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| Badalian-Very G, Vergilio JA, Degar BA, MacConaill LE, Brandner B, Calicchio ML, Kuo FC, Ligon AH, Stevenson KE, Kehoe SM, Garraway LA, Hahn WC, Meyerson M, Fleming MD, Rollins BJ |
Recurrent BRAF mutations in Langerhans cell histiocytosis. |
Blood 2010 Sep 16; 116: 1919 |
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| Langerhans cell histiocytosis (LCH) has a broad spectrum of clinical behaviors; some cases are self-limited, whereas others involve multiple organs and cause significant mortality. Although Langerhans cells in LCH are clonal, their benign morphology and their lack (to date) of reported recurrent genomic abnormalities have suggested that LCH may not be a neoplasm. Here, using 2 orthogonal technologies for detecting cancer-associated mutations in formalin-fixed, paraffin-embedded material, we identified the oncogenic BRAF V600E mutation in 35 of 61 archived specimens (57%). TP53 and MET mutations were also observed in one sample each. BRAF V600E tended to appear in younger patients but was not associated with disease site or stage. Langerhans cells stained for phospho-mitogen-activated protein kinase kinase (phospho-MEK) and phospho-extracellular signal-regulated kinase (phospho-ERK) regardless of mutation status. High prevalence, recurrent BRAF mutations in LCH indicate that it is a neoplastic disease that may respond to RAF pathway inhibitors. |
| Badalian-Very G, Vergilio JA, Fleming M, Rollins BJ |
Pathogenesis of Langerhans cell histiocytosis. |
Annual review of pathology 2013 Jan 24; 8: 1 |
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| Langerhans cell histiocytosis (LCH) combines in one nosological category a group of diseases that have widely disparate clinical manifestations but are all characterized by accumulation of proliferating cells with surface markers and ultrastructural features similar to cutaneous Langerhans cells (LCs). Despite this unified nosology, important questions about LCH remain unanswered. First, despite having phenotypic features of LCs, LCH cell gene-expression patterns differ from those in LCs. Although this observation suggests that LCH may arise from an earlier precursor, it is not necessarily inconsistent with the hypothesis that LCs are the cell of origin for LCH. Second, LCH's prominent inflammatory component and occasional benign clinical course suggest that LCH may not be a neoplasm. However, the demonstration that LCH cells are clonal, along with the recent discovery of activating BRAF mutations in LCH cells, strongly suggests that LCH is a neoplastic disease. These new observations point the way to rationally targeted therapies. |
| Bernard F, Thomas C, Bertrand Y, Munzer M, Landman Parker J, Ouache M, Colin VM, Perel Y, Chastagner P, Vermylen C, Donadieu J |
Multi-centre pilot study of 2-chlorodeoxyadenosine and cytosine arabinoside combined chemotherapy in refractory Langerhans cell histiocytosis with haematological dysfunction. |
European Journal of Cancer 2005, 41: 2682-9. Epub 2005 Apr 7. |
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| The aim of this study was to assess the efficacy and adverse effects of 2-chlorodeoxyadenosine (2-CdA) and cytosine arabinoside (Ara-C) in children with refractory Langerhans cell histiocytosis (LCH) and haematopoietic dysfunction. Ten patients, with a median age at diagnosis of 0.5 years, were enrolled in this study. Treatment comprised at least two courses of Ara-C (1000 mg/m(2)/d) and 2-CdA (9 mg/m(2)/d) administered for 5d every 4 weeks; subsequent median follow-up was 2.8 years (range 0.03-6.4 years). Among the 7 patients who received at least two courses of therapy, disease activity decreased in 6 patients, and control of disease was achieved in all patients after a median delay of 5.5 months. All patients suffered World Health Organisation (WHO) grade 4 haematological toxicity. Two septic deaths occurred shortly after administration of the first course of 2-CdA/Ara-C; a third patient was withdrawn from the trial after the first course and subsequently died following haematopoietic stem cell transplantation. This series is small, but we conclude that 2-CdA and Ara-C combined chemotherapy probably has major activity in childhood refractory Langerhans cell histiocytosis. |
| Berres ML, Lim KP, Peters T, Price J, Takizawa H, Salmon H, Idoyaga J, Ruzo A, Lupo PJ, Hicks MJ, Shih A, Simko SJ, Abhyankar H, Chakraborty R, Leboeuf M, Beltrão M, Lira SA, Heym KM, Bigley V, Collin M, Manz MG, McClain K, Merad M, Allen CE |
BRAF-V600E expression in precursor versus differentiated dendritic cells defines clinically distinct LCH risk groups. |
The Journal of experimental medicine 2014 Apr 7; 211: 669 |
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| Langerhans cell histiocytosis (LCH) is a clonal disorder with elusive etiology, characterized by the accumulation of CD207(+) dendritic cells (DCs) in inflammatory lesions. Recurrent BRAF-V600E mutations have been reported in LCH. In this study, lesions from 100 patients were genotyped, and 64% carried the BRAF-V600E mutation within infiltrating CD207(+) DCs. BRAF-V600E expression in tissue DCs did not define specific clinical risk groups but was associated with increased risk of recurrence. Strikingly, we found that patients with active, high-risk LCH also carried BRAF-V600E in circulating CD11c(+) and CD14(+) fractions and in bone marrow (BM) CD34(+) hematopoietic cell progenitors, whereas the mutation was restricted to lesional CD207(+) DC in low-risk LCH patients. Importantly, BRAF-V600E expression in DCs was sufficient to drive LCH-like disease in mice. Consistent with our findings in humans, expression of BRAF-V600E in BM DC progenitors recapitulated many features of the human high-risk LCH, whereas BRAF-V600E expression in differentiated DCs more closely resembled low-risk LCH. We therefore propose classification of LCH as a myeloid neoplasia and hypothesize that high-risk LCH arises from somatic mutation of a hematopoietic progenitor, whereas low-risk disease arises from somatic mutation of tissue-restricted precursor DCs. |
| Bode SF, Bogdan C, Beutel K, Behnisch W, Greiner J, Henning S, Jorch N, Jankofsky M, Jakob M, Schmid I, Veelken N, Vraetz T, Janka G, Ehl S, Lehmberg K |
Hemophagocytic Lymphohistiocytosis in Imported Pediatric Visceral Leishmaniasis in a Nonendemic Area. |
The Journal of pediatrics 2014 May 2; |
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| To describe characteristics of visceral leishmaniasis-associated hemophagocytic lymphohistiocytosis (HLH) with focus on diagnostic clues and pitfalls, including the frequency of central nervous system (CNS) involvement, and to determine the efficacy of liposomal amphotericin B (L-AmB). |
| Bollini G, Jouve JL, Gentet JC, Jacquemier M, Bouyala JM |
Bone lesions in histiocytosis X. |
Journal of pediatric orthopedics 1991 Jul-Aug; 11: 469 |
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| Sixty-two patients with histiocytosis X were followed for an average of 5 years. The patients were classified into three groups: general visceral types (14 cases), multiple eosinophilic granulomas (nine cases), and solitary eosinophilic granulomas (39 cases). One hundred bony lesions were noted in 60 of the 62 patients. The bone lesions showed progressive improvement in single and multiple eosinophilic granulomas independent of treatment type. After biopsy, patients received no treatment unless there was a dangerous extension into the soft tissues because of its site, i.e., in the skull. In the general visceral types, chemotherapy was effective in visceral sites and in extensions of the tumor outside the bone but did not alter the natural history of the bony lesion. |
| Brady, LW, Heilmann, HP, Molls M, Nieder, C (eds) |
Radiotherapy for Non-Malignant Disorders. Chapter: Langerhans Cell Histiocytosis, ed. Olschewski,T, Seegenschmiedt,MH, Micke,O |
Springer Verlag 2008, 397 |
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| Bucau M, Dahan H, Meignin V, Toubert ME, Tazi A, Cochand-Priollet B |
FNA cytology revealing Langerhans cell histiocytosis and papillary thyroid carcinoma. |
Cytopathology : official journal of the British Society for Clinical Cytology 2014 Mar 25; |
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