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Nature Reviews. Disease Primers Oct 2021The historic term 'histiocytosis' meaning 'tissue cell' is used as a unifying concept for diseases characterized by pathogenic myeloid cells that share histological... (Review)
Review
The historic term 'histiocytosis' meaning 'tissue cell' is used as a unifying concept for diseases characterized by pathogenic myeloid cells that share histological features with macrophages or dendritic cells. These cells may arise from the embryonic yolk sac, fetal liver or postnatal bone marrow. Prior classification schemes align disease designation with terminal phenotype: for example, Langerhans cell histiocytosis (LCH) shares CD207 antigen with physiological epidermal Langerhans cells. LCH, Erdheim-Chester disease (ECD), juvenile xanthogranuloma (JXG) and Rosai-Dorfman disease (RDD) are all characterized by pathological ERK activation driven by activating somatic mutations in MAPK pathway genes. The title of this Primer (Histiocytic disorders) was chosen to differentiate the above diseases from Langerhans cell sarcoma and malignant histiocytosis, which are hyperproliferative lesions typical of cancer. By comparison LCH, ECD, RDD and JXG share some features of malignant cells including activating MAPK pathway mutations, but are not hyperproliferative. 'Inflammatory myeloproliferative neoplasm' may be a more precise nomenclature. By contrast, haemophagocytic lymphohistiocytosis is associated with macrophage activation and extreme inflammation, and represents a syndrome of immune dysregulation. These diseases affect children and adults in varying proportions depending on which of the entities is involved.
Topics: Erdheim-Chester Disease; Histiocytosis, Langerhans-Cell; Histiocytosis, Sinus; Humans; Inflammation; Xanthogranuloma, Juvenile
PubMed: 34620874
DOI: 10.1038/s41572-021-00307-9 -
Blood Jun 2016The histiocytoses are rare disorders characterized by the accumulation of macrophage, dendritic cell, or monocyte-derived cells in various tissues and organs of children... (Review)
Review
The histiocytoses are rare disorders characterized by the accumulation of macrophage, dendritic cell, or monocyte-derived cells in various tissues and organs of children and adults. More than 100 different subtypes have been described, with a wide range of clinical manifestations, presentations, and histologies. Since the first classification in 1987, a number of new findings regarding the cellular origins, molecular pathology, and clinical features of histiocytic disorders have been identified. We propose herein a revision of the classification of histiocytoses based on histology, phenotype, molecular alterations, and clinical and imaging characteristics. This revised classification system consists of 5 groups of diseases: (1) Langerhans-related, (2) cutaneous and mucocutaneous, and (3) malignant histiocytoses as well as (4) Rosai-Dorfman disease and (5) hemophagocytic lymphohistiocytosis and macrophage activation syndrome. Herein, we provide guidelines and recommendations for diagnoses of these disorders.
Topics: Adult; Dendritic Cells; Female; Histiocytic Disorders, Malignant; Histiocytosis, Langerhans-Cell; Histiocytosis, Non-Langerhans-Cell; Humans; Macrophages; Male
PubMed: 26966089
DOI: 10.1182/blood-2016-01-690636 -
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 -
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 -
Blood Jun 2018Rosai-Dorfman-Destombes disease (RDD) is a rare non-Langerhans cell histiocytosis characterized by accumulation of activated histiocytes within affected tissues. RDD,... (Review)
Review
Rosai-Dorfman-Destombes disease (RDD) is a rare non-Langerhans cell histiocytosis characterized by accumulation of activated histiocytes within affected tissues. RDD, which now belongs to the R group of the 2016 revised histiocytosis classification, is a widely heterogeneous entity with a range of clinical phenotypes occurring in isolation or in association with autoimmune or malignant diseases. Recent studies have found , , , and mutations in lesional tissues, raising the possibility of a clonal origin in some forms of RDD. More than 1000 reports have been published in the English literature; however, there is a lack of consensus regarding approach for the clinical management of RDD. Although in most cases RDD can be observed or treated with local therapies, some patients with refractory or multifocal disease experience morbidity and mortality. Here we provide the first consensus multidisciplinary recommendations for the diagnosis and management of RDD. These recommendations were discussed at the 32nd Histiocyte Society Meeting by an international group of academic clinicians and pathologists with expertise in RDD. We include guidelines for clinical, laboratory, pathologic, and radiographic evaluation of patients with RDD together with treatment recommendations based on clinical experience and review of the literature.
Topics: Adrenal Cortex Hormones; Biopsy; Disease Management; Genetic Predisposition to Disease; Histiocytes; Histiocytosis, Sinus; Humans; Immunotherapy; Mutation; Practice Guidelines as Topic; Prognosis; Radiotherapy
PubMed: 29720485
DOI: 10.1182/blood-2018-03-839753 -
Lancet (London, England) Jul 2021Histiocytoses constitute a heterogeneous group of rare disorders, characterised by infiltration of almost any organ by myeloid cells with diverse macrophage or dendritic... (Review)
Review
Histiocytoses constitute a heterogeneous group of rare disorders, characterised by infiltration of almost any organ by myeloid cells with diverse macrophage or dendritic cell phenotypes. Histiocytoses can start at any age. Diagnosis is based on histology in combination with appropriate clinical and radiological findings. The low incidence and broad spectrum of clinical manifestations often leads to diagnostic delay, especially for adults. In most cases, biopsy specimens infiltrated by histiocytes have somatic mutations in genes activating the MAP kinase cell-signalling pathway. These mutations might also be present in blood cells and haematopoietic progenitors of patients with multisystem disease. A comprehensive range of investigations and molecular typing are essential to accurately predict prognosis, which can vary from spontaneous resolution to life-threatening disseminated disease. Targeted therapies with BRAF or MEK inhibitors have revolutionised salvage treatment. However, the type and duration of treatment are still debated, and the prevention of neurological sequelae remains a crucial issue.
Topics: Adult; Delayed Diagnosis; Histiocytes; Histiocytosis, Langerhans-Cell; Humans; MAP Kinase Kinase Kinases; Macrophages; Mutation; Rare Diseases
PubMed: 33901419
DOI: 10.1016/S0140-6736(21)00311-1 -
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 -
Blood Reviews Nov 2016Most knowledge of hemophagocytic syndromes (HPSs) including hemophagocytic lymphohistiocytosis (HLH) is derived from pediatric studies; literature on adult HPS/HLH... (Meta-Analysis)
Meta-Analysis Review
Most knowledge of hemophagocytic syndromes (HPSs) including hemophagocytic lymphohistiocytosis (HLH) is derived from pediatric studies; literature on adult HPS/HLH predominantly consists of small retrospective studies with clinical and methodological heterogeneity. The aims of this systematic scoping review were to provide an overview of existing literature on adult HPS/HLH, describe current practices in diagnosis and treatment, and propose priorities for future research. Articles from Ovid Medline, Embase and Pubmed (1975-2015) describing 10 or more unique adults (age>15years) with HPS/HLH were included. 82 publications were eligible: 10 were prospective and 72 were retrospective. Of the six distinct diagnostic criteria, the HLH-2004 criteria were by far the most commonly used. A minority of studies tested for genetic abnormalities (12), soluble interleukin-2 receptor (11), and/or NK function (11) in a subset of patients. Most centers used steroids and either etoposide-based (HLH-94/HLH-2004) or doxorubicin-based (CHOP) initial therapy regimens. Allogeneic hematopoietic cell therapy for treatment of adult HLH has rarely been reported. Mortality in larger treatment focused studies ranged from 20 to 88%. Developing adult-specific diagnostic criteria based on widely evaluable features of secondary HPS/HLH and establishing standard initial therapies are priorities for future research.
Topics: Combined Modality Therapy; Disease Susceptibility; Humans; Lymphohistiocytosis, Hemophagocytic; Practice Guidelines as Topic; Prognosis; Treatment Outcome
PubMed: 27238576
DOI: 10.1016/j.blre.2016.05.001 -
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 May 2020Erdheim-Chester disease (ECD) is a rare histiocytosis that was recently recognized as a neoplastic disorder owing to the discovery of recurrent activating MAPK... (Review)
Review
Erdheim-Chester disease (ECD) is a rare histiocytosis that was recently recognized as a neoplastic disorder owing to the discovery of recurrent activating MAPK (RAS-RAF-MEK-ERK) pathway mutations. Typical findings of ECD include central diabetes insipidus, restrictive pericarditis, perinephric fibrosis, and sclerotic bone lesions. The histopathologic diagnosis of ECD is often challenging due to nonspecific inflammatory and fibrotic findings on histopathologic review of tissue specimens. Additionally, the association of ECD with unusual tissue tropism and an insidious onset often results in diagnostic errors and delays. Most patients with ECD require treatment, except for a minority of patients with minimally symptomatic single-organ disease. The first ECD consensus guidelines were published in 2014 on behalf of the physicians and researchers within the Erdheim-Chester Disease Global Alliance. With the recent molecular discoveries and the approval of the first targeted therapy (vemurafenib) for BRAF-V600-mutant ECD, there is a need for updated clinical practice guidelines to optimize the diagnosis and treatment of this disease. This document presents consensus recommendations that resulted from the International Medical Symposia on ECD in 2017 and 2019. Herein, we include the guidelines for the clinical, laboratory, histologic, and radiographic evaluation of ECD patients along with treatment recommendations based on our clinical experience and review of literature in the molecular era.
Topics: Clinical Trials as Topic; Erdheim-Chester Disease; Female; Histiocytosis, Langerhans-Cell; Humans; MAP Kinase Signaling System; Male; Molecular Targeted Therapy; Mutation; Prognosis; Proto-Oncogene Proteins B-raf
PubMed: 32187362
DOI: 10.1182/blood.2019003507