Successful treatment of multiple relapsed-refractory Langerhans cell histiocytosis with cyclosporine.

Langerhans cell histiocytosis is a rare hematologic disorder and patients who fail first-line treatment have a poor prognosis, and require more intensive treatment. We present an infant diagnosed with multisystem Langerhans cell histiocytosis refractory to multimodal therapy who was successfully treated with cyclosporine. Cyclosporine might be an effective alternative drug as nonmyelosuppressive rescue therapy for multiple relapsed-refractory Langerhans cell histiocytosis that has not achieved remission with cladribine and cytarabine therapy.

High prevalence of BRAFV600E in patients with cholestasis, sclerosing cholangitis or liver fibrosis secondary to Langerhans cell histiocytosis.

Targeted therapies with MAPK inhibitors have proven to modulate the clinical manifestations of patients with Langerhans cell histiocytosis (LCH). We explored the presence of BRAFV600E mutation in our cohort of patients with LCH and cholestasis, sclerosing cholangitis, or liver fibrosis that presented resistance to chemotherapy. The BRAFV600E mutation was detected either in the diagnosis (skin and bone) or liver biopsy in our cohort of 13 patients. Thus, we observed a high incidence of BRAFV600E mutation in 100% either in diagnostic biopsy (skin and bone) or liver biopsy in patients with progressive liver disease, sequela, or liver transplant requirement.

Langerhans cell histiocytosis in a young patient with Pitt-Hopkins syndrome.

Pitt-Hopkins syndrome (PTHS, MIM #610954) is a rare neurodevelopmental disease characterized by the association of intellectual disability, characteristic facial gestalt and episodes of abnormal and irregular breathing. PTHS is due to heterozygous loss-of-function variants in the TCF4 gene (transcription factor 4, MIM #602272) encoding for a basic helix-loop-helix transcription factor. TCF4 is highly expressed during early development of the nervous system, and it is involved in cellular differentiation and proliferation. Since the first clinical description in 1978, less than 200 PTHS patients have been described. A comprehensive phenotype, especially regarding cancer predisposition, is not yet well defined. We report the case of a 7-year-old boy affected by PTHS with a 4-week history of progressive swelling of the frontal bones diagnosed with Langerhans cell histiocytosis.

[A smoking, coughing young adult]. / Een rokende, hoestende jonge man.

A 30-year old man who smoked, presented with cough, dyspnoea and fatigue. Radiography showed diffuse bilateral symmetrical nodules, partially cavitating. The histopathological findings from the thoracoscopic wedge resection were specific for pulmonary Langerhans cell histiocytosis. The patient immediately quit smoking, which resulted in less complaints and decreased abnormalities on the x-ray.

Pulmonary Langerhans Cell Histiocytosis.

Pulmonary Langerhans cell histiocytosis (PLCH) is a diffuse cystic lung disease that is strongly associated with exposure to cigarette smoke. Recently, activating pathogenic mutations in the mitogen-activated protein kinase pathway have been described in the dendritic cells in patients with PLCH and have firmly established PLCH to be an inflammatory myeloid neoplasm. Disease course and prognosis in PLCH are highly variable among individual patients, ranging from spontaneous resolution to development of pulmonary hypertension and progression to terminal respiratory failure. A subset of patients with PLCH may have extrapulmonary involvement, typically involving the skeletal system in the form of lytic lesions, skin lesions, or the central nervous system most commonly manifesting in the form of diabetes insipidus. Smoking cessation is the cornerstone of treatment in patients with PLCH and can lead to disease regression or stabilization in a substantial proportion of patients. Further insight into the underlying molecular pathogenesis of PLCH has paved the way for the future development of disease-specific biomarkers and targeted treatment options directed against the central disease-driving mutations.

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

Pulmonary Langerhans cell histiocytosis (PLCH) is a rare smoking-related lung disease characterized by dendritic cell (DC) accumulation, bronchiolocentric nodule formation, and cystic lung remodeling. Approximately 50% of patients with PLCH harbor somatic BRAF-V600E mutations in cells of the myeloid/monocyte lineage. However, the rarity of the disease and lack of animal models have impeded the study of PLCH pathogenesis. Here, we establish a cigarette smoke-exposed (CS-exposed) BRAF-V600E-mutant mouse model that recapitulates many hallmark characteristics of PLCH. We show that CD11c-targeted expression of BRAF-V600E increases DC responsiveness to stimuli, including the chemokine CCL20, and that mutant cell accumulation in the lungs of CS-exposed mice is due to both increased cellular viability and enhanced recruitment. Moreover, we report that the chemokine CCL7 is secreted from DCs and human peripheral blood monocytes in a BRAF-V600E-dependent manner, suggesting a possible mechanism for recruitment of cells known to dominate PLCH lesions. Inflammatory lesions and airspace dilation in BRAF-V600E mice in response to CS are attenuated by transitioning animals to filtered air and treatment with a BRAF-V600E inhibitor, PLX4720. Collectively, this model provides mechanistic insights into the role of myelomonocytic cells and the BRAF-V600E mutation and CS exposure in PLCH pathogenesis and provides a platform to develop biomarkers and therapeutic targets.

Post-scabietic nodules: Mimicker of infantile indeterminate cell histiocytosis and potential diagnostic pitfall.

Indeterminate cell histiocytosis (ICH) is an extremely rare disease and little is known about its etiology. Patients usually present with nodular, dermal proliferations of indeterminate cells, which characteristically resemble Langerhans cells but lack Birbeck granules. The clinical course is highly variable, ranging from spontaneous regression to rapid progression with reports of extracutaneous involvement, subsequent acute myeloid leukemias, and associated B-cell lymphomas. Rare cases of ICH-like reactions have been reported in the setting of scabies infestations as well as in patients who had been bitten by ticks and mosquitos. We present a successfully treated case of indeterminate cell-rich post scabietic nodules in an otherwise healthy 8-month-old boy and review the literature on similar cases. Clinical context is essential for correct interpretation of these indolent ICH-mimicking lesions, and to avert unnecessary patient anxiety and aggressive management.

Pediatric Langerhans cell histiocytosis: state of the science and future directions.

Langerhans cell histiocytosis (LCH) is an inflammatory neoplasm of myeloid origin characterized by the presence of classic CD1a+/CD207+ cells. An ongoing debate over the grouping of LCH was finally settled in favor of neoplasm after the discovery of the BRAF V600E mutation in 2010. The pathologic cells were found to involve an almost universal activation of the MAPK/ERK pathway, with mutations identified in most kinases upstream of ERK (RAS/RAF/MEK). The clinical presentation of LCH is a mixed bag, ranging from self-resolving localized disease to fulminant, fatal disseminated disease. The current standard of care for patients with multisystem LCH, who have high relapse rates, continues to be combination treatment with vinblastine and prednisone. Patients treated with BRAF and MEK inhibitors have shown a significant and sustained response in early-phase trials. During the current decade, researchers have described an extensive genomic landscape for LCH that has significantly enlarged our understanding of the biology and pathogenesis of this disease, especially neurodegenerative LCH. These advances have opened the door to studies of precision medicine and targeted therapy in LCH. Disease reactivation, long-term sequelae, very high-risk disease, and neurodegenerative LCH represent ongoing challenges. A renewed understanding of the biology of this disease, coupled with targeted therapies, may help in overcoming most of these challenges.

Pulmonary histiocytosis: beyond Langerhans cell histiocytosis related to smoking. / Histiocitosis pulmonar: más allá de la histiocitosis de células de Langerhans relacionada con el tabaco.

OBJECTIVE: To review the imaging findings for the different types of pulmonary histiocytosis. In particular, in addition to the well-known pulmonary Langerhans cell histiocytosis related to smoking and its possible appearance in nonsmokers, we focus on non-Langerhans cell histiocytosis in Rosai-Dorfman disease and Erdheim-Chester disease. We also review the etiopathogenesis, histology, clinical presentation, and treatment of pulmonary histiocytosis. CONCLUSION: Langerhans cell histiocytosis, Rosai-Dorfman disease, and Erdheim-Chester disease are idiopathic diseases in which the proliferation and infiltration of histiocytes is the histologic finding that confirms the diagnosis. Langerhans cell histiocytosis manifests as nodules and cysts that spare the costophrenic angles; it typically appears in smokers. Although it is uncommon in nonsmokers, Langerhans cell histiocytosis should also be considered in nonsmokers treated with chemotherapy and radiotherapy in whom cavitated nodules appear and should be included in the differential diagnosis together with metastatic disease and opportunistic infections. Rosai-Dorfman disease and Erdheim-Chester disease present with less specific thoracic findings such as adenopathies, interstitial thickening, and pleural effusion. In Erdheim-Chester disease, the characteristic extrathoracic manifestations are usually key for the diagnosis.

Langerhans Cell Histiocytosis of the Skull in a Burr Hole Site Covered with Hydroxyapatite Material.

BACKGROUND: Langerhans cell histiocytosis (LCH) is a rare dendritic histiocytic disorder that affects the bones, especially the skull. Langerhans cell histiocytosis (LCH) developing in a burr hole site for chronic subdural hematoma is extremely rare. CASE DESCRIPTION: A 53-year-old man underwent a burr hole irrigation for chronic subdural hematoma, and the burr hole was covered with a burr hole button made of hydroxyapatite. Seven months after the first surgery, the connective tissue rapidly proliferated around the burr hole button, and the pathologic diagnosis was LCH. LCH recurred at 13 and 19 months after the first operation, with curettage performed each time. At 3 months after the final operation, no recurrence was identified on magnetic resonance imaging. CONCLUSIONS: If there is rapid proliferation of connective tissue at an operative site where artificial material has been used, LCH should be considered.

Current understanding and management of pulmonary Langerhans cell histiocytosis.

Pulmonary Langerhans cell histiocytosis (PLCH) is a diffuse lung disease that usually affects young adult smokers. PLCH affects different lung compartments; bronchiolar, interstitial and pulmonary vascular dysfunction may coexist to varying extents, resulting in diverse phenotypes. Analyses of PLCH tissues have identified activating mutations of specific mitogen-activated protein kinases (BRAFV600E and others). The current consensus is that PLCH represents a myeloid neoplasm with inflammatory properties: the myeloid tumour cells exhibit surface CD1a expression and up to 50% of the cells harbour activating BRAF or other MAPK mutations. PLCH may be associated with multisystem disease. The detection of disease outside of the thorax is facilitated by whole body positron emission tomography. The natural history of PLCH is unpredictable. In some patients, disease may remit or stabilise following smoking cessation. Others develop progressive lung disease, often associated with evidence of airflow limitation and pulmonary vascular dysfunction. Due to the inability to accurately predict the natural history, it is important that all patients undergo longitudinal follow-up at least twice a year for the first few years following diagnosis. The treatment of PLCH is challenging and should be individualised. While there is no general consensus regarding the role of immunosuppression or chemotherapy in management, selected patients may experience improvement in lung function with therapy. Determination of BRAFV600E or other mutations may assist with the development of an individualised approach to therapy. Patients with progressive disease should be referred to specialised centres and considered for a trial of pharmacotherapy or evaluated for transplantation.

Idiopathic thrombocytopenic purpura in childhood, Langerhans cell histiocytosis in adulthood: More than a chance association?

Described herein, a case of Langerhans cell histiocytosis (LCH) in an adult with Idiopathic Thrombocytopenic Purpura (ITP) diagnosed at age ten. She presented with cranial diabetes insipidus, later developed hypogonadotrophic hypogonadism and multiple cervical lympadenopathy from which histopathology of excisional biopsy confirmed LCH. Magnetic resonance imaging showed thickened pituitary stalk. Association of ITP and LCH is unknown but the question of LCH presenting as isolated thrombocytopenia in childhood only to be discovered in adulthood when there was pituitary and bone involvement remains. It reemphasizes the need for high index of suspicion and the challenges in diagnosing LCH at the outset.

Histiocytoses: emerging neoplasia behind inflammation.

Histiocytoses are disorders characterised by inflammation and the accumulation of cells derived from the monocyte and macrophage lineages, which results in tissue damage. Although they are often considered rare disorders with protean clinical manifestations, considerable advances in the understanding of their genetics have led to increased clinical recognition of these conditions, and fuelled further insights into their pathogenesis. In this Review, we describe insights into the cells of origin, molecular pathology, clinical features, and treatment strategies for some of the most common histiocytic disorders, including Langerhans cell histiocytosis, Erdheim-Chester disease, and Rosai-Dorfman disease. With the discovery of recurrent mutations affecting the mitogen-activated protein kinase and mTOR-AKT pathways in some of these histiocytoses, our understanding of these diseases has now evolved from the concept of a primary inflammatory condition to that of a clonal neoplastic disease. This understanding has led to the development of effective mechanism-based therapeutic strategies for patients with histiocytic diseases.

Primary pulmonary Langerhans cell histiocytosis associated with smoking in an adolescent boy.

Pulmonary Langerhans cell histiocytosis (PLCH) is a well known entity in adults but is exceedingly rare in children. It is better described in adults than in children. Smoking is a major etiological factor in adulthood. We report a case of a previously healthy 16-year-old male with a history of cigarette smoking, who presented with cough with sputum, breathlessness, easy fatigability and loss of appetite for two weeks. He was first diagnosed with bronchiectasis according to the cystic pulmonary changes demonstrated by computed tomography. After appropriate treatment, there was no sign of clinical improvement. A lung biopsy confirmed Langerhans cell histiocytosis (LCH). The definitive diagnosis was isolated pulmonary LCH. PLCH should be considered in the etiology of cystic lung diseases. Isolated pulmonary LCH is rare so such cases are needed to be reported and followed-up to understand the treatment response and course of this illness.

[Adult Langerhans cell histiocytosis]. / Histiocytose à cellules de Langerhans de l'adulte.

Langerhans cell histiocytosis (LCH) is a rare disease affecting both genders and can occur at any age. It often evolves through successive flares, and its severity varies from benign forms that don't require treatment to life threatening disease. Some patients have important functional impairment with psychological and social consequences and prolonged disability. LCH may affect only one organ, with uni- or multifocal involvement or be multisystem disease involving multiple organs. The organs most frequently involved are bones, lung, skin and the endocrinal system. Pulmonary LCH is strongly related to smoking. Some patients have mixed histocytosis combining LCH and other histiocytic disorders. The diagnosis relies on the histological study of tissues samples, and shows tissue infiltration with large cell with pale cytoplasm and reniform nucleus, staining for CD1a and Langerin (CD207) on immunohistochemistry. The BRAFV600E mutation is observed in tissue samples in approximately half of patients and the activation of the RAS-RAF-MEK-ERK pathway has been shown to be constantly activated in LCH lesions, regardless the BRAF status. These findings represent an important forward step in the understanding of the physiopathology of the disease. Treatment must be adapted to the severity of the disease and goes from conservative observation to systemic chemotherapy. Therapies targeting the RAS-RAF-MEK-ERK pathway are promising treatments for progressive disease.