A phase II trial using thalidomide for Langerhans cell histiocytosis

BACKGROUND: Few new drugs for treatment of Langerhans cell histiocytosis (LCH) have been studied. Tumor necrosis factor-alpha (TNF-alpha) is a prime therapeutic target since it appears to be present in elevated amounts in LCH lesions. Thalidomide inhibits TNF-alpha production by affecting the gene promoter as well as other anti-cytokine effects. PROCEDURES: A Phase II trial of thalidomide for treatment of LCH patients who had failed primary and at least one secondary regimen was conducted. Sixteen patients were enrolled: nine males and seven females ranging in age from 19 months to 45 years. Six patients were high risk (HR) because of spleen, liver, lung, or bone marrow involvement. The low risk (LR) patients included six with bone/skin LCH, one with multiple bone, one with skin/bone/pituitary, one with skin/bone/brain, and one with skin only disease involvement. Fifteen patients remained on treatment from 3 weeks to over 1 year. RESULTS: Among the LR patients there were four complete responses, three partial responses, and two with no response to thalidomide. No HR patient responded to thalidomide and all died of pulmonary, liver, or bone marrow failure. Thalidomide may have played a role in the pulmonary failure. Other toxicities that required stopping therapy included neutropenia, peripheral neuropathy, and fatigue. CONCLUSIONS: Thalidomide is an effective therapy for some LR patients with LCH, but showed no significant responses in HR patients. Dose-limiting toxicities may reduce its efficacy in LR patients. Additional trials with improved anti-TNF therapies would appear warranted.     

HLAs in children with minimal change disease and other types of nephrotic syndrome in the southern part of Turkey

The aim of this study was to investigate the human leukocyte antigen (HLA) profile of children with nephrotic syndrome in the southern part of Turkey. Seventy-eight children with nephrotic syndrome were studied for the frequency of class I and class II human leukocyte antigens. Forty-seven of them were steroid sensitive nephrotic syndrome (minimal change disease-MCD) and 31 were other types of nephrotic syndrome. The results were compared with 133 healthy subjects for HLA groups. HLA B13, Cw5, Cw7, DR4, DR7, DRw10, Drw15(2) and DQ2 in the MCD group and HLA A31, B8, B13, B17, Cw2, Cw6, Cw7, DRw10 and DRw12 in the non-MCD group were found significantly increased when compared to healthy controls. MCD patients with frequent relapses had higher frequencies of both Cw6 and DR1 (p < 0.005) and MCD patients with infrequent relapses had a higher frequency of Cw7 (p < 0.05). In conclusion, HLA groups may help in the early diagnosis of these variants.     

Predictors of outcome in children with Langerhans cell histiocytosis

BACKGROUND: Our goal was to examine the clinical course of patients with Langerhans cell histiocytosis (LCH), with a special emphasis on bone disease and to attempt to identify and examine the factors that may predict reactivation and overall prognosis. PROCEDURE: We conducted a retrospective chart review of 132 consecutive pediatric patients treated at Children's Hospital Los Angeles for LCH from 1984 to 2001. RESULTS: The risk for reactivation after initial management is significantly higher for patients with multiple bone and those with multiple organ involvement as compared with patients who had a single bone lesion (hazard ratios are 7.1 and 11.6). Patients younger than 1 year in the multiple organ group have an increased risk of death at 2 years when compared with the older patients in that group (hazard ration = 6.2, P = 0.022). Endocrine abnormalities were seen in 20% and 7.5% of patients with or without skull lesions respectively. CONCLUSIONS: Patients with LCH involving only the bones have a significantly better outcome than those with other organ involvement. Patients with multiple organ involvement who are less than 1 year of age are at high risk of death and should be approached more aggressively upfront.     

Serum levels of interleukin-1 receptor antagonist and tumor necrosis factor-alpha are elevated in children with Langerhans cell histiocytosis

PURPOSE: Langerhans cell histiocytosis (LCH) is a rare disease with variable prognosis in which lesions and clinical features suggest that pro- and anti-inflammatory cytokines may be involved in its pathogenesis. The authors wished to evaluate whether serum levels of interleukin-1 receptor agonist (IL-1Ra) and tumor necrosis factor-alpha (TNF-alpha) are elevated in children with LCH and decrease after chemotherapy. PATIENTS AND METHODS: Circulating levels of IL-1Ra and TNF-alpha were measured in 23 and 8 children with LCH, respectively, and 7 pediatric controls using commercially available ELISA kits. All patients fulfilled the Histiocyte Society LCH Protocols criteria for diagnosis, stratification, and treatment. RESULTS: Pretreatment concentrations of IL-1Ra and TNF-alpha were found to be significantly elevated in patients with LCH compared with controls. Among LCH substages, a significant difference in IL-1Ra values was observed between individuals with single-system single-site disease vs. multisystem disease with risk-organ dysfunction. In all eight patients evaluated, IL-1Ra levels decreased after 6 weeks of chemotherapy. Lower values of TNF were observed in three patients after treatment. A positive and significant correlation between IL-1Ra and TNF serum concentrations was found. CONCLUSIONS: Patients with LCH have elevated levels of IL-1Ra and TNF, which decrease after chemotherapy.     

人类白细胞抗原与儿童郎格罕组织细胞增生症关联的研究

目的 探讨郎格罕见组织细胞增生症是否与免疫遗传学有关,方法 采用国际标准人类白细胞抗原（ＨＬＡ）抗血清和国际标准微量淋巴细胞毒试验方法,对北京地区经北京儿童医院确诊的４８例年龄为２．５～１５岁的郎格罕组织细胞增生症患者进行了ＨＬＡ－Ａ,ＨＬＡ－Ｂ,ＨＬＡ－ＤＲ抗原检测,并以１００例北京健康成人作为对照组进行分析。结果 本病患儿呈显著增高的抗原有ＨＬＡ－ＤＲ３（ＲＲ＝７．４６,Ｐｃ〈０．０１）和ＨＬ     

Normal monocyte-derived dendritic cell function in patients with Langerhans-cell-histiocytosis

BACKGROUND: Langerhans cell histiocytosis (LCH) is a histiocytic disease, characterized by the lesional accumulation of dendritic Langerhans cells together with T cells and eosinophils. The cause of this disease is unknown. Langerhans cells are bone marrow-derived dendritic cells (DCs), which can develop from CD34(+) hematopoietic progenitor cells as well as from monocytes. PROCEDURE: To test whether LCH patients have a general functional defect present in cells of their DC lineage, we generated immature DCs by culturing monocytes from nine patients with single- or multisystem LCH with GM-CSF and IL-4, and analyzed their phenotype and function before and after an in vitro maturation stimulus. Immature DCs were analyzed for their phenotype and cytokine production, DCs matured in response to TNF-alpha plus PGE(2) were analyzed for their phenotype, their stimulatory capacity in MLR, cell aggregation, and activation-induced apoptosis. RESULTS: In summary, no difference was found between both immature as well as mature DCs generated from patients and controls regarding the expression of CD1a, CD80, CD86, MHC class I, and MCH class II antigens. Similarly, no difference was found regarding IL-10, -12, and TNF-alpha production, as well as regarding cell aggregation and apoptosis in response to external stimuli. CONCLUSIONS: The absence of gross functional abnormalities in DCs generated from monocytes from patients with LCH makes the existence of a severe functional defect affecting all cells of the DC lineage in these patients unlikely.     

Whole-body MRI of Langerhans cell histiocytosis: comparison with radiography and bone scintigraphy

Background In Langerhans cell histiocytosis (LCH) evaluation of the extent of disease is one of the major predictors of patient outcome. Historically this is undertaken using plain radiography and bone scintigraphy. Recently, whole-body (WB) MRI has been reported to be useful in detecting skeletal and extraskeletal metastases in both adults and children. Objective To evaluate the usefulness of WB MRI in patients with LCH in comparison with plain radiography and bone scintigraphy. Materials and methods In nine children (1–7 years of age; mean 3.3 years) who had a pathological diagnosis of LCH and had either plain radiography or bone scintigraphy for comparison, 43 WB MR examinations were performed. Skeletal and extraskeletal lesions of the disease on WB MRI were compared with those on plain radiography and bone scintigraphy. Results LCH showed unifocal single-system involvement in one patient, multifocal single-system involvement in three, and multifocal multisystem disease in five. WB MRI identified additional skeletal lesions in three (38%) of eight patients, compared with plain radiography, and in two (25%) of eight, compared with bone scintigraphy. WB MRI detected extraskeletal lesions of the disease in five (56%) of the nine patients exclusively, except for one patient whose lung lesions were also detected on plain radiography. In two patients, treatment was changed according to WB MRI findings. Conclusion WB MRI is a useful initial and follow-up diagnostic method to assess the extent of LCH because WB MRI not only identifies more skeletal lesions of the disease than do plain radiography and bone scintigraphy, but also detects extraskeletal lesions of the disease.     

Skelettbefall bei Langerhanszellhistiozytose

Langerhans cell histiocytosis is a reactive disorder of the dendritic cell system and is characterized by proliferation of cells bearing the phenotype of the normal Langerhans cells. Bone lesions are the most common manifestation of LCH and account for about 1% of all childhood bone tumors. They occur in about 80% of paediatric cases of LCH, either in the form of isolated bony disease (single system LCH) or within the context of a multisystem disease (multisystem LCH). Images of LCH bone lesions are not pathognomonic, and histopathological confirmation of the diagnosis is therefore mandatory. LCH confined to the skeleton has an excellent prognosis, and only local treatment (curettage, intralesional steroids) is given in most cases. In cases of extended lesions in weight-bearing bones or of multiple bone lesions systemic therapy may be indicated.     

An infant with self‐healing cutaneous Langerhans cell histiocytosis followed by isolated thymic relapse

Thymic involvement with Langerhans cell histiocytosis (LCH) typically occurs in children as part of multi‐system (M‐S) LCH. Patients who develop skin‐only LCH during infancy may either follow a self‐healing course with spontaneous regression or may progress to M‐S involvement. We describe a male infant who developed isolated thymic LCH after spontaneous complete regression of isolated cutaneous lesions. His erythrocyte sedimentation rate and C‐reactive protein increased temporarily during the skin‐only stage of LCH, and increased again considerably during the thymic relapse. Even for patients with skin‐only LCH, these laboratory data might indicate possible relapse or late progression of the disease. Pediatr Blood Cancer 2009;53:229–231. © 2009 Wiley‐Liss, Inc.     

Use of indomethacin in Langerhans cell histiocytosis

BACKGROUND: Because prostaglandin (PG) E2 has been identified in the bone lesions of Langerhans cell histiocytosis (LCH), we speculated that indomethacin, a potent PG inhibitor, may be useful in patients with symptomatic LCH involving the bony skeleton. PROCEDURE: We used indomethacin to treat patients in whom we wanted to avoid steroids or chemotherapy, or in whom these treatments did not provide complete symptom relief. Ten children with bony LCH between 1984 and 1995 were treated; six had single-system bone disease and four had multisystem disease involving the bony skeleton and other organs. RESULTS: The dose of indomethacin ranged from 1 to 2.5 mg/kg/day (9-200 mg/day) in divided doses and was given for 1-16 weeks (mean, 6 weeks). Eight patients had a complete response to treatment, defined as complete resolution of symptoms for 4 weeks. One patient was withdrawn from treatment because of concern regarding the potential of indomethacin to induce seizures and a second patient, with suppurative skin lesions overlying a lytic skull defect, did not respond. CONCLUSIONS: Indomethacin is a useful therapy for LCH involving the bony skeleton and may have a role as first-line treatment in single-system bone disease. Whether it has a specific role in slowing disease progression or merely acts as an analgesic has not yet been established.     

The Study of HLA, ICA and Autoantibodies in Japanese Type 1 Diabetes Mellitus

HLA, ICA (islet cell antibody) and autoantibodies were studied in 65 Japanese patients with type 1 diabetes mellitus to elucidate the existence of immuno-genetic heterogeneity. Patients with autoantibodies had increased frequencies of HLA DRw9 antigen and of HLA haplotype of Bw61-DRw9, and a slow decay of ICA, while patients without autoantibodies had increased frequencies of HLA DR4 antigen and of HLA haplotype of Bw54-DR4, and a rapid decay of ICA. These findings support the concept of immunogenetic heterogeneity in Japanese type 1 diabetes mellitus.     

Elevated serum levels of the decoy receptor osteoprotegerin in children with Langerhans cell histiocytosis

Langerhans cell histiocytosis (LCH) is characterized by an accumulation of dendritic Langerhans cells in granulomatous lesions in the bone, skin, and other sites in the body. The pathogenesis of the disease remains unknown. We measured serum levels of the decoy receptor osteoprotegerin (OPG), an important regulator of bone metabolism as well as immune responses, in 18 children with single system (SS) or multi-system (MS) forms of LCH and 20 pediatric controls. OPG levels were significantly increased in LCH patients at diagnosis when compared with controls, and pretreatment levels of OPG were elevated in MS compared with SS patients. Moreover, OPG levels in LCH patients were elevated in patients with involvement of risk organs (liver, lungs, hematopoietic system, or spleen) when compared with patients without risk organ involvement, indicative of an association between OPG values and disease severity. We also observed a positive correlation between serum levels of OPG and tumor necrosis factor (TNF)-alpha, a pro-inflammatory cytokine, at the time of onset of disease. These findings show, for the first time, that serum OPG levels are elevated in LCH patients, and suggest that OPG may play a role in the pathogenesis of this enigmatic disease.     

Central diabetes insipidus as presenting symptom of Langerhans cell histiocytosis

BACKGROUND AND OBJECTIVES: Central diabetes insipidus (CDI) is a rare disorder associated with various underlying diseases. Among the systemic diseases that may cause CDI, Langerhans cell histiocytosis (LCH) is the most common. Therefore, in patients with endocrinologically proven CDI, a comprehensive diagnostic evaluation is crucial to identify possible extracranial sites of LCH. The goal of the diagnostic evaluation is to yield histopathological proof of the underlying disease. If possible, this histopathological proof should be provided by a biopsy of extracranial lesions to avoid a potentially hazardous biopsy of the pituitary stalk. STUDY DESIGN: In this retrospective study we included 54 patients registered at the LCH study reference center in whom the onset of CDI preceded the diagnosis of LCH, and we investigated their presentation and course to define a clinical pattern characteristic for LCH. RESULTS: In 49/54 patients (91%) the detection and biopsy of extracranial lesions led to the diagnosis of LCH. The most frequently involved organs were bones, skin, and lungs; 86% of the patients with bone lesions had skull lesions. In 18% of the patients extracranial lesions were already found at presentation of CDI, in another 51% of the patients extracranial lesions were found within 1 year from onset of CDI. CONCLUSIONS: These observations underline that a comprehensive search for extracranial lesions at presentation and during the first year thereafter may help to achieve a specific diagnosis without a pituitary stalk biopsy.     

Radiation therapy in the management of Langerhans cell histiocytosis

Twenty-two patients with Langerhans cell histiocytosis (LCH) were managed in the UCLA Department of Radiation Oncology from 1974 to 1987. Their median age was 17 years (range 1-42 years) and median followup 4.5 years (range 1-13 years). Fourteen patients had disease localized to a bone (13) or a soft tissue (one). Eight patients had LCH involving multiple bones (3) or soft tissues plus bones (5). Nine of 10 patients less than 19 years old had disease confined to bone(s) compared to 7 of 12 older patients. Fifty-six sites of LCH (40 bone, 16 soft tissue) were irradiated. Pediatric patients received therapy to 15 sites (14 bone, 1 soft tissue) and adults 41 sites (26 bone, 15 soft tissue). Median dose for bone lesions was 900 cGy (range 600-1,500) and for soft tissue 1,500 cGy (range 600-2,600). Local control was achieved in 46 of 56 sites (82%). Control rates for bone and soft tissue lesions were 35 of 40 (88%) and 11 of 16 (69%), respectively. Fifteen of 15 sites in pediatric patients were controlled compared to 29 of 41 (72%) in adults. Ten sites (18%) recurred 10 months to 4 years after irradiation. Recurrences were in-field and noted only in adults with involvement of multiple soft tissues plus bones. All recurrent soft tissue lesions had been treated with orthovoltage. Five patients developed new foci of LCH subsequent to irradiation. Four of these patients had disease involving soft tissues and bones. One patient with progressive LCH initially presented with a single bone lesion. The acute and chronic effects of radiation therapy were minimal. One patient suffered transient enlargement of adenopathy. An elevated serum TSH level was detected 9 years after irradiation of a cervical vertebra in another patient.     

Cholestasis, sclerosing cholangitis, and liver transplantation in Langerhans cell Histiocytosis

OBJECTIVE: To analyze features and outcomes of cholestasis, sclerosing cholangitis (SC), and liver transplantation (LTx) in patients with Langerhans cell Histiocytosis (LCH) between October 1987 and June 1999. STUDY DESIGN: Of 182 cases with LCH, 36 had hepatic involvement and 12 of those presented with cholestasis. These 12 were the focus of our study. Their median age was 23 months (range: 3-36). Hepatomegaly or hepatosplenomegaly was found in 11 of the 12; elevations of alkaline phosphatase, transaminases, gamma glutamyl transpeptidase (GGT), and less frequently direct bilirubin were detected. Sonography, liver biopsy, and cholangiography were consistent with the diagnosis of SC in 11 patients. None of the biopsies revealed Langerhans cells (LC). Frequently associated lesions of skin, bone, and ear were noted. Early patients were treated with Vinblastine/prednisone for 8 weeks, later patients with the LCH I and LCH II protocols of the Histiocyte Society (HS). RESULTS: Median follow-up was 28 months (range: 10-86). Three patients improved and remained without signs of progressive SC at 27, 32, and 86 months. Nine had progressive liver sequelae resistant to chemotherapy. Of these nine, five received LTx, three died before LTx with progressive SC, and one awaits LTx. Three LTx patients survive without disease reactivation 14, 25, and 37 months post-transplant. Two patients died less than one month after LTx, due to renal failure and sepsis in the first patient and bowel volvulus with perforation followed by sepsis in the second one. CONCLUSIONS: SC is a frequent and usually progressive sequela of multisystem LCH in our institution. LTx has become the treatment of choice for the majority of patients and should be considered early in cases with severe hepatic involvement.     

p53 expression in biopsies from children with Langerhans cell histiocytosis

PURPOSE: Langerhans cell histiocytosis (LCH) is a rare pediatric and adult disease causing skin rashes, osteolytic bone lesions, tumorous growth in various organs, and in some patients, organ dysfunction. The cause of the disease is obscure, and it is not yet understood why some patients develop single-system lesions only without relapse, whereas others develop fatal multiorgan disease. The expression of p53 tumor suppressor gene product detected immunohistochemically can be used as a guideline to alterations in DNA repair control and apoptosis. The authors have chosen to analyze p53 expression in biopsies from children with LCH and correlate it with clinical manifestation and outcome in a broad range of organs. PATIENTS AND METHODS: The study was performed on 50 specimens from 32 children (19 boys and 13 girls), median age 3 1/4 years, range 5 months to 12 1/3 years with a definite diagnosis of LCH based on CD1a positivity. The slides were stained with p53 antibody and semiquantitatively evaluated using a grading system from 1 to 5 as an estimate for 0% to 20%, 20% to 40%, 40% to 60%, 60% to 80%, and 80% to 100% p53-positive for pathologic Langerhans cells (pLC), respectively. RESULTS: The p53 protein was expressed in various degrees in pLC in all lesions. The degree of p53 expression could not be correlated to either clinical manifestation or outcome. CONCLUSIONS: An increased expression of p53 in pLC indicates an altered DNA repair control with or without abnormal control of apoptosis.     

Thymic Langerhans cell histiocytosis mimicking lymphoma

Langerhans cell histiocytosis (LCH) is a rare disorder characterized by clonal expansion of antigen presenting Langerhans cells. Different clinical features can be seen according to the involved organs and systems. Multisystem disease with organ dysfunction is more common in infants, whereas single system disease is usually observed in older children. The disease can affect any system or organ throughout the body. Thymus is a rarely involvement site reported in LCH and usually is accompanied by skin, bone or lung disease. Here we report a 12-year-old male with thymic involvement by LCH clinically mimicking lymphoma.     

HLA and leukemia: is it a simple allelic association?

The first association between a disease and MHC antigens was established for viral leukemogenesis in mice. Since then, numerous studies in humans have been carried out and the data obtained suggest that Cw3 and Cw4 may be markers for leukemia susceptibility genes. Given the relatively weak relevance of HLA-C locus antigens in immune response, unrecognized properties of Cw3 and Cw4 should be considered to explain this association. Family studies have consistently revealed limited heterogeneity of HLA antigens in those families, increased parental HLA antigen sharing resulting in increased homozygosity among offspring and high frequency of recombinations within the MHC. Furthermore, the HLA genotype of leukemic patients was found more frequently among their siblings than the anticipated 25 percent. Another significant deviation from the Mendelian expectation was increased HLA-DR identity of offspring to that of their mother in those families. These and other observations imply that in leukemia families unknown MHC-linked recessive factors linked to Cw3 and Cw4 alleles may be susceptibility genes which also cause segregation distortion of HLA genes and probably developmental errors.     

Immunohistochemical detection of the apoptosis-related proteins FADD, FLICE, and FLIP in Langerhans cell histiocytosis

Langerhans cell histiocytosis (LCH) is characterized by an accumulation of dendritic Langerhans cells in granulomatous lesions in various organs. The etiology of LCH remains enigmatic. Fas/APO-1/CD95 belongs to the "death receptor" family of apoptosis regulators and has been implicated in the downregulation of immune responses. The authors examined the expression of three proteins that are engaged in the Fas signaling cascade-FADD/Fas-associated death domain-containing protein, FLICE/FADD-like interleukin-1beta-converting enzyme (both pro-apoptotic), and FLIP/FLICE-inhibitory protein (anti-apoptotic)-in lesions from LCH patients. Immunohistochemistry was performed on paraffin-embedded tissue specimens from 43 children with LCH. The infiltrates were scored according to the amount of positive pathologic Langerhans cells (pLCs). In all investigated specimens, the majority of the pLCs expressed FADD, active FLICE, and FLIP. The clinical outcome of the disease could not be correlated to the expression of the investigated proteins. This study shows a high expression of the apoptosis-related proteins FADD, active FLICE, and FLIP in pLCs. The authors previously showed that pLCs express Fas and Fas ligand. Taken together, these findings suggest that the Fas signaling pathway may be involved in the pathogenesis of LCH.     

Coeliac disease, enamel defects and HLA typing

The presence of dental enamel defects in coeliac disease and their relation to hypocalcaemia or a particular HLA class in 82 Italian children with coeliac disease was studied. Demarcated opacities or hypoplasia were detected in 23 subjects (group 1) while minimal or no dental lesions were found in the remaining 59 patients (group 2); in 189 normal controls, enamel lesions were significantly less frequent than in patients with coeliac disease (14.8% versus 28.0%; p < 0.005). No statistically significant differences were found for age at diagnosis and calcium concentrations between groups 1 and 2. Regression analysis showed a correlation between age at diagnosis and number of teeth with enamel defects. In our patients, the presence of HLA DR3 antigen significantly increased the risk of dental lesions, while genotype DR5,7 seemed to protect against enamel defects. A logistic regression analysis of the variables age, serum calcium concentrations, number of affected teeth, type of enamel defect and DR antigens showed that only DR antigens discriminated coeliac disease patients with from those without enamel defects.