MAPK mutations and cigarette smoke promote the pathogenesis of pulmonary Langerhans cell histiocytosis

Liu, Huan; Osterburg, Andrew R.; Flury, Jennifer L.; Swank, Zulma; McGraw, Dennis W.; Gupta, Nishant; Wikenheiser-Brokamp, Kathryn A.; Kumar, Ashish; Tazi, Abdellatif; Inoue, Yoshikazu; Hirose, Masaki; McCormack, Francis X.; Borchers, Michael T.

doi:10.1172/jci.insight.132048

Cited by 27 publications

(20 citation statements)

References 62 publications

(73 reference statements)

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“…Tobacco smoke plays a major role in the development of PLCH ( 21 ). It causes inflammatory cell accumulation in the lungs; these cells include LCs, which release cytokines such as tumor necrosis factor alpha, interleukin 1 beta, granulocyte-macrophage colony-stimulating factor, transforming growth factor beta, and the dendritic cell chemokine (chemokine ligand 20) ( 22 ).…”

Section: Pathogenesismentioning

confidence: 99%

Update on Pulmonary Langerhans Cell Histiocytosis

Radzikowska¹

2021

Front. Med.

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Pulmonary Langerhans cell (LC) histiocytosis (PLCH) has unknown cause and is a rare neoplastic disorder characterized by the infiltration of lungs and various organs by bone marrow-derived Langerhans cells with an accompanying strong inflammatory response. These cells carry somatic mutations of BRAF gene and/or NRAS, KRAS, and MAP2K1 genes, which cause activation of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling pathway. PLCH occurs predominantly in young smokers, without gender predominance. Lungs might be involved as an isolated organ or as part of a multiorgan disease. High-resolution computed chest tomography plays an outstanding role in PLCH diagnosis. The typical radiological picture of PLCH is the presence of small intralobular nodules, “tree in bud” opacities, cavitated nodules, and thin- and thick-walled cysts, frequently confluent. Histological examination of the lesion and demonstration of characteristic eosinophilic granulomas with the presence of LCs that display antigen CD1a or CD207 in immunohistochemistry are required for definite diagnosis. Smoking cessation is the most important recommendation for PLCH patients, but treatment of progressive PLCH and multisystem disease is based on chemotherapy. Recently, new targeted therapies have been implemented.

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Section: Pathogenesismentioning

confidence: 99%

Update on Pulmonary Langerhans Cell Histiocytosis

Radzikowska¹

2021

Front. Med.

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“…Interestingly, pulmonary LCH is almost always associated with smoking ( 46 ). Liu ( 47 ) provided mechanistic insight into the role of tobacco smoke in the development of pulmonary Langerhans cell histiocytosis (PLCH) using a smoking mouse model. However, only a few of the reported cases of primary lung LCS considered the smoking history.…”

Section: Discussionmentioning

confidence: 99%

Epstein–Barr Virus-Positive Langerhans Cell Sarcoma: Is There a Link? A Case Report

et al. 2022

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Langerhans cell sarcoma (LCS) is an extremely rare, malignant neoplasm that originates from Langerhans cells (LCs). Fewer than 70 cases have been reported in the English-language literature. LCS typically involves multiple organs, including the skin, lymph nodes, lungs, bone, bone marrow, liver, spleen, and soft tissues. Several etiological factors for LCS have been proposed, including immunosuppression, virus infection, and prior hematological disease. We report a rare case of LCS with Epstein–Barr virus (EBV) infection; bilateral cervical giant cysts were the initial manifestation. To our knowledge, this is the first report of LCS with EBV infection. The case information was complete, and the relevant literature was reviewed to gain insight into LCS. The case raises new questions on the oncogenic character of EBV.

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“…Various upstream somatic mutations of the mitogenic activated protein kinase (MAPK) pathway might play a role in LCH (3,(15)(16)(17). The BRAF gene is a serine/suferanine kinase involving signal transmission in the MAPK pathway, and its mutation has been found in PLCH at a rate of 36-64% (3,(18)(19)(20).…”

Section: Discussionmentioning

confidence: 99%

Adult pulmonary Langerhans cell histiocytosis might consist of two distinct groups: isolated form and extrapulmonary recidivism type

Wang¹,

Xie²,

Miao³

et al. 2021

Ann Transl Med

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Background: Adult pulmonary Langerhans cell histiocytosis (PLCH) is a rare form of Langerhans cell histiocytosis (LCH) that typically occurs in cigarette smokers. The clinical course of PLCH is unpredictable; the disease may resolve spontaneously, or lead to multi-organ failure and death. To better understand this idiopathic disease, we retrospectively overviewed a cohort of Asian patients with PLCHs.Methods: Herein, we have provided detailed clinicopathological features and molecular findings of PLCHs in a Southwestern Chinese population, including the expressions of apoptotic protein P16, programmed cell death 1 (PD-1), and programmed cell death-ligand 1 (PD-L1). Importantly, the BRAF V600E mutation was observed in this cohort.Results: In accordance with the follow up data, the cohort was subdivided into two groups, an isolated pulmonary group and extrapulmonary recidivism group. Among the isolated group, the participants were predominantly young males (<40 years old), with a history of smoking, respiratory symptoms (cough and difficulty breathing), showed more cystic lesions in computed tomography (CT) scanning, had more cellular Langerhans granulomas under the microscope, overexpression of P16 (66.7%), high PD-1 (100%) and low PD-L1 (33.3%) expressions, and no BRAF V600E mutation was detected. In contrast, the extrapulmonary recidivism group showed significantly older age (>40 years old), recurrent spontaneous pneumothorax, more nodular changes in CT scanning, more interstitial fibrosis histologically, expression rates of 100% of P16, 66.7% of PD-1, and 33.3% of PD-L1; and importantly, BRAF V600E mutation was detected in 33.3% of this subdivision. Conclusions:We found that adult PLCH might consist of two distinct groups: an isolated form and extrapulmonary recidivism PLCH. Overexpression of P16 could be a diagnostic biomarker for PLCH. An extremely low mutation rate of the BRAF gene in adult PLCH in our cohort indicated that there might be other pathogeneses for this disease among Asian patients.

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MAPK mutations and cigarette smoke promote the pathogenesis of pulmonary Langerhans cell histiocytosis

Cited by 27 publications

References 62 publications

Update on Pulmonary Langerhans Cell Histiocytosis

Update on Pulmonary Langerhans Cell Histiocytosis

Epstein–Barr Virus-Positive Langerhans Cell Sarcoma: Is There a Link? A Case Report

Adult pulmonary Langerhans cell histiocytosis might consist of two distinct groups: isolated form and extrapulmonary recidivism type

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