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Nature Medicine May 2021Langerhans cell histiocytosis (LCH) is a potentially fatal condition characterized by granulomatous lesions with characteristic clonal mononuclear phagocytes (MNPs)...
Langerhans cell histiocytosis (LCH) is a potentially fatal condition characterized by granulomatous lesions with characteristic clonal mononuclear phagocytes (MNPs) harboring activating somatic mutations in mitogen-activated protein kinase (MAPK) pathway genes, most notably BRAF. We recently discovered that the BRAF mutation can also affect multipotent hematopoietic progenitor cells (HPCs) in multisystem LCH disease. How the BRAF mutation in HPCs leads to LCH is not known. Here we show that enforced expression of the BRAF mutation in early mouse and human multipotent HPCs induced a senescence program that led to HPC growth arrest, apoptosis resistance and a senescence-associated secretory phenotype (SASP). SASP, in turn, promoted HPC skewing toward the MNP lineage, leading to the accumulation of senescent MNPs in tissue and the formation of LCH lesions. Accordingly, elimination of senescent cells using INK-ATTAC transgenic mice, as well as pharmacologic blockade of SASP, improved LCH disease in mice. These results identify senescent cells as a new target for the treatment of LCH.
Topics: Animals; Apoptosis; Cell Proliferation; Cellular Senescence; Cytokines; Hematopoietic Stem Cells; Histiocytosis, Langerhans-Cell; Humans; Langerhans Cells; Mice; Mice, Inbred C57BL; Mice, Transgenic; Proto-Oncogene Proteins B-raf; Sirolimus; TOR Serine-Threonine Kinases
PubMed: 33958797
DOI: 10.1038/s41591-021-01304-x -
Respiratory Care Jan 2020Diffuse cystic lung diseases (DCLDs) are a group of diverse pulmonary disorders with varying pathophysiology that are characterized by the presence of thin-walled,... (Review)
Review
Diffuse cystic lung diseases (DCLDs) are a group of diverse pulmonary disorders with varying pathophysiology that are characterized by the presence of thin-walled, air-filled spaces within lung parenchyma. High-resolution computed tomography plays a crucial role in the evaluation of DCLDs, and cyst characteristics such as morphology, distribution, and the presence of other associated radiologic findings can help distinguish between different DCLDs. DCLDs can be classified according to their underlying pathophysiology as neoplastic, genetic, lymphoproliferative, infectious, associated with other forms of interstitial lung disease, or related to smoking. In this review we will provide a clinical overview on the most common DCLDs that are encountered in clinical practice: lymphangioleiomyomatosis, pulmonary Langerhans cell histiocytosis, Birt-Hogg-Dubé syndrome, and lymphoid interstitial pneumonia/follicular bronchiolitis, with a focus on practical aspects that can help clinicians in the optimal diagnosis and management of patients with DCLDs.
Topics: Amyloidosis; Birt-Hogg-Dube Syndrome; Diagnosis, Differential; Histiocytosis, Langerhans-Cell; Humans; Lung; Lung Diseases; Lung Diseases, Interstitial; Lymphangioleiomyomatosis; Smoking; Tomography, X-Ray Computed
PubMed: 31615921
DOI: 10.4187/respcare.07117 -
Science Immunology Dec 2022Langerhans cell histiocytosis (LCH) is a potentially fatal neoplasm characterized by the aberrant differentiation of mononuclear phagocytes, driven by mitogen-activated...
Langerhans cell histiocytosis (LCH) is a potentially fatal neoplasm characterized by the aberrant differentiation of mononuclear phagocytes, driven by mitogen-activated protein kinase (MAPK) pathway activation. LCH cells may trigger destructive pathology yet remain in a precarious state finely balanced between apoptosis and survival, supported by a unique inflammatory milieu. The interactions that maintain this state are not well known and may offer targets for intervention. Here, we used single-cell RNA-seq and protein analysis to dissect LCH lesions, assessing LCH cell heterogeneity and comparing LCH cells with normal mononuclear phagocytes within lesions. We found LCH discriminatory signatures pointing to senescence and escape from tumor immune surveillance. We also uncovered two major lineages of LCH with DC2- and DC3/monocyte-like phenotypes and validated them in multiple pathological tissue sites by high-content imaging. Receptor-ligand analyses and lineage tracing in vitro revealed Notch-dependent cooperativity between DC2 and DC3/monocyte lineages during expression of the pathognomonic LCH program. Our results present a convergent dual origin model of LCH with MAPK pathway activation occurring before fate commitment to DC2 and DC3/monocyte lineages and Notch-dependent cooperativity between lineages driving the development of LCH cells.
Topics: Humans; Cell Lineage; Histiocytosis, Langerhans-Cell; Cell Differentiation; Monocytes; Neoplasms
PubMed: 36525505
DOI: 10.1126/sciimmunol.add3330 -
Blood Advances Nov 2023Advances 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...
Advances 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.
Topics: Humans; Adult; Adolescent; Retrospective Studies; Neoplasms, Second Primary; Histiocytosis, Langerhans-Cell; Neoplasms; Spleen
PubMed: 37698994
DOI: 10.1182/bloodadvances.2023010706 -
Academic Pathology 2022
PubMed: 35600746
DOI: 10.1016/j.acpath.2022.100018 -
Haematologica Apr 2024The standard treatment for Langerhans cell histiocytosis (LCH) is chemotherapy, although the failure rates are high. Since MAP-kinase activating mutations are found in...
The standard treatment for Langerhans cell histiocytosis (LCH) is chemotherapy, although the failure rates are high. Since MAP-kinase activating mutations are found in most cases, BRAF- and MEK-inhibitors have been used successfully to treat patients with refractory or relapsed disease. However, data on long-term responses in children are limited and there are no data on the use of these inhibitors as first-line therapy. We treated 34 patients (26 with LCH, 2 with juvenile xanthogranuloma, 2 with Rosai-Dorfman disease, and 4 with presumed single site-central nervous system histiocytosis) with dabrafenib and/or trametinib, either as first line or after relapse or failure of chemotherapy. Sixteen patients, aged 1.3-21 years, had disease that was recurrent or refractory to chemotherapy, nine of whom had multisystem LCH with risk-organ involvement. With a median treatment duration of 4.3 years, 15 (94%) patients have sustained favorable responses. Eighteen patients, aged 0.2-45 years, received an inhibitor as first-line treatment. All of these have had sustained favorable responses, with a median treatment duration of 2.5 years. Three patients with presumed isolated central nervous system/pituitary stalk histiocytosis had stabilization or improvement of their disease. Overall, inhibitors were well tolerated. Five patients with single-system LCH discontinued therapy and remain off therapy without recurrence. In contrast, all four patients with multisystem disease who discontinued therapy had to restart treatment. Our data suggest that children suffering from histiocytoses can be treated safely and effectively with dabrafenib or trametinib. Additional studies are, however, needed to determine the long-term safety and optimal duration of therapy.
Topics: Child; Humans; Histiocytosis, Langerhans-Cell; Imidazoles; Oximes; Mutation; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones
PubMed: 37731389
DOI: 10.3324/haematol.2023.283295 -
Iranian Journal of Otorhinolaryngology Jul 2023Multifocal Langerhans' cell histocytosis is a rare condition that can affect multiple organs and manifest in various scenarios. While the condition is more commonly...
INTRODUCTION
Multifocal Langerhans' cell histocytosis is a rare condition that can affect multiple organs and manifest in various scenarios. While the condition is more commonly found in children, it can also occur in adults.
CASE REPORT
A 43-year-old female presented with refractory otorrhea and had a rubbery neck mass in the left mid-cervical area, as well as an itchy eczematoid lesion in the left parietal area. The otic lesion was eventually resected, and histopathologic examination confirmed the diagnosis of Langerhans histiocytosis.
CONCLUSIONS
Although rare in adults, Langerhans histiocytosis should be considered as one of the differential diagnoses for ear canal polyps. If diagnosed, medical treatment should be pursued.
PubMed: 37497157
DOI: 10.22038/IJORL.2023.65286.3238 -
Asian Journal of Surgery Jul 2022
Topics: Chest Pain; Histiocytosis, Langerhans-Cell; Humans; Sternum
PubMed: 35277320
DOI: 10.1016/j.asjsur.2022.02.038 -
European Respiratory Review : An... Sep 2020Diffuse cystic lung diseases include a group of heterogeneous disorders characterised by the presence of cysts within the lung parenchyma, sometimes showing a...
Diffuse cystic lung diseases include a group of heterogeneous disorders characterised by the presence of cysts within the lung parenchyma, sometimes showing a characteristic computed tomography scan pattern that allows diagnosis. The pathogenetic mechanisms underlying cyst formation in the lung are still not clear and a number of hypotheses have been postulated according to the different aetiologies: ball-valve effect, ischaemic dilatation of small airways and alveoli related to infiltration and obstruction of small vessels and capillaries that supply the terminal bronchioles and connective tissue degradation by matrix metalloproteases. A wide number of lung cyst diseases have been classified into six diagnostic groups according to the aetiology: neoplastic, congenital/genetic, lymphoproliferative, infective, associated with interstitial lung diseases, and other causes. This article focuses on lymphangioleiomyomatosis, pulmonary Langerhans cell histiocytosis and Erdheim-Chester disease, Birt-Hogg-Dubé, follicular bronchiolitis and lymphocytic interstitial pneumonia, light-chain deposition disease and amyloidosis, congenital lung disease associated with aberrant lung development and growth, and cystic lung disease associated with neoplastic lesion. These cystic diseases are epidemiologically considered as ultra-rare conditions as they affect fewer than one individual per 50 000 or fewer than 20 individuals per million. Despite the rarity of this group of disorders, the increasing use of high-resolution computed tomography has improved the diagnostic yield, even in asymptomatic patients allowing prompt and correct therapy and management without the need for a biopsy.
Topics: Birt-Hogg-Dube Syndrome; Diagnosis, Differential; Histiocytosis, Langerhans-Cell; Humans; Lung Diseases; Lung Diseases, Interstitial; Lymphangioleiomyomatosis
PubMed: 32878971
DOI: 10.1183/16000617.0163-2019 -
Anales de Pediatria Aug 2022Langerhans cell histiocytosis (LCH) is a type of myeloid neoplasia that can affect different organs or tissues and exhibits substantial variability in its clinical...
Langerhans cell histiocytosis (LCH) is a type of myeloid neoplasia that can affect different organs or tissues and exhibits substantial variability in its clinical presentation and biological behaviour, so it may mimic different diseases. Performance of different clinical assessments and laboratory and imaging tests is recommended to determine the extent of involvement, which may be of a single location or multisystemic, and the presence or absence of dysfunction in risk organs, such as the haematopoietic system, liver and spleen. The diagnosis must be confirmed by histological examination of a biopsy sample. Molecular tests have identified mutations in the mitogen-activated protein kinase (MAPK) pathway, which has expanded treatment options. The diagnosis is complex and there is controversy regarding the management of certain cases. Treatment recommendations depend on the location of the lesions and the extent of involvement. International collaborative studies have demonstrated the effectiveness of prolonged combination therapies such as vinblastine and prednisone in severe or multisystemic forms, and anti-inflammatory drugs such as indomethacin and other cytostatic combinations have proven beneficial. Langerhans cell histiocytosis is a good example of the importance of precision medicine and the benefit of identifying molecular targets, common to different neoplasms, to develop new therapies. MAPK pathway inhibitors offer an alternative treatment option in refractory cases and neurodegenerative forms of LCH. Molecular testing can contribute to the prognosis, treatment and follow-up of LCH, especially in severe forms of disease.
Topics: Combined Modality Therapy; Histiocytosis, Langerhans-Cell; Humans; Mutation; Neoplasms; Prognosis
PubMed: 35869015
DOI: 10.1016/j.anpede.2022.05.005