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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Introducci&#243;n</span><p id="par0005" class="elsevierStylePara elsevierViewall">La telomerasa es una enzima formada por una subunidad catal&#237;tica &#40;telomerasa transcriptasa inversa o TERT&#41; y un &#225;cido ribonucleico &#40;TERC&#41;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">1</span></a>&#46; Es bien conocido que juega un papel importante en el mantenimiento de los tel&#243;meros y la senescencia celular&#46; En condiciones normales&#44; su expresi&#243;n est&#225; presente &#250;nicamente en las c&#233;lulas de la l&#237;nea germinal&#44; tejidos fetales y c&#233;lulas madre&#46; Por el contrario&#44; las c&#233;lulas som&#225;ticas del resto de los tejidos carecen de actividad telomer&#225;sica&#44; lo que conlleva a un acortamiento progresivo de sus tel&#243;meros tras repetidas divisiones celulares&#46; Numerosos estudios han demostrado que la actividad telomer&#225;sica se detecta en m&#225;s del 90&#37; de las neoplasias malignas<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">2</span></a>&#44; incluyendo diversos tipos de c&#225;ncer cut&#225;neo<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">3</span></a>&#46; Concretamente en las neoplasias melanoc&#237;ticas&#44; varios estudios han identificado un incremento de la actividad telomer&#225;sica en las c&#233;lulas neopl&#225;sicas desde nevus a melanoma&#44; con la m&#225;xima actividad telomer&#225;sica detectada en melanomas metast&#225;sicos<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">4</span></a>&#46; De forma adicional&#44; recientemente se ha demostrado la implicaci&#243;n de las mutaciones en el promotor del gen <span class="elsevierStyleItalic">TERT</span> en la patogenia del melanoma<a class="elsevierStyleCrossRefs" href="#bib0195"><span class="elsevierStyleSup">5&#44;6</span></a>&#46; Diversos estudios han identificado mutaciones recurrentes en la regi&#243;n promotora del gen <span class="elsevierStyleItalic">TERT</span> &#40;c&#46;1-146C&#62;T&#44; c&#46;1-124C&#62;T&#44; c&#46;1-124&#47;-125CC&#62;TT&#44; c&#46;1-138&#47;-139 CC&#62;TT&#41; en un 22-71&#37; de melanomas espor&#225;dicos asociadas a individuos de mayor edad&#44; con melanomas en &#225;reas fotoexpuestas&#44; del subtipo histol&#243;gico nodular&#44; mayor &#237;ndice de Breslow&#44; presencia de ulceraci&#243;n y alto &#237;ndice mit&#243;tico<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">7&#8211;9</span></a>&#46; Estudios en tejido y l&#237;neas celulares han corroborado que estas mutaciones conllevan una mayor expresi&#243;n de telomerasa al crearse nuevos sitios de uni&#243;n para factores de transcripci&#243;n de la familia ETS<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">9&#8211;12</span></a>&#46; Se ha demostrado que la presencia de dichas mutaciones es un factor pron&#243;stico independiente que se asocia a menor supervivencia libre de enfermedad y supervivencia global<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">8&#44;13</span></a>&#46; Adicionalmente&#44; se ha descrito que dicha asociaci&#243;n con la supervivencia var&#237;a en funci&#243;n del tipo de mutaci&#243;n identificada&#44; y es modificada por la presencia del polimorfismo rs2853669<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">14&#44;15</span></a>&#46; Asimismo&#44; estudios recientes han demostrado el valor pron&#243;stico de la longitud de los tel&#243;meros&#44; al haber identificado menores tasas de supervivencia en pacientes con menor longitud<a class="elsevierStyleCrossRefs" href="#bib0250"><span class="elsevierStyleSup">16&#44;17</span></a>&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">Por tanto&#44; parece que la expresi&#243;n de telomerasa juega un papel importante en la carcinog&#233;nesis de los melanomas&#44; sin embargo son escasos los estudios que analizan su expresi&#243;n a nivel de prote&#237;na&#44; y los que est&#225;n disponibles incluyen series cortas con un escaso n&#250;mero de melanomas&#46; De forma adicional&#44; el estudio de la expresi&#243;n de telomerasa podr&#237;a ser de utilidad para la estratificaci&#243;n de los pacientes en funci&#243;n de su pron&#243;stico&#46; El objetivo del presente estudio es analizar la expresi&#243;n de telomerasa por inmunohistoquimia en una serie de melanomas &#40;primarios y metast&#225;sicos&#41; y nevus melanoc&#237;ticos&#44; y correlacionar los niveles de expresi&#243;n con las caracter&#237;sticas cl&#237;nico-patol&#243;gicas y evolutivas de los pacientes&#44; as&#237; como con las mutaciones en el promotor del gen <span class="elsevierStyleItalic">TERT</span>&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Material y m&#233;todos</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Pacientes y muestras seleccionadas</span><p id="par0015" class="elsevierStylePara elsevierViewall">Estudio observacional retrospectivo realizado en el Servicio de Dermatolog&#237;a y Anatom&#237;a Patol&#243;gica del Hospital Universitario y Polit&#233;cnico La Fe en una muestra de 85 pacientes diagnosticados de melanoma y 22 pacientes con nevus melanoc&#237;ticos &#40;cinco nevus intrad&#233;rmicos&#44; siete compuestos y diez displ&#225;sicos&#41; atendidos durante el periodo comprendido entre 1 enero del 2014 y 1 diciembre de 2016&#46; Se seleccionaron aquellas muestras en las que se dispon&#237;a de muestra suficiente en el bloque de parafina para realizar la tinci&#243;n inmunohistoqu&#237;mica&#46; En el caso de los melanomas primarios&#44; se incluyeron &#250;nicamente aquellos con componente invasivo&#44; clasificados en los cuatro subtipos histol&#243;gicos principales &#40;lentigo melanoma maligno&#44; melanoma de extensi&#243;n superficial&#44; melanoma nodular y melanoma lentiginoso acral&#41;&#44; y en los que se dispon&#237;a del estudio del promotor del gen <span class="elsevierStyleItalic">TERT</span>&#46; En los 85 pacientes con melanoma se estudi&#243; el tumor primario y adicionalmente&#44; en 12 de ellos se estudi&#243; tambi&#233;n una met&#225;stasis de melanoma&#46; De cada uno de los pacientes con melanoma se recogieron las caracter&#237;sticas cl&#237;nico-patol&#243;gicas &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">tabla 1</a>&#41;&#46; El &#237;ndice de Breslow se categoriz&#243; de acuerdo con la &#250;ltima clasificaci&#243;n de la AJCC &#40;&#8804;1&#44;00&#44; 1&#44;01-2&#44; 2&#44;01-4 y &#62; 4<span class="elsevierStyleHsp" style=""></span>mm&#41;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">18</span></a>&#59; el &#237;ndice mit&#243;tico se expres&#243; como el n&#250;mero de mitosis por mil&#237;metro cuadrado y se categoriz&#243; seg&#250;n la presencia o ausencia de mitosis&#59; la regresi&#243;n histol&#243;gica se defini&#243; seg&#250;n lo descrito previamente<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">19</span></a>&#44; y se categoriz&#243; en ausente o presente&#59; y la velocidad de crecimiento se defini&#243; acorde a lo descrito previamente<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">20</span></a>&#46; Todos los pacientes manifestaron por escrito su consentimiento para participar en el estudio&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Expresi&#243;n de telomerasa mediante inmunohistoquimia</span><p id="par0020" class="elsevierStylePara elsevierViewall">La tinci&#243;n inmunohistoqu&#237;mica se realiz&#243; en cortes de 5<span class="elsevierStyleHsp" style=""></span>&#956;m utilizando el anticuerpo monoclonal hTERT &#40;Rockland&#41; de acuerdo a lo descrito previamente<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">21</span></a>&#46; Como control negativo se realiz&#243; la misma t&#233;cnica con omisi&#243;n del anticuerpo&#46; En el caso de los melanomas en los que se dispon&#237;a de varios bloques&#44; se seleccionaron aquellos con mayor porcentaje de celularidad tumoral&#46; La valoraci&#243;n de la expresi&#243;n de telomerasa de todas las muestras incluidas se realiz&#243; por dos observadores independientes &#40;BU y RB&#41;&#46; En los casos con discrepancias en las observaciones de ambos investigadores&#44; se tomaron para el an&#225;lisis las observaciones del investigador con mayor experiencia &#40;RB&#41;&#46; Se cuantific&#243; la extensi&#243;n de la expresi&#243;n mediante el establecimiento de una puntuaci&#243;n basada en el porcentaje de c&#233;lulas con positividad&#44; 0&#58; 0&#37;&#44; 1&#58; &#60; 10&#37;&#44; 2&#58; 10-50&#37; y 3&#58; &#62; 50&#37;&#46; La intensidad de la expresi&#243;n se clasific&#243; del 0-3 &#40;0&#58; ausente&#59; 1&#58; leve&#59; 2&#58; moderada&#59; 3&#58; intensa&#41;&#46; El patr&#243;n de expresi&#243;n se clasific&#243; en homog&#233;neo o heterog&#233;neo en funci&#243;n de la uniformidad de la expresi&#243;n en las c&#233;lulas tumorales&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">An&#225;lisis estad&#237;stico</span><p id="par0025" class="elsevierStylePara elsevierViewall">El an&#225;lisis descriptivo de las variables se analiz&#243; mediante frecuencias absolutas y relativas&#46; El an&#225;lisis inferencial de las variables cualitativas se realiz&#243; mediante pruebas basadas en la ley de &#967;<span class="elsevierStyleSup">2</span>&#46; El an&#225;lisis de SLE y SG se calcularon mediante el m&#233;todo de Kaplan-Meier&#46; El grado de acuerdo entre los observadores independientes se evalu&#243; mediante el coeficiente Kappa &#40;&#954;&#41;&#46; Para el an&#225;lisis se utiliz&#243; el paquete estad&#237;stico SPSS tomando como l&#237;mite de significaci&#243;n P &#60; 0&#44;05&#46;</p></span></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Resultados</span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Expresi&#243;n de telomerasa en piel sana</span><p id="par0030" class="elsevierStylePara elsevierViewall">En la piel sana perilesional a las lesiones melanoc&#237;ticas se observ&#243; expresi&#243;n de telomerasa a nivel de la epidermis&#44; el fol&#237;culo piloso&#44; las gl&#225;ndulas sudor&#237;paras y seb&#225;ceas as&#237; como en el endotelio de los vasos de la dermis&#46; La expresi&#243;n a nivel de la epidermis y fol&#237;culos era leve&#44; mientras que era moderada e intensa a nivel de las gl&#225;ndulas sudor&#237;paras y seb&#225;ceas&#44; respectivamente &#40;<a class="elsevierStyleCrossRef" href="#fig0005">fig&#46; 1</a>&#41; <a class="elsevierStyleCrossRef" href="#sec0065">&#40;figs&#46; S1- S3 del material adicional disponible en la versi&#243;n electr&#243;nica&#41;</a>&#46; La expresi&#243;n en estos anejos cut&#225;neos se emple&#243; como control positivo en todos los casos analizados&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Expresi&#243;n de telomerasa en las neoplasias melanoc&#237;ticas</span><p id="par0035" class="elsevierStylePara elsevierViewall">El grado de concordancia observado en los tres par&#225;metros analizados por ambos investigadores fue bueno&#44; con un &#237;ndice &#954; de 0&#44;65 en la intensidad&#44; 0&#44;83 en la extensi&#243;n&#44; y 0&#44;73 en el patr&#243;n de expresi&#243;n de telomerasa&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">En todas las neoplasias melanoc&#237;ticas analizadas se demostr&#243; expresi&#243;n de telomerasa&#46; En el caso de los melanomas primarios&#44; en el 59&#37; &#40;50&#47;85&#41; de los casos el patr&#243;n de la expresi&#243;n era homog&#233;neo en toda la celularidad tumoral &#40;<a class="elsevierStyleCrossRef" href="#sec0065">fig&#46; S4 del material adicional&#41;</a>&#44; mientras que en el 41&#37; &#40;35&#47;85&#41; era heterog&#233;neo&#44; con diferente intensidad en la expresi&#243;n entre las c&#233;lulas tumorales &#40;<a class="elsevierStyleCrossRef" href="#fig0010">fig&#46; 2</a>&#41; &#40;<a class="elsevierStyleCrossRef" href="#sec0065">fig&#46; S5 del material adicional&#41;</a>&#46; En la mayor&#237;a de los casos analizados &#40;95&#37;&#59; 81&#47;85&#41; se observ&#243; expresi&#243;n en &#62; 50&#37; de la celularidad tumoral &#40;fig&#46; S6 del material adicional&#41; y solo en un caso se observ&#243; expresi&#243;n en &#60; 10&#37; del infiltrado tumoral &#40;<a class="elsevierStyleCrossRef" href="#sec0065">fig&#46; S7 del material adicional&#41;</a>&#46; Con respecto a la intensidad&#44; en el 41&#37; &#40;35&#47;85&#41; de las muestras la expresi&#243;n era intensa &#40;fig&#46; S8 del material adicional&#41;&#44; en el 51&#37; &#40;43&#47;85&#41; era moderada &#40;fig&#46; S9 del material adicional&#41;&#44; y solo en el 8&#37; &#40;7&#47;85&#41; era leve &#40;<a class="elsevierStyleCrossRef" href="#sec0065">fig&#46; S10 del material adicional&#41;</a>&#46; En aquellos melanomas en los que exist&#237;a una lesi&#243;n n&#233;vica precursora &#40;5&#37;&#59; 4&#47;85&#41;&#44; se observaba expresi&#243;n intensa de telomerasa en las c&#233;lulas tumorales del melanoma&#44; pero con expresi&#243;n leve en las c&#233;lulas n&#233;vicas acompa&#241;antes &#40;<a class="elsevierStyleCrossRef" href="#fig0015">fig&#46; 3</a>a-d&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0045" class="elsevierStylePara elsevierViewall">En los melanomas metast&#225;sicos&#44; el patr&#243;n de la expresi&#243;n era homog&#233;neo en el 67&#37; &#40;8&#47;12&#41; y heterog&#233;neo en el 33&#37; &#40;4&#47;12&#41;&#46; Se observ&#243; expresi&#243;n de hTERT en &#62; 50&#37; de la celularidad tumoral en el 100&#37; de las muestras&#44; siendo intensa en el 42&#37; &#40;5&#47;12&#41;&#44; moderada en el 50&#37; &#40;6&#47;12&#41;&#44; y leve en el 8&#44;3&#37; &#40;1&#47;12&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0020">fig&#46; 4</a>&#41;&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia><p id="par0050" class="elsevierStylePara elsevierViewall">La expresi&#243;n de telomerasa en los nevus melanoc&#237;ticos presentaba un patr&#243;n homog&#233;neo en el 100&#37; de los nevus melanoc&#237;ticos&#44; con una extensi&#243;n en &#62; 50&#37; de la celularidad tumoral en el 91&#37; &#40;20&#47;22&#41;&#46; La intensidad de la expresi&#243;n era leve en el 64&#37; &#40;14&#47;22&#41;&#44; moderada en el 32&#37; &#40;7&#47;22&#41; e intensa en el 4&#37; &#40;1&#47;22&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0025">fig&#46; 5</a>&#41;&#46;</p><elsevierMultimedia ident="fig0025"></elsevierMultimedia><p id="par0055" class="elsevierStylePara elsevierViewall">En cuanto a las diferencias de expresi&#243;n en funci&#243;n de las caracter&#237;sticas cl&#237;nico-patol&#243;gicas de los melanomas primarios&#44; el patr&#243;n de expresi&#243;n heterog&#233;neo se asoci&#243; a los melanomas de r&#225;pido crecimiento &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;028&#41;&#44; con &#237;ndice de Breslow &#62; 4<span class="elsevierStyleHsp" style=""></span>mm &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;004&#41;&#44; con presencia de mitosis &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;032&#41;&#44; y con mutaciones en el promotor del gen <span class="elsevierStyleItalic">TERT</span> &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;002&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">tabla 1</a>&#41;&#46; El patr&#243;n de expresi&#243;n no mostr&#243; diferencias significativas entre los diferentes tipos de mutaci&#243;n en el promotor del gen <span class="elsevierStyleItalic">TERT</span> &#40;c&#46;1-146C&#62;T&#44; c&#46;1-124C&#62;T&#44; y c&#46;1-124&#47;-125CC&#62;TT&#41;&#46; No se observaron diferencias estad&#237;sticamente significativas con la intensidad ni con la extensi&#243;n de la expresi&#243;n &#40;tabla S1 del material adicional&#41;&#46; La intensidad de la expresi&#243;n result&#243; mayor en los melanomas del subtipo lentigo melanoma maligno&#44; y menor en los lentiginosos acrales&#44; aunque este dato no alcanz&#243; significaci&#243;n estad&#237;stica &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;523&#41;&#46; En el an&#225;lisis de supervivencia no se observaron diferencias estad&#237;sticamente significativas en funci&#243;n de la expresi&#243;n de telomerasa&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">El an&#225;lisis comparativo de los nevus con melanomas primarios y metast&#225;sicos demostr&#243; que la expresi&#243;n de telomerasa en los nevus era menos intensa que en los melanomas primarios y metast&#225;sicos &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#41; y que a diferencia de los melanomas&#44; era caracter&#237;stico un patr&#243;n de expresi&#243;n homog&#233;neo en toda la celularidad tumoral &#40;p &#60; 0&#44;001&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0030">fig&#46; 6</a>&#41;&#46; Con respecto a los melanomas&#44; no se identificaron diferencias estad&#237;sticamente significativas entre los melanomas primarios y metast&#225;sicos&#46; Adicionalmente&#44; en el caso de los nevus cabe destacar que la intensidad era menor en los nevus intrad&#233;rmicos&#44; seguidos de los compuestos y de los displ&#225;sicos&#44; aunque este dato no alcanz&#243; significaci&#243;n estad&#237;stica &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;054&#41;&#46;</p><elsevierMultimedia ident="fig0030"></elsevierMultimedia></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Discusi&#243;n</span><p id="par0065" class="elsevierStylePara elsevierViewall">Los resultados del presente estudio demuestran que la expresi&#243;n de telomerasa est&#225; presente en todas las neoplasias melanoc&#237;ticas analizadas&#44; y que existe una tendencia a incrementarse de forma progresiva desde nevus a melanomas&#44; por lo que podr&#237;a estar implicada en la progresi&#243;n tumoral de este tipo de neoplasias&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">En los melanomas primarios de nuestra serie hemos demostrado que el patr&#243;n de expresi&#243;n heterog&#233;neo se asocia a melanomas de mayor agresividad &#40;melanomas de r&#225;pido crecimiento&#44; con espesor tumoral &#62; 4<span class="elsevierStyleHsp" style=""></span>mm&#44; con mitosis y mutaciones en el promotor de <span class="elsevierStyleItalic">TERT</span>&#41;&#44; hecho que no estaba reportado anteriormente&#46; Estos resultados contrastan con los reportados recientemente por Hugdahl et al<span class="elsevierStyleItalic">&#46;</span>&#44; que describen una expresi&#243;n de telomerasa homog&#233;nea en la mayor parte de sus casos<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">22</span></a>&#46; Sin embargo&#44; nuestros hallazgos podr&#237;an estar en relaci&#243;n con los reportador por Kohli et al<span class="elsevierStyleItalic">&#46;</span>&#44; que describen una expresi&#243;n de telomerasa no nucleolar de forma heterog&#233;nea en los melanomas pero no en lesiones benignas<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">23</span></a>&#46; Este patr&#243;n de expresi&#243;n heterog&#233;neo podr&#237;a ser consecuencia de la denominada heterogeneidad intratumoral en el melanoma&#44; que se ha asociado a la presencia de distintas subpoblaciones tumorales&#44; y que se relaciona con la resistencia a los tratamientos sist&#233;micos<a class="elsevierStyleCrossRefs" href="#bib0290"><span class="elsevierStyleSup">24&#44;25</span></a>&#46; Por otro lado&#44; no podemos descartar que la heterogeneidad observada en nuestro estudio se deba a un defecto en la tinci&#243;n&#44; si bien es poco probable ya que en ninguna de las lesiones melanoc&#237;ticas benignas observamos este patr&#243;n&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">A diferencia de otros estudios&#44; en nuestra serie la intensidad y la extensi&#243;n de la expresi&#243;n de telomerasa han sido independientes de las caracter&#237;sticas cl&#237;nico-patol&#243;gicas&#46; Hugdahl et al<span class="elsevierStyleItalic">&#46;</span>&#44; reportaron asociaci&#243;n estad&#237;sticamente significativa entre la expresi&#243;n de telomerasa &#40;44&#37; de los melanomas primarios de su serie&#41; y el espesor tumoral<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">22</span></a>&#59; y Zygouris et al<span class="elsevierStyleItalic">&#46;</span> describieron asociaci&#243;n con el &#237;ndice de Breslow y la ulceraci&#243;n<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">26</span></a>&#46; A su vez nuestros resultados contrastan con varios estudios en los que analizan la actividad telomer&#225;sica&#44; como es el de Ram&#237;rez et al<span class="elsevierStyleItalic">&#46;</span><a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">27</span></a>&#44; en el que se demostraba mayor actividad telomer&#225;sica en melanomas con mayor espesor tumoral&#44; mayor nivel de Clark y mitosis&#59; los resultados de Miracco et al<span class="elsevierStyleItalic">&#46;</span><a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">28</span></a> en los que la actividad telomer&#225;sica tambi&#233;n se asociaba al &#237;ndice de Breslow y al nivel de Clark&#59; y a lo publicado por Carvahlo et al<span class="elsevierStyleItalic">&#46;</span><a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">29</span></a> donde se demostraba mayor actividad telomer&#225;sica en los melanomas ulcerados&#44; con mayor Breslow&#44; mitosis&#44; invasi&#243;n vascular y satelitosis&#46; En nuestra serie los melanomas del subtipo lentigo melanoma maligno han demostrado mayor intensidad de expresi&#243;n&#44; aunque este dato no ha alcanzado significaci&#243;n estad&#237;stica&#46; Este &#250;ltimo hallazgo no concuerda con lo descrito en la serie de P&#243;pulo et al&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">8</span></a>&#44; en la que la expresi&#243;n de telomerasa &#250;nicamente se asociaba al subtipo histol&#243;gico de extensi&#243;n superficial&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">Con respecto a las mutaciones en el promotor del gen <span class="elsevierStyleItalic">TERT</span>&#44; acorde a lo descrito por otros autores<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">8&#44;9</span></a>&#44; en una publicaci&#243;n previa hemos descrito una prevalencia del 33&#37;&#44; y una asociaci&#243;n a melanomas de mayor espesor tumoral&#44; ulcerados&#44; con mitosis&#44; y del subtipo histol&#243;gico nodular<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">30</span></a>&#46; Al igual que en otros estudios&#44; en la presente serie no hemos encontrado diferencias en la expresi&#243;n de telomerasa por inmunohistoquimia entre los melanomas mutados y los no mutados<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">8&#44;22&#44;23</span></a>&#46; Este hallazgo contrasta con varias publicaciones previas en las que se demostraba mayor expresi&#243;n de telomerasa en los melanomas portadores de mutaciones en el promotor<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">9&#8211;12</span></a>&#46; Dicha discrepancia podr&#237;a deberse a que en estos estudios se analiza la expresi&#243;n de telomerasa a nivel del ARN mensajero y no de la prote&#237;na&#44; y por tanto pueden existir otros mecanismos moleculares que regulen su expresi&#243;n&#46; De hecho&#44; varios estudios se han centrado en la regulaci&#243;n epigen&#233;tica de la expresi&#243;n de telomerasa&#46; En este sentido&#44; se ha descrito que la regulaci&#243;n postranscripcional del gen <span class="elsevierStyleItalic">TERT</span> mediante expresi&#243;n de microRNA&#44; puede reprimir la expresi&#243;n de telomerasa<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">31&#44;32</span></a>&#59; y adicionalmente&#44; que la hipermetilaci&#243;n en el ADN del gen <span class="elsevierStyleItalic">TERT</span> puede incrementar la expresi&#243;n de telomerasa<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">33</span></a>&#46; A este respecto&#44; podr&#237;a resultar de utilidad medir la longitud de los tel&#243;meros y&#47;o la actividad telomer&#225;sica y correlacionarlo con la presencia de la mutaci&#243;n&#44; con el fin de dilucidar si solo los mutados tienen aumento de actividad&#44; o bien los <span class="elsevierStyleItalic">wild-type</span> tambi&#233;n tienen mayor actividad telomer&#225;sica mediante esos otros mecanismos moleculares&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">De forma adicional&#44; hemos identificado niveles variables de expresi&#243;n de telomerasa en una serie de 22 nevus melanoc&#237;ticos&#44; con una expresi&#243;n leve en la gran mayor&#237;a de las muestras&#44; y con una tendencia a incrementarse la expresi&#243;n desde nevus intrad&#233;rmicos&#44; a nevus displ&#225;sicos&#46; Asimismo&#44; cabe destacar que en todos los melanomas con lesi&#243;n n&#233;vica precursora&#44; la expresi&#243;n de telomerasa en el nevus acompa&#241;ante era mucho menos intensa que en las c&#233;lulas tumorales de los melanomas&#46; Estos resultados sugieren un posible papel de la telomerasa en la progresi&#243;n tumoral de las neoplasias melanoc&#237;ticas&#46; De hecho&#44; varios autores han analizado la actividad telomer&#225;sica en diferentes tipos de neoplasias melanoc&#237;ticas&#44; y han demostrado que la expresi&#243;n de telomerasa se incrementa de forma progresiva desde nevus comunes a nevus displ&#225;sicos y melanomas<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">4&#44;34</span></a>&#46; A pesar de estas diferencias en la expresi&#243;n de telomerasa entre nevus y melanoma&#44; dado que la expresi&#243;n puede ser variable en ambos tipos de neoplasias&#44; se ha demostrado que no es de utilidad en el diagn&#243;stico diferencial<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">30</span></a>&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">En el presente estudio la expresi&#243;n de telomerasa se ha analizado mediante imnunohistoqu&#237;mica&#44; a diferencia de la mayor&#237;a de los estudios publicados previamente en los que se analizaba la actividad telomer&#225;sica utilizando el Protocolo de amplificaci&#243;n de las secuencias repetitivas telom&#233;ricas &#40;TRAP&#41;<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">4&#44;23&#8211;25</span></a>&#46; El estudio mediante inmunohistoquimia tiene la ventaja de que es un m&#233;todo sencillo&#44; barato&#44; que se realiza en muestras parafinadas&#44; y que permite visualizar la intensidad y la extensi&#243;n de la expresi&#243;n no solo en las c&#233;lulas de inter&#233;s&#44; sino tambi&#233;n en la piel sana adyacente&#46; De hecho&#44; acorde a lo descrito previamente<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">30</span></a>&#44; hemos identificado niveles variables de expresi&#243;n de telomerasa no solo en las c&#233;lulas tumorales&#44; sino tambi&#233;n en la epidermis&#44; los fol&#237;culos pilosos&#44; las gl&#225;ndulas&#44; los vasos de la dermis e incluso en el infiltrado inflamatorio acompa&#241;ante&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">En conclusi&#243;n&#44; los resultados de este estudio ponen de manifiesto que la expresi&#243;n de telomerasa est&#225; presente en la totalidad de las neoplasias melanoc&#237;ticas analizadas&#44; con mayor expresi&#243;n en los melanomas que en los nevus&#46; En el caso de los melanomas primarios&#44; la expresi&#243;n de forma heterog&#233;nea se asocia a un fenotipo de mayor agresividad&#44; sin embargo la intensidad de la expresi&#243;n es independiente de las caracter&#237;sticas cl&#237;nico-patol&#243;gicas de los tumores&#46; Asimismo&#44; se demuestra que no existen diferencias en la expresi&#243;n de telomerasa en funci&#243;n del estado mutacional del gen <span class="elsevierStyleItalic">TERT</span>&#44; por lo que deben existir otros mecanismos moleculares adicionales que regulen la expresi&#243;n del gen <span class="elsevierStyleItalic">TERT</span> en los melanomas&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Financiaci&#243;n</span><p id="par0100" class="elsevierStylePara elsevierViewall">Este trabajo se ha realizado gracias a las ayudas concedidas por la Fundaci&#243;n Piel Sana &#40;Ayuda de la Fundaci&#243;n de la AEDV &#171;EUROMELANOMA 2016&#187;&#41;&#44; el ISCIII &#40;PI16&#47;01559&#41;&#44; el IISLaFe &#40;2014&#47;0370&#41;&#44; y la Conseller&#237;a de Educaci&#243;n&#44; Investigaci&#243;n&#44; Cultura y Deporte &#40;GV&#47;2016&#47;064&#41;&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Conflicto de intereses</span><p id="par0105" class="elsevierStylePara elsevierViewall">Los autores declaran no tener ning&#250;n conflicto de intereses&#46;</p></span></span>"
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          "titulo" => "Abstract"
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              "titulo" => "Background and objectives"
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              "titulo" => "Pacientes y muestras seleccionadas"
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              "titulo" => "Expresi&#243;n de telomerasa mediante inmunohistoquimia"
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              "titulo" => "An&#225;lisis estad&#237;stico"
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              "identificador" => "sec0035"
              "titulo" => "Expresi&#243;n de telomerasa en piel sana"
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              "identificador" => "sec0040"
              "titulo" => "Expresi&#243;n de telomerasa en las neoplasias melanoc&#237;ticas"
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          "titulo" => "Conflicto de intereses"
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    "fechaRecibido" => "2018-04-13"
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            0 => "Telomerasa"
            1 => "<span class="elsevierStyleItalic">Telomerase reverse transcriptase</span> &#40;TERT&#41;"
            2 => "Melanoma"
            3 => "Nevus"
            4 => "Inmunohistoquimia"
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            0 => "Telomerase"
            1 => "Telomerase reverse transcriptase &#40;TERT&#41;"
            2 => "Melanoma"
            3 => "Nevus"
            4 => "Immunohistochemistry"
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    "resumen" => array:2 [
      "es" => array:3 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Introducci&#243;n y objetivos</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La telomerasa es una enzima implicada en el mantenimiento de los tel&#243;meros y la senescencia celular&#46; Numerosos estudios han demostrado que en m&#225;s del 90&#37; de las neoplasias malignas se detecta actividad telomer&#225;sica&#46; El objetivo del presente estudio es analizar la expresi&#243;n de telomerasa por inmunohistoqu&#237;mica en una serie de neoplasias melanoc&#237;ticas&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Material y m&#233;todos</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Estudio observacional retrospectivo realizado en una serie de 85 melanomas primarios&#44; 12 metast&#225;sicos y 22 nevus melanoc&#237;ticos&#46; La expresi&#243;n de telomerasa se analiz&#243; empleando el anticuerpo monoclonal hTERT &#40;Rockland&#41;&#46; El an&#225;lisis de los datos se realiz&#243; con el programa SPSS&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Resultados</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">En todas las neoplasias melanoc&#237;ticas analizadas se demostr&#243; expresi&#243;n de telomerasa&#46; En el caso de los melanomas predomin&#243; el patr&#243;n de expresi&#243;n heterog&#233;neo&#44; y la expresi&#243;n moderada o intensa&#46; En los nevus result&#243; m&#225;s frecuente una expresi&#243;n homog&#233;nea con intensidad leve&#46; El patr&#243;n de expresi&#243;n heterog&#233;neo se asoci&#243; a los melanomas de r&#225;pido crecimiento &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;028&#41;&#44; con Breslow &#62; 4<span class="elsevierStyleHsp" style=""></span>mm &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;004&#41;&#44; con mitosis &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;032&#41;&#44; y con mutaciones en el gen TERT &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;002&#41;&#46; En el caso de los nevus&#44; la intensidad fue menor en los nevus intrad&#233;rmicos&#44; seguidos de los compuestos y de los dipl&#225;sicos &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;054&#41;&#46;</p></span> <span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Conclusiones</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">La expresi&#243;n de telomerasa est&#225; presente en la totalidad de las neoplasias melanoc&#237;ticas&#44; con mayor expresi&#243;n en los melanomas que en los nevus&#46; En el caso de los melanomas&#44; la expresi&#243;n de forma heterog&#233;nea se asocia a un fenotipo de mayor agresividad&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
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            "titulo" => "Introducci&#243;n y objetivos"
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          1 => array:2 [
            "identificador" => "abst0015"
            "titulo" => "Material y m&#233;todos"
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          2 => array:2 [
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Background and objectives</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Telomerase is an enzyme involved in maintaining the length of telomeres and cell senescence&#46; Numerous studies have shown that in more than 90&#37; of malignant tumors telomerase activity is detected&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Material and methods</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Retrospective observational study in a series of 85 cases of primary melanomas&#44; 12 metastatic melanomas&#44; and 22 melanocytic nevi&#46; We used the monoclonal antibody hTERT &#40;human telomerase reverse transcriptase&#44; Rockland&#41; to assess telomerase activity&#46; The SPSS software package was used to analyze data&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Results</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Telomerase expression was present in all the melanocytic neoplasms analyzed&#46; Expression was heterogenous and moderate or high in the melanomas&#46; In contrast&#44; expression was homogeneous and lower in the nevi&#46; Heterogeneous expression was associated with rapid melanoma growth &#40;<span class="elsevierStyleItalic">P<span class="elsevierStyleHsp" style=""></span></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;028&#41;&#44; a Breslow thickness of more than 4 mm &#40;<span class="elsevierStyleItalic">P<span class="elsevierStyleHsp" style=""></span></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;004&#41;&#44; mitosis &#40;<span class="elsevierStyleItalic">P<span class="elsevierStyleHsp" style=""></span></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;032&#41;&#44; and mutations in the <span class="elsevierStyleItalic">TERT</span> gene &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;002&#41;&#46; Activity was less intense in intradermal nevi&#44; and more intense in compound and dysplastic nevi &#40;<span class="elsevierStyleItalic">P<span class="elsevierStyleHsp" style=""></span></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;054&#41;&#46;</p></span> <span id="abst0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Conclusions</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Telomerase expression is found in all melanocytic neoplasms but is higher in melanomas than in nevi&#46; A heterogeneous pattern of expression in melanomas is associated with more aggressive tumors&#46;</p></span>"
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          "es" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Expresi&#243;n intensa de telomerasa en las gl&#225;ndulas seb&#225;ceas &#40;x100&#41;&#46;</p>"
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          "es" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Expresi&#243;n de telomerasa con patr&#243;n heterog&#233;neo en un melanoma primario &#40;x100&#41;&#46;</p>"
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          "es" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">a&#41; Melanoma asociado a nevus intrad&#233;rmico &#40;H&#38;E&#59; x40&#41;&#46; b&#41; Detalle del nevus intrad&#233;rmico asociado al melanoma &#40;H&#38;E&#59; x100&#41;&#46; c&#41; Expresi&#243;n de telomerasa intensa en las c&#233;lulas tumorales del melanoma y leve en las c&#233;lulas n&#233;vicas &#40;x40&#41;&#46; d&#41; Detalle de la expresi&#243;n leve de telomerasa en las c&#233;lulas del nevus &#40;x100&#41;&#46;</p>"
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          "es" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Expresi&#243;n de telomerasa intensa en un melanoma metast&#225;sico &#40;x100&#41;&#46;</p>"
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          "es" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Expresi&#243;n de telomerasa leve en un nevus melanoc&#237;tico intrad&#233;rmico &#40;x100&#41;&#46;</p>"
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          "es" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">a&#41; Patr&#243;n de expresi&#243;n de telomerasa en melanomas y nevus con predominio de expresi&#243;n homog&#233;nea en los nevus melanoc&#237;ticos&#46; b&#41; Descenso progresivo en la intensidad de la expresi&#243;n de telomerasa desde melanomas metast&#225;sicos a nevus&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td-with-role" title="table-head ; entry_with_role_rowhead " align="left" valign="top" scope="col">Variable&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col">Total &#40;n &#61; 85&#41;&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">Patr&#243;n expresi&#243;n</th></tr><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  " align="" valign="top" scope="col">&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">Hom&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">Het&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">p valor&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="" valign="top" scope="col" style="border-bottom: 2px solid black">&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">N &#40;&#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">N &#40;&#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">N &#40;&#37;&#41;&nbsp;\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">&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" title="table-entry  " colspan="5" align="left" valign="top"><span class="elsevierStyleItalic">Edad</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>&#60; 40&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5 &#40;5&#44;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2 &#40;40&#44;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3 &#40;60&#44;0&#41;&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;678&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>40-65&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">45 &#40;52&#44;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">27&#40;60&#44;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">18 &#40;40&#44;0&#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></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>&#62; 65&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">35 &#40;41&#44;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">21 &#40;60&#44;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">14 &#40;40&#44;0&#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></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" 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="5" align="left" valign="top"><span class="elsevierStyleItalic">Sexo</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>Var&#243;n&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">46 &#40;54&#44;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">29 &#40;63&#44;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">17 &#40;37&#44;0&#41;&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;526&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>Mujer&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">39 &#40;45&#44;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">21 &#40;53&#44;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">18 &#40;46&#44;2&#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></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" 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="5" align="left" valign="top"><span class="elsevierStyleItalic">Localizaci&#243;n</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>Cabeza y cuello&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">9 &#40;10&#44;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2 &#40;22&#44;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">7&#40;77&#44;8&#41;&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;025&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>Tronco&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">45 &#40;52&#44;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">32 &#40;71&#44;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">13 &#40;28&#44;9&#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></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>Miembros superiores&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">14 &#40;16&#44;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5 &#40;35&#44;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">9 &#40;64&#44;3&#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></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>Miembros inferiores&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">14 &#40;16&#44;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">9 &#40;64&#44;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5 &#40;35&#44;7&#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></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>Acral&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3 &#40;3&#44;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2 &#40;66&#44;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1 &#40;33&#44;3&#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></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" 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="5" align="left" valign="top"><span class="elsevierStyleItalic">Subtipo histol&#243;gico</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>Lentigo maligno melanoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3 &#40;3&#44;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0 &#40;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3 &#40;100&#41;&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;017&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>Melanoma extensi&#243;n superficial&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">64 &#40;75&#44;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">43 &#40;67&#44;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">21 &#40;32&#44;8&#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></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>Melanoma nodular&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">15 &#40;17&#44;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5 &#40;33&#44;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10 &#40;66&#44;7&#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></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>Melanoma lentiginoso acral&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3 &#40;3&#44;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2 &#40;66&#44;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1 &#40;33&#44;3&#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></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" 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="5" align="left" valign="top"><span class="elsevierStyleItalic">&#205;ndice de Breslow</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>&#60; 1mm&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">40 &#40;47&#44;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">29 &#40;72&#44;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">11 &#40;27&#44;5&#41;&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;004&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>1-2mm&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">29 &#40;34&#44;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">15 &#40;55&#44;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">13 &#40;44&#44;8&#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></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>2-4mm&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6 &#40;7&#44;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4 &#40;66&#44;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2 &#40;33&#44;3&#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></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>&#62; 4mm&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10 &#40;11&#44;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1 &#40;10&#44;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">9 &#40;90&#44;0&#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></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" 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="5" align="left" valign="top"><span class="elsevierStyleItalic">Ulceraci&#243;n</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>No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">69 &#40;81&#44;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">43 &#40;62&#44;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">26 &#40;37&#44;7&#41;&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;141&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">7 &#40;43&#44;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">9 &#40;56&#44;3&#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></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" 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="5" align="left" valign="top"><span class="elsevierStyleItalic">Mitosis</span>&#47;mm<span class="elsevierStyleSup">2</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>&#60; 1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">43 &#40;50&#44;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">30 &#40;69&#44;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">13 &#40;30&#44;2&#41;&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;032&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>&#8805; 1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">42 &#40;49&#44;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">19 &#40;47&#44;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">22 &#40;52&#44;4&#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></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" 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="5" align="left" valign="top"><span class="elsevierStyleItalic">Regresi&#243;n</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>No&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">23 &#40;53&#44;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">20 &#40;46&#44;5&#41;&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;215&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>S&#237;&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">27 &#40;64&#44;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">15 &#40;35&#44;7&#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></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" 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="5" align="left" valign="top"><span class="elsevierStyleItalic">Estadio tumoral</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>Localizado&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">73 &#40;85&#44;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">43 &#40;59&#44;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">29 &#40;40&#44;3&#41;&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;580&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 locorregional&#47;distancia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12 &#40;14&#44;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">7 &#40;58&#44;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5 &#40;41&#44;7&#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></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" 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="5" align="left" valign="top"><span class="elsevierStyleItalic">Tasa de crecimiento</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>Lento crecimiento&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">70 &#40;82&#44;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">25 &#40;64&#44;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">45 &#40;35&#44;7&#41;&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;028&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 &#40;33&#44;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10 &#40;66&#44;7&#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></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" 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="5" align="left" valign="top"><span class="elsevierStyleItalic">Evoluci&#243;n cl&#237;nica &#40;&#37;&#41;</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>Enfermedad estable&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">69 &#40;81&#44;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">41 &#40;57&#44;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">30 &#40;42&#44;3&#41;&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;242&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">3 &#40;42&#44;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4 &#40;57&#44;1&#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></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>&#201;xitus&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">3 &#40;100&#44;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0 &#40;0&#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
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">37 &#40;66&#44;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">19 &#40;33&#44;9&#41;&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;002&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">6 &#40;27&#44;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12 &#40;72&#44;7&#41;&nbsp;\t\t\t\t\t\t\n
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