Multifocal Langerhans Cell Histiocytosis Research Articles

Phase II study in children and adults under 40 years with newly diagnosed Langerhans cell histiocytosis: protocol for an LCH-19-MSMFB clinical trial in Japan

IntroductionAlthough the prognosis of Langerhans cell histiocytosis (LCH) is excellent, the high recurrence rate and permanent consequences, such as central diabetes insipidus and LCH-associated neurodegenerative diseases, remain to be resolved....

Persistent purple erythematous rash: Langerhans cell histiocytosis

Langerhans cell histiocytosis (LCH) is an uncommon yet serious inflammatory neoplasia that frequently affects children. Skin and bone manifestations are frequent and may be isolated or associated with visceral or systemic disorders. Diagnosis is clinicopathologic, established upon typical clinical findings and immunohistochemical and histological analyses of a biopsy taken from the lesions. Prognosis depends on onset age and the quantity of affected organs. Treatment is often necessary for LCH if systemic involvement exists. Herein, we report a rare case of multifocal LCH of late onset. Key words: Histiocytosis, Langerhans cell histiocytosis, Inflammation, Systemic manifestations

HDAC3 Is Required for Pathognomonic Features of Langerhans Cell Histiocytes

Langerhans cell histiocytosis (LCH) is a pediatric inflammatory myeloid neoplasm that develops due to dysregulated myeloid cell development. BRAFV600E is the most common disease-causing mutation and constitutively activates the mitogen-activated protein kinase (MAPK) pathway in myeloid lineage precursors leading to the key pathognomonic features of LCH cells. Enhanced myelopoiesis and reduced CCR7 expression promote accumulation of LCH cells in tissues by simultaneously increasing the production of pathological DCs and preventing tissue egress. Furthermore, LCH cells acquire an oncogene induced senescence-associated secretory phenotype (SASP) that depends on mammalian target of rapamycin (mTOR), which is hallmarked by increased expression of anti-apoptotic proteins, inflammatory cytokines, and matrix metalloproteinases enhancing survival of LCH cells and promoting recruitment of inflammatory immune cells forming characteristic granulomatous lesions. These pathognomonic features result in the accumulation of LCH cells in any organ causing a wide range of clinical symptoms. Frontline therapy for LCH involves combination chemotherapy and steroidal anti-inflammatories, or MAPK inhibitors, which have significant toxicity and fail to eliminate disease causing precursors. New therapeutic approaches are urgently needed. Here, using multiple genetic mouse models, we show that normal epidermal Langerhans cells (LCs) depend on HDAC3 for their development, differentiation, and survival. Integrative RNA and chromatin-immunoprecipitation-sequencing show loss of HDAC3 abrogates the expression of master regulators of myeloid development and function including Csf1r, Spi1, Id2 and Runx3. LCH cells are also known to rely on Csf1r and Pu.1 for their development and homeostasis, thus we hypothesized that LCH cells similarly rely on HDAC3 for their development and survival. CD11c Cre LSL-BRAFV600E ( BRAFV600E CD11c) mice develop severe multifocal LCH with pronounced lesion development in their livers and lungs, hepatosplenomegaly, and a reduced lifespan due to the accumulation of pathological dendritic cells (DCs). We generated BRAFV600E CD11c HDAC3 fl/fl ( BRAFV600E HD3KO) mice, which produce pathological DCs that simultaneously express BRAFV600E and harbor a conditional deletion in the deacetylase domain of HDAC3. Compared to BRAFV600E CD11c mice, BRAFV600E HD3KO mice exhibited significantly less hepatosplenomegaly, reduced lesional burden (Panel A), attenuated disease progression, and improved survival indicating reduced LCH disease burden. Compared to BRAFV600E CD11c flow cytometry showed BRAFV600E HD3KO had reduced numbers of LCH cells in lungs and livers linking improved disease outcomes to abrogation of pathological DCs. Flow cytometric analysis of circulating myeloid cells further found reduced frequency of circulating DCs and DC progenitors, indicating that a lack of HDAC3 activity prevents the development of pathological DCs (Panel B). LCH-like cells can be generated in vitro by culturing BRAFV600E CD11c bone marrow with granulocyte-monocyte colony-stimulating factor (GM-CSF), providing a valuable drug screening tool. Treating LCH-like cells with RGFP966, an HDAC3-specific inhibitor, increased apoptosis indicated by annexin-V and DAPI staining, reduced expression of Bcl-2, increased CCR7 expression, and decreased S6 phosphorylation (an indication of decreased mTOR activity), showing that pharmacological inhibition of HDAC3 may prove therapeutically efficacious by abrogating pathognomonic features of LCH cells. Together, our findings identify HDAC3 as a critical epigenetic regulator for both healthy and pathological LCs. We further show, HDAC3 is required for multiple pathognomonic features of LCH cells and could be a promising drug target. Furthermore, if HDAC3 is required for the development of pathological DC and DC progenitors, HDAC3 blockade would address a great need in treatment of patients with LCH.

Long-term outcomes among adults with Langerhans cell histiocytosis

AbstractAdvances in the treatment of Langerhans cell histiocytosis (LCH) have resulted in a growing survivor population. There is a lack of data on long-term outcomes among adults with LCH. We conducted a retrospective record review of 219 adults (aged ≥18 years) with LCH. Most common presentation was multisystem (34.2%), followed by single-system pulmonary (32%), unifocal (28.3%), and single-system multifocal (5.5%) LCH. Risk organ involvement (the liver, spleen, or bone marrow) was seen in 8.7% of cases, and 40 of 88 (45.5%) tested cases were BRAFV600E. At a median follow-up of 74 months, 5-year progression-free survival (PFS) was 58.3% and estimated median PFS was 83 months. Median overall survival (OS) was not reached; 5- and 10-year OS rates were 88.7% and 74.5%, respectively. Risk organ involvement was associated with worse PFS (hazard ratio [HR], 4.5) and OS (HR, 10.8). BRAFV600E was not associated with risk organ involvement or survival. When compared with matched unaffected US population, individuals with LCH had a significantly higher risk of overall mortality (standardized mortality ratio [SMR], 2.66), specifically among those aged <55 years at diagnosis (SMR, 5.94) and those with multisystem disease (SMR, 4.12). Second cancers occurred in 16.4% cases, including diverse hematologic and solid organ malignancies. LCH-associated deaths constituted 36.1% of deaths and occurred within 5 years of diagnosis. After 5 years, non-LCH causes of death, including second cancers, chronic obstructive pulmonary disease, and cardiovascular diseases, predominated. Our study highlights, to our knowledge, for the first time, that adults with LCH experience early and late mortality from non-LCH causes and the need for development of targeted survivorship programs to improve outcomes.

Multiple Langerhans cell histiocytosis with spinal involvement.

The aim of this study was to report the long-term prognosis of patients with multiple Langerhans cell histiocytosis (LCH) involving the spine, and to analyze the risk factors for progression-free survival (PFS). We included 28 patients with multiple LCH involving the spine treated between January 2009 and August 2021. Kaplan-Meier methods were applied to estimate overall survival (OS) and PFS. Univariate Cox regression analysis was used to identify variables associated with PFS. Patients with multiple LCH involving the spine accounted for 15.4% (28/182 cases) of all cases of spinal LCH: their lesions primarily involved the thoracic and lumbar spines. The most common symptom was pain, followed by neurological dysfunction. All patients presented with osteolytic bone destruction, and 23 cases were accompanied by a paravertebral soft-tissue mass. The incidence of vertebra plana was low, whereas the oversleeve-like sign was a more common finding. The alkaline phosphatase was significantly higher in patients with single-system multifocal bone LCH than in patients with multisystem LCH. At final follow-up, one patient had been lost to follow-up, two patients had died, three patients had local recurrence, six patients had distant involvement, and 17 patients were alive with disease. The median PFS and OS were 50.5 months (interquartile range (IQR) 23.5 to 63.1) and 60.5 months (IQR 38.0 to 73.3), respectively. Stage (hazard ratio (HR) 4.324; p < 0.001) and chemotherapy (HR 0.203; p < 0.001) were prognostic factors for PFS. Pain is primarily due to segmental instability of the spine from its destruction by LCH. Chemotherapy can significantly improve PFS, and radiotherapy has achieved good results in local control. The LCH lesions in some patients will continue to progress. It may initially appear as an isolated or single-system LCH, but will gradually involve multiple sites or systems. Therefore, long-term follow-up and timely intervention are important for patients with spinal LCH.

Aggressive Systemic Mastocytosis with a Relatively Non-aggressive Course

Background: Mastocytosis is a heterogeneous group of disorders that is characterized by excessive proliferation and pathologic accumulation of mast cells in various body tissues. The mast cells also have abnormal morphology and aberrant expression of surface receptors. Clinical Description: A 4-year-old boy was brought with a history of generalized skin lesions since birth and abdominal distension for 3 years. The diagnosis had not been established to date. General physical examination revealed severe acute malnutrition, pallor, dental staining, facial hypertrichosis, polymorphous skin lesions (cicatricial alopecia, diffuse erythema, multiple plaques of variable diameter, skin-colored nodules, and hypertrophic irregular scars), and positive Darier's sign. He also had hepatosplenomegaly. The differentials considered were congenital erythropoietic porphyria, systemic mastocytosis (SM), multifocal Langerhans cell histiocytosis, and linear immunoglobulin A bullous dermatosis. The presence of mast cells on skin biopsy and elevated serum tryptase levels led us to suspect SM and perform bone marrow studies. The diagnosis of “aggressive” SM was initially made on the application of the diagnostic criteria but revised to “smoldering” SM with the emergence of Vitamin B12 deficiency as the probable cause of pancytopenia. Management: Management was planned by a multidisciplinary team: pediatrician, dermatologist, and hematopathologist. The parents were counseled about the nature, natural history, treatment options, and prognosis of the disorder. The child was provided with nutritional rehabilitation and medication for the cutaneous symptoms (selective histamine H1 receptor inverse agonist, H2-receptor antagonist, and application of topical tacrolimus and calamine lotion). Conclusion: The prognosis varies according to subtype. Careful correlation of clinical and laboratory investigations is required when applying the diagnostic criteria for staging.

Treatment and Outcomes of Unifocal and Multifocal Osseous Pelvic Langerhans Cell Histiocytosis Lesions in a Pediatric Population.

IntroductionLangerhans cell histiocytosis (LCH) is a rare, clonal disorder characterized by proliferation and tissue infiltration by myeloid dendritic cells, most commonly occurring in pediatric populations. It often manifests as skeletal lesions with possible pelvic involvement. Few studies have characterized and reviewed outcomes after treatment of isolated pelvic LCH lesions.MethodsA retrospective single-institution review was conducted on diagnoses of patients younger than 18 with a diagnosis of unifocal or multifocal skeletal LCH lesions involving the pelvis. Clinical presentations, lesion sites, focal classification, radiographic findings, treatments, complications, and recurrence rates were reviewed.ResultsTwenty patients had unifocal or multifocal LCH pelvic lesions (11 males, nine females). The median age at diagnosis was 3.5 years (0.8-21.6). Eight cases (40%) involved unifocal lesions, and twelve (60%) involved multifocal lesions, with the most common associated skeletal disease occurring at the ilium. 100% of cases had a lytic bone lesion with no pathologic fractures. All cases were treated nonoperatively with chemotherapy medications, corticosteroids, or observation alone. 75% of cases were treated with chemotherapy with a 100% resolution rate. The median length of follow-up was 4.5 years (0.4-16.7). ConclusionOur study found that chemotherapy alone or chemotherapy with corticosteroid supplementation are appropriate options for unifocal pelvic LCH lesions. In contrast, pelvic lesions that are part of a multifocal presentation may be managed adequately with varied chemotherapy regimens. Corticosteroid therapy and observation alone may also be reasonable for a single organ system, multifocal, skeletal lesions that are anatomically accessible for biopsy and small in number or size.

18F-fluorodeoxyglucose-positron emission tomography/computed tomography delineates involved sites in the cervical spine in Langerhans cell histiocytosis.

Langerhans cell histiocytosis (LCH), a granulomatous tumorous lesion consisting of CD1a-positive clonal immature dendritic cells in association with various inflammatory cells, develops in tissues including bone, skin, lungs, and lymph nodes. When bone LCH exhibits osteolytic lesions, the spine is often involved, and each part of the vertebral body, vertebral arch, and vertebral spinous process can be affected. Such vertebral LCH can occur at the onset of disease and in relapse. To confirm pathological sites, a computed tomography (CT) scan is generally used to characterize lytic lesions of vertebrae, while MRI is suitable for delineating marrow and soft tissue. Additionally, to identify specific locations, 18F-fluorodeoxyglucose-positron emission tomography/CT (FDG-PET/CT) is useful. We describe three LCH cases showing characteristic cervical spinal involvement. Case 1: A 39-year-old woman complained of right temporal pain and was found to have osteolytic lesions of right temporal/sphenoid/petrous bones. She also had central diabetes insipidus (CDI). After the diagnosis of LCH from biopsied tissue, she was treated with chemotherapy and attained remission. Four years later, she complained of neck/shoulder pain associated with herpes zoster in the right arm. PET/CT revealed a cervical spine (C3)-vertical body lesion (Figure 1A). With a revised chemotherapy regimen, she attained a second remission. Case 2: A 70-year-old man, a heavy smoker for more than 40 years, complained of shortness of breath, and a chest X-ray revealed characteristic honeycomb lungs. PET/CT showed hot lesions in the lungs, cervical spine (C3) right vertebral arch (Figure1B), and ribs. Lung lesion biopsy confirmed the diagnosis of LCH. He had no CDI and was treated with irradiation to the cervical spine and with chemotherapy. Case 3: A 40-year-old man who had severe atopic dermatitis since the age of 20 complained of nuchal pain after a traffic accident. He was also noted to have lymphadenopathy in the bilateral axillary and inguinal areas. PET/CT revealed hot signals at the spinous process of the cervical spine (C6) (Figure 1C) and lymph node lesions. Biopsy of the C6 lesion confirmed LCH. He attained a remission treated with chemotherapy and zoledronic acid. Three years later, relapse at the lymph nodes was noted, but not in the C6 lesion. He was treated with chemotherapy for refractory LCH and attained a second remission. An analysis of 76 cases of vertebral LCH by Huang et al. [1] consisted of 40 children and 36 adults, with a male to female ratio of 55:21. Lesions were predominantly in the cervical spine, followed by the thoracic and lumbosacral spines. In an analysis of 30 LCH patients with cervical spine involvement by Jiang et al. [2], 14 had atlantoaxial lesions (C1 and C2), and 16 had sub-axial (C3–C7) lesions. Chemotherapy is recommended for the management of cervical spine lesions in cases of multifocal LCH. In our three cases, two patients had spinal involvement at onset while the other developed it at relapse. All received chemotherapy because of multifocal LCH lesions. In summary, as an imaging study of cervical spine involvement in LCH, PET/CT seems to be useful for pinpointing the involved sites of vertebrae. None The authors declare no conflict of interest.

Lung Transplant in a Patient With Multifocal Langerhans Cell Histiocytosis After Chemotherapy With Cladribine: A Case Report

Langerhans cell histiocytosis (LCH) is a rare inflammatory disorder of myeloid dendritic cells with mutations involving KRAS, BRAF and/or NRAS, and MAP2K1 genes. We describe the case of a 58-year-old female previous smoker with multifocal LCH involving the lungs, pituitary gland and mandibular bone. Initial treatment with 6 cycles of cladribine showed improvement in her extrapulmonary lesions, however, her lung disease progressed and after qualification and assessment tests she underwent uncomplicated double lung transplant surgery and was discharged home. We highlight that in select patients with well managed and controlled extrapulmonary LCH, such an invasive procedure as lung transplant is possible.

Phenotypes and prognostic factors in adults with Langerhans cell histiocytosis.

7049 Background: Langerhans cell histiocytosis (LCH) can manifest as single system (SS) disease, multisystem (MS) disease, or pulmonary LCH (smoking-related). There is a paucity of data on prognostic factors including risk organ (RO) involvement (liver, spleen, and bone marrow) in adult LCH, which we sought to address in this study. Methods: Single-center retrospective study of patients ≥18y diagnosed with LCH from 1998 to 2020. Univariate and multivariate analyses for progression free survival (PFS) and overall survival (OS) were conducted using age, sex, organ involvement, LCH subtype, year of diagnosis, BRAF V600E status, and treatments. Results: We included 219 patients with LCH; median age 43y (range 19-88), females 51%, SS unifocal (23%), SS multifocal (6%), pulmonary (31%) and MS (40%). Commonly involved organs included lung (53%), bone (42%), skin (24%), pituitary (16%), and CNS (12%). BRAF V600E was positive in 40/88 (46%). Median follow-up duration was 6.1y (95% CI, 5.1- 7.1). On univariate analysis, factors associated with worse PFS were bone LCH, RO involvement, multifocal/MS LCH, and radiation therapy alone; those with worse OS included RO involvement, MS disease, BRAF V600E+, and age ≥45y at diagnosis. In multivariate analysis, BRAF V600E and age ≥45y at diagnosis were associated with worse mortality (Table). Median PFS was not reached (NR-NR) for SS unifocal LCH, 5mo (0-12.7) for SS multifocal LCH, 110mo (84.7-135.3) for pulmonary LCH, and 27mo (17.2-36.8) for MS LCH. 5-year OS was 97.4% for SS unifocal LCH, 100% for SS multifocal LCH, 96.1% for pulmonary LCH, and 79.9% for MS LCH. 41 (18.7%) developed a second primary malignancy (SPM), of which 11 were hematologic neoplasms. There was a trend towards a higher prevalence of SPMs in patients with BRAF V600E (28% vs. 17%; p = 0.22). Conclusions: In our large single-center study, PFS for multifocal and MS LCH was worse than SS unifocal or pulmonary LCH. RO involvement was not associated with outcomes in multivariate analysis. Overall prognosis was excellent for all subtypes except MS LCH. BRAF V600E and older age were associated with worse OS. The prevalence of SPMs was very high and needs to be explored further.[Table: see text]

BRAFV600E frequency and impact on outcomes in adults with langerhans cell histiocytosis.

7050 Background: Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasm manifesting as unifocal, multifocal, multisystem (MS) or pulmonary LCH (smoking-related). In pediatric LCH, somatic BRAFV600E prevalence is reported at 55-70%, and associated with increased risk of multisystem disease and early treatment failure. Our aim was to describe the prevalence of BRAFV600E mutation and evaluate its association with clinical manifestations and outcomes in adults with LCH. Methods: A retrospective review of adult patients diagnosed with LCH consecutively seen at Mayo Clinic from 2011 to 2020 was performed.Evaluation of association of BRAFV600E mutational status and clinical factors was conducted by the Chi-square test for independence. Progression-free survival (PFS) and overall survival (OS) were analyzed via the Kaplan Meier method and compared with the log-rank test to assess the effect of BRAFV600E. Results: Of the total LCH cohort ( n= 128), 88 patients with available BRAFV600E results were included in the study. Median age at diagnosis was 41y (range 19 - 88); 52.3% were male. 40 (45.5%) patients had a BRAFV600E mutation. Increasing age was associated with BRAFV600E (10-year increase OR 1.42, 95%CI 1.07-1.89; p= 0.017). No correlation was observed between BRAFV600E status and site of disease, risk organ (RO: liver, spleen, marrow) involvement, or MS disease. Patients with BRAFV600E were 4 times more likely to receive targeted therapy ( BRAF inhibitor) than non- BRAFV600E patients ( p= 0.018). After a median follow up of 46 mo (95% CI 30.8-61.2), PFS was similar between BRAFV600E and non- BRAFV600E patients ( p= 0.167). However, patients with BRAFV600E had a worse 3-year OS compared with non- BRAFV600E patients (84% vs. 97.1%, p= 0.027). Patients who died had a significantly higher age at LCH diagnosis (median 62 vs. 38 years; p= 0.0002). Conclusions: In our cohort of adults with LCH, BRAFV600E was less frequent than reported in pediatric literature and was associated with worse OS. The frequency of BRAFV600E was positively correlated with increasing age. Contrary to reports in pediatric LCH, there were no significant associations between BRAFV600E and high-risk or multisystem disease.[Table: see text]

Multifocal adult Langerhans cell histiocytosis with diabetes insipidus as the initial symptom: a case report and literature review

: Langerhans cell histiocytosis (LCH) is a disease characterized by the proliferation of Langerhans cells in one or more organs. The cause of the disease is not very clear, it can occur at any age, but it is more common in infants, there is currently no uniform treatment for LCH. Here we report a case of "polyuria, thirsty and polydipsia" as the first manifestation of an adult female patient. It gradually developed into multiple lesions and multiple systems involving pituitary, skull, left clavicle, spine and left femoral head and so on. LCH was confirmed in this patient by pathological section which was langerin (+ +). The adult multifocal LCH cases admitted as central diabetes insipidus (CDI) were very rare in our department, for the patients with pituitary stalk thickening, bone tissue and multiple organ involvement, the possibility of LCH should be considered and histopathological biopsy should be carried out, which is very important for the diagnosis and treatment.

Pediatric langerhans cell histiocytosis of the temporal bone: A rare case report and review of literature

Langerhans cell histiocytosis (LCH) is a rare cancer involving clonal proliferation of Langerhans cells (LCs) resembling epidermal dendritic cells. It can involve any organ or system. Temporal bone LCH is often confused with ear inflammatory lesions and malignant tumors. Diagnosis is based on clinical, radiological, and pathological findings. The definitive diagnosis is made on biopsy and by immunohistochemical demonstration of CD 1a and or Langerin positivity in the clonally neoplastic cells. The course of LCH is variable from spontaneous regression to repeated recurrences and death. The main form of treatment is chemotherapy. We describe a case of multifocal multisystem LCH in a 4-year-old child who presented with recurrent chronic suppurative otitis media and an external auditory canal polyp.

Langerhans cell histiocytosis: Diagnosis and Management

Langerhans cell histiocytosis (LCH) is a rare disorder characterized by abnormal clonal proliferation of Langerhans dendritic cells. The incidence of LCH is 1 to 3 cases per 1 million children worldwide, and occurs most frequently in children of 1–4 years of age. The etiopathogenesis of LCH, whether it is neoplastic or reactive, is still controversial. Langerhans cell histiocytosis has a wide spectrum of clinical features, and dermatological abnormalities usually occur early. The most frequent lesions are elevated yellowish-red translucent papules about 1–2 mm in diameter and generally located in seborrheic areas. The most recent classification (the Histiocyte Society study 2017) categorized LCH into four groups; a single system with involvement of unifocal or multifocal organs, lung LCH, and multi-system LCH with either low- or high-risk multiorgan involvement. The definitive diagnosis of LCH are typical morphology along with Birbeck granules and/or positive results on CD1a antigen stain on cells found on lesions. Treatment of LCH is multimodal, determined based on age, extent of lesion, organ involvement, and organ location. Keywords: histiocytosis, Langerhans cells, dendritic cells, children

Analysis of the Incidence and Diagnostic Pattern of Langerhans Cell Histiocytosis from the Population-Wide Healthcare Database in Korea

Introduction Langerhans cell histiocytosis (LCH) is a rare disease involving clonal proliferation of Langerhans cells. The reported incidence of LCH ranges from 0.5-5.4 cases per million persons per year, according to the prospective registry-based reports. However, due to the rarity of the disease and the limitation of prospective registries, the comprehensive understanding of nation-wide epidemiology has been limited. This study aimed to analyze the incidence by age and diagnostic patterns of LCH using the population-wide healthcare database in Korea. M ethods The claims data of the Health Insurance Review and Assessment (HIRA) contain information of 46 million patients per year, which accounts for about 95% of the total population of South Korea. The data include information regarding diagnoses, hospitalization, and prescription drugs. Since 2005, the "National cancer registration and reimbursement program" has been implemented, which reimburse for 90% of the medical expenses of patients with malignant diseases, including LCH. Therefore, all the patients with LCH have been registered in the database after a definite diagnosis. From the HIRA open data source, we extracted a claim data of patients corresponding to diagnosis codes of C95.0 (Multifocal and multisystemic -disseminated LCH), C96.5 (Multifocal and unisystemic LCH), or C96.6 (Unifocal LCH) during the period of 2010-2017. Data for 2010-2011 was used as a reference for overlapping patients, and the actual analysis was conducted with data from 2012 to 2017. Results During the period, a total of 59,929 insurance statements were issued, and 53,446 statements with only one identical diagnostic code and confirmative workups were selected for final analysis. The total incidence cases during the period of 2012 to 2017 were 899 cases, and the average number of the annual incidence was 150 cases. The incidence was 3.0 cases per million persons per year. There was a male predominance with a male-to-female ratio of 1.63:1 (558 cases:341 cases) in a whole cohort. For the detailed diagnosis codes, C96.6 was the most frequent as 93.4%, followed by C96.0 as 4.9%, and C96.5 as 1.7%. The average age at diagnosis was 26.6 years (range, 0.2~87 years) in all incidence cases, and 26.6 years for C96.0 group, 29.5 years for C96.5 group, and 25.9 years for C96.6 group, respectively. When patients were grouped by age at diagnosis, the age group of 0-4 years showed the highest annual incidence of 17.9 cases per million, followed by the group of 5-9 years as 8.9 cases per million, and the age group over 70 years showed the lowest annual incidence of 1.1 cases per million (Figure 1). There were no seasonal trends in the diagnosis of LCH. At diagnosis, 21.6% of patients were diagnosed at the department of neurosurgery, 21.5% at pediatrics, 19.3% at internal medicine, and 16.8% at orthopedic surgery. For examinations conducted at the time of diagnosis, simple radiography was conducted in 84.9% of patients, computed tomography in 32%, magnetic resonance imaging in 39.6%, bone scan in 47.1%, and bone marrow examination in 22.9% of patients. For treatment, most of the patients (93.7%) received at least one modality of treatments after diagnosis; 42.7% of patients underwent surgery only, 30.4% received topical steroids only, 12.6% underwent surgery followed by chemotherapy, and 10.5% received chemotherapy. For chemotherapy, vinblastine was the most frequently prescribed drug as used in 82.9% of patients who received chemotherapy, followed by methotrexate in 39.4%, and mercaptopurine in 38.9%. Conclusions This study was the first big data analysis regarding LCH in Korea, and the annual incidence of LCH was 3.0 cases per million persons per year. The incidence was highest at 0-4 years of age, and the incidence was significantly decreased with age. We plan to conduct further research on the treatment and outcomes of Korean LCH patients in conjunction with the data of ongoing prospective registry. Figure 1. The annual incidence of Langerhans Cell Histiocytosis by age at diagnosis Figure 1 Disclosures No relevant conflicts of interest to declare.

Langerhans cell histiocytosis in children: a case report and brief review of the literature

Langerhans cell histiocytosis (LCH), formerly known as histiocytosis X, is a non-malignant disease involving clonal proliferation of Langerhans cells. It is an orphan disease affecting mainly the child and the young adult. Its etiology is still unknown, and its clinical spectrum is quite wide. Systemic treatment incorporating steroids and cytostatic drugs for at least one year has improved prognosis of multisystem LCH and represents the current standard of care. We report the case of a multifocal bone LCH in a 2-year-old girl affecting the frontal and parietal bones, associated with emphysematous bulla. The diagnosis was confirmed with histological examination. The evolution was favorable after treatment. Based on this observation, we will make a brief review of the literature to present the clinical, histological, radiological, therapeutic and evolutionary aspects of this orphan disease.

Spontaneous and complete regeneration of a vertebra plana after surgical curettage of an eosinophilic granuloma

The eosinophilic granuloma is a unifocal or multifocal Langerhans cell histiocytosis characterized by an expanding proliferation of Langerhans cells in bones. Skeletal LCH is a rare condition, and vertebral regeneration in cases of vertebral body collapse is even rarer. We report the case of a girl with spontaneous complete healing. A 3-year-old girl was referred for nighttime back pain, with no fever and no neurologic signs. Within a few days, she developed sudden painful restriction of all spine movements. X-ray and computed tomography (CT) of the spine showed reduced T7 vertebral body height (vertebra plana).The patient underwent T7 curettage and the histopathological exam was suggestive of LCH. Two additional skull lesions were found and therefore she underwent chemotherapy. After 7years of follow-up, total vertebral reconstruction was observed. Despite the rarity of the condition and despite the rarity of vertebral body lesion resolution, total vertebral body reconstruction was observed over a 7-year period. Long-term follow-up is necessary for a better understanding of the final outcome of patients with EG.

Bisphosphonate Therapy in Langerhans Cell Histiocytosis: An International Retrospective Descriptive Study

▪Introduction: Langerhans cell histiocytosis (LCH) is a monoclonal disorder characterized by proliferation and accumulation of atypical Langerhans cells and in up to 55% of all cases somatic mutations in BRAF proves to be the driver. Although uncommon, it is potentially fatal and carries significant morbidity. Bone involvement in LCH can be destructive, painful and often associated with pathologic fractures. There is no consensus in the treatment strategies for bone LCH which could vary from simple curettage with biopsy and/or intralesional steroids to more toxic systemic chemotherapy. However, the number of treatments for this disease is limited and other options need to be explored. Bisphosphonates are osteoclast inhibitors that can target certain osteoclast markers expressed by the multinucleated giant cells in the skin, bone and lymph nodes LCH lesions and can potentially be used to alleviate bone pain and possibly control the progression of disease activity.Purpose: To evaluate the efficacy and safety of bisphosphonates in treating bone LCH and extra-osseous disease.Methods: An international multicenter retrospective chart review was conducted in children and adults with LCH who received bisphosphonates between 1995 and 2014.Results: Eighteen patients were identified from 4 centers. All received bisphosphonates therapy either at diagnosis or at ≥ 1st reactivation. Median age at start of bisphosphonates was 23.7 years (range 5.7-38.3 years), and median follow-up time post-bisphosphonate therapy was 2.8 years (range 0.9-5.0 years). Patients had either single system bone disease or bone lesions as part of their multisystem disease. Patients were treated with different bisphosphonates with majority received zoledronic acid (n=10), followed by pamidronate (n=4) and alendronate (n= 3); one patient received both pamidronate and zoledronic acid. All patients reported significant reduction in pain to either no or mild pain after administration of bisphosphonates. Thirteen of 18 patients (72%) achieved complete remission (CR) in their bone lesions, including lesions in skin (n=1), lung (n=1) and pituitary (n=1); 2 had partial response and 3 had no response. Among the 13 CR patients, 12 had no active disease for a median of 4.1 years (range 2.8 - 5.1 years) and 1 developed radiographic neurodegeneration after 2 years. Bisphosphonate therapy was well tolerated by all patients with no major toxicity. Progression-free survival (PFS) was 75 ± 11% at 3 years, with a trend favoring better PFS (P=0.24) in patients with no or first reactivation compared with those having ≥ 2 reactivations.Conclusion: Bisphosphonates is a well-tolerated medication that can significantly improve bone pain in patients with bone LCH, and may even be effective in treating extra-osseous disease. A prospective randomized trial evaluating the role of bisphosphonates in multifocal bone LCH is warranted. DisclosuresNo relevant conflicts of interest to declare.

Recent advances in Langerhans cell histiocytosis.

The purpose of this review is to provide an updated overview of the pathogenesis and treatment of Langerhans cell histiocytosis (LCH). The pathogenesis of LCH remains obscure and the optimal treatment for LCH has not been established, although incremental progress has been made. Proinflammatory cytokines and chemokines are known to play a role in LCH, which suggests that LCH is an immune disorder. However, the oncogenic BRAF mutation is also detected in more than half of LCH patients, which suggests that LCH is a neoplastic disorder. Remaining major issues in the treatment of LCH are how to rescue patients who have risk-organ involvement but do not respond to first-line therapy, the optimal treatment for the orphan disease of multifocal adult LCH, and how to reduce and treat central nervous system-related consequences, such as central diabetes insipidus and neurodegeneration. More research is needed to better understand the pathogenesis of this disease and to resolve the treatment issues.

Multifocal Langerhans cell histiocytosis in an adult with a pathological fracture of the mandible and spontaneous malunion: A case report.

Langerhans cell histiocytosis (LCH) is rare in the adult population and even rarer with jaw involvement. The current study presents the case of a 39-year-old male who complained of recurrent pain, swelling of the gingiva and an occasional pus-like discharge in the right mandible for one year. The patient was previously prescribed antibiotics, but this did not resolve the problem. An initial panoramic radiograph showed an osteolytic lesion and bone fracture in the right mandible. Eight months later, a new radiograph showed the spontaneous malunion of the fractured mandible. The patient was eventually diagnosed with Langerhans cell histiocytosis by histopathology and immunohistochemistry. Further lesions were found in the ribs and ilium by nuclear bone scanning. The patient was subsequently treated with systemic chemotherapy, and the lesions are currently effectively being controlled. This study is the first to show that spontaneous intralesional bone regeneration may lead to reunification of the mandible fracture caused by LCH in an adult.