Diagnosis and Treatment of Neuroendocrine Lung Tumors

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array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1790 "Ancho" => 3081 "Tamanyo" => 237255 ] ] "descripcion" => array:1 [ "en" => "Level of physical activity in subgroups defined by asthma control according to GEMA (top figure) and the patient (lower figure) (controlled/uncontrolled [partially controlled/poorly controlled])." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "María del Carmen Vennera, César Picado, Lys Herráez, Jordi Galera, Jordi Casafont" "autores" => array:6 [ 0 => array:2 [ "nombre" => "María del Carmen" "apellidos" => "Vennera" ] 1 => array:2 [ "nombre" => "César" "apellidos" => "Picado" ] 2 => array:2 [ "nombre" => "Lys" "apellidos" => "Herráez" ] 3 => array:2 [ "nombre" => "Jordi" "apellidos" => "Galera" ] 4 => array:2 [ "nombre" => "Jordi" "apellidos" => "Casafont" ] 5 => array:1 [ "colaborador" => "on behalf of the Study Group CONTROL" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1579212914001967?idApp=UINPBA00003Z" "url" => "/15792129/0000005000000009/v1_201408240420/S1579212914001967/v1_201408240420/en/main.assets" ] "en" => array:19 [ "idiomaDefecto" => true "cabecera" => "Review" "titulo" => "Diagnosis and Treatment of Neuroendocrine Lung Tumors" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "392" "paginaFinal" => "396" ] ] "autores" => array:1 [ 0 => array:3 [ "autoresLista" => "Julio Sánchez de Cos Escuín" "autores" => array:1 [ 0 => array:3 [ "nombre" => "Julio" "apellidos" => "Sánchez de Cos Escuín" "email" => array:2 [ 0 => "juli1949@separ.es" 1 => "jsdce@ya.com" ] ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Sección de Neumología, Hospital San Pedro de Alcántara, Cáceres, Spain" "identificador" => "aff0005" ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Diagnóstico y tratamiento de los tumores pulmonares neuroendocrinos" ] ] "textoCompleto" => "IntroductionNeuroendocrine cells are derived from primitive pluripotent cells and are characterized by production of neurotransmitters and lack of axons and synapses. The tumors they produce in various organs are classified into 3 groups, anterior, middle and posterior, according to their embryonic origin in the gastrointestinal tract. These tumors may arise not only from the lung but from various regions of the digestive system.<a class="elsevierStyleCrossRefs" href="#bib0005">1,2</a> Pulmonary neuroendocrine tumors (PNT) represent approximately 25%–30% of primitive lung cancers (LC). Of these, 80% are anaplastic small cell lung cancers (SCLC), 12% are large cell neuroendocrine carcinomas (LCNEC) and the remaining 8% are typical carcinoid (TC) and atypical carcinoid (AC) tumors, the latter being the most uncommon.<a class="elsevierStyleCrossRefs" href="#bib0015">3–5</a> As discussed below, the prognosis for these tumors is very variable and although some, such as TCs, are associated with good life expectancy, they should not be described as “benign” as they all have metastatic potential.<a class="elsevierStyleCrossRef" href="#bib0015">3</a> At present, these tumors are classified according to their grade of malignancy as: low grade (TC), intermediate grade (AC) and high grade (LCNEC and SCLC) (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). The latest World Health Organization lung tumor classification (2004) also includes other entities, such as diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) and tumorlets.<a class="elsevierStyleCrossRefs" href="#bib0030">6–8</a> The latter are accumulations of neuroendocrine cells generally found in the airways that invade the basement membrane. Their appearance is similar to that of carcinoid tumors but they measure less than 0.5cm. They are usually found by chance and do not cause symptoms.<a class="elsevierStyleCrossRef" href="#bib0035">7</a> Although the significance and natural history of DIPNECHs has not been well determined, they are considered by many as the earliest manifestation of neuroendocrine disease and classed as precancerous lesions.<a class="elsevierStyleCrossRef" href="#bib0040">8</a> They are often associated with chronic bronchopulmonary lesions, such as bronchiectasis and fibrosis, so in this setting they are considered reactive lesions. They rarely occur in previously normal lungs, and if they do, they may develop into carcinoid tumors.<a class="elsevierStyleCrossRef" href="#bib0015">3</a><elsevierMultimedia ident="tbl0005"></elsevierMultimedia>With regard to the histological classification of these tumors, some criteria for the definition of the various types are shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>. Surgical specimens often have to be examined to determine diagnosis, particularly in the case of LCNEC. When only small biopsy specimens from fiberoptic bronchoscopy are available, it may be very difficult to establish a precise diagnosis. In addition to the mitotic index, the presence or absence of necrosis and the structure of the tumor, the immunohistochemical detection of various neuroendocrine markers, such as chromogranin A, synaptophysin or CD56 and other molecular changes may be an aid to identification.<a class="elsevierStyleCrossRefs" href="#bib0015">3,7,9</a> LCNEC does not always display all the features that characterize this lineage; therefore, in terms of the overall group of large cell carcinomas, the possible spectrum of neuroendocrine differentiation varies widely<a class="elsevierStyleCrossRefs" href="#bib0030">6,7</a> (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>). Moreover, the Ki-67 proliferation marker has recently been identified as possibly useful for distinguishing between low and high grade tumors, particularly when only small biopsies or cytological specimens are available.<a class="elsevierStyleCrossRefs" href="#bib0015">3,8</a> Despite the availability of these techniques, differential diagnosis of the disease is often complicated and careful evaluation by experienced pathologists is required.<a class="elsevierStyleCrossRef" href="#bib0040">8</a> Recent studies suggest that as LCNEC is relatively rare and difficult to diagnose, it may be underdiagnosed, and although it frequently resembles conventional non-small cell lung cancer (NSCLC) both clinically and morphologically, its biological characteristics and prognosis are different, and more importantly, its sensitivity to various chemotherapy (CT) regimens appears to be closer to that of SCLC.<a class="elsevierStyleCrossRef" href="#bib0045">9</a><elsevierMultimedia ident="tbl0010"></elsevierMultimedia>Clinical Presentation and DiagnosisLow grade PNTs appear at an earlier age (mean 40–50 years) than most LCs and are not clearly associated with tobacco smoking or gender, while high grade PNTs are mainly diagnosed in men over 60 years of age and are closely related with smoking. Carcinoid tumors are central in 75% of the cases and initial symptoms are cough, hemoptysis, wheezing, recurrent pneumonia or chest pain.<a class="elsevierStyleCrossRefs" href="#bib0010">2,5</a> Paraneoplastic syndromes are uncommon: carcinoid syndrome, considered characteristic, is more common in the gastrointestinal presentation of the disease and only appears in 1%–3% of tumors of pulmonary origin. Others, including Cushing's syndrome (1%–2% of cases), acromegaly, etc., are even less common. However, when a thorough endocrine evaluation is performed, hypersecretion may be found in up to 15% of patients, the majority of whom do not have clinical symptoms.<a class="elsevierStyleCrossRef" href="#bib0025">5</a>Peripheral pulmonary carcinoid tumors are usually detected by chance. The biological behavior of LCNEC and SCLC is more aggressive, so they are more likely to produce metastasis and are often advanced when diagnosed. SCLC commonly occurs with paraneoplastic syndromes of various types (endocrine, neuromuscular, hematological, etc.), the most common of which is insufficient antidiuretic hormone secretion that may occur in up to 40% of cases.<a class="elsevierStyleCrossRef" href="#bib0050">10</a>Diagnosis and StagingLike other more common LCs, the starting point for suspected diagnosis is generally an abnormal image on chest X-ray. Other imaging tests to be performed for defining the anatomical characteristics of the tumor and possible distant metastases, including chest computed tomography (CT), magnetic resonance, scintigraphy, etc., are also similar, so the guidelines for the diagnosis and staging of LC in general<a class="elsevierStyleCrossRefs" href="#bib0055">11–13</a> are also applicable in these patients. Since most tumors are central, a biopsy specimen is usually obtained by fiberoptic bronchoscopy. If the tumor is peripheral, transthoracic biopsy or aspiration may be the first option, although the small size of cytological specimens and biopsies can be a limiting factor for precise diagnosis, as has been mentioned previously. Thus, after the specimen has been examined, a larger specimen may have to be obtained in a second intervention.For staging, carcinoid tumors show some specific biological features that limit the efficacy of tests such as positron emission tomography (PET). These slow-growing tumors have low glucose uptake, so 18F-fluordeoxyglucose PET is of little use, particularly in TCs.<a class="elsevierStyleCrossRef" href="#bib0010">2</a> However, new radiotracers, such as 111In-octreotide or 68Ga-DOTATATE, have been developed that, given their special affinity for the somatostatin receptors often present in low grade tumors, are of great utility in diagnosis and staging.<a class="elsevierStyleCrossRef" href="#bib0025">5</a> The usefulness of both 18F-fluordeoxyglucose and 68Ga-DOTATATE was recently evaluated with PET/CT in a group of neuroendocrine tumors of different grades. The authors found an inverse infinity for both radiotracers for low and high grade tumors. High grade tumors showed great avidity for 18F-fluordeoxyglucose and low avidity for 68Ga-DOTATATE, while the opposite was true in low grade tumors.<a class="elsevierStyleCrossRef" href="#bib0070">14</a>68Ga-DOTATATE is not yet available in many centers, but it is currently thought to be of great value in planning interventions and for detecting recurrence of low grade carcinoid tumors.As discussed below, the most common therapeutic option for low grade PNTs is surgery, but the rapid dissemination of high grade tumors often rules out this approach. However, classification using the tumor, node, metastasis (TNM) system is useful for both groups. The latest edition of the TNM classification is not only more accurate, but has also shown greater universality and its prognostic value in both SCLC and carcinoid tumors has been confirmed.<a class="elsevierStyleCrossRefs" href="#bib0075">15–18</a>PrognosisAs mentioned above, the PNT spectrum encompasses a range of tumors with important pathological, biological and clinical differences. Consequently, life expectancy also differs greatly. Most carcinoid tumors are diagnosed in TNM stages I and II, are mostly operable, and 5-year survival is over 90%. In contrast, most LCNECs and SCLCs are diagnosed in advanced stages, are candidates only for treatment with CT and radiotherapy, and long-term survival is very low (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>).<a class="elsevierStyleCrossRefs" href="#bib0010">2,9,19</a><elsevierMultimedia ident="tbl0015"></elsevierMultimedia>The Spanish Neuroendocrine Tumor Group (EMETNE) analyzed survival data from a large series of resected carcinoid tumors, finding that the histological subtype, the presence or absence of mediastinal node involvement and distant metastases were the factors that most influenced prognosis.<a class="elsevierStyleCrossRefs" href="#bib0100">20,21</a> Other authors studying the AC subgroup found that a high mitotic index, size of primary tumor >3.5cm and female sex were independent indicators for poor prognosis.<a class="elsevierStyleCrossRef" href="#bib0110">22</a>Given the difficulties encountered in the pathological diagnosis of LCNECs and their rarity, few studies analyzing prognostic factors have been published, although TNM staging appears to be of value in this respect.<a class="elsevierStyleCrossRefs" href="#bib0025">5,9</a> Although survival among resected patients varies widely depending on staging, it seems that, if staging is similar, patients with LCNEC have poorer life expectancy that those with NSCLC.<a class="elsevierStyleCrossRef" href="#bib0045">9</a> Lastly, in the case of SCLCs, many studies on prognostic indicators have been available for some time.<a class="elsevierStyleCrossRef" href="#bib0115">23</a> In this review, only the expediency of using the new TNM classification in this entity is mentioned, although the simple and traditional subdivision into two groups, limited or extended disease (limited to one hemithorax or extended beyond that), still has practical value.TreatmentIf SCLCs are excluded, PNTs represent a small proportion of primitive lung cancers and the various types show wide biological heterogeneity. This explains the insufficient number of clinical trials comparing large, homogeneous patient groups, and the consequent low grade of scientific evidence for many of the treatment regimens discussed. With the exception of SCLCs, there are few randomized studies supporting the currently used regimens. This does not mean that there are no firm indications backed up by experience, such as resection of most TNM stage I and II carcinoid tumors, given the excellent survival results of this procedure. The treatment of each of the various PNT groups is discussed individually below.Carcinoid TumorsTCs and ACs, of low and intermediate grade, respectively, are almost always candidates for surgery, and most TNM stage I and II tumors have high life expectancy (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>).<a class="elsevierStyleCrossRefs" href="#bib0010">2,5,20,21</a> Lobectomy is the most commonly performed procedure, although for central tumors, sleeve resections may be performed to preserve lung parenchyma.<a class="elsevierStyleCrossRefs" href="#bib0010">2,19</a> In elderly patients with poor lung function and peripheral tumors, smaller resections, such as segmentectomy or wedge resection may be the only option, although these procedures are not considered adequate from an oncological point of view, given the small but real metastatic potential of these tumors.<a class="elsevierStyleCrossRef" href="#bib0095">19</a> The relapse rate ranges between 5% and 30% and is higher in ACs and patients with mediastinal node involvement.<a class="elsevierStyleCrossRefs" href="#bib0010">2,19,20</a> For this reason, adjuvant treatment with CT and/or thoracic radiation therapy (TRT) is recommended, although efficacy has not been demonstrated.<a class="elsevierStyleCrossRefs" href="#bib0010">2,5,19,24</a> There are no clear, evidence-based recommendations on the best approach in the case of incomplete resection, distant relapse or even in those rare cases in which the carcinoid tumor at the time of diagnosis is in a sufficiently advanced stage (TNM IIIB or IV) as to be considered inoperable. A recent guideline recommends TRT for TCs with mediastinal involvement and combined CT and TRT for ACs,<a class="elsevierStyleCrossRef" href="#bib0125">25</a> although the grade of evidence is low. The most commonly used CT regimen is based on platinum derivatives and etoposide (similar to the standard SCLC regimen), although limited experiences have also been published with other drugs, such as streptozotocin, doxorubicin with 5-fluorouracil, temozolamide or everolimus.<a class="elsevierStyleCrossRefs" href="#bib0025">5,25,26</a> The rate of favorable responses (mainly partial remissions) did not exceed 20%–30% in the best series.<a class="elsevierStyleCrossRefs" href="#bib0020">4,5,19,26</a>In the symptomatic treatment of carcinoid syndrome, somatostatin analogs, such as octreotide and similar derivatives, e.g., lanreotide, have been used for their antisecretory effects. They are administered intramuscularly and have shown moderate efficacy in controlling symptoms, although they do not lack adverse effects.<a class="elsevierStyleCrossRefs" href="#bib0005">1,2,5</a> In patients with symptomatic advanced gastrointestinal neuroendocrine tumors, a recent randomized trial showed better results with the combination of octreotide and everolimus (an inhibitor of the metabolic pathways involved in the pathogenesis of these tumors, e.g., m-TOR) than with octreotide alone.<a class="elsevierStyleCrossRef" href="#bib0135">27</a> Interferon-alpha<a class="elsevierStyleCrossRef" href="#bib0140">28</a> and combinations of interferon with the antiangiogenic bevacizumab<a class="elsevierStyleCrossRef" href="#bib0145">29</a> have also been studied. However, the very limited experience available due to the rarity of carcinoid syndrome and the fact that these compounds are not free of adverse effects suggest that patients who are potential candidates for these treatments should be referred to specialist centers.<a class="elsevierStyleCrossRef" href="#bib0025">5</a>Large Cell Neuroendocrine CarcinomaAs discussed above, LCNEC shares some morphologic features with other lineages and is often difficult to identify, particularly when the available biopsy specimens are small. Although LCNEC is classified within the group of non-microcytic large cell carcinomas, it is more similar in its molecular profile and biological behavior to SCLC.<a class="elsevierStyleCrossRefs" href="#bib0045">9,30</a> In any case, for TNM stages I and II, surgery is considered standard treatment.<a class="elsevierStyleCrossRefs" href="#bib0010">2,5,31</a> However, poor long term survival (between 27% and 67% at 5 years in stage I resected patients<a class="elsevierStyleCrossRef" href="#bib0155">31</a>) suggests that multimodal adjuvant treatment with CT and/or TRT may be appropriate. Various retrospective analyses have found greater survival in patients receiving adjuvant CT with platinum derivatives and etoposide, similar to the standard regiment for SCLC.<a class="elsevierStyleCrossRefs" href="#bib0045">9,31</a> These results appear to be confirmed by a prospective Japanese study which reported a reduced rate of relapse and longer 5-year survival in patients who received adjuvant treatment.<a class="elsevierStyleCrossRef" href="#bib0155">31</a>Since LCNEC is generally diagnosed in advanced stages, CT is the only treatment option. Given the diagnostic difficulties of typing and confusion about positioning this entity in the histologic classification of LCs, some recent treatment guidelines do not appear to distinguish between this variety and other SCLCs.<a class="elsevierStyleCrossRef" href="#bib0125">25</a> However, several retrospective analyses coincide in finding improved survival and response rates with CT regimens similar to those used for SCLC (cisplatin and etoposide) compared to those used for NSCLS.<a class="elsevierStyleCrossRefs" href="#bib0045">9,32–34</a> A recent phase II trial found a partial remission rate of 46.7% with combined irinotecan and cisplatin, very similar to the 50%–60% reported in previous studies.<a class="elsevierStyleCrossRefs" href="#bib0160">32–34</a> These data suggest that LCNECs are sensitive to the same agents used in SCLC, although the response rate in the former is somewhat lower. Lastly, although the rate of epidermal growth factor receptor mutations in these tumors is unknown, the report of a case of LCNEC with positive mutation and an excellent response to gefitinib<a class="elsevierStyleCrossRef" href="#bib0180">36</a> suggests that this aspect may be of therapeutic interest.<a class="elsevierStyleCrossRef" href="#bib0175">35</a>A simplified schematic of treatment options is presented in <a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>.<elsevierMultimedia ident="tbl0020"></elsevierMultimedia>For the much more common SCLC, numerous treatment guidelines based on large randomized trials are available.<a class="elsevierStyleCrossRefs" href="#bib0125">25,37</a> Surgery is currently reserved for a small number of stage I patients with an acceptable general condition, after possible hidden metastases have been ruled out by thorough evaluation (less than 3% of all SCLCs).<a class="elsevierStyleCrossRef" href="#bib0185">37</a> In other patients with disease limited to the chest (LD), the treatment of choice is based on the concurrent combination of CT and TRT (<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>). Early initiation of hyperfractionated radiation therapy twice a day from the first or second cycle along with platinum-based CT plus etoposide every 21 days for a total of 4–6 cycles is recommended. For extended disease (contralateral and/or extrathoracic pulmonary metastases) (ED), CT consisting of etoposide plus platinum or irinotecan should be administered. Prophylactic cranial irradiation is currently indicated in the case of objective, complete or partial response, in both LD and ED,<a class="elsevierStyleCrossRefs" href="#bib0125">25,37</a> given the high rate of central nervous system relapse. Lastly, with regard to new targeted or specific anti-target treatments, none of the compounds tested has shown efficacy in this type of LC.<a class="elsevierStyleCrossRef" href="#bib0185">37</a>Since PNTs, with the exception of SCLCs, make up a tiny proportion of all LCs, the subtypes have very distinct biological features and histologic typing is often difficult, it is understandable that the available scientific evidence is insufficient to serve as a basis for therapeutic recommendations. To achieve this objective, as already proposed in the IASLC meetings,<a class="elsevierStyleCrossRef" href="#bib0045">9</a> international collaboration among the various existing registries is essential to allow clinical trials with sufficient numbers of patients to be conducted.FundingThis paper did not receive funding from any source.Conflict of InterestsThere are no conflicts of interests associated with this paper." "textoCompletoSecciones" => array:1 [ "secciones" => array:12 [ 0 => array:2 [ "identificador" => "xres364402" "titulo" => "Abstract" ] 1 => array:2 [ "identificador" => "xpalclavsec344006" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xres364401" "titulo" => "Resumen" ] 3 => array:2 [ "identificador" => "xpalclavsec344005" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Clinical Presentation and Diagnosis" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Diagnosis and Staging" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Prognosis" ] 8 => array:3 [ "identificador" => "sec0025" "titulo" => "Treatment" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0030" "titulo" => "Carcinoid Tumors" ] 1 => array:2 [ "identificador" => "sec0035" "titulo" => "Large Cell Neuroendocrine Carcinoma" ] ] ] 9 => array:2 [ "identificador" => "sec0040" "titulo" => "Funding" ] 10 => array:2 [ "identificador" => "sec0045" "titulo" => "Conflict of Interests" ] 11 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2014-01-07" "fechaAceptado" => "2014-02-03" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec344006" "palabras" => array:4 [ 0 => "Pulmonary neuroendocrine tumors" 1 => "Diagnosis" 2 => "Treatment" 3 => "Classification" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec344005" "palabras" => array:4 [ 0 => "Tumores pulmonares neuroendocrinos" 1 => "Diagnóstico" 2 => "Tratamiento" 3 => "Clasificación" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Pulmonary neuroendocrine tumors (PNT) encompass a broad spectrum of tumors including typical carcinoid (TC) and atypical (AC) tumors, large-cell neuroendocrine carcinoma (LCNEC) and small-cell lung cancer (SCLC). Although no variety can be considered benign, AC and TC have a much lower metastatic potential, are usually diagnosed in early stages, and most are candidates for surgical treatment. Several chemotherapy (CT) regimens are available in the case of recurrence or in advanced stages, although scientific evidence is insufficient. LCNEC, which is currently classified alongside large-cell carcinomas, have molecular features, biological behavior and CT sensitivity profile closely resembling SCLC. Pathological diagnosis is often difficult, despite the availability of immunohistochemical techniques, and surgical specimens may be necessary. The diagnostic tests used are similar to those used in other lung tumors, with some differences in the optimal tracer in positron emission tomography. The new TNM classification is useful for staging these tumors. Carcinoid syndrome, very rare in PNT, may cause symptoms that are difficult to control and requires special therapy with somatostatin analogs and other drugs. Overall, with the exception of SCLC, new trials are needed to provide a response to the many questions arising with regard to the best treatment in each lineage and each stage." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "Los tumores neuroendocrinos pulmonares (TNP) abarcan un amplio espectro de tumores que incluyen los carcinoides típicos (CT) y atípicos (CA), el carcinoma neuroendocrino de células grandes (CNCG) y el carcinoma microcítico de pulmón (CMP). Aunque ninguna variedad puede considerarse benigna, los CA y CT tienen un potencial metastásico mucho menor, habitualmente se diagnostican en estadios tempranos y la mayoría son subsidiarios de tratamiento quirúrgico. Se dispone de varias pautas de quimioterapia (QT) en caso de recidiva o en estadios avanzados, aunque la evidencia científica es insuficiente. Los CNCG, encuadrados en la clasificación actual junto a los carcinomas de células grandes, tienen rasgos moleculares, conducta biológica y perfil de sensibilidad a la QT que los asemejan más a los CMP. Con frecuencia su diagnóstico anatomopatológico es difícil, pese al uso de técnicas de inmunohistoquímica, y pueden ser necesarias muestras quirúrgicas. Las pruebas diagnósticas a utilizar son similares a las empleadas en otros tumores de pulmón, con algunas diferencias en cuanto al trazador óptimo que se usa en la tomografía de emisión de positrones. La nueva clasificación TNM es de utilidad en la estadificación de estos tumores. El síndrome carcinoide, muy infrecuente en los TNP, puede dar síntomas de difícil control que requieren medicación especial con análogos de la somatostatina y otros fármacos. En general, y con la excepción del CMP, se necesitan nuevos ensayos que den respuesta a numerosos interrogantes sobre el mejor tratamiento a aplicar en cada estirpe y cada estadio." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Sánchez de Cos Escuín J. Diagnóstico y tratamiento de los tumores pulmonares neuroendocrinos. Arch Bronconeumol. 2014;50:392–396." ] ] "multimedia" => array:4 [ 0 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "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=""><thead title="thead"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</td><td 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" style="border-bottom: 2px solid black">Typical carcinoid \t\t\t\t\t\t\n \t\t\t\t</td><td 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" style="border-bottom: 2px solid black">Atypical carcinoid \t\t\t\t\t\t\n \t\t\t\t</td><td 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" style="border-bottom: 2px solid black">Large cell neuroendocrine carcinoma \t\t\t\t\t\t\n \t\t\t\t</td><td 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" style="border-bottom: 2px solid black">Small cell lung cancer \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><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">% Of primitive pulmonary tumors \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\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%–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">0.1%–0.2% \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">2%–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">15%–20% \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">Differentiation grade \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Low \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Intermediate \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">High \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">High \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">Mitotic count per 2mm2 field \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\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">2–10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">>10 (media: 70) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">>10 (media: 80) \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">Necrosis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Absent \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Present. Focal \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Extensive \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Extensive \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">Lymphatic metastases at diagnosis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5%–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">40%–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">60%–80% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">60%–80% \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">Distant metastases at diagnosis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\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%–5% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">20%–25% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\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% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">60%–70% \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab546861.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Characteristics of Pulmonary Neuroendocrine Tumors." ] ] 1 => array:7 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "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=""><thead title="thead"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</td><td 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" style="border-bottom: 2px solid black">Neuroendocrine morphology \t\t\t\t\t\t\n \t\t\t\t</td><td 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" style="border-bottom: 2px solid black">Neuroendocrine features on immunohistochemistry or electronic microscopy \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><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">Large cell neuroendocrine carcinoma \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\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">Yes \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">Large cell carcinoma with neuroendocrine morphology \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\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" title="\n \t\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 cell carcinoma with neuroendocrine differentiation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\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></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">Large cell carcinoma with no neuroendocrine features \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\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></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab546864.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Morphologic Features and Neuroendocrine Differentiation in Large Cell Lung Carcinomas." ] ] 2 => array:7 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "tablatextoimagen" => array:2 [ 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"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="5" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">5-Year and median survival</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</td><td 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" style="border-bottom: 2px solid black">Stage I% \t\t\t\t\t\t\n \t\t\t\t</td><td 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" style="border-bottom: 2px solid black">Stage II% \t\t\t\t\t\t\n \t\t\t\t</td><td 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" style="border-bottom: 2px solid black">Stage III% \t\t\t\t\t\t\n \t\t\t\t</td><td 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" style="border-bottom: 2px solid black">Stage IV median survival (months) \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><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">Typical carcinoid \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">99–100 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">75–96 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">50–93 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" 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" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Atypical carcinoid \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">71–100 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">33–100 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">22–50 \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="" 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" title="\n \t\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 cell neuroendocrine \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">33 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">23 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" 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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">(9.2–12.6) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab546863.png" ] ] 1 => 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"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</td><td 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" style="border-bottom: 2px solid black">Limited disease % median (months) \t\t\t\t\t\t\n \t\t\t\t</td><td 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" style="border-bottom: 2px solid black">Extended disease % median (months) \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><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">Small cell lung cancer \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">20–25 (18–24) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><10%<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> (10) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab546860.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "<10% at 2 years." ] ] ] "descripcion" => array:1 [ "en" => "Pulmonary Neuroendocrine Tumor Survival." ] ] 3 => array:7 [ "identificador" => "tbl0020" "etiqueta" => "Table 4" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "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"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</td><td 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" style="border-bottom: 2px solid black">Stages I and II \t\t\t\t\t\t\n \t\t\t\t</td><td 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" style="border-bottom: 2px solid black">Stage III \t\t\t\t\t\t\n \t\t\t\t</td><td 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" style="border-bottom: 2px solid black">Stage IV \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><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">Typical carcinoid \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\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">Surgery<a class="elsevierStyleCrossRef" href="#tblfn0010">a</a>Adjuvant TRT? \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CTSymptomatic treatment of carcinoid syndrome? \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">Atypical carcinoid \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\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">Surgery<a class="elsevierStyleCrossRef" href="#tblfn0010">a</a>Adjuvant CT and/or TRT? \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CTSymptomatic treatment of carcinoid syndrome? \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">Large cell endocrine \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">SurgeryAdjuvant CT and/or TRT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Multimodal treatment<a class="elsevierStyleCrossRef" href="#tblfn0015">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">CT (etoposide and platinum-based regimens) \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">Small cell carcinoma \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\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<a class="elsevierStyleCrossRef" href="#tblfn0020">c</a>Concurrent CT and TRT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Concurrent CT and TRT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CT \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab546862.png" ] ] ] "notaPie" => array:3 [ 0 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "a" "nota" => "Standard resection if considered operable." ] 1 => array:3 [ "identificador" => "tblfn0015" "etiqueta" => "b" "nota" => "In these cases, multimodal treatment should include CT and/or TRT. In some cases, surgery may also be attempted, but there are no evidence-based recommendations (see text)." ] 2 => array:3 [ "identificador" => "tblfn0020" "etiqueta" => "c" "nota" => "Recent recommendations limit the use of surgery in SCLC to stage I cases after a detailed staging process." ] ] ] "descripcion" => array:1 [ "en" => "Treatment of Pulmonary Neuroendocrine Tumors." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:37 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Carcinoids tumors" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "M.H. Kulke" 1 => "R.J. 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Diagnosis and Treatment of Neuroendocrine Lung Tumors

Diagnóstico y tratamiento de los tumores pulmonares neuroendocrinos

Julio Sánchez de Cos Escuín

Sección de Neumología, Hospital San Pedro de Alcántara, Cáceres, Spain

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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">Neuroendocrine cells are derived from primitive pluripotent cells and are characterized by production of neurotransmitters and lack of axons and synapses&#46; The tumors they produce in various organs are classified into 3 groups&#44; anterior&#44; middle and posterior&#44; according to their embryonic origin in the gastrointestinal tract&#46; These tumors may arise not only from the lung but from various regions of the digestive system&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;2</span></a> Pulmonary neuroendocrine tumors &#40;PNT&#41; represent approximately 25&#37;&#8211;30&#37; of primitive lung cancers &#40;LC&#41;&#46; Of these&#44; 80&#37; are anaplastic small cell lung cancers &#40;SCLC&#41;&#44; 12&#37; are large cell neuroendocrine carcinomas &#40;LCNEC&#41; and the remaining 8&#37; are typical carcinoid &#40;TC&#41; and atypical carcinoid &#40;AC&#41; tumors&#44; the latter being the most uncommon&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#8211;5</span></a> As discussed below&#44; the prognosis for these tumors is very variable and although some&#44; such as TCs&#44; are associated with good life expectancy&#44; they should not be described as &#8220;benign&#8221; as they all have metastatic potential&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> At present&#44; these tumors are classified according to their grade of malignancy as&#58; low grade &#40;TC&#41;&#44; intermediate grade &#40;AC&#41; and high grade &#40;LCNEC and SCLC&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; The latest World Health Organization lung tumor classification &#40;2004&#41; also includes other entities&#44; such as diffuse idiopathic pulmonary neuroendocrine cell hyperplasia &#40;DIPNECH&#41; and tumorlets&#46;<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6&#8211;8</span></a> The latter are accumulations of neuroendocrine cells generally found in the airways that invade the basement membrane&#46; Their appearance is similar to that of carcinoid tumors but they measure less than 0&#46;5<span class="elsevierStyleHsp" style=""></span>cm&#46; They are usually found by chance and do not cause symptoms&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> Although the significance and natural history of DIPNECHs has not been well determined&#44; they are considered by many as the earliest manifestation of neuroendocrine disease and classed as precancerous lesions&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> They are often associated with chronic bronchopulmonary lesions&#44; such as bronchiectasis and fibrosis&#44; so in this setting they are considered reactive lesions&#46; They rarely occur in previously normal lungs&#44; and if they do&#44; they may develop into carcinoid tumors&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0010" class="elsevierStylePara elsevierViewall">With regard to the histological classification of these tumors&#44; some criteria for the definition of the various types are shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46; Surgical specimens often have to be examined to determine diagnosis&#44; particularly in the case of LCNEC&#46; When only small biopsy specimens from fiberoptic bronchoscopy are available&#44; it may be very difficult to establish a precise diagnosis&#46; In addition to the mitotic index&#44; the presence or absence of necrosis and the structure of the tumor&#44; the immunohistochemical detection of various neuroendocrine markers&#44; such as chromogranin A&#44; synaptophysin or CD56 and other molecular changes may be an aid to identification&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;7&#44;9</span></a> LCNEC does not always display all the features that characterize this lineage&#59; therefore&#44; in terms of the overall group of large cell carcinomas&#44; the possible spectrum of neuroendocrine differentiation varies widely<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6&#44;7</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46; Moreover&#44; the Ki-67 proliferation marker has recently been identified as possibly useful for distinguishing between low and high grade tumors&#44; particularly when only small biopsies or cytological specimens are available&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;8</span></a> Despite the availability of these techniques&#44; differential diagnosis of the disease is often complicated and careful evaluation by experienced pathologists is required&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> Recent studies suggest that as LCNEC is relatively rare and difficult to diagnose&#44; it may be underdiagnosed&#44; and although it frequently resembles conventional non-small cell lung cancer &#40;NSCLC&#41; both clinically and morphologically&#44; its biological characteristics and prognosis are different&#44; and more importantly&#44; its sensitivity to various chemotherapy &#40;CT&#41; regimens appears to be closer to that of SCLC&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a></p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Clinical Presentation and Diagnosis</span><p id="par0015" class="elsevierStylePara elsevierViewall">Low grade PNTs appear at an earlier age &#40;mean 40&#8211;50 years&#41; than most LCs and are not clearly associated with tobacco smoking or gender&#44; while high grade PNTs are mainly diagnosed in men over 60 years of age and are closely related with smoking&#46; Carcinoid tumors are central in 75&#37; of the cases and initial symptoms are cough&#44; hemoptysis&#44; wheezing&#44; recurrent pneumonia or chest pain&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;5</span></a> Paraneoplastic syndromes are uncommon&#58; carcinoid syndrome&#44; considered characteristic&#44; is more common in the gastrointestinal presentation of the disease and only appears in 1&#37;&#8211;3&#37; of tumors of pulmonary origin&#46; Others&#44; including Cushing&#39;s syndrome &#40;1&#37;&#8211;2&#37; of cases&#41;&#44; acromegaly&#44; etc&#46;&#44; are even less common&#46; However&#44; when a thorough endocrine evaluation is performed&#44; hypersecretion may be found in up to 15&#37; of patients&#44; the majority of whom do not have clinical symptoms&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Peripheral pulmonary carcinoid tumors are usually detected by chance&#46; The biological behavior of LCNEC and SCLC is more aggressive&#44; so they are more likely to produce metastasis and are often advanced when diagnosed&#46; SCLC commonly occurs with paraneoplastic syndromes of various types &#40;endocrine&#44; neuromuscular&#44; hematological&#44; etc&#46;&#41;&#44; the most common of which is insufficient antidiuretic hormone secretion that may occur in up to 40&#37; of cases&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Diagnosis and Staging</span><p id="par0025" class="elsevierStylePara elsevierViewall">Like other more common LCs&#44; the starting point for suspected diagnosis is generally an abnormal image on chest X-ray&#46; Other imaging tests to be performed for defining the anatomical characteristics of the tumor and possible distant metastases&#44; including chest computed tomography &#40;CT&#41;&#44; magnetic resonance&#44; scintigraphy&#44; etc&#46;&#44; are also similar&#44; so the guidelines for the diagnosis and staging of LC in general<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11&#8211;13</span></a> are also applicable in these patients&#46; Since most tumors are central&#44; a biopsy specimen is usually obtained by fiberoptic bronchoscopy&#46; If the tumor is peripheral&#44; transthoracic biopsy or aspiration may be the first option&#44; although the small size of cytological specimens and biopsies can be a limiting factor for precise diagnosis&#44; as has been mentioned previously&#46; Thus&#44; after the specimen has been examined&#44; a larger specimen may have to be obtained in a second intervention&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">For staging&#44; carcinoid tumors show some specific biological features that limit the efficacy of tests such as positron emission tomography &#40;PET&#41;&#46; These slow-growing tumors have low glucose uptake&#44; so <span class="elsevierStyleSup">18</span>F-fluordeoxyglucose PET is of little use&#44; particularly in TCs&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> However&#44; new radiotracers&#44; such as <span class="elsevierStyleSup">111</span>In-octreotide or <span class="elsevierStyleSup">68</span>Ga-DOTATATE&#44; have been developed that&#44; given their special affinity for the somatostatin receptors often present in low grade tumors&#44; are of great utility in diagnosis and staging&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> The usefulness of both <span class="elsevierStyleSup">18</span>F-fluordeoxyglucose and <span class="elsevierStyleSup">68</span>Ga-DOTATATE was recently evaluated with PET&#47;CT in a group of neuroendocrine tumors of different grades&#46; The authors found an inverse infinity for both radiotracers for low and high grade tumors&#46; High grade tumors showed great avidity for <span class="elsevierStyleSup">18</span>F-fluordeoxyglucose and low avidity for <span class="elsevierStyleSup">68</span>Ga-DOTATATE&#44; while the opposite was true in low grade tumors&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a><span class="elsevierStyleSup">68</span>Ga-DOTATATE is not yet available in many centers&#44; but it is currently thought to be of great value in planning interventions and for detecting recurrence of low grade carcinoid tumors&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">As discussed below&#44; the most common therapeutic option for low grade PNTs is surgery&#44; but the rapid dissemination of high grade tumors often rules out this approach&#46; However&#44; classification using the tumor&#44; node&#44; metastasis &#40;TNM&#41; system is useful for both groups&#46; The latest edition of the TNM classification is not only more accurate&#44; but has also shown greater universality and its prognostic value in both SCLC and carcinoid tumors has been confirmed&#46;<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15&#8211;18</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Prognosis</span><p id="par0040" class="elsevierStylePara elsevierViewall">As mentioned above&#44; the PNT spectrum encompasses a range of tumors with important pathological&#44; biological and clinical differences&#46; Consequently&#44; life expectancy also differs greatly&#46; Most carcinoid tumors are diagnosed in TNM stages I and II&#44; are mostly operable&#44; and 5-year survival is over 90&#37;&#46; In contrast&#44; most LCNECs and SCLCs are diagnosed in advanced stages&#44; are candidates only for treatment with CT and radiotherapy&#44; and long-term survival is very low &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;9&#44;19</span></a></p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0045" class="elsevierStylePara elsevierViewall">The Spanish Neuroendocrine Tumor Group &#40;EMETNE&#41; analyzed survival data from a large series of resected carcinoid tumors&#44; finding that the histological subtype&#44; the presence or absence of mediastinal node involvement and distant metastases were the factors that most influenced prognosis&#46;<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">20&#44;21</span></a> Other authors studying the AC subgroup found that a high mitotic index&#44; size of primary tumor &#62;3&#46;5<span class="elsevierStyleHsp" style=""></span>cm and female sex were independent indicators for poor prognosis&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">Given the difficulties encountered in the pathological diagnosis of LCNECs and their rarity&#44; few studies analyzing prognostic factors have been published&#44; although TNM staging appears to be of value in this respect&#46;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;9</span></a> Although survival among resected patients varies widely depending on staging&#44; it seems that&#44; if staging is similar&#44; patients with LCNEC have poorer life expectancy that those with NSCLC&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> Lastly&#44; in the case of SCLCs&#44; many studies on prognostic indicators have been available for some time&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> In this review&#44; only the expediency of using the new TNM classification in this entity is mentioned&#44; although the simple and traditional subdivision into two groups&#44; limited or extended disease &#40;limited to one hemithorax or extended beyond that&#41;&#44; still has practical value&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Treatment</span><p id="par0055" class="elsevierStylePara elsevierViewall">If SCLCs are excluded&#44; PNTs represent a small proportion of primitive lung cancers and the various types show wide biological heterogeneity&#46; This explains the insufficient number of clinical trials comparing large&#44; homogeneous patient groups&#44; and the consequent low grade of scientific evidence for many of the treatment regimens discussed&#46; With the exception of SCLCs&#44; there are few randomized studies supporting the currently used regimens&#46; This does not mean that there are no firm indications backed up by experience&#44; such as resection of most TNM stage I and II carcinoid tumors&#44; given the excellent survival results of this procedure&#46; The treatment of each of the various PNT groups is discussed individually below&#46;</p><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Carcinoid Tumors</span><p id="par0060" class="elsevierStylePara elsevierViewall">TCs and ACs&#44; of low and intermediate grade&#44; respectively&#44; are almost always candidates for surgery&#44; and most TNM stage I and II tumors have high life expectancy &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;5&#44;20&#44;21</span></a> Lobectomy is the most commonly performed procedure&#44; although for central tumors&#44; sleeve resections may be performed to preserve lung parenchyma&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;19</span></a> In elderly patients with poor lung function and peripheral tumors&#44; smaller resections&#44; such as segmentectomy or wedge resection may be the only option&#44; although these procedures are not considered adequate from an oncological point of view&#44; given the small but real metastatic potential of these tumors&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> The relapse rate ranges between 5&#37; and 30&#37; and is higher in ACs and patients with mediastinal node involvement&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;19&#44;20</span></a> For this reason&#44; adjuvant treatment with CT and&#47;or thoracic radiation therapy &#40;TRT&#41; is recommended&#44; although efficacy has not been demonstrated&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;5&#44;19&#44;24</span></a> There are no clear&#44; evidence-based recommendations on the best approach in the case of incomplete resection&#44; distant relapse or even in those rare cases in which the carcinoid tumor at the time of diagnosis is in a sufficiently advanced stage &#40;TNM IIIB or IV&#41; as to be considered inoperable&#46; A recent guideline recommends TRT for TCs with mediastinal involvement and combined CT and TRT for ACs&#44;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> although the grade of evidence is low&#46; The most commonly used CT regimen is based on platinum derivatives and etoposide &#40;similar to the standard SCLC regimen&#41;&#44; although limited experiences have also been published with other drugs&#44; such as streptozotocin&#44; doxorubicin with 5-fluorouracil&#44; temozolamide or everolimus&#46;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;25&#44;26</span></a> The rate of favorable responses &#40;mainly partial remissions&#41; did not exceed 20&#37;&#8211;30&#37; in the best series&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;5&#44;19&#44;26</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">In the symptomatic treatment of carcinoid syndrome&#44; somatostatin analogs&#44; such as octreotide and similar derivatives&#44; e&#46;g&#46;&#44; lanreotide&#44; have been used for their antisecretory effects&#46; They are administered intramuscularly and have shown moderate efficacy in controlling symptoms&#44; although they do not lack adverse effects&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;2&#44;5</span></a> In patients with symptomatic advanced gastrointestinal neuroendocrine tumors&#44; a recent randomized trial showed better results with the combination of octreotide and everolimus &#40;an inhibitor of the metabolic pathways involved in the pathogenesis of these tumors&#44; e&#46;g&#46;&#44; m-TOR&#41; than with octreotide alone&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> Interferon-alpha<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> and combinations of interferon with the antiangiogenic bevacizumab<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> have also been studied&#46; However&#44; the very limited experience available due to the rarity of carcinoid syndrome and the fact that these compounds are not free of adverse effects suggest that patients who are potential candidates for these treatments should be referred to specialist centers&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Large Cell Neuroendocrine Carcinoma</span><p id="par0070" class="elsevierStylePara elsevierViewall">As discussed above&#44; LCNEC shares some morphologic features with other lineages and is often difficult to identify&#44; particularly when the available biopsy specimens are small&#46; Although LCNEC is classified within the group of non-microcytic large cell carcinomas&#44; it is more similar in its molecular profile and biological behavior to SCLC&#46;<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9&#44;30</span></a> In any case&#44; for TNM stages I and II&#44; surgery is considered standard treatment&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;5&#44;31</span></a> However&#44; poor long term survival &#40;between 27&#37; and 67&#37; at 5 years in stage I resected patients<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a>&#41; suggests that multimodal adjuvant treatment with CT and&#47;or TRT may be appropriate&#46; Various retrospective analyses have found greater survival in patients receiving adjuvant CT with platinum derivatives and etoposide&#44; similar to the standard regiment for SCLC&#46;<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9&#44;31</span></a> These results appear to be confirmed by a prospective Japanese study which reported a reduced rate of relapse and longer 5-year survival in patients who received adjuvant treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">Since LCNEC is generally diagnosed in advanced stages&#44; CT is the only treatment option&#46; Given the diagnostic difficulties of typing and confusion about positioning this entity in the histologic classification of LCs&#44; some recent treatment guidelines do not appear to distinguish between this variety and other SCLCs&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> However&#44; several retrospective analyses coincide in finding improved survival and response rates with CT regimens similar to those used for SCLC &#40;cisplatin and etoposide&#41; compared to those used for NSCLS&#46;<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9&#44;32&#8211;34</span></a> A recent phase II trial found a partial remission rate of 46&#46;7&#37; with combined irinotecan and cisplatin&#44; very similar to the 50&#37;&#8211;60&#37; reported in previous studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">32&#8211;34</span></a> These data suggest that LCNECs are sensitive to the same agents used in SCLC&#44; although the response rate in the former is somewhat lower&#46; Lastly&#44; although the rate of epidermal growth factor receptor mutations in these tumors is unknown&#44; the report of a case of LCNEC with positive mutation and an excellent response to gefitinib<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a> suggests that this aspect may be of therapeutic interest&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">A simplified schematic of treatment options is presented in <a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#46;</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia><p id="par0085" class="elsevierStylePara elsevierViewall">For the much more common SCLC&#44; numerous treatment guidelines based on large randomized trials are available&#46;<a class="elsevierStyleCrossRefs" href="#bib0125"><span class="elsevierStyleSup">25&#44;37</span></a> Surgery is currently reserved for a small number of stage I patients with an acceptable general condition&#44; after possible hidden metastases have been ruled out by thorough evaluation &#40;less than 3&#37; of all SCLCs&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a> In other patients with disease limited to the chest &#40;LD&#41;&#44; the treatment of choice is based on the concurrent combination of CT and TRT &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41;&#46; Early initiation of hyperfractionated radiation therapy twice a day from the first or second cycle along with platinum-based CT plus etoposide every 21 days for a total of 4&#8211;6 cycles is recommended&#46; For extended disease &#40;contralateral and&#47;or extrathoracic pulmonary metastases&#41; &#40;ED&#41;&#44; CT consisting of etoposide plus platinum or irinotecan should be administered&#46; Prophylactic cranial irradiation is currently indicated in the case of objective&#44; complete or partial response&#44; in both LD and ED&#44;<a class="elsevierStyleCrossRefs" href="#bib0125"><span class="elsevierStyleSup">25&#44;37</span></a> given the high rate of central nervous system relapse&#46; Lastly&#44; with regard to new targeted or specific anti-target treatments&#44; none of the compounds tested has shown efficacy in this type of LC&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">Since PNTs&#44; with the exception of SCLCs&#44; make up a tiny proportion of all LCs&#44; the subtypes have very distinct biological features and histologic typing is often difficult&#44; it is understandable that the available scientific evidence is insufficient to serve as a basis for therapeutic recommendations&#46; To achieve this objective&#44; as already proposed in the IASLC meetings&#44;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> international collaboration among the various existing registries is essential to allow clinical trials with sufficient numbers of patients to be conducted&#46;</p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Funding</span><p id="par0095" class="elsevierStylePara elsevierViewall">This paper did not receive funding from any source&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Conflict of Interests</span><p id="par0100" class="elsevierStylePara elsevierViewall">There are no conflicts of interests associated with this paper&#46;</p></span></span>"
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              "titulo" => "Carcinoid Tumors"
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              "titulo" => "Large Cell Neuroendocrine Carcinoma"
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    "fechaRecibido" => "2014-01-07"
    "fechaAceptado" => "2014-02-03"
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          "clase" => "keyword"
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            0 => "Pulmonary neuroendocrine tumors"
            1 => "Diagnosis"
            2 => "Treatment"
            3 => "Classification"
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          "palabras" => array:4 [
            0 => "Tumores pulmonares neuroendocrinos"
            1 => "Diagn&#243;stico"
            2 => "Tratamiento"
            3 => "Clasificaci&#243;n"
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        "titulo" => "Abstract"
        "resumen" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Pulmonary neuroendocrine tumors &#40;PNT&#41; encompass a broad spectrum of tumors including typical carcinoid &#40;TC&#41; and atypical &#40;AC&#41; tumors&#44; large-cell neuroendocrine carcinoma &#40;LCNEC&#41; and small-cell lung cancer &#40;SCLC&#41;&#46; Although no variety can be considered benign&#44; AC and TC have a much lower metastatic potential&#44; are usually diagnosed in early stages&#44; and most are candidates for surgical treatment&#46; Several chemotherapy &#40;CT&#41; regimens are available in the case of recurrence or in advanced stages&#44; although scientific evidence is insufficient&#46; LCNEC&#44; which is currently classified alongside large-cell carcinomas&#44; have molecular features&#44; biological behavior and CT sensitivity profile closely resembling SCLC&#46; Pathological diagnosis is often difficult&#44; despite the availability of immunohistochemical techniques&#44; and surgical specimens may be necessary&#46; The diagnostic tests used are similar to those used in other lung tumors&#44; with some differences in the optimal tracer in positron emission tomography&#46; The new TNM classification is useful for staging these tumors&#46; Carcinoid syndrome&#44; very rare in PNT&#44; may cause symptoms that are difficult to control and requires special therapy with somatostatin analogs and other drugs&#46; Overall&#44; with the exception of SCLC&#44; new trials are needed to provide a response to the many questions arising with regard to the best treatment in each lineage and each stage&#46;</p>"
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        "resumen" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Los tumores neuroendocrinos pulmonares &#40;TNP&#41; abarcan un amplio espectro de tumores que incluyen los carcinoides t&#237;picos &#40;CT&#41; y at&#237;picos &#40;CA&#41;&#44; el carcinoma neuroendocrino de c&#233;lulas grandes &#40;CNCG&#41; y el carcinoma microc&#237;tico de pulm&#243;n &#40;CMP&#41;&#46; Aunque ninguna variedad puede considerarse benigna&#44; los CA y CT tienen un potencial metast&#225;sico mucho menor&#44; habitualmente se diagnostican en estadios tempranos y la mayor&#237;a son subsidiarios de tratamiento quir&#250;rgico&#46; Se dispone de varias pautas de quimioterapia &#40;QT&#41; en caso de recidiva o en estadios avanzados&#44; aunque la evidencia cient&#237;fica es insuficiente&#46; Los CNCG&#44; encuadrados en la clasificaci&#243;n actual junto a los carcinomas de c&#233;lulas grandes&#44; tienen rasgos moleculares&#44; conducta biol&#243;gica y perfil de sensibilidad a la QT que los asemejan m&#225;s a los CMP&#46; Con frecuencia su diagn&#243;stico anatomopatol&#243;gico es dif&#237;cil&#44; pese al uso de t&#233;cnicas de inmunohistoqu&#237;mica&#44; y pueden ser necesarias muestras quir&#250;rgicas&#46; Las pruebas diagn&#243;sticas a utilizar son similares a las empleadas en otros tumores de pulm&#243;n&#44; con algunas diferencias en cuanto al trazador &#243;ptimo que se usa en la tomograf&#237;a de emisi&#243;n de positrones&#46; La nueva clasificaci&#243;n TNM es de utilidad en la estadificaci&#243;n de estos tumores&#46; El s&#237;ndrome carcinoide&#44; muy infrecuente en los TNP&#44; puede dar s&#237;ntomas de dif&#237;cil control que requieren medicaci&#243;n especial con an&#225;logos de la somatostatina y otros f&#225;rmacos&#46; En general&#44; y con la excepci&#243;n del CMP&#44; se necesitan nuevos ensayos que den respuesta a numerosos interrogantes sobre el mejor tratamiento a aplicar en cada estirpe y cada estadio&#46;</p>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0025">Please cite this article as&#58; S&#225;nchez de Cos Escu&#237;n J&#46; Diagn&#243;stico y tratamiento de los tumores pulmonares neuroendocrinos&#46; Arch Bronconeumol&#46; 2014&#59;50&#58;392&#8211;396&#46;</p>"
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">Typical carcinoid&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">Atypical carcinoid&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">Large cell neuroendocrine carcinoma&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">Small cell lung cancer&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&#37; Of primitive pulmonary tumors&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
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                  \t\t\t\t">1&#37;&#8211;2&#37;&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">0&#46;1&#37;&#8211;0&#46;2&#37;&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">2&#37;&#8211;3&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">15&#37;&#8211;20&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">Differentiation grade&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">Low&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">Intermediate&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">High&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">High&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">Mitotic count per 2<span class="elsevierStyleHsp" style=""></span>mm<span class="elsevierStyleSup">2</span> field&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">&#60;2&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&#8211;10&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">&#62;10 &#40;media&#58; 70&#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">&#62;10 &#40;media&#58; 80&#41;&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">Necrosis&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">Absent&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">Present&#46; Focal&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">Extensive&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">Extensive&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">Lymphatic metastases at diagnosis&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">5&#37;&#8211;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">40&#37;&#8211;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">60&#37;&#8211;80&#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">60&#37;&#8211;80&#37;&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">Distant metastases at diagnosis&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;&#8211;5&#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">20&#37;&#8211;25&#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">40&#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">60&#37;&#8211;70&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab546861.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Characteristics of Pulmonary Neuroendocrine Tumors&#46;</p>"
        ]
      ]
      1 => array:7 [
        "identificador" => "tbl0010"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "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=""><thead title="thead"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td 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" style="border-bottom: 2px solid black">Neuroendocrine morphology&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td 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" style="border-bottom: 2px solid black">Neuroendocrine features on immunohistochemistry or electronic microscopy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></thead><tbody title="tbody"><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">Large cell neuroendocrine carcinoma&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">Yes&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">Large cell carcinoma with neuroendocrine morphology&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" title="\n
                  \t\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 cell carcinoma with neuroendocrine differentiation&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></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">Large cell carcinoma with no neuroendocrine features&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></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab546864.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Morphologic Features and Neuroendocrine Differentiation in Large Cell Lung Carcinomas&#46;</p>"
        ]
      ]
      2 => array:7 [
        "identificador" => "tbl0015"
        "etiqueta" => "Table 3"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:2 [
          "tablatextoimagen" => array:2 [
            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"><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="5" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">5-Year and median survival</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td 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" style="border-bottom: 2px solid black">Stage <span class="elsevierStyleSmallCaps">I</span>&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td 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" style="border-bottom: 2px solid black">Stage <span class="elsevierStyleSmallCaps">II</span>&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td 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" style="border-bottom: 2px solid black">Stage <span class="elsevierStyleSmallCaps">III</span>&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td 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" style="border-bottom: 2px solid black">Stage <span class="elsevierStyleSmallCaps">IV</span> median survival &#40;months&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></thead><tbody title="tbody"><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">Typical carcinoid&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">99&#8211;100&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">75&#8211;96&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">50&#8211;93&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="" 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" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Atypical carcinoid&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">71&#8211;100&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">33&#8211;100&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">22&#8211;50&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="" 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" title="\n
                  \t\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 cell neuroendocrine&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">33&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">23&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#40;9&#46;2&#8211;12&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab546863.png"
              ]
            ]
            1 => 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"><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td 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" style="border-bottom: 2px solid black">Limited disease &#37; median &#40;months&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td 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" style="border-bottom: 2px solid black">Extended disease &#37; median &#40;months&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></thead><tbody title="tbody"><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">Small cell lung cancer&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">20&#8211;25 &#40;18&#8211;24&#41;&nbsp;\t\t\t\t\t\t\n
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Article information

ISSN: 15792129
Original language: English

DOI:10.1016/j.arbr.2014.06.014

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Year/Month	Html	Pdf	Total

2024 November	1	0	1
2024 October	66	28	94
2024 September	75	36	111
2024 August	108	44	152
2024 July	101	36	137
2024 June	61	33	94
2024 May	95	45	140
2024 April	31	37	68
2024 March	39	21	60
2024 February	28	38	66
2024 January	3	0	3
2023 July	2	0	2
2023 March	7	2	9
2023 February	49	34	83
2023 January	43	40	83
2022 December	58	60	118
2022 November	70	35	105
2022 October	62	30	92
2022 September	45	32	77
2022 August	79	55	134
2022 July	71	38	109
2022 June	40	25	65
2022 May	58	45	103
2022 April	113	32	145
2022 March	133	40	173
2022 February	128	36	164
2022 January	69	39	108
2021 December	62	28	90
2021 November	81	48	129
2021 October	104	58	162
2021 September	75	51	126
2021 August	91	46	137
2021 July	89	32	121
2021 June	106	63	169
2021 May	219	27	246
2021 April	341	126	467
2021 March	338	87	425
2021 February	317	46	363
2021 January	231	32	263
2020 December	219	37	256
2020 November	176	40	216
2020 October	175	40	215
2020 September	168	26	194
2020 August	185	43	228
2020 July	168	35	203
2020 June	199	27	226
2020 May	180	21	201
2020 April	208	52	260
2020 March	245	34	279
2020 February	178	31	209
2020 January	160	30	190
2019 December	190	31	221
2019 November	273	39	312
2019 October	275	25	300
2019 September	271	21	292
2019 August	280	29	309
2019 July	282	23	305
2019 June	317	37	354
2019 May	244	33	277
2019 April	168	50	218
2019 March	167	44	211
2019 February	131	34	165
2019 January	137	26	163
2018 December	119	23	142
2018 November	179	40	219
2018 October	200	25	225
2018 September	153	15	168
2018 July	2	0	2
2018 May	37	0	37
2018 April	81	4	85
2018 March	142	4	146
2018 February	136	9	145
2018 January	275	3	278
2017 December	77	8	85
2017 November	78	2	80
2017 October	56	9	65
2017 September	80	9	89
2017 August	90	13	103
2017 July	86	6	92
2017 June	106	10	116
2017 May	106	11	117
2017 April	107	12	119
2017 March	119	13	132
2017 February	79	1	80
2017 January	58	8	66
2016 December	69	6	75
2016 November	101	7	108
2016 October	68	19	87
2016 September	136	17	153
2016 August	97	24	121
2016 July	42	15	57
2016 March	2	0	2
2016 February	1	0	1
2015 December	2	0	2
2015 October	87	4	91
2015 September	95	19	114
2015 August	72	29	101
2015 July	71	27	98
2015 June	52	18	70
2015 May	72	36	108
2015 April	61	19	80
2015 March	71	18	89
2015 February	61	11	72
2015 January	53	21	74
2014 December	47	41	88
2014 November	1	0	1
2014 October	0	1	1
2014 September	1	0	1

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