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Background and Aims Liver involvement portends poor prognosis in adults. We aimed to characterize the clinical features, liver function tests, radiologic findings, molecular profiles, therapeutic approaches and outcomes of adults patients with Langerhans cell histiocytosis (LCH) with liver involvement. Methods We conducted a retrospective analysis of all adults with LCH (≥ 18 years) seen at Peking Union Medical College Hospital (Beijing, China) between January 2001 and December 2022. Results Among the 445 newly diagnosed adults with LCH, 90 patients had liver involvement at diagnosis and 22 patients at relapse. The median age was 32 years (range, 18–66 years). Of 112 evaluable patients, 108 had full liver function testing, including alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase (ALP), γ-glutamyl transpeptidase (GGT), and total bilirubin and albumin. Elevated ALP was seen in 63.0% and GGT in 86.1%; 14.8% had elevated bilirubin. Next-generation sequencing of 54 patients revealed frequent BRAFN486_P490 (29.6%), BRAFV600E (18.5%), and MAP2K1 (14.8%). Outcomes After a median 40 months’ follow-up (range 1-168 months), 3-year progression-free survival (PFS) and overall survival were 49.7% and 86.6% respectively. In multivariable analyses, ≥3 abnormal liver function tests (HR 3.384, 95% CI 1.550–7.388, P = .002) associated with inferior PFS; immunomodulatory drug therapy (HR 0.073, 95% CI, 0.010-0.541, P = .010) correlated with superior PFS versus chemotherapy. Conclusions In summary, elevated GGT and ALP were common in adults with LCH liver involvement. Greater than equal to 3 abnormal liver function tests predicted poor outcomes. Immunomodulatory drug therapy was associated with favorable progression-free survival compared to chemotherapy. Liver involvement often indicates a poor prognosis in adult patients. This article reports clinical features, liver function tests, radiologic findings, molecular profiles, therapeutic approaches, and outcomes of adults patients with Langerhans cell histiocytosis with liver involvement.

Langerhans Cell Histiocytosis (LCH) is an orphan disease of clonal dendritic cells which may affect any organ of the body. Most of the knowledge about the diagnosis and therapy is based on pedriatic studies. Adult LCH patients are often evaluated by physicians who focus on only the most obviously affected organ without sufficient evaluation of other systems, resulting in patients being underdiagnosed and/or incompletely staged. Furthermore they may be treated with pediatric-based therapies which are less effective and sometimes more toxic for adults. The published literature on adult LCH cases lacks a comprehensive discussion on the differences between pediatric and adult patients and there are no recommendations for evaluation and comparative therapies. In order to fill this void, a number of experts in this field cooperated to develop the first recommendations for management of adult patients with LCH. Key questions were selected according to the clinical relevance focusing on diagnostic work up, therapy, and follow up. Based on the available literature up to December 2012, recommendations were established, drafts were commented by the entire group, and redrafted by the executive editor. The quality of evidence of the recommendations is predominantly attributed to the level of expert opinion. Final agreement was by consensus.

Background Langerhans cell histiocytosis is a rare disorder characterized by abnormal proliferation of Langerhans cells, primarily affecting children and occasionally adults. Etiology remains enigmatic, with genetic and environmental factors implicated. Diagnosis relies on histopathology and clinical manifestations, often necessitating a multidisciplinary approach. Case presentation We report a unique case of Langerhans cell histiocytosis with perianal lesions as initial manifestations in a 41-year-old Chinese deaf male patient with a history of perianal abscess. Examination revealed erosion and plaque-like changes in the mucosa around the anus. Histopathology and immunohistochemistry confirmed Langerhans cell histiocytosis, and a whole-body positron emission tomography-computed tomography scan revealed no other organ involvement, indicating monosystemic disease. Then, 3 months post-treatment, the patient declined a repeated magnetic resonance imaging scan during outpatient follow-up owing to no significant discomfort reported, which resulted in loss to follow-up and discontinuation of treatment. Conclusion This case suggests that perianal lesions may be a manifestation of Langerhans cell histiocytosis, and underscores the importance of whole-body positron emission tomography-computed tomography scanning for follow-up in instances of pure skin involvement.

A spectrum of diseases formerly known as histiocytosis X and now called Langerhans-cell histiocytosis is characterized by ERK pathway activation (including BRAF V600E mutations) and diverse clinical manifestations involving bone, skin, lung, and pituitary.

Langerhans cell histiocytosis (LCH) is a rare systemic disorder characterized by the accumulation of CD1a+/Langerin+ LCH cells and wide‐ranging organ involvement. Langerhans cell histiocytosis was formerly referred to as histiocytosis X, until it was renamed in 1987. Langerhans cell histiocytosis β was named for its morphological similarity to skin Langerhans cells. Studies have shown that LCH cells originate from myeloid dendritic cells rather than skin Langerhans cells. There has been significant debate regarding whether LCH should be defined as an immune disorder or a neoplasm. A breakthrough in understanding the pathogenesis of LCH occurred in 2010 when a gain‐of‐function mutation in BRAF (V600E) was identified in more than half of LCH patient samples. Studies have since reported that 100% of LCH cases show ERK phosphorylation, indicating that LCH is likely to be a clonally expanding myeloid neoplasm. Langerhans cell histiocytosis is now defined as an inflammatory myeloid neoplasm in the revised 2016 Histiocyte Society classification. Randomized trials and novel approaches have led to improved outcomes for pediatric patients, but no well‐defined treatments for adult patients have been developed to date. Although LCH is not fatal in all cases, delayed diagnosis or treatment can result in serious impairment of organ function and decreased quality of life. This study summarizes recent advances in the pathophysiology and treatment of adult LCH, to raise awareness of this “orphan disease”. Recent studies have shown that Langerhans cell histiocytosis (LCH) is a clonally expanding myeloid neoplasm. Although LCH is not always fatal, delayed diagnosis or treatment can result in serious impairment of organ function and decreased quality of life. This study summarizes recent advances in the pathophysiology and treatment of adult LCH, to raise awareness of this “orphan disease”.

Langerhans cell histiocytosis (LCH) is a rare (about 3–5 cases per million children aged 0–14 years), non-malignant disease characterized by proliferation and accumulation of clonal dendritic cells, extreme clinical heterogeneity, and an unpredictable course. Three large-scale, international, prospective therapeutic studies (LCH-I to III) for multisystem LCH (MS-LCH) have been conducted by the Histiocyte Society since 1991. The cumulative lessons from these studies are summarized in this review. Patients with MS-LCH represent a heterogeneous group with respect to disease severity and outcome, therefore treatment stratification and risk-tailored treatment are mandatory. The risk for mortality can be predicted based on involvement of ‘risk organs’ (e.g. hematopoietic system, liver, and/or spleen) at diagnosis and on response to initial therapy (assessed after 6–12 weeks of treatment). Thus, patients without involvement of risk organs (low-risk group) are not at risk for mortality but need systemic therapy in order to control the disease activity and avoid reactivations and permanent consequences. Patients with risk organ involvement (risk group) are at risk for mortality, and lack of therapy response defines a subgroup with a particularly dismal prognosis (high-risk group). Those patients in the risk group who respond to therapy and survive are at risk for reactivations and permanent consequences. The LCH-I study compared the efficacy of vinblastine and etoposide, and concluded that they are equivalent single-agent treatments for children with MS-LCH. However, the results of this trial were inferior with respect to response rate at week 6, disease reactivation rate, and sequelae, when compared with historical trials using more intensive regimens. The combination of prednisolone and vinblastine was established as a standard first-line treatment through the LCH-II and LCH-III studies. The regimen consists of one to two 6-week courses (continuous oral corticosteroids 40 mg/m 2 /day for 4 weeks, tapered over 2 weeks plus weekly vinblastine intravenous push) of initial therapy, followed by a continuation phase (three weekly pulses of oral prednisolone 40 mg/m 2 /day for 5 days plus a vinblastine injection). The addition of a third drug to the standard combination (etoposide in LCH-II and methotrexate in LCH-III) failed to significantly improve survival in the risk group. The remaining mortality in the risk group is about 20%, and up to 40% in the high-risk group. Concerning low-risk MS-LCH, comparison of results of the LCH-II study with historical data suggested that the remaining reactivation rate of about 50% (and possibly permanent consequences) could be reduced by prolongation of the total treatment duration. To study this hypothesis, in the low-risk group of the LCH-III study standard maintenance therapy was randomly given for a total treatment duration of 6 and 12 months. Unpublished preliminary data from this recently closed trial suggested that prolongation of the treatment duration may significantly improve reactivation-free survival. In summary, several studies have shown that systemic therapy is indicated for all patients with MS-LCH. A standard two-drug regimen consisting of an initial ‘intensive’ phase for 6–12 weeks, followed by a less intensive ‘maintenance phase’ for a total treatment duration of at least 12 months is recommended for patients treated outside of clinical trials. Non-responders, particularly those with progressive disease in risk organs, are eligible for experimental salvage approaches. Remaining questions will be addressed in the upcoming LCH-IV trial, which is in the process of intensive preparation.

Histiocytic neoplasms, a rare and heterogeneous group of disorders, primarily include Erdheim-Chester disease, Langerhans cell histiocytosis, and Rosai-Dorfman disease. Due to their diverse clinical manifestations, the greatest challenge posed by these neoplasms is the establishment of a diagnosis, which often leads to a delay in institution of appropriate therapy. Recent insights into their genomic architecture demonstrating mitogen-activated protein kinase/extracellular signal–regulated kinase pathway mutations have now enabled potential treatment with targeted therapies in most patients. This consensus statement represents a joint document from a multidisciplinary group of physicians at Mayo Clinic who specialize in the management of adult histiocytic neoplasms. It consists of evidence- and consensus-based recommendations on when to suspect these neoplasms and what tests to order for the diagnosis and initial evaluation. In addition, it also describes the histopathologic and individual organ manifestations of these neoplasms to help the clinicians in identifying their key features. With uniform guidelines that aid in identifying these neoplasms, we hope to improve the awareness that may lead to their timely and correct diagnosis.

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.

Langerhans cell histiocytosis (LCH) is a heterogeneous histiocytosis characterized by proliferation of Langerhans cells. While less common, manifestations of digestive tract involvement in LCH remain largely unrevealed. We conducted a retrospective analysis of demographics, clinical, endoscopic, genetic and follow-up data from 13 adult patients with pathologically confirmed gastrointestinal involvement of LCH (LCH-GI), in a single-center cohort of 465 patients. Digestive tract involvement was observed in 2.80% of LCH patients. At LCH-GI diagnosis, 7 patients (53.8%) had unifocal lesions, and 6 patients (46.2%) had multisystem disease. 6 patients (46.2%) experienced no gastrointestinal symptoms at LCH-GI onset, while others were symptomatic. Stomach was most commonly affected (61.5%), followed by esophagus (23.1%), colon (7.7%) and anus (7.7%). Endoscopic findings varied among 12 patients, including submucosal bulge (8 patients, 66.7%) and non-bulging lesions (4 patients, 33.3%) such as erosions, coarse granular mucosa, and regional abnormal coloration. Among 8 patients with genetic analysis, BRAFV600E mutation was detected in 5 patients (62.5%). The estimated 1-year overall survival rate was 91.7%. Progression-free survival of patients with submucosal bulges under endoscopy was significantly better than those with non-bulging lesions. This study presents 13 cases of LCH with digestive tract involvement. We emphasize the importance of endoscopy and biopsy for pathological examination of lesions such as submucosal bulges and erosions under endoscopy to assist in early detection of LCH. Comprehensive systemic assessment and regular endoscopic monitoring are essential in patient management. Treatment should be individualized with dynamic adjustments during follow-up.

Langerhans cell histiocytosis (LCH) is a rare and clinically heterogeneous hematological disease characterized by the accumulation of mononuclear phagocytes in various tissues and organs. LCH is often characterized by activating mutations of the mitogen-activated protein kinase (MAPK) pathway with BRAF V600E being the most recurrent mutation. Although this discovery has greatly helped in understanding the disease and in developing better investigational tools, the process of malignant transformation and the cell of origin are still not fully understood. In this review, we focus on the newest updates regarding the molecular pathogenesis of LCH and novel suggested pathways with treatment potential.