Langerhans cell histiocytosis (LCH) is a rare neoplastic disorder caused by somatic genetic alterations in hematopoietic precursor cells differentiating into CD1a+/CD207+ histiocytes. LCH clinical manifestation is highly heterogeneous. BRAF and MAP2K1 mutations account for ∼80% of genetic driver alterations in neoplastic LCH cells. However, their clinical associations remain incompletely understood. Here, we present an international clinicogenomic study of childhood LCH, investigating 377 patients genotyped for at least BRAFV600E. MAPK pathway gene alterations were detected in 300 (79.6%) patients, including 191 (50.7%) with BRAFV600E, 54 with MAP2K1 mutations, 39 with BRAF exon 12 mutations, 13 with rare BRAF alterations, and 3 with ARAF or KRAS mutations. Our results confirm that BRAFV600E associates with lower age at diagnosis and higher prevalence of multisystem LCH, high-risk disease, and skin involvement. Furthermore, BRAFV600E appeared to correlate with a higher prevalence of central nervous system (CNS)-risk bone lesions. In contrast, MAP2K1 mutations associated with a higher prevalence of single-system (SS)-bone LCH, and BRAF exon 12 deletions seemed to correlate with more lung involvement. Although BRAFV600E correlated with reduced event-free survival in the overall cohort, neither BRAF nor MAP2K1 mutations associated with event-free survival when patients were stratified by disease extent. Thus, the correlation of BRAFV600E with inferior clinical outcome is (primarily) driven by its association with disease extents known for high rates of progression or relapse, including multisystem LCH. These findings advance our understanding of factors underlying the remarkable clinical heterogeneity of LCH but also question the independent prognostic value of lesional BRAFV600E status.

Cergentis BV Utrecht The Netherlands

Childhood Cancer Research Unit Department of Women's and Children's Health Karolinska Institutet Stockholm Sweden

Children's Cancer Research Institute St Anna Kinderkrebsforschung Medical University of Vienna Vienna Austria

Department of Hematology Oncology The Hospital for Sick Children University of Toronto Toronto ON Canada

Department of Immunology Erasmus MC Rotterdam The Netherlands

Department of Internal Medicine Clinical Immunology Erasmus Medical Center Rotterdam The Netherlands

Department of Pathology Amsterdam University Medical Centers Amsterdam The Netherlands

Department of Pathology and Molecular Medicine 2nd Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic

Department of Pathology Erasmus MC University Medical Center Rotterdam Rotterdam The Netherlands

Department of Pathology Leiden University Medical Center Leiden The Netherlands

Department of Pathology The Hospital for Sick Children University of Toronto Toronto ON Canada

Department of Pathology University Medical Center Groningen Groningen The Netherlands

Department of Pediatric Hematology and Oncology 2nd Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic

Department of Pediatric Oncology Astrid Lindgren Children's Hospital Karolinska University Hospital Stockholm Sweden

Department of Pediatric Oncology Emma Children's Hospital Amsterdam University Medical Centers Amsterdam The Netherlands

Department of Pediatric Oncology Sophia Children's Hospital Erasmus MC Rotterdam The Netherlands

Department of Pediatrics and Adolescent Medicine Rigshospitalet Copenhagen University Hospital Copenhagen Denmark

Department of Pediatrics Leiden University Medical Center Leiden The Netherlands

Pediatric Hematology Oncology Department Meyer Children's University Hospital Florence Italy

Princess Máxima Center for Pediatric Oncology Utrecht The Netherlands

Zobrazit více v PubMed

Maarten Egeler R, van Halteren AGS, Hogendoorn PCW, Laman JD, Leenen PJM. Langerhans cell histiocytosis: fascinating dynamics of the dendritic cell-macrophage lineage. Immunol Rev. 2010;234(1):213–232. PubMed

Emile J-F, Abla O, Fraitag S, et al. Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages. Blood. 2016;127(22):2672–2681. PubMed PMC

Allen CE, Beverley PCL, Collin M, et al. The coming of age of Langerhans cell histiocytosis. Nat Immunol. 2020;21(1):1–7. PubMed

Allen CE, Merad M, McClain KL. Langerhans-cell histiocytosis. N Engl J Med. 2018;379(9):856–868. PubMed PMC

Rodriguez-Galindo C, Allen CE. Langerhans cell histiocytosis. Blood. 2020;135(16):1319–1331. PubMed

Lahey ME. Prognostic factors in histiocytosis X. Am J Pediatr Hematol Oncol. 1981;3(1):57–60. PubMed

Ladisch S, Gadner H. Treatment of Langerhans cell histiocytosis--evolution and current approaches. Br J Cancer Suppl. 1994;23(70 (Suppl XXIII)):S41–S46. PubMed PMC

Sterlich K, Minkov M. Childhood Langerhans Cell Histiocytosis: Epidemiology, Clinical Presentations, Prognostic Factors, and Therapeutic Approaches. Rare Dis. - Diagnostic Ther. Odyssey. 2021;4

Haupt R, Minkov M, Astigarraga I, et al. Langerhans cell histiocytosis (LCH): guidelines for diagnosis, clinical work-up, and treatment for patients till the age of 18 years. Pediatr Blood Cancer. 2013;60(2):175–184. PubMed PMC

Héritier S, Emile J-F, Barkaoui M-A, et al. BRAF mutation correlates with high-risk Langerhans cell histiocytosis and increased resistance to first-line therapy. J Clin Oncol. 2016;34(25):3023–3030. PubMed PMC

Gadner H, Grois N, Pötschger U, et al. Improved outcome in multisystem Langerhans cell histiocytosis is associated with therapy intensification. Blood. 2008;111(5):2556–2562. PubMed

Gadner H, Minkov M, Grois N, et al. Therapy prolongation improves outcome in multisystem Langerhans cell histiocytosis. Blood. 2013;121(25):5006–5014. PubMed

Donadieu J, Bernard F, van Noesel M, et al. Cladribine and cytarabine in refractory multisystem Langerhans cell histiocytosis: results of an international phase 2 study. Blood. 2015;126(12):1415–1423. PubMed PMC

Egeler RM, Katewa S, Leenen PJM, et al. Langerhans cell histiocytosis is a neoplasm and consequently its recurrence is a relapse: in memory of Bob Arceci. Pediatr Blood Cancer. 2016;63(10):1704–1712. PubMed

Badalian-Very G, Vergilio J-A, Degar BA, et al. Recurrent BRAF mutations in Langerhans cell histiocytosis. Blood. 2010;116(11):1919–1923. PubMed PMC

Berres M-L, Lim KPH, Peters T, et al. BRAF-V600E expression in precursor versus differentiated dendritic cells defines clinically distinct LCH risk groups. J Exp Med. 2014;211(4):669–683. PubMed PMC

Durham BH, Lopez Rodrigo E, Picarsic J, et al. Activating mutations in CSF1R and additional receptor tyrosine kinases in histiocytic neoplasms. Nat Med. 2019;25(12):1839–1842. PubMed PMC

Hayase T, Saito S, Shioda Y, et al. Analysis of the BRAF and MAP2K1 mutations in patients with Langerhans cell histiocytosis in Japan. Int J Hematol. 2020;112(4):560–567. PubMed

Yang Y, Wang C, Wang D, et al. Clinical study of MAP2K1-mutated Langerhans cell histiocytosis in children. J Cancer Res Clin Oncol. 2022;148(9):2517–2527. PubMed PMC

Feng S, Han L, Yue M, et al. Frequency detection of BRAF V600E mutation in a cohort of pediatric Langerhans cell histiocytosis patients by next-generation sequencing. Orphanet J Rare Dis. 2021;16(1):272. PubMed PMC

Nelson DS, Quispel W, Badalian-Very G, et al. Somatic activating ARAF mutations in Langerhans cell histiocytosis. Blood. 2014;123(20):3152–3155. PubMed

Chakraborty R, Hampton OA, Shen X, et al. Mutually exclusive recurrent somatic mutations in MAP2K1 and BRAF support a central role for ERK activation in LCH pathogenesis. Blood. 2014;124(19):3007–3015. PubMed PMC

Brown N, Furtado L, Betz B, Kiel M. High prevalence of somatic MAP2K1 mutations in BRAF V600E negative Langerhans cell histiocytosis. Blood. 2014;124(10):1655–1659. PubMed

Nelson DS, van Halteren A, Quispel WT, et al. MAP2K1 and MAP3K1 mutations in Langerhans cell histiocytosis. Genes Chromosomes Cancer. 2015;54(6):361–368. PubMed

Chakraborty R, Burke TM, Hampton OA, et al. Alternative genetic mechanisms of BRAF activation in Langerhans cell histiocytosis. Blood. 2016;128(21):2533–2537. PubMed PMC

Diamond EL, Durham BH, Haroche J, et al. Diverse and targetable kinase alterations drive histiocytic neoplasms. Cancer Discov. 2016;6(2):154–165. PubMed PMC

Lee LH, Gasilina A, Roychoudhury J, et al. Real-time genomic profiling of histiocytoses identifies early-kinase domain BRAF alterations while improving treatment outcomes. JCI Insight. 2017;2(3) PubMed PMC

Héritier S, Hélias-Rodzewicz Z, Chakraborty R, et al. New somatic BRAF splicing mutation in Langerhans cell histiocytosis. Mol Cancer. 2017;16(1):115. PubMed PMC

Héritier S, Emile J-F, Hélias-Rodzewicz Z, Donadieu J. Progress towards molecular-based management of childhood Langerhans cell histiocytosis. Arch Pediatr. 2019;26(5):301–307. PubMed

McGinnis LM, Nybakken G, Ma L, Arber DA. Frequency of MAP2K1, TP53, and U2AF1 mutations in BRAF-mutated Langerhans cell histiocytosis. Am J Surg Pathol. 2018;42(7):885–890. PubMed

Jouenne F, Chevret S, Bugnet E, et al. Genetic landscape of adult Langerhans cell histiocytosis with lung involvement. Eur Respir J. 2020;55(2) PubMed

Kemps PG, Hebeda KM, Pals ST, et al. Spectrum of histiocytic neoplasms associated with diverse haematological malignancies bearing the same oncogenic mutation. J Pathol Clin Res. 2021;7(1):10–26. PubMed PMC

Ronceray L, Pötschger U, Janka G, Gadner H, Minkov M. Pulmonary involvement in pediatric-onset multisystem Langerhans cell histiocytosis: effect on course and outcome. J Pediatr. 2012;161(1):129–133.e3. PubMed

Grois N, Pötschger U, Prosch H, et al. Risk factors for diabetes insipidus in Langerhans cell histiocytosis. Pediatr Blood Cancer. 2006;46(2):228–233. PubMed

Grois N, Fahrner B, Arceci RJ, et al. Central nervous system disease in Langerhans cell histiocytosis. J Pediatr. 2010;156(6):873–881.e1. PubMed

Chellapandian D, Shaikh F, van den Bos C, et al. Management and outcome of patients with Langerhans cell histiocytosis and single-bone CNS-risk lesions: a multi-institutional retrospective study. Pediatr Blood Cancer. 2015;62(12):2162–2166. PubMed

Kemps PG, Zondag TC, Steenwijk EC, et al. Apparent lack of BRAFV600E derived HLA class I presented neoantigens hampers neoplastic cell targeting by CD8+ T cells in Langerhans cell histiocytosis. Front Immunol. 2020;10:3045. PubMed PMC

Melloul S, Hélias-Rodzewicz Z, Cohen-Aubart F, et al. Highly sensitive methods are required to detect mutations in histiocytoses. Haematologica. 2019;104(3):e97–e99. PubMed PMC

van Eijk R, Licht J, Schrumpf M, et al. Rapid KRAS, EGFR, BRAF and PIK3CA mutation analysis of fine needle aspirates from non-small-cell lung cancer using allele-specific qPCR. PLoS One. 2011;6(3) PubMed PMC

van Eijk R, Stevens L, Morreau H, van Wezel T. Assessment of a fully automated high-throughput DNA extraction method from formalin-fixed, paraffin-embedded tissue for KRAS, and BRAF somatic mutation analysis. Exp Mol Pathol. 2013;94(1):121–125. PubMed

Xiao Y, van Halteren AGS, Lei X, et al. Bone marrow–derived myeloid progenitors as driver mutation carriers in high- and low-risk Langerhans cell histiocytosis. Blood. 2020;136(19):2188–2199. PubMed

Cohen D, Hondelink LM, Solleveld-Westerink N, et al. Optimizing mutation and fusion detection in NSCLC by sequential DNA and RNA sequencing. J Thorac Oncol. 2020;15(6):1000–1014. PubMed

de Vree PJP, de Wit E, Yilmaz M, et al. Targeted sequencing by proximity ligation for comprehensive variant detection and local haplotyping. Nat Biotechnol. 2014;32(10):1019–1025. PubMed

Allahyar A, Pieterse M, Swennenhuis J, et al. Robust detection of translocations in lymphoma FFPE samples using targeted locus capture-based sequencing. Nat Commun. 2021;12(1):3361. PubMed PMC

Schemper M, Smith TL. A note on quantifying follow-up in studies of failure time. Control Clin Trials. 1996;17(4):343–346. PubMed

Chen S-H, Zhang Y, Van Horn RD, et al. Oncogenic BRAF deletions that function as homodimers and are sensitive to inhibition by RAF dimer inhibitor LY3009120. Cancer Discov. 2016;6(3):300–315. PubMed

Foster SA, Whalen DM, Özen A, et al. Activation mechanism of oncogenic deletion mutations in BRAF, EGFR, and HER2. Cancer Cell. 2016;29(4):477–493. PubMed

Yap J, Deepak RNVK, Tian Z, et al. The stability of R-spine defines RAF inhibitor resistance: a comprehensive analysis of oncogenic BRAF mutants with in-frame insertion of αC-β4 loop. Sci Adv. 2021;7(24) PubMed PMC

Ducassou S, Seyrig F, Thomas C, et al. Thymus and mediastinal node involvement in childhood Langerhans cell histiocytosis: long-term follow-up from the French national cohort. Pediatr Blood Cancer. 2013;60(11):1759–1765. PubMed PMC

Picarsic J, Egeler RM, Chikwava K, Patterson K, Jaffe R. Histologic patterns of thymic involvement in Langerhans cell proliferations: a clinicopathologic study and review of the literature. Pediatr Dev Pathol. 2015;18(2):127–138. PubMed

Yao J-F, Wang D, Ma H-H, et al. Characteristics and treatment outcomes of pediatric Langerhans cell histiocytosis with thymic involvement. J Pediatr. 2022;244(0):194–202.e5. PubMed

Kansal R, Quintanilla-Martinez L, Datta V, et al. Identification of the V600D mutation in Exon 15 of the BRAF oncogene in congenital, benign Langerhans cell histiocytosis. Genes Chromosomes Cancer. 2013;52(1):99–106. PubMed

Janssen LJF, Brons PPT, Schreuder HWB, et al. Image gallery: a rare abscess-like presentation of Langerhans cell histiocytosis. Br J Dermatol. 2017;176(4):e33. PubMed

Kambouchner M, Emile J-F, Copin M-C, et al. Childhood pulmonary Langerhans cell histiocytosis: a comprehensive clinical-histopathological and BRAFV600E mutation study from the French national cohort. Hum Pathol. 2019;89:51–61. PubMed

Della Valle V, Donadieu J, Sileo C, et al. Chest computed tomography findings for a cohort of children with pulmonary Langerhans cell histiocytosis. Pediatr Blood Cancer. 2020;67(10) PubMed

Le Louet S, Barkaoui M-A, Miron J, et al. Childhood Langerhans cell histiocytosis with severe lung involvement: a nationwide cohort study. Orphanet J Rare Dis. 2020;15(1):241. PubMed PMC

Zarnegar S, Durham BH, Khattar P, et al. Novel activating BRAF fusion identifies a recurrent alternative mechanism for ERK activation in pediatric Langerhans cell histiocytosis. Pediatr Blood Cancer. 2018;65(1) PubMed PMC

Zanwar S, Abeykoon JP, Dasari S, et al. Clinical and therapeutic implications of BRAF fusions in histiocytic disorders. Blood Cancer J. 2022;12(6):97. PubMed PMC

Zhang R, Wang C-J, Zhao Y-Z, et al. Genetic landscape and its prognostic significance in children with Langerhans cell histiocytosis. Pediatr Blood Cancer. 2022;69(S1):S28–S29. e29453.

Zhou X, Edmonson MN, Wilkinson MR, et al. Exploring genomic alteration in pediatric cancer using ProteinPaint. Nat Genet. 2016;48(1):4–6. PubMed PMC

Minkov M, Pötschger U, Thacker N, et al. Additive prognostic impact of gastrointestinal involvement in severe multisystem Langerhans cell histiocytosis. J Pediatr. 2021;237:65–70.e3. PubMed

Héritier S, Barkaoui M-A, Miron J, et al. Incidence and risk factors for clinical neurodegenerative Langerhans cell histiocytosis: a longitudinal cohort study. Br J Haematol. 2018;183(4):608–617. PubMed

Chen J, Zhao A-L, Duan M-H, et al. Diverse kinase alterations and myeloid-associated mutations in adult histiocytosis. Leukemia. 2022;36(2):573–576. PubMed

Cao X, Duan M, Zhao A, et al. Treatment outcomes and prognostic factors of patients with adult Langerhans cell histiocytosis. Am J Hematol. 2022;97(2):203–208. PubMed

Stathi D, Yavropoulou MP, Allen CE, et al. Prevalence of the BRAF V600E mutation in Greek adults with Langerhans cell histiocytosis. Pediatr Hematol Oncol. 2022;39(6):540–548. PubMed

Yuan J, Ng WH, Tian Z, et al. Activating mutations in MEK1 enhance homodimerization and promote tumorigenesis. Sci Signal. 2018;11(554) PubMed

Hanrahan AJ, Sylvester BE, Chang MT, et al. Leveraging systematic functional analysis to benchmark an in silico framework distinguishes driver from passenger MEK mutants in cancer. Cancer Res. 2020;80(19):4233–4243. PubMed PMC

Gao Y, Chang MT, McKay D, et al. Allele-specific mechanisms of activation of MEK1 mutants determine their properties. Cancer Discov. 2018;8(5):648–661. PubMed PMC

Kemps PG, Picarsic J, Durham BH, et al. ALK-positive histiocytosis: a new clinicopathologic spectrum highlighting neurologic involvement and responses to ALK inhibition. Blood. 2022;139(2):256–280. PubMed PMC

Hyman DM, Diamond EL, Vibat CRT, et al. Prospective blinded study of BRAF V600E mutation detection in cell-free DNA of patients with systemic histiocytic disorders. Cancer Discov. 2015;5(1):64–71. PubMed PMC

Héritier S, Hélias-Rodzewicz Z, Lapillonne H, et al. Circulating cell-free BRAF V600E as a biomarker in children with Langerhans cell histiocytosis. Br J Haematol. 2017;178(3):457–467. PubMed

Schwentner R, Kolenová A, Jug G, et al. Longitudinal assessment of peripheral blood BRAFV600E levels in patients with Langerhans cell histiocytosis. Pediatr Res. 2019;85(6):856–864. PubMed

Eckstein OS, Visser J, Rodriguez-Galindo C, Allen CE. Clinical responses and persistent BRAF V600E+ blood cells in children with LCH treated with MAPK pathway inhibition. Blood. 2019;133(15):1691–1694. PubMed PMC

Donadieu J, Larabi IA, Tardieu M, et al. Vemurafenib for refractory multisystem Langerhans cell histiocytosis in children: an international observational study. J Clin Oncol. 2019;37(31):2857–2865. PubMed PMC

Cui L, Zhang L, Ma H-H, et al. Circulating cell-free BRAF V600E during chemotherapy is associated with prognosis of children with Langerhans cell histiocytosis. Haematologica. 2020;105(9):e444–e447. PubMed PMC

Wang C-J, Cui L, Ma H-H, et al. BRAF V600E Mutation in cell-free DNA, rather than in lesion tissues, at diagnosis is an independent prognostic factor in children with Langerhans cell histiocytosis. Mol Cancer Therapeut. 2021;20(7):1316–1323. PubMed

Poch R, Le Louet S, Hélias-Rodzewicz Z, et al. A circulating subset of BRAF V600E -positive cells in infants with high-risk Langerhans cell histiocytosis treated with BRAF inhibitors. Br J Haematol. 2021;194(4):745–749. PubMed

Eder SK, Schwentner R, Ben Soussia P, et al. Vemurafenib acts as a molecular on-off switch governing systemic inflammation in Langerhans cell histiocytosis. Blood Adv. 2022;6(3):970–975. PubMed PMC

Kudo K, Toki T, Kanezaki R, et al. BRAF V600E-positive cells as molecular markers of bone marrow disease in pediatric Langerhans cell histiocytosis. Haematologica. 2022;107(7):1719–1725. PubMed PMC

McClain KL, Chakraborty R. BRAF V600E vs cell of origin: what governs LCH? Blood. 2021;138(14):1203–1204. PubMed

McClain KL, Bigenwald C, Collin M, et al. Histiocytic disorders. Nat Rev Dis Prim. 2021;7(1):73. PubMed PMC

Zeng K, Wang Z, Ohshima K, et al. BRAF V600E mutation correlates with suppressive tumor immune microenvironment and reduced disease-free survival in Langerhans cell histiocytosis. OncoImmunology. 2016;5(7) PubMed PMC

Sengal A, Velazquez J, Hahne M, et al. Overcoming T-cell exhaustion in LCH: PD-1 blockade and targeted MAPK inhibition are synergistic in a mouse model of LCH. Blood. 2021;137(13):1777–1791. PubMed PMC

Milne P, Bigley V, Bacon CM, et al. Hematopoietic origin of Langerhans cell histiocytosis and Erdheim-Chester disease in adults. Blood. 2017;130(2):167–175. PubMed PMC

Milne P, Abhyankar HA, Scull BP, et al. Cellular distribution of mutations and association with disease risk in Langerhans cell histiocytosis without BRAFV600E. Blood Adv. 2022;6(16):4901–4904. PubMed PMC

Halbritter F, Farlik M, Schwentner R, et al. Epigenomics and single-cell sequencing define a developmental hierarchy in Langerhans cell histiocytosis. Cancer Discov. 2019;9(10):1406–1421. PubMed PMC

Cerami E, Gao J, Dogrusoz U, et al. The cBio Cancer Genomics Portal: an open platform for exploring multidimensional cancer genomics data [figure] Cancer Discov. 2012;2(5):401–404. PubMed PMC

Gao J, Aksoy BA, Dogrusoz U, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013;6(269):pl1. PubMed PMC

NTRK1-rearranged histiocytosis: clinicopathologic and molecular features