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(Langerhans Cell Histiocytosis, Erdheim–Chester Disease, Destombes–Rosai–Dorfman Disease): from Oncogenic Mutations to Inflammatory Disorders

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(Langerhans Cell Histiocytosis, Erdheim–Chester Disease, Destombes–Rosai–Dorfman Disease): from Oncogenic Mutations to Inflammatory Disorders Current Oncology Reports (2019) 21: 62 https://doi.org/10.1007/s11912-019-0810-6 LYMPHOMAS (MR SMITH, SECTION EDITOR) Systemic Histiocytosis (Langerhans Cell Histiocytosis, Erdheim–Chester Disease, Destombes–Rosai–Dorfman Disease): from Oncogenic Mutations to Inflammatory Disorders Matthias Papo1 & Fleur Cohen-Aubart1 & Ludovic Trefond1 & Adeline Bauvois1 & Zahir Amoura1 & Jean-François Emile2 & Julien Haroche1 Published online: 21 May 2019 # Springer Science+Business Media, LLC, part of Springer Nature 2019 Abstract Purpose of Review Provide an overview of recent progress in decoding the pathogenesis and treatment of systemic histiocytoses. Recent Findings Advances in molecular techniques over the last few years, enabling the identification of several MAPK mutations in lesion histiocytes, have revolutionized our understanding of histiocytosis that led to a revised classification and new treatments. Summary Since the 2010 discovery of the BRAFV600E mutation in 57% of Langerhans cell histiocytosis (LCH) lesions, several other kinase mutations have been found, mostly in the MAPK pathway, and also in other key signaling pathways, in LCH, Erdheim–Chester Disease (ECD) and, less frequently, Destombes–Rosai–Dorfman disease (RDD). Those revolutionary break- throughs enhanced our understanding of the pathogenesis of histiocytosis and led to trials with targeted therapies that demon- strated notable efficacy. Keywords Langerhans cell histiocytosis . Erdheim–Chester disease . Destombes–Rosai–Dorfman disease . Myeloid neoplasm Introduction Classifying these three disorders under the term “histiocytoses” was actually accurate, as confirmed by the piv- Langerhans cell histiocytosis (LCH), Erdheim–Chester dis- otal breakthrough in our understanding of their pathogeneses ease (ECD), and Destombes–Rosai–Dorfman disease (RDD) over the past few years, i.e., the discovery of recurrent are rare inflammatory diseases that can be localized in a single mitogen–activated protein kinase (MAPK) pathway mutations organ or systemic with multi-organ involvement. They share in LCH, ECD, and sometimes RDD [1, 2, 3••]. histopathological features: tissue infiltration by histiocytes, Those findings, in addition to expanding our knowledge and with or without Langerhans cell (LC) markers, and inflamma- generating a new revised classification [4], led to targeted- tory cells, and sometimes affect several organs. therapy trials which obtained good responses [5, 6, 7•]. This article is part of the Topical Collection on Lymphomas * Julien Haroche Zahir Amoura [email protected] [email protected] Matthias Papo Jean-François Emile [email protected] [email protected] Fleur Cohen-Aubart 1 Assistance Publique–Hôpitaux de Paris, Service de Médecine Interne [email protected] 2, Centre National de Références des Histiocytoses, Hôpital Pitié–Salpêtrière, Sorbonne Université, 47–83, Boulevard de Ludovic Trefond l’Hôpital, 75651 Paris Cedex 13, France [email protected] 2 EA4340-BECCOH, Versailles University, & Département de Adeline Bauvois Pathologie, Hôpital Ambroise Paré, AP-HP, 9 Avenue Charles de [email protected] Gaulle, 92100 Boulogne, France 62 Page 2 of 10 Curr Oncol Rep (2019) 21: 62 This review on LCH, ECD, and RDD focuses on recent in all lesions of both diseases [1]. BRAF-activating muta- molecular discoveries, their clinical pictures at onset, and cur- tions, including in-frame deletions, fusions, and duplica- rent standard of care. tions, have been described in LCH lesions in the past few years [3••, 15, 16]. But BRAF is not the only mutated gene in histiocytosis able to activate the MAPK pathway. Pathogenesis: Oncogene Mutations The results of whole exome and targeted next-generation in Hematopoietic Cells Leading sequencing studies demonstrated mutations of MAP2K1 to Inflammatory Histiocytic Disorders (which encodes MEK1) in 25% of LCH patients that were mutually exclusive of BRAF mutations [17–19]. ARAF, V600E Discovery of the BRAF Mutation: a Key KRAS,andNRAS mutations have also been described in to the Origin of Histiocytoses LCH but at lower rates than BRAF and MAP2K1 [20] (Fig. 1a). LCH origin was largely unknown until 2010, when a mass In ECD, a combined whole exome and transcriptome spectrometry study targeting cancer genes highlighted the nu- analysis of several tissue samples also found frequent cleotide variant BRAFV600E in 35 (57%) of 61 LCH samples MAP2K1, ARAF, NRAS,andKRAS mutations, and trans- [1]. The BRAFV600E mutation is involved in 7% of human locations involving BRAF, ALK,andNTRK1.Mutations cancers [8], some of which might benefit from targeted ther- in MAP2K1 were found in about 30% of the patients, apy [9]. This oncogene mutation renders the MAPK pathway while KRAS or NRAS mutations were present in 27% constitutively active, because BRAF is a pivotal kinase in the [3••, 21](Fig.1a). RAS–RAF–MEK signaling pathway, which is involved in However, the MAPK pathway is not the only signaling several cell functions, such as proliferation, apoptosis, angio- pathway involved in histiocytosis pathogenesis, since ac- genesis, migration, and survival [8]. tivating PIK3CA mutations were also found in 11% of According to multivariate logistic regression analyses of ECD patients [21]. Those mutations activate the PI3K– the characteristics of a large French cohort including 315 pe- AKT pathway, which can also be induced through the diatric LCH patients, BRAFV600E mutations were associated MAPK pathway. Moreover, CD68+ histiocytes express with risk organ (i.e., liver, spleen, and hematological system) cytoplasmic phosphorylated mechanistic target of involvement and multi-organ disease [10]. In 2012, a pyrose- rapamycin (mTOR) and p70S6K [22]. quencing study on 93 patients with different histiocytoses According to recent studies, 14% and 12.5% of RDD found 38% of those with LCH had the BRAFV600E mutation, patients, respectively, had MAP2K1 and KRAS mutations and 54% of ECD [2], but not in other histiocytic diseases [23– 26](Fig.1a). Altogether, the frequency of mutated (RDD, juvenile xanthogranuloma, histiocytic sarcoma, cases in RDD is lower than in LCH or ECD; this may xanthoma disseminatum, interdigitating cell sarcoma, or be due to the very low variant allele frequency. Very re- necrobiotic granuloma). Immunohistochemical analyses of cently, activating CSF1R (alsoknownasM-CSFR)muta- ECD tissue samples with a BRAFV600E-selective antibody tions were identified in some patients with different confirmed the mutation’s expression in the typical foamy his- histiocytoses [27]. tiocytes and Touton giant cells but not in lymphocytes, fibro- blasts, or endothelial cells. In a series of 23 patients with both LCH and ECD lesions, 82% had BRAFV600E mutations, sug- Fig. 1 Langerhans cell histiocytosis (LCH), Erdheim–Chester disease gesting a link between the pathogeneses of these two entities – – V600E (ERD), and Destombes Rosai Dorfman disease. a Pie charts of their [11]. ECD patients harboring the BRAF mutation had relative frequencies of activating signaling pathway mutations. b more cerebellar involvement, diabetes insipidus, retro-orbital Ontogenies of BRAF-mutated histiocytes in LCH and ECD. ① infiltration, and cardiac manifestations, especially the right Acquisition of epigenetic regulation gene mutations in bone marrow stem cells or myeloid progenitors (example here: TET2)leadingto atrial pseudotumors [12]. Notably, patients with LCH or ② V600E clonal hematopoiesis. Primary or secondary acquisition of the ECD lesions carrying the BRAF mutation tended have a BRAFV600E mutation in bone marrow stem cells or myeloid progenitors. more severe disease phenotype. More recently, BRAF muta- ③ Circulating monocytes and dendritic cells (DCs) harboring the V600E tions were reported in two RDD cases [13, 14] but data on BRAF mutation derived from mutated myeloid progenitors. ④ Migration of BRAFV600E-bearing DCs or monocytes to tissue and large cohorts are lacking. differentiation into either CD1a+ Langerin+ Langerhans cells (leading to LCH) or CD68+ CD163+ foamy histiocytes (leading to ECD). ⑤ V600E BRAF Is Not the Only Signaling Pathway Acquisition of the JAK2V617F mutation in bone marrow stem cells/ Mutation in Systemic Histiocytoses progenitors, promoted by underlying clonal hematopoiesis, leading to associated myeloproliferative neoplasm (MPN)/myelodysplastic syndrome (MDS). ⑥ Acquisition of BRAFV600E in yolk sac and fetal Intriguingly, 50–60% of LCH or ECD patients carry the liver hematopoietic progenitors, hypothetically leading to V600E BRAF mutation but the MAPK pathway is activated neurodegenerative LCH manifestations Curr Oncol Rep (2019) 21: 62 Page 3 of 10 62 a Langerhans cell Erdheim–Chester Destombes–Rosai–Dorfman histiocytosis disease disease BRAFV600E MAP2K1 MAP2K1 MAP2K1 N/KRAS PIK3CA BRAFV600E N/KRAS V600E Unknown ARAF BRAF ARAF N/KRAS Fusions: BRAF, Fusions: BRAF, ALK, NTRK1 Unknown ETV3-NCOA2 MAP3K1 Unknown CSF1R BRAF Indels ERBB3 ARAF b 1 TET2 Bone-marrow stem cells & myeloid progenitors 2 Fetal liver and yolk-sac stem V617F cells & myeloid progenitors 5 JAK2 BRAFV600E JAK2V617F BRAFV600E TET2 TET2 TET2 Associated MPN/MDS 3 6 TET2 Circulating monocytes & DCs BRAFV600E TET2 BRAFV600E Tissue CD1a+ Langerin+ Tissue CD68+ CD163+ Langerhans cell CD1a – Langerin – BRAFV600E 4 BRAFV600E foamy histiocyte • Impaired migration Erdheim–Chester Langerhans cell • Apoptosis inhibition disease histiocytosis • Inflammation 62 Page 4 of 10 Curr Oncol Rep (2019) 21: 62 Cell-of-Origin: Embryogenic or Adult Hematopoiesis? with
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