Implicación pronóstica de la expresión de telomerasa en adenomas hipofisarios

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Aunque la mayoría de los AH son benignos<a class="elsevierStyleCrossRef" href="#bib0110">3</a>, hay un subgrupo cuya presentación y actividad biológica están en el límite entre benignidad y malignidad. A pesar de los progresos en la comprensión de la patogénesis de los AH, no se ha identificado ningún marcador para predecir de forma independiente su comportamiento agresivo.El telómero es una estructura especializada situada al final del cromosoma eucariótico, cuya función es impedir que las células normales se reproduzcan indefinidamente<a class="elsevierStyleCrossRef" href="#bib0115">4</a>. La persistencia de los telómeros es atribuible a la telomerasa, una enzima ribonucleoproteica encargada de mantener la homeostasis y la integridad cromosómica. Está compuesta por 3 subunidades: telomerasa humana transcriptasa inversa, telomerasa humana ácido ribonucleico y telomerasa asociada a la proteína 1. El desequilibrio entre los telómeros y esta enzima, o su activación, es un paso crítico en el desarrollo del cáncer<a class="elsevierStyleCrossRef" href="#bib0120">5</a>.La actividad de la telomerasa es incuantificable en la mayoría de las células normales<a class="elsevierStyleCrossRef" href="#bib0125">6</a>. Se expresa en células inmortalizadas, como las tumorales<a class="elsevierStyleCrossRef" href="#bib0130">7</a>, y el grado de expresión se correlaciona directamente con el pronóstico en determinados tumores<a class="elsevierStyleCrossRefs" href="#bib0135">8–10</a>.El objetivo de este estudio fue analizar la utilidad pronóstica de la expresión inmunohistoquímica de telomerasa en muestras de tejido hipofisario tumoral de pacientes con AH, seguidos durante al menos 8 años.Pacientes y métodosSe trata de un estudio descriptivo, retrospectivo, de muestras de 51 AH procedentes de 26 mujeres y 25 hombres con una edad media de 54,5±14,5 años y un seguimiento clínico de al menos 8 años. El diagnóstico de AH se basó en el cuadro clínico-biológico y en el examen histopatológico, según los criterios de la OMS<a class="elsevierStyleCrossRef" href="#bib0150">11</a>. Treinta y tres tumores fueron no funcionantes (NF), 13 producían hormona de crecimiento, 4, hormona adrenocorticotrópica y uno, prolactina.Los estudios histopatológicos se realizaron en secciones de tejido que se tiñeron con técnicas histoquímicas (hematoxilina-eosina y reticulina) e inmunohistoquímicas (con anticuerpos primarios específicos contra todas las hormonas adenohipofisarias, así como con el marcador de proliferación celular –Ki-67– y el gen supresor tumoral p53). La expresión de telomerasa se estudió mediante inmunohistoquímica automatizada (Ventana BenchMark XT, EE. UU.) utilizando anticuerpos policlonales (origen: Abcam, dilución: 1/100). El número de células tumorales teñidas se calculó semicuantitativamente por el mismo patólogo y el resultado se clasificó como negativo o positivo (con 3 variantes:<10%, 10-50% y>50% de las células en 500-1.000 células tumorales) (<a class="elsevierStyleCrossRef" href="#fig0005">fig. 1</a>). En casos equívocos, el porcentaje se calculó con un programa procesador de imagen de análisis inmunohistoquímico (ImageJ 1.49, National Institutes of Health, EE. UU.).<elsevierMultimedia ident="fig0005"></elsevierMultimedia>Como grupo control se examinaron muestras de 10 hipófisis normales, obtenidas de autopsias de sujetos de entre 26 y 83 años (media 67,8±12,9 años). La expresión de telomerasa se correlacionó con la progresión o recurrencia del tumor.Se realizaron análisis estadísticos y comparativos básicos apropiados para las distribuciones de datos, utilizando el test exacto de Fisher de 2 colas para comparar los datos categóricos y la prueba t de Student no pareada para comparar los subgrupos con la expresión de telomerasa. La significación estadística se definió como un valor de p<0,05.ResultadosDel total de 51 AH, 40 se clasificaron como típicos y 11 como atípicos. La expresión de telomerasa fue positiva en 43 casos (84,3%), de los que 17 (33,3%) mostraron un marcaje de células tumorales<10% y 26 (51%)≥10%. En ninguna de las hipófisis normales la expresión superó el 10%.Dentro de los 40 AH típicos, 8 (20%) no expresaron telomerasa, 13 (32,5%)<10%, 13 (32,5%) entre 10-50% y 6 (15%)>50%. En cuanto a los 11 AH atípicos, la expresión de telomerasa fue<10% en 4, entre 10-50% en 3 (27,3%) y>50% en los 4 (36,4%) restantes.Por subtipo histológico, los valores medianos más altos del índice de telomerasa se observaron en AH inmunosecretores de hormona estimulante de la tiroides (40% de células tumorales teñidas) y de hormonas foliculoestimulante y luteinizante (28,6%), ambos clínicamente NF, seguidos por tumores secretores de hormona adrenocorticotrópica responsables de una enfermedad de Cushing (25%). De los tumores con positividad inmunohistoquímica para prolactina, los 2 que se observaron con marcación>50% eran atípicos. Ninguno de los AH secretores de hormona de crecimiento presentó inmunomarcación para telomerasa≥10% (p=0,0001).No se observó correlación entre la expresión de telomerasa humana transcriptasa inversa y Ki-67 o p53 (p=0,4986). Tampoco se encontraron diferencias de expresión relacionadas con la edad, el sexo o el tamaño del tumor, ni entre pacientes con tumores neurorradiológicamente invasivos en comparación con los no invasivos.En el último seguimiento clínico, 18 pacientes (35,3%) mostraron progresión o recurrencia tumoral. La expresión de telomerasa fue mayor del 10% en pacientes con recidiva (p=0,0399) y en aquellos que tenían adenomas NF (p=0,0034) (<a class="elsevierStyleCrossRef" href="#tbl0005">tabla 1</a>).<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>DiscusiónEn este estudio realizado en muestras de tejido de AH, el 84,3% de los tumores mostraron expresión de telomerasa, que se asoció a recurrencia de la enfermedad cuando se detectó en más del 10% de las células tumorales.Hasta la fecha, no se ha entendido bien el mecanismo completo de activación de la recurrencia e invasión<a class="elsevierStyleCrossRefs" href="#bib0140">9,12,13</a>. Además, dado que la actividad de telomerasa aumenta en tumores con alto potencial metastásico<a class="elsevierStyleCrossRef" href="#bib0165">14</a>, se ha planteado que podría utilizarse para predecir metástasis. En los AH, son indicadores potenciales de agresividad la invasión local, el crecimiento tumoral o el mantenimiento postoperatorio de la función hormonal<a class="elsevierStyleCrossRefs" href="#bib0170">15,16</a>.En 2 estudios<a class="elsevierStyleCrossRefs" href="#bib0140">9,13</a> se detectó expresión de telomerasa en el 13% de los macroadenomas invasivos. En el nuestro, el 84,3% de los AH expresó telomerasa, en contraste con el 36% reportado por Martins et al.<a class="elsevierStyleCrossRef" href="#bib0180">17</a> utilizando técnicas de reacción en cadena de la polimerasa cuantitativa. Al igual que este último estudio<a class="elsevierStyleCrossRef" href="#bib0180">17</a> y otros<a class="elsevierStyleCrossRef" href="#bib0185">18</a>, no observamos diferencias entre tejido hipofisario neoplásico y normal (grupo control). Un tercio de los tumores presentaron el mismo tipo de marcación que el grupo control, lo que tal vez se explique por su semejanza con el tejido normal y la baja actividad mitótica de la mayoría de los AH<a class="elsevierStyleCrossRef" href="#bib0180">17</a>.Los AH son generalmente típicos, con escasa atipia celular/nuclear, mitosis infrecuentes y Ki-67<3%<a class="elsevierStyleCrossRef" href="#bib0190">19</a> (concretamente en AH típicos el Ki-67 fue del 2,82%); el 52,5% de estos AH o fueron negativos o expresaron<10% de telomerasa. Los AH atípicos presentaron un índice mitótico elevado, un Ki-67>3% (6,73%) y una extensa inmunopositividad para p53; todos fueron positivos para telomerasa y dos tercios la expresaron≥10%. No obstante, al contrario que Harada et al.<a class="elsevierStyleCrossRef" href="#bib0160">13</a>, no observamos ninguna relación entre el número de células positivas a telomerasa y el porcentaje de células tumorales positivas para Ki-67 y p53.A diferencia de Can et al.<a class="elsevierStyleCrossRef" href="#bib0185">18</a>, que no hallaron ninguna relación entre la expresión nuclear de telomerasa humana transcriptasa inversa y las características clínico-patológicas, en nuestro estudio se encontró una mayor expresión en pacientes con recurrencia o progresión tumoral y en pacientes con adenomas NF en comparación con los funcionantes. Esto apunta a que en pacientes con un índice de telomerasa≥10% probablemente exista un mayor riesgo de recurrencia tumoral, justificándose así una monitorización más frecuente.Respecto a las limitaciones del estudio, destaca el pequeño tamaño muestral (51 pacientes, con un amplio rango de edad y distintos grupos histológicos de AH). Esta heterogeneidad podría restringir el hallazgo de diferencias entre grupos.En conclusión, se evidencia que el índice de inmunomarcación de telomerasa≥10% podría utilizarse como factor pronóstico de recurrencia o progresión de los AH, tras observarse una mayor expresión de este marcador en las recurrencias tumorales. Esta conclusión es preliminar y se requieren estudios más amplios para confirmar estos resultados." "textoCompletoSecciones" => array:1 [ "secciones" => array:9 [ 0 => array:3 [ "identificador" => "xres1009110" "titulo" => "Resumen" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Objetivos" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Pacientes y métodos" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusiones" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec968748" "titulo" => "Palabras clave" ] 2 => array:3 [ "identificador" => "xres1009109" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Objectives" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Patients and methods" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusions" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec968747" "titulo" => "Keywords" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introducción" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Pacientes y métodos" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Resultados" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Discusión" ] 8 => array:1 [ "titulo" => "Bibliografía" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2017-07-11" "fechaAceptado" => "2017-12-14" "PalabrasClave" => array:2 [ "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec968748" "palabras" => array:4 [ 0 => "Adenoma hipofisario" 1 => "Biomarcador" 2 => "Inmunohistoquímica" 3 => "Telomerasa transcriptasa inversa" ] ] ] "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec968747" "palabras" => array:4 [ 0 => "Pituitary adenoma" 1 => "Biomarker" 2 => "Immunohistochemistry" 3 => "Telomerase reverse transcriptase" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "es" => array:3 [ "titulo" => "Resumen" "resumen" => "ObjetivosAnalizar el valor pronóstico de la expresión de telomerasa en pacientes con adenomas hipofisarios (AH) seguidos durante al menos 8 años. Pacientes y métodosEstudio retrospectivo de las muestras de 51 AH (40 típicos y 11 atípicos) de pacientes sometidos a cirugía transesfenoidal entre 2006 y 2008, y de 10 hipófisis normales obtenidas por autopsia. Se evaluó la expresión de telomerasa por inmunohistoquímica correlacionándola con la de Ki-67 y p53. ResultadosSe observó expresión de telomerasa en 43 AH (84,3%, 32 de los 40 típicos y en los 11 atípicos), siendo mayor en los casos clínicamente no funcionantes (p=0,0034) y muy escasa en los pacientes con acromegalia (p=0,0001). Hubo una asociación significativa entre el porcentaje de células tumorales (>10%) y la recurrencia del adenoma (p=0,039). No hubo correlación con la expresión de Ki-67 y p53 (p=0,4986) ni se observaron diferencias en función de la edad, el sexo, el tamaño o la invasividad tumoral. ConclusionesUn índice de expresión de telomerasa mayor del 10% en el tejido hipofisario tumoral se asoció a recurrencia o progresión del AH, especialmente en los no funcionantes." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Objetivos" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Pacientes y métodos" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusiones" ] ] ] "en" => array:3 [ "titulo" => "Abstract" "resumen" => "ObjectivesTo analyse the prognostic value of telomerase expression in patients with pituitary adenomas (PAs) followed-up for at least 8 years. Patients and methodsA retrospective study was conducted of samples from 51 PAs (40 typical and 11 atypical) from patients who underwent transsphenoidal surgery between 2006 and 2008 and from 10 normal pituitary glands obtained by autopsy. Telomerase expression was assessed by immunohistochemistry, correlating the expression with that of Ki-67 and p53. ResultsWe observed telomerase expression in 43 PAs (84.3%, 32 of the 40 typical PAs and in the 11 atypical PAs), which was higher in the clinically nonfunctioning cases (P=.0034) and very rare in the patients with acromegaly (P=.0001). There was a significant association between the percentage of tumour cells (>10%) and the recurrence of the adenoma (P=.039). There was no correlation with the expression of Ki-67 and p53 (P=.4986), and there were no differences according to age, sex, tumour size and invasiveness. ConclusionsA telomerase expression rate greater than 10% in the pituitary tumour tissue was associated with recurrence or progression of the PA, especially in the nonfunctioning cases." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Objectives" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Patients and methods" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusions" ] ] ] ] "multimedia" => array:2 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figura 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1120 "Ancho" => 1500 "Tamanyo" => 441077 ] ] "descripcion" => array:1 [ "es" => "Puntuación semicuantitativa de la expresión inmunohistoquímica de telomerasa (×400): A) negativa; B) menos del 10% de células tumorales positivas; C) 10-50% de células tumorales positivas; D) más del 50% de células tumorales positivas." ] ] 1 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Tabla 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Tabla " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "ACTH: hormona adrenocorticotrópica; DE: desviación estándar; FSH: hormona foliculoestimulante; GH: hormona de crecimiento; LH: hormona luteinizante; PRL: prolactina; RM: resonancia magnética; TSH: hormona estimulante de la tiroides." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " colspan="3" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Tipo de adenoma hipofisario</th><th class="td" title="table-head " colspan="2" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Expresión de telomerasa</th><th class="td" title="table-head " align="" valign="top" scope="col"> \t\t\t\t\t\t\n \t\t\t\t</th></tr><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Características \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Total \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Adenoma típico \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Adenoma atípico \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">(<10%) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">(≥10%) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">p \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Número de pacientes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">51 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">40 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">25 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">26 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Edad media en años±DE (rango) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">54,5±14,5 (29-81) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">53,6±14,5 (29-77) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">50,8±12,5 (29-81) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="7" align="left" valign="top"></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Sexo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0,5793 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Femenino \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">26 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">21 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">14 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Masculino \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">25 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">19 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">14 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="7" align="left" valign="top"></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Cuadro clínico \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Prolactinomas \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1,0000 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Acromegalia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">13 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">13 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0,0001 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Enfermedad de Cushing \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0,6098 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">No funcionantes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">33 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">25 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">22 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0,0034 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="7" align="left" valign="top"></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Tamaño del tumor \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0,3238 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Microadenoma \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Macroadenoma \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">40 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">30 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">18 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">22 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="7" align="left" valign="top"></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Extensión/invasión extraselar en RM \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0,2913 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Recurrencia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">18 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">13 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0,0399 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="7" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="7" align="left" valign="top">Subtipo histopatológico</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">PRL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1,0000 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">GH \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">13 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">13 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0,0001 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">ACTH (enfermedad de Cushing) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0,6098 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">ACTH «silente» \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0,3497 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">FSH/LH \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">14 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0,0266 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">TSH \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1,0000 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Hipófisis normal \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1709064.png" ] ] ] ] "descripcion" => array:1 [ "es" => "Características clínicas e histopatológicas de 51 pacientes con adenoma hipofisario" ] ] ] "bibliografia" => array:2 [ "titulo" => "Bibliografía" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:19 [ 0 => array:3 [ "identificador" => "bib0100" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "CBTRUS statistical report: Primary brain and central nervous system tumors diagnosed in the United States in 2008-2012" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "Q.T. 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ORIGINAL BREVE

Implicación pronóstica de la expresión de telomerasa en adenomas hipofisarios

Prognostic implications of telomerase expression in pituitary adenomas

F. Tortosaa,b,

Autor para correspondencia

franciscotortosa.pathology@gmail.com

Autor para correspondencia.

, S.M. Webbb

a Servicio de Anatomía Patológica, Centro Hospitalar Lisboa Norte, EPE-Hospital de Santa Maria, Lisboa, Portugal

b Departamento de Medicina/Endocrinología, Hospital de la Santa Creu i Sant Pau, Instituto de Investigación Biomédica Sant Pau, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Unidad 747, Instituto de Salud Carlos III, Universitat Autònoma de Barcelona (UAB), Barcelona, España

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          "es" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Puntuaci&#243;n semicuantitativa de la expresi&#243;n inmunohistoqu&#237;mica de telomerasa &#40;&#215;400&#41;&#58; A&#41; negativa&#59; B&#41; menos del 10&#37; de c&#233;lulas tumorales positivas&#59; C&#41; 10-50&#37; de c&#233;lulas tumorales positivas&#59; D&#41; m&#225;s del 50&#37; de c&#233;lulas tumorales positivas&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introducci&#243;n</span><p id="par0005" class="elsevierStylePara elsevierViewall">Los tumores de la gl&#225;ndula hipofisaria y de la regi&#243;n selar representan aproximadamente el 15&#37; de los tumores cerebrales<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">1</span></a>&#44; siendo el adenoma hipofisario &#40;AH&#41; el m&#225;s com&#250;n<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">2</span></a>&#46; Aunque la mayor&#237;a de los AH son benignos<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">3</span></a>&#44; hay un subgrupo cuya presentaci&#243;n y actividad biol&#243;gica est&#225;n en el l&#237;mite entre benignidad y malignidad&#46; A pesar de los progresos en la comprensi&#243;n de la patog&#233;nesis de los AH&#44; no se ha identificado ning&#250;n marcador para predecir de forma independiente su comportamiento agresivo&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">El tel&#243;mero es una estructura especializada situada al final del cromosoma eucari&#243;tico&#44; cuya funci&#243;n es impedir que las c&#233;lulas normales se reproduzcan indefinidamente<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">4</span></a>&#46; La persistencia de los tel&#243;meros es atribuible a la telomerasa&#44; una enzima ribonucleoproteica encargada de mantener la homeostasis y la integridad cromos&#243;mica&#46; Est&#225; compuesta por 3 subunidades&#58; telomerasa humana transcriptasa inversa&#44; telomerasa humana &#225;cido ribonucleico y telomerasa asociada a la prote&#237;na 1&#46; El desequilibrio entre los tel&#243;meros y esta enzima&#44; o su activaci&#243;n&#44; es un paso cr&#237;tico en el desarrollo del c&#225;ncer<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">5</span></a>&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">La actividad de la telomerasa es incuantificable en la mayor&#237;a de las c&#233;lulas normales<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">6</span></a>&#46; Se expresa en c&#233;lulas inmortalizadas&#44; como las tumorales<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">7</span></a>&#44; y el grado de expresi&#243;n se correlaciona directamente con el pron&#243;stico en determinados tumores<a class="elsevierStyleCrossRefs" href="#bib0135"><span class="elsevierStyleSup">8&#8211;10</span></a>&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">El objetivo de este estudio fue analizar la utilidad pron&#243;stica de la expresi&#243;n inmunohistoqu&#237;mica de telomerasa en muestras de tejido hipofisario tumoral de pacientes con AH&#44; seguidos durante al menos 8 a&#241;os&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Pacientes y m&#233;todos</span><p id="par0025" class="elsevierStylePara elsevierViewall">Se trata de un estudio descriptivo&#44; retrospectivo&#44; de muestras de 51 AH procedentes de 26 mujeres y 25 hombres con una edad media de 54&#44;5<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>14&#44;5 a&#241;os y un seguimiento cl&#237;nico de al menos 8 a&#241;os&#46; El diagn&#243;stico de AH se bas&#243; en el cuadro cl&#237;nico-biol&#243;gico y en el examen histopatol&#243;gico&#44; seg&#250;n los criterios de la OMS<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">11</span></a>&#46; Treinta y tres tumores fueron no funcionantes &#40;NF&#41;&#44; 13 produc&#237;an hormona de crecimiento&#44; 4&#44; hormona adrenocorticotr&#243;pica y uno&#44; prolactina&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">Los estudios histopatol&#243;gicos se realizaron en secciones de tejido que se ti&#241;eron con t&#233;cnicas histoqu&#237;micas &#40;hematoxilina-eosina y reticulina&#41; e inmunohistoqu&#237;micas &#40;con anticuerpos primarios espec&#237;ficos contra todas las hormonas adenohipofisarias&#44; as&#237; como con el marcador de proliferaci&#243;n celular &#8211;Ki-67&#8211; y el gen supresor tumoral p53&#41;&#46; La expresi&#243;n de telomerasa se estudi&#243; mediante inmunohistoqu&#237;mica automatizada &#40;Ventana BenchMark XT&#44; EE&#46; UU&#46;&#41; utilizando anticuerpos policlonales &#40;origen&#58; Abcam&#44; diluci&#243;n&#58; 1&#47;100&#41;&#46; El n&#250;mero de c&#233;lulas tumorales te&#241;idas se calcul&#243; semicuantitativamente por el mismo pat&#243;logo y el resultado se clasific&#243; como negativo o positivo &#40;con 3 variantes&#58;<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>10&#37;&#44; 10-50&#37; y<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>50&#37; de las c&#233;lulas en 500-1&#46;000 c&#233;lulas tumorales&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0005">fig&#46; 1</a>&#41;&#46; En casos equ&#237;vocos&#44; el porcentaje se calcul&#243; con un programa procesador de imagen de an&#225;lisis inmunohistoqu&#237;mico &#40;ImageJ 1&#46;49&#44; National Institutes of Health&#44; EE&#46; UU&#46;&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0035" class="elsevierStylePara elsevierViewall">Como grupo control se examinaron muestras de 10 hip&#243;fisis normales&#44; obtenidas de autopsias de sujetos de entre 26 y 83 a&#241;os &#40;media 67&#44;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>12&#44;9 a&#241;os&#41;&#46; La expresi&#243;n de telomerasa se correlacion&#243; con la progresi&#243;n o recurrencia del tumor&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">Se realizaron an&#225;lisis estad&#237;sticos y comparativos b&#225;sicos apropiados para las distribuciones de datos&#44; utilizando el test exacto de Fisher de 2 colas para comparar los datos categ&#243;ricos y la prueba <span class="elsevierStyleItalic">t</span> de Student no pareada para comparar los subgrupos con la expresi&#243;n de telomerasa&#46; La significaci&#243;n estad&#237;stica se defini&#243; como un valor de p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;05&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Resultados</span><p id="par0045" class="elsevierStylePara elsevierViewall">Del total de 51 AH&#44; 40 se clasificaron como t&#237;picos y 11 como at&#237;picos&#46; La expresi&#243;n de telomerasa fue positiva en 43 casos &#40;84&#44;3&#37;&#41;&#44; de los que 17 &#40;33&#44;3&#37;&#41; mostraron un marcaje de c&#233;lulas tumorales<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>10&#37; y 26 &#40;51&#37;&#41;<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>10&#37;&#46; En ninguna de las hip&#243;fisis normales la expresi&#243;n super&#243; el 10&#37;&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">Dentro de los 40 AH t&#237;picos&#44; 8 &#40;20&#37;&#41; no expresaron telomerasa&#44; 13 &#40;32&#44;5&#37;&#41;<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>10&#37;&#44; 13 &#40;32&#44;5&#37;&#41; entre 10-50&#37; y 6 &#40;15&#37;&#41;<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>50&#37;&#46; En cuanto a los 11 AH at&#237;picos&#44; la expresi&#243;n de telomerasa fue<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>10&#37; en 4&#44; entre 10-50&#37; en 3 &#40;27&#44;3&#37;&#41; y<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>50&#37; en los 4 &#40;36&#44;4&#37;&#41; restantes&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">Por subtipo histol&#243;gico&#44; los valores medianos m&#225;s altos del &#237;ndice de telomerasa se observaron en AH inmunosecretores de hormona estimulante de la tiroides &#40;40&#37; de c&#233;lulas tumorales te&#241;idas&#41; y de hormonas foliculoestimulante y luteinizante &#40;28&#44;6&#37;&#41;&#44; ambos cl&#237;nicamente NF&#44; seguidos por tumores secretores de hormona adrenocorticotr&#243;pica responsables de una enfermedad de Cushing &#40;25&#37;&#41;&#46; De los tumores con positividad inmunohistoqu&#237;mica para prolactina&#44; los 2 que se observaron con marcaci&#243;n<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>50&#37; eran at&#237;picos&#46; Ninguno de los AH secretores de hormona de crecimiento present&#243; inmunomarcaci&#243;n para telomerasa<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>10&#37; &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;0001&#41;&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">No se observ&#243; correlaci&#243;n entre la expresi&#243;n de telomerasa humana transcriptasa inversa y Ki-67 o p53 &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;4986&#41;&#46; Tampoco se encontraron diferencias de expresi&#243;n relacionadas con la edad&#44; el sexo o el tama&#241;o del tumor&#44; ni entre pacientes con tumores neurorradiol&#243;gicamente invasivos en comparaci&#243;n con los no invasivos&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">En el &#250;ltimo seguimiento cl&#237;nico&#44; 18 pacientes &#40;35&#44;3&#37;&#41; mostraron progresi&#243;n o recurrencia tumoral&#46; La expresi&#243;n de telomerasa fue mayor del 10&#37; en pacientes con recidiva &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;0399&#41; y en aquellos que ten&#237;an adenomas NF &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;0034&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">tabla 1</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Discusi&#243;n</span><p id="par0070" class="elsevierStylePara elsevierViewall">En este estudio realizado en muestras de tejido de AH&#44; el 84&#44;3&#37; de los tumores mostraron expresi&#243;n de telomerasa&#44; que se asoci&#243; a recurrencia de la enfermedad cuando se detect&#243; en m&#225;s del 10&#37; de las c&#233;lulas tumorales&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">Hasta la fecha&#44; no se ha entendido bien el mecanismo completo de activaci&#243;n de la recurrencia e invasi&#243;n<a class="elsevierStyleCrossRefs" href="#bib0140"><span class="elsevierStyleSup">9&#44;12&#44;13</span></a>&#46; Adem&#225;s&#44; dado que la actividad de telomerasa aumenta en tumores con alto potencial metast&#225;sico<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">14</span></a>&#44; se ha planteado que podr&#237;a utilizarse para predecir met&#225;stasis&#46; En los AH&#44; son indicadores potenciales de agresividad la invasi&#243;n local&#44; el crecimiento tumoral o el mantenimiento postoperatorio de la funci&#243;n hormonal<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">15&#44;16</span></a>&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">En 2 estudios<a class="elsevierStyleCrossRefs" href="#bib0140"><span class="elsevierStyleSup">9&#44;13</span></a> se detect&#243; expresi&#243;n de telomerasa en el 13&#37; de los macroadenomas invasivos&#46; En el nuestro&#44; el 84&#44;3&#37; de los AH expres&#243; telomerasa&#44; en contraste con el 36&#37; reportado por Martins et al&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">17</span></a> utilizando t&#233;cnicas de reacci&#243;n en cadena de la polimerasa cuantitativa&#46; Al igual que este &#250;ltimo estudio<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">17</span></a> y otros<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">18</span></a>&#44; no observamos diferencias entre tejido hipofisario neopl&#225;sico y normal &#40;grupo control&#41;&#46; Un tercio de los tumores presentaron el mismo tipo de marcaci&#243;n que el grupo control&#44; lo que tal vez se explique por su semejanza con el tejido normal y la baja actividad mit&#243;tica de la mayor&#237;a de los AH<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">17</span></a>&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">Los AH son generalmente t&#237;picos&#44; con escasa atipia celular&#47;nuclear&#44; mitosis infrecuentes y Ki-67<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>3&#37;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">19</span></a> &#40;concretamente en AH t&#237;picos el Ki-67 fue del 2&#44;82&#37;&#41;&#59; el 52&#44;5&#37; de estos AH o fueron negativos o expresaron<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>10&#37; de telomerasa&#46; Los AH at&#237;picos presentaron un &#237;ndice mit&#243;tico elevado&#44; un Ki-67<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>3&#37; &#40;6&#44;73&#37;&#41; y una extensa inmunopositividad para p53&#59; todos fueron positivos para telomerasa y dos tercios la expresaron<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>10&#37;&#46; No obstante&#44; al contrario que Harada et al&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">13</span></a>&#44; no observamos ninguna relaci&#243;n entre el n&#250;mero de c&#233;lulas positivas a telomerasa y el porcentaje de c&#233;lulas tumorales positivas para Ki-67 y p53&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">A diferencia de Can et al&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">18</span></a>&#44; que no hallaron ninguna relaci&#243;n entre la expresi&#243;n nuclear de telomerasa humana transcriptasa inversa y las caracter&#237;sticas cl&#237;nico-patol&#243;gicas&#44; en nuestro estudio se encontr&#243; una mayor expresi&#243;n en pacientes con recurrencia o progresi&#243;n tumoral y en pacientes con adenomas NF en comparaci&#243;n con los funcionantes&#46; Esto apunta a que en pacientes con un &#237;ndice de telomerasa<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>10&#37; probablemente exista un mayor riesgo de recurrencia tumoral&#44; justific&#225;ndose as&#237; una monitorizaci&#243;n m&#225;s frecuente&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">Respecto a las limitaciones del estudio&#44; destaca el peque&#241;o tama&#241;o muestral &#40;51 pacientes&#44; con un amplio rango de edad y distintos grupos histol&#243;gicos de AH&#41;&#46; Esta heterogeneidad podr&#237;a restringir el hallazgo de diferencias entre grupos&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">En conclusi&#243;n&#44; se evidencia que el &#237;ndice de inmunomarcaci&#243;n de telomerasa<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>10&#37; podr&#237;a utilizarse como factor pron&#243;stico de recurrencia o progresi&#243;n de los AH&#44; tras observarse una mayor expresi&#243;n de este marcador en las recurrencias tumorales&#46; Esta conclusi&#243;n es preliminar y se requieren estudios m&#225;s amplios para confirmar estos resultados&#46;</p></span></span>"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Objetivos</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Analizar el valor pron&#243;stico de la expresi&#243;n de telomerasa en pacientes con adenomas hipofisarios &#40;AH&#41; seguidos durante al menos 8 a&#241;os&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Pacientes y m&#233;todos</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Estudio retrospectivo de las muestras de 51 AH &#40;40 t&#237;picos y 11 at&#237;picos&#41; de pacientes sometidos a cirug&#237;a transesfenoidal entre 2006 y 2008&#44; y de 10 hip&#243;fisis normales obtenidas por autopsia&#46; Se evalu&#243; la expresi&#243;n de telomerasa por inmunohistoqu&#237;mica correlacion&#225;ndola con la de Ki-67 y p53&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Resultados</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Se observ&#243; expresi&#243;n de telomerasa en 43 AH &#40;84&#44;3&#37;&#44; 32 de los 40 t&#237;picos y en los 11 at&#237;picos&#41;&#44; siendo mayor en los casos cl&#237;nicamente no funcionantes &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;0034&#41; y muy escasa en los pacientes con acromegalia &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;0001&#41;&#46; Hubo una asociaci&#243;n significativa entre el porcentaje de c&#233;lulas tumorales &#40;&#62;<span class="elsevierStyleHsp" style=""></span>10&#37;&#41; y la recurrencia del adenoma &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;039&#41;&#46; No hubo correlaci&#243;n con la expresi&#243;n de Ki-67 y p53 &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;4986&#41; ni se observaron diferencias en funci&#243;n de la edad&#44; el sexo&#44; el tama&#241;o o la invasividad tumoral&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusiones</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Un &#237;ndice de expresi&#243;n de telomerasa mayor del 10&#37; en el tejido hipofisario tumoral se asoci&#243; a recurrencia o progresi&#243;n del AH&#44; especialmente en los no funcionantes&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
            "identificador" => "abst0005"
            "titulo" => "Objetivos"
          ]
          1 => array:2 [
            "identificador" => "abst0010"
            "titulo" => "Pacientes y m&#233;todos"
          ]
          2 => array:2 [
            "identificador" => "abst0015"
            "titulo" => "Resultados"
          ]
          3 => array:2 [
            "identificador" => "abst0020"
            "titulo" => "Conclusiones"
          ]
        ]
      ]
      "en" => array:3 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Objectives</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">To analyse the prognostic value of telomerase expression in patients with pituitary adenomas &#40;PAs&#41; followed-up for at least 8 years&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Patients and methods</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">A retrospective study was conducted of samples from 51 PAs &#40;40 typical and 11 atypical&#41; from patients who underwent transsphenoidal surgery between 2006 and 2008 and from 10 normal pituitary glands obtained by autopsy&#46; Telomerase expression was assessed by immunohistochemistry&#44; correlating the expression with that of Ki-67 and p53&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Results</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">We observed telomerase expression in 43 PAs &#40;84&#46;3&#37;&#44; 32 of the 40 typical PAs and in the 11 atypical PAs&#41;&#44; which was higher in the clinically nonfunctioning cases &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;0034&#41; and very rare in the patients with acromegaly &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;0001&#41;&#46; There was a significant association between the percentage of tumour cells &#40;&#62;<span class="elsevierStyleHsp" style=""></span>10&#37;&#41; and the recurrence of the adenoma &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;039&#41;&#46; There was no correlation with the expression of Ki-67 and p53 &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;4986&#41;&#44; and there were no differences according to age&#44; sex&#44; tumour size and invasiveness&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusions</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">A telomerase expression rate greater than 10&#37; in the pituitary tumour tissue was associated with recurrence or progression of the PA&#44; especially in the nonfunctioning cases&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
            "identificador" => "abst0025"
            "titulo" => "Objectives"
          ]
          1 => array:2 [
            "identificador" => "abst0030"
            "titulo" => "Patients and methods"
          ]
          2 => array:2 [
            "identificador" => "abst0035"
            "titulo" => "Results"
          ]
          3 => array:2 [
            "identificador" => "abst0040"
            "titulo" => "Conclusions"
          ]
        ]
      ]
    ]
    "multimedia" => array:2 [
      0 => array:7 [
        "identificador" => "fig0005"
        "etiqueta" => "Figura 1"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr1.jpeg"
            "Alto" => 1120
            "Ancho" => 1500
            "Tamanyo" => 441077
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        ]
        "descripcion" => array:1 [
          "es" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Puntuaci&#243;n semicuantitativa de la expresi&#243;n inmunohistoqu&#237;mica de telomerasa &#40;&#215;400&#41;&#58; A&#41; negativa&#59; B&#41; menos del 10&#37; de c&#233;lulas tumorales positivas&#59; C&#41; 10-50&#37; de c&#233;lulas tumorales positivas&#59; D&#41; m&#225;s del 50&#37; de c&#233;lulas tumorales positivas&#46;</p>"
        ]
      ]
      1 => array:8 [
        "identificador" => "tbl0005"
        "etiqueta" => "Tabla 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at1"
            "detalle" => "Tabla "
            "rol" => "short"
          ]
        ]
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">ACTH&#58; hormona adrenocorticotr&#243;pica&#59; DE&#58; desviaci&#243;n est&#225;ndar&#59; FSH&#58; hormona foliculoestimulante&#59; GH&#58; hormona de crecimiento&#59; LH&#58; hormona luteinizante<span class="elsevierStyleCrossOut">&#59;</span> PRL&#58; prolactina&#59; RM&#58; resonancia magn&#233;tica&#59; TSH&#58; hormona estimulante de la tiroides&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " colspan="3" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Tipo de adenoma hipofisario</th><th class="td" title="table-head  " colspan="2" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Expresi&#243;n de telomerasa</th><th class="td" title="table-head  " align="" valign="top" scope="col">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Caracter&#237;sticas&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Total&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Adenoma t&#237;pico&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Adenoma at&#237;pico&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">&#40;&#60;<span class="elsevierStyleHsp" style=""></span>10&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">&#40;&#8805;<span class="elsevierStyleHsp" style=""></span>10&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">p&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">N&#250;mero de pacientes</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">51&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">40&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">25&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">26&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Edad media en a&#241;os</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#177;</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">DE &#40;rango&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">54&#44;5<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>14&#44;5 &#40;29-81&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">53&#44;6<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>14&#44;5 &#40;29-77&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">50&#44;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>12&#44;5 &#40;29-81&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="7" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Sexo</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;5793&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Femenino&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">26&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">21&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Masculino&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">25&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">19&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="7" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Cuadro cl&#237;nico</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Prolactinomas&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#44;0000&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Acromegalia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;0001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Enfermedad de Cushing&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;6098&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>No funcionantes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">33&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">25&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">22&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;0034&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="7" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Tama&#241;o del tumor</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;3238&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Microadenoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Macroadenoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">40&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">30&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">18&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">22&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="7" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Extensi&#243;n&#47;invasi&#243;n extraselar en RM</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;2913&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">18&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;0399&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#44;0000&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;0001&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;6098&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;3497&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;0266&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>TSH&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#44;0000&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "es" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Caracter&#237;sticas cl&#237;nicas e histopatol&#243;gicas de 51 pacientes con adenoma hipofisario</p>"
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Información del artículo

ISSN: 00142565
Idioma original: Español

DOI:10.1016/j.rce.2017.12.002

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