Histiocytosis | Medicina Clínica (English Edition)

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(A) Las células de Langerhans son monótonas con núcleo hendido y citoplasma amplio (H&E 400x). (B) Expresión variable para S-100 con positividad nuclear y citoplasmática (400x). (C) Positividad intensa de membrana para CD1a (400x). (D) Pápulas eritematosas confluentes en paladar duro de aspecto brillante y translucido, que corresponden a infiltración por histiocitosis. (E) Radiografía ósea simple con lesión osteolítica en fémur distal. (F) TC torácica de alta resolución con lesiones quísticas intrapulmonares y pequeños nódulos centrolobulillares." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Gemma Rocamora-Blanch, Fina Climent, Xavier Solanich" "autores" => array:3 [ 0 => array:2 [ "nombre" => "Gemma" "apellidos" => "Rocamora-Blanch" ] 1 => array:2 [ "nombre" => "Fina" "apellidos" => "Climent" ] 2 => array:2 [ "nombre" => "Xavier" "apellidos" => "Solanich" ] ] ] ] ] "idiomaDefecto" => "es" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "S238702062300311X" "doi" => "10.1016/j.medcle.2023.05.009" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S238702062300311X?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0025775323002208?idApp=UINPBA00004N" "url" => "/00257753/0000016100000004/v1_202308141143/S0025775323002208/v1_202308141143/es/main.assets" ] ] "itemSiguiente" => array:19 [ "pii" => "S2387020623003145" "issn" => "23870206" "doi" => "10.1016/j.medcle.2023.04.018" "estado" => "S300" "fechaPublicacion" => "2023-08-25" "aid" => "6267" "copyright" => "Elsevier España, S.L.U." 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Amber colour reflects complement activation by different pathways; green colour reflects complement regulatory factors; red colour shows the main pathway and complement molecules involved in the pathogenesis of neutrophil anti-cytoplasmic antibody-associated vasculitis; (X red) deficiency of factor H. Ag-Ac: antigen-antibody; ANCA: anti-neutrophil anti-cytoplasmic antibody. The colours in the figure are only available in the electronic version of the journal." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Manuel Heras Benito" "autores" => array:1 [ 0 => array:2 [ "nombre" => "Manuel" "apellidos" => "Heras Benito" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0025775323002191" "doi" => "10.1016/j.medcli.2023.04.007" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0025775323002191?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020623003108?idApp=UINPBA00004N" "url" => "/23870206/0000016100000004/v1_202308280911/S2387020623003108/v1_202308280911/en/main.assets" ] "en" => array:20 [ "idiomaDefecto" => true "cabecera" => "Review" "titulo" => "Histiocytosis" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "166" "paginaFinal" => "175" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Gemma Rocamora-Blanch, Fina Climent, Xavier Solanich" "autores" => array:3 [ 0 => array:4 [ "nombre" => "Gemma" "apellidos" => "Rocamora-Blanch" "email" => array:1 [ 0 => "grocamora@bellvitgehospital.cat" ] "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "Fina" "apellidos" => "Climent" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] 1 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] ] ] 2 => array:3 [ "nombre" => "Xavier" "apellidos" => "Solanich" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Servicio de Medicina Interna, Hospital Universitari de Bellvitge, L’Hospitalet de Llobregat, Barcelona, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Instituto de Investigación Biomédica de Bellvitge (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Servicio de Anatomía Patológica, Hospital Universitari de Bellvitge, L’Hospitalet de Llobregat, Barcelona, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Histiocitosis" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1847 "Ancho" => 2925 "Tamanyo" => 879992 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0130" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Langerhans cell histiocytosis. (A) Langerhans cells have a monotonous morphology with a cleaved nucleus and large cytoplasm (H&E 400×). (B) Variable expression for nuclear/cytoplasmic positive S-100 (400×). (C) Intense CD1a-positive membrane (400×). (D) Confluent erythematous papules on the hard palate with a shiny, translucent appearance, corresponding to infiltration by histiocytosis. (E) Plain bone X-ray with osteolytic lesion in the distal femur. (F) High resolution thoracic CT scan with intrapulmonary cystic lesions and small centrilobular nodules." ] ] ] "textoCompleto" => "IntroductionHistiocytoses are a group of diseases characterised by the proliferation of macrophages and dendritic cells in different tissues, resulting in tissue damage.<a class="elsevierStyleCrossRefs" href="#bib0005">1,2</a>There are about 100 subtypes of histiocytosis. The first classification of histiocytoses was published in 1987 by the Working Group of the Histiocyte Society and consisted of 3 categories based on histological features: Langerhans cell-related, non-Langerhans cell-related and malignant histiocytoses. In 2016, the Histiocyte Society published a new classification dividing histiocytoses into 5 groups based on clinical, radiological, pathological, phenotypic and molecular characteristics (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<a class="elsevierStyleCrossRefs" href="#bib0010">2,3</a><elsevierMultimedia ident="tbl0005"></elsevierMultimedia>The different histiocytoses are considered rare diseases, although their epidemiology is not well established.<a class="elsevierStyleCrossRef" href="#bib0020">4</a> The clinical manifestations are highly variable, ranging from mild forms with single organ involvement to severe, life-threatening multisystemic forms. Due to its rarity and diversity of presentation, reaching a definitive diagnosis can be difficult and there is often a significant diagnostic delay.<a class="elsevierStyleCrossRefs" href="#bib0005">1,4,5</a> There is a need for these patients to be cared for in multidisciplinary units with expertise in this type of disease.In this review we will focus on the most common histiocytoses among adults: Langerhans cell histiocytosis (LCH), Erdheim-Chester disease (ECD) and Rosai-Dorfman disease (RDD). These 3 entities have a similar pathophysiology with accumulation of clonal mononuclear phagocytes, although the pathological cell has a different origin or phenotype in each of these processes.<a class="elsevierStyleCrossRef" href="#bib0015">3</a> These 3 types of histiocytosis pose a major diagnostic challenge given their rarity, overlapping and coexistence with other haematological malignancies. In patients with unexplained cytopenias, bone marrow biopsy should be considered because of possible concomitant bone marrow processes, such as haemophagocytic lymphohistiocytosis or myeloid neoplasms.<a class="elsevierStyleCrossRefs" href="#bib0030">6,7</a>Immunohistochemical (IHC) analysis plays a key role in the diagnosis and should be performed when histiocytosis is suspected. The basic IHC panel should include CD163/CD68, S100, CD1a, langerin/CD207 and factor xiiia as indicated.<a class="elsevierStyleCrossRef" href="#bib0025">5</a> Carcinoma, melanoma, lymphoma and sarcoma markers can be useful for differential diagnosis.<a class="elsevierStyleCrossRef" href="#bib0040">8</a> In addition, IHC can detect the presence of BRAF V600E (VE1) or ALK<a class="elsevierStyleCrossRef" href="#bib0045">9</a> rearrangements (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>).<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>Molecular pathology studies of these neoplasms frequently show mutations in the MAPK/ERK (mitogen-activated protein kinase) pathway. A small subset of cases shows activation of the phosphoinositide 3-kinase (PI3K) (PI3K/AKT) pathway. Next generation sequencing (NGS) studies of tumour tissue can identify mutations in the genes of these pathways, which is useful for diagnosis and therapeutic decision-making. The study of somatic mutations and fusions can be performed in a staggered or parallel manner, depending on the clinical needs and protocols of each centre. Polymerase chain reaction specific for the BRAF V600E allele is recommended if IHC is not available, or if the result is equivocal or negative. If no mutation in BRAF is detected, an NGS panel including the rest of the genes involved in the pathogenesis of these entities should be performed. The study of fusions using an RNA-based molecular panel should cover the BRAF, ALK and NTRK1 rearrangements.<a class="elsevierStyleCrossRefs" href="#bib0025">5,7,9</a> Peripheral blood NGS studies are an alternative if biopsy of the affected tissue is not feasible.<a class="elsevierStyleCrossRef" href="#bib0025">5</a> The study of molecular alterations can be useful for diagnosis, has prognostic implications and can help in making therapeutic decisions. The presence of molecular alterations typical of ECD is key to the diagnosis in those patients who do not present with typical clinical features<a class="elsevierStyleCrossRef" href="#bib0050">10</a> (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>).Due to the paucity of prospective studies in adults, the evidence supporting the treatment of histiocytosis is largely based on small retrospective studies, case series, or extrapolation from prospective studies in children. Increased understanding of its pathogenesis over the last decade has led to the development of targeted therapeutic strategies that have shown very satisfactory results.<a class="elsevierStyleCrossRef" href="#bib0035">7</a> However, none of these drugs has been approved by the health authorities, so their use is off-label.Langerhans cell histiocytosisIntroduction/epidemiologyLCH is a rare heterogeneous histiocytic neoplasm that can occur at any age, although it is more common in children (<15 years), with 5–9 cases per million, than in adults (>15 years), with 1−2 cases per million.<a class="elsevierStyleCrossRefs" href="#bib0035">7,11</a> Latino children have been reported to be at higher risk of developing this disease.<a class="elsevierStyleCrossRef" href="#bib0060">12</a>Clinical manifestationsAlthough some cases are mild and/or asymptomatic, LCH is a life-threatening disease that can progress rapidly or be refractory to treatment or present with isolated single organ or multisystem involvement.<a class="elsevierStyleCrossRef" href="#bib0005">1</a> Organs typically affected in LCH are bone (80%), skin (33%), pituitary gland (25%), liver (15%), spleen (15%), bone marrow (15%), lungs (15%), lymph nodes (5%–10%) and central nervous system (CNS) (excluding pituitary gland) (2%–4%).<a class="elsevierStyleCrossRefs" href="#bib0015">3,13,14</a> Life-threatening organs are considered to be the liver, spleen, heart and CNS.<a class="elsevierStyleCrossRef" href="#bib0005">1</a>Patients with LCH may present with constitutional symptoms such as fever, night sweats, fatigue or myalgias. Multifocal bone involvement has been described without manifestations in other organs. Bone lesions are typically lytic and cortical (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).<a class="elsevierStyleCrossRefs" href="#bib0010">2,7</a> These bone injuries can cause pain.<a class="elsevierStyleCrossRef" href="#bib0015">3</a> Cutaneous involvement may present as an erythematous rash, subcutaneous nodules or xanthelasmas. Although there are cases of LCH affecting only the CNS, it is often accompanied by multisystem disease.<a class="elsevierStyleCrossRef" href="#bib0035">7</a> Endocrine disorders such as diabetes insipidus are common in LCH.<a class="elsevierStyleCrossRef" href="#bib0075">15</a> LCH-associated neurodegeneration (ND-LCH) is a serious complication that can develop rapidly or years after the diagnosis of LCH. Cerebellar dysfunction typically occurs as a consequence of cerebellar or brainstem involvement.<a class="elsevierStyleCrossRefs" href="#bib0080">16,17</a> Bone lesions in the mastoid, sphenoid, orbit, temporal bone and clivus are associated with an increased risk of CNS involvement.<a class="elsevierStyleCrossRef" href="#bib0090">18</a> The risk of developing ND-LCH is higher in individuals with BRAF V600E compared to patients without mutation.<a class="elsevierStyleCrossRef" href="#bib0095">19</a> The pulmonary form of LCH is typical of adults and is associated with smoking. The most characteristic lung involvement consists of nodular cystic lesions predominantly in the upper lobes.<a class="elsevierStyleCrossRefs" href="#bib0010">2,5,7,11</a>,<a class="elsevierStyleCrossRefs" href="#bib0075">15,20</a> In disseminated forms, the liver (hepatomegaly, acute hepatitis or sclerosing cholangitis in chronic forms), spleen (diffusely infiltrated or focal lesions, clinically manifesting as splenomegaly) and/or bone marrow (may present with cytopenias) are usually affected. The gastrointestinal tract can be affected at any location. In the mouth, it can affect the gums, causing tooth loss.<a class="elsevierStyleCrossRef" href="#bib0015">3</a><elsevierMultimedia ident="fig0005"></elsevierMultimedia>DiagnosisIt is based on clinical manifestations, radiological findings and pathological anatomy. A biopsy of the affected tissue is necessary in all cases as definitive diagnosis requires identification of the LCH cell population, and also because of its therapeutic implications.<a class="elsevierStyleCrossRefs" href="#bib0010">2,7</a>Initial diagnostic tests depend on the clinical manifestations. Whole body FDG-PET/CT should be considered for patients with suspected multisystem disease as it is superior to all other imaging techniques for the detection of active lesions, with the exception of lung lesions.<a class="elsevierStyleCrossRef" href="#bib0105">21</a> Even in the absence of neurological symptoms, we may be confronted with an abnormal brain magnetic resonance imaging (MRI) scan.<a class="elsevierStyleCrossRef" href="#bib0035">7</a> In cases with diabetes insipidus, the first change observed on MRI may be an enlargement of the pituitary stalk with T1 hypointensity, which may later extend to the rest of the pituitary and hypothalamus. Signal changes in grey or white matter with cortical atrophy can be observed in ND-LCH.<a class="elsevierStyleCrossRef" href="#bib0090">18</a> Brain MRI findings may mimic primary CNS tumours, brain metastases or inflammatory granulomatous diseases.<a class="elsevierStyleCrossRef" href="#bib0035">7</a> A high-resolution chest computed tomography (CT) can detect lung nodules in early stages, and irregular cysts can be observed in later stages.<a class="elsevierStyleCrossRef" href="#bib0025">5</a> Functional respiratory testing should be considered to assess for obstructive airway disease, air trapping and DLCO.<a class="elsevierStyleCrossRef" href="#bib0075">15</a>LCH lesions often show histiocytes mixed with a significant infiltration of inflammatory cells. On haematoxylin and eosin (H&E) staining, neoplastic LCH cells are mononucleated, typically with a coffee bean-shaped nucleus. Binucleated or multinucleated cells with the typical Langerhans cell cleft can be identified. Abundant eosinophils are often, but not always, observed. If very prominent they may produce micro-abscesses with Charcot-Leyden crystals.<a class="elsevierStyleCrossRef" href="#bib0010">2</a> Fibrosis may develop, particularly in the bone. IHC is characterised by the presence of CD1a and CD207 (langerin) positives. Langerhans cells are also positive for S100.<a class="elsevierStyleCrossRefs" href="#bib0015">3,7</a> Activation of the MAPK pathway is universal in all patients with LCH<a class="elsevierStyleCrossRefs" href="#bib0045">9,22–25</a> (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>). The BRAF V600E mutation is more commonly detected in younger patients, and is associated with increased severity, multisystem involvement and recurrence.<a class="elsevierStyleCrossRef" href="#bib0055">11</a> The same somatic mutation is identified in each of the patient's LCH lesions, and in case of recurrence, the original mutation is detected again.<a class="elsevierStyleCrossRef" href="#bib0015">3</a>TreatmentTreatment decisions should be made on the basis of the sites affected and the extent of the disease.<a class="elsevierStyleCrossRef" href="#bib0075">15</a> Spontaneous remissions have been documented, so a watchful waiting approach may be reasonable in asymptomatic cases without organ dysfunction.<a class="elsevierStyleCrossRef" href="#bib0045">9</a>In the presence of a unifocal bone lesion, a watchful waiting approach may be appropriate if the lesions are asymptomatic and isolated. It should be treated if the injury is located in a load-bearing area, causes deformity, there is a risk of spinal cord compression or there is a risk of CNS involvement. If the lesion is small (<5cm), curettage is recommended, avoiding radical excision because of the risk of permanent deformity. Glucocorticoid infiltrations may be effective. Radiotherapy may be considered in patients with ≤2 bone lesions if they are not surgically treatable or if they recur after surgery. Bisphosphonates for the treatment of multifocal bone disease are supported by small retrospective studies and case series.<a class="elsevierStyleCrossRef" href="#bib0130">26</a> In large lesions (>5cm), ≥2 bone lesions or lesions with a difficult-to-access location, systemic treatment is indicated.<a class="elsevierStyleCrossRefs" href="#bib0005">1,9,15</a>Isolated skin involvement may resolve spontaneously and a watchful waiting attitude can be maintained.<a class="elsevierStyleCrossRef" href="#bib0135">27</a> Surgery should only be performed for solitary lesions, and only if surgery will not cause disfigurement. If treatment is necessary, topical treatments such as psoralen with ultraviolet light,<a class="elsevierStyleCrossRef" href="#bib0140">28</a> or topical nitrogen<a class="elsevierStyleCrossRef" href="#bib0145">29</a> can be administered. If this is not sufficient or if the skin involvement is extensive, glucocorticoids can be used, sometimes in combination with methotrexate, hydroxyurea or thalidomide.<a class="elsevierStyleCrossRefs" href="#bib0005">1,9</a>Most cases of lung involvement improve after quitting smoking. Systemic treatment should be initiated if lung involvement is symptomatic, progressive or persists after smoking cessation. Prednisone may be effective,<a class="elsevierStyleCrossRef" href="#bib0075">15</a> with radiographic improvements, but there may be no improvement in respiratory function.<a class="elsevierStyleCrossRef" href="#bib0150">30</a> In extensive involvement or progression despite the above measures, systemic treatment should be initiated. More severe cases may require lung transplantation.<a class="elsevierStyleCrossRefs" href="#bib0005">1,3</a>Systemic treatment is indicated in LCH with multisystem involvement, multifocal/large/difficult-to-access bone lesions, isolated life-threatening organ lesions or risk of CNS involvement (facial lesions), and lung involvement that does not resolve with smoking cessation (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>). Systemic treatment in adults is not as well established as in paediatrics.<a class="elsevierStyleCrossRef" href="#bib0075">15</a> Vinblastine/prednisone is the standard treatment in children, but its efficacy is lower in adults (overall response rate [ORR] of 26%).<a class="elsevierStyleCrossRef" href="#bib0155">31</a> In adults, regimens with cytarabine (ORR: 79%),<a class="elsevierStyleCrossRef" href="#bib0155">31</a> cladribine (ORR: 75%–79%),<a class="elsevierStyleCrossRefs" href="#bib0160">32,33</a> or cytarabine/methotrexate (ORR: 87%)<a class="elsevierStyleCrossRef" href="#bib0170">34</a> have shown greater efficacy. Cytarabine is the least toxic of the 3 regimens, with serious adverse events occurring in 20%, compared to 37% and 75% with cladribine and vinblastine/prednisone, respectively.<a class="elsevierStyleCrossRef" href="#bib0045">9</a><elsevierMultimedia ident="tbl0015"></elsevierMultimedia>The discovery of BRAF V600E and other mutations that hyperactivate the MAPK/ERK pathway has led to the incorporation of targeted therapies. The VE-BASKET trial evaluated the efficacy of vemurafenib, an BRAF inhibitor. Twenty-six adults with LCH (4 patients) and ECD (22 patients) with the BRAF V600E mutation, with an ORR of 61.5%<a class="elsevierStyleCrossRef" href="#bib0175">35</a> were included. A metabolic response measured with FDG-PET/CT was achieved in all patients. In this trial all patients required dose reduction due to toxicities that in some cases were severe. Dabrafenib (a second-generation BRAF inhibitor) with a better safety profile has shown good results in case series. A phase ii trial evaluated cobimetinib (MEK inhibitor) for the treatment of systemic histiocytosis, irrespective of the presence of somatic mutations. Eighteen adult patients with histiocytosis (12 ECD, 2 LCH, 2 RDD, 2 mixed) with an 89% ORR were included.<a class="elsevierStyleCrossRef" href="#bib0180">36</a> The most common adverse events leading to dose reduction were decreased ejection fraction, rash and diarrhoea. Other targeted therapies have been evaluated depending on the molecular alteration detected<a class="elsevierStyleCrossRef" href="#bib0045">9</a> (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>). The optimal duration and dose of MAPK/ERK inhibitor treatment is not well established.<a class="elsevierStyleCrossRef" href="#bib0015">3</a>For the treatment of relapses or refractory LCH, it is recommended to use a different drug than the one initially used. In selected refractory cases, haematopoietic stem cell transplantation may be considered.<a class="elsevierStyleCrossRef" href="#bib0005">1</a>Erdheim-Chester's diseaseIntroduction/epidemiologyIt is a rare histiocytic neoplasm affecting mostly adults (mean age 55 years) and predominantly male (3:1). Childhood onset is exceptional.<a class="elsevierStyleCrossRefs" href="#bib0015">3,37</a> From its description in 1930 to the present day, about 1500 cases have been published.<a class="elsevierStyleCrossRef" href="#bib0015">3</a> The median time from onset to diagnosis is very high (2.7 years in a series of 261 patients).<a class="elsevierStyleCrossRef" href="#bib0050">10</a> Up to 20% of patients with ECD may have concomitant lesions typical of LCH.<a class="elsevierStyleCrossRef" href="#bib0190">38</a>Clinical manifestationsAlthough there are cases of unifocal and/or asymptomatic disease, it usually manifests as a multisystemic and potentially fatal disease. The prognosis depends mainly on the organs involved. CNS and cardiovascular involvement are associated with a worse prognosis.<a class="elsevierStyleCrossRef" href="#bib0050">10</a>Constitutional symptoms such as fever, night sweats, fatigue or myalgias may occur. Bone involvement is the most common manifestation (80%–95%) and is secondary to long bone osteosclerosis of the metaphysis and diaphysis (mainly in the lower limbs) (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>). These lesions may be asymptomatic or cause pain.<a class="elsevierStyleCrossRefs" href="#bib0050">10,39</a> The most common cardiovascular involvement is thickening of the aorta (coated aorta). Periaortic infiltration can involve the thoracic and abdominal portions and can extend into the main branches. It is usually asymptomatic and is not associated with aneurysm or dissection.<a class="elsevierStyleCrossRef" href="#bib0050">10</a> Retroperitoneal fibrosis is seen in one third of patients and may be complicated by bilateral ureterohydronephrosis. In ECD, fibrosis completely surrounds the aorta, compared to idiopathic retroperitoneal fibrosis, where the posterior wall of the aorta is rarely affected.<a class="elsevierStyleCrossRef" href="#bib0050">10</a> Up to 63% of patients may have fatty infiltration around the kidneys (“hairy kidney” sign), a manifestation rarely seen in RDD and not described in LCH.<a class="elsevierStyleCrossRefs" href="#bib0050">10,40</a> Adrenal hypertrophy may be observed if perirenal infiltration extends to the adrenal gland. Coronary infiltration is seen in 23% of patients and can be complicated by coronary stenosis and acute myocardial infarction.<a class="elsevierStyleCrossRefs" href="#bib0050">10,40</a> Pericardial involvement is common (29%) and may develop as pericardial thickening and/or effusion. Infiltration/pseudotumor (36%) is characteristic, typically involving the right coronary sulcus and right atrial wall.<a class="elsevierStyleCrossRefs" href="#bib0050">10,40</a> Pulmonary involvement has been reported in up to 30%−50% of cases.<a class="elsevierStyleCrossRef" href="#bib0200">40</a> Pleural, parenchymal involvement with interstitial pattern, thickening of interlobular septa, or more rarely with micronodules, ground-glass opacities, parenchymal consolidation, and cysts have been described. It affects the nervous system in up to 55% of cases. The most common manifestations are cerebellar syndromes (41%) or pyramidal syndromes (45%), although they may also manifest as headache, seizures, sensory disturbances, neuropsychiatric symptoms, cognitive impairment, facial paralysis.<a class="elsevierStyleCrossRefs" href="#bib0015">3,10</a> Degenerative cerebellar involvement is seen in 17% of patients and is often refractory to treatment. Diabetes insipidus (25%) is usually among the first manifestations and may precede the diagnosis by years. In patients with pituitary dysfunction, growth hormone deficiency, hyperprolactinaemia, FSH and LH deficiency, TSH or adrenal hormone deficiency may be detected.<a class="elsevierStyleCrossRef" href="#bib0050">10</a> Intracranial artery involvement has also been reported and may lead to ischaemia. A quarter of patients develop exophthalmos due to retro-orbital soft tissue infiltration. Sinus infiltration is also common (mainly maxillary and sphenoidal).<a class="elsevierStyleCrossRef" href="#bib0205">41</a> Xanthelasmas are common as cutaneous symptoms, (22%), classically periorbital. Non-specific plaques or papulonodular lesions may also be observed, mainly affecting the lower limbs, back and/or trunk.<a class="elsevierStyleCrossRefs" href="#bib0200">40,42</a> Gum infiltration and dental involvement, enteropathy and secondary sclerosing cholangitis have also been reported. Rarely, infiltration of organs such as lymph nodes, breast, pancreas or thyroid may be observed.<a class="elsevierStyleCrossRef" href="#bib0050">10</a><elsevierMultimedia ident="fig0010"></elsevierMultimedia>Concomitant myeloid neoplasm may occur in 3%–10% of ECDs<a class="elsevierStyleCrossRef" href="#bib0050">10</a> and is more common in older males. Cases of macrophage activation syndrome have been reported, associating a worse outcome.DiagnosisIt is based on clinical manifestations, radiological findings and pathological anatomy.<a class="elsevierStyleCrossRef" href="#bib0050">10</a> Patients with the BRAF V600E mutation are more likely to have cerebellar involvement, diabetes insipidus, retro-orbital infiltration and cardiac manifestations, especially pseudotumours in the right atrium.<a class="elsevierStyleCrossRefs" href="#bib0030">6,40</a>The multisystemic nature of this disease requires a thorough physical examination. A neurocognitive study may be necessary in selected cases. Full body FDG-PET/CT (including lower limbs) assesses bone involvement better than techniques such as scintigraphy, and also allows assessment of other organ involvement.<a class="elsevierStyleCrossRefs" href="#bib0050">10,39</a> Gadolinium MRI is a very useful test to assess CNS involvement. Common findings include dural thickening, cerebellar and brainstem hyperintensities, white matter enhancement and pituitary stalk thickening. Diabetes insipidus is almost always irreversible, although radiological infiltration of the pituitary may decrease with treatment.<a class="elsevierStyleCrossRef" href="#bib0215">43</a> Cerebrospinal fluid analysis is usually normal.<a class="elsevierStyleCrossRef" href="#bib0050">10</a> Very characteristic lesions such as circumferential thickening of the aorta (“coated aorta”) or other arteries, as well as infiltration of the renal capsule with the characteristic “hairy kidney” sign can be observed on CT. Cardiac involvement should be assessed with echocardiography and/or cardiac MRI.<a class="elsevierStyleCrossRef" href="#bib0050">10</a>Histological study shows the presence of sheets of epithelioid histiocytes in early lesions that become more xanthomatous with Touton-type giant cells. Fibrosis is an important component in most sites, as is lymphocyte aggregation. Less common are eosinophils, neutrophils and plasma cells. On IHC the histiocytes are CD68+ CD163+ FXIIIa+, CD1a- (non-Langerhans cell histiocytes) and CD207- (langerin).<a class="elsevierStyleCrossRef" href="#bib0050">10</a> The possible presence of S100-positive cells with emperipolesis poses a challenge in distinguishing ECD from RDD. Most of the somatic mutations typical of ECD overlap greatly with those described in patients with LCH<a class="elsevierStyleCrossRef" href="#bib0045">9</a> (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>).TreatmentThe multisystemic nature of ECD often requires systemic therapy. Nevertheless, in asymptomatic patients without critical organ involvement (heart and CNS), a watchful waiting approach can be followed. In contrast to LCH, no cases of spontaneous resolution of the disease have been observed.<a class="elsevierStyleCrossRef" href="#bib0015">3</a>Since the identification of the BRAF V600E mutation in patients with ECD, excellent results have been reported with BRAF inhibitors (see the “Treatment of LCH” section).<a class="elsevierStyleCrossRefs" href="#bib0050">10,23,44</a> Observational studies indicate that the efficacy of these drugs is maintained,<a class="elsevierStyleCrossRef" href="#bib0225">45</a> and that doses lower than those recommended in the SmPC are able to prevent progression with a lower rate of adverse effects.<a class="elsevierStyleCrossRef" href="#bib0230">46</a> Dabrafenib also appears to be effective with a less toxic profile than vemurafenib.<a class="elsevierStyleCrossRef" href="#bib0235">47</a> As discussed above, cobimetinib was shown to be highly effective in patients with ECD, regardless of whether any mutations in the MAPK/ERK pathway have been identified. Other targeted therapies may be administered depending on the molecular alteration detected<a class="elsevierStyleCrossRef" href="#bib0045">9</a> (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>).Before the advent of targeted therapies, multiple systemic treatments were administered based primarily on retrospective, single-centre studies or case series. The drug with the most evidence is pegylated interferon alfa-2a. This drug is associated with increased survival, as well as improvement of exophthalmos, hydronephrosis, xanthelasmas and decreased C-reactive protein.<a class="elsevierStyleCrossRef" href="#bib0240">48</a> Although high-dose interferon alpha was associated with clinical and/or radiological improvements in half of the patients with severe CNS and cardiovascular involvement,<a class="elsevierStyleCrossRef" href="#bib0245">49</a> most authors now recommend the use of targeted therapies to treat this type of severe manifestations. Multiple systemic therapies such as glucocorticoids, cladribine, methotrexate, sirolimus, infliximab, anakinra and many others have been tried, most of them with partial responses.<a class="elsevierStyleCrossRefs" href="#bib0045">9,10</a>Rosai-Dorfman diseaseIntroduction/epidemiologyIt is a rare systemic histiocytosis that usually affects children and young adults (mean age of onset 20.6 years), although it can occur at any age. It is more common in males of African descent<a class="elsevierStyleCrossRef" href="#bib0010">2</a>; however, the cutaneous presentation occurs more often in females.<a class="elsevierStyleCrossRef" href="#bib0250">50</a>It has been associated with autoimmune disorders (systemic lupus erythematosus, juvenile idiopathic arthritis, autoimmune haemolytic anaemia), neoplastic diseases (lymphomas, cutaneous sarcomas or myelodysplastic syndrome), germline genetic diseases such as those caused by mutations in the gene SLC29A3 (associated with Faisalabad histiocytosis, syndrome H or hypertrichotic pigmented dermatosis with diabetes) or mutations in the gene TNFRSF (autoimmune proliferative syndrome type i).<a class="elsevierStyleCrossRefs" href="#bib0015">3,5,51,52</a>Clinical manifestationsClassic RDD typically presents with massive, painless lateral cervical lymphadenopathy and constitutional symptoms (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>). Mediastinal, inguinal and retroperitoneal nodes may also be involved.<a class="elsevierStyleCrossRefs" href="#bib0010">2,53</a> Non-massive lymphadenopathy (1−2cm) or subcutaneous lesions have been reported in adults.<a class="elsevierStyleCrossRefs" href="#bib0025">5,52</a> The prognosis is generally favourable, although it worsens with increasing numbers of affected lymphadenopathy groups.<a class="elsevierStyleCrossRef" href="#bib0255">51</a><elsevierMultimedia ident="fig0015"></elsevierMultimedia>Extranodal involvement has been described in almost half of the patients. Prognosis is also related to the number of extranodal systems affected. The most common is cutaneous in the form of subcutaneous lesions, which are neither painful nor pruritic.<a class="elsevierStyleCrossRef" href="#bib0255">51</a> Upper respiratory tract (nose, sinuses), lungs (pleural effusion, interstitial lung disease), eyes/retroorbital tissue, soft tissue, kidneys and retroperitoneum may also be affected.<a class="elsevierStyleCrossRefs" href="#bib0010">2,3,51,54</a> Bone involvement usually consists of multifocal lytic lesions in the diaphysis or metaphysis. Rarely affects the CNS, with characteristic intracranial lesions mimicking meningioma.<a class="elsevierStyleCrossRefs" href="#bib0010">2,3,51,54</a>DiagnosisAs in all other histiocytoses, a physical and radiological examination of each of the potentially affected organs and histopathological confirmation are necessary. The patient should be assessed for any of the diseases associated with RDD.Full body FDG-PET/CT is useful for initial evaluation as well as for assessing response to treatment. Brain MRI is usually superior to FDG-PET/CT for assessing CNS and ENT/orbital lesions, respectively. The presence of emperipolesis phenomena in cerebrospinal fluid allows differentiation of RDD from meningioma.<a class="elsevierStyleCrossRefs" href="#bib0010">2,3,51,54</a>Histopathological analysis of RDD is characterised by expansion of the lymph node sinuses by large histiocytes accompanied by lymphocytes and plasma cells, causing significant sinusoidal dilatation. The histiocytes are large, with a round or oval nucleus, a prominent nucleolus and large, pale cytoplasm. The so-called emperipolesis, which consists of the presence of lymphocytes and plasma cells in the intracytoplasmic vacuoles of histiocytes, is characteristic but not specific for this disease.<a class="elsevierStyleCrossRef" href="#bib0025">5</a> Abundant plasma cells in the medullary cords and around the venules are typical. In some cases, these plasma cells have IgG4<a class="elsevierStyleCrossRef" href="#bib0025">5</a> expression. Fibrosis can be significant, especially in the meninges or paraspinal lesions. On IHC the histiocytes express S100 and are also positive for CD68, CD163 and CD14 and negative for CD1a and CD207.<a class="elsevierStyleCrossRefs" href="#bib0010">2,5</a>BRAF V600E mutation is not usually detected in RDD, but mutations in NRAS, KRAS, MAP2K1 and ARAF are identified in up to one-third of patients with RDD.<a class="elsevierStyleCrossRefs" href="#bib0275">55–57</a> These findings suggest, as in LCH and ECD, that it is a neoplastic process.<a class="elsevierStyleCrossRef" href="#bib0280">56</a> If there is a family history of RDD, an assessment for germline mutations in SLC29A3 may be indicated, and if the patient has typical manifestations of autoimmune lymphoproliferative syndrome, the study of the FAS gene may be recommended.<a class="elsevierStyleCrossRef" href="#bib0255">51</a>TreatmentThere is still no established treatment regimen, as recommendations are mainly based on retrospective, single-centre studies or case series.<a class="elsevierStyleCrossRefs" href="#bib0015">3,51</a> Disease recurrence occurs in about one third of patients.<a class="elsevierStyleCrossRef" href="#bib0260">52</a>In mild, asymptomatic cases, clinical observation is an option because 20%–50% show spontaneous remission. Surgery is a reasonable option if the disease is unifocal or to treat symptomatic lesions in the CNS, sinuses or upper airways.<a class="elsevierStyleCrossRef" href="#bib0255">51</a>Systemic therapy is recommended for multifocal, unresectable, symptomatic involvement and for the treatment of relapsed/refractory disease (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>). Just over half of patients respond to first-line glucocorticoid therapy, although relapse on tapering or discontinuation of treatment is common.<a class="elsevierStyleCrossRef" href="#bib0260">52</a> Cladribine is one of the most commonly used systemic therapies for recurrence, with responses of up to 67%.<a class="elsevierStyleCrossRef" href="#bib0260">52</a> Rituximab has been used to treat massive lymphadenopathy conditions or if associated with autoimmune disease.<a class="elsevierStyleCrossRef" href="#bib0290">58</a> Sirolimus may be effective in cases associated with autoimmune lymphoproliferative syndrome or having associated autoimmune phenomena.<a class="elsevierStyleCrossRef" href="#bib0295">59</a> Lenalidomide or thalidomide<a class="elsevierStyleCrossRefs" href="#bib0005">1,51</a> has been used successfully in patients with refractory skin involvement. Other drugs that have been used in cases of refractory disease include cytarabine, methotrexate, vinblastine, 6-mercaptopurine, azathioprine or clofarabine.<a class="elsevierStyleCrossRefs" href="#bib0045">9,51</a> Radiotherapy (30−50Gy) could be effective in treating refractory ocular or soft tissue involvement with modest efficacy.<a class="elsevierStyleCrossRef" href="#bib0255">51</a>The evidence supporting the use of targeted therapies is still sparse and based primarily on experience with ECD and LCH. The somatic MAPK/ERK mutations found in RDD have led to the primary use of MEK inhibitors (cobimetinib or trametinib). Most authors have used these drugs in severe cases or in cases refractory to other therapies.<a class="elsevierStyleCrossRef" href="#bib0045">9</a>FundingThis work has not received any funding.Conflict of interestAll authors declare that they have no conflicts of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:12 [ 0 => array:3 [ "identificador" => "xres1954783" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1682738" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1954784" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1682737" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Langerhans cell histiocytosis" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Introduction/epidemiology" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Clinical manifestations" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Diagnosis" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Treatment" ] ] ] 6 => array:3 [ "identificador" => "sec0035" "titulo" => "Erdheim-Chester's disease" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0040" "titulo" => "Introduction/epidemiology" ] 1 => array:2 [ "identificador" => "sec0045" "titulo" => "Clinical manifestations" ] 2 => array:2 [ "identificador" => "sec0050" "titulo" => "Diagnosis" ] 3 => array:2 [ "identificador" => "sec0055" "titulo" => "Treatment" ] ] ] 7 => array:3 [ "identificador" => "sec0060" "titulo" => "Rosai-Dorfman disease" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0065" "titulo" => "Introduction/epidemiology" ] 1 => array:2 [ "identificador" => "sec0070" "titulo" => "Clinical manifestations" ] 2 => array:2 [ "identificador" => "sec0075" "titulo" => "Diagnosis" ] 3 => array:2 [ "identificador" => "sec0080" "titulo" => "Treatment" ] ] ] 8 => array:2 [ "identificador" => "sec0085" "titulo" => "Funding" ] 9 => array:2 [ "identificador" => "sec0090" "titulo" => "Conflict of interest" ] 10 => array:2 [ "identificador" => "xack685290" "titulo" => "Acknowledgements" ] 11 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2023-02-16" "fechaAceptado" => "2023-05-04" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1682738" "palabras" => array:5 [ 0 => "Histiocytosis" 1 => "Langerhans" 2 => "Erdheim-Chester" 3 => "Rosai-Dorfman" 4 => "BRAF V600E" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1682737" "palabras" => array:5 [ 0 => "Histiocitosis" 1 => "Langerhans" 2 => "Erdheim-Chester" 3 => "Rosai-Dorfman" 4 => "BRAF V600E" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Histiocytosis is a group of rare diseases characterized by inflammation and accumulation of cells derived from monocytes and macrophages in different tissues. The symptoms are highly variable, from mild forms with involvement of a single organ to severe multisystem forms that can be life compromising. The diagnosis of histiocytosis is based on the clinic, radiological findings and pathological anatomy. A biopsy of the affected tissue is recommended in all cases as it may have therapeutic implications. During the last decade, some mutations have been identified in the affected tissue that condition activation of the MAPK/ERK and PI3K/AKT pathway, in a variable proportion depending on the type of histiocytosis. In this review we mainly focus on Langerhans Cell Histiocytosis, Erdheim-Chester Disease and Rosai-Dorfman Disease." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "Las histiocitosis son un grupo de enfermedades raras que se caracterizan por la inflamación y acúmulo de células derivadas de los monocitos y macrófagos en diferentes tejidos. La clínica es muy variable, desde formas leves con afectación de un solo órgano a formas multisistémicas graves que pueden comprometer la vida. Su diagnóstico se basa en la clínica, hallazgos radiológicos y la anatomía patológica. Se recomienda realizar una biopsia del tejido afecto en todos los casos dado que puede tener implicaciones terapéuticas. En este sentido, durante la última década se ha identificado mutaciones en tejido afecto que condicionan activación de la vía de las proteínas cinasas activadas por mitógenos (MAPK/ERK) y fosfatidilinositol 3 kinasa (PI3K/AKT), en proporción variable, en función del tipo de histiocitosis. En esta revisión nos centramos fundamentalmente en la histiocitosis de Células de Langerhans, la Enfermedad de Erdheim-Chester y la Enfermedad de Rosai-Dorfman." ] ] "multimedia" => array:6 [ 0 => array:8 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1847 "Ancho" => 2925 "Tamanyo" => 879992 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0130" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Langerhans cell histiocytosis. (A) Langerhans cells have a monotonous morphology with a cleaved nucleus and large cytoplasm (H&E 400×). (B) Variable expression for nuclear/cytoplasmic positive S-100 (400×). (C) Intense CD1a-positive membrane (400×). (D) Confluent erythematous papules on the hard palate with a shiny, translucent appearance, corresponding to infiltration by histiocytosis. (E) Plain bone X-ray with osteolytic lesion in the distal femur. (F) High resolution thoracic CT scan with intrapulmonary cystic lesions and small centrilobular nodules." ] ] 1 => array:8 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1666 "Ancho" => 2072 "Tamanyo" => 642457 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0135" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Erdheim-Chester disease. (A) Paratrabecular fibroinflammatory proliferation (H&E 50×). (B) Higher magnification shows xanthomatous histiocytes accompanied by lymphocytes and plasma cells (H&E 400×). (C) CD68-positive (100×) and (D) factor xiiia-positive (100x) histiocytes. (E) FDG-PET/CT with sclerotic lesions in distal femur diaphysis and proximal third of both tibias and condyles. (F) Brain MRI and FDG-PET/CT with sellar and suprasellar involvement with cavernous sinus, Meckel’s cave, sphenoidal fissure, maxillary sinus, meningeal, occipital and cerebellar infiltration. (G) Axial and sagittal plane in cardiac MRI with thickening (arrow) of the right atrial roof and coronary sulcus with filamentous images. (H) FDG-PET/CT with increased glucose metabolism in both renal parenchyma with bilateral spiculated bands infiltrating the perirenal space (“hairy kidney” sign). (I) FDG-PET/CT with retroperitoneal infiltration at periaortic level and with bilateral involvement of the perirenal space and pararenal fasciae leading to secondary hydronephrosis." ] ] 2 => array:8 [ "identificador" => "fig0015" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1115 "Ancho" => 1808 "Tamanyo" => 344585 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0140" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Rosai-Dorfman disease. (A) Skin lesion with histiocytes in a lymphocyte and plasma cell-rich background (H&E 10×). (B) Emperipolesis is evident in S-100 positive histiocytic cells (200×). (C) FDG-PET/CT with hypermetabolic bone lesions in the axial skeleton. (D) Erythematous papules on the lateral face with redness and oedema of the pinna. (E) Right lateral cervical hypermetabolic lymphadenopathy (level IIB) and slight increase of another subcentimetric lymph node (level IIA). (F) Left retroperitoneal lesion with involvement of the crural, upper renal pole and abdominal aorta with mild focal increase in periaortic uptake." ] ] 3 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0145" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Group L \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Langerhans cell histiocytosis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Histiocytosis of undetermined cells \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Erdheim-Chester disease \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Langerhans cell histiocytosis/Erdheim-Chester disease \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Group C \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cutaneous non-Langerhans cell histiocytosis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Non-familial xanthogranuloma: includes Rosai-Dorfman disease. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Familial xanthogranuloma: includes juvenile xanthogranuloma. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cutaneous non-Langerhans cell histiocytosis with a major systemic component \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Group R \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Sporadic Rosai-Dorfman disease \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Classical Rosai-Dorfman disease \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Extra-nodal Rosai-Dorfman disease \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Rosai-Dorfman disease with neoplasm or immune disease \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Unclassified \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Familial Rosai-Dorfman disease \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Group M \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Primary malignant histiocytosis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Secondary malignant histiocytosis (in association with other haematological malignancies) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Group H \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Primary haemophagocytic lymphohistiocytosis (hereditary) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Secondary haemophagocytic lymphohistiocytosis (non-Mendelian haemophagocytic lymphohistiocytosis) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Haemophagocytic lymphohistiocytosis of uncertain origin \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3254071.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Classification of histiocytoses. Langerhans cell-related (group L), cutaneous and mucocutaneous (group C), malignant histiocytosis (group M), Rosai-Dorfman disease (group R), haemophagocytic lymphohistiocytosis and macrophage activation syndrome (group H)." ] ] 4 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0150" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "ALK: anaplastic lymphoma kinase; ARAF: rapidly accelerated fibrosarcoma A-type; BRAF: rapidly accelerated fibrosarcoma B-type; CSF1R: CSF1R: Colony Stimulating Factor 1 Receptor; KRAS: Kirsten rat sarcoma viral oncogene homolog k-ras protein; MAP2K1: Mitogen-Activated Protein Kinase Kinase 1; MAP2K2: Mitogen-Activated Protein Kinase Kinase 2; MAP3K1: Mitogen-Activated Protein Kinase Kinase Kinase 1; NTRK1: neurotrophic tyrosine receptor kinase 1; NRAS: neuroblastoma ras viral oncogene homolog; PI3K: phosphatidylinositol 3-kinase; PIK3CA: Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha; PIK3CD: Phosphoinositide 3-kinase delta; RAF1: rapidly accelerated fibrosarcoma C-type; RAS: Rat sarcoma.+: weakly positive.++: strongly positive.+/-: positive or negative.-: negative.Adapted from Goyal et al.<a class="elsevierStyleCrossRef" href="#bib0125">25</a>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Disease \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Langerhans cell histiocytosis \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Erdheim-Chester disease \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Rosai-Dorfman disease \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " colspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">[0,1-4]Pathological features</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">-Xanthomatous histiocytes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">-Touton's giant cells \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Yes (mainly in dermis) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">-Emperipolesis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Rare \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Abundant \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " colspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">[0,1-4]Cytological characteristics</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">-Nuclei \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Oval; irregular, reticular nuclear contours or grooves \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Round to oval; small; without grooves \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Large; hypochromatic \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">-Nucleoli \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Barely visible \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Barely visible \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Prominent \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">-Cytoplasm \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Abundant, eosinophilic \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Classically abundant, amorphous lipid-laden or granular/xanthomatous \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Frothy, clear without xanthomatous features; common emperipolesis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Other cells \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">abundant eosinophils, eosinophilic microabscesses \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Inflammatory cells including lymphocytes and plasma cells, fibrosis, rarely eosinophils \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Mature plasma cells, polyclonal, IgG4 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " colspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">[0,1-4]Immunophenotype</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CD68 (cytoplasmic) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ (paranuclear cytoplasmic dot)(paranuclear cytoplasmic dot)(paranuclear cytoplasmic dot) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">++ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">++ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CD163 (surface) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">++ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">++ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CD14 (surface) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">++ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">++ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CD1a (surface) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">++ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Langerin (CD207) (cytoplasmic) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">++ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cyclin D1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+/− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+/− \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">S100 (cytoplasmic/nuclear) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+/− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Factor xiiia (cytoplasmic) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+/− \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Fascin (cytoplasmic) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">BRAF V600E (VE1) (cytoplasmic)<a class="elsevierStyleCrossRef" href="#tblfn0010">b</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+/-<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+/-<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">- (only case reports) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ALK (cytoplasmic)<a class="elsevierStyleCrossRef" href="#tblfn0015">c</a>ALK (cytoplasmic)<a class="elsevierStyleCrossRef" href="#tblfn0015">c</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NTRK1 (cytoplasmic) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+/− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " colspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">[0,1-4]Molecular characteristics</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">BRAF V600E (VE1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">55% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">50% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MAP2K1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">15% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">18% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">15% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">RAS isoforms (KRAS, NRAS) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">30% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">BRAF deletions \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PI3K isoforms (PIK3CA, PIK3CD) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ARAF \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Other BRAF missense \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">RAF1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MAP2K2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MAP3K1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Reported \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">One case (amplification) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CSF1R \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">BRAF fusions \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ALK fusions \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NTRK1 fusions \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3254072.png" ] ] ] "notaPie" => array:3 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "Moderate to strong positives should correlate with molecular alteration; BRAF VE1, ALK and phosphorylated receptor tyrosine kinase (pTRK) are mutually exclusive." ] 1 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "b" "nota" => "Negative or equivocal immunohistochemistry for BRAF V600E (VE1) does not exclude BRAF V600E mutated. A next-generation sequencing panel should be used to cover common mutations, including BRAF, MAP2K1, NRAS, KRAS." ] 2 => array:3 [ "identificador" => "tblfn0015" "etiqueta" => "c" "nota" => "BRAF, ALK and NTRK1 fusions are recommended for assessment in histiocytosis with a next-generation sequencing panel that does not reveal mutations in BRAF or other mitogen-activated protein kinase (MAPK/ERK) pathways." ] ] ] "descripcion" => array:1 [ "en" => "Pathological, immunohistochemical and molecular features of Langerhans cell histiocytosis, Erdheim-Chester disease and Rosai-Dorfman disease<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a>." ] ] 5 => array:8 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0155" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "ALK: anaplastic lymphoma kinase; ALPS: autoimmune lymphoproliferative syndrome; BRAF: rapidly accelerated fibrosarcoma B-type; CNS: central nervous system; CSF1R: Colony Stimulating Factor 1 Receptor; MAPK/ERK: mitogen-activated protein kinases; NTRK: neurotrophic tyrosine receptor kinase; PIK3CA: Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha; RET: RET proto-oncogene;Adapted from Go et al.<a class="elsevierStyleCrossRef" href="#bib0045">9</a>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Recommended regimes \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Alternative regimes \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Regimes useful in certain circumstances \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " colspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">[0,1-4]Langerhans cell histiocytosis</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="8" align="left" valign="middle">[2.0]Multisystem or pulmonary</td><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">BRAF V600F mutation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">BRAF V600F mutation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">[2,0]Crizotinib for ALK fusions \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Vemurafenib \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Dabrafenib \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pexidartinib for CSF1R mutation \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MAPK/ERK pathway mutation, mutation not detected, or test not available. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MAPK/ERK pathway mutation, mutation not detected, or test not available. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Larotrectinib for NTRK fusion \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cobimetinib \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Trametinib \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Entrectinib for NTRK fusion \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Regardless of the mutation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Regardless of the mutation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Sirolimus or everolimus for PIK3CA mutation. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cytarabine \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Methotrexate \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Selpercatinib for RET fusions \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cladribine \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hydroxyurea \t\t\t\t\t\t\n \t\t\t\t</td><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Methotrexate/cytarabine \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Vinblastine/prednisone \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="7" align="left" valign="middle">[2.0]CNS lesions</td><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">BRAF V600F mutation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">BRAF V600F mutation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">[2,0]Crizotinib for ALK fusions \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Vemurafenib \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Dabrafenib \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pexidartinib for CSF1R mutation \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MAPK/ERK pathway mutation, mutation not detected, or test not available. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MAPK/ERK pathway mutation, or mutation not detected, test not available. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Larotrectinib for NTRK fusion \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cobimetinib \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Trametinib \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Entrectinib for NTRK fusion \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Regardless of the mutation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Regardless of the mutation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Sirolimus or everolimus for PIK3CA mutation. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Methotrexate/cytarabine \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cytarabine \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Selpercatinib for RET fusions \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cladribine \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Methotrexate at high doses \t\t\t\t\t\t\n \t\t\t\t</td><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Bone involvement \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Surgery \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">In cases of multisystem bone involvement use the regimens described in the multisystem involvement section. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Radiotherapy (10−20Gy) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Zoledronic acid \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pamidronate \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cutaneous involvement \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Methotrexate \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Thalidomide \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hydroxyurea \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Lenalidomide \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " colspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">[0,1-4]Erdheim Chester disease</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="9" align="left" valign="middle">[2.0]Isolated symptomatic or multisystemic</td><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">BRAF V600F mutation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">BRAF V600F mutation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">[2,0]Crizotinib for ALK fusions \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Vemurafenib \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Dabrafenib \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pexidartinib for CSF1R mutation \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MAPK/ERK pathway mutation, mutation not detected, or test not available. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MAPK/ERK pathway mutation, mutation not detected, or test not available. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Larotrectinib for NTRK fusion \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cobimetinib \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Trametinib \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Entrectinib for NTRK fusion \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Regardless of mutation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Regardless of the mutation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Sirolimus or everolimus for PIK3CA mutation. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pegylated interferon alfa-2a \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Interferon alfa-2a \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Selpercatinib for RET fusions \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cladribine \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Sirolimus with prednisone \t\t\t\t\t\t\n \t\t\t\t</td><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Methotrexate \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Anakinra \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " colspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">[0,1-4]Rosai-Dorfman disease</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="10" align="left" valign="middle">Isolated symptomatic or multisystemic</td><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MAPK/ERK pathway mutation, mutation not detected or test not available. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MAPK/ERK pathway mutation, mutation not detected or test not available. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">[1,0]Crizotinib for ALK fusions \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cobimetinib \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Trametinib \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pexidartinib for CSF1R mutation \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Regardless of the mutation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Regardless of the mutation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Larotrectinib for NTRK fusion \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Prednisone or other corticosteroids \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Vinblastine with prednisone \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Entrectinib for NTRK fusion \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cladribine \t\t\t\t\t\t\n \t\t\t\t</td><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Everolimus for PIK3CA mutation. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cytarabine \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Selpercatinib for RET fusions \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Methotrexate \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Sirolimus if associated with ALPS \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Regardless of the mutation \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Rituximab for massive lymphadenopathy or autoimmunity \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Lenalidomide or thalidomide for isolated skin involvement \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3254073.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Treatment regimen in Langerhans cell histiocytosis, Erdheim-Chester disease and Rosai-Dorfman disease." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:59 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Highlights of the management of adult histiocytic disorders: langerhans cell histiocytosis, Erdheim-Chester disease, Rosai-Dorfman disease, and hemophagocytic lymphohistiocytosis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "H.A. Salama" 1 => "A.R. Jazieh" 2 => "A.Y. Alhejazi" 3 => "A. Absi" 4 => "S. Alshieban" 5 => "M. Alzahrani" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.clml.2020.08.007" "Revista" => array:6 [ "tituloSerie" => "Clin Lymphoma Myeloma Leuk." "fecha" => "2021" "volumen" => "21" "paginaInicial" => "e66" "paginaFinal" => "e75" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/32943371" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J.F. Emile" 1 => "O. Abla" 2 => "S. Fraitag" 3 => "A. Horne" 4 => "J. Haroche" 5 => "J. Donadieu" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1182/blood-2016-01-690636" "Revista" => array:6 [ "tituloSerie" => "Blood." "fecha" => "2016" "volumen" => "127" "paginaInicial" => "2672" "paginaFinal" => "2681" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26966089" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0015" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Histiocytic disorders" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "K.L. McClain" 1 => "C. Bigenwald" 2 => "M. Collin" 3 => "J. Haroche" 4 => "R.A. Marsh" 5 => "M. Merad" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/s41572-021-00307-9" "Revista" => array:5 [ "tituloSerie" => "Nat Rev Dis Primers." "fecha" => "2021" "volumen" => "7" "paginaInicial" => "73" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/34620874" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0020" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "CNS Langerhans cell histiocytosis: common hematopoietic origin for HCL-associated neurodegeneration and mass lesions" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "K.L. McClain" 1 => "J. Picarsic" 2 => "R. Chakraborty" 3 => "D. Zinn" 4 => "H. Lin" 5 => "H. Abhyankar" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/cncr.31348" "Revista" => array:6 [ "tituloSerie" => "Cancer." "fecha" => "2018" "volumen" => "124" "paginaInicial" => "2607" "paginaFinal" => "2620" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29624648" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0025" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The Mayo Clinic Histiocytosis Working Group Consensus Statement for the diagnosis and evaluation of adult patients with histiocytic neoplasms: Erdheim-Chester disease, Langerhans cell histiocytosis, and Rosai-Dorfman disease" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "G. Goyal" 1 => "J.R. Young" 2 => "M.J. Koster" 3 => "W.O. Tobin" 4 => "R. Vassallo" 5 => "J.H. Ryu" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.mayocp.2019.02.023" "Revista" => array:6 [ "tituloSerie" => "Mayo Clin Proc." "fecha" => "2019" "volumen" => "94" "paginaInicial" => "2054" "paginaFinal" => "2071" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31472931" "web" => "Medline" ] ] ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0030" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Erdheim-Chester disease: a concise review" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M. Papo" 1 => "J.F. Emile" 2 => "T.T. Maciel" 3 => "P. Bay" 4 => "A. Baber" 5 => "O. Hermine" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s11926-019-0865-2" "Revista" => array:5 [ "tituloSerie" => "Curr Rheumatol Rep." "fecha" => "2019" "volumen" => "21" "paginaInicial" => "66" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31807955" "web" => "Medline" ] ] ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib0035" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Histiocytoses: emerging neoplasia behind inflammation" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J. Haroche" 1 => "F. Cohen-Aubart" 2 => "B.J. Rollins" 3 => "J. Donadieu" 4 => "F. Charlotte" 5 => "A. Idbaih" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S1470-2045(17)30031-1" "Revista" => array:6 [ "tituloSerie" => "Lancet Oncol." "fecha" => "2017" "volumen" => "18" "paginaInicial" => "e113" "paginaFinal" => "e125" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28214412" "web" => "Medline" ] ] ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib0040" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The International Consensus Classification of Mature Lymphoid Neoplasms: a report from the Clinical Advisory Committee" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "E. Campo" 1 => "E.S. Jaffe" 2 => "J.R. Cook" 3 => "L. Quintanilla-Martinez" 4 => "S.H. Swerdlow" 5 => "K.C. Anderson" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1182/blood.2022015851" "Revista" => array:6 [ "tituloSerie" => "Blood." "fecha" => "2022" "volumen" => "140" "paginaInicial" => "1229" "paginaFinal" => "1253" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/35653592" "web" => "Medline" ] ] ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib0045" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Histiocytic neoplasms, version 2.2021, NCCN Clinical Practice Guidelines in Oncology" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "R.S. Go" 1 => "E. Jacobsen" 2 => "R. Baiocchi" 3 => "I. Buhtoiarov" 4 => "E.B. Butler" 5 => "P.K. Campbell" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.6004/jnccn.2021.0053" "Revista" => array:6 [ "tituloSerie" => "J Natl Compr Canc Netw." "fecha" => "2021" "volumen" => "19" "paginaInicial" => "1277" "paginaFinal" => "1303" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/34781268" "web" => "Medline" ] ] ] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib0050" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Erdheim-Chester disease" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "J. Haroche" 1 => "F. Cohen-Aubart" 2 => "Z. Amoura" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Blood." "fecha" => "2020" "volumen" => "135" "paginaInicial" => "1311" "paginaFinal" => "1318" ] ] ] ] ] ] 10 => array:3 [ "identificador" => "bib0055" "etiqueta" => "11" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Treatment outcomes and prognostic factors of patients with adult Langerhans cell histiocytosis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "X.X. Cao" 1 => "M.H. Duan" 2 => "A.L. Zhao" 3 => "H. Cai" 4 => "J. Chen" 5 => "X.M. Gao" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/ajh.26412" "Revista" => array:6 [ "tituloSerie" => "Am J Hematol." "fecha" => "2022" "volumen" => "97" "paginaInicial" => "203" "paginaFinal" => "208" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/34797941" "web" => "Medline" ] ] ] ] ] ] ] ] 11 => array:3 [ "identificador" => "bib0060" "etiqueta" => "12" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Ethnicity, race, and socioeconomic status influence incidence of Langerhans cell histiocytosis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "K.B. Ribeiro" 1 => "B. Degar" 2 => "C.B. Antoneli" 3 => "B. Rollins" 4 => "C. Rodriguez-Galindo" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/pbc.25404" "Revista" => array:6 [ "tituloSerie" => "Pediatr Blood Cancer." "fecha" => "2015" "volumen" => "62" "paginaInicial" => "982" "paginaFinal" => "987" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25586293" "web" => "Medline" ] ] ] ] ] ] ] ] 12 => array:3 [ "identificador" => "bib0065" "etiqueta" => "13" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Descriptive epidemiology of childhood Langerhans cell histiocytosis in France, 2000-2004" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "A. Guyot-Goubin" 1 => "J. Donadieu" 2 => "M. Barkaoui" 3 => "S. Bellec" 4 => "C. Thomas" 5 => "J. Clavel" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/pbc.21498" "Revista" => array:6 [ "tituloSerie" => "Pediatr Blood Cancer." "fecha" => "2008" "volumen" => "51" "paginaInicial" => "71" "paginaFinal" => "75" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18260117" "web" => "Medline" ] ] ] ] ] ] ] ] 13 => array:3 [ "identificador" => "bib0070" "etiqueta" => "14" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Langerhans-cell histiocytosis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "C.E. Allen" 1 => "M. Merad" 2 => "K.L. McClain" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMra1607548" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med." "fecha" => "2018" "volumen" => "379" "paginaInicial" => "856" "paginaFinal" => "868" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30157397" "web" => "Medline" ] ] ] ] ] ] ] ] 14 => array:3 [ "identificador" => "bib0075" "etiqueta" => "15" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Management of adult patients with Langerhans cell histiocytosis: recommendations from an expert panel on behalf of Euro-Histio-Net" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M. Girschikofsky" 1 => "M. Arico" 2 => "D. Castillo" 3 => "A. Chu" 4 => "C. Doberauer" 5 => "J. Fichter" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1186/1750-1172-8-72" "Revista" => array:5 [ "tituloSerie" => "Orphanet J Rare Dis." "fecha" => "2013" "volumen" => "8" "paginaInicial" => "72" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23672541" "web" => "Medline" ] ] ] ] ] ] ] ] 15 => array:3 [ "identificador" => "bib0080" "etiqueta" => "16" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Evaluation and treatment of Langerhans cell histiocytosis patients with central nervous system abnormalities: current views and new vistas" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "E.A. Yeh" 1 => "J. Greenberg" 2 => "O. Abla" 3 => "G. Longoni" 4 => "E. Diamond" 5 => "M. Hermiston" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "Pediatr Blood Cancer." "fecha" => "2018" "volumen" => "65" "paginaInicial" => "75" ] ] ] ] ] ] 16 => array:3 [ "identificador" => "bib0085" "etiqueta" => "17" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Incidence and risk factors for clinical neurodegenerative Langerhans cell histiocytosis: a longitudinal cohort study" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "S. Héritier" 1 => "M.A. Barkaoui" 2 => "J. Miron" 3 => "C. Thomas" 4 => "D. Moshous" 5 => "A. Lambilliotte" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/bjh.15577" "Revista" => array:6 [ "tituloSerie" => "Br J Haematol." "fecha" => "2018" "volumen" => "183" "paginaInicial" => "608" "paginaFinal" => "617" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30421536" "web" => "Medline" ] ] ] ] ] ] ] ] 17 => array:3 [ "identificador" => "bib0090" "etiqueta" => "18" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Central nervous system disease in Langerhans cell histiocytosis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "N. Grois" 1 => "B. Fahrner" 2 => "R.J. Arceci" 3 => "J.I. Henter" 4 => "K. McClain" 5 => "H. Lassmann" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jpeds.2010.03.001" "Revista" => array:6 [ "tituloSerie" => "J Pediatr." "fecha" => "2010" "volumen" => "156" "paginaInicial" => "873" "paginaFinal" => "881" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20434166" "web" => "Medline" ] ] ] ] ] ] ] ] 18 => array:3 [ "identificador" => "bib0095" "etiqueta" => "19" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "BRAF mutation correlates with high-risk Langerhans cell histiocytosis and increased resistance to first-line therapy" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "S. Héritier" 1 => "J.F. Emile" 2 => "M.A. Barkaoui" 3 => "C. Thomas" 4 => "S. Fraitag" 5 => "S. Boudjemaa" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1200/JCO.2015.65.9508" "Revista" => array:6 [ "tituloSerie" => "J Clin Oncol." "fecha" => "2016" "volumen" => "34" "paginaInicial" => "3023" "paginaFinal" => "3030" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27382093" "web" => "Medline" ] ] ] ] ] ] ] ] 19 => array:3 [ "identificador" => "bib0100" "etiqueta" => "20" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Current understanding and management of pulmonary Langerhans cell histiocytosis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "R. Vassallo" 1 => "S. Harari" 2 => "A. Tazi" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1136/thoraxjnl-2017-210125" "Revista" => array:6 [ "tituloSerie" => "Thorax." "fecha" => "2017" "volumen" => "72" "paginaInicial" => "937" "paginaFinal" => "945" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28689173" "web" => "Medline" ] ] ] ] ] ] ] ] 20 => array:3 [ "identificador" => "bib0105" "etiqueta" => "21" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "18F-fluorodeoxyglucose positron emission tomography-computed tomography in the management of adult multisystem Langerhans cell histiocytosis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J. Obert" 1 => "L. Vercellino" 2 => "A. Van Der Gucht" 3 => "C. de Margerie-Mellon" 4 => "E. Bugnet" 5 => "S. Chevret" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s00259-016-3521-3" "Revista" => array:6 [ "tituloSerie" => "Eur J Nucl Med Mol Imaging." "fecha" => "2017" "volumen" => "44" "paginaInicial" => "598" "paginaFinal" => "610" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27645693" "web" => "Medline" ] ] ] ] ] ] ] ] 21 => array:3 [ "identificador" => "bib0110" "etiqueta" => "22" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Recurrent BRAF mutations in Langerhans cell histiocytosis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "G. Badalian-Very" 1 => "J.A. Vergilio" 2 => "B.A. Degar" 3 => "L.E. MacConaill" 4 => "B. Brandner" 5 => "M.L. Calicchio" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1182/blood-2010-04-279083" "Revista" => array:6 [ "tituloSerie" => "Blood." "fecha" => "2010" "volumen" => "116" "paginaInicial" => "1919" "paginaFinal" => "1923" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20519626" "web" => "Medline" ] ] ] ] ] ] ] ] 22 => array:3 [ "identificador" => "bib0115" "etiqueta" => "23" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "High prevalence of BRAF V600E mutations in Erdheim-Chester disease but not in other non-Langerhans cell histiocytoses" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J. Haroche" 1 => "F. Charlotte" 2 => "L. Arnaud" 3 => "A. von Deimling" 4 => "Z. Hélias-Rodzewicz" 5 => "B. Hervier" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1182/blood-2012-05-430140" "Revista" => array:6 [ "tituloSerie" => "Blood." "fecha" => "2012" "volumen" => "120" "paginaInicial" => "2700" "paginaFinal" => "2703" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22879539" "web" => "Medline" ] ] ] ] ] ] ] ] 23 => array:3 [ "identificador" => "bib0120" "etiqueta" => "24" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Progress in understanding the pathogenesis of Langerhans cell histiocytosis: back to Histiocytosis X?" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "M.L. Berres" 1 => "M. Merad" 2 => "C.E. Allen" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/bjh.13247" "Revista" => array:6 [ "tituloSerie" => "Br J Haematol." "fecha" => "2015" "volumen" => "169" "paginaInicial" => "3" "paginaFinal" => "13" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25430560" "web" => "Medline" ] ] ] ] ] ] ] ] 24 => array:3 [ "identificador" => "bib0125" "etiqueta" => "25" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Erdheim-Chester disease: consensus recommendations for evaluation, diagnosis, and treatment in the molecular era" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "G. Goyal" 1 => "M.L. Heany" 2 => "M. Collin" 3 => "F. Cohen-Aubart" 4 => "A. Vaglio" 5 => "B. Durham" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1182/blood.2019003507" "Revista" => array:6 [ "tituloSerie" => "Blood." "fecha" => "2020" "volumen" => "135" "paginaInicial" => "1929" "paginaFinal" => "1945" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/32187362" "web" => "Medline" ] ] ] ] ] ] ] ] 25 => array:3 [ "identificador" => "bib0130" "etiqueta" => "26" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Bisphosphonates in Langerhans cell histiocytosis: an international retrospective case series" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "D. Chellapandian" 1 => "P. Makras" 2 => "G. Kaltsas" 3 => "C. van den Bos" 4 => "L. Naccache" 5 => "R. Rampal" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Mediterr J Hematol Infect Dis." "fecha" => "2016" "volumen" => "8" ] ] ] ] ] ] 26 => array:3 [ "identificador" => "bib0135" "etiqueta" => "27" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Differentiating skin-limited and multisystem Langerhans cell histiocytosis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "S.J. Simko" 1 => "B. Garmezy" 2 => "H. Abhyankar" 3 => "P.J. Lupo" 4 => "R. Chakraborty" 5 => "K.P. Lim" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jpeds.2014.07.063" "Revista" => array:6 [ "tituloSerie" => "J Pediatr." "fecha" => "2014" "volumen" => "165" "paginaInicial" => "990" "paginaFinal" => "996" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25441388" "web" => "Medline" ] ] ] ] ] ] ] ] 27 => array:3 [ "identificador" => "bib0140" "etiqueta" => "28" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Satisfactory remission achieved by PUVA therapy in Langerhans cell hisiocytosis in an elderly patient" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "H. Sakai" 1 => "M. Ibe" 2 => "H. Takahashi" 3 => "S. Matsuo" 4 => "K. Okamoto" 5 => "I. Makino" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1346-8138.1996.tb03966.x" "Revista" => array:6 [ "tituloSerie" => "J Dermatol." "fecha" => "1996" "volumen" => "23" "paginaInicial" => "42" "paginaFinal" => "46" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8720257" "web" => "Medline" ] ] ] ] ] ] ] ] 28 => array:3 [ "identificador" => "bib0145" "etiqueta" => "29" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Long term follow up of topical mustine treatment for cutaneous langerhans cell histiocytosis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "P.H. Hoeger" 1 => "V.R. Nanduri" 2 => "J.I. Harper" 3 => "D.A. Atherton" 4 => "J. Pritchard" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1136/adc.82.6.483" "Revista" => array:6 [ "tituloSerie" => "Arch Dis Child." "fecha" => "2000" "volumen" => "82" "paginaInicial" => "483" "paginaFinal" => "487" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10833183" "web" => "Medline" ] ] ] ] ] ] ] ] 29 => array:3 [ "identificador" => "bib0150" "etiqueta" => "30" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Clinical and radiologic features, lung function and therapeutic results in pulmonary histiocytosis X" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "N. Schönfeld" 1 => "W. Frank" 2 => "S. Wenig" 3 => "P. Uhrmeister" 4 => "E. Allica" 5 => "H. Preussler" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1159/000196248" "Revista" => array:6 [ "tituloSerie" => "Respiration." "fecha" => "1993" "volumen" => "60" "paginaInicial" => "38" "paginaFinal" => "44" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8480089" "web" => "Medline" ] ] ] ] ] ] ] ] 30 => array:3 [ "identificador" => "bib0155" "etiqueta" => "31" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Optimal therapy for adults with Langerhans cell histiocytosis bone lesions" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "M.A. Cantu" 1 => "P.J. Lupo" 2 => "M. Bilgi" 3 => "M.J. Hicks" 4 => "C.E. Allen" 5 => "K.L. McClain" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "PLoS One." "fecha" => "2012" "volumen" => "7" ] ] ] ] ] ] 31 => array:3 [ "identificador" => "bib0160" "etiqueta" => "32" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Cladribine activity in adult Langerhans-cell histiocytosis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "A. Saven" 1 => "C. Burian" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Blood." "fecha" => "1999" "volumen" => "93" "paginaInicial" => "4125" "paginaFinal" => "4130" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10361109" "web" => "Medline" ] ] ] ] ] ] ] ] 32 => array:3 [ "identificador" => "bib0165" "etiqueta" => "33" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Single-agent cladribine as an effective front-line therapy for adults with Langerhans cell histiocytosis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "G. Goyal" 1 => "J.P. Abeykoon" 2 => "M. Hu" 3 => "J.R. Young" 4 => "M.V. Shah" 5 => "N.N. Bennani" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/ajh.26119" "Revista" => array:6 [ "tituloSerie" => "Am J Hematol." "fecha" => "2021" "volumen" => "96" "paginaInicial" => "E146" "paginaFinal" => "E150" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/33539584" "web" => "Medline" ] ] ] ] ] ] ] ] 33 => array:3 [ "identificador" => "bib0170" "etiqueta" => "34" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Methotrexate and cytarabine for adult patients with newly diagnosed Langerhans cell histiocytosis: a single arm, single center, prospective phase 2 study" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "X.X. Cao" 1 => "J. Li" 2 => "A.L. Zhao" 3 => "T.H. He" 4 => "X.M. Gao" 5 => "H.C. Cai" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/ajh.25864" "Revista" => array:6 [ "tituloSerie" => "Am J Hematol." "fecha" => "2020" "volumen" => "95" "paginaInicial" => "E235" "paginaFinal" => "E238" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/32395858" "web" => "Medline" ] ] ] ] ] ] ] ] 34 => array:3 [ "identificador" => "bib0175" "etiqueta" => "35" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Vemurafenib for BRAF V600-Mutant Erdheim-Chester disease and Langerhans cell histiocytosis: analysis of data from the histology-independent, Phase 2, open-label VE-BASKET study" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "E.L. Diamond" 1 => "V. Subbiah" 2 => "A.C. Lockhart" 3 => "J.Y. Blay" 4 => "I. Puzanov" 5 => "I. Chau" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1001/jamaoncol.2017.5029" "Revista" => array:6 [ "tituloSerie" => "JAMA Oncol." "fecha" => "2018" "volumen" => "4" "paginaInicial" => "384" "paginaFinal" => "388" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29188284" "web" => "Medline" ] ] ] ] ] ] ] ] 35 => array:3 [ "identificador" => "bib0180" "etiqueta" => "36" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Efficacy of MEK inhibition in patients with histiocytic neoplasms" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "E.L. Diamond" 1 => "B.H. Durham" 2 => "G.A. Ulaner" 3 => "E. Drill" 4 => "J. Buthorn" 5 => "M. Ki" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/s41586-019-1012-y" "Revista" => array:6 [ "tituloSerie" => "Nature." "fecha" => "2019" "volumen" => "567" "paginaInicial" => "521" "paginaFinal" => "524" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30867592" "web" => "Medline" ] ] ] ] ] ] ] ] 36 => array:3 [ "identificador" => "bib0185" "etiqueta" => "37" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Erdheim-Chester disease in childhood: a challenging diagnosis and treatment" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "T.A. Tran" 1 => "M. Fabre" 2 => "D. Pariente" 3 => "I. Craiu" 4 => "J. Haroche" 5 => "F. Charlotte" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1097/MPH.0b013e3181b76827" "Revista" => array:6 [ "tituloSerie" => "J Pediatr Hematol Oncol." "fecha" => "2009" "volumen" => "31" "paginaInicial" => "782" "paginaFinal" => "786" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19755920" "web" => "Medline" ] ] ] ] ] ] ] ] 37 => array:3 [ "identificador" => "bib0190" "etiqueta" => "38" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Association of both Langerhans cell histiocytosis and Erdheim-Chester disease linked to the BRAFV600E mutation" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "B. Hervier" 1 => "J. Haroche" 2 => "L. Arnaud" 3 => "F. Charlotte" 4 => "J. Donadieu" 5 => "A. Néel" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1182/blood-2013-12-543793" "Revista" => array:6 [ "tituloSerie" => "Blood." "fecha" => "2014" "volumen" => "124" "paginaInicial" => "1119" "paginaFinal" => "1126" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24894769" "web" => "Medline" ] ] ] ] ] ] ] ] 38 => array:3 [ "identificador" => "bib0195" "etiqueta" => "39" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Consensus guidelines for the diagnosis and clinical management of Erdheim-Chester disease" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "E.L. Diamond" 1 => "L. Dagna" 2 => "D.M. Hyman" 3 => "G. Cavalli" 4 => "F. Janku" 5 => "J. Estrada-Veras" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1182/blood-2014-03-561381" "Revista" => array:6 [ "tituloSerie" => "Blood." "fecha" => "2014" "volumen" => "124" "paginaInicial" => "483" "paginaFinal" => "492" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24850756" "web" => "Medline" ] ] ] ] ] ] ] ] 39 => array:3 [ "identificador" => "bib0200" "etiqueta" => "40" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Phenotypes and survival in Erdheim-Chester disease: results from a 165-patient cohort" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "F. Cohen-Aubart" 1 => "J.F. Emile" 2 => "F. Carrat" 3 => "Z. Helias-Rodzewicz" 4 => "V. Taly" 5 => "F. Charlotte" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/ajh.25055" "Revista" => array:6 [ "tituloSerie" => "Am J Hematol." "fecha" => "2018" "volumen" => "93" "paginaInicial" => "E114" "paginaFinal" => "E117" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29396850" "web" => "Medline" ] ] ] ] ] ] ] ] 40 => array:3 [ "identificador" => "bib0205" "etiqueta" => "41" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The clinical spectrum of Erdheim-Chester disease: an observational cohort study" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J.I. Estrada-Veras" 1 => "K.J. O’Brien" 2 => "L.C. Boyd" 3 => "R.H. Dave" 4 => "B. Durham" 5 => "L. Xi" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1182/bloodadvances.2016001784" "Revista" => array:6 [ "tituloSerie" => "Blood Adv." "fecha" => "2017" "volumen" => "1" "paginaInicial" => "357" "paginaFinal" => "366" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28553668" "web" => "Medline" ] ] ] ] ] ] ] ] 41 => array:3 [ "identificador" => "bib0210" "etiqueta" => "42" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Cutaneous manifestations of Erdheim-Chester disease (EEC): clinical, pathological, and molecular features in a monocentric series of 40 patients" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "F. Chasset" 1 => "S. Barete" 2 => "F. Charlotte" 3 => "F. Cohen-Aubart" 4 => "L. Arnaud" 5 => "F. Le Pelletier" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jaad.2015.11.007" "Revista" => array:6 [ "tituloSerie" => "J Am Acad Dermatol." "fecha" => "2016" "volumen" => "74" "paginaInicial" => "513" "paginaFinal" => "520" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26785805" "web" => "Medline" ] ] ] ] ] ] ] ] 42 => array:3 [ "identificador" => "bib0215" "etiqueta" => "43" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Endocrine manifestations in a monocentric cohort of 64 patients with Erdheim-Chester disease" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:4 [ 0 => "C. Courtillot" 1 => "S. Laugier Robiolle" 2 => "F. Cohen Aubart" 3 => "M. Leban" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1210/jc.2015-3357" "Revista" => array:6 [ "tituloSerie" => "J Clin Endocrinol Metab." "fecha" => "2016" "volumen" => "101" "paginaInicial" => "305" "paginaFinal" => "313" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26565949" "web" => "Medline" ] ] ] ] ] ] ] ] 43 => array:3 [ "identificador" => "bib0220" "etiqueta" => "44" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Dramatic efficacy of vemurafenib in both multisystemic and refractory Erdheim-Chester disease and Langerhans cell histiocytosis harboring the BRAF V600E mutation" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J. Haroche" 1 => "F. Cohen-Aubart" 2 => "J.F. Emile" 3 => "L. Arnaud" 4 => "P. Maksud" 5 => "F. Charlotte" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1182/blood-2012-07-446286" "Revista" => array:6 [ "tituloSerie" => "Blood." "fecha" => "2013" "volumen" => "121" "paginaInicial" => "1495" "paginaFinal" => "1500" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23258922" "web" => "Medline" ] ] ] ] ] ] ] ] 44 => array:3 [ "identificador" => "bib0225" "etiqueta" => "45" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Reproducible and sustained efficacy of targeted therapy with vemurafenib in patients with BRAF(V600E)-mutated Erdheim-Chester disease" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J. Haroche" 1 => "F. Cohen-Aubart" 2 => "J.F. Emile" 3 => "P. Maksud" 4 => "A. Drier" 5 => "D. Tolédano" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1200/JCO.2014.57.1950" "Revista" => array:6 [ "tituloSerie" => "J Clin Oncol." "fecha" => "2015" "volumen" => "33" "paginaInicial" => "411" "paginaFinal" => "418" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25422482" "web" => "Medline" ] ] ] ] ] ] ] ] 45 => array:3 [ "identificador" => "bib0230" "etiqueta" => "46" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Low-dose vemurafenib monotherapy in BRAFV600E-mutated Erdheim-Chester disease" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "G.J. Ruan" 1 => "A. Hazim" 2 => "J.P. Abeykoon" 3 => "C. Scheckel" 4 => "R. Vassallo" 5 => "J.H. Ryu" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1080/10428194.2020.1783447" "Revista" => array:6 [ "tituloSerie" => "Leuk Lymphoma." "fecha" => "2020" "volumen" => "61" "paginaInicial" => "2733" "paginaFinal" => "2737" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/32608295" "web" => "Medline" ] ] ] ] ] ] ] ] 46 => array:3 [ "identificador" => "bib0235" "etiqueta" => "47" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Single-agent dabrafenib for BRAFV600E-mutated histiocytosis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "A. Bhatia" 1 => "G. Ulaner" 2 => "R. Rampal" 3 => "D.M. Hyman" 4 => "O. Abdel-Wahab" 5 => "B.H. Durham" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3324/haematol.2017.185298" "Revista" => array:6 [ "tituloSerie" => "Haematologica." "fecha" => "2018" "volumen" => "103" "paginaInicial" => "e177" "paginaFinal" => "e180" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29472347" "web" => "Medline" ] ] ] ] ] ] ] ] 47 => array:3 [ "identificador" => "bib0240" "etiqueta" => "48" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Variability in the efficacy of interferon-alpha in Erdheim-Chester disease by patient and site of involvement: results in eight patients" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J. Haroche" 1 => "Z. Amoura" 2 => "S.G. Trad" 3 => "B. Wechsler" 4 => "P. Cluzel" 5 => "P.A. Grenier" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/art.22165" "Revista" => array:6 [ "tituloSerie" => "Arthritis Rheum." "fecha" => "2006" "volumen" => "54" "paginaInicial" => "3330" "paginaFinal" => "3336" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17009306" "web" => "Medline" ] ] ] ] ] ] ] ] 48 => array:3 [ "identificador" => "bib0245" "etiqueta" => "49" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Treatment of Erdheim-Chester disease with long-term high-dose interferon-α" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "B. Hervier" 1 => "L. Arnaud" 2 => "F. Charlotte" 3 => "B. Wechsler" 4 => "J.C. Piette" 5 => "Z. Amoura" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.semarthrit.2011.11.004" "Revista" => array:6 [ "tituloSerie" => "Semin Arthritis Rheum." "fecha" => "2012" "volumen" => "41" "paginaInicial" => "907" "paginaFinal" => "913" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22300602" "web" => "Medline" ] ] ] ] ] ] ] ] 49 => array:3 [ "identificador" => "bib0250" "etiqueta" => "50" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Cutaneous Rosai-Dorfman disease: clinicopathological profiles, spectrum and evolution of 21 lesions in six patients" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "K.H. Wang" 1 => "W.Y. Chen" 2 => "H.N. Liu" 3 => "C.C. Huang" 4 => "W.R. Lee" 5 => "C.H. Hu" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1365-2133.2005.06917.x" "Revista" => array:6 [ "tituloSerie" => "Br J Dermatol." "fecha" => "2006" "volumen" => "154" "paginaInicial" => "277" "paginaFinal" => "286" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16433797" "web" => "Medline" ] ] ] ] ] ] ] ] 50 => array:3 [ "identificador" => "bib0255" "etiqueta" => "51" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Consensus recommendations for the diagnosis and clinical management of Rosai-Dorfman-Destombes disease" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "O. Abla" 1 => "E. Jacobsen" 2 => "J. Picarsic" 3 => "Z. Krenova" 4 => "R. Jaffe" 5 => "J.F. Emile" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1182/blood-2018-03-839753" "Revista" => array:6 [ "tituloSerie" => "Blood." "fecha" => "2018" "volumen" => "131" "paginaInicial" => "2877" "paginaFinal" => "2890" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29720485" "web" => "Medline" ] ] ] ] ] ] ] ] 51 => array:3 [ "identificador" => "bib0260" "etiqueta" => "52" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Clinicopathological features, treatment approaches, and outcomes in Rosai-Dorfman disease" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "G. Goyal" 1 => "A. Ravindran" 2 => "J.R. Young" 3 => "M.V. Shah" 4 => "N.N. Bennani" 5 => "M.M. Patnaik" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3324/haematol.2019.219626" "Revista" => array:7 [ "tituloSerie" => "Haematologica." "fecha" => "2020" "volumen" => "105" "paginaInicial" => "348" "paginaFinal" => "357" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31004029" "web" => "Medline" ] ] "itemHostRev" => array:3 [ "pii" => "S0092867415017171" "estado" => "S300" "issn" => "00928674" ] ] ] ] ] ] ] 52 => array:3 [ "identificador" => "bib0265" "etiqueta" => "53" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Disease characteristics, radiologic patterns, comorbid diseases, and ethnic differences in 32 patients with Rosai-Dorfman disease" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M. Elshikh" 1 => "D. Schellingerhout" 2 => "J. Rayan" 3 => "A. Taher" 4 => "A.K. Elsayes" 5 => "B. Mujtaba" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1097/RCT.0000000000000983" "Revista" => array:6 [ "tituloSerie" => "J Comput Assist Tomogr." "fecha" => "2020" "volumen" => "44" "paginaInicial" => "450" "paginaFinal" => "461" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31972751" "web" => "Medline" ] ] ] ] ] ] ] ] 53 => array:3 [ "identificador" => "bib0270" "etiqueta" => "54" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Updates on histiocytic disorders" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "S.R. Vaiselbuh" 1 => "Y.T. Bryceson" 2 => "C.E. Allen" 3 => "J.A. Whitlock" 4 => "O. Abla" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/pbc.25017" "Revista" => array:6 [ "tituloSerie" => "Pediatr Blood Cancer." "fecha" => "2014" "volumen" => "61" "paginaInicial" => "1329" "paginaFinal" => "1335" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24610771" "web" => "Medline" ] ] ] ] ] ] ] ] 54 => array:3 [ "identificador" => "bib0275" "etiqueta" => "55" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Diverse and targetable kinase alterations drive histiocytic neoplasms" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "E.L. Diamond" 1 => "B.H. Durham" 2 => "J. Haroche" 3 => "Z. Yao" 4 => "J. Ma" 5 => "S.A. Parikh" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1158/2159-8290.CD-15-0913" "Revista" => array:6 [ "tituloSerie" => "Cancer Discov." 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Review

Histiocytosis

Histiocitosis

Gemma Rocamora-Blancha,b,

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grocamora@bellvitgehospital.cat

Corresponding author.

, Fina Climentb,c, Xavier Solanicha,b

a Servicio de Medicina Interna, Hospital Universitari de Bellvitge, L’Hospitalet de Llobregat, Barcelona, Spain

b Instituto de Investigación Biomédica de Bellvitge (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Spain

c Servicio de Anatomía Patológica, Hospital Universitari de Bellvitge, L’Hospitalet de Llobregat, Barcelona, Spain

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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Langerhans cell histiocytosis&#46; &#40;A&#41; Langerhans cells have a monotonous morphology with a cleaved nucleus and large cytoplasm &#40;H&#38;E 400&#215;&#41;&#46; &#40;B&#41; Variable expression for nuclear&#47;cytoplasmic positive S-100 &#40;400&#215;&#41;&#46; &#40;C&#41; Intense CD1a-positive membrane &#40;400&#215;&#41;&#46; &#40;D&#41; Confluent erythematous papules on the hard palate with a shiny&#44; translucent appearance&#44; corresponding to infiltration by histiocytosis&#46; &#40;E&#41; Plain bone X-ray with osteolytic lesion in the distal femur&#46; &#40;F&#41; High resolution thoracic CT scan with intrapulmonary cystic lesions and small centrilobular nodules&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Histiocytoses are a group of diseases characterised by the proliferation of macrophages and dendritic cells in different tissues&#44; resulting in tissue damage&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">There are about 100 subtypes of histiocytosis&#46; The first classification of histiocytoses was published in 1987 by the Working Group of the Histiocyte Society and consisted of 3 categories based on histological features&#58; Langerhans cell-related&#44; non-Langerhans cell-related and malignant histiocytoses&#46; In 2016&#44; the <span class="elsevierStyleItalic">Histiocyte Society</span> published a new classification dividing histiocytoses into 5 groups based on clinical&#44; radiological&#44; pathological&#44; phenotypic and molecular characteristics &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;3</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0015" class="elsevierStylePara elsevierViewall">The different histiocytoses are considered rare diseases&#44; although their epidemiology is not well established&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> The clinical manifestations are highly variable&#44; ranging from mild forms with single organ involvement to severe&#44; life-threatening multisystemic forms&#46; Due to its rarity and diversity of presentation&#44; reaching a definitive diagnosis can be difficult and there is often a significant diagnostic delay&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;4&#44;5</span></a> There is a need for these patients to be cared for in multidisciplinary units with expertise in this type of disease&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">In this review we will focus on the most common histiocytoses among adults&#58; Langerhans cell histiocytosis &#40;LCH&#41;&#44; Erdheim-Chester disease &#40;ECD&#41; and Rosai-Dorfman disease &#40;RDD&#41;&#46; These 3 entities have a similar pathophysiology with accumulation of clonal mononuclear phagocytes&#44; although the pathological cell has a different origin or phenotype in each of these processes&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> These 3 types of histiocytosis pose a major diagnostic challenge given their rarity&#44; overlapping and coexistence with other haematological malignancies&#46; In patients with unexplained cytopenias&#44; bone marrow biopsy should be considered because of possible concomitant bone marrow processes&#44; such as haemophagocytic lymphohistiocytosis or myeloid neoplasms&#46;<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6&#44;7</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Immunohistochemical &#40;IHC&#41; analysis plays a key role in the diagnosis and should be performed when histiocytosis is suspected&#46; The basic IHC panel should include CD163&#47;CD68&#44; S100&#44; CD1a&#44; langerin&#47;CD207 and factor <span class="elsevierStyleSmallCaps">xiii</span>a as indicated&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> Carcinoma&#44; melanoma&#44; lymphoma and sarcoma markers can be useful for differential diagnosis&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> In addition&#44; IHC can detect the presence of <span class="elsevierStyleItalic">BRAF</span> V600E &#40;VE1&#41; or ALK<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> rearrangements &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0030" class="elsevierStylePara elsevierViewall">Molecular pathology studies of these neoplasms frequently show mutations in the MAPK&#47;ERK &#40;mitogen-activated protein kinase&#41; pathway&#46; A small subset of cases shows activation of the phosphoinositide 3-kinase &#40;PI3K&#41; &#40;PI3K&#47;AKT&#41; pathway&#46; Next generation sequencing &#40;NGS&#41; studies of tumour tissue can identify mutations in the genes of these pathways&#44; which is useful for diagnosis and therapeutic decision-making&#46; The study of somatic mutations and fusions can be performed in a staggered or parallel manner&#44; depending on the clinical needs and protocols of each centre&#46; Polymerase chain reaction specific for the <span class="elsevierStyleItalic">BRAF</span> V600E allele is recommended if IHC is not available&#44; or if the result is equivocal or negative&#46; If no mutation in <span class="elsevierStyleItalic">BRAF</span> is detected&#44; an NGS panel including the rest of the genes involved in the pathogenesis of these entities should be performed&#46; The study of fusions using an RNA-based molecular panel should cover the <span class="elsevierStyleItalic">BRAF&#44; ALK and NTRK1</span> rearrangements&#46;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;7&#44;9</span></a> Peripheral blood NGS studies are an alternative if biopsy of the affected tissue is not feasible&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> The study of molecular alterations can be useful for diagnosis&#44; has prognostic implications and can help in making therapeutic decisions&#46; The presence of molecular alterations typical of ECD is key to the diagnosis in those patients who do not present with typical clinical features<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">Due to the paucity of prospective studies in adults&#44; the evidence supporting the treatment of histiocytosis is largely based on small retrospective studies&#44; case series&#44; or extrapolation from prospective studies in children&#46; Increased understanding of its pathogenesis over the last decade has led to the development of targeted therapeutic strategies that have shown very satisfactory results&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> However&#44; none of these drugs has been approved by the health authorities&#44; so their use is off-label&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Langerhans cell histiocytosis</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Introduction&#47;epidemiology</span><p id="par0040" class="elsevierStylePara elsevierViewall">LCH is a rare heterogeneous histiocytic neoplasm that can occur at any age&#44; although it is more common in children &#40;&#60;15 years&#41;&#44; with 5&#8211;9 cases per million&#44; than in adults &#40;&#62;15 years&#41;&#44; with 1&#8722;2 cases per million&#46;<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7&#44;11</span></a> Latino children have been reported to be at higher risk of developing this disease&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Clinical manifestations</span><p id="par0045" class="elsevierStylePara elsevierViewall">Although some cases are mild and&#47;or asymptomatic&#44; LCH is a life-threatening disease that can progress rapidly or be refractory to treatment or present with isolated single organ or multisystem involvement&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Organs typically affected in LCH are bone &#40;80&#37;&#41;&#44; skin &#40;33&#37;&#41;&#44; pituitary gland &#40;25&#37;&#41;&#44; liver &#40;15&#37;&#41;&#44; spleen &#40;15&#37;&#41;&#44; bone marrow &#40;15&#37;&#41;&#44; lungs &#40;15&#37;&#41;&#44; lymph nodes &#40;5&#37;&#8211;10&#37;&#41; and central nervous system &#40;CNS&#41; &#40;excluding pituitary gland&#41; &#40;2&#37;&#8211;4&#37;&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;13&#44;14</span></a> Life-threatening organs are considered to be the liver&#44; spleen&#44; heart and CNS&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">Patients with LCH may present with constitutional symptoms such as fever&#44; night sweats&#44; fatigue or myalgias&#46; Multifocal bone involvement has been described without manifestations in other organs&#46; Bone lesions are typically lytic and cortical &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;7</span></a> These bone injuries can cause pain&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Cutaneous involvement may present as an erythematous rash&#44; subcutaneous nodules or xanthelasmas&#46; Although there are cases of LCH affecting only the CNS&#44; it is often accompanied by multisystem disease&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> Endocrine disorders such as diabetes insipidus are common in LCH&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> LCH-associated neurodegeneration &#40;ND-LCH&#41; is a serious complication that can develop rapidly or years after the diagnosis of LCH&#46; Cerebellar dysfunction typically occurs as a consequence of cerebellar or brainstem involvement&#46;<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">16&#44;17</span></a> Bone lesions in the mastoid&#44; sphenoid&#44; orbit&#44; temporal bone and clivus are associated with an increased risk of CNS involvement&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> The risk of developing ND-LCH is higher in individuals with <span class="elsevierStyleItalic">BRAF</span> V600E compared to patients without mutation&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> The pulmonary form of LCH is typical of adults and is associated with smoking&#46; The most characteristic lung involvement consists of nodular cystic lesions predominantly in the upper lobes&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;5&#44;7&#44;11</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15&#44;20</span></a> In disseminated forms&#44; the liver &#40;hepatomegaly&#44; acute hepatitis or sclerosing cholangitis in chronic forms&#41;&#44; spleen &#40;diffusely infiltrated or focal lesions&#44; clinically manifesting as splenomegaly&#41; and&#47;or bone marrow &#40;may present with cytopenias&#41; are usually affected&#46; The gastrointestinal tract can be affected at any location&#46; In the mouth&#44; it can affect the gums&#44; causing tooth loss&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Diagnosis</span><p id="par0055" class="elsevierStylePara elsevierViewall">It is based on clinical manifestations&#44; radiological findings and pathological anatomy&#46; A biopsy of the affected tissue is necessary in all cases as definitive diagnosis requires identification of the LCH cell population&#44; and also because of its therapeutic implications&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;7</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">Initial diagnostic tests depend on the clinical manifestations&#46; Whole body FDG-PET&#47;CT should be considered for patients with suspected multisystem disease as it is superior to all other imaging techniques for the detection of active lesions&#44; with the exception of lung lesions&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> Even in the absence of neurological symptoms&#44; we may be confronted with an abnormal brain magnetic resonance imaging &#40;MRI&#41; scan&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> In cases with diabetes insipidus&#44; the first change observed on MRI may be an enlargement of the pituitary stalk with T1 hypointensity&#44; which may later extend to the rest of the pituitary and hypothalamus&#46; Signal changes in grey or white matter with cortical atrophy can be observed in ND-LCH&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> Brain MRI findings may mimic primary CNS tumours&#44; brain metastases or inflammatory granulomatous diseases&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> A high-resolution chest computed tomography &#40;CT&#41; can detect lung nodules in early stages&#44; and irregular cysts can be observed in later stages&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> Functional respiratory testing should be considered to assess for obstructive airway disease&#44; air trapping and DLCO&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">LCH lesions often show histiocytes mixed with a significant infiltration of inflammatory cells&#46; On haematoxylin and eosin &#40;H&#38;E&#41; staining&#44; neoplastic LCH cells are mononucleated&#44; typically with a coffee bean-shaped nucleus&#46; Binucleated or multinucleated cells with the typical Langerhans cell cleft can be identified&#46; Abundant eosinophils are often&#44; but not always&#44; observed&#46; If very prominent they may produce micro-abscesses with Charcot-Leyden crystals&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Fibrosis may develop&#44; particularly in the bone&#46; IHC is characterised by the presence of CD1a and CD207 &#40;langerin&#41; positives&#46; Langerhans cells are also positive for S100&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;7</span></a> Activation of the MAPK pathway is universal in all patients with LCH<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9&#44;22&#8211;25</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46; The <span class="elsevierStyleItalic">BRAF</span> V600E mutation is more commonly detected in younger patients&#44; and is associated with increased severity&#44; multisystem involvement and recurrence&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> The same somatic mutation is identified in each of the patient&#39;s LCH lesions&#44; and in case of recurrence&#44; the original mutation is detected again&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Treatment</span><p id="par0070" class="elsevierStylePara elsevierViewall">Treatment decisions should be made on the basis of the sites affected and the extent of the disease&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> Spontaneous remissions have been documented&#44; so a watchful waiting approach may be reasonable in asymptomatic cases without organ dysfunction&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">In the presence of a unifocal bone lesion&#44; a watchful waiting approach may be appropriate if the lesions are asymptomatic and isolated&#46; It should be treated if the injury is located in a load-bearing area&#44; causes deformity&#44; there is a risk of spinal cord compression or there is a risk of CNS involvement&#46; If the lesion is small &#40;&#60;5<span class="elsevierStyleHsp" style=""></span>cm&#41;&#44; curettage is recommended&#44; avoiding radical excision because of the risk of permanent deformity&#46; Glucocorticoid infiltrations may be effective&#46; Radiotherapy may be considered in patients with &#8804;2 bone lesions if they are not surgically treatable or if they recur after surgery&#46; Bisphosphonates for the treatment of multifocal bone disease are supported by small retrospective studies and case series&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> In large lesions &#40;&#62;5<span class="elsevierStyleHsp" style=""></span>cm&#41;&#44; &#8805;2 bone lesions or lesions with a difficult-to-access location&#44; systemic treatment is indicated&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;9&#44;15</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">Isolated skin involvement may resolve spontaneously and a watchful waiting attitude can be maintained&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> Surgery should only be performed for solitary lesions&#44; and only if surgery will not cause disfigurement&#46; If treatment is necessary&#44; topical treatments such as psoralen with ultraviolet light&#44;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> or topical nitrogen<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> can be administered&#46; If this is not sufficient or if the skin involvement is extensive&#44; glucocorticoids can be used&#44; sometimes in combination with methotrexate&#44; hydroxyurea or thalidomide&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;9</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">Most cases of lung involvement improve after quitting smoking&#46; Systemic treatment should be initiated if lung involvement is symptomatic&#44; progressive or persists after smoking cessation&#46; Prednisone may be effective&#44;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> with radiographic improvements&#44; but there may be no improvement in respiratory function&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> In extensive involvement or progression despite the above measures&#44; systemic treatment should be initiated&#46; More severe cases may require lung transplantation&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;3</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">Systemic treatment is indicated in LCH with multisystem involvement&#44; multifocal&#47;large&#47;difficult-to-access bone lesions&#44; isolated life-threatening organ lesions or risk of CNS involvement &#40;facial lesions&#41;&#44; and lung involvement that does not resolve with smoking cessation &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46; Systemic treatment in adults is not as well established as in paediatrics&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> Vinblastine&#47;prednisone is the standard treatment in children&#44; but its efficacy is lower in adults &#40;<span class="elsevierStyleItalic">overall response rate</span> &#91;<span class="elsevierStyleItalic">ORR</span>&#93; of 26&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> In adults&#44; regimens with cytarabine &#40;<span class="elsevierStyleItalic">ORR&#58;</span> 79&#37;&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> cladribine &#40;<span class="elsevierStyleItalic">ORR&#58;</span> 75&#37;&#8211;79&#37;&#41;&#44;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">32&#44;33</span></a> or cytarabine&#47;methotrexate &#40;<span class="elsevierStyleItalic">ORR&#58;</span> 87&#37;&#41;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> have shown greater efficacy&#46; Cytarabine is the least toxic of the 3 regimens&#44; with serious adverse events occurring in 20&#37;&#44; compared to 37&#37; and 75&#37; with cladribine and vinblastine&#47;prednisone&#44; respectively&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a></p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0095" class="elsevierStylePara elsevierViewall">The discovery of <span class="elsevierStyleItalic">BRAF</span> V600E and other mutations that hyperactivate the MAPK&#47;ERK pathway has led to the incorporation of targeted therapies&#46; The VE-BASKET trial evaluated the efficacy of vemurafenib&#44; an <span class="elsevierStyleItalic">BRAF</span> inhibitor&#46; Twenty-six adults with LCH &#40;4 patients&#41; and ECD &#40;22 patients&#41; with the <span class="elsevierStyleItalic">BRAF</span> V600E mutation&#44; with an <span class="elsevierStyleItalic">ORR</span> of 61&#46;5&#37;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a> were included&#46; A metabolic response measured with FDG-PET&#47;CT was achieved in all patients&#46; In this trial all patients required dose reduction due to toxicities that in some cases were severe&#46; Dabrafenib &#40;a second-generation <span class="elsevierStyleItalic">BRAF</span> inhibitor&#41; with a better safety profile has shown good results in case series&#46; A phase <span class="elsevierStyleSmallCaps">ii</span> trial evaluated cobimetinib &#40;MEK inhibitor&#41; for the treatment of systemic histiocytosis&#44; irrespective of the presence of somatic mutations&#46; Eighteen adult patients with histiocytosis &#40;12 ECD&#44; 2 LCH&#44; 2 RDD&#44; 2 mixed&#41; with an 89&#37; ORR were included&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a> The most common adverse events leading to dose reduction were decreased ejection fraction&#44; rash and diarrhoea&#46; Other targeted therapies have been evaluated depending on the molecular alteration detected<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46; The optimal duration and dose of MAPK&#47;ERK inhibitor treatment is not well established&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">For the treatment of relapses or refractory LCH&#44; it is recommended to use a different drug than the one initially used&#46; In selected refractory cases&#44; haematopoietic stem cell transplantation may be considered&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Erdheim-Chester&#39;s disease</span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Introduction&#47;epidemiology</span><p id="par0105" class="elsevierStylePara elsevierViewall">It is a rare histiocytic neoplasm affecting mostly adults &#40;mean age 55 years&#41; and predominantly male &#40;3&#58;1&#41;&#46; Childhood onset is exceptional&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;37</span></a> From its description in 1930 to the present day&#44; about 1500 cases have been published&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> The median time from onset to diagnosis is very high &#40;2&#46;7 years in a series of 261 patients&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> Up to 20&#37; of patients with ECD may have concomitant lesions typical of LCH&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Clinical manifestations</span><p id="par0110" class="elsevierStylePara elsevierViewall">Although there are cases of unifocal and&#47;or asymptomatic disease&#44; it usually manifests as a multisystemic and potentially fatal disease&#46; The prognosis depends mainly on the organs involved&#46; CNS and cardiovascular involvement are associated with a worse prognosis&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">Constitutional symptoms such as fever&#44; night sweats&#44; fatigue or myalgias may occur&#46; Bone involvement is the most common manifestation &#40;80&#37;&#8211;95&#37;&#41; and is secondary to long bone osteosclerosis of the metaphysis and diaphysis &#40;mainly in the lower limbs&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46; These lesions may be asymptomatic or cause pain&#46;<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10&#44;39</span></a> The most common cardiovascular involvement is thickening of the aorta &#40;coated aorta&#41;&#46; Periaortic infiltration can involve the thoracic and abdominal portions and can extend into the main branches&#46; It is usually asymptomatic and is not associated with aneurysm or dissection&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> Retroperitoneal fibrosis is seen in one third of patients and may be complicated by bilateral ureterohydronephrosis&#46; In ECD&#44; fibrosis completely surrounds the aorta&#44; compared to idiopathic retroperitoneal fibrosis&#44; where the posterior wall of the aorta is rarely affected&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> Up to 63&#37; of patients may have fatty infiltration around the kidneys &#40;&#8220;hairy kidney&#8221; sign&#41;&#44; a manifestation rarely seen in RDD and not described in LCH&#46;<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10&#44;40</span></a> Adrenal hypertrophy may be observed if perirenal infiltration extends to the adrenal gland&#46; Coronary infiltration is seen in 23&#37; of patients and can be complicated by coronary stenosis and acute myocardial infarction&#46;<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10&#44;40</span></a> Pericardial involvement is common &#40;29&#37;&#41; and may develop as pericardial thickening and&#47;or effusion&#46; Infiltration&#47;pseudotumor &#40;36&#37;&#41; is characteristic&#44; typically involving the right coronary sulcus and right atrial wall&#46;<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10&#44;40</span></a> Pulmonary involvement has been reported in up to 30&#37;&#8722;50&#37; of cases&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a> Pleural&#44; parenchymal involvement with interstitial pattern&#44; thickening of interlobular septa&#44; or more rarely with micronodules&#44; ground-glass opacities&#44; parenchymal consolidation&#44; and cysts have been described&#46; It affects the nervous system in up to 55&#37; of cases&#46; The most common manifestations are cerebellar syndromes &#40;41&#37;&#41; or pyramidal syndromes &#40;45&#37;&#41;&#44; although they may also manifest as headache&#44; seizures&#44; sensory disturbances&#44; neuropsychiatric symptoms&#44; cognitive impairment&#44; facial paralysis&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;10</span></a> Degenerative cerebellar involvement is seen in 17&#37; of patients and is often refractory to treatment&#46; Diabetes insipidus &#40;25&#37;&#41; is usually among the first manifestations and may precede the diagnosis by years&#46; In patients with pituitary dysfunction&#44; growth hormone deficiency&#44; hyperprolactinaemia&#44; FSH and LH deficiency&#44; TSH or adrenal hormone deficiency may be detected&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> Intracranial artery involvement has also been reported and may lead to ischaemia&#46; A quarter of patients develop exophthalmos due to retro-orbital soft tissue infiltration&#46; Sinus infiltration is also common &#40;mainly maxillary and sphenoidal&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a> Xanthelasmas are common as cutaneous symptoms&#44; &#40;22&#37;&#41;&#44; classically periorbital&#46; Non-specific plaques or papulonodular lesions may also be observed&#44; mainly affecting the lower limbs&#44; back and&#47;or trunk&#46;<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">40&#44;42</span></a> Gum infiltration and dental involvement&#44; enteropathy and secondary sclerosing cholangitis have also been reported&#46; Rarely&#44; infiltration of organs such as lymph nodes&#44; breast&#44; pancreas or thyroid may be observed&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a></p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0120" class="elsevierStylePara elsevierViewall">Concomitant myeloid neoplasm may occur in 3&#37;&#8211;10&#37; of ECDs<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> and is more common in older males&#46; Cases of macrophage activation syndrome have been reported&#44; associating a worse outcome&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Diagnosis</span><p id="par0125" class="elsevierStylePara elsevierViewall">It is based on clinical manifestations&#44; radiological findings and pathological anatomy&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> Patients with the <span class="elsevierStyleItalic">BRAF</span> V600E mutation are more likely to have cerebellar involvement&#44; diabetes insipidus&#44; retro-orbital infiltration and cardiac manifestations&#44; especially pseudotumours in the right atrium&#46;<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6&#44;40</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">The multisystemic nature of this disease requires a thorough physical examination&#46; A neurocognitive study may be necessary in selected cases&#46; Full body FDG-PET&#47;CT &#40;including lower limbs&#41; assesses bone involvement better than techniques such as scintigraphy&#44; and also allows assessment of other organ involvement&#46;<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10&#44;39</span></a> Gadolinium MRI is a very useful test to assess CNS involvement&#46; Common findings include dural thickening&#44; cerebellar and brainstem hyperintensities&#44; white matter enhancement and pituitary stalk thickening&#46; Diabetes insipidus is almost always irreversible&#44; although radiological infiltration of the pituitary may decrease with treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a> Cerebrospinal fluid analysis is usually normal&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> Very characteristic lesions such as circumferential thickening of the aorta &#40;&#8220;coated aorta&#8221;&#41; or other arteries&#44; as well as infiltration of the renal capsule with the characteristic &#8220;hairy kidney&#8221; sign can be observed on CT&#46; Cardiac involvement should be assessed with echocardiography and&#47;or cardiac MRI&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">Histological study shows the presence of sheets of epithelioid histiocytes in early lesions that become more xanthomatous with Touton-type giant cells&#46; Fibrosis is an important component in most sites&#44; as is lymphocyte aggregation&#46; Less common are eosinophils&#44; neutrophils and plasma cells&#46; On IHC the histiocytes are CD68&#43; CD163&#43; FXIIIa&#43;&#44; CD1a- &#40;non-Langerhans cell histiocytes&#41; and CD207- &#40;langerin&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> The possible presence of S100-positive cells with emperipolesis poses a challenge in distinguishing ECD from RDD&#46; Most of the somatic mutations typical of ECD overlap greatly with those described in patients with LCH<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Treatment</span><p id="par0140" class="elsevierStylePara elsevierViewall">The multisystemic nature of ECD often requires systemic therapy&#46; Nevertheless&#44; in asymptomatic patients without critical organ involvement &#40;heart and CNS&#41;&#44; a watchful waiting approach can be followed&#46; In contrast to LCH&#44; no cases of spontaneous resolution of the disease have been observed&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">Since the identification of the BRAF V600E mutation in patients with ECD&#44; excellent results have been reported with BRAF inhibitors &#40;see the &#8220;Treatment of LCH&#8221; section&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10&#44;23&#44;44</span></a> Observational studies indicate that the efficacy of these drugs is maintained&#44;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a> and that doses lower than those recommended in the SmPC are able to prevent progression with a lower rate of adverse effects&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">46</span></a> Dabrafenib also appears to be effective with a less toxic profile than vemurafenib&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">47</span></a> As discussed above&#44; cobimetinib was shown to be highly effective in patients with ECD&#44; regardless of whether any mutations in the MAPK&#47;ERK pathway have been identified&#46; Other targeted therapies may be administered depending on the molecular alteration detected<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">Before the advent of targeted therapies&#44; multiple systemic treatments were administered based primarily on retrospective&#44; single-centre studies or case series&#46; The drug with the most evidence is pegylated interferon alfa-2a&#46; This drug is associated with increased survival&#44; as well as improvement of exophthalmos&#44; hydronephrosis&#44; xanthelasmas and decreased C-reactive protein&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a> Although high-dose interferon alpha was associated with clinical and&#47;or radiological improvements in half of the patients with severe CNS and cardiovascular involvement&#44;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">49</span></a> most authors now recommend the use of targeted therapies to treat this type of severe manifestations&#46; Multiple systemic therapies such as glucocorticoids&#44; cladribine&#44; methotrexate&#44; sirolimus&#44; infliximab&#44; anakinra and many others have been tried&#44; most of them with partial responses&#46;<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9&#44;10</span></a></p></span></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Rosai-Dorfman disease</span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Introduction&#47;epidemiology</span><p id="par0155" class="elsevierStylePara elsevierViewall">It is a rare systemic histiocytosis that usually affects children and young adults &#40;mean age of onset 20&#46;6 years&#41;&#44; although it can occur at any age&#46; It is more common in males of African descent<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a>&#59; however&#44; the cutaneous presentation occurs more often in females&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">50</span></a></p><p id="par0160" class="elsevierStylePara elsevierViewall">It has been associated with autoimmune disorders &#40;systemic lupus erythematosus&#44; juvenile idiopathic arthritis&#44; autoimmune haemolytic anaemia&#41;&#44; neoplastic diseases &#40;lymphomas&#44; cutaneous sarcomas or myelodysplastic syndrome&#41;&#44; germline genetic diseases such as those caused by mutations in the gene <span class="elsevierStyleItalic">SLC29A3</span> &#40;associated with Faisalabad histiocytosis&#44; syndrome H or hypertrichotic pigmented dermatosis with diabetes&#41; or mutations in the gene <span class="elsevierStyleItalic">TNFRSF</span> &#40;autoimmune proliferative syndrome type <span class="elsevierStyleSmallCaps">i</span>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;5&#44;51&#44;52</span></a></p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Clinical manifestations</span><p id="par0165" class="elsevierStylePara elsevierViewall">Classic RDD typically presents with massive&#44; painless lateral cervical lymphadenopathy and constitutional symptoms &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46; Mediastinal&#44; inguinal and retroperitoneal nodes may also be involved&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;53</span></a> Non-massive lymphadenopathy &#40;1&#8722;2<span class="elsevierStyleHsp" style=""></span>cm&#41; or subcutaneous lesions have been reported in adults&#46;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;52</span></a> The prognosis is generally favourable&#44; although it worsens with increasing numbers of affected lymphadenopathy groups&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">51</span></a></p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0170" class="elsevierStylePara elsevierViewall">Extranodal involvement has been described in almost half of the patients&#46; Prognosis is also related to the number of extranodal systems affected&#46; The most common is cutaneous in the form of subcutaneous lesions&#44; which are neither painful nor pruritic&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">51</span></a> Upper respiratory tract &#40;nose&#44; sinuses&#41;&#44; lungs &#40;pleural effusion&#44; interstitial lung disease&#41;&#44; eyes&#47;retroorbital tissue&#44; soft tissue&#44; kidneys and retroperitoneum may also be affected&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;3&#44;51&#44;54</span></a> Bone involvement usually consists of multifocal lytic lesions in the diaphysis or metaphysis&#46; Rarely affects the CNS&#44; with characteristic intracranial lesions mimicking meningioma&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;3&#44;51&#44;54</span></a></p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Diagnosis</span><p id="par0175" class="elsevierStylePara elsevierViewall">As in all other histiocytoses&#44; a physical and radiological examination of each of the potentially affected organs and histopathological confirmation are necessary&#46; The patient should be assessed for any of the diseases associated with RDD&#46;</p><p id="par0180" class="elsevierStylePara elsevierViewall">Full body FDG-PET&#47;CT is useful for initial evaluation as well as for assessing response to treatment&#46; Brain MRI is usually superior to FDG-PET&#47;CT for assessing CNS and ENT&#47;orbital lesions&#44; respectively&#46; The presence of emperipolesis phenomena in cerebrospinal fluid allows differentiation of RDD from meningioma&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;3&#44;51&#44;54</span></a></p><p id="par0185" class="elsevierStylePara elsevierViewall">Histopathological analysis of RDD is characterised by expansion of the lymph node sinuses by large histiocytes accompanied by lymphocytes and plasma cells&#44; causing significant sinusoidal dilatation&#46; The histiocytes are large&#44; with a round or oval nucleus&#44; a prominent nucleolus and large&#44; pale cytoplasm&#46; The so-called emperipolesis&#44; which consists of the presence of lymphocytes and plasma cells in the intracytoplasmic vacuoles of histiocytes&#44; is characteristic but not specific for this disease&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> Abundant plasma cells in the medullary cords and around the venules are typical&#46; In some cases&#44; these plasma cells have IgG4<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> expression&#46; Fibrosis can be significant&#44; especially in the meninges or paraspinal lesions&#46; On IHC the histiocytes express S100 and are also positive for CD68&#44; CD163 and CD14 and negative for CD1a and CD207&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;5</span></a></p><p id="par0190" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">BRAF</span> V600E mutation is not usually detected in RDD&#44; but mutations in <span class="elsevierStyleItalic">NRAS&#44; KRAS&#44; MAP2K1</span> and <span class="elsevierStyleItalic">ARAF</span> are identified in up to one-third of patients with RDD&#46;<a class="elsevierStyleCrossRefs" href="#bib0275"><span class="elsevierStyleSup">55&#8211;57</span></a> These findings suggest&#44; as in LCH and ECD&#44; that it is a neoplastic process&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">56</span></a> If there is a family history of RDD&#44; an assessment for germline mutations in SLC29A3 may be indicated&#44; and if the patient has typical manifestations of autoimmune lymphoproliferative syndrome&#44; the study of the FAS gene may be recommended&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">51</span></a></p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Treatment</span><p id="par0195" class="elsevierStylePara elsevierViewall">There is still no established treatment regimen&#44; as recommendations are mainly based on retrospective&#44; single-centre studies or case series&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;51</span></a> Disease recurrence occurs in about one third of patients&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">52</span></a></p><p id="par0200" class="elsevierStylePara elsevierViewall">In mild&#44; asymptomatic cases&#44; clinical observation is an option because 20&#37;&#8211;50&#37; show spontaneous remission&#46; Surgery is a reasonable option if the disease is unifocal or to treat symptomatic lesions in the CNS&#44; sinuses or upper airways&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">51</span></a></p><p id="par0205" class="elsevierStylePara elsevierViewall">Systemic therapy is recommended for multifocal&#44; unresectable&#44; symptomatic involvement and for the treatment of relapsed&#47;refractory disease &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46; Just over half of patients respond to first-line glucocorticoid therapy&#44; although relapse on tapering or discontinuation of treatment is common&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">52</span></a> Cladribine is one of the most commonly used systemic therapies for recurrence&#44; with responses of up to 67&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">52</span></a> Rituximab has been used to treat massive lymphadenopathy conditions or if associated with autoimmune disease&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">58</span></a> Sirolimus may be effective in cases associated with autoimmune lymphoproliferative syndrome or having associated autoimmune phenomena&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">59</span></a> Lenalidomide or thalidomide<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;51</span></a> has been used successfully in patients with refractory skin involvement&#46; Other drugs that have been used in cases of refractory disease include cytarabine&#44; methotrexate&#44; vinblastine&#44; 6-mercaptopurine&#44; azathioprine or clofarabine&#46;<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9&#44;51</span></a> Radiotherapy &#40;30&#8722;50<span class="elsevierStyleHsp" style=""></span>Gy&#41; could be effective in treating refractory ocular or soft tissue involvement with modest efficacy&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">51</span></a></p><p id="par0210" class="elsevierStylePara elsevierViewall">The evidence supporting the use of targeted therapies is still sparse and based primarily on experience with ECD and LCH&#46; The somatic MAPK&#47;ERK mutations found in RDD have led to the primary use of MEK inhibitors &#40;cobimetinib or trametinib&#41;&#46; Most authors have used these drugs in severe cases or in cases refractory to other therapies&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a></p></span></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Funding</span><p id="par0215" class="elsevierStylePara elsevierViewall">This work has not received any funding&#46;</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Conflict of interest</span><p id="par0220" class="elsevierStylePara elsevierViewall">All authors declare that they have no conflicts of interest&#46;</p></span></span>"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Histiocytosis is a group of rare diseases characterized by inflammation and accumulation of cells derived from monocytes and macrophages in different tissues&#46; The symptoms are highly variable&#44; from mild forms with involvement of a single organ to severe multisystem forms that can be life compromising&#46; The diagnosis of histiocytosis is based on the clinic&#44; radiological findings and pathological anatomy&#46; A biopsy of the affected tissue is recommended in all cases as it may have therapeutic implications&#46; During the last decade&#44; some mutations have been identified in the affected tissue that condition activation of the MAPK&#47;ERK and PI3K&#47;AKT pathway&#44; in a variable proportion depending on the type of histiocytosis&#46; In this review we mainly focus on Langerhans Cell Histiocytosis&#44; Erdheim-Chester Disease and Rosai-Dorfman Disease&#46;</p></span>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">Las histiocitosis son un grupo de enfermedades raras que se caracterizan por la inflamaci&#243;n y ac&#250;mulo de c&#233;lulas derivadas de los monocitos y macr&#243;fagos en diferentes tejidos&#46; La cl&#237;nica es muy variable&#44; desde formas leves con afectaci&#243;n de un solo &#243;rgano a formas multisist&#233;micas graves que pueden comprometer la vida&#46; Su diagn&#243;stico se basa en la cl&#237;nica&#44; hallazgos radiol&#243;gicos y la anatom&#237;a patol&#243;gica&#46; Se recomienda realizar una biopsia del tejido afecto en todos los casos dado que puede tener implicaciones terap&#233;uticas&#46; En este sentido&#44; durante la &#250;ltima d&#233;cada se ha identificado mutaciones en tejido afecto que condicionan activaci&#243;n de la v&#237;a de las prote&#237;nas cinasas activadas por mit&#243;genos &#40;MAPK&#47;ERK&#41; y fosfatidilinositol 3 kinasa &#40;PI3K&#47;AKT&#41;&#44; en proporci&#243;n variable&#44; en funci&#243;n del tipo de histiocitosis&#46; En esta revisi&#243;n nos centramos fundamentalmente en la histiocitosis de C&#233;lulas de Langerhans&#44; la Enfermedad de Erdheim-Chester y la Enfermedad de Rosai-Dorfman&#46;</p></span>"
      ]
    ]
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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Langerhans cell histiocytosis&#46; &#40;A&#41; Langerhans cells have a monotonous morphology with a cleaved nucleus and large cytoplasm &#40;H&#38;E 400&#215;&#41;&#46; &#40;B&#41; Variable expression for nuclear&#47;cytoplasmic positive S-100 &#40;400&#215;&#41;&#46; &#40;C&#41; Intense CD1a-positive membrane &#40;400&#215;&#41;&#46; &#40;D&#41; Confluent erythematous papules on the hard palate with a shiny&#44; translucent appearance&#44; corresponding to infiltration by histiocytosis&#46; &#40;E&#41; Plain bone X-ray with osteolytic lesion in the distal femur&#46; &#40;F&#41; High resolution thoracic CT scan with intrapulmonary cystic lesions and small centrilobular nodules&#46;</p>"
        ]
      ]
      1 => array:8 [
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        "etiqueta" => "Fig&#46; 2"
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          "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Erdheim-Chester disease&#46; &#40;A&#41; Paratrabecular fibroinflammatory proliferation &#40;H&#38;E 50&#215;&#41;&#46; &#40;B&#41; Higher magnification shows xanthomatous histiocytes accompanied by lymphocytes and plasma cells &#40;H&#38;E 400&#215;&#41;&#46; &#40;C&#41; CD68-positive &#40;100&#215;&#41; and &#40;D&#41; factor <span class="elsevierStyleSmallCaps">xiii</span>a-positive &#40;100x&#41; histiocytes&#46; &#40;E&#41; FDG-PET&#47;CT with sclerotic lesions in distal femur diaphysis and proximal third of both tibias and condyles&#46; &#40;F&#41; Brain MRI and FDG-PET&#47;CT with sellar and suprasellar involvement with cavernous sinus&#44; Meckel&#8217;s cave&#44; sphenoidal fissure&#44; maxillary sinus&#44; meningeal&#44; occipital and cerebellar infiltration&#46; &#40;G&#41; Axial and sagittal plane in cardiac MRI with thickening &#40;arrow&#41; of the right atrial roof and coronary sulcus with filamentous images&#46; &#40;H&#41; FDG-PET&#47;CT with increased glucose metabolism in both renal parenchyma with bilateral spiculated bands infiltrating the perirenal space &#40;&#8220;hairy kidney&#8221; sign&#41;&#46; &#40;I&#41; FDG-PET&#47;CT with retroperitoneal infiltration at periaortic level and with bilateral involvement of the perirenal space and pararenal fasciae leading to secondary hydronephrosis&#46;</p>"
        ]
      ]
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        "etiqueta" => "Fig&#46; 3"
        "tipo" => "MULTIMEDIAFIGURA"
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Rosai-Dorfman disease&#46; &#40;A&#41; Skin lesion with histiocytes in a lymphocyte and plasma cell-rich background &#40;H&#38;E 10&#215;&#41;&#46; &#40;B&#41; Emperipolesis is evident in S-100 positive histiocytic cells &#40;200&#215;&#41;&#46; &#40;C&#41; FDG-PET&#47;CT with hypermetabolic bone lesions in the axial skeleton&#46; &#40;D&#41; Erythematous papules on the lateral face with redness and oedema of the pinna&#46; &#40;E&#41; Right lateral cervical hypermetabolic lymphadenopathy &#40;level IIB&#41; and slight increase of another subcentimetric lymph node &#40;level IIA&#41;&#46; &#40;F&#41; Left retroperitoneal lesion with involvement of the crural&#44; upper renal pole and abdominal aorta with mild focal increase in periaortic uptake&#46;</p>"
        ]
      ]
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        "etiqueta" => "Table 1"
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Group L</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic"><span class="elsevierStyleHsp" style=""></span>Langerhans cell histiocytosis</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic"><span class="elsevierStyleHsp" style=""></span>Histiocytosis of undetermined cells</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic"><span class="elsevierStyleHsp" style=""></span>Erdheim-Chester disease</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic"><span class="elsevierStyleHsp" style=""></span>Langerhans cell histiocytosis&#47;Erdheim-Chester disease</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Group C</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic"><span class="elsevierStyleHsp" style=""></span>Cutaneous non-Langerhans cell histiocytosis</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Non-familial xanthogranuloma&#58; includes Rosai-Dorfman disease&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Familial xanthogranuloma&#58; includes juvenile xanthogranuloma&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic"><span class="elsevierStyleHsp" style=""></span>Cutaneous non-Langerhans cell histiocytosis with a major systemic component</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Group R</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic"><span class="elsevierStyleHsp" style=""></span>Sporadic Rosai-Dorfman disease</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Classical Rosai-Dorfman disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Extra-nodal Rosai-Dorfman disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Rosai-Dorfman disease with neoplasm or immune disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Unclassified&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Familial Rosai-Dorfman disease</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Group M</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic"><span class="elsevierStyleHsp" style=""></span>Primary malignant histiocytosis</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic"><span class="elsevierStyleHsp" style=""></span>Secondary malignant histiocytosis &#40;in association with other haematological malignancies&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Group H</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic"><span class="elsevierStyleHsp" style=""></span>Primary haemophagocytic lymphohistiocytosis &#40;hereditary&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic"><span class="elsevierStyleHsp" style=""></span>Secondary haemophagocytic lymphohistiocytosis &#40;non-Mendelian haemophagocytic lymphohistiocytosis&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic"><span class="elsevierStyleHsp" style=""></span>Haemophagocytic lymphohistiocytosis of uncertain origin</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Classification of histiocytoses&#46; Langerhans cell-related &#40;group L&#41;&#44; cutaneous and mucocutaneous &#40;group C&#41;&#44; malignant histiocytosis &#40;group M&#41;&#44; Rosai-Dorfman disease &#40;group R&#41;&#44; haemophagocytic lymphohistiocytosis and macrophage activation syndrome &#40;group H&#41;&#46;</p>"
        ]
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          "leyenda" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">ALK&#58; anaplastic lymphoma kinase&#59; ARAF&#58; rapidly accelerated fibrosarcoma A-type&#59; BRAF&#58; rapidly accelerated fibrosarcoma B-type&#59; CSF1R&#58; CSF1R&#58; Colony Stimulating Factor 1 Receptor&#59; KRAS&#58; Kirsten rat sarcoma viral oncogene homolog k-ras protein&#59; MAP2K1&#58; Mitogen-Activated Protein Kinase Kinase 1&#59; MAP2K2&#58; Mitogen-Activated Protein Kinase Kinase 2&#59; MAP3K1&#58; Mitogen-Activated Protein Kinase Kinase Kinase 1&#59; NTRK1&#58; neurotrophic tyrosine receptor kinase 1&#59; NRAS&#58; neuroblastoma ras viral oncogene homolog&#59; PI3K&#58; phosphatidylinositol 3-kinase&#59; PIK3CA&#58; Phosphatidylinositol-4&#44;5-Bisphosphate 3-Kinase Catalytic Subunit Alpha&#59; PIK3CD&#58; Phosphoinositide 3-kinase delta&#59; RAF1&#58; rapidly accelerated fibrosarcoma C-type&#59; RAS&#58; Rat sarcoma&#46;</p><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">&#43;&#58; weakly positive&#46;</p><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">&#43;&#43;&#58; strongly positive&#46;</p><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">&#43;&#47;-&#58; positive or negative&#46;</p><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">-&#58; negative&#46;</p><p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Adapted from Goyal et al&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a></p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Langerhans cell histiocytosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Erdheim-Chester disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Rosai-Dorfman disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " colspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#91;0&#44;1-4&#93;<span class="elsevierStyleBold">Pathological features</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">-Xanthomatous histiocytes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">-Touton&#39;s giant cells&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Yes &#40;mainly in dermis&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">-Emperipolesis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Rare&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Abundant&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " colspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#91;0&#44;1-4&#93;<span class="elsevierStyleBold">Cytological characteristics</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">-Nuclei&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Oval&#59; irregular&#44; reticular nuclear contours or grooves&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Round to oval&#59; small&#59; without grooves&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Large&#59; hypochromatic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">-Nucleoli&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Barely visible&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Barely visible&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Prominent&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">-Cytoplasm&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Abundant&#44; eosinophilic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Classically abundant&#44; amorphous lipid-laden or granular&#47;xanthomatous&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Frothy&#44; clear without xanthomatous features&#59; common emperipolesis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Other cells&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">abundant eosinophils&#44; eosinophilic microabscesses&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Inflammatory cells including lymphocytes and plasma cells&#44; fibrosis&#44; rarely eosinophils&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mature plasma cells&#44; polyclonal&#44; IgG4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " colspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#91;0&#44;1-4&#93;<span class="elsevierStyleBold">Immunophenotype</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CD68 &#40;cytoplasmic&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43; <span class="elsevierStyleItalic">&#40;paranuclear cytoplasmic dot&#41;</span>&#40;paranuclear cytoplasmic dot&#41;&#40;paranuclear cytoplasmic dot&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CD163 &#40;surface&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CD14 &#40;surface&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CD1a &#40;surface&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Langerin &#40;CD207&#41; &#40;cytoplasmic&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cyclin D1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&#47;&#8722;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&#47;&#8722;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">S100 &#40;cytoplasmic&#47;nuclear&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&#47;&#8722;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Factor <span class="elsevierStyleSmallCaps">xiii</span>a &#40;cytoplasmic&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&#47;&#8722;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Fascin &#40;cytoplasmic&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">BRAF</span> V600E &#40;VE1&#41; &#40;cytoplasmic&#41;<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&#47;-<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&#47;-<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">- &#40;only <span class="elsevierStyleItalic">case reports</span>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ALK &#40;cytoplasmic&#41;<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a>ALK &#40;cytoplasmic&#41;<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NTRK1 &#40;cytoplasmic&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&#47;&#8722;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " colspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#91;0&#44;1-4&#93;<span class="elsevierStyleBold">Molecular characteristics</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">BRAF</span> V600E &#40;VE1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">55&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">50&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MAP2K1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">15&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">18&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">15&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">RAS</span> isoforms &#40;<span class="elsevierStyleItalic">KRAS&#44; NRAS</span>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">30&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">BRAF</span> deletions&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">PI3K</span> isoforms &#40;<span class="elsevierStyleItalic">PIK3CA&#44; PIK3CD</span>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ARAF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Other <span class="elsevierStyleItalic">BRAF missense</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">RAF1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MAP2K2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MAP3K1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Reported&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">One case &#40;amplification&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CSF1R&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">BRAF</span> fusions&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">ALK</span> fusions&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">NTRK1</span> fusions&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab3254072.png"
              ]
            ]
          ]
          "notaPie" => array:3 [
            0 => array:3 [
              "identificador" => "tblfn0005"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Moderate to strong positives should correlate with molecular alteration&#59; BRAF VE1&#44; ALK and phosphorylated receptor tyrosine kinase &#40;pTRK&#41; are mutually exclusive&#46;</p>"
            ]
            1 => array:3 [
              "identificador" => "tblfn0010"
              "etiqueta" => "b"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Negative or equivocal immunohistochemistry for <span class="elsevierStyleItalic">BRAF</span> V600E &#40;VE1&#41; does not exclude <span class="elsevierStyleItalic">BRAF</span> V600E mutated&#46; A next-generation sequencing panel should be used to cover common mutations&#44; including <span class="elsevierStyleItalic">BRAF&#44; MAP2K1&#44; NRAS&#44; KRAS</span>&#46;</p>"
            ]
            2 => array:3 [
              "identificador" => "tblfn0015"
              "etiqueta" => "c"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0015">BRAF&#44; ALK and NTRK1 fusions are recommended for assessment in histiocytosis with a next-generation sequencing panel that does not reveal mutations in BRAF or other mitogen-activated protein kinase &#40;MAPK&#47;ERK&#41; pathways&#46;</p>"
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Pathological&#44; immunohistochemical and molecular features of Langerhans cell histiocytosis&#44; Erdheim-Chester disease and Rosai-Dorfman disease<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&#46;</p>"
        ]
      ]
      5 => array:8 [
        "identificador" => "tbl0015"
        "etiqueta" => "Table 3"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
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          "leyenda" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">ALK&#58; anaplastic lymphoma kinase&#59; ALPS&#58; autoimmune lymphoproliferative syndrome&#59; BRAF&#58; rapidly accelerated fibrosarcoma B-type&#59; CNS&#58; central nervous system&#59; CSF1R&#58; Colony Stimulating Factor 1 Receptor&#59; MAPK&#47;ERK&#58; mitogen-activated protein kinases&#59; NTRK&#58; neurotrophic tyrosine receptor kinase&#59; PIK3CA&#58; Phosphatidylinositol-4&#44;5-Bisphosphate 3-Kinase Catalytic Subunit Alpha&#59; RET&#58; RET proto-oncogene&#59;</p><p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Adapted from Go et al&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a></p>"
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Recommended regimes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Alternative regimes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Regimes useful in certain circumstances&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " colspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#91;0&#44;1-4&#93;<span class="elsevierStyleBold">Langerhans cell histiocytosis</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="8" align="left" valign="middle">&#91;2&#46;0&#93;Multisystem or pulmonary</td><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold"><span class="elsevierStyleItalic">BRAF</span> V600F mutation</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold"><span class="elsevierStyleItalic">BRAF</span> V600F mutation</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#91;2&#44;0&#93;Crizotinib for <span class="elsevierStyleItalic">ALK</span> fusions&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Vemurafenib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dabrafenib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pexidartinib for <span class="elsevierStyleItalic">CSF1R</span> mutation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">MAPK&#47;ERK pathway mutation&#44; mutation not detected&#44; or test not available</span>&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">MAPK&#47;ERK pathway mutation&#44; mutation not detected&#44; or test not available</span>&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Larotrectinib for <span class="elsevierStyleItalic">NTRK</span> fusion&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cobimetinib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Trametinib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Entrectinib for <span class="elsevierStyleItalic">NTRK</span> fusion&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Regardless of the mutation</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Regardless of the mutation</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Sirolimus or everolimus for <span class="elsevierStyleItalic">PIK3CA mutation</span>&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cytarabine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Methotrexate&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Selpercatinib for <span class="elsevierStyleItalic">RET</span> fusions&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cladribine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hydroxyurea&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Methotrexate&#47;cytarabine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Vinblastine&#47;prednisone&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="7" align="left" valign="middle">&#91;2&#46;0&#93;CNS lesions</td><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold"><span class="elsevierStyleItalic">BRAF</span> V600F mutation</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold"><span class="elsevierStyleItalic">BRAF</span> V600F mutation</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#91;2&#44;0&#93;Crizotinib for <span class="elsevierStyleItalic">ALK</span> fusions&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Vemurafenib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dabrafenib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pexidartinib for <span class="elsevierStyleItalic">CSF1R</span> mutation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">MAPK&#47;ERK pathway mutation&#44; mutation not detected&#44; or test not available</span>&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">MAPK&#47;ERK pathway mutation&#44; or mutation not detected&#44; test not available</span>&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Larotrectinib for <span class="elsevierStyleItalic">NTRK</span> fusion&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cobimetinib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Trametinib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Entrectinib for <span class="elsevierStyleItalic">NTRK</span> fusion&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Regardless of the mutation</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Regardless of the mutation</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Sirolimus or everolimus for <span class="elsevierStyleItalic">PIK3CA mutation</span>&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Methotrexate&#47;cytarabine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cytarabine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Selpercatinib for <span class="elsevierStyleItalic">RET</span> fusions&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cladribine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Methotrexate at high doses&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Bone involvement&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Surgery&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">In cases of multisystem bone involvement use the regimens described in the multisystem involvement section&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Radiotherapy &#40;10&#8722;20<span class="elsevierStyleHsp" style=""></span>Gy&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Zoledronic acid&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pamidronate&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cutaneous involvement&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Methotrexate&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Thalidomide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hydroxyurea&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Lenalidomide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " colspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#91;0&#44;1-4&#93;<span class="elsevierStyleBold">Erdheim Chester disease</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="9" align="left" valign="middle">&#91;2&#46;0&#93;Isolated symptomatic or multisystemic</td><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold"><span class="elsevierStyleItalic">BRAF</span> V600F mutation</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold"><span class="elsevierStyleItalic">BRAF</span> V600F mutation</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#91;2&#44;0&#93;Crizotinib for <span class="elsevierStyleItalic">ALK</span> fusions&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Vemurafenib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dabrafenib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pexidartinib for <span class="elsevierStyleItalic">CSF1R</span> mutation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">MAPK&#47;ERK pathway mutation&#44; mutation not detected&#44; or test not available</span>&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">MAPK&#47;ERK pathway mutation&#44; mutation not detected&#44; or test not available</span>&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Larotrectinib for <span class="elsevierStyleItalic">NTRK</span> fusion&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cobimetinib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Trametinib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Entrectinib for <span class="elsevierStyleItalic">NTRK</span> fusion&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Regardless of mutation</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Regardless of the mutation</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Sirolimus or everolimus for <span class="elsevierStyleItalic">PIK3CA mutation</span>&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pegylated interferon alfa-2a&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Interferon alfa-2a&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Selpercatinib for <span class="elsevierStyleItalic">RET</span> fusions&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cladribine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Sirolimus with prednisone&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Methotrexate&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Anakinra&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " colspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#91;0&#44;1-4&#93;<span class="elsevierStyleBold">Rosai-Dorfman disease</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="10" align="left" valign="middle">Isolated symptomatic or multisystemic</td><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">MAPK&#47;ERK pathway mutation&#44; mutation not detected or test not available</span>&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">MAPK&#47;ERK pathway mutation&#44; mutation not detected or test not available</span>&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#91;1&#44;0&#93;Crizotinib for <span class="elsevierStyleItalic">ALK</span> fusions&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cobimetinib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Trametinib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pexidartinib for <span class="elsevierStyleItalic">CSF1R</span> mutation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Regardless of the mutation</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Regardless of the mutation</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Larotrectinib for <span class="elsevierStyleItalic">NTRK</span> fusion&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Prednisone or other corticosteroids&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Vinblastine with prednisone&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Entrectinib for <span class="elsevierStyleItalic">NTRK</span> fusion&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cladribine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Everolimus for <span class="elsevierStyleItalic">PIK3CA mutation</span>&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cytarabine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Selpercatinib for <span class="elsevierStyleItalic">RET</span> fusions&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Methotrexate&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Sirolimus if associated with ALPS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Regardless of the mutation</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Rituximab for massive lymphadenopathy or autoimmunity&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Lenalidomide or thalidomide for isolated skin involvement&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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      "titulo" => "References"
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        0 => array:2 [
          "identificador" => "bibs0005"
          "bibliografiaReferencia" => array:59 [
            0 => array:3 [
              "identificador" => "bib0005"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Highlights of the management of adult histiocytic disorders&#58; langerhans cell histiocytosis&#44; Erdheim-Chester disease&#44; Rosai-Dorfman disease&#44; and hemophagocytic lymphohistiocytosis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "H&#46;A&#46; Salama"
                            1 => "A&#46;R&#46; Jazieh"
                            2 => "A&#46;Y&#46; Alhejazi"
                            3 => "A&#46; Absi"
                            4 => "S&#46; Alshieban"
                            5 => "M&#46; Alzahrani"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.clml.2020.08.007"
                      "Revista" => array:6 [
                        "tituloSerie" => "Clin Lymphoma Myeloma Leuk&#46;"
                        "fecha" => "2021"
                        "volumen" => "21"
                        "paginaInicial" => "e66"
                        "paginaFinal" => "e75"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/32943371"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "bib0010"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "J&#46;F&#46; Emile"
                            1 => "O&#46; Abla"
                            2 => "S&#46; Fraitag"
                            3 => "A&#46; Horne"
                            4 => "J&#46; Haroche"
                            5 => "J&#46; Donadieu"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1182/blood-2016-01-690636"
                      "Revista" => array:6 [
                        "tituloSerie" => "Blood&#46;"
                        "fecha" => "2016"
                        "volumen" => "127"
                        "paginaInicial" => "2672"
                        "paginaFinal" => "2681"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26966089"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib0015"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Histiocytic disorders"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "K&#46;L&#46; McClain"
                            1 => "C&#46; Bigenwald"
                            2 => "M&#46; Collin"
                            3 => "J&#46; Haroche"
                            4 => "R&#46;A&#46; Marsh"
                            5 => "M&#46; Merad"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/s41572-021-00307-9"
                      "Revista" => array:5 [
                        "tituloSerie" => "Nat Rev Dis Primers&#46;"
                        "fecha" => "2021"
                        "volumen" => "7"
                        "paginaInicial" => "73"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/34620874"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            3 => array:3 [
              "identificador" => "bib0020"
              "etiqueta" => "4"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "CNS Langerhans cell histiocytosis&#58; common hematopoietic origin for HCL-associated neurodegeneration and mass lesions"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "K&#46;L&#46; McClain"
                            1 => "J&#46; Picarsic"
                            2 => "R&#46; Chakraborty"
                            3 => "D&#46; Zinn"
                            4 => "H&#46; Lin"
                            5 => "H&#46; Abhyankar"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/cncr.31348"
                      "Revista" => array:6 [
                        "tituloSerie" => "Cancer&#46;"
                        "fecha" => "2018"
                        "volumen" => "124"
                        "paginaInicial" => "2607"
                        "paginaFinal" => "2620"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29624648"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            4 => array:3 [
              "identificador" => "bib0025"
              "etiqueta" => "5"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The Mayo Clinic Histiocytosis Working Group Consensus Statement for the diagnosis and evaluation of adult patients with histiocytic neoplasms&#58; Erdheim-Chester disease&#44; Langerhans cell histiocytosis&#44; and Rosai-Dorfman disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "G&#46; Goyal"
                            1 => "J&#46;R&#46; Young"
                            2 => "M&#46;J&#46; Koster"
                            3 => "W&#46;O&#46; Tobin"
                            4 => "R&#46; Vassallo"
                            5 => "J&#46;H&#46; Ryu"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.mayocp.2019.02.023"
                      "Revista" => array:6 [
                        "tituloSerie" => "Mayo Clin Proc&#46;"
                        "fecha" => "2019"
                        "volumen" => "94"
                        "paginaInicial" => "2054"
                        "paginaFinal" => "2071"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31472931"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            5 => array:3 [
              "identificador" => "bib0030"
              "etiqueta" => "6"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Erdheim-Chester disease&#58; a concise review"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "M&#46; Papo"
                            1 => "J&#46;F&#46; Emile"
                            2 => "T&#46;T&#46; Maciel"
                            3 => "P&#46; Bay"
                            4 => "A&#46; Baber"
                            5 => "O&#46; Hermine"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s11926-019-0865-2"
                      "Revista" => array:5 [
                        "tituloSerie" => "Curr Rheumatol Rep&#46;"
                        "fecha" => "2019"
                        "volumen" => "21"
                        "paginaInicial" => "66"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31807955"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            6 => array:3 [
              "identificador" => "bib0035"
              "etiqueta" => "7"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Histiocytoses&#58; emerging neoplasia behind inflammation"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "J&#46; Haroche"
                            1 => "F&#46; Cohen-Aubart"
                            2 => "B&#46;J&#46; Rollins"
                            3 => "J&#46; Donadieu"
                            4 => "F&#46; Charlotte"
                            5 => "A&#46; Idbaih"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/S1470-2045(17)30031-1"
                      "Revista" => array:6 [
                        "tituloSerie" => "Lancet Oncol&#46;"
                        "fecha" => "2017"
                        "volumen" => "18"
                        "paginaInicial" => "e113"
                        "paginaFinal" => "e125"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28214412"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            7 => array:3 [
              "identificador" => "bib0040"
              "etiqueta" => "8"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The International Consensus Classification of Mature Lymphoid Neoplasms&#58; a report from the Clinical Advisory Committee"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "E&#46; Campo"
                            1 => "E&#46;S&#46; Jaffe"
                            2 => "J&#46;R&#46; Cook"
                            3 => "L&#46; Quintanilla-Martinez"
                            4 => "S&#46;H&#46; Swerdlow"
                            5 => "K&#46;C&#46; Anderson"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1182/blood.2022015851"
                      "Revista" => array:6 [
                        "tituloSerie" => "Blood&#46;"
                        "fecha" => "2022"
                        "volumen" => "140"
                        "paginaInicial" => "1229"
                        "paginaFinal" => "1253"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/35653592"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            8 => array:3 [
              "identificador" => "bib0045"
              "etiqueta" => "9"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Histiocytic neoplasms&#44; version 2&#46;2021&#44; NCCN Clinical Practice Guidelines in Oncology"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "R&#46;S&#46; Go"
                            1 => "E&#46; Jacobsen"
                            2 => "R&#46; Baiocchi"
                            3 => "I&#46; Buhtoiarov"
                            4 => "E&#46;B&#46; Butler"
                            5 => "P&#46;K&#46; Campbell"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.6004/jnccn.2021.0053"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Natl Compr Canc Netw&#46;"
                        "fecha" => "2021"
                        "volumen" => "19"
                        "paginaInicial" => "1277"
                        "paginaFinal" => "1303"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/34781268"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            9 => array:3 [
              "identificador" => "bib0050"
              "etiqueta" => "10"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Erdheim-Chester disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "J&#46; Haroche"
                            1 => "F&#46; Cohen-Aubart"
                            2 => "Z&#46; Amoura"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Blood&#46;"
                        "fecha" => "2020"
                        "volumen" => "135"
                        "paginaInicial" => "1311"
                        "paginaFinal" => "1318"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            10 => array:3 [
              "identificador" => "bib0055"
              "etiqueta" => "11"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Treatment outcomes and prognostic factors of patients with adult Langerhans cell histiocytosis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "X&#46;X&#46; Cao"
                            1 => "M&#46;H&#46; Duan"
                            2 => "A&#46;L&#46; Zhao"
                            3 => "H&#46; Cai"
                            4 => "J&#46; Chen"
                            5 => "X&#46;M&#46; Gao"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/ajh.26412"
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Hematol&#46;"
                        "fecha" => "2022"
                        "volumen" => "97"
                        "paginaInicial" => "203"
                        "paginaFinal" => "208"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/34797941"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            11 => array:3 [
              "identificador" => "bib0060"
              "etiqueta" => "12"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Ethnicity&#44; race&#44; and socioeconomic status influence incidence of Langerhans cell histiocytosis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "K&#46;B&#46; Ribeiro"
                            1 => "B&#46; Degar"
                            2 => "C&#46;B&#46; Antoneli"
                            3 => "B&#46; Rollins"
                            4 => "C&#46; Rodriguez-Galindo"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/pbc.25404"
                      "Revista" => array:6 [
                        "tituloSerie" => "Pediatr Blood Cancer&#46;"
                        "fecha" => "2015"
                        "volumen" => "62"
                        "paginaInicial" => "982"
                        "paginaFinal" => "987"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25586293"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            12 => array:3 [
              "identificador" => "bib0065"
              "etiqueta" => "13"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Descriptive epidemiology of childhood Langerhans cell histiocytosis in France&#44; 2000-2004"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "A&#46; Guyot-Goubin"
                            1 => "J&#46; Donadieu"
                            2 => "M&#46; Barkaoui"
                            3 => "S&#46; Bellec"
                            4 => "C&#46; Thomas"
                            5 => "J&#46; Clavel"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/pbc.21498"
                      "Revista" => array:6 [
                        "tituloSerie" => "Pediatr Blood Cancer&#46;"
                        "fecha" => "2008"
                        "volumen" => "51"
                        "paginaInicial" => "71"
                        "paginaFinal" => "75"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18260117"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            13 => array:3 [
              "identificador" => "bib0070"
              "etiqueta" => "14"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Langerhans-cell histiocytosis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "C&#46;E&#46; Allen"
                            1 => "M&#46; Merad"
                            2 => "K&#46;L&#46; McClain"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJMra1607548"
                      "Revista" => array:6 [
                        "tituloSerie" => "N Engl J Med&#46;"
                        "fecha" => "2018"
                        "volumen" => "379"
                        "paginaInicial" => "856"
                        "paginaFinal" => "868"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30157397"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            14 => array:3 [
              "identificador" => "bib0075"
              "etiqueta" => "15"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Management of adult patients with Langerhans cell histiocytosis&#58; recommendations from an expert panel on behalf of Euro-Histio-Net"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "M&#46; Girschikofsky"
                            1 => "M&#46; Arico"
                            2 => "D&#46; Castillo"
                            3 => "A&#46; Chu"
                            4 => "C&#46; Doberauer"
                            5 => "J&#46; Fichter"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1186/1750-1172-8-72"
                      "Revista" => array:5 [
                        "tituloSerie" => "Orphanet J Rare Dis&#46;"
                        "fecha" => "2013"
                        "volumen" => "8"
                        "paginaInicial" => "72"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23672541"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            15 => array:3 [
              "identificador" => "bib0080"
              "etiqueta" => "16"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Evaluation and treatment of Langerhans cell histiocytosis patients with central nervous system abnormalities&#58; current views and new vistas"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "E&#46;A&#46; Yeh"
                            1 => "J&#46; Greenberg"
                            2 => "O&#46; Abla"
                            3 => "G&#46; Longoni"
                            4 => "E&#46; Diamond"
                            5 => "M&#46; Hermiston"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:4 [
                        "tituloSerie" => "Pediatr Blood Cancer&#46;"
                        "fecha" => "2018"
                        "volumen" => "65"
                        "paginaInicial" => "75"
                      ]
                    ]
                  ]
                ]
              ]
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            16 => array:3 [
              "identificador" => "bib0085"
              "etiqueta" => "17"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Incidence and risk factors for clinical neurodegenerative Langerhans cell histiocytosis&#58; a longitudinal cohort study"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "S&#46; H&#233;ritier"
                            1 => "M&#46;A&#46; Barkaoui"
                            2 => "J&#46; Miron"
                            3 => "C&#46; Thomas"
                            4 => "D&#46; Moshous"
                            5 => "A&#46; Lambilliotte"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/bjh.15577"
                      "Revista" => array:6 [
                        "tituloSerie" => "Br J Haematol&#46;"
                        "fecha" => "2018"
                        "volumen" => "183"
                        "paginaInicial" => "608"
                        "paginaFinal" => "617"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30421536"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            17 => array:3 [
              "identificador" => "bib0090"
              "etiqueta" => "18"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Central nervous system disease in Langerhans cell histiocytosis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "N&#46; Grois"
                            1 => "B&#46; Fahrner"
                            2 => "R&#46;J&#46; Arceci"
                            3 => "J&#46;I&#46; Henter"
                            4 => "K&#46; McClain"
                            5 => "H&#46; Lassmann"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jpeds.2010.03.001"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Pediatr&#46;"
                        "fecha" => "2010"
                        "volumen" => "156"
                        "paginaInicial" => "873"
                        "paginaFinal" => "881"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20434166"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            18 => array:3 [
              "identificador" => "bib0095"
              "etiqueta" => "19"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "BRAF mutation correlates with high-risk Langerhans cell histiocytosis and increased resistance to first-line therapy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "S&#46; H&#233;ritier"
                            1 => "J&#46;F&#46; Emile"
                            2 => "M&#46;A&#46; Barkaoui"
                            3 => "C&#46; Thomas"
                            4 => "S&#46; Fraitag"
                            5 => "S&#46; Boudjemaa"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1200/JCO.2015.65.9508"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Clin Oncol&#46;"
                        "fecha" => "2016"
                        "volumen" => "34"
                        "paginaInicial" => "3023"
                        "paginaFinal" => "3030"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27382093"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            19 => array:3 [
              "identificador" => "bib0100"
              "etiqueta" => "20"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Current understanding and management of pulmonary Langerhans cell histiocytosis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "R&#46; Vassallo"
                            1 => "S&#46; Harari"
                            2 => "A&#46; Tazi"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1136/thoraxjnl-2017-210125"
                      "Revista" => array:6 [
                        "tituloSerie" => "Thorax&#46;"
                        "fecha" => "2017"
                        "volumen" => "72"
                        "paginaInicial" => "937"
                        "paginaFinal" => "945"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28689173"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            20 => array:3 [
              "identificador" => "bib0105"
              "etiqueta" => "21"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "18F-fluorodeoxyglucose positron emission tomography-computed tomography in the management of adult multisystem Langerhans cell histiocytosis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "J&#46; Obert"
                            1 => "L&#46; Vercellino"
                            2 => "A&#46; Van Der Gucht"
                            3 => "C&#46; de Margerie-Mellon"
                            4 => "E&#46; Bugnet"
                            5 => "S&#46; Chevret"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s00259-016-3521-3"
                      "Revista" => array:6 [
                        "tituloSerie" => "Eur J Nucl Med Mol Imaging&#46;"
                        "fecha" => "2017"
                        "volumen" => "44"
                        "paginaInicial" => "598"
                        "paginaFinal" => "610"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27645693"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            21 => array:3 [
              "identificador" => "bib0110"
              "etiqueta" => "22"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Recurrent BRAF mutations in Langerhans cell histiocytosis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "G&#46; Badalian-Very"
                            1 => "J&#46;A&#46; Vergilio"
                            2 => "B&#46;A&#46; Degar"
                            3 => "L&#46;E&#46; MacConaill"
                            4 => "B&#46; Brandner"
                            5 => "M&#46;L&#46; Calicchio"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1182/blood-2010-04-279083"
                      "Revista" => array:6 [
                        "tituloSerie" => "Blood&#46;"
                        "fecha" => "2010"
                        "volumen" => "116"
                        "paginaInicial" => "1919"
                        "paginaFinal" => "1923"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20519626"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            22 => array:3 [
              "identificador" => "bib0115"
              "etiqueta" => "23"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "High prevalence of BRAF V600E mutations in Erdheim-Chester disease but not in other non-Langerhans cell histiocytoses"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "J&#46; Haroche"
                            1 => "F&#46; Charlotte"
                            2 => "L&#46; Arnaud"
                            3 => "A&#46; von Deimling"
                            4 => "Z&#46; H&#233;lias-Rodzewicz"
                            5 => "B&#46; Hervier"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1182/blood-2012-05-430140"
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                        "tituloSerie" => "Blood&#46;"
                        "fecha" => "2012"
                        "volumen" => "120"
                        "paginaInicial" => "2700"
                        "paginaFinal" => "2703"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22879539"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            23 => array:3 [
              "identificador" => "bib0120"
              "etiqueta" => "24"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Progress in understanding the pathogenesis of Langerhans cell histiocytosis&#58; back to Histiocytosis X&#63;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "M&#46;L&#46; Berres"
                            1 => "M&#46; Merad"
                            2 => "C&#46;E&#46; Allen"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/bjh.13247"
                      "Revista" => array:6 [
                        "tituloSerie" => "Br J Haematol&#46;"
                        "fecha" => "2015"
                        "volumen" => "169"
                        "paginaInicial" => "3"
                        "paginaFinal" => "13"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25430560"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            24 => array:3 [
              "identificador" => "bib0125"
              "etiqueta" => "25"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Erdheim-Chester disease&#58; consensus recommendations for evaluation&#44; diagnosis&#44; and treatment in the molecular era"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "G&#46; Goyal"
                            1 => "M&#46;L&#46; Heany"
                            2 => "M&#46; Collin"
                            3 => "F&#46; Cohen-Aubart"
                            4 => "A&#46; Vaglio"
                            5 => "B&#46; Durham"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1182/blood.2019003507"
                      "Revista" => array:6 [
                        "tituloSerie" => "Blood&#46;"
                        "fecha" => "2020"
                        "volumen" => "135"
                        "paginaInicial" => "1929"
                        "paginaFinal" => "1945"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/32187362"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            25 => array:3 [
              "identificador" => "bib0130"
              "etiqueta" => "26"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Bisphosphonates in Langerhans cell histiocytosis&#58; an international retrospective case series"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "D&#46; Chellapandian"
                            1 => "P&#46; Makras"
                            2 => "G&#46; Kaltsas"
                            3 => "C&#46; van den Bos"
                            4 => "L&#46; Naccache"
                            5 => "R&#46; Rampal"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Mediterr J Hematol Infect Dis&#46;"
                        "fecha" => "2016"
                        "volumen" => "8"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            26 => array:3 [
              "identificador" => "bib0135"
              "etiqueta" => "27"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Differentiating skin-limited and multisystem Langerhans cell histiocytosis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "S&#46;J&#46; Simko"
                            1 => "B&#46; Garmezy"
                            2 => "H&#46; Abhyankar"
                            3 => "P&#46;J&#46; Lupo"
                            4 => "R&#46; Chakraborty"
                            5 => "K&#46;P&#46; Lim"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jpeds.2014.07.063"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Pediatr&#46;"
                        "fecha" => "2014"
                        "volumen" => "165"
                        "paginaInicial" => "990"
                        "paginaFinal" => "996"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25441388"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            27 => array:3 [
              "identificador" => "bib0140"
              "etiqueta" => "28"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Satisfactory remission achieved by PUVA therapy in Langerhans cell hisiocytosis in an elderly patient"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "H&#46; Sakai"
                            1 => "M&#46; Ibe"
                            2 => "H&#46; Takahashi"
                            3 => "S&#46; Matsuo"
                            4 => "K&#46; Okamoto"
                            5 => "I&#46; Makino"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/j.1346-8138.1996.tb03966.x"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Dermatol&#46;"
                        "fecha" => "1996"
                        "volumen" => "23"
                        "paginaInicial" => "42"
                        "paginaFinal" => "46"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8720257"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            28 => array:3 [
              "identificador" => "bib0145"
              "etiqueta" => "29"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Long term follow up of topical mustine treatment for cutaneous langerhans cell histiocytosis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "P&#46;H&#46; Hoeger"
                            1 => "V&#46;R&#46; Nanduri"
                            2 => "J&#46;I&#46; Harper"
                            3 => "D&#46;A&#46; Atherton"
                            4 => "J&#46; Pritchard"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1136/adc.82.6.483"
                      "Revista" => array:6 [
                        "tituloSerie" => "Arch Dis Child&#46;"
                        "fecha" => "2000"
                        "volumen" => "82"
                        "paginaInicial" => "483"
                        "paginaFinal" => "487"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10833183"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            29 => array:3 [
              "identificador" => "bib0150"
              "etiqueta" => "30"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Clinical and radiologic features&#44; lung function and therapeutic results in pulmonary histiocytosis X"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "N&#46; Sch&#246;nfeld"
                            1 => "W&#46; Frank"
                            2 => "S&#46; Wenig"
                            3 => "P&#46; Uhrmeister"
                            4 => "E&#46; Allica"
                            5 => "H&#46; Preussler"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1159/000196248"
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                        "tituloSerie" => "Respiration&#46;"
                        "fecha" => "1993"
                        "volumen" => "60"
                        "paginaInicial" => "38"
                        "paginaFinal" => "44"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8480089"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            30 => array:3 [
              "identificador" => "bib0155"
              "etiqueta" => "31"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Optimal therapy for adults with Langerhans cell histiocytosis bone lesions"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "M&#46;A&#46; Cantu"
                            1 => "P&#46;J&#46; Lupo"
                            2 => "M&#46; Bilgi"
                            3 => "M&#46;J&#46; Hicks"
                            4 => "C&#46;E&#46; Allen"
                            5 => "K&#46;L&#46; McClain"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "PLoS One&#46;"
                        "fecha" => "2012"
                        "volumen" => "7"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            31 => array:3 [
              "identificador" => "bib0160"
              "etiqueta" => "32"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Cladribine activity in adult Langerhans-cell histiocytosis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "A&#46; Saven"
                            1 => "C&#46; Burian"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Blood&#46;"
                        "fecha" => "1999"
                        "volumen" => "93"
                        "paginaInicial" => "4125"
                        "paginaFinal" => "4130"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10361109"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            32 => array:3 [
              "identificador" => "bib0165"
              "etiqueta" => "33"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Single-agent cladribine as an effective front-line therapy for adults with Langerhans cell histiocytosis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "G&#46; Goyal"
                            1 => "J&#46;P&#46; Abeykoon"
                            2 => "M&#46; Hu"
                            3 => "J&#46;R&#46; Young"
                            4 => "M&#46;V&#46; Shah"
                            5 => "N&#46;N&#46; Bennani"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/ajh.26119"
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Hematol&#46;"
                        "fecha" => "2021"
                        "volumen" => "96"
                        "paginaInicial" => "E146"
                        "paginaFinal" => "E150"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/33539584"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            33 => array:3 [
              "identificador" => "bib0170"
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              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
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                      "autores" => array:1 [
                        0 => array:2 [
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                            1 => "J&#46; Li"
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                            4 => "X&#46;M&#46; Gao"
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                    0 => array:2 [
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            34 => array:3 [
              "identificador" => "bib0175"
              "etiqueta" => "35"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Vemurafenib for BRAF V600-Mutant Erdheim-Chester disease and Langerhans cell histiocytosis&#58; analysis of data from the histology-independent&#44; Phase 2&#44; open-label VE-BASKET study"
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                            1 => "V&#46; Subbiah"
                            2 => "A&#46;C&#46; Lockhart"
                            3 => "J&#46;Y&#46; Blay"
                            4 => "I&#46; Puzanov"
                            5 => "I&#46; Chau"
                          ]
                        ]
                      ]
                    ]
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                  "host" => array:1 [
                    0 => array:2 [
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                        "tituloSerie" => "JAMA Oncol&#46;"
                        "fecha" => "2018"
                        "volumen" => "4"
                        "paginaInicial" => "384"
                        "paginaFinal" => "388"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29188284"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
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              "identificador" => "bib0180"
              "etiqueta" => "36"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Efficacy of MEK inhibition in patients with histiocytic neoplasms"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "E&#46;L&#46; Diamond"
                            1 => "B&#46;H&#46; Durham"
                            2 => "G&#46;A&#46; Ulaner"
                            3 => "E&#46; Drill"
                            4 => "J&#46; Buthorn"
                            5 => "M&#46; Ki"
                          ]
                        ]
                      ]
                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/s41586-019-1012-y"
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                        "fecha" => "2019"
                        "volumen" => "567"
                        "paginaInicial" => "521"
                        "paginaFinal" => "524"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30867592"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            36 => array:3 [
              "identificador" => "bib0185"
              "etiqueta" => "37"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Erdheim-Chester disease in childhood&#58; a challenging diagnosis and treatment"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "T&#46;A&#46; Tran"
                            1 => "M&#46; Fabre"
                            2 => "D&#46; Pariente"
                            3 => "I&#46; Craiu"
                            4 => "J&#46; Haroche"
                            5 => "F&#46; Charlotte"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1097/MPH.0b013e3181b76827"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Pediatr Hematol Oncol&#46;"
                        "fecha" => "2009"
                        "volumen" => "31"
                        "paginaInicial" => "782"
                        "paginaFinal" => "786"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19755920"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            37 => array:3 [
              "identificador" => "bib0190"
              "etiqueta" => "38"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Association of both Langerhans cell histiocytosis and Erdheim-Chester disease linked to the BRAFV600E mutation"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
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                            1 => "J&#46; Haroche"
                            2 => "L&#46; Arnaud"
                            3 => "F&#46; Charlotte"
                            4 => "J&#46; Donadieu"
                            5 => "A&#46; N&#233;el"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
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                        "tituloSerie" => "Blood&#46;"
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                        "volumen" => "124"
                        "paginaInicial" => "1119"
                        "paginaFinal" => "1126"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24894769"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
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            38 => array:3 [
              "identificador" => "bib0195"
              "etiqueta" => "39"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Consensus guidelines for the diagnosis and clinical management of Erdheim-Chester disease"
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                          "etal" => true
                          "autores" => array:6 [
                            0 => "E&#46;L&#46; Diamond"
                            1 => "L&#46; Dagna"
                            2 => "D&#46;M&#46; Hyman"
                            3 => "G&#46; Cavalli"
                            4 => "F&#46; Janku"
                            5 => "J&#46; Estrada-Veras"
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                      ]
                    ]
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                        "paginaInicial" => "483"
                        "paginaFinal" => "492"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24850756"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            39 => array:3 [
              "identificador" => "bib0200"
              "etiqueta" => "40"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Phenotypes and survival in Erdheim-Chester disease&#58; results from a 165-patient cohort"
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                          "etal" => true
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                            1 => "J&#46;F&#46; Emile"
                            2 => "F&#46; Carrat"
                            3 => "Z&#46; Helias-Rodzewicz"
                            4 => "V&#46; Taly"
                            5 => "F&#46; Charlotte"
                          ]
                        ]
                      ]
                    ]
                  ]
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                      "doi" => "10.1002/ajh.25055"
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                        "tituloSerie" => "Am J Hematol&#46;"
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                        "volumen" => "93"
                        "paginaInicial" => "E114"
                        "paginaFinal" => "E117"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29396850"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0205"
              "etiqueta" => "41"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The clinical spectrum of Erdheim-Chester disease&#58; an observational cohort study"
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                          "etal" => true
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                            2 => "L&#46;C&#46; Boyd"
                            3 => "R&#46;H&#46; Dave"
                            4 => "B&#46; Durham"
                            5 => "L&#46; Xi"
                          ]
                        ]
                      ]
                    ]
                  ]
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                      "doi" => "10.1182/bloodadvances.2016001784"
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                        "tituloSerie" => "Blood Adv&#46;"
                        "fecha" => "2017"
                        "volumen" => "1"
                        "paginaInicial" => "357"
                        "paginaFinal" => "366"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28553668"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            41 => array:3 [
              "identificador" => "bib0210"
              "etiqueta" => "42"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Cutaneous manifestations of Erdheim-Chester disease &#40;EEC&#41;&#58; clinical&#44; pathological&#44; and molecular features in a monocentric series of 40 patients"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
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                            1 => "S&#46; Barete"
                            2 => "F&#46; Charlotte"
                            3 => "F&#46; Cohen-Aubart"
                            4 => "L&#46; Arnaud"
                            5 => "F&#46; Le Pelletier"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jaad.2015.11.007"
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                        "fecha" => "2016"
                        "volumen" => "74"
                        "paginaInicial" => "513"
                        "paginaFinal" => "520"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26785805"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            42 => array:3 [
              "identificador" => "bib0215"
              "etiqueta" => "43"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Endocrine manifestations in a monocentric cohort of 64 patients with Erdheim-Chester disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:4 [
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                            2 => "F&#46; Cohen Aubart"
                            3 => "M&#46; Leban"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1210/jc.2015-3357"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Clin Endocrinol Metab&#46;"
                        "fecha" => "2016"
                        "volumen" => "101"
                        "paginaInicial" => "305"
                        "paginaFinal" => "313"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26565949"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            43 => array:3 [
              "identificador" => "bib0220"
              "etiqueta" => "44"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Dramatic efficacy of vemurafenib in both multisystemic and refractory Erdheim-Chester disease and Langerhans cell histiocytosis harboring the BRAF V600E mutation"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
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                            1 => "F&#46; Cohen-Aubart"
                            2 => "J&#46;F&#46; Emile"
                            3 => "L&#46; Arnaud"
                            4 => "P&#46; Maksud"
                            5 => "F&#46; Charlotte"
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                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
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                        "tituloSerie" => "Blood&#46;"
                        "fecha" => "2013"
                        "volumen" => "121"
                        "paginaInicial" => "1495"
                        "paginaFinal" => "1500"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23258922"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
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              "identificador" => "bib0225"
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Reproducible and sustained efficacy of targeted therapy with vemurafenib in patients with BRAF&#40;V600E&#41;-mutated Erdheim-Chester disease"
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                        0 => array:2 [
                          "etal" => true
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                            1 => "F&#46; Cohen-Aubart"
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                            3 => "P&#46; Maksud"
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                            5 => "D&#46; Tol&#233;dano"
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                        ]
                      ]
                    ]
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                  "host" => array:1 [
                    0 => array:2 [
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                        "tituloSerie" => "J Clin Oncol&#46;"
                        "fecha" => "2015"
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                        "paginaInicial" => "411"
                        "paginaFinal" => "418"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25422482"
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                          ]
                        ]
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                ]
              ]
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              "identificador" => "bib0230"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Low-dose vemurafenib monotherapy in BRAFV600E-mutated Erdheim-Chester disease"
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                          "etal" => true
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                            4 => "R&#46; Vassallo"
                            5 => "J&#46;H&#46; Ryu"
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                        ]
                      ]
                    ]
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                  "host" => array:1 [
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                        "tituloSerie" => "Leuk Lymphoma&#46;"
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                        "paginaInicial" => "2733"
                        "paginaFinal" => "2737"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/32608295"
                            "web" => "Medline"
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                ]
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            46 => array:3 [
              "identificador" => "bib0235"
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Single-agent dabrafenib for BRAFV600E-mutated histiocytosis"
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                        ]
                      ]
                    ]
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                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29472347"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            47 => array:3 [
              "identificador" => "bib0240"
              "etiqueta" => "48"
              "referencia" => array:1 [
                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Variability in the efficacy of interferon-alpha in Erdheim-Chester disease by patient and site of involvement&#58; results in eight patients"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
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                            1 => "Z&#46; Amoura"
                            2 => "S&#46;G&#46; Trad"
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                            4 => "P&#46; Cluzel"
                            5 => "P&#46;A&#46; Grenier"
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                        ]
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                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/art.22165"
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                        "tituloSerie" => "Arthritis Rheum&#46;"
                        "fecha" => "2006"
                        "volumen" => "54"
                        "paginaInicial" => "3330"
                        "paginaFinal" => "3336"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17009306"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            48 => array:3 [
              "identificador" => "bib0245"
              "etiqueta" => "49"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Treatment of Erdheim-Chester disease with long-term high-dose interferon-&#945;"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "B&#46; Hervier"
                            1 => "L&#46; Arnaud"
                            2 => "F&#46; Charlotte"
                            3 => "B&#46; Wechsler"
                            4 => "J&#46;C&#46; Piette"
                            5 => "Z&#46; Amoura"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.semarthrit.2011.11.004"
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                        "tituloSerie" => "Semin Arthritis Rheum&#46;"
                        "fecha" => "2012"
                        "volumen" => "41"
                        "paginaInicial" => "907"
                        "paginaFinal" => "913"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22300602"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            49 => array:3 [
              "identificador" => "bib0250"
              "etiqueta" => "50"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Cutaneous Rosai-Dorfman disease&#58; clinicopathological profiles&#44; spectrum and evolution of 21 lesions in six patients"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
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                            1 => "W&#46;Y&#46; Chen"
                            2 => "H&#46;N&#46; Liu"
                            3 => "C&#46;C&#46; Huang"
                            4 => "W&#46;R&#46; Lee"
                            5 => "C&#46;H&#46; Hu"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/j.1365-2133.2005.06917.x"
                      "Revista" => array:6 [
                        "tituloSerie" => "Br J Dermatol&#46;"
                        "fecha" => "2006"
                        "volumen" => "154"
                        "paginaInicial" => "277"
                        "paginaFinal" => "286"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16433797"
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                      ]
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              ]
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Consensus recommendations for the diagnosis and clinical management of Rosai-Dorfman-Destombes disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "O&#46; Abla"
                            1 => "E&#46; Jacobsen"
                            2 => "J&#46; Picarsic"
                            3 => "Z&#46; Krenova"
                            4 => "R&#46; Jaffe"
                            5 => "J&#46;F&#46; Emile"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1182/blood-2018-03-839753"
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                        "tituloSerie" => "Blood&#46;"
                        "fecha" => "2018"
                        "volumen" => "131"
                        "paginaInicial" => "2877"
                        "paginaFinal" => "2890"
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                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29720485"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            51 => array:3 [
              "identificador" => "bib0260"
              "etiqueta" => "52"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Clinicopathological features&#44; treatment approaches&#44; and outcomes in Rosai-Dorfman disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "G&#46; Goyal"
                            1 => "A&#46; Ravindran"
                            2 => "J&#46;R&#46; Young"
                            3 => "M&#46;V&#46; Shah"
                            4 => "N&#46;N&#46; Bennani"
                            5 => "M&#46;M&#46; Patnaik"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3324/haematol.2019.219626"
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                        "tituloSerie" => "Haematologica&#46;"
                        "fecha" => "2020"
                        "volumen" => "105"
                        "paginaInicial" => "348"
                        "paginaFinal" => "357"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31004029"
                            "web" => "Medline"
                          ]
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                          "pii" => "S0092867415017171"
                          "estado" => "S300"
                          "issn" => "00928674"
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                  ]
                ]
              ]
            ]
            52 => array:3 [
              "identificador" => "bib0265"
              "etiqueta" => "53"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Disease characteristics&#44; radiologic patterns&#44; comorbid diseases&#44; and ethnic differences in 32 patients with Rosai-Dorfman disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "M&#46; Elshikh"
                            1 => "D&#46; Schellingerhout"
                            2 => "J&#46; Rayan"
                            3 => "A&#46; Taher"
                            4 => "A&#46;K&#46; Elsayes"
                            5 => "B&#46; Mujtaba"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1097/RCT.0000000000000983"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Comput Assist Tomogr&#46;"
                        "fecha" => "2020"
                        "volumen" => "44"
                        "paginaInicial" => "450"
                        "paginaFinal" => "461"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31972751"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            53 => array:3 [
              "identificador" => "bib0270"
              "etiqueta" => "54"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Updates on histiocytic disorders"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "S&#46;R&#46; Vaiselbuh"
                            1 => "Y&#46;T&#46; Bryceson"
                            2 => "C&#46;E&#46; Allen"
                            3 => "J&#46;A&#46; Whitlock"
                            4 => "O&#46; Abla"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/pbc.25017"
                      "Revista" => array:6 [
                        "tituloSerie" => "Pediatr Blood Cancer&#46;"
                        "fecha" => "2014"
                        "volumen" => "61"
                        "paginaInicial" => "1329"
                        "paginaFinal" => "1335"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24610771"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "etiqueta" => "55"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Diverse and targetable kinase alterations drive histiocytic neoplasms"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "E&#46;L&#46; Diamond"
                            1 => "B&#46;H&#46; Durham"
                            2 => "J&#46; Haroche"
                            3 => "Z&#46; Yao"
                            4 => "J&#46; Ma"
                            5 => "S&#46;A&#46; Parikh"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1158/2159-8290.CD-15-0913"
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                        "tituloSerie" => "Cancer Discov&#46;"
                        "fecha" => "2016"
                        "volumen" => "6"
                        "paginaInicial" => "154"
                        "paginaFinal" => "165"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26566875"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            55 => array:3 [
              "identificador" => "bib0280"
              "etiqueta" => "56"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Mutually exclusive recurrent KRAS and MAP2K1 mutations in Rosai-Dorfman disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "S&#46; Garces"
                            1 => "L&#46;J&#46; Medeiros"
                            2 => "K&#46;P&#46; Patel"
                            3 => "S&#46; Li"
                            4 => "S&#46; Pina-Oviedo"
                            5 => "J&#46; Li"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/modpathol.2017.55"
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                        "tituloSerie" => "Mod Pathol&#46;"
                        "fecha" => "2017"
                        "volumen" => "30"
                        "paginaInicial" => "1367"
                        "paginaFinal" => "1377"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28664935"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0285"
              "etiqueta" => "57"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Is Rosai-Dorfman disease a reactve process&#63; Detection of a MAP2K1 L115V mutation in a case of Rosai-Dorfman disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "M&#46;S&#46; Matter"
                            1 => "M&#46; Bihl"
                            2 => "D&#46; Juskevicius"
                            3 => "A&#46; Tzankov"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s00428-017-2173-4"
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                        "tituloSerie" => "Virchows Arch&#46;"
                        "fecha" => "2017"
                        "volumen" => "471"
                        "paginaInicial" => "545"
                        "paginaFinal" => "547"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28597077"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0290"
              "etiqueta" => "58"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Management and outcomes of sinus histiocytosis with massive lymphadenopathy &#40;Rosai Dorfman Disease&#41;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "E&#46;C&#46; Namoglu"
                            1 => "M&#46;E&#46; Hughes"
                            2 => "J&#46;P&#46; Plastaras"
                            3 => "D&#46;J&#46; Landsburg"
                            4 => "A&#46; Maity"
                            5 => "S&#46;D&#46; Nasta"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1080/10428194.2019.1703971"
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                        "tituloSerie" => "Leuk Lymphoma&#46;"
                        "fecha" => "2020"
                        "volumen" => "61"
                        "paginaInicial" => "905"
                        "paginaFinal" => "911"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31876204"
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                      ]
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              ]
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Successful treatment of recurrent autoimmune cytopenias in the context of sinus histiocytosis with massive lymphadenopathy using sirolimus"
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                          "etal" => false
                          "autores" => array:5 [
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                            1 => "R&#46;J&#46; Arceci"
                            2 => "C&#46;J&#46; Gamper"
                            3 => "D&#46;T&#46; Teachey"
                            4 => "E&#46;S&#46; Schafer"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/pbc.25770"
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                        "tituloSerie" => "Pediatr Blood Cancer&#46;"
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                        "paginaInicial" => "358"
                        "paginaFinal" => "360"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26452062"
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        "texto" => "<p id="par0225" class="elsevierStylePara elsevierViewall">We wish to thank Joaquim Marcoval &#40;Dermatology&#41;&#44; Montserrat Cort&#233;s and Azahara Palomar &#40;Nuclear Medicine&#41;&#44; Jose Antonio Narv&#225;ez &#40;Radiology&#41;&#44; Vanesa Vicens and Maria Molina &#40;Pneumology&#41;&#44; Eva M&#46;<span class="elsevierStyleSup">a</span> Gonzalez-Barca and Montserrat Arnan &#40;Haematology&#41;&#44; Eduard Claver &#40;Cardiology&#41;&#44; Antonio Martinez-Yelamos &#40;Neurology&#41;&#44; Manuel Perez-Maraver &#40;Endocrinology&#41;&#44; Xavier Sanjuan and Mar Varela &#40;Pathological Anatomy&#41;&#44; Conxi L&#225;zaro &#40;Genetics&#41;&#44; for the multidisciplinary care of patients with histiocytosis at the Hospital Universitari de Bellvitge - Institut Catal&#224; d&#39;Oncologia&#46;</p>"
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