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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 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 -
Hematological Oncology Jun 2021Children with Langerhnans cell histiocytosis (LCH) develop granulomatous lesions with characteristic clonal CD207+ dendritic cells that can arise as single lesions or... (Review)
Review
Children with Langerhnans cell histiocytosis (LCH) develop granulomatous lesions with characteristic clonal CD207+ dendritic cells that can arise as single lesions or life-threatening disseminated disease. Despite the wide range of clinical presentations, LCH lesions are histologically indistinguishable based on severity of disease, and uncertain classification as an immune versus neoplastic disorder has historically challenged the development of optimal clinical strategies for patients with LCH. Recently, activating somatic mutations in MAPK pathway genes, most notably BRAFV600E, have been discovered in almost all cases of LCH. Further, the stage of myeloid differentiation in which the mutation arises defines the extent of disease and risk of developing LCH-associated neurodegeneration. MAPK activation in LCH precursor cells drives myeloid differentiation, inhibits migration, and inhibits apoptosis, resulting in accumulation of resilient pathologic dendritic cells that recruit and activate T cells. Recurrent somatic mutations in MAPK pathway genes have also been identified in related histiocytic disorders: juvenile xanthogranuloma, Erdheim-Chester disease, and Rosai-Dorfman disease. New insights into pathogenesis support reclassification of these conditions as a myeloid neoplastic disorders. Continued research will uncover opportunities to identify novel targets and inform personalized therapeutic strategies based on cell of origin, somatic mutation, inherited risk factors, and residual disease.
Topics: Amino Acid Substitution; Cell Differentiation; Cell Movement; Dendritic Cells; Histiocytosis, Langerhans-Cell; Humans; MAP Kinase Signaling System; Mutation, Missense; Precision Medicine; Proto-Oncogene Proteins B-raf; T-Lymphocytes
PubMed: 34105821
DOI: 10.1002/hon.2857 -
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 -
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 -
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 -
Actas Dermo-sifiliograficas Nov 2020Juvenile xanthogranulomas (JXGs) are rare, benign lesions that belong to the large group of non-Langerhans cell histiocytoses. JXG presents with 1 or more erythematous... (Review)
Review
Juvenile xanthogranulomas (JXGs) are rare, benign lesions that belong to the large group of non-Langerhans cell histiocytoses. JXG presents with 1 or more erythematous or yellowish nodules that are usually located on the head or neck. Most JXG lesions are congenital or appear during the first year of life. Extracutaneous involvement is rare, but the literature traditionally suggests investigating the possibility of ocular compromise. JXG is mainly a clinical diagnosis, but a skin biopsy may sometimes be needed for confirmation. JXGs on the skin are self-limiting and usually do not require treatment. This review describes the clinical and therapeutic aspects of JXG, emphasizing available evidence and the diagnosis of extracutaneous involvement.
Topics: Biopsy; Histiocytosis, Non-Langerhans-Cell; Humans; Skin; Xanthogranuloma, Juvenile
PubMed: 32721389
DOI: 10.1016/j.ad.2020.07.004 -
Korean Journal of Radiology Sep 2019Lung cysts are commonly seen on computed tomography (CT), and cystic lung diseases show a wide disease spectrum. Thus, correct diagnosis of cystic lung diseases is a... (Review)
Review
Lung cysts are commonly seen on computed tomography (CT), and cystic lung diseases show a wide disease spectrum. Thus, correct diagnosis of cystic lung diseases is a challenge for radiologists. As the first diagnostic step, cysts should be distinguished from cavities, bullae, pneumatocele, emphysema, honeycombing, and cystic bronchiectasis. Second, cysts can be categorized as single/localized versus multiple/diffuse. Solitary/localized cysts include incidental cysts and congenital cystic diseases. Multiple/diffuse cysts can be further categorized according to the presence or absence of associated radiologic findings. Multiple/diffuse cysts without associated findings include lymphangioleiomyomatosis and Birt-Hogg-Dubé syndrome. Multiple/diffuse cysts may be associated with ground-glass opacity or small nodules. Multiple/diffuse cysts with nodules include Langerhans cell histiocytosis, cystic metastasis, and amyloidosis. Multiple/diffuse cysts with ground-glass opacity include pneumocystis pneumonia, desquamative interstitial pneumonia, and lymphocytic interstitial pneumonia. This stepwise radiologic diagnostic approach can be helpful in reaching a correct diagnosis for various cystic lung diseases.
Topics: Amyloidosis; Birt-Hogg-Dube Syndrome; Cysts; Diagnosis, Differential; Histiocytosis, Langerhans-Cell; Humans; Lung Diseases; Lymphangioleiomyomatosis; Pneumonia, Pneumocystis; Tomography, X-Ray Computed
PubMed: 31464115
DOI: 10.3348/kjr.2019.0057 -
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