reactivation and high mortality demands a more appropriate therapeutic regimen in tropical areas like Vietnam.     

Hemophagocytic Lymphohistiocytosis: Clinical Analysis of 103 Adult Patients

To investigate the clinical features of adult patients with hemophagocytic lymphohistiocytosis (HLH) and to explore possible risk factors for death, we retrospectively reviewed the medical records of 103 adult HLH patients hospitalized from 1997 to 2012. We analyzed the underlying diseases, clinical characteristics, 1aboratory findings, outcomes, and prognostic factors. The most common cause of HLH was hematologic malignancies (n = 49), followed by infectious diseases (n = 24) and autoimmune disorders (n = 14); 24 cases were of unknown etiology. Eight patients had a combination of underlying diseases. HLH was clinically characterized by high fever (96.1%), splenomegaly (79.6%), hepatomegaly (65.0%), lymphadenopathy (53.4%), proteinuria (31.1%), skin rash (25.2%), gastrointestinal hemorrhage (14.6%), disseminated intravascular coagulation (13.6%), increased creatinine (7.8%), and central nervous system involvement (12.6%) including altered mental status (9.7%) and cranial hemorrhage (2.9%). Laboratory abnormalities included cytopenia (99.0%), serum ferritin >500 ug/L (98.4%), liver dysfunction (98.1%), hypertriglyceridemia (88.5%), hemophagocytosis in bone marrow smear (87.4%), and hypofibrinogenemia (60.9%).In addition to the treatment they received for the underlying causes, patients received therapy for HLH consisting of corticosteroids, immunosuppressive drugs, and intravenous immunoglobulin. Twenty-six patients (25.2%) recovered after treatment, and 19 of them achieved long-term remission during follow-up. Seventy-seven patients (74.8%) died because of tumor, sepsis, multiple organ failure, or HLH-related organ hemorrhage and coagulopathy. The deceased patients were more likely to be older at disease onset, male, and to present with splenomegaly and thrombocytopenia, compared to the survivors. Treatment for the underlying diseases combined with corticosteroids, immunosuppressive agents, and immunoglobulin therapy may improve the prognosis of HLH. More attention should be paid to high-risk patients to prevent the development of serious complications associated with HLH.Key words/Abbreviations: hemophagocytic lymphohistiocytosis, lymphoma, autoimmune diseases, clinical manifestation, prognosis, risk factor, AOSD = adult-onset Still disease, CNS = central nervous system, DIC = disseminated intravascular coagulation, CMV = cytomegalovirus, EBV = Epstein-Barr virus, HLH = hemophagocytic lymphohistiocytosis, IVIg = intravenous immunoglobulin, MAS = macrophage-activation syndrome, NK = natural killer, RA = rheumatoid arthritis, SLE = systemic lupus erythematosus     

Splenectomy in haemophagocytic lymphohistiocytosis: report of histopathological changes with CD19+ B-cell depletion and therapeutic results

The pathogenesis of haemophagocytic lymphohistiocytosis (HLH) in children without a known familial pattern of inheritance is often difficult to establish. Splenic enlargement, one of the main clinical findings in this disorder, has led to the use of splenectomy for uncontrollable coagulopathy, persistent cytopenia or both. This procedure is also thought to be a useful tool in making a differential diagnosis in cases of the immunochemotherapy-resistant HLH. We report here five cases of splenectomized childhood HLH, in which subsets of mononuclear spleen cells were analysed either by flow cytometry or immunohistochemistry, and the results were compared with those from cases of hereditary spherocytosis (controls). There was a statistically significant depletion of CD19+ B cells in the HLH cases (3.8 +/- 3.2% vs. 52.6 +/- 4.5%, P < 0. 0001) associated with an increase of T cells in three cases and of natural killer cells in another. The histopathological findings included atrophic white pulps, B-cell depletion with fibrosis and haemosiderosis in all five cases. Despite temporary therapeutic benefits, three of the HLH patients had a rapidly deteriorating post-splenectomy course and all three eventually died. These results demonstrate striking depletion of B cells in the enlarged spleens of children with HLH, which may be an intrinsic feature of HLH pathogenesis. Further study is needed to establish the therapeutic value of splenectomy in this disease.     

Central nervous system involvement in adults with haemophagocytic lymphohistiocytosis: a single-center study

Hemophagocytic lymphohistiocytosis (HLH) is a rare multisystem disorder characterized by proliferation and diffuse infiltration multiple organs with histiocytes, including the central nervous system (CNS). Neurological manifestations of HLH have been recognized in different studies with children, but they remain relatively ill-defined in adults with HLH. From March 2008 to October 2014, 289 adult patients with HLH were admitted to our center. Clinical, radiological, and cerebral spinal fluid (CSF) data of the patients with CNS involvement were reviewed, and a retrospective study in our single-center was carried out. CNS involvement was observed in 29 patients (10%) either in their diagnosis process or during disease course. CNS symptoms included disturbance of consciousness, cranial nerve palsies, seizures, headache, limb paralysis, irritability, meningism, and memory loss. CSF analysis was conducted in 17 patients (59%). Among them, 11 patients (65%) were reported as having abnormal CSF. Neuroradiological studies were performed in 25 patients (86%). Among the 13 cases that underwent CT scan, one patient hemorrhaged. Single or multiple hypodense foci were detected in the other 2 patients. Magnetic resonance imaging (MRI) abnormalities were found in 15 patients, including focal lesions in cortical and adjacent subcortical regions with or without variable nodular or ring contrast-enhancement, multiple lesions in white matter, diffuse white matter signal changes, and meningeal enhancement. Basal ganglia, cerebellum, and brainstem lesions were also observed. CNS involvement could also be found in adult patients with HLH, but not as frequent as it was in children. The clinical manifestations could be diversified. By carrying out rigorous CNS examinations, an early diagnosis could be made and it was of the utmost importance for the prevention of further lesions.     

Familial dilated cardiomyopathy in patients transplanted for idiopathic dilated cardiomyopathy

OBJECTIVE: To evaluate the prevalence, clinical features, and pattern of inheritance of familial dilated cardiomyopathy (DCM) in heart transplant patients. PATIENTS AND METHOD: Patients with idiopathic DCM who had undergone heart transplantation were invited to participate. Patients with alcohol abuse were excluded. A clinical evaluation, 12-lead ECG, echocardiogram, blood tests, and DNA extraction were performed in patients and relatives. Familial DCM was defined as the presence of at least one relative with idiopathic DCM. Possible familial DCM was considered when at least one relative had left ventricular enlargement (LVE) (> 112% predicted LVEDD). RESULTS: One hundred and ninety-nine relatives of 43 families were studied. DCM was familial in 11 probands (25.6%) and possibly familial in 11 (25.6%). Fifteen relatives had DCM (7.5%), 26 (13.1%) LVE, and 5 (2.5%) hypertrophic cardiomyopathy. The pattern of inheritance was autosomal dominant in most families. Five probands (3 with familial DCM) had antecedents of consanguinity and possible recessive inheritance. Six probands (14%, 1 with familial DCM) had relatives with conduction system defects. Creatine kinase was moderately increased in 9 relatives (4.5%), 3 of them with LVE. Fifteen patients had at least moderate alcohol intake. Three of them had familial DCM (relatives without alcohol abuse) and 6 had possible familial DCM. CONCLUSIONS: The prevalence of familial DCM is high in patients who undergo heart transplant. Left ventricular enlargement, conduction system abnormalities, and elevated creatine kinase may be early markers of familial disease. Hypertrophic cardiomyopathy is present in some relatives of patients with idiopathic DCM. Familial DCM is present in patients with a previous diagnosis of alcoholic DCM.     

A proportion of patients with lymphoma may harbor mutations of the perforin gene

Perforin mutations have been demonstrated in a proportion of patients diagnosed with the familial form of hemophagocytic lymphohistiocytosis (HLH). In the present study, we evaluated whether some patients with lymphoma sharing clinical characteristics with HLH might harbor mutations of the perforin gene. We analyzed 29 patients and found that 4 patients, who developed either Hodgkin or non-Hodgkin lymphoma, had biallelic mutations of the perforin gene. One of these 4 patients, a 19-year-old female with T-cell lymphoma, had a brother carrying the same mutations who developed HLH. In 2 of the 4 patients with biallelic mutations of the perforin gene, we evaluated perforin expression by flow cytometry and natural killer (NK) activity and both were found to be absent. Moreover, we documented the presence of monoallelic mutations of the perforin gene in 4 more patients. One of these 4 latter patients also carried a mutation of the Fas gene. These data indicate that perforin deficiency, either alone or in combination with other mutations of genes involved in lymphocyte survival or functional activity, may be present in patients with lymphoma. These findings suggest that perforin also plays a key role in the mechanisms of immune surveillance that prevent tumor growth and/or development.     

Clinical characterization of familial isolated pituitary adenomas

CONTEXT: Familial pituitary adenomas occur rarely in the absence of multiple endocrine neoplasia type 1 (MEN1) and Carney complex (CNC). OBJECTIVE: Our objective was to characterize the clinical and genealogical features of non-MEN1/CNC familial isolated pituitary adenomas (FIPA). DESIGN AND SETTING: We conducted a retrospective study of clinical and genealogical characteristics of FIPA cases and performed a comparison with a sporadic population at 22 university hospitals in Belgium, Italy, France, and The Netherlands. RESULTS: Sixty-four FIPA families including 138 affected individuals were identified [55 prolactinomas, 47 somatotropinomas, 28 nonsecreting adenomas (NS), and eight ACTH-secreting tumors]. Cases were MEN1/PRKAR1A-mutation negative. First-degree relationships predominated (75.6%) among affected individuals. A single tumor phenotype occurred in 30 families (homogeneous), and heterogeneous phenotypes occurred in 34 families. FIPA cases were younger at diagnosis than sporadic cases (P = 0.015); tumors were diagnosed earlier in the first vs. the second generation of multigenerational families. Macroadenomas were more frequent in heterogeneous vs. homogeneous FIPA families (P = 0.036). Prolactinomas from heterogeneous families were larger and had more frequent suprasellar extension (P = 0.004) than sporadic cases. Somatotropinomas occurred as isolated familial somatotropinoma cases and within heterogeneous FIPA families; isolated familial somatotropinoma cases represented 18% of FIPA cases and were younger at diagnosis than patients with sporadic somatotropinomas. Familial NS cases were younger at diagnosis (P = 0.03) and had more frequently invasive tumors (P = 0.024) than sporadic cases. CONCLUSIONS: Homogeneous and heterogeneous expression of prolactinomas, somatotropinomas, NS, and Cushing's disease can occur within families in the absence of MEN1/CNC. FIPA and sporadic cases have differing clinical characteristics. FIPA may represent a novel endocrine neoplasia classification that requires further genetic characterization.     

Treatment of hemophagocytic lymphohistiocytosis with HLH-94 immunochemotherapy and bone marrow transplantation

Hemophagocytic lymphohistiocytosis (HLH) comprises familial (primary) hemophagocytic lymphohistiocytosis (FHL) and secondary HLH (SHLH), both clinically characterized by fever, hepatosplenomegaly, and cytopenia. FHL, an autosomal recessive disease invariably fatal when untreated, is associated with defective triggering of apoptosis and reduced cytotoxic activity, resulting in a widespread accumulation of T lymphocytes and activated macrophages. In 1994 the Histiocyte Society initiated a prospective international collaborative therapeutic study (HLH-94), aiming at improved survival. It combined chemotherapy and immunotherapy (etoposide, corticosteroids, cyclosporin A, and, in selected patients, intrathecal methotrexate), followed by bone marrow transplantation (BMT) in persistent, recurring, and/or familial disease. Between July 1, 1994, and June 30, 1998, 113 eligible patients aged no more than 15 years from 21 countries started HLH-94. All had either an affected sibling (n = 25) and/or fulfilled the Histiocyte Society diagnostic criteria. At a median follow-up of 3.1 years, the estimated 3-year probability of survival overall was 55% (95% confidence interval +/- 9%), and in the familial cases, 51% (+/- 20%). Twenty enrolled children were alive and off therapy for more than 12 months without BMT. For patients who received transplants (n = 65), died prior to BMT (n = 25), or were still on therapy (n = 3), the 3-year survival was 45% (+/- 10%). The 3-year probability of survival after BMT was 62% (+/- 12%). HLH-94 is very effective, allowing BMT in most patients. Survival of children with HLH has been greatly improved.