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We assessed relapse patterns in paediatric patients with relapsed Langerhans cell histiocytosis (LCH) who were initially treated with the JLSG-96/02 protocol. We analysed 187 relapse events in 101 relapsed LCH patients [31 with multifocal bone (MFB) and 70 with multisystem (MS) at LCH diagnosis] among a total 317 patients enrolled in JLSG-96/-02 studies. Relapse of LCH was defined as an exacerbation of the non-active disease (NAD) condition. Of the 317 patients, 101 (31.9%) had the first relapse at 1.5 years after initiation of therapy. The first relapse and subsequent relapses did not differ between patients with MFB and MS disease. Of the 187 relapse events, relapse occurred as a single-system disease (n = 159; 85%), in which isolated bone relapse (n = 104; 55%) was the most common. Relapse at MS disease with the risk of organ involvement is extremely rare. After relapse(s), most patients underwent chemotherapy (122/187; 65%) and 87% of them achieved NAD status again. The incidence of permanent consequences was significantly higher in patients with relapses than in those without relapses. In the JLSG cohort, bone relapse most occurred in both MFB and MS patients. Most relapses could be effectively controlled by repeated administration of the initial chemotherapy., (© 2022 British Society for Haematology and John Wiley & Sons Ltd.)

Background: Bone lesions of Langerhans cell histiocytosis (LCH) may be triggered by trauma., Methods: The characteristics of pediatric patients in the JLSG-02 study cohort who developed a bone lesion at the trauma site at diagnosis of LCH were analyzed retrospectively., Results: Of the 261 pediatric patients with LCH, 12 (4.6%), of median age 4.9 years, had trauma-triggered bone LCH lesions at diagnosis, making them significantly older than the remaining patients (P = 0.006). Trauma sites included the craniofacial regions in 10 patients and the lumbar spine and pelvis in one patient each. At the time of trauma, six patients had a bump at the site, whereas none had extradural hematomas or bone fractures. The median time from trauma to onset was 4 weeks. Of these 12 patients, three had isolated bone (IB) disease; four had multifocal bone (MFB) disease, including the bone lesion at the trauma site; and five had multisystem disease, including four with lesions in neighboring tissue and one with polyuria (posterior pituitary lesion) more than 1 year before the trauma-triggered bone lesion. Treatment responses were good in all 12 patients and none died, but relapses were observed in two patients, one each with IB and MFB disease., Conclusions: About 5% of pediatric patients with LCH developed new trauma-triggered bone lesions at a relatively old age. These lesions can manifest as IB, or, in patients with underlying LCH diseases, as MFB or multisystem. Good clinical outcomes were observed in these patients., (© 2022 Japan Pediatric Society.)

Langerhans cell histiocytosis (LCH) is a rare inflammatory myeloid neoplasia derived from immature myeloid dendritic cells with the mitogen-activated protein kinase (MAPK) pathway gene mutation. LCH is rarely fatal, but patients develop various permanent consequences (PCs). We report the frequencies of LCH-related PCs in paediatric patients (n = 317) treated by the JLSG-96/02 AraC-containing regimens. One-third of LCH patients had at least one PC at a median follow-up of 12 years. Central nervous system (CNS)-related PCs (neurological and endocrinological) accounted for 21·5%, non-CNS-related 16·7%. We require novel therapeutic measures to further reduce the frequency of LCH-related PCs., (© 2020 British Society for Haematology and John Wiley & Sons Ltd.)

In Langerhans cell histiocytosis (LCH), somatic gene mutations in the mitogen-activated protein kinase pathway have been identified in more than 80% of cases in Western countries, in which mutually exclusive BRAF and MAP2K1 mutations are involved. Among them, BRAF V600E mutation is the major contributor (50-60%). In 59 patients (50 children and nine adults) with LCH (not including pulmonary LCH) in Japan, we first screened for BRAF V600E in all patients followed by target sequencing for other gene mutations in 17 of BRAF V600E-negative patients. As a result, BRAF V600E mutation was detected in 27/59 (46%) patients. We also identified BRAF mutations other than V600E in five and MAP2K1 mutations in nine patients. Thus, gene mutations in BRAF or MAP2K1 were identified in 41/44 (93%) of the fully tested patients. Regarding the correlation of clinical features and genotype in pediatric patients, we found that BRAF V600E mutation status was not correlated with sex, age at diagnosis, disease extent, response to first-line therapy, relapse, or CNS-related sequelae. Interestingly, MAP2K1 exon 2 in-frame deletion was related to the risk organ involvement; however, further studies are required to clarify the impact of these gene mutations on the clinical features of patients with LCH.

A 2-year and 4-month-old boy developed Langerhans cell histiocytosis (LCH) at the left parietal region of the skull. After treatment with chemotherapy, the patient achieved remission but experienced three relapses. After 3 years, he complained of headache, blurred vision, and lethargy. Brain magnetic resonance imaging revealed multiple dura-based meningeal masses. Biopsy was performed, and the patient was then diagnosed with juvenile xanthogranuloma (JXG). The analysis of both LCH/JXG tissues revealed BRAF V600E mutation. The JXG masses were not responsive to prednisolone, which was injected locally, radiotherapy (24 Gy), and chemotherapy (2-chlorodeoxy-adenosine). In addition, since the patient developed macrophage activation syndrome associated with systemic JXG progression, he received unrelated cord blood transplantation (u-CBT) at the age of 10 years and 11 months. Engraftment was performed at day 42, and significant GVHD was not observed. Four months after CBT, the patient was treated with infliximab (Remicade ® ) and dexamethasone palmitate (Limethasone ® ). The size of the intracranial JXG masses gradually decreased after u-CBT and disappeared after 4 years. Currently, the patient is doing well at the age of 25 years and is receiving androgen replacement therapy.

The efficacy of and indications for hematopoietic stem cell transplantation (HSCT) in pediatric Langerhans cell histiocytosis (LCH) remain undetermined. This retrospective study analyzed 30 children with refractory LCH who underwent HSCT in Japan between 1996 and 2014. Eleven patients received a myeloablative conditioning (MAC) regimen, while 19 patients received a reduced-intensity conditioning (RIC) regimen. Among the 26 patients with complete data, 23 patients had risk organ (RO) involvement during clinical course. Disease status at HSCT was no active disease (NAD) (4), active disease-regression (AD-r) (2), active disease-stable (AD-s) (4), and active disease-progressive (AD-p) (16). Seventeen of the 30 patients (57%) were alive with a median follow-up of 433 days (range 9-5307) after HSCT. Death occurred within 3 months after HSCT in eight of 13 patients. RIC and MAC patients were similar in both overall survival (OS) (56.8% vs. 63.6%, respectively, p = 0.789) and failure-free survival (56.8% vs. 54.6%, respectively, p = 0.938). Regarding disease status at HSCT, the six patients with NAD/AD-r experienced better outcomes than the 20 with AD-s/AD-p (5-year OS, 100% vs. 54.5%, respectively, p = 0.040). Disease state at the time of HSCT was the most important prognostic factor.

Purpose: We analyzed central diabetes insipidus (CDI) development in pediatric patients with Langerhans cell histiocytosis (LCH) treated according to the Japan LCH Study Group (JLSG) regimen, which is the combination chemotherapy including cytarabine (Ara-C)., Methods: Retrospective data from 317 patients (multisystem disease (MS), n = 206; multiple focal bone (MFB), n = 111) treated according to the JLSG-96/02 regimens were analyzed., Results: The median follow-up duration was 10.6 years (range, 0.1-21.1). A total of 50/317 (15.8%) patients developed CDI (MFB, n = 4; MS, n = 46). Of the 50 cases, CDI was already present at the time of LCH diagnosis (pre-CDI) in 25, and it newly developed after the diagnosis and initiation of treatment (post-CDI) in the other 25 cases. The cumulative incidence of post-CDI at 10-year calculated by Kaplan-Meier analysis was 9.0% for total and 12.0% for MS patients. A positive correlation with LCH lesions at the CNS risk sites at diagnosis was found in pre-CDI cases (17/164 vs 8/171; P = 0.0359), but not in post-CDI cases (14/129 vs 11/163; P = 0.254). Multivariate analysis showed that relapse at the CNS risk sites was significantly associated with post-CDI development (hazard ratio: 4.70; 95% CI, 1.29-17.1, P < 0.05)., Conclusions: In the JLSG-96/02 studies, CDI developed in 15.8% of the cohort in which half as pre- and the other half as post-CDI. Relapse, particularly at the CNS risk sites, was linked with the development of post-CDI., (© 2018 Wiley Periodicals, Inc.)

Langerhans cell histiocytosis (LCH) with single-system (SS) multifocal bone (MFB) lesions is rarely fatal, but patients may experience relapses and develop LCH-associated sequelae. To evaluate effect on outcomes of pediatric multifocal LCH, we tested a treatment protocol modified from the Japan Langerhans Cell Histiocytosis Study Group (JLSG)-96 study. We assessed the outcomes of all consecutive newly diagnosed pediatric patients with LCH with SS-MFB lesions who were treated with JLSG-02 protocol in 2002-2009. JLSG-02 was modified from JLSG-96 as follows: increased prednisolone dosage at the induction phase and extension of maintenance therapy duration from 24 to 48 weeks. In total, 82 patients with a median follow-up duration of 8.0 years were eligible for analysis. At 6 weeks, 92.7% responded to induction; however, 27.6% of responders experienced relapses. In total, 4.8% developed central nervous system-related sequelae, including central diabetes insipidus and neurodegeneration, which were associated with relapse. None of the patients died. The 5-year event-free survival rates were not different between JLSG-02 and -96 cohort (66.7 vs. 65.1%; p = 0.697). Modification of previous treatment protocol did not contribute to improvement of outcomes in LCH with SS-MFB lesions.

Objective: Langerhans cell histiocytosis (LCH) is characterized by immature dendritic cell proliferation, infiltration of LCH lesions by various inflammatory cells, and a lesional cytokine storm. It is classified into three groups on the basis of disease extent, namely, multisystem with risk-organ involvement (MS+), multisystem without risk-organ involvement (MS-), and single-system (SS) disease. We comprehensively analyzed whether serum levels of cytokines/chemokines reflect the disease extent., Methods: Serum samples from 52 children with LCH (eight, 25, and 19 with MS+, MS-, and SS, respectively) and 34 control children were analyzed quantitatively for 48 humoral factors. DNA samples extracted from biopsied LCH lesions from 12 patients were tested for BRAF V600E status., Results: The LCH patients had significantly higher serum levels of IL-1Ra, IL-3, IL-6, IL-8, IL-9, IL-10, IL12, IL-13, IL-15, IL-17, IL-18, TNF-α, G-CSF, M-CSF, MIF, HGF, VEGF, CCL2, CCL3, CCL7, CXCL1, and CXCL9 than the controls by univariate analysis. Of these IL-9, IL-15 and MIF were significant by multivariate analysis; but not differed between MS and SS diseases. MS disease associated with significantly higher IL-2R, IL-3, IL-8, IL-18, M-CSF, HGF, CCL2, CXCL1, and CXCL9 levels than SS disease by univariate analysis. Of these, CCL2 and M-CSF were significant by multivariate analysis. IL-18 levels were significantly higher in MS+ disease than MS- disease. The LCH patients with BRAF V600E mutation had higher serum levels of CCL7., Conclusion: Numerous inflammatory cytokines and chemokines play a role in LCH. Of those, more specific ones reflect the disease extent (MS vs. SS and MS+ vs. MS-) or the BRAF V600E mutation status. It is thought that the most responsible cytokines and chemokines involved in the poor outcome may become future candidate therapeutic targets in LCH., (Copyright © 2017. Published by Elsevier Ltd.)

The JLSG-96 study reported very low mortality rates for children newly diagnosed with multifocal Langerhans cell histiocytosis (LCH). The JLSG-02 study was performed to further improve the prognosis from 2002 to 2009. The present study compared the therapeutic results of these two studies in terms of multisystem disease. All patients were treated with 6 weeks of the Induction A regimen, comprising cytarabine, vincristine and prednisolone, followed by maintenance therapy. Poor responders to Induction A were switched to Induction B. JLSG-02 has been revised from JLSG-96 in the following respects: prednisolone dosage during Induction A increased; duration of maintenance therapy extended from 24 to 48 weeks; cyclosporine introduced to Induction B for progressive disease. One hundred forty-seven children with multisystem LCH were evaluated. Of these, 84 were positive for risk of organ involvement (RO) and 63 were RO-negative. At the 6-week point, 76.2 % of RO+ and 93.7 % of RO- patients responded to Induction A. Five-year event-free survival (EFS) was 46.2 % [95 % confidence (CI), 35.5-56.9] for RO+ and 69.7 % (58.4-81.1) for RO-, which was significantly superior to that in JLSG-96 [26.8 % (13.3-40.4) and 38.9 % (16.4-61.4), respectively]. The intensified induction and prolonged maintenance regimens in JLSG-02 improved EFS in patients with multisystem LCH.

We report a case of a 49-year-old woman with biopsy-proven multisystemic Langerhans cell histiocytosis (LCH) with hypothalamic involvement documented on F-FDG PET/CT. Chemotherapy with a combination of vinblastine, prednisolone, methotrexate, and 6-mercaptopurine was carried out. Two months later, a 90% reduction of the hypothalamic tumor mass was noted on magnetic resonance imaging, but with no signs of pathological F-FDG accumulation. The patient died 4 months later, and we found no signs of LCH on autopsy. Our case highlights the need for further studies regarding the role of F-FDG PET/CT in the assessment of treatment response in patients with LCH.

Diseases of the central nervous system (CNS) are common in patients with Langerhans cell histiocytosis (LCH). Besides active LCH lesions, neurodegenerative (ND) lesions of the cerebellum and/or basal ganglia may occur as late sequelae of LCH. While the etiology of this ND disease remains unclear, biomarkers in cerebrospinal fluid (CSF) may reflect the activity of CNS disease in these patients. However, no well-planned CSF studies have yet been performed in patients at high risk for ND-CNS-LCH. Potential parallels with other neuroinflammatory/neurodegenerative disease suggest the utility of examining these other disorders in establishing strategies for the prevention and/or treatment of ND-CNS-LCH., (Copyright © 2015 Elsevier Inc. All rights reserved.)

We propose Langerhans cell histiocytosis (LCH) is an inflammatory process that is prolonged by mutations. We hypothesize that Merkel cell polyomavirus (MCPyV) infection triggers an interleukin-1 (IL-1) activation loop that underlies the pathogenesis of LCH. Langerhans cells (LCs) are antigen presenting cells in the skin. When LCs encounter exogenous antigens, they migrate from the epidermis into draining lymphoid tissues to initiate T-cell activity. It has been proposed that LC migration-related factors, including E-cadherin, matrix metalloproteinase, and Notch ligand induce LCH activity. We found that the tyrosine phosphatase SHP-1, which binds IL-1 receptor-associated kinase 1, is expressed at a significantly higher level in LCH affecting multiple organ systems (MS-LCH) than in LCH affecting a single organ system (SS-LCH). IL-1 stimulates T helper 17 cells and their signature cytokine IL-17 had been a matter of controversy. We detected higher levels of IL-17A receptor expression in MS-LCH than in SS-LCH and proposed an IL-17 endocrine model that could settle the controversy. IL-1 is the first cytokine secreted in response to sensitizers and promotes LC migration from sentinel tissues. Myeloid differentiation primary response 88 (MyD88), downstream of the IL-1 receptor, has functions in both RAS signaling and inflammation, leading to human cell transformation. In 2010, an activating mutation in the B-rapidly accelerated fibrosarcoma gene (BRAF) V600E was found in LCH. This BRAF mutation induces phosphorylation of the extracellular signal-regulated kinase (ERK) that may play an important role with MyD88 in LCH pathogenesis. However, phosphorylated ERK (pERK) is rapidly dephosphorylated by dual specificity phosphatase 6 (DUSP6), and limited proliferation is predicted in BRAF mutant cells. MyD88 binds pERK via its D-domain, thereby preventing pERK-DUSP6 interaction and maintaining ERK in an active, phosphorylated state. We detected MCPyV-DNA in the peripheral blood cells of two out of three patients with LCH in high-risk organs but not in those of patients with LCH in non-high-risk organs (0/12; P = .029). MCPyV infection can trigger precursor LCH cells with BRAF mutation to produce IL-1; the IL-1 loop is amplified in all LCH subclasses. Our model indicates both BRAF mutation and IL-1 loop regulation as potential therapeutic targets.

The follow-up of eight Japanese children with Langerhans cell histiocytosis (LCH)-related neurodegenerative central nervous system (ND-CNS) disease who were treated with intravenous immunoglobulin (IVIG) for >3 years is described. The patients developed ND-CNS disease at a median age of 5.2 (range 3.5-10.0) years and received IVIG treatment for a median duration of 6.5 + (range 3.7 to 10+) years. After a median follow-up period of 11.6 + (8.3+ to 13.9+) years after ND-CNS disease diagnosis, the median Expanded Disability Status Scale (EDSS) score of the eight patients was 4.0 (range 2.0-9.5). At the last follow-up as of March 2014, three patients have low EDSS scores (<3.0) and can walk without any assistance. Another three patients have EDSS scores of 3.5-4.5 and can walk by themselves, albeit occasionally with supports. However, the remaining two patients are wheelchair bound or bed ridden. The school performance of seven of the eight patients was below average. IVIG appeared to be most beneficial when it was administered soon after ND-CNS disease diagnosis when the EDSS scores were low (1.0-2.5). The patients who began receiving IVIG when their high EDSS scores were higher (4.5-7.0) appeared to obtain less benefit. To prevent progression of ND-CNS disease in patients with LCH, it is recommended to introduce IVIG early and to continue this therapy for >3 years.

Osteopontin (OPN) acts as an osteoclast activator, a proinflammatory cytokine, and a chemokine attracting histiocytes/monocytes and is abundantly expressed in Langerhans cell histiocytosis (LCH). We investigated whether serum OPN levels are related to disease types in LCH. Fifty-eight newly diagnosed LCH patients were studied; eight with risk organ (liver, spleen and/or hematopoietic) involvements positive multisystem (MS+) disease, 27 with risk organ involvement negative multisystem (MS-) disease and 23 with single system (SS) disease. Pediatric patients with non-inflammatory disease (n=27) were used as controls. All of patients with MS+ disease were younger than 3 years. Serum OPN levels and 44 kinds of humoral factors were measured by ELISA and Bio-Plex suspension array system, respectively. In the patients younger than 3 years, the median serum OPN level (interquartile range) was 240.3 ng/ml (137.6-456.0) in MS+ (n=8); 92.7 ng/ml (62.0-213.8) in MS- (n=14) and 72.5 ng/ml (55.6-94.0) in SS (n=9) and 74.4 ng/ml (42.2-100.0) in control (n=12). The OPN values were significantly higher in the MS+ group than the MS-, SS and control groups (p=0.044, p=0.001 and p=0.002, respectively), but not different between the MS-, SS and control groups. In the patients older than 3 years, the median level of serum OPN (IQR) was 56.2 ng/ml (22.9-77.5) in MS- (n=13), 58.9 ng/ml (31.0-78.7) in SS (n=14) and 41.9 (28.9-54.1) in control (n=15). These values did not differ significantly between each group. The serum OPN levels were positively correlated with the serum IL-6, CCL2, IL-18, IL-8 and IL-2 receptor concentration. OPN may be involved in risk organ dissemination and poor prognosis of LCH through the function as inflammatory cytokine/chemokine., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Langerhans cell histiocytosis (LCH) is a group of granulomatous disorders in which abnormal Langerhans cells proliferate as either a localized lesion in a single bone or disseminated disease involving two or more organs or systems. Because the different LCH forms exhibit significantly elevated levels of inflammatory molecules, including pro-inflammatory cytokines and tissue-degrading enzymes, we investigated for a possible viral trigger in LCH pathogenesis. We looked for Merkel cell polyomavirus (MCPyV) in peripheral blood cells and tissues using quantitative real-time PCR and immunohistochemistry staining with anti-MCPyV large T-antigen antibody. Our findings revealed elevated amounts of MCPyV DNA in the peripheral blood cells of 2 of 3 patients affected by LCH with high-risk organ involvement (RO+) and absence of MCPyV DNA in the blood cells in all 12 LCH-RO- patients (P = .029). With lower viral loads (0.002-0.033 copies/cell), an elevated number of MCPyV DNA sequences was detected in 12 LCH tissues in comparison with control tissues obtained from patients with reactive lymphoid hyperplasia (0/5; P = .0007), skin diseases not related to LCH in children younger than 2 years (0/11; P = .0007), or dermatopathic lymphadenopathy (5/20; P = .0002). The data, including frequent but lower viral loads and low large-T antigen expression rate (2/13 LCH tissues), suggest that development of LCH as a reactive rather than a neoplastic process may be related to MCPyV infection., (© 2013.)

Langerhans cell histiocytosis (LCH) is a lymphoproliferative disorder consisting of abnormal Langerhans cell-like cells and other lymphoid cells. LCH presents as either a multisystem LCH (LCH-MS) or a single-system LCH (LCH-SS). Currently, neither the pathogeneses nor the factors that define these disease subclasses have been elucidated. The interleukin (IL)-17A autocrine LCH model and IL-17A-targeted therapies have been proposed and have engendered much controversy. Those authors showed high serum IL-17A levels in LCH and argued that serum IL-17A-dependent fusion activities in vitro, rather than serum IL-17A levels, correlated with LCH severity (i.e. the IL-17A paradox). In contrast, others could not confirm the IL-17A autocrine model. So began the controversy on IL-17A, which still continues. We approached the IL-17A controversy and the IL-17A paradox from a new perspective in considering the expression levels of IL-17A receptor (IL-17RA). We detected higher levels of IL-17RA protein expression in LCH-MS (n = 10) as compared to LCH-SS (n = 9) (P = 0.041) by immunofluorescence. We reconfirmed these data by re-analyzing GSE16395 mRNA data. We found that serum levels of IL-17A were higher in LCH (n = 38) as compared to controls (n = 20) (P = 0.005) with no significant difference between LCH subclasses. We propose an IL-17A endocrine model and stress that changes in IL-17RA expression levels are important for defining LCH subclasses. We hypothesize that these IL-17RA data could clarify the IL-17A controversy and the IL-17A paradox. As a potential treatment of LCH-MS, we indicate the possibility of an IL-17RA-targeted therapy.

Little information is available regarding effective systemic therapies for adult Langerhans cell histiocytosis (LCH). The Japan LCH Study Group has formulated an ambulatory treatment regimen for adult patients with LCH. In total, 14 patients (median age 43 years, range 20-70 years) with multifocal LCH with biopsy-confirmed histology were enrolled. None had received cytoreductive agents for LCH previously. Four had single system (SS) and ten had multi system (MS) disease. All were treated with the Special C regimen, which consists of vinblastine/prednisolone and methotrexate with daily 6-mercaptopurine for 36 weeks. At the end of the therapeutic regimen, all SS patients achieved no active disease (NAD), and six of the ten MS patients showed a response (NAD in two, partial response in four). At the last follow-up (median 34 months), 11 patients were alive (NAD in eight and active disease in three). Of the three deceased, one died of hemorrhage during the Special C treatment, and two of infections during subsequent therapy. Although this study is limited by the small sample size, this ambulatory regimen shows signs of efficacy for adult LCH. This was particularly evident for patients with multifocal SS disease, but half of those with MS disease also benefited.

To determine the ability of recent systemic chemotherapy protocols to reduce the incidence of central diabetes insipidus (CDI) in Langerhans cell histiocytosis (LCH), 43 CDI cases that belonged to a cohort of 348 pediatric patients with multi-focal LCH who were treated with the JLSG-96/-02 protocols were analyzed. The overall incidence of CDI was 12.4%, but in 24 cases CDI was already present at the time LCH was diagnosed. Thus, CDI developed during or after systemic chemotherapy over a follow-up period of 5.0 (0.2-14.7) years in only 19 patients (5.9%), with 7.4% at 5-year cumulative risk by Kaplan-Meier analysis. In two cases, complete resolution of CDI was noted. Anterior pituitary hormone deficiency was detected in 13 cases, while CDI-associated neurodegenerative disease was observed in six cases. The JLSG-96/-02 protocol appears to effectively reduce the occurrence of CDI. However, novel therapeutic measures are required to reverse pre-existing CDI and to prevent CDI-associated neurological complications.

We report four cases of adult-onset Langerhans cell histiocytosis (LCH) with central nervous system (CNS) lesions in the hypothalamic-pituitary region. The first clinical symptoms were diabetes insipidus (two patients), hypothyroidism (one patient), and decreased libido/erectile dysfunction (one patient). Diagnosis was delayed as the CNS lesion was not initially suspected to be secondary to LCH, with a median time from symptom onset to treatment of 3.0 (range <1-5.3) years. In three patients, the tumor mass was effectively reduced by chemotherapy; however, all patients continue to exhibit hypopituitarism. Early diagnosis and initiation of treatment are required to improve the outcome of CNS-LCH in adult patients.

Langerhans cell histiocytosis (LCH) is a proliferative disorder of Langerhans cell (LC)-like CD1a-positive cell (LCH cell) with unknown causes. LCH consists of two subtypes: single-system LCH (LCH-SS) with favorable prognosis and multisystem LCH (LCH-MS) with poor prognosis. LCH has been indicated as a neoplastic disorder from monoclonal characteristics of LCH cells. This study aimed to investigate an expression of tyrosine phosphatase SHP-1 in LCH, since its expression levels were variously reported in many tumors, overexpression in ovarian cancers (a candidate oncoprotein), and downregulation by methylation in gastric cancers, prostate cancers, malignant lymphomas, and leukemias (a putative tumor suppressor). By immunohistochemistry (IHC), the SHP-1 expression in LCs and LCH cells was compared in LCH (two subtypes: LCH-SS = 21, LCH-MS = 12), dermatopathic lymphadenopathy (DLA) (n = 9) and normal epidermal LCs (n = 3) near LCH lesion. IHC results were analyzed semiquantitatively using a Photoshop software. The mean intensity score (IS) of DLA, LCH-SS, LCH-MS, and LCs were 47, 100, 139, and 167 (in arbitrary unit), respectively. The IS had significant differences among LCH-SS, LCH-MS, and DLA (p < 0.01). SHP-1 is expressed significantly higher in LCH-MS than in LCH-SS. SHP-1 can be a progression marker of LCH. SHP-1 is also useful for differential diagnosis between LCH in lymph nodes and DLA.

Langerhans cell histiocytosis (LCH) can be a single system or multi-system disease. Both disease types can be associated with multi-focal bone lesions, but their bone involvement patterns have not been compared systematically. Of the new pediatric LCH cases enrolled into the JLSG-02 study during 2002-2007, 67 cases of single system multifocal bone (SMFB) LCH and 97 cases of multi-system bone (MSB) LCH were analyzed to determine if the bone involvement patterns differ in these two types, and whether these differences correlate with outcome. Statistical analysis was performed with Mann-Whitney U test, Fisher's exact test, and other measures. Onset ages were higher for SMFB (P < 0.001), but the two types did not differ in the number of bone lesions per patient. The skull was most frequently affected in both types, followed by the spine. Lesions in the temporal bone (P = 0.002), ear-petrous bone (P < 0.001), orbita (P = 0.003), and zygomatic bone (P = 0.016) were significantly more common in MSB. The two types did not differ in response to treatment, but MSB was associated with a significantly higher incidence of diabetes insipidus (DI) (P < 0.001). Novel measures are required in preventing the development of DI in MSB-type LCH patients with "risk" bone lesions.

Diabetes insipidus and neurodegenerative disease are the two major CNS complications of Langerhans cell histiocytosis (LCH). Once it has developed, diabetes insipidus is permanent, while the outcome of neurodegenerative disease is dismal. The development of these CNS-LCH complications is closely correlated with "CNS-risk" organ involvement, namely, the presence at diagnosis of LCH lesions in cranio-facial areas. Based on recent data showing the beneficial effects of intravenous immunoglobulin (IVIG) treatment on inflammatory diseases of the CNS, we are currently testing whether monthly IVIG treatment (0.4 g/kg/dose) can alleviate the progression of neurodegenerative disease in LCH patients. We also hypothesize that the incidence of CNS complications could be reduced by the prophylactic administration of high dose IVIG therapy (2 g/kg/dose), combined with conventional induction chemotherapy, that is provided before CNS lesions are detected in "CNS-risk"-LCH patients.

Clinical features, brain magnetic resonance imaging findings and EDSS scores of 11 patients with neurodegenerative central nervous system Langerhans cell histiocytosis were analyzed in Japan. All patients initially had multi-system-type Langerhans cell histiocytosis; 8 at 1-2 years of age and 3 at a later age. Neurodegenerative central nervous system Langerhans cell histiocytosis disease developed after a median time interval of 3.9 years from initial diagnosis. With a median follow-up of 4.5 years, 6 patients showed progression of disease with an EDSS score >3. This study demonstrates the importance of early detection of neurodegenerative central nervous system Langerhans cell histiocytosis by brain magnetic resonance imaging, particularly in the follow-up of patients who developed multi-system-type Langerhans cell histiocytosis in early infancy.

Background: In rare cases, patients with Langerhans cell histiocytosis (LCH) develop neurodegenerative CNS disease (ND-CNS-LCH). Management of ND-CNS-LCH has not been established., Methods: We treated five pediatric patients with a combination of intravenous immunoglobulin (IVIG) and chemotherapy (steroid +/- vinblastine +/- 6-mercaptopurine +/- methotrexate). Prior to the therapy, three of the five patients had cerebellar ataxia while the remaining two had abnormal MRI findings without apparent neurological deficits. IVIG was given monthly or twice monthly at the dosage of 250-400 mg/kg/dose., Results: The four patients administered more than 23 doses of IVIG and chemotherapy remained in a stable condition and did not show significant progression signs in neurological deficits or brain MRI findings during the 30-month follow-up period (median; range: 19+ to 38+) following the initiation of therapy for ND-CNS-LCH., Conclusion: The IVIG-containing treatment may be promising for ND-CNS-LCH; however, its effectiveness remains to be further tested in more patients as well as in a randomized trial., ((c) 2007 Wiley-Liss, Inc.)

Background: The treatment outcome of multifocal childhood Langerhans cell histiocytosis (LCH) has not been satisfactory and has resulted in poor therapeutic responses with high mortality and a high incidence of reactivation with late sequelae. To overcome these issues, the Japan LCH Study Group-96 (JLSG-96) protocol was conducted prospectively from 1996 to 2001 in Japan., Methods: Newly diagnosed children with multifocal LCH were classified into 2 groups: a single-system multisite (SS-m) group and a multisystem (MS) group. All patients initially were treated on Protocol A, which consisted of 6 weeks of induction therapy with combined cytosine arabinoside, vincristine (VCR), and prednisolone (PSL) followed by 6 months of maintenance therapy. Patients who had a poor response to the induction of Protocol A were switched to a salvage regimen (Protocol B), which consisted of an intensive combination of doxorubicin, cyclophosphamide, VCR, and PSL., Results: In total, 91 patients were treated, including 32 patients in the SS-m group and 59 patients in the MS group. At the median 5-year follow-up, 96.9% of patients in the SS-m group and 78.0% of patients in the MS group had good response status. Diabetes insipidus developed in 3.1% of patients in the SS-m group and in 8.9% of patients in the MS group. The overall survival rate at 5 years for the SS-m and MS groups was 100% and 94.4% +/- 3.2%, respectively., Conclusions: The JLSG-96 protocol attained very low mortality for pediatric patients with multifocal LCH., (Copyright 2006 American Cancer Society.)

Background: To determine useful biochemical markers in Langerhans cell histiocytosis (LCH), we analyzed the serum levels of soluble CD154 (sCD154), IL2 receptor (sIL2-R), receptor activator of NF-kappaB ligand (sRANKL), and osteoprotegerin (OPG)., Procedure: Our study included 46 newly diagnosed LCH patients (single-system multi-site (SM type): n = 20, and multi-system multi-site (MM type): n = 26) who were treated with the JLSG-02 protocol between 2002 and 2004. The median age of the patients was 3.8 years old (range 0-18). sCD154, sIL2-R, sRANKL, and OPG were measured by ELISA at diagnosis (n = 46) and after 6-weeks of induction therapy (n = 14)., Results: The values of sCD154, sIL-2R, sRANKL, and OPG, and the sRANKL/OPG ratio in sera were significantly higher in patients with LCH compared with controls (1.83 +/- 1.38 vs. 0.22 +/- 0.16 ng/ml, P < 0.001; 1,600 +/- 1,060 vs. 420 +/- 160 pg/ml, P < 0.001; 1.72 +/- 1.20 vs. 1.04 +/- 1.09 pmol/L, P = 0.019; 6.34 +/- 2.94 vs. 3.71 +/- 2.03 pmol/L, P < 0.001; and 0.40 +/- 0.45 vs. 0.16 +/- 0.17, P = 0.023, respectively). Serum levels of sIL-2R were significantly elevated in the MM type compared with the SM type (2,050 +/- 1,060 vs. 870 +/- 340 pg/ml, P < 0.001). Serum OPG levels were also significantly elevated in the MM type compared with the SM type (7.58 +/- 2.72 vs. 5.13 +/- 2.69 pmol/L, P = 0.008) and negatively correlated with the number of bone lesions (r = -0.56, P = 0.007). In contrast, the sRANKL/OPG ratios were significantly higher in the SM type than the MM type (0.57 +/- 0.54 vs. 0.19 +/- 0.14, P = 0.002) and positively correlated with the number of bone lesions (r = 0.34, P = 0.040). In patients who responded to the induction therapy, serum levels of sIL-2R, sRANKL, and OPG, and the sRANKL/OPG ratio decreased significantly after the therapy (1,170 +/- 600 vs. 730 +/- 290 pg/ml, P = 0.029; 2.19 +/- 1.06 vs. 1.24 +/- 0.66 pmol/L, P < 0.001; 6.13 +/- 2.40 vs. 4.72 +/- 2.03 pmol/L, P = 0.040; and 0.57 +/- 0.52 vs. 0.41 +/- 0.37, P = 0.02, respectively). In the three patients who did not respond to the induction therapy, the serum levels of sCD154 increased significantly after the therapy (1.3 +/- 1.1 vs. 2.7 +/- 1.2, P = 0.004)., Conclusions: Serum levels of sIL-2R and sCD154 could be useful as indicators of inflammation and sRANKL/OPG ratios as markers of osteolytic activity in LCH patients.

The pathogenetic mechanisms of the central nervous system (CNS) problems associated with Langerhans cell histiocytosis (LCH) are not well established. Effective treatment strategies for these CNS complications are not yet available, while diabetes insipidus, also associated with LCH, can be managed effectively. Three Japanese boys with LCH who developed cerebellar ataxia were evaluated. Similar pediatric cases from the literature are also discussed. All three patients initially developed multifocal LCH lesions during early childhood (age <3 years) that responded well to chemotherapy; however, two of the three patients later developed diabetes insipidus. Ataxia, associated with mild developmental delay, was noted in the patients between the ages of 4 to 8 years. Analysis of these three cases, along with previously reported cases, indicates that the median age of onset of LCH was 2.5 (range 0.1-6.5) years and the median age of onset of cerebellar lesions/ataxia was 7 (range 3.5-16.5) years. Although the incidence of cerebellar LCH involvement is low, delayed onset of CNS disease must be monitored during follow-up care of pediatric LCH patients. Brain magnetic resonance imaging is strongly recommended for early detection of cerebellar lesions, but it remains to be determined whether there are any therapeutic measures to prevent exacerbation of CNS disease.

We report a case of a girl with Langerhans cell histiocytosis (LCH) of multifocal bone disease, who developed recurrent bacterial meningitis and unilateral sensorineural hearing loss during the relapsing course of the disease. Mondini dysplasia, a congenital inner ear anomaly, was suspected by high resolution computed tomographic scan and the dysplasia with cerebrospinal fluid leakage was confirmed by surgery in the ipsilateral ear showing hearing loss. Although rare, congenital inner ear anomalies such as Mondini dysplasia should be kept in mind in pediatric patients with hearing impairment and/or recurrent bacterial meningitis during chemotherapy for various types of neoplasms including LCH., (Copyright 2004 Wiley-Liss, Inc.)

Juvenile xanthogranuloma (JXG), one of the most common forms of non-Langerhans cell histiocytosis (LCH), usually presents in young children as spontaneously regressing cutaneous lesions. However, the systemic type of JXG is difficult to treat in newborn infants, and fatal cases have been reported. In the patient described here, solid masses were discovered by fetal sonography during the 38th gestational week. At birth she had multiple tumors on the back, cheek, and hip as well as marked hepatosplenomegaly accompanied by respiratory failure. Laboratory results indicated pancytopenia, obstructive liver dysfunction, and coagulopathy. Brain magnetic resonance imaging revealed a tumor at the left pontine angle, and dysmorphic histiocytes were present in her spinal fluid. She was diagnosed with systemic JXG by histopathologic findings of the hip mass. The LCH-based multiagent chemotherapy including cytarabine, vincristine, methotrexate, and prednisolone ameliorated the symptoms rapidly. She was treated for 12 months and is currently doing well as a normally developing 2-year-old.

There exists limited information about the usefulness of hemopoietic stem cell transplantation (HSCT) for the treatment of patients with refractory Langerhans cell histiocytosis (LCH). We report here four Japanese pediatric patients with multisystem LCH disease who underwent HSCT between 1994 and 1997. Two of the four patients are doing well without any relapse. However, neither of them shows improved sequelae 3 to 4 years after allogeneic HSCT, although the graft was rejected in one of the cases. The remaining two patients died of septic shock. A review of the literature of 11 patients revealed four fatalities after the use of HSCT in the treatment of LCH. Three of these were due to active LCH and three deaths occurred within 2 months after HSCT. To establish the usefulness of HSCT for refractory LCH, further studies are required.