BRAFV600E frequency and impact on outcomes in adults with langerhans cell histiocytosis.

7050 Background: Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasm manifesting as unifocal, multifocal, multisystem (MS) or pulmonary LCH (smoking-related). In pediatric LCH, somatic BRAFV600E prevalence is reported at 55-70%, and associated with increased risk of multisystem disease and early treatment failure. Our aim was to describe the prevalence of BRAFV600E mutation and evaluate its association with clinical manifestations and outcomes in adults with LCH. Methods: A retrospective review of adult patients diagnosed with LCH consecutively seen at Mayo Clinic from 2011 to 2020 was performed.Evaluation of association of BRAFV600E mutational status and clinical factors was conducted by the Chi-square test for independence. Progression-free survival (PFS) and overall survival (OS) were analyzed via the Kaplan Meier method and compared with the log-rank test to assess the effect of BRAFV600E. Results: Of the total LCH cohort ( n= 128), 88 patients with available BRAFV600E results were included in the study. Median age at diagnosis was 41y (range 19 - 88); 52.3% were male. 40 (45.5%) patients had a BRAFV600E mutation. Increasing age was associated with BRAFV600E (10-year increase OR 1.42, 95%CI 1.07-1.89; p= 0.017). No correlation was observed between BRAFV600E status and site of disease, risk organ (RO: liver, spleen, marrow) involvement, or MS disease. Patients with BRAFV600E were 4 times more likely to receive targeted therapy ( BRAF inhibitor) than non- BRAFV600E patients ( p= 0.018). After a median follow up of 46 mo (95% CI 30.8-61.2), PFS was similar between BRAFV600E and non- BRAFV600E patients ( p= 0.167). However, patients with BRAFV600E had a worse 3-year OS compared with non- BRAFV600E patients (84% vs. 97.1%, p= 0.027). Patients who died had a significantly higher age at LCH diagnosis (median 62 vs. 38 years; p= 0.0002). Conclusions: In our cohort of adults with LCH, BRAFV600E was less frequent than reported in pediatric literature and was associated with worse OS. The frequency of BRAFV600E was positively correlated with increasing age. Contrary to reports in pediatric LCH, there were no significant associations between BRAFV600E and high-risk or multisystem disease.[Table: see text]

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Clinical characteristics and outcome of pediatric patients diagnosed with Langerhans cell histiocytosis in pediatric hematology and oncology centers in Poland

BMC Cancer ◽

10.1186/s12885-020-07366-3 ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Anna Raciborska ◽

Katarzyna Bilska ◽

Jadwiga Węcławek-Tompol ◽

Olga Gryniewicz-Kwiatkowska ◽

Małgorzata Hnatko-Kołacz ◽

...

Keyword(s):

Langerhans Cell Histiocytosis ◽

Systemic Treatment ◽

Langerhans Cell ◽

Rank Test ◽

Entire Group ◽

Older Children ◽

Multisystem Disease ◽

Pediatric Hematology ◽

Increased Risk ◽

Treatment Data

Abstract Background Langerhans cell histiocytosis (LCH) affects 1–2 in 1,000,000 people. The disease is not associated with increased risk of treatment failure (especially among older children), but appropriate procedures implemented in advance can eliminate complications which might appear and significantly worsen the patients’ quality of life. Thus, we sought to evaluate the clinical features, management, and outcome of children with LCH treated in Polish pediatric hematology-oncology centers. Materials and methods One hundred eighty two patients with LCH were treated according to the Histiocytic Society Guidelines between 2010 and 2017. The participating centers were requested to provide the following data: demographic, clinical, as well as local or systemic treatment data and patients’ outcome. Overall survival (OS) and event free survival (EFS) were estimated by Kaplan-Meier methods and compared using the log-rank test. Results Sixty nine percent of children were classified as single system (SS). The patients with SS disease were significantly older as compared to the children with multisystem disease (MS), 6 vs. 2.3 years respectively (p 0.003). Bones were involved in 76% of patients. Systemic treatment was applied to 47% of children with SS disease and 98% with MS disease. Fourteen patients relapsed while two children died. OS and EFS in entire group were 0.99 and 0.91 respectively (with median follow-up 4.3 years). Conclusion The treatment of LCH in Polish centers was effective, however, new approaches, including mutation analyses and good inter-center cooperation, are needed to identify patients who might require modification or intensification of treatment.

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Pediatric Langerhans Cell Histiocytosis (LCH) Clinical Outcome in Hospital Civil De Guadalajara, México

Blood ◽

10.1182/blood-2018-99-115794 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4951-4951 ◽

Cited By ~ 1

Author(s):

Katterine Rojas Rodríguez ◽

Veronica Soto ◽

Carlos Rodriguez-Galindo ◽

Paola M. Friedrich ◽

Edwin Guzmán ◽

...

Keyword(s):

Clinical Outcome ◽

Langerhans Cell Histiocytosis ◽

Disease Risk ◽

Conflicts Of Interest ◽

Systemic Disease ◽

Giant Cells ◽

Langerhans Cell ◽

Induction Treatment ◽

Multisystem Disease ◽

Clonal Proliferation

Abstract Pediatric Langerhans cell histiocytosis (LCH) clinical outcome in Hospital Civil de Guadalajara, México. Introduction : LCH results from clonal proliferation of functionally and immunophenotyped inmature round Langerhans cells along with eosinophiles, machrophages, lymphocytes and ocasionally multinucleated giant cells (1). Its incidence is 2-10 cases by million of children below 15 yr in US (2). Our objective was to describe the clinical characteristics and treatment outcome of patients with LCH at Departement of Hematology-Oncology of Hospital Civil de Guadalajara México. Methods: It was a retrospective design and 41 pediatric patients below 18 yr were included. The diagnosis was corroborated by pathology and immunohistochemistry. Variables as age, gender, localised vs systemic disease, risk organ commitment, global survival (GS) and event free survival (EFS) were analysed. We used descriptive and inferencial statistics with SPSS program. Results: There were included 41 patients from January 1st 2012 to December 31st 2017. Relation male:female was 1.1:1. Mean presentation was localised disease (58%). Bone was the principal affected structure (34%) and it was 71% to be combined with lung, lymph node and CNS compromise. Risk organ commitment was presented in 32%, being more frecquent bone marrow and liver in 22% each one. Time induction treatment was equal or below 12 weeks in 66% of patients. The 25% of patients had reactivation of LCH, with similar lesions to the beggining in 19.5%. We found statistically significant differences between dead patients (DP) (14.6%) and not dead patients (NDP) (85.4%) in clinical presentation: localised (0% in DP vs 69% in NDP) and systemic disease (100% vs 31%) (p=0,003) and risk organ commitment (100% in DP vs 20% in NDP) (p=0,000). Median age of 13 vs 24 months was for DP and NDP respectively. Conclusion: Dead patients were younger than 13 months old, with systemic disease, and risk organ commitment. We found a later asking of medical advice in DP (6 months) vs NDP (2 months). Keys words: langerhans cell histiocytosis, multisystem disease, risk organ Figure. Figure. Disclosures No relevant conflicts of interest to declare.

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BRAF V600E Mutation: A Significant Biomarker for Prediction of Disease Relapse in Pediatric Langerhans Cell Histiocytosis

Pediatric and Developmental Pathology ◽

10.1177/1093526619847859 ◽

2019 ◽

Vol 22 (5) ◽

pp. 449-455 ◽

Cited By ~ 7

Author(s):

Erdener Ozer ◽

Akin Sevinc ◽

Dilek Ince ◽

Resmiye Yuzuguldu ◽

Nur Olgun

Keyword(s):

Langerhans Cell Histiocytosis ◽

Direct Sequencing ◽

Prognostic Significance ◽

Braf V600e Mutation ◽

Langerhans Cell ◽

Braf V600e ◽

Erk Pathway ◽

Disease Relapse ◽

Multisystem Disease ◽

Mutational Status

Langerhans cell histiocytosis (LCH) is a rare disease presenting with usually a localized disease but sometimes a widespread aggressive disorder especially in children. Among the somatic mutations in RAF-MEK-ERK pathway, especially BRAF mutation has been detected so far in LCH. We aimed in this study to investigate the prognostic significance of the mutations of target genes playing a role in the RAF-MEK-ERK pathway in pediatric LCH. Mutation analyses were performed on tumor DNA extracted from formalin-fixed paraffin-embedded biopsy specimens of 38 pediatric LCH cases using a direct sequencing technique for BRAF, ARAF, MAP2K1, and MAP3K1 genes. The mutational status was correlated statistically with survival, clinical progression (disease relapse), and the established clinical prognostic parameters of LCH such as age, gender, localization, multisystem disease, central nervous system risk lesions, and risk organ or special-site involvement. BRAF V600E mutation was detected in 14 cases (36.8%), whereas ARAF mutation was found in only 1 case. No mutations were identified for MAP2K1 and MAP3K1 genes. The association of BRAF V600E mutation was significant in children with multisystem disease, younger age (<2 years), skin, and special organ involvement. BRAF V600E mutation was an independent predictive parameter for disease relapse. We therefore conclude that BRAF V600E mutation may be a significant marker for predicting disease progression in LCH and a candidate for targeted therapy for children with disease relapse and multisystem disease.

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CLINICAL FEATURES AND OUTCOME IN CHILDREN WITH LANGERHANS CELL HISTIOCYTOSIS. A SINGLE INSTITUTION EXPERIENCE FROM PAKISTAN

Pakistan Armed Forces Medical Journal ◽

10.51253/pafmj.v71i6.4022 ◽

2022 ◽

Vol 71 (6) ◽

pp. 2194-2201

Author(s):

Nida Noor ◽

Rabia Muhammad Wali ◽

Annis -Ur- Rehman ◽

Muhammad Abu Bakar

Keyword(s):

Langerhans Cell Histiocytosis ◽

Clinical Manifestations ◽

Langerhans Cell ◽

Single System ◽

Single Institution ◽

Multisystem Disease ◽

Disease Mortality ◽

Multisystem Involvement ◽

Related Mortality

Objective: To find out the clinical manifestations, treatment given and outcome of children with diagnosis of Langerhans cell histiocytosis. Study Design: Retrospective observational study. Place and Duration of Study: Shaukat Khanum Cancer Hospital, Lahore Pakistan, from Jan 2005 to Dec 2015. Methodology: Medical charts were reviewed in detail along with the available imaging for the patients. The data included age at the time of diagnosis, extent of the disease, involvement of risk organs, treatment given, response at 6th week of chemotherapy and at the end of the treatment, and outcome in terms of disease progression during the treatment, relapse of disease on follow up and cause of death either due to treatment related mortality or disease complications. Results: There were 29 patients, 12 patients (41%) had single system and 17 (58%) had multisystem involvement. 7 patients (41%) had risk organ involvement in the multisystem group. All the patients of multisystem and 6 patients of single system were treated according to the Langerhans cell histiocytosis III protocol. Commonest sites of involvement were bone in 22 (75%), followed by lymph nodes in 18 (62%) patients. Disease relapse was seen in 6 patients and all of them had multisystem disease. Mortality was observed only in multisystem Langerhans cell histiocytosis patients and more than 50% were risk organ positive. Conclusion: Langerhans cell histiocytosis is a highly heterogeneous disease. Some forms are curable without chemotherapy, while the multisystem disease requires aggressive treatment. However, despite intensive treatment, the multisystem disease and risk organs involved have poor...........

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Retrospective analysis of clinical manifestations and treatment outcomes of patients diagnosed with langerhans cell histiocytosis from a tertiary cancer hospital in South India

International Journal of Research in Medical Sciences ◽

10.18203/2320-6012.ijrms20202255 ◽

2020 ◽

Vol 8 (6) ◽

pp. 2128

Author(s):

Roshan Koshy Jacob ◽

Shashidhar V. Karpurmath ◽

Manjunath Nandennavar ◽

Veerendra Angadi

Keyword(s):

Treatment Outcomes ◽

Retrospective Analysis ◽

Langerhans Cell Histiocytosis ◽

Clinical Manifestations ◽

Langerhans Cell ◽

Single System ◽

Multisystem Disease ◽

Cancer Hospital ◽

Mucosal Involvement

Background: Langerhans cell histiocytosis (LCH) comprises a diverse group of disorders where pathologic Langerhans cells accumulate in a variety of organs. Aims and objectives of the study is to analyse the clinical manifestations and treatment outcomes of patients diagnosed with LCH in a tertiary cancer hospital in South India.Methods: Retrospective analysis of the case records of patients presenting with histological proven case of LCH over a period of 7 years from 2011 to 2018, being treated at Vydehi Institute of Medical Sciences and Research Centre.Results: 10 patients with biopsy proven LCH were included. The median age of diagnosis was 8 years (range 1 to 73 years) and 3 patients aged 18 years or older at the time of diagnosis. The male: female ratio was 3:2. Multisystem involvement was found in 4 patients (40%) and Single system Involvement in remaining 6 patients. Isolated bone lesions were found in 4 patients (40%), 1 patient had isolated Lymph node involvement; 1 patient had oral cavity lesion. None of the 4 patients with multisystem diseases had skin/mucosal involvement; 3 had bony involvement, 2 patients had lung involvement. One patients with multisystem disease expired while 5 patients were lost to follow-up. 4 out of the 10 patients are on regular follow-up and are in remission.Conclusions: Despite limitation by the retrospective nature, this descriptive study was done to provide further disease information regarding Indian population. Data from this study clearly confirms the known fact that most of the patients with Single System LCH have a very good response rate. Patients with multisystem disease have the highest risk of disease related mortality and morbidity as one among the 4 patients with multisystem disease died just after initiating treatment.

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Vemurafenib acts as molecular on-off switch governing systemic inflammation in Langerhans cell histiocytosis

Blood Advances ◽

10.1182/bloodadvances.2021005442 ◽

2021 ◽

Author(s):

Sebastian K Eder ◽

Raphaela Schwentner ◽

Philipp Ben Soussia ◽

Giulo Abagnale ◽

Andishe Attarbaschi ◽

...

Keyword(s):

Inflammatory Cytokines ◽

Systemic Inflammation ◽

Langerhans Cell Histiocytosis ◽

Bone Marrow Cells ◽

Clinical Manifestations ◽

Serum Levels ◽

Cell Types ◽

Salvage Chemotherapy ◽

Langerhans Cell ◽

Multisystem Disease

Langerhans cell histiocytosis (LCH) is a neoplasm marked by the accumulation of CD1A+CD207+ cells. It is most commonly driven by a somatic, activating mutation in the BRAF serine-threonine kinase (BRAFV600E). Multisystem disease with risk-organ involvement requires myelotoxic chemotherapy, making BRAF-inhibitors an attractive treatment option. Here, we present a comprehensive analysis of the course of an LCH patient treated with the combination of vemurafenib and salvage chemotherapy who achieved sustained clinical and molecular remission. We show that there is no relationship between peripheral bloodBRAFV600E levels and clinical presentation during treatment with vemurafenib, but that vemurafenib leads to a fast, efficient, but reversible inhibition of clinical manifestations of systemic inflammation. In line, serum levels of inflammatory cytokines exactly mirror vemurafenib administration. Genotyping analysis identified the BRAFV600E mutation in multiple hematopoietic cell types, including NK cells and granulocytes. Single-cell transcriptome analyses of peripheral blood and bone marrow cells at time of diagnosis and during treatment indicate that RAF-inhibition abrogates the expression of inflammatory cytokines previously implicated in LCH such as IL1B and CXCL8. Together, our data suggest that while the CD1A+CD207+histiocytes are the hallmark of LCH, other BRAF-mutated cell populations may contribute significantly to morbidity in patients with multisystem LCH.

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Paediatric Langerhans Cell Histiocytosis Disease: Long-Term Sequelae in the Hypothalamic Endocrine System

Hormone Research in Paediatrics ◽

10.1159/000517040 ◽

2021 ◽

pp. 1-9

Author(s):

Elisa Vaiani ◽

Guido Felizzia ◽

Fabiana Lubieniecki ◽

Jorge Braier ◽

Alicia Belgorosky

Keyword(s):

Anterior Pituitary ◽

Langerhans Cell Histiocytosis ◽

Endocrine System ◽

Langerhans Cell ◽

Hormone Deficiency ◽

Bone Lesions ◽

Pituitary Hormone ◽

Multisystem Disease ◽

Anterior Pituitary Hormone

Langerhans cell histiocytosis (LCH) is a disorder of the mononuclear phagocyte system that can affect almost any organ and system. The most common central nervous system (CNS) manifestation in LCH is the infiltration of the hypothalamic-pituitary region leading to destruction and neurodegeneration of CNS tissue. The latter causes the most frequent endocrinological manifestation, that is, central diabetes insipidus (CDI), and less often anterior pituitary hormone deficiency (APD). The reported incidence of CDI is estimated between 11.5 and 24% and is considered a risk factor for neurodegenerative disease and APD. Three risk factors for development of CDI are recognized in the majority of the studies: (1) multisystem disease, (2) the occurrence of reactivations or active disease for a prolonged period, and (3) the presence of craniofacial bone lesions. Since CDI may occur as the first manifestation of LCH, differential diagnosis of malignant diseases like germ cell tumours must be made. APD is almost always associated with CDI and can appear several years after the diagnosis of CDI. Growth hormone is the most commonly affected anterior pituitary hormone. Despite significant advances in the knowledge of LCH in recent years, little progress has been made in preventing long-term sequelae such as those affecting the hypothalamic-pituitary system.

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AGO2 expression levels and related genetic polymorphisms: influence in renal cell progression and aggressive phenotypes

Pharmacogenomics ◽

10.2217/pgs-2021-0072 ◽

2021 ◽

Author(s):

Ana Luísa Teixeira ◽

Ana Sofia Patrão ◽

Francisca Dias ◽

Carlos Silva ◽

Isabel Vieira ◽

...

Keyword(s):

Cancer Progression ◽

Renal Cell ◽

Progression Free Survival ◽

Rank Test ◽

Mrna Levels ◽

Free Survival ◽

Increased Risk ◽

Cell Progression ◽

Progression Risk ◽

Circulating Levels

Aim: Renal cell carcinoma (RCC) is the most lethal urological cancer and up to 40% of patients submitted to surgery will relapse. Thus, the study aim was to analyze the associations of AGO2 SNPs with RCC patients’ prognosis, and evaluate their effect on AGO2 mRNA levels. Materials & methods: The AGO2 rs4961280, rs3928672 and rs11996715 polymorphisms and the relative quantification of AGO2 mRNA levels were analyzed by real-time PCR. Results: We observed that AGO2 rs4961280 AC + AA genotypes carriers presented a higher cancer progression risk (OR= 3.13, p < 0.001), a reduced progression-free survival (log rank test, p = 0.003) and an increased risk of an early relapse (HR= 2.26, p = 0.008). In fact, these patients also presented higher circulating levels of AGO2 mRNA (p = 0.043), with the high levels being associated with more aggressive tumors. Conclusion: The AGO2 rs4961280 AA/AC genotypes are unfavorable RCC prognostic biomarkers, with the AGO2 levels being a useful RCC aggressive phenotype biomarker.

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Adult-onset Neurological Langerhans Cell histiocytosis and Response to Treatment

Austin Journal of Clinical Neurology ◽

10.26420/austinjclinneurol.2021.1146 ◽

2021 ◽

Vol 8 (1) ◽

Author(s):

Al-Hader R ◽

◽

Suneja A ◽

Memon AB ◽

Mukherje A ◽

...

Keyword(s):

Langerhans Cell Histiocytosis ◽

Brain Magnetic Resonance Imaging ◽

Langerhans Cell ◽

Response To Therapy ◽

Response To Treatment ◽

Adult Onset ◽

Multisystem Disease ◽

Clonal Proliferation ◽

Magnetic Resonance Imaging Mri ◽

Mass Lesions

Introduction: Langerhans Cell Histiocytosis (LCH) is a rare form of cancer that mostly affects children and rarely adults. LCH involves an abnormal clonal proliferation of Langerhans cells in the bone marrow. These cells are capable of migrating from the skin to lymph nodes. Therefore, it is characterized as a multisystem disease. Neurological manifestations are not common, and often patients’ present with endocrine dysfunction with neuroimaging findings of hypothalamic and pituitary masses can mimic pituitary adenoma. Here, we discuss two instances of unusual adult-onset, primary neurological LCH in patients with a positive response to therapy-these two patients presented with mass lesion and neurodegenerative form of LCH, respectively. LCH can manifest features of mass lesions or neurodegeneration on brain Magnetic Resonance Imaging (MRI). Since it is rare in adults, it is crucial to identify this condition as timely treatment can have a better prognosis.

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Childhood Langerhans cell histiocytosis with severe lung involvement: a nationwide cohort study

Orphanet Journal of Rare Diseases ◽

10.1186/s13023-020-01495-5 ◽

2020 ◽

Vol 15 (1) ◽

Author(s):

Solenne Le Louet ◽

Mohamed-Aziz Barkaoui ◽

Jean Miron ◽

Claire Galambrun ◽

Nathalie Aladjidi ◽

...

Keyword(s):

Targeted Therapy ◽

Langerhans Cell Histiocytosis ◽

Treatment Guidelines ◽

Langerhans Cell ◽

Infection Prophylaxis ◽

Lung Involvement ◽

Multisystem Disease ◽

Abnormal Chest ◽

Life Threatening ◽

Severe Lung

Abstract Background Lung involvement in childhood Langerhans cell histiocytosis (LCH) is infrequent and rarely life threatening, but occasionally, severe presentations are observed. Methods Among 1482 children (< 15 years) registered in the French LCH registry (1994–2018), 111 (7.4%) had lung involvement. This retrospective study included data for 17 (1.1%) patients that required one or more intensive care unit (ICU) admissions for respiratory failure. Results The median age was 1.3 years at the first ICU hospitalization. Of the 17 patients, 14 presented with lung involvement at the LCH diagnosis, and 7 patients (41%) had concomitant involvement of risk-organ (hematologic, spleen, or liver). Thirty-five ICU hospitalizations were analysed. Among these, 22 (63%) were secondary to a pneumothorax, 5 (14%) were associated with important cystic lesions without pneumothorax, and 8 (23%) included a diffuse micronodular lung infiltration in the context of multisystem disease. First-line vinblastine–corticosteroid combination therapy was administered to 16 patients; 12 patients required a second-line therapy (cladribine: n = 7; etoposide-aracytine: n = 3; targeted therapy n = 2). A total of 6 children (35%) died (repeated pneumothorax: n = 3; diffuse micronodular lung infiltration in the context of multisystem disease: n = 2; following lung transplantation: n = 1). For survivors, the median follow-up after ICU was 11.2 years. Among these, 9 patients remain asymptomatic despite abnormal chest imaging. Conclusions Severe lung involvement is unusual in childhood LCH, but it is associated with high mortality. Treatment guidelines should be improved for this group of patients: viral infection prophylaxis and early administration of a new LCH therapy, such as targeted therapy.

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