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Prognostic implications of telomerase expression in pituitary adenomas
Implicación pronóstica de la expresión de telomerasa en adenomas hipofisarios
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, Spain
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Tortosa, S.M. Webb" "autores" => array:2 [ 0 => array:4 [ "nombre" => "F." "apellidos" => "Tortosa" "email" => array:1 [ 0 => "franciscotortosa.pathology@gmail.com" ] "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] 2 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "S.M." "apellidos" => "Webb" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Servicio de Anatomía Patológica, Centro Hospitalar Lisboa Norte, EPE-Hospital de Santa Maria, Lisboa, Portugal" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "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, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Implicación pronóstica de la expresión de telomerasa en adenomas hipofisarios" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1120 "Ancho" => 1500 "Tamanyo" => 441559 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Semiquantitative score for the immunohistochemical expression of telomerase (400×): (A) negative; (B) <10% of positive tumor cells; (C) 10–50% of positive tumor cells; (D) >50% of positive tumor cells.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Background</span><p id="par0005" class="elsevierStylePara elsevierViewall">Pituitary gland and sellar region tumors represent approximately 15% of brain tumors,<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">1</span></a> with pituitary adenomas (PAs) the most common neoplasms.<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">2</span></a> Although most PAs are benign,<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">3</span></a> there is a subgroup whose presentation and biological activity are borderline between benignity and malignancy. Despite progress in understanding the pathogenesis of PAs, no marker has been identified to independently predict their aggressive behavior.</p><p id="par0010" class="elsevierStylePara elsevierViewall">Telomeres are a specialized structure located at the end of the eukaryotic chromosome whose function is to prevent normal cells from reproducing indefinitely.<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">4</span></a> The persistence of telomeres is attributable to the telomerase, a ribonucleoprotein enzyme charged with maintaining homeostasis and chromosomal integrity. Telomerase is composed of 3 subunits: human telomerase reverse transcriptase, human telomerase ribonucleic acid and telomerase-associated protein 1. An imbalance between telomeres and this enzyme (or its activation) is a critical step in the development of cancer.<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">5</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Telomerase's activity level is unquantifiable in most normal cells<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">6</span></a> but is expressed in immortalized cells, such as tumor cells.<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">7</span></a> The degree of expression is directly correlated with the prognosis in certain tumors.<a class="elsevierStyleCrossRefs" href="#bib0135"><span class="elsevierStyleSup">8–10</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">The aim of this study was to analyze the prognostic utility of the immunohistochemical expression of telomerase in samples of pituitary tumor tissue from patients with PA, followed for at least 8 years.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Patients and methods</span><p id="par0025" class="elsevierStylePara elsevierViewall">A descriptive, retrospective study was conducted of samples from 51 PAs from 26 women and 25 men with a mean age of 54.5<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>14.5 years and a clinical follow-up of at least 8 years. The PA diagnosis was based on the clinical/biological condition and on the histopathological examination, according to the WHO criteria.<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">11</span></a> Thirty-three tumors were nonfunctional (NF), 13 produced growth hormones, 4 produced adrenocorticotropic hormones and 1 produced prolactin.</p><p id="par0030" class="elsevierStylePara elsevierViewall">The histopathology studies were performed with tissue sections that were stained with histochemical (hematoxylin–eosin and reticulin) and immunohistochemical techniques (with specific primary antibodies against all anterior pituitary hormones, with a marker of cell proliferation [Ki-67] and with a marker of the tumor suppressor gene p53). Telomerase expression was studied using automated immunohistochemistry (Ventana BenchMark XT, US) using polyclonal antibodies (origin, Abcam; dilution, 1/100). The number of stained tumor cells was calculated semiquantitatively by the same pathologist, and the result was classified as negative or positive (with 3 variants: <10%, 10–50% and >50% of the cells in 500–1000 tumor cells) (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). In equivocal cases, the percentage was calculated with an image processing program for immunohistochemical analysis (Image J 1.49, National Institutes of Health, US).</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0035" class="elsevierStylePara elsevierViewall">As a control group, samples of 10 normal pituitary glands were examined, which were obtained from autopsies of patients between 26 and 83 years of age (mean age, 67.8<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>12.9 years). Telomerase expression was correlated with tumor progression or recurrence.</p><p id="par0040" class="elsevierStylePara elsevierViewall">We performed basic comparative and statistical analyses for the data distributions, using a 2-tailed Fisher's exact test to compare the categorical data and an unpaired Student's <span class="elsevierStyleItalic">t</span>-test to compare the subgroups with the telomerase expression. Statistical significance was defined as a <span class="elsevierStyleItalic">p</span>-value <0.05.</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Results</span><p id="par0045" class="elsevierStylePara elsevierViewall">Of the total of 51 PAs, 40 were classified as typical and 11 as atypical. Telomerase expression was positive in 43 cases (84.3%), of which 17 (33.3%) showed tumor cell staining of <10% and 26 (51%) showed ≥10%. The expression did not exceed 10% in any of the normal pituitary glands.</p><p id="par0050" class="elsevierStylePara elsevierViewall">Of the 40 typical PAs, 8 (20%) did not express telomerase, 13 (32.5%) expressed <10%, 13 (32.5%) expressed 10–50%, and 6 (15%) expressed >50%. Of the 11 atypical PAs, the telomerase expression was <10% in 4, 10–50% in 3 (27.3%) and >50% in the remaining 4 (36.4%).</p><p id="par0055" class="elsevierStylePara elsevierViewall">By histological subtype, the highest median telomerase index values were observed in thyroid-stimulating hormone-secreting PAs (40% of stained tumor cells) and follicle-stimulating and luteinizing hormone-secreting PAs (28.6%), both clinically NF, followed by adrenocorticotropic hormone-secreting tumors responsible for Cushing's disease (25%). Of the tumors that were immunohistochemically positive for prolactin, the 2 with >50% staining were atypical. None of the growth hormone-secreting PAs showed ≥10% telomerase immunostaining (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.0001).</p><p id="par0060" class="elsevierStylePara elsevierViewall">There was no correlation between human telomerase reverse transcriptase expression and Ki-67 or p53 (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.4986). There were also no differences in expression related to age, sex, tumor size or between neuroradiologically invasive tumors and noninvasive tumors.</p><p id="par0065" class="elsevierStylePara elsevierViewall">In the last clinical follow-up, 18 patients (35.3%) had tumor progression or recurrence. Telomerase expression was greater than 10% in the patients with recurrence (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.0399) and in those who had NF adenomas (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.0034) (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Discussion</span><p id="par0070" class="elsevierStylePara elsevierViewall">In this study performed on PA tissue samples, 84.3% of the tumors showed telomerase expression, which was associated with disease recurrence when detected in more than 10% of the tumor cells.</p><p id="par0075" class="elsevierStylePara elsevierViewall">The complete activation mechanism for recurrence and invasion is still not well understood.<a class="elsevierStyleCrossRefs" href="#bib0140"><span class="elsevierStyleSup">9,12,13</span></a> Given that telomerase activity increases in tumors with high metastatic potential,<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">14</span></a> it has been suggested that the activity could be used to predict metastasis. Local invasion, tumor growth and the postoperative maintenance of the hormonal function are potential indicators of aggressiveness in PAs.<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">15,16</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">Two studies<a class="elsevierStyleCrossRefs" href="#bib0140"><span class="elsevierStyleSup">9,13</span></a> detected telomerase expression in 13% of invasive macroadenomas. In our study, 84.3% of the PAs expressed telomerase compared with 36% reported by Martins et al. using quantitative polymerase chain reaction techniques.<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">17</span></a> As with Martins et al. study<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">17</span></a> and others,<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">18</span></a> we observed no differences between the neoplastic and normal pituitary tissue (control group). A third of the tumors presented the same type of staining as the control group, which could be due to their similarity to normal tissue and the low mitotic activity of most PAs.<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">17</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">PAs are generally typical, with scarce cellular/nuclear atypia, infrequent mitosis and Ki-67<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>3%<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">19</span></a> (specifically, Ki-67 was 2.82% in typical PAs); 52.5% of these PA were negative or expressed <10% of telomerase. The atypical PAs had a high mitotic index, a Ki-67<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>3% (6.73%) and extensive immunopositivity for p53; all were telomerase positive and two-thirds expressed telomerase<span class="elsevierStyleHsp" style=""></span>≥<span class="elsevierStyleHsp" style=""></span>10%. Unlike Harada et al.,<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">13</span></a> however, we did not observe a relationship between the number of telomerase-positive cells and the percentage of tumor cells positive for Ki-67 and p53.</p><p id="par0090" class="elsevierStylePara elsevierViewall">Unlike Can et al.<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">18</span></a> who found no relationship between the nuclear expression of human telomerase reverse transcriptase and the clinical–pathological characteristics, we found greater expression in patients with tumor recurrence or progression and in patients with NF adenomas compared with those with functioning adenomas. This finding indicates that patients with a telomerase index<span class="elsevierStyleHsp" style=""></span>≥<span class="elsevierStyleHsp" style=""></span>10% probably have a greater tumor recurrence risk, thereby justifying more frequent monitoring.</p><p id="par0095" class="elsevierStylePara elsevierViewall">The study's limitations include the small sample size (51 patients, with a broad age range and different histological PA groups). This heterogeneity could limit the finding of differences between the groups.</p><p id="par0100" class="elsevierStylePara elsevierViewall">In conclusion, we have shown that a telomerase immunostaining index<span class="elsevierStyleHsp" style=""></span>≥<span class="elsevierStyleHsp" style=""></span>10% could be used as a prognostic factor for the recurrence or progression of PAs, after observing greater expression of this marker in tumor recurrences. This conclusion is preliminary and requires more extensive studies to confirm these results.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:9 [ 0 => array:3 [ "identificador" => "xres1009453" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Objectives" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Patients and methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec968990" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1009454" "titulo" => "Resumen" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Objetivos" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Pacientes y métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec968991" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Background" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Patients and methods" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Results" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Discussion" ] 8 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2017-07-11" "fechaAceptado" => "2017-12-14" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec968990" "palabras" => array:4 [ 0 => "Pituitary adenoma" 1 => "Biomarker" 2 => "Immunohistochemistry" 3 => "Telomerase reverse transcriptase" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec968991" "palabras" => array:4 [ 0 => "Adenoma hipofisario" 1 => "Biomarcador" 2 => "Inmunohistoquímica" 3 => "Telomerasa transcriptasa inversa" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Objectives</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">To analyze the prognostic value of telomerase expression in patients with pituitary adenomas (PAs) followed-up for at least 8 years.</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Patients and methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">A 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.</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">We 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 (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.0034) and very rare in the patients with acromegaly (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.0001). There was a significant association between the percentage of tumor cells (>10%) and the recurrence of the adenoma (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.039). There was no correlation with the expression of Ki-67 and p53 (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.4986), and there were no differences according to age, sex, tumor size and invasiveness.</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">A telomerase expression rate greater than 10% in the pituitary tumor tissue was associated with recurrence or progression of the PA, especially in the nonfunctioning cases.</p></span>" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Objectives" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Patients and methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Objetivos</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Analizar el valor pronóstico de la expresión de telomerasa en pacientes con adenomas hipofisarios (AH) seguidos durante al menos 8 años.</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Pacientes y métodos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Estudio 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.</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Se 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<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0,0034) y muy escasa en los pacientes con acromegalia (p<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0,0001). Hubo una asociación significativa entre el porcentaje de células tumorales (>10%) y la recurrencia del adenoma (p<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0,039). No hubo correlación con la expresión de Ki-67 y p53 (p<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0,4986) ni se observaron diferencias en función de la edad, el sexo, el tamaño o la invasividad tumoral.</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Un 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.</p></span>" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Objetivos" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Pacientes y métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Tortosa F, Webb S. Implicación pronóstica de la expresión de telomerasa en adenomas hipofisarios. Rev Clin Esp. 2018;218:128–132.</p>" ] ] "multimedia" => array:2 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1120 "Ancho" => 1500 "Tamanyo" => 441559 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Semiquantitative score for the immunohistochemical expression of telomerase (400×): (A) negative; (B) <10% of positive tumor cells; (C) 10–50% of positive tumor cells; (D) >50% of positive tumor cells.</p>" ] ] 1 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Abbreviations</span>: ACTH, adrenocorticotropic hormone; FSH, follicle-stimulating hormone; GH, growth hormone; LH, luteinizing hormone; PRL, prolactin; MRI, magnetic resonance imaging; SD; standard deviation; TSH, thyroid-stimulating hormone.</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-with-role" title="table-head ; entry_with_role_rowhead " align="left" valign="top" scope="col">Characteristics \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">Type of pituitary adenoma</th><th class="td" title="table-head " colspan="2" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Telomerase expression</th><th class="td" title="table-head " align="left" valign="top" scope="col"><span class="elsevierStyleItalic">p</span> \t\t\t\t\t\t\n \t\t\t\t</th></tr><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \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">Typical adenoma \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">Atypical adenoma \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="" valign="top" scope="col" style="border-bottom: 2px solid black"> \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">Number of patients</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">51 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">40 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">25 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" 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"><span class="elsevierStyleItalic">Mean age, years</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">±</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">SD (range)</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">54.5<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>14.5 (29–81) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">53.6<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>14.5 (29–77) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">50.8<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>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"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="6" align="left" valign="top"><span class="elsevierStyleItalic">Sex</span></td><td class="td" title="table-entry " align="char" 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"><span class="elsevierStyleHsp" style=""></span>Female \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">26 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">21 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">14 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" 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"><span class="elsevierStyleHsp" style=""></span>Male \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">25 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">19 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" 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"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="7" align="left" valign="top"><span class="elsevierStyleItalic">Clinical condition</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="elsevierStyleHsp" style=""></span>Prolactinomas \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" 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"><span class="elsevierStyleHsp" style=""></span>Acromegaly \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">13 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">13 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" 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"><span class="elsevierStyleHsp" style=""></span>Cushing's disease \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" 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"><span class="elsevierStyleHsp" style=""></span>Nonfunctional \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">33 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">25 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">22 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" 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"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="6" align="left" valign="top"><span class="elsevierStyleItalic">Tumor size</span></td><td class="td" title="table-entry " align="char" 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"><span class="elsevierStyleHsp" style=""></span>Microadenoma \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" 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"><span class="elsevierStyleHsp" style=""></span>Macroadenoma \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">40 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">30 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">18 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" 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"><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">Extrasellar extension/invasion in MRI</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" 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"><span class="elsevierStyleItalic">Recurrence</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">18 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">13 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" 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"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="7" align="left" valign="top"><span class="elsevierStyleItalic">Histopathological subtype</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="elsevierStyleHsp" style=""></span>PRL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" 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"><span class="elsevierStyleHsp" style=""></span>GH \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">13 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">13 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" 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"><span class="elsevierStyleHsp" style=""></span>ACTH (Cushing's disease) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" 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"><span class="elsevierStyleHsp" style=""></span>“Silent” ACTH \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" 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"><span class="elsevierStyleHsp" style=""></span>FSH/LH \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">14 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" 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"><span class="elsevierStyleHsp" style=""></span>TSH \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.0000 \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">Normal pituitary glands</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" 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="char" valign="top">10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" 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 => "xTab1709670.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Clinical and histopathological characteristics of the 51 patients with pituitary adenoma.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "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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