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The New England Journal of Medicine Aug 2018
Review
Topics: Cell Differentiation; Histiocytosis, Langerhans-Cell; Humans; Mitogen-Activated Protein Kinase Kinases; Myeloid Cells
PubMed: 30157397
DOI: 10.1056/NEJMra1607548 -
Cancer Science Dec 2018Langerhans cell histiocytosis (LCH) is a rare systemic disorder characterized by the accumulation of CD1a+/Langerin+ LCH cells and wide-ranging organ involvement.... (Review)
Review
Langerhans cell histiocytosis (LCH) is a rare systemic disorder characterized by the accumulation of CD1a+/Langerin+ LCH cells and wide-ranging organ involvement. Langerhans cell histiocytosis was formerly referred to as histiocytosis X, until it was renamed in 1987. Langerhans cell histiocytosis β was named for its morphological similarity to skin Langerhans cells. Studies have shown that LCH cells originate from myeloid dendritic cells rather than skin Langerhans cells. There has been significant debate regarding whether LCH should be defined as an immune disorder or a neoplasm. A breakthrough in understanding the pathogenesis of LCH occurred in 2010 when a gain-of-function mutation in BRAF (V600E) was identified in more than half of LCH patient samples. Studies have since reported that 100% of LCH cases show ERK phosphorylation, indicating that LCH is likely to be a clonally expanding myeloid neoplasm. Langerhans cell histiocytosis is now defined as an inflammatory myeloid neoplasm in the revised 2016 Histiocyte Society classification. Randomized trials and novel approaches have led to improved outcomes for pediatric patients, but no well-defined treatments for adult patients have been developed to date. Although LCH is not fatal in all cases, delayed diagnosis or treatment can result in serious impairment of organ function and decreased quality of life. This study summarizes recent advances in the pathophysiology and treatment of adult LCH, to raise awareness of this "orphan disease".
Topics: Adult; Combined Modality Therapy; Extracellular Signal-Regulated MAP Kinases; Histiocytosis, Langerhans-Cell; Humans; Mutation; Phosphorylation; Proto-Oncogene Mas; Proto-Oncogene Proteins B-raf; Randomized Controlled Trials as Topic; Rare Diseases; Signal Transduction
PubMed: 30281871
DOI: 10.1111/cas.13817 -
Blood Apr 2022Langerhans cell histiocytosis (LCH) can affect children and adults with a wide variety of clinical manifestations, including unifocal, single-system multifocal,...
Langerhans cell histiocytosis (LCH) can affect children and adults with a wide variety of clinical manifestations, including unifocal, single-system multifocal, single-system pulmonary (smoking-associated), or multisystem disease. The existing paradigms in the management of LCH in adults are mostly derived from the pediatric literature. Over the last decade, the discovery of clonality and MAPK-ERK pathway mutations in most cases led to the recognition of LCH as a hematopoietic neoplasm, opening the doors for treatment with targeted therapies. These advances have necessitated an update of the existing recommendations for the diagnosis and treatment of LCH in adults. This document presents consensus recommendations that resulted from the discussions at the annual Histiocyte Society meeting in 2019, encompassing clinical features, classification, diagnostic criteria, treatment algorithm, and response assessment for adults with LCH. The recommendations favor the use of 18F-Fluorodeoxyglucose positron emission tomography-based imaging for staging and response assessment in the majority of cases. Most adults with unifocal disease may be cured by local therapies, while the first-line treatment for single-system pulmonary LCH remains smoking cessation. Among patients not amenable or unresponsive to these treatments and/or have multifocal and multisystem disease, systemic treatments are recommended. Preferred systemic treatments in adults with LCH include cladribine or cytarabine, with the emerging role of targeted (BRAF and MEK inhibitor) therapies. Despite documented responses to treatments, many patients struggle with a high symptom burden from pain, fatigue, and mood disorders that should be acknowledged and managed appropriately.
Topics: Adult; Child; Cladribine; Consensus; Histiocytosis, Langerhans-Cell; Humans; MAP Kinase Signaling System; Mutation
PubMed: 35271698
DOI: 10.1182/blood.2021014343 -
Blood Apr 2020Langerhans cell histiocytosis (LCH) is caused by clonal expansion of myeloid precursors that differentiate into CD1a+/CD207+ cells in lesions that leads to a spectrum of... (Review)
Review
Langerhans cell histiocytosis (LCH) is caused by clonal expansion of myeloid precursors that differentiate into CD1a+/CD207+ cells in lesions that leads to a spectrum of organ involvement and dysfunction. The pathogenic cells are defined by constitutive activation of the MAPK signaling pathway. Treatment of LCH is risk-adapted: patients with single lesions may respond well to local treatment, whereas patients with multisystem disease require systemic therapy. Although survival rates for patients without organ dysfunction is excellent, mortality rates for patients with organ dysfunction may reach 20%. Despite progress made in the treatment of LCH, disease reactivation rates remain above 30%, and standard second-line treatment is yet to be established. Treatment failure is associated with increased risks for death and long-term morbidity, including LCH-associated neurodegeneration. Early case series report promising clinical responses in patients with relapsed and refractory LCH treated with BRAF or MEK inhibitors, although potential for this strategy to achieve cure remains uncertain.
Topics: Animals; Histiocytosis, Langerhans-Cell; Humans; MAP Kinase Signaling System; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf
PubMed: 32106306
DOI: 10.1182/blood.2019000934 -
Advances in Respiratory Medicine 2017Pulmonary Langerhans' cell histiocytosis (PLCH) is a rare disorder of unknown cause characterised by the infiltration of the lungs and other organs by the bone marrow... (Review)
Review
Pulmonary Langerhans' cell histiocytosis (PLCH) is a rare disorder of unknown cause characterised by the infiltration of the lungs and other organs by the bone marrow derived Langerhans' cells, which carry mutations of BRAF gene and/or NRAS, KRAS and MAP2K1 genes. It occurs predominantly in young smokers, without gender predominance. The disease is characterised by formation of eosinophilic granulomas with the presence of Langerhans' cells infiltrating and destroying distal airways. High-resolution computed tomography of the chest (HRCT) plays an outstanding role in PLCH diagnosis. The typical radiological picture of PLCH is the presence of small intralobular nodules, often forming 'tree in bud' lesions, cavitated nodules, thin- and thick-walled cystic lesions frequently confluent. Definite diagnosis requires the finding of characteristic lesions in histological examination and demonstration of antigen CD1a or CD207 presenting cells in immunohistochemistry. Smoking cessation is the most important recommendation for PLCH patients. There are no evidence based data regarding systemic steroid therapy. The treatment of progressive PLCH is based on cladribine or cytarabine as salvage therapy. The prognosis is good, and over 85% of patients survive 10 years.
Topics: Adult; Bronchi; Female; Histiocytosis, Langerhans-Cell; Humans; Lung; Male; Risk Factors; Smoking; Tomography, Spiral Computed
PubMed: 29083024
DOI: 10.5603/ARM.a2017.0046 -
Radiologia Dec 2022The term cystic lung disease encompasses a heterogeneous group of entities characterised by round lung lesions that correspond to cysts with fine walls, which usually...
The term cystic lung disease encompasses a heterogeneous group of entities characterised by round lung lesions that correspond to cysts with fine walls, which usually contain air. The differential diagnosis of these lesions can be challenging, requiring both clinical and radiological perspectives. Entities such as pulmonary emphysema and cystic bronchiectasis can simulate cystic disease. High-resolution computed tomography (HRCT) is the imaging technique of choice for the evaluation and diagnosis of cystic lung disease, because it confirms the presence of lung disease and establishes the correct diagnosis of the associated complications. In many cases, the diagnosis can be established based on the HRCT findings, thus making histologic confirmation unnecessary. For these reasons, radiologists need to be familiar with the different presentations of these entities. A wide variety of diseases are characterised by the presence of diffuse pulmonary cysts. Among these, the most common are lymphangioleiomyomatosis, which may or may not be associated with tuberous sclerosis, Langerhans cell histiocytosis, and lymphocytic interstitial pneumonia. Other, less common entities include Birt-Hogg-Dubé syndrome, amyloidosis, and light-chain deposit disease. This article describes the characteristics and presentations of some of these entities, emphasizing the details that can help differentiate among them.
Topics: Humans; Lung Diseases, Interstitial; Lung; Lymphangioleiomyomatosis; Histiocytosis, Langerhans-Cell; Cysts
PubMed: 36737165
DOI: 10.1016/j.rxeng.2022.09.005 -
Neuro-oncology Sep 2021Histiocytoses are heterogeneous hematopoietic diseases characterized by the accumulation of CD68(+) cells with various admixed inflammatory infiltrates. The... (Review)
Review
Histiocytoses are heterogeneous hematopoietic diseases characterized by the accumulation of CD68(+) cells with various admixed inflammatory infiltrates. The identification of the pivotal role of the mitogen-activated protein kinase (MAPK) pathway has opened new avenues of research and therapeutic approaches. We review the neurologic manifestations of 3 histiocytic disorders with frequent involvement of the brain and spine: Langerhans cell histiocytosis (LCH), Erdheim-Chester disease (ECD), and Rosai-Dorfman-Destombes disease (RDD). Central nervous system (CNS) manifestations occur in 10%-25% of LCH cases, with both tumorous or neurodegenerative forms. These subtypes differ by clinical and radiological presentation, pathogenesis, and prognosis. Tumorous or degenerative neurologic involvement occurs in 30%-40% of ECD patients and affects the hypothalamic-pituitary axis, meninges, and brain parenchyma. RDD lesions are typically tumorous with meningeal or parenchymal masses with strong contrast enhancement. Unlike LCH and ECD, neurodegenerative lesions or syndromes have not been described with RDD. Familiarity with principles of evaluation and treatment both shared among and distinct to each of these 3 diseases is critical for effective management. Refractory or disabling neurohistiocytic involvement should prompt the consideration for use of targeted kinase inhibitor therapies.
Topics: Central Nervous System; Erdheim-Chester Disease; Histiocytosis, Langerhans-Cell; Histiocytosis, Sinus; Humans; Prognosis
PubMed: 33993305
DOI: 10.1093/neuonc/noab107 -
Pediatric Blood & Cancer Feb 2013These guidelines for the management of patients up to 18 years with Langerhans cell histiocytosis (LCH) have been set up by a group of experts involved in the Euro...
These guidelines for the management of patients up to 18 years with Langerhans cell histiocytosis (LCH) have been set up by a group of experts involved in the Euro Histio Net project who participated in national or international studies and in peer reviewed publications. Existing guidelines were reviewed and changed where new evidence was available in the literature up to 2012. Data and publications have been ranked according to evidence based medicine and when there was a lack of published data, consensus between experts was sought. Guidelines for diagnosis, initial clinical work-up, and treatment and long-term follow-up of LCH patients are presented.
Topics: Adolescent; Child; Child, Preschool; Histiocytosis, Langerhans-Cell; Humans
PubMed: 23109216
DOI: 10.1002/pbc.24367 -
British Journal of Haematology Dec 2019
Topics: Histiocytosis, Langerhans-Cell; Humans; Molecular Targeted Therapy; Mutation; Neoplasms; Neurodegenerative Diseases
PubMed: 31309539
DOI: 10.1111/bjh.16099 -
Oncology (Williston Park, N.Y.) Feb 2016Langerhans cell histiocytosis is a disorder characterized by lesions that include CD207+ dendritic cells along with an inflammatory infiltrate. Langerhans cell... (Review)
Review
Langerhans cell histiocytosis is a disorder characterized by lesions that include CD207+ dendritic cells along with an inflammatory infiltrate. Langerhans cell histiocytosis has a highly variable clinical presentation, ranging from a single lesion to potentially fatal disseminated disease. The uncertainty as to whether Langerhans cell histiocytosis is a reactive or a neoplastic disease has resulted in a long-standing debate on this question, and the limited understanding of the pathogenesis of the disease has impeded clinical improvement for patients. The current standard of care for multisystem Langerhans cell histiocytosis, empirically derived chemotherapy with vinblastine and prednisone, cures fewer than 50% of patients, and optimal therapies for relapse and neurodegenerative disease remain uncertain. Recent research advances support a model in which Langerhans cell histiocytosis arises due to pathologic activation of the mitogen-activated protein kinase (MAPK) pathway in myeloid precursors. Redefinition of Langerhans cell histiocytosis as a myeloid neoplastic disorder driven by hyperactive ERK supports the potential of chemotherapy with efficacy against immature myeloid cells, as well as mutation-specific targeted therapy.
Topics: Animals; Antigens, CD; Disease Progression; Enzyme Activation; Histiocytosis, Langerhans-Cell; Humans; Langerhans Cells; Lectins, C-Type; Mannose-Binding Lectins; Mitogen-Activated Protein Kinases; Molecular Targeted Therapy; Prednisone; Protein Kinase Inhibitors; Signal Transduction; Treatment Outcome; Vinblastine
PubMed: 26888790
DOI: No ID Found