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1.
Int J Hematol ; 112(4): 560-567, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32654047

RESUMO

In Langerhans cell histiocytosis (LCH), somatic gene mutations in the mitogen-activated protein kinase pathway have been identified in more than 80% of cases in Western countries, in which mutually exclusive BRAF and MAP2K1 mutations are involved. Among them, BRAF V600E mutation is the major contributor (50-60%). In 59 patients (50 children and nine adults) with LCH (not including pulmonary LCH) in Japan, we first screened for BRAF V600E in all patients followed by target sequencing for other gene mutations in 17 of BRAF V600E-negative patients. As a result, BRAF V600E mutation was detected in 27/59 (46%) patients. We also identified BRAF mutations other than V600E in five and MAP2K1 mutations in nine patients. Thus, gene mutations in BRAF or MAP2K1 were identified in 41/44 (93%) of the fully tested patients. Regarding the correlation of clinical features and genotype in pediatric patients, we found that BRAF V600E mutation status was not correlated with sex, age at diagnosis, disease extent, response to first-line therapy, relapse, or CNS-related sequelae. Interestingly, MAP2K1 exon 2 in-frame deletion was related to the risk organ involvement; however, further studies are required to clarify the impact of these gene mutations on the clinical features of patients with LCH.


Assuntos
Estudos de Associação Genética , Histiocitose de Células de Langerhans/genética , MAP Quinase Quinase 1/genética , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Japão , Sistema de Sinalização das MAP Quinases/genética , Masculino
2.
Virchows Arch ; 477(5): 749-753, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32372223

RESUMO

Langerhans cell histiocytosis (LCH) is characterized by mutations of the RAS-RAF-MAPK signaling pathway. We analyzed MAP2K1, NRAS and KIT mutation incidence in skin lesions of BRAF wild-type (wt) LCH patients. We evaluated the occurrence of MAP2K1, NRAS and KIT mutations in seven LCH and one indeterminate cell histiocytosis (ICH) patients. MAP2K1 mutation frequency was found to be 3/7 (42.9%) in LCH and also found in ICH. Similarly, the KIT mutation frequency was found to be equally prevalent (4/7, 57.1%) in LCH and also occurred in ICH. Involvement of KIT exons in LCH-ICH indicated that exon 9/11/18 were equally prevalent followed by exon 13. This exploratory analysis on BRAF-wt LCH revealed a KIT mutation rate comparable to MAP2K1. Although the detected KIT mutations are different from activating mutations found in other KIT-dependent neoplasms, our data suggest that KIT-inhibitors might have a role in treating BRAF-wt LCH patients.


Assuntos
Histiocitose de Células de Langerhans/genética , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-kit/genética , Dermatopatias/genética , Adolescente , Adulto , Idoso , Feminino , GTP Fosfo-Hidrolases/genética , Predisposição Genética para Doença , Histiocitose de Células de Langerhans/patologia , Histiocitose de Células de Langerhans/terapia , Humanos , Lactente , MAP Quinase Quinase 1/genética , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Taxa de Mutação , Fenótipo , Prognóstico , Dermatopatias/patologia , Dermatopatias/terapia , Adulto Jovem
3.
Blood ; 135(16): 1319-1331, 2020 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-32106306

RESUMO

Langerhans cell histiocytosis (LCH) is caused by clonal expansion of myeloid precursors that differentiate into CD1a+/CD207+ cells in lesions that leads to a spectrum of organ involvement and dysfunction. The pathogenic cells are defined by constitutive activation of the MAPK signaling pathway. Treatment of LCH is risk-adapted: patients with single lesions may respond well to local treatment, whereas patients with multisystem disease require systemic therapy. Although survival rates for patients without organ dysfunction is excellent, mortality rates for patients with organ dysfunction may reach 20%. Despite progress made in the treatment of LCH, disease reactivation rates remain above 30%, and standard second-line treatment is yet to be established. Treatment failure is associated with increased risks for death and long-term morbidity, including LCH-associated neurodegeneration. Early case series report promising clinical responses in patients with relapsed and refractory LCH treated with BRAF or MEK inhibitors, although potential for this strategy to achieve cure remains uncertain.


Assuntos
Histiocitose de Células de Langerhans/patologia , Histiocitose de Células de Langerhans/terapia , Animais , Histiocitose de Células de Langerhans/diagnóstico , Histiocitose de Células de Langerhans/genética , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Mutação/efeitos dos fármacos , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo
4.
Sci Rep ; 10(1): 2203, 2020 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-32042034

RESUMO

Susceptibility to diseases is common to humans and dinosaurs. Since much of the biological history of every living creature is shaped by its diseases, recognizing them in fossilized bone can furnish us with important information on dinosaurs' physiology and anatomy, as well as on their daily activities and surrounding environment. In the present study, we examined the vertebrae of two humans from skeletal collections with Langerhans Cell Histiocytosis (LCH), a benign osteolytic tumor-like disorder involving mainly the skeleton; they were diagnosed in life, along with two hadrosaur vertebrae with an apparent lesion. Macroscopic and microscopic analyses of the hadrosaur vertebrae were compared to human LCH and to other pathologies observed via an extensive pathological survey of a human skeletal collection, as well as a three-dimensional reconstruction of the lesion and its associated blood vessels from a µCT scan. The hadrosaur pathology findings were indistinguishable from those of humans with LCH, supporting that diagnosis. This report suggests that hadrosaurids had suffered from larger variety of pathologies than previously reported. Furthermore, it seems that LCH may be independent of phylogeny.


Assuntos
Dinossauros , Fósseis/patologia , Histiocitose de Células de Langerhans/veterinária , Coluna Vertebral/patologia , Adulto , Animais , Pré-Escolar , Fósseis/diagnóstico por imagem , Histiocitose de Células de Langerhans/diagnóstico , Histiocitose de Células de Langerhans/genética , Histiocitose de Células de Langerhans/patologia , Humanos , Imageamento Tridimensional , Masculino , Filogenia , Coluna Vertebral/diagnóstico por imagem , Microtomografia por Raio-X
6.
Am J Otolaryngol ; 41(2): 102369, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31870640

RESUMO

OBJECTIVE: Langerhans cell histiocytosis (LCH) is a rare clinical disorder. We retrospectively analysed the clinical manifestations, treatments and prognoses of LCH cases involving the ear, nose, and neck. MATERIALS AND METHODS: 28 cases with confirmed LCH in ear, nose or neck were reviewed. We recorded patient age, sex, chief complaints, accompanying symptoms, lesional sites, radiological data, treatments and pathologies. Whole-exome sequencing was performed on the patient diagnosed with LCH and Treacher-Collins syndrome (TCS). RESULTS: The mean age was 14.86 years. Most LCH was in the ear (93%), usually in the mastoid. The most common symptoms were an ear mass and a purulent discharge. Imaging was not very useful. Treatments included surgery, chemotherapy, and radioactive particle implantation. Some cases exhibited multisystem involvement. Most patients enjoyed good prognoses. One patient was diagnosed with both temporal LCH and TCS. Whole-exome sequencing revealed a heterozygous c.261_272delAGGTACCCTTCC(p.87_91delRGTLPinsR) mutation in exon 2 of the POLR1D gene (NM_015972). CONCLUSION: LCH mostly occurs in children. In head and neck it affects principally the mastoid part of the temporal bone. Treatments include surgery, chemotherapy, and irradiation. Most patients enjoy good prognoses. LCH accompanied by TCS is rare and increases the difficulty of diagnosis; molecular data aid in TCS identification.


Assuntos
Orelha , Histiocitose de Células de Langerhans , Pescoço , Nariz , Adolescente , Adulto , Terapia Combinada , RNA Polimerases Dirigidas por DNA/genética , Éxons/genética , Feminino , Histiocitose de Células de Langerhans/diagnóstico , Histiocitose de Células de Langerhans/genética , Histiocitose de Células de Langerhans/patologia , Histiocitose de Células de Langerhans/terapia , Humanos , Masculino , Processo Mastoide , Mutação , Prognóstico , Estudos Retrospectivos , Adulto Jovem
7.
Rinsho Ketsueki ; 60(9): 1308-1316, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31597857

RESUMO

Whether Langerhans cell histiocytosis (LCH) is an inflammatory disorder or a neoplasm is an ongoing debate. On the basis of the identification of the BRAF V600E mutation in 2010, LCH should be defined as an inflammatory myeloid neoplasia. Mutually exclusive BRAF V600E (50-60%) and MAP2K1 (12-25%) mutation renders the ERK activation. BRAF V600E mutations were detected in approximately 50-60% of patients with Erdheim-Chester disease (ECD), and these patients are being treated with vemurafenib, a selective BRAF V600 kinase inhibitor, approved by the US Food and Drug Administration. The Japan Langerhans cell histiocytosis study group-02 protocol study showed five-year overall survival rate of 92% and event-free survival of 46% in risk-organ involvement of positive multi-system LCH. We aimed to improve the quality of life by reducing relapses and development of late complications. It is essential to achieve a close cooperation between hematologists catering to pediatric and adult patients with LCH. Furthermore, novel targeted therapies of MAPK inhibitors are required along with intensified chemotherapy to achieve better outcomes in patients with LCH in Japan.


Assuntos
Histiocitose de Células de Langerhans/genética , Proteínas Proto-Oncogênicas B-raf/genética , Adulto , Criança , Intervalo Livre de Doença , Doença de Erdheim-Chester/tratamento farmacológico , Doença de Erdheim-Chester/genética , Humanos , Japão , Mutação , Qualidade de Vida , Taxa de Sobrevida , Vemurafenib/uso terapêutico
8.
PLoS One ; 14(9): e0222400, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31527903

RESUMO

Langerhans cell histiocytosis (LCH) is characterized by the accumulation of Langerin (CD207)-expressing histiocytes. Mutational activation of mitogen-activated protein kinase pathway genes, in particular BRAF, drives most cases. To test whether activated BRAF is sufficient for the development of LCH, we engineered mice to express BRAF V600E under the control of the human Langerin promoter. These mice have shortened survivals, smaller lymphoid organs, absent Leydig cells, and fewer epidermal LCs than controls, but do not accumulate histiocytes. To test whether the absence of histiocyte proliferation could be due to oncogene-induced senescence, we engineered homozygous Pten loss in the same cells that expressed BRAF V600E. Like mice with intact Pten, these mice have shortened survivals, smaller thymi, and absent Leydig cells. However, loss of Pten also leads to the accumulation of CD207+ histiocytes in spleen, thymus, and some lymph nodes. While many CD207+ histiocytes in the thymus are CD8-, reminiscent of LCH cells, the CD207+ histiocytes in the spleen and lymph nodes are CD8+. These mice also accumulate large numbers of CD207- cells in the lamina propria (LP) of the small intestine. Both the lymphoid and LP phenotypes are likely due to human Langerin promoter-driven BRAF V600E expression in resident CD8+ dendritic cells in the former and LP dendritic cells in the latter and confirm that Pten loss is required to overcome inhibitory pathways induced by BRAF V600E expression. The complex phenotype of these mice is a consequence of the multiple murine cell types in which the human Langerin promoter is active.


Assuntos
Histiócitos/patologia , Histiocitose de Células de Langerhans/genética , Histiocitose de Células de Langerhans/patologia , PTEN Fosfo-Hidrolase/genética , Proteínas Proto-Oncogênicas B-raf/genética , Deleção de Sequência/genética , Animais , Antígenos de Superfície/genética , Linfócitos T CD8-Positivos/patologia , Proliferação de Células/genética , Células Dendríticas/patologia , Humanos , Intestino Delgado/patologia , Masculino , Camundongos , Fenótipo , Regiões Promotoras Genéticas/genética
9.
Arch Pediatr ; 26(5): 301-307, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31281037

RESUMO

Langerhans cell histiocytosis (LCH) is characterized by inflammatory lesions containing abundant CD1a+ CD207+ histiocytes that lead to the destruction of affected tissues. This disease has a remarkable pleiotropic clinical presentation and most commonly affects young children. Although the current mortality rate is very low for childhood LCH patients (<2%), reactivation frequently occurs after a long period of disease control and the rates of permanent complications and sequelae remain high. Advances in genomic sequencing technologies in this past decade have highlighted somatic molecular alterations responsible for the disease in around 80% of childhood LCH cases. More than half of these cases harbored the BRAFV600E mutation, and most other mutations also concerned proteins involved in the MAPKinase pathway. In addition to improving what is known about the LCH pathology, this molecular knowledge provides opportunities to optimize patient management. The BRAFV600E mutation is associated with more severe presentations of the disease, a high reactivation rate, and a high permanent complication rate; this mutation therefore paves the way for future stratified management approaches. These therapies may be based on the patient's molecular status as well as other clinical characteristics of the disease that are independently associated with undesired events. Moreover, as observed in patients with solid tumors, the BRAFV600E allele can be detected in the circulating cell-free DNA of patients with severe BRAFV600E-mutated LCH. Quantification of the plasmatic BRAFV600E load for this group of patients can precisely monitor response to therapy. Finally, targeted therapies, such as BRAF inhibitors, are new therapeutic options especially designed for refractory multisystemic LCH involving risk organs. However, the long-term efficacy, long-term tolerance, optimal protocol scheme, and appropriate modalities of administration for these innovative therapies for children still need to be defined, a huge challenge.


Assuntos
Histiocitose de Células de Langerhans/tratamento farmacológico , Histiocitose de Células de Langerhans/genética , Terapia de Alvo Molecular , Inibidores de Proteínas Quinases/uso terapêutico , Criança , Marcadores Genéticos , Histiocitose de Células de Langerhans/diagnóstico , Histiocitose de Células de Langerhans/patologia , Humanos , Imidazóis/uso terapêutico , MAP Quinase Quinase 1/antagonistas & inibidores , MAP Quinase Quinase 1/genética , Mutação , Oximas/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/genética , Vemurafenib/uso terapêutico
10.
Virchows Arch ; 475(6): 795-798, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31317311

RESUMO

The traditional concept of unidirectional maturation of hematopoietic cells has been called into question due to the recognition of lineage plasticity, which is increasingly found also in the clonal evolution of hematopoietic and lymphoid malignancies. Here we present an unusual case of a patient with TP53-mutated chronic lymphocytic leukemia (CLL) treated with a PI3Kδ inhibitor evolving to clonally related Langerhans cell histiocytosis (LCH) with acquired BRAF V600E and STK11 mutations and loss of expression of PAX-5 and other examined B cell markers. In indolent B cell lymphoma, transformation to a more aggressive high-grade lymphoma occurs frequently during the course of disease and is thought to be caused by clonal evolution. Our case further supports the concept of significant lineage plasticity in lymphomas and raises the question of a potential role of novel pharmacologic agents in clonal evolution.


Assuntos
Evolução Clonal , Histiocitose de Células de Langerhans/patologia , Ilhotas Pancreáticas/patologia , Leucemia Linfocítica Crônica de Células B/patologia , Neoplasias Pancreáticas/patologia , Feminino , Histiocitose de Células de Langerhans/genética , Humanos , Leucemia Linfocítica Crônica de Células B/diagnóstico , Linfoma não Hodgkin/diagnóstico , Linfoma não Hodgkin/patologia , Pessoa de Meia-Idade
11.
BMC Cancer ; 19(1): 514, 2019 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-31142285

RESUMO

BACKGROUND: Crystal-storing histiocytosis (CSH) is a rare lesion characterized by sheets of crystal-laden non-neoplastic histiocytes. CSH shows a prominent association with lymphoproliferative disorders that express monoclonal immunoglobulins, mainly multiple myeloma (MM), lymphoplasmacytic lymphoma (LPL) and monoclonal gammopathy of undetermined significance (MGUS). However, no aggressive B cell lymphoma has been reported to be associated with CSH. CASE PRESENTATION: A 74-year-old Chinese woman presented with multiple subcutaneous masses, abdominal pain, and fever. An IgM kappa type of monoclonal gammopathy (MG) was noted by immunofixation performed on the patient's serum. Computed tomographic (CT) scan revealed subcutaneous masses on the left upper arm and at the waist and multiple low-density lesions in the spleen. Microscopically, sections of subcutaneous masses revealed sheets of large polygonal and spindle cells with abundant eosinophilic cytoplasm, round to ovoid eccentric nuclei, reticulate chromatin, and median nucleoli. Massive needle-shaped crystals were confined to the cytoplasm. Immunohistochemically, these crystal-containing cells were positive for CD68/PGM1, CD163, IgM, and Igκ. Meanwhile, the splenic tumour was diagnosed as diffuse large B-cell lymphoma (DLBCL), non-germinal-centre B (non-GCB) subtype (Hans algorithm). Immunohistochemistry for IgM was positive in the cytoplasm of some neoplastic cells. Immunoglobulin heavy chain (IgH) gene rearrangement was detected by PCR analysis of the subcutaneous mass and the splenic tumour. CONCLUSION: To the best of our knowledge, this is the first case of generalized CSH with DLBCL and MG. Although the rarity of CSH and separate locations of CSH and lymphoma led to a diagnostic dilemma, the presence of MG was a clue to appreciate the relation between CSH and DLBCL. This case stressed a full investigation into the underlying lymphoproliferative disorder for integrated diagnosis and correct treatments.


Assuntos
Histiocitose de Células de Langerhans/diagnóstico por imagem , Linfoma Difuso de Grandes Células B/diagnóstico por imagem , Paraproteinemias/diagnóstico por imagem , Idoso , Feminino , Rearranjo Gênico , Histiocitose de Células de Langerhans/genética , Histiocitose de Células de Langerhans/metabolismo , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/metabolismo , Paraproteinemias/genética , Paraproteinemias/metabolismo , Tomografia Computadorizada por Raios X
12.
Pediatr Dev Pathol ; 22(5): 449-455, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31072207

RESUMO

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.


Assuntos
Histiocitose de Células de Langerhans/genética , Histiocitose de Células de Langerhans/patologia , Proteínas Proto-Oncogênicas B-raf/genética , Adolescente , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Predisposição Genética para Doença , Humanos , Lactente , Recém-Nascido , Masculino , Mutação , Recidiva
13.
Acta pediatr. esp ; 77(3/4): e53-e56, mar.-abr. 2019. ilus
Artigo em Espanhol | IBECS | ID: ibc-188583

RESUMO

Introducción: La histiocitosis/reticulohistiocitosis congénita autolimitada (HCAL) es una variante infrecuente de histiocitosis de células de Langerhans presente de forma congénita o neonatal, de etiología desconocida. La presentación usualmente es múltiple, aunque en un 25% de los casos es solitaria. Caso clínico: Presentamos el caso de un neonato con una lesión localizada en el abdomen, caracterizada por una úlcera de 1 cm, cubierta por una costra amarilla-marrón fibrinoide con un borde bien definido, eritematoso y sobreelevado. El paciente presentaba un excelente estado general, sin otras lesiones ni presencia de adenopatías o visceromegalias. Se indicaron estudios para descartar una patología infecciosa y se realizó una biopsia cutánea. El estudio histopatológico e inmunohistoquímico confirmó el diagnóstico de HCAL. Resultados: Se descartaron lesiones extracutáneas. La lesión involucionó sin requerir tratamiento, resolviéndose de manera satisfactoria en 3 meses, sin afectación extracutánea hasta la fecha


Introduction: Congenital self-healing histiocytosis/reticulohistiocytosis (CSHH) is an infrequent variant of Langerhans cell histiocytosis present congenitally or neonatally. Etiology is unknown. The presentation is usually multiple, however in 25% of the cases the appearance would be solitary. Case report: We present the case of a neonate with a lesion located in the abdomen, characterized by a 1 cm ulcer, covered by a yellow-brown fibrinoid scab with a well-defined, erythematous and raised border. The patient was in excellent general condition, without other lesions, or the presence of lymphadenopathy or visceromegaly. Studies were indicated to rule out infectious pathology and a skin biopsy was performed. The histopathological and immunohistochemical study confirmed the diagnosis of CSHH. Results: Extracutaneous lesions were ruled out. The lesion involuted without requiring treatment resolving satisfactorily in 3 months, without extracutaneous commitment to date


Assuntos
Humanos , Masculino , Recém-Nascido , Histiocitose/congênito , Histiocitose/diagnóstico , Úlcera Cutânea/diagnóstico , Histiocitose de Células de Langerhans/patologia , Imuno-Histoquímica , Histiocitose de Células de Langerhans/diagnóstico , Histiocitose de Células de Langerhans/genética , Biópsia
14.
Ann Hematol ; 98(7): 1617-1626, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30923995

RESUMO

Langerhans cell histiocytosis (LCH) is a clonal histiocytic disorder with recurrent mutations of BRAF and MAP2K1, but data on the impact of genetic features on progression and long-term sequelae are sparse. Cases of pediatric LCH with long-term follow-up from our institution were analyzed for mutations in BRAFV600 and MAP2K1 exons 2 and 3 by immunostaining with mutation-specific VE1 antibody, as well as allele-specific PCR and sequencing, respectively. Clinical and follow-up data were obtained from our files and a questionnaire sent to all former patients. Sixteen of 37 (43%) evaluable cases showed BRAFV600E, one case a BRAFV600D and eleven (30%) a MAP2K1 mutation. Nine cases were unmutated for both genes. All cases with risk organ involvement showed either BRAFV600 or MAP2K1 mutation. Patients with BRAFV600 mutation excluding Hashimoto-Pritzker cases had a significantly higher risk for relapses (p = 0.02). Long-term sequelae were present in 19/46 (41%) patients (median follow-up 12.5 years, range 1.0 to 30.8) with a trend for higher rates in mutated cases (mutated = 9/17, 53% versus non-BRAFV600/MAP2K1 mutated = 2/7, 29%). In addition, 8/9 cases with skin involvement including all Hashimoto-Pritzker cases (n = 3) were positive for BRAFV600E. Infants below 2 years more frequently had BRAFV600 mutations (p = 0.013). Despite favorable prognosis, pediatric LCH shows a high frequency of relapses and long-term medical sequelae.


Assuntos
Histiocitose de Células de Langerhans/genética , MAP Quinase Quinase 1/genética , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Adolescente , Criança , Pré-Escolar , Feminino , Seguimentos , Histiocitose de Células de Langerhans/epidemiologia , Histiocitose de Células de Langerhans/patologia , Histiocitose de Células de Langerhans/terapia , Humanos , Lactente , Masculino , Estudos Retrospectivos , Fatores de Risco , Dermatopatias/epidemiologia , Dermatopatias/genética , Dermatopatias/patologia , Dermatopatias/terapia
15.
BMC Cancer ; 19(1): 170, 2019 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-30795755

RESUMO

BACKGROUND: Langerhans cell histiocytosis (LCH) is a rare clonal disease, characterized by hyperproliferation of Langerhans cells. It may rarely involve the thyroid gland. Its association with papillary thyroid carcinoma (PTC) is extremely rare; with only few case reports available in the English literature. BRAF mutations are implicated in the development of papillary thyroid carcinoma, and have also been identified in Langerhans cell histiocytosis. CASE PRESENTATION: Here we present a rare case of a 36-year-old Indonesian female patient with dysphagia associated with neck mass which was complicated by skin sinus formation. The diagnosis of PTC was rendered on fine needle aspiration (FNA). Debulking thyroidectomy revealed co-existeence of PTC and LCH. On subsequent molecular testing, BRAF V600E and V600K mutations were detected in tissues macrodissected from both lesions, respectively. To the best of our knowledge, this case is the first case to report two different BRAF mutations in tissues of a Langerhans cell histiocytosis and a papillary thyroid carcinoma co-existing in the thyroid gland. The patient received chemotherapy of etoposide combined with prednisone. At the most recent follow-up, the patient is in a stable clinical condition. CONCLUSIONS: The coexistence of a PTC with LCH harboring BRAF mutation may suggest etiologic relation between the two conditions that involves the BRAF gene. Clinically, it may suggest an aggressive, locally advanced thyroid cancer, an impression that may reflect on the selected surgical management, chemotherapy and BRAF mutation-targeting therapy to these patients.


Assuntos
Histiocitose de Células de Langerhans/diagnóstico , Mutação/genética , Proteínas Proto-Oncogênicas B-raf/genética , Câncer Papilífero da Tireoide/diagnóstico , Glândula Tireoide/patologia , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proliferação de Células , Procedimentos Cirúrgicos de Citorredução , Transtornos de Deglutição , Etoposídeo/uso terapêutico , Feminino , Histiocitose de Células de Langerhans/genética , Histiocitose de Células de Langerhans/terapia , Humanos , Prednisona/uso terapêutico , Câncer Papilífero da Tireoide/genética , Câncer Papilífero da Tireoide/terapia , Tireoidectomia
18.
Int J Cancer ; 144(1): 117-124, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30098202

RESUMO

Langerhans cell histiocytosis (LCH) is the most common histiocytosis with constitutive activation of the RAS-RAF-MEK-ERK (MAPKinase) cell signaling pathway. We analyzed 89 cases of BRAF and MAP2K1 mutations by Sanger sequencing, of which 18 cases showed that these two gene mutations are negative. Whole genome sequencing of suitable specimens in these negative cases revealed a translocation from the 3 intron of PLEKHA6 to the 13 intron of NTRK3 in one case. We identified that this translocation could cause a novel fusion mutation, PLEKHA6-NTRK3. Overexpression of the PLEKHA6-NTRK3 mutant in NIH 3T3 cells enhanced MAPKinase pathway activation, promote cell growth. Our result suggested that a new mutation need be included in LCH molecular screening panel to better define its prevalence in LCH.


Assuntos
Histiocitose de Células de Langerhans/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Receptor trkC/genética , Proteínas Recombinantes de Fusão/genética , Adolescente , Animais , Proliferação de Células/genética , Criança , Pré-Escolar , Feminino , Histiocitose de Células de Langerhans/patologia , Humanos , Lactente , Masculino , Camundongos , Mutação , Células NIH 3T3
19.
J Dermatol ; 46(2): 161-165, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30536719

RESUMO

Histiocytoses, including Langerhans cell histiocytosis (LCH), juvenile or adult xanthogranuloma (AXG) and Rosai-Dorfman disease (RDD), are rare disorders characterized by the proliferation of cells derived from monocyte/macrophage lineages. A few cases of LCH coexisting with xanthogranuloma or RDD have been reported. The etiology of these diseases remains unclear. However, oncogenic BRAFV 600E mutations have been identified in LCH. Here, we report the case of a 26-year-old Japanese man with a 3-month history of a solitary occipital nodule. No abnormality was detected in his other organs, and a total resection of the nodule was performed. Histopathological examination revealed the coexistence of LCH and AXG with prominent emperipolesis characteristic of RDD. Immunohistochemistry showed that most of the large histiocytes were positive for CD68, weakly positive or negative for S100, and negative for CD207 and CD1a, supporting the diagnosis of AXG. The tumor cells with emperipolesis did not show S100-positive findings characteristic of RDD. The focally aggregated oval histiocytic cells were positive for CD1a, CD207, CD68 and S100, and were compatible with the immunophenotype of LCH cells. In addition, these cells were positive for BRAFV 600E mutation. The tumor cells in our patient exhibited a cellular morphology characteristic of multiple histiocytoses in a solitary cutaneous nodule, which may imply an etiological association among LCH, AXG and RDD. To our knowledge, this is the first report of a BRAFV 600E mutation-positive case of LCH coexisting with AXG. Because patients with BRAFV 600E mutation have higher risks of multisystemic LCH and recurrence, we should carefully follow up the patient.


Assuntos
Histiocitose de Células de Langerhans/diagnóstico , Células de Langerhans/patologia , Xantogranuloma Necrobiótico/diagnóstico , Proteínas Proto-Oncogênicas B-raf/genética , Adulto , Histiocitose de Células de Langerhans/complicações , Histiocitose de Células de Langerhans/genética , Histiocitose de Células de Langerhans/patologia , Humanos , Masculino , Xantogranuloma Necrobiótico/complicações , Xantogranuloma Necrobiótico/genética , Xantogranuloma Necrobiótico/patologia
20.
Am J Dermatopathol ; 41(1): 29-36, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30252693

RESUMO

Langerhans cell (LC) histiocytoma is a neonatal tumor that often consists of a single, ulcerated nodule. Systemic involvement is rare, and LC histiocytoma is considered to be a variant of congenital, self-healing LC histiocytosis (also referred to as Hashimoto-Pritzker disease). In view of its low prevalence, LC histiocytoma is not always diagnosed in a clinical examination and requires histological confirmation. Furthermore, the histological and molecular features of LC histiocytoma have not been well characterized. Here, we report on 6 cases of this rare disease and review the corresponding literature. LC histiocytoma differs from classical self-healing LC histiocytosis with regard to the pathological features; we found that LC histiocytoma was associated with massive infiltration by histiocytes of various sizes and shapes (although often large) throughout the dermis and the superficial subcutis. Epidermotropism was rare, mitotic figures were not inconspicuous, and necrotic or calcified areas were often present. Immunohistochemical assessment revealed a mixture of different types of histiocytes (with CD1a CD207, CD1a CD207, and CD1a CD207 CD163 cells). Genetic testing was performed in 5 cases; it revealed a BRAF mutation (p.V600E and p.485_490delinsF) in 2 cases, a HRAS mutation (p.T58I) in 1 case, a combination of 2 PTEN mutations in another case (p.I224M and p. R234W), and no mutations in the fifth case. All the lesions regressed spontaneously, and none recurred during follow-up.


Assuntos
Histiócitos/patologia , Histiocitoma Fibroso Benigno/patologia , Histiocitose de Células de Langerhans/patologia , Células de Langerhans/patologia , Neoplasias Cutâneas/patologia , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Feminino , Predisposição Genética para Doença , Histiócitos/química , Histiocitoma Fibroso Benigno/química , Histiocitoma Fibroso Benigno/genética , Histiocitose de Células de Langerhans/genética , Histiocitose de Células de Langerhans/metabolismo , Humanos , Lactente , Recém-Nascido , Células de Langerhans/química , Masculino , Mutação , Regressão Neoplásica Espontânea , Fenótipo , Neoplasias Cutâneas/química , Neoplasias Cutâneas/genética
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