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        "titulo" => "Longitudinal Study of Different Progression Patterns in High-Risk Cutaneous Squamous Cell Carcinoma"
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          "es" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Supervivencia hasta la aparici&#243;n de la primera recurrencia en los carcinomas cut&#225;neos de c&#233;lulas escamosas de alto riesgo &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>222&#41;&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introducci&#243;n</span><p id="par0005" class="elsevierStylePara elsevierViewall">El carcinoma epidermoide cut&#225;neo &#40;CEC&#41; es la segunda neoplasia cut&#225;nea maligna en frecuencia tras el carcinoma basocelular en nuestro pa&#237;s<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">1</span></a>&#46; Tambi&#233;n es la segunda causa de mortalidad por c&#225;ncer de piel tras el melanoma<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">1</span></a>&#46; Es un tumor con un bajo potencial metast&#225;sico&#46; El CEC metastatiza preferentemente por v&#237;a linf&#225;tica en el 3-5&#37; de los casos&#44; dependiendo de la localizaci&#243;n&#44; del tama&#241;o&#44; de la invasi&#243;n en profundidad&#44; de la invasi&#243;n perineural o de la afectaci&#243;n &#243;sea<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">2</span></a>&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">Por otro lado&#44; la biopsia selectiva del ganglio centinela &#40;BSGC&#41; es una t&#233;cnica quir&#250;rgica que se desarroll&#243; ampliamente en otros tumores&#44; como el melanoma&#44; en base a su propensi&#243;n a las met&#225;stasis regionales linf&#225;ticas&#44; sin que tuviera un impacto en la supervivencia de estos pacientes<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">3</span></a>&#46; En el caso del CEC&#44; la utilidad de la BSGC es a&#250;n desconocida&#44; siendo su porcentaje de positividad del 8-10&#37;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">4</span></a>&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Existen pocos estudios publicados sobre la historia natural en t&#233;rminos de progresi&#243;n del CEC<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">5</span></a>&#44; o bien que se hayan focalizado en el tiempo de evoluci&#243;n de las distintas formas de recidiva en la progresi&#243;n de este tumor&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">Comprender y analizar c&#243;mo progresan los CEC ayudar&#237;a a dise&#241;ar estrategias diagn&#243;sticas&#44; terap&#233;uticas y de seguimiento de estos pacientes&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">El objetivo primario de este estudio es analizar las diferentes v&#237;as de progresi&#243;n del CEC &#40;recurrencia local&#44; satelitosis&#44; recurrencia linf&#225;tica regional o met&#225;stasis a distancia&#41; junto con el tiempo de evoluci&#243;n de estas&#46; Como objetivos secundarios se analiza la relaci&#243;n de las distintas variables cl&#237;nicas y patol&#243;gicas con las diferentes formas de progresi&#243;n&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Material y m&#233;todo</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Participantes y dise&#241;o del estudio</span><p id="par0030" class="elsevierStylePara elsevierViewall">Se dise&#241;&#243; un estudio multic&#233;ntrico observacional retrospectivo incluyendo pacientes de ocho hospitales de referencia que participan en el proyecto SQUAMATA&#46; Este proyecto se focaliza en el estudio de factores pron&#243;sticos del CEC y ha sido descrito previamente<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">6</span></a>&#46; Los hospitales participantes son el Hospital Universitario de Salamanca&#44; Salamanca &#40;Espa&#241;a&#41;&#59; el Instituto Valenciano de Oncolog&#237;a&#44; Valencia &#40;Espa&#241;a&#41;&#59; el Hospital Germans Trias i Pujol&#44; Badalona &#40;Espa&#241;a&#41;&#59; el Hospital Cl&#237;nic&#44; Barcelona &#40;Espa&#241;a&#41;&#59; el Hospital Universitari Vall d&#8217;Hebron&#44; Barcelona &#40;Espa&#241;a&#41;&#59; el Hospital Universitario Central de Asturias&#44; Oviedo &#40;Espa&#241;a&#41;&#59; el Hospital San Cecilio&#44; Granada &#40;Espa&#241;a&#41;&#44; y la University Hospital Citt&#224; della Salute e della Scienza di Torino&#44; Tur&#237;n &#40;Italia&#41;&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">Se incluy&#243; a los pacientes diagnosticados de un CEC de alto riesgo entre el 1 de enero de 2000 y el 31 de diciembre de 2020&#46; Se consider&#243; como un CEC de alto riesgo aquel tumor con di&#225;metro &#8805;<span class="elsevierStyleHsp" style=""></span>2<span class="elsevierStyleHsp" style=""></span>cm&#44; un grosor tumoral &#8805;<span class="elsevierStyleHsp" style=""></span>6<span class="elsevierStyleHsp" style=""></span>mm&#44; la presencia de invasi&#243;n perineural o linfovascular&#44; una mala diferenciaci&#243;n histol&#243;gica&#44; la invasi&#243;n m&#225;s all&#225; de la grasa subcut&#225;nea&#44; la localizaci&#243;n en oreja o labio y la inmunosupresi&#243;n del paciente &#40;trasplante de &#243;rgano s&#243;lido&#44; leucemia linfoc&#237;tica cr&#243;nica&#44; tratamiento inmunosupresor cr&#243;nico o insuficiencia renal cr&#243;nica&#41;&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">En el caso de la presencia de m&#250;ltiples CEC&#44; solo el tumor con caracter&#237;sticas de mayor riesgo fue incluido en la base de datos&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">El estudio fue aprobado por el comit&#233; &#233;tico del Hospital Universitario Reina Sof&#237;a de C&#243;rdoba &#40;registro n&#46;&#176; 3958&#41;&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">El seguimiento de los distintos centros es similar y se basa fundamentalmente en las gu&#237;as de la NCCN<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">7</span></a>&#44; con un seguimiento de los pacientes cada 3-6<span class="elsevierStyleHsp" style=""></span>meses los dos primeros a&#241;os y cada 6-12<span class="elsevierStyleHsp" style=""></span>meses a partir del tercer a&#241;o&#44; siendo anual a partir del quinto a&#241;o&#46; En caso de enfermedad regional&#44; los controles son cada 2-3<span class="elsevierStyleHsp" style=""></span>meses el primer a&#241;o&#44; cada 4-6<span class="elsevierStyleHsp" style=""></span>meses hasta el tercer a&#241;o y cada 6-12<span class="elsevierStyleHsp" style=""></span>meses a partir del cuarto a&#241;o&#46; Las pruebas de imagen usadas en los controles son la ecograf&#237;a&#44; la tomograf&#237;a axial computarizada &#40;TAC&#41; y&#44; en casos donde se quer&#237;a valorar la extensi&#243;n local de tejidos&#44; la resonancia magn&#233;tica &#40;RM&#41;&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">Para el prop&#243;sito del estudio se registr&#243; la primera v&#237;a de progresi&#243;n&#46; En funci&#243;n de esta se definieron cuatro grupos&#58; recurrencia local &#40;RL&#41;&#44; recurrencia linf&#225;tica regional &#40;L&#41;&#44; satelitosis&#47;met&#225;stasis en tr&#225;nsito &#40;S&#41; y met&#225;stasis a distancia &#40;M&#41;&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">La implicaci&#243;n de estas cuatro v&#237;as de progresi&#243;n puede definir distintos patrones de diseminaci&#243;n&#44; similar a como se han descrito cl&#225;sicamente para el melanoma<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">8&#44;9</span></a>&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">Para aquellos pacientes que terminaron en exitus por la enfermedad&#44; se describieron siete patrones o rutas de diseminaci&#243;n&#58; patr&#243;n RL-Ex&#44; desarrollo de RL y exitus &#40;Ex&#41;&#59; patr&#243;n RL-M-EX&#44; desarrollo de RL&#44; posteriormente M y Ex&#59; patr&#243;n RL-L-Ex&#44; desarrollo de RL&#44; posteriormente L y posterior Ex&#59; patr&#243;n RL-L-M-EX&#44; desarrollo de RL&#44; posteriormente L&#44; M y finalmente Ex&#59; patr&#243;n L-Ex&#44; desarrollo directamente de L y posterior Ex&#59; patr&#243;n L-M-Ex&#44; desarrollo de L&#44; posteriormente M y posterior Ex&#44; y finamente patr&#243;n S-Ex&#44; con el desarrollo de S y posterior Ex&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">Se us&#243; el test de chi-cuadrado para comparar las diferencias entre las distintas v&#237;as metast&#225;sicas &#40;RL&#44; L&#44; S y M&#41; y las distintas variables cl&#237;nicas y patol&#243;gicas categ&#243;ricas &#40;g&#233;nero&#44; inmunosupresi&#243;n&#44; localizaci&#243;n en cabeza&#47;cuello&#44; tronco&#47;extremidades y manos&#47;pies&#44; di&#225;metro &#8804;<span class="elsevierStyleHsp" style=""></span>20<span class="elsevierStyleHsp" style=""></span>mm vs&#46; &#62;<span class="elsevierStyleHsp" style=""></span>20<span class="elsevierStyleHsp" style=""></span>mm&#44; grosor tumoral &#8804;<span class="elsevierStyleHsp" style=""></span>6 vs&#46; &#62;<span class="elsevierStyleHsp" style=""></span>6<span class="elsevierStyleHsp" style=""></span>mm&#44; invasi&#243;n perineural&#44; invasi&#243;n linfovascular&#44; grado de diferenciaci&#243;n&#44; clasificaci&#243;n de la <span class="elsevierStyleItalic">American Joint Committee on Cancer</span> &#40;AJCC&#41;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">10</span></a> y clasificaci&#243;n del Brigham and Woman Hospital &#40;BWH&#41;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">11</span></a>&#46; La edad fue evaluada con la prueba de Kruskas-Wallis&#46; Las pruebas significativas fueron evaluadas con an&#225;lisis <span class="elsevierStyleItalic">post hoc</span>&#44; con valores de p ajustados mediante el m&#233;todo de Holm&#46; Se compar&#243; mediante las curvas de Kaplan-Meier &#40;KM&#41; y la prueba del logaritmo de los rangos el tiempo hasta la observaci&#243;n de las diferentes formas de progresi&#243;n&#46; De forma similar&#44; se compararon las curvas de KM para las met&#225;stasis linf&#225;ticas regionales como primera recidiva o tras recurrencia local por un lado&#44; y las mismas met&#225;stasis linf&#225;ticas regionales en funci&#243;n de si progresaban regionalmente a met&#225;stasis sist&#233;micas o bien si permanec&#237;a vivo el paciente&#46; Por &#250;ltimo&#44; se valor&#243; el tiempo hasta progresi&#243;n en funci&#243;n del tipo de recidiva local&#44; regional o a distancia&#46; Se consider&#243; un nivel de significaci&#243;n de p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;05&#46; Se utiliz&#243; el programa estad&#237;stico SPSS &#40;IBM Corp&#46; Released 2011&#46; IBM SPSS Statistics for Windows&#44; Version 20&#46;0&#46; Armonk&#44; NY&#58; IBM Corp&#46;&#41;&#46;</p></span></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Resultados</span><p id="par0075" class="elsevierStylePara elsevierViewall">Se incluyeron un total de 1&#46;346 pacientes con CEC primario de alto riesgo&#44; de los cuales el 16&#44;5&#37; &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>222&#41; experiment&#243; alg&#250;n tipo de reca&#237;da en su seguimiento&#46; La mediana de seguimiento fue de 33<span class="elsevierStyleHsp" style=""></span>meses&#46; La <a class="elsevierStyleCrossRef" href="#tbl0005">tabla 1</a> refleja las caracter&#237;sticas cl&#237;nicas y patol&#243;gicas de la poblaci&#243;n en funci&#243;n de las distintas v&#237;as de progresi&#243;n&#46; &#218;nicamente se hallaron diferencias estad&#237;sticamente significativas en cuanto al estado de inmunosupresi&#243;n&#44; el di&#225;metro tumoral y la probabilidad de exitus tanto por la neoplasia como por cualquier causa&#46; La v&#237;a de diseminaci&#243;n m&#225;s frecuente tanto en inmunocompetentes como en inmunodeprimidos fue la diseminaci&#243;n linf&#225;tica &#40;71&#44;8&#37; y 51&#37;&#44; respectivamente&#41;&#44; mientras que las recurrencias locales y la diseminaci&#243;n mediante satelitosis fueron relativamente m&#225;s frecuentes en los pacientes inmunodeprimidos &#40;40&#37; vs&#46; 24&#44;6&#37; en inmunocompetentes&#41;&#46; Las recidivas linf&#225;ticas fueron algo m&#225;s frecuentes en los pacientes inmunocompetentes &#40;71&#44;8&#37; vs&#46; 51&#44;1&#37;&#41;&#46; Los tumores que hicieron diseminaci&#243;n linf&#225;tica fueron de mediana 5<span class="elsevierStyleHsp" style=""></span>mm mayores en su di&#225;metro que los que recurrieron localmente &#40;25<span class="elsevierStyleHsp" style=""></span>mm vs 20<span class="elsevierStyleHsp" style=""></span>mm&#44; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;01&#41;&#46; En cuanto a los tumores que hicieron satelitosis como primera v&#237;a de diseminaci&#243;n&#44; se observ&#243; que la mayor&#237;a fueron tumores &#8804;<span class="elsevierStyleHsp" style=""></span>20<span class="elsevierStyleHsp" style=""></span>mm &#40;77&#44;8&#37;&#41;&#44; a diferencia de los que hicieron recidiva linf&#225;tica&#44; que en su mayor&#237;a fueron superiores a los 2<span class="elsevierStyleHsp" style=""></span>cm &#40;61&#44;0&#37;&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0080" class="elsevierStylePara elsevierViewall">En referencia a la estadificaci&#243;n&#44; destaca como la totalidad de los tumores T4 de la AJCC y T3 de la BWH se diseminaron de forma preferente a los ganglios linf&#225;ticos &#40;100&#37;&#41;&#46; Por otra parte&#44; los tumores de bajo riesgo T1 que progresaron lo hicieron casi en igual medida en forma de recurrencias locales o bien ganglionares &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">tabla 1</a>&#41;&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">En cuanto a mortalidad seg&#250;n las v&#237;as&#44; se observ&#243; que los tumores que debutaron con una recidiva local presentaban menor porcentaje de mortalidad espec&#237;fica que los que lo hicieron en los ganglios &#40;23&#37; vs 47&#44;5&#37;&#44; p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#41; y tambi&#233;n una menor mortalidad global &#40;44&#46;6&#37; vs 68&#44;3&#37;&#44; p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;005&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">tabla 1</a>&#41;&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">Es de remarcar que ni la edad&#44; el sexo&#44; la localizaci&#243;n&#44; el grado de diferenciaci&#243;n&#44; el grosor tumoral&#44; la invasi&#243;n perineural o linfovascular ni la estadificaci&#243;n se distribuyeron de forma significativamente distinta entre las distintas v&#237;as de diseminaci&#243;n&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">La <a class="elsevierStyleCrossRef" href="#fig0005">figura 1</a> refleja las distintas v&#237;as metast&#225;sicas en la progresi&#243;n del CEC primario&#46; La v&#237;a de progresi&#243;n m&#225;s frecuente fue la linf&#225;tica &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>139 &#91;62&#44;6&#37;&#93;&#41;&#44; seguida de las recurrencias locales &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>74 &#91;33&#44;3&#37;&#93;&#41; y las satelitosis &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>9 &#91;4&#44;4&#37;&#93;&#41;&#46; En 12 casos de recurrencia local &#40;16&#44;2&#37; de RL&#41; hubo progresi&#243;n linf&#225;tica posterior&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0100" class="elsevierStylePara elsevierViewall">En conjunto&#44; de todos los casos con recidiva regional linf&#225;tica&#44; en 31 casos &#40;20&#44;5&#37; de L&#41; progresaron a met&#225;stasis sist&#233;micas&#46; Solo se describi&#243; un caso de recurrencia local y que desarroll&#243; met&#225;stasis sist&#233;micas directamente&#46; No se hallaron met&#225;stasis sist&#233;micas como primera v&#237;a de progresi&#243;n&#44; ni met&#225;stasis linf&#225;ticas tras satelitosis&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">Los exitus de los pacientes con CEC fueron en su mayor&#237;a debidos a progresi&#243;n regional linf&#225;tica de su enfermedad &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>47 &#91;54&#44;6&#37; de los exitus&#93;&#41; seguido de las met&#225;stasis sist&#233;micas &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>27 &#91;31&#44;4&#37; de los exitus&#93;&#41;&#46; Las progresiones locales fueron el motivo de exitus en el 11&#44;6&#37; &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>10&#41; de los exitus&#46; Finalmente&#44; se registraron 2 fallecimientos por satelitosis &#40;2&#44;3&#37; de los exitus&#41;&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">Las distintas v&#237;as metast&#225;sicas y de progresi&#243;n del CEC de los casos con resultado de exitus se representan en la <a class="elsevierStyleCrossRef" href="#fig0010">figura 2</a>&#46; La v&#237;a metast&#225;sica m&#225;s frecuente fue la ruta L-Ex &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>42 &#91;49&#44;4&#37;&#93;&#41;&#44; seguida por la L-M-Ex &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>24 &#91;28&#44;2&#37;&#93;&#41;&#46; La siguiente en frecuencia es la ruta RL-Ex &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>9 &#91;10&#44;6&#37;&#93;&#41;&#46; El resto de las v&#237;as metast&#225;sicas y de progresi&#243;n fueron de 5 o menos casos&#46; Llama la atenci&#243;n que&#44; con independencia de la v&#237;a metast&#225;sica&#44; todas las recidivas regionales linf&#225;ticas aparecieron de media entre los 13 y los 18<span class="elsevierStyleHsp" style=""></span>meses de seguimiento&#44; as&#237; como los exitus por la enfermedad ocurrieron entre los 26 y 35<span class="elsevierStyleHsp" style=""></span>meses de media desde el diagn&#243;stico para las distintas v&#237;as metast&#225;sicas m&#225;s frecuentes&#46; Curiosamente&#44; se observ&#243; una tendencia a un mayor tiempo hasta exitus en aquellos casos con met&#225;stasis<span class="elsevierStyleHsp" style=""></span>L y posterior desarrollo de met&#225;stasis sist&#233;micas &#40;ruta L-M-Ex&#41; con respecto a aquellos casos que &#250;nicamente progresaron a nivel local &#40;ruta RL-Ex&#41;&#44; por satelitosis &#40;ruta S-Ex&#41; o a nivel regional &#40;ruta L-Ex&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0115" class="elsevierStylePara elsevierViewall">El an&#225;lisis de supervivencia hasta la reca&#237;da en funci&#243;n del tipo de v&#237;a &#40;RL&#44; L y S&#41; no mostr&#243; diferencias entre estas &#40;<a class="elsevierStyleCrossRef" href="#fig0020">fig&#46; 3</a>&#41;&#46; Tampoco se apreciaron diferencias en el tiempo de supervivencia hasta la aparici&#243;n de met&#225;stasis linf&#225;ticas en funci&#243;n de si eran la primera recidiva o bien tras recidiva local &#40;<a class="elsevierStyleCrossRef" href="#fig0025">fig&#46; 4</a>&#41;&#46; Por &#250;ltimo&#44; el tiempo transcurrido hasta la aparici&#243;n de las met&#225;stasis linf&#225;ticas no se correlacion&#243; con el pron&#243;stico&#44; determinado como ausencia de posteriores progresiones respecto a progresi&#243;n a met&#225;stasis sist&#233;micas o progresi&#243;n regional hasta el fallecimiento del paciente &#40;<a class="elsevierStyleCrossRef" href="#fig0030">fig&#46; 5</a>&#41;&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia><elsevierMultimedia ident="fig0025"></elsevierMultimedia><elsevierMultimedia ident="fig0030"></elsevierMultimedia></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Discusi&#243;n</span><p id="par0120" class="elsevierStylePara elsevierViewall">El presente estudio muestra que la progresi&#243;n m&#225;s frecuente para los CEC de alto riesgo es la v&#237;a linf&#225;tica&#44; y que esta v&#237;a es pr&#225;cticamente obligatoria antes del desarrollo de met&#225;stasis sist&#233;micas&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">El proceso metast&#225;sico es un complejo proceso en el que unas c&#233;lulas gen&#233;ticamente inestables se adaptan a un microambiente tisular diferente a su tejido de origen<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">12</span></a>&#46; Este proceso no es aleatorio&#44; sino que las c&#233;lulas tumorales generalmente tienen cierta apetencia por tejidos determinados en funci&#243;n de la estirpe tumoral en un modelo de diseminaci&#243;n denominado originalmente &#171;semilla y terreno&#187; por Paget en el siglo<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleSmallCaps">xix</span><a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">13</span></a>&#46; Este modelo explica por qu&#233; ciertos tumores como el c&#225;ncer de mama frecuentemente metastatizan en pulm&#243;n&#44; hueso&#44; h&#237;gado o cerebro&#44; mientras que otros&#44; como el c&#225;ncer de pr&#243;stata&#44; lo hace m&#225;s en hueso&#46; O bien que el melanoma uveal caracter&#237;sticamente metastatice m&#225;s a h&#237;gado&#44; o bien los sarcomas a pulm&#243;n<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">12</span></a>&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">En el caso de los CEC&#44; la implicaci&#243;n m&#225;s importante de estos hallazgos ser&#237;a el manejo locorregional de la enfermedad&#46; M&#225;s de la mitad de los pacientes en el estudio fallecen por progresi&#243;n de las met&#225;stasis regionales linf&#225;ticas&#44; lo que plantea si una disecci&#243;n linf&#225;tica electiva podr&#237;a beneficiar a estos pacientes&#44; como en el caso del carcinoma de c&#233;lulas escamosas de la cavidad oral<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">14</span></a>&#46; Sin embargo&#44; los estudios observacionales disponibles presentan resultados contrapuestos&#46; Amit et al&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">15</span></a> no demostraron en un estudio observacional beneficio de la disecci&#243;n ganglionar electiva en pacientes con CEC frente a la observaci&#243;n&#46; Por el contrario&#44; Xiao et al&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">16</span></a>&#44; en otro estudio observacional&#44; s&#237; observaron mejor&#237;a en la supervivencia en los pacientes sometidos a una disecci&#243;n ganglionar electiva y parotidectom&#237;a superficial&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">Esta progresi&#243;n ordenada y gradual que muestra el CEC desde el tumor primario al ganglio linf&#225;tico regional y de aqu&#237; a la diseminaci&#243;n metast&#225;sica es la base te&#243;rica ideal que avala la utilizaci&#243;n terap&#233;utica de la biopsia selectiva del ganglio centinela &#40;BSGC&#41;&#46; Es precisamente lo que hace d&#233;cadas se denomin&#243; &#171;hip&#243;tesis de la incubadora&#187;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">17</span></a> por los defensores de la BSGC en el melanoma&#44; en contraposici&#243;n con la &#171;hip&#243;tesis del marcador&#187;&#44; que establec&#237;a que la presencia de met&#225;stasis en los ganglios linf&#225;ticos regionales constituye no un paso previo&#44; sino un marcador de que el tumor ya se habr&#237;a diseminado a otros &#243;rganos<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">18&#44;19</span></a>&#46; La observaci&#243;n de que el tiempo medio de supervivencia es mayor para las v&#237;as metast&#225;sicas que implican la aparici&#243;n de met&#225;stasis sist&#233;micas &#40;<a class="elsevierStyleCrossRef" href="#fig0010">fig&#46; 2</a>&#41; con respecto a las mismas v&#237;as pero sin la diseminaci&#243;n sist&#233;mica apoya en cierta medida esta &#171;hip&#243;tesis de la incubadora&#187;&#44; hecho que no se observa en estudios similares para el melanoma<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">8&#44;9</span></a>&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">De forma parad&#243;jica&#44; mientras que en el melanoma se dispone de un ensayo cl&#237;nico que ha evaluado el papel de la BSGC<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">3</span></a>&#44; sin que este haya demostrado un beneficio en la supervivencia&#44; no se dispone a&#250;n de un ensayo que haya evaluado lo mismo en el CEC&#46; Existen&#44; no obstante&#44; algunos estudios observacionales que han comparado a pacientes con CEC sometidos a BSGC con pacientes solo con observaci&#243;n sin que se haya observado diferencia en la supervivencia&#46; En esta l&#237;nea&#44; nuestro grupo ha encontrado diferencias en un reciente estudio observacional cuando se ha estratificado por estado inmunol&#243;gico del paciente&#44; observ&#225;ndose una clara ventaja en la supervivencia libre de progresi&#243;n &#250;nicamente en pacientes inmunocompetentes sometidos a BSGC &#40;datos no publicados&#41;&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">El problema para la indicaci&#243;n de esta t&#233;cnica&#44; as&#237; como la predicci&#243;n en general de met&#225;stasis linf&#225;ticas y sist&#233;micas&#44; est&#225; lejos de ser resuelto&#44; ya que solo el 4-5&#37; de los pacientes desarrollar&#225;n met&#225;stasis linf&#225;ticas&#44; y de ellos solo una cuarta parte&#44; met&#225;stasis sist&#233;micas&#46; En una revisi&#243;n sistem&#225;tica reciente&#44; la positividad de la BSGC en el CEC ronda el 8&#37;&#44; sin que se hayan identificado a&#250;n claros factores predictores de afectaci&#243;n<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">4</span></a>&#46; La evidencia actual sobre las alteraciones gen&#233;ticas en la regulaci&#243;n del ciclo celular&#44; la supresi&#243;n tumoral&#44; la invasi&#243;n tisular y microambiente y la interacci&#243;n con el sistema inmune est&#225; a&#250;n lejos de ofrecer dianas concretas que puedan predecir con m&#225;s exactitud los pacientes que van a progresar<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">20</span></a>&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">En nuestra serie&#44; el 11&#44;6&#37; de las muertes espec&#237;ficas fueron por progresi&#243;n local&#46; Estos datos muestran la importancia del control local de CEC&#46; En una reciente revisi&#243;n sistem&#225;tica&#44; la invasi&#243;n profunda m&#225;s all&#225; de la grasa&#44; o bien&#44; y en menor medida&#44; la desmoplasia son los factores histol&#243;gicos que m&#225;s predicen esta recurrencia<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">21</span></a>&#44; siendo la cirug&#237;a de Mohs la opci&#243;n preferida para el control local del CEC<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">21</span></a>&#46; En una reciente revisi&#243;n&#44; el &#233;xito de la BSGC en el CEC cut&#225;neo no se vio afectada tanto si se hizo de forma sincr&#243;nica como asincr&#243;nica con la cirug&#237;a&#44; incluyendo cirug&#237;a de Mohs<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">22</span></a>&#46; Esto es importante en el contexto actual&#44; en el que la cirug&#237;a de Mohs es un procedimiento cada vez m&#225;s frecuente y la realizaci&#243;n de la BSGC tendr&#237;a que ser llevada a cabo tras el procedimiento<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">23</span></a>&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">Como conclusi&#243;n&#44; la v&#237;a metast&#225;sica m&#225;s frecuente de diseminaci&#243;n para el CEC es la v&#237;a linf&#225;tica&#46; Esta v&#237;a es pr&#225;cticamente necesaria para la diseminaci&#243;n sist&#233;mica&#46; La progresi&#243;n regional de las met&#225;stasis linf&#225;ticas es tambi&#233;n la causa principal de fallecimiento&#46; Las medidas enfocadas al control regional de este tumor&#44; como la BSGC&#44; la disecci&#243;n ganglionar electiva o la radioterapia adyuvante&#44; podr&#237;an tener un papel en la mejora de la supervivencia en esta enfermedad&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Financiaci&#243;n</span><p id="par0160" class="elsevierStylePara elsevierViewall">Este estudio ha sido financiado por la Fundaci&#243;n Piel Sana de la Academia Espa&#241;ola de Dermatolog&#237;a y Venereolog&#237;a&#46; La investigaci&#243;n de JC est&#225; parcialmente financiada por el Instituto de Salud Carlos<span class="elsevierStyleHsp" style=""></span>III &#40;cofinanciado por la Uni&#243;n Europea&#41; a trav&#233;s del proyecto PI21&#47;1207&#44; por la Gerencia Regional de Salud de Castilla y Le&#243;n &#40;GRS2549&#47;A&#47;22&#41;&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Conflicto de intereses</span><p id="par0165" class="elsevierStylePara elsevierViewall">Los autores declaran no tener ning&#250;n conflicto de intereses&#46;</p></span></span>"
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    "fechaRecibido" => "2023-09-15"
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            0 => "Carcinoma cut&#225;neo de c&#233;lulas escamosas"
            1 => "Pron&#243;stico"
            2 => "Met&#225;stasis neopl&#225;sica"
            3 => "Met&#225;stasis linf&#225;tica"
            4 => "Progresi&#243;n de la enfermedad"
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            0 => "Cutaneous squamous cell carcinoma"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Antecedentes y objetivo</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">El carcinoma cut&#225;neo de c&#233;lulas escamosas &#40;CEC&#41; es la segunda causa de fallecimientos por c&#225;ncer de piel en Europa&#46; Existen pocos estudios que hayan analizado las distintas v&#237;as de progresi&#243;n de este tumor en su historia natural&#46; El objetivo principal del presente estudio ha sido analizar las diferentes v&#237;as metast&#225;sicas&#44; as&#237; como de progresi&#243;n&#44; y su aparici&#243;n temporal en la evoluci&#243;n del CEC&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Material y m&#233;todo</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Estudio observacional retrospectivo multic&#233;ntrico de los CEC consecutivos de alto riesgo englobados en el proyecto SQUAMATA&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Resultados</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">De los 1&#46;346 pacientes incluidos&#44; tuvieron reca&#237;da 222 pacientes&#46; La v&#237;a de progresi&#243;n m&#225;s frecuente fue la v&#237;a linf&#225;tica &#40;62&#44;6&#37;&#41;&#46; El 20&#44;2&#37; de los casos con progresi&#243;n linf&#225;tica desarrollaron met&#225;stasis a distancia&#46; Un solo caso &#40;3&#44;1&#37;&#41; de met&#225;stasis a distancia fue tras recidiva local sin met&#225;stasis linf&#225;ticas previas&#46; La mediana del tiempo hasta el exitus por la enfermedad fue mayor en los pacientes que desarrollaron met&#225;stasis sist&#233;micas que en aquellos fallecidos por progresi&#243;n locorregional&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusiones</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">El fallecimiento de los pacientes con CEC es mayoritariamente por progresi&#243;n regional de sus met&#225;stasis linf&#225;ticas&#46; La aparici&#243;n de met&#225;stasis a distancia se asocia pr&#225;cticamente siempre &#40;96&#44;9&#37;&#41; a la progresi&#243;n metast&#225;sica linf&#225;tica previa&#46; En el futuro&#44; por tanto&#44; se hacen necesarios nuevos estudios que valoren el manejo regional del CEC tanto en su manejo quir&#250;rgico como adyuvante&#46;</p></span>"
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        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Background and objective</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Cutaneous squamous cell carcinoma &#40;cSCC&#41; is the second leading cause of skin cancer mortality in Europe&#46; Few studies have analyzed the different pathways of this tumor progression in its natural history&#46; The main objective of this study was to analyze the different metastatic and progression pathways and their temporal occurrence in the evolution of cSCC&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Material and method</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">We conducted a multicenter&#44; retrospective&#44; and observational study of consecutive high-risk sSCCs included in the SQUAMATA project&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Results</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">A total of 222 out of the 1346 patients included relapsed&#46; The most frequent route of progression was the lymphatic one &#40;62&#46;6&#37;&#41;&#46; A total of 20&#46;2&#37; of the cases with lymphatic progression developed distant metastases&#46; Only 1 case &#40;3&#46;1&#37;&#41; of distant metastasis followed local recurrence without previous lymphatic metastasis&#46; The median time to disease-related mortality was longer in patients who developed systemic metastases than in those who died of locoregional progression&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusions</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">The mortality of patients with cSCC is mostly due to the regional progression of their lymphatic metastases&#46; The appearance of distant metastases is practically always &#40;96&#46;9&#37;&#41; associated with previous lymphatic metastatic progression&#46; Therefore&#44; in the future&#44; new studies will be needed to assess the regional management of cSCC in both surgical and adjuvant therapies&#46;</p></span>"
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          "es" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Supervivencia hasta recurrencia linf&#225;tica en funci&#243;n de si los pacientes permanec&#237;an libres de enfermedad&#44; fallec&#237;an por progresi&#243;n regional de su enfermedad&#44; o bien progresaban a met&#225;stasis sist&#233;micas &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>152&#41;&#46;</p>"
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          "leyenda" => "<p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">AJCC-8&#58; 8&#46;<span class="elsevierStyleSup">a</span> Clasificaci&#243;n del <span class="elsevierStyleItalic">American Joint Committee on Cancer</span>&#59; BWH&#58; clasificaci&#243;n del <span class="elsevierStyleItalic">Brigham and Woman Hospital</span>&#59; L&#58; linf&#225;tica&#59; ND&#58; no disponible&#59; NS&#58; no estad&#237;sticamente significativo&#59; Q1&#44;Q2&#58; primer y tercer cuartiles&#59; RL&#58; recurrencia local&#59; S&#58; satelitosis&#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" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Caracter&#237;sticas de la muestra<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">V&#237;a diseminaci&#243;n recurrencia local &#40;RL&#41; &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>74&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">V&#237;a diseminaci&#243;n satelitosis &#40;S&#41; &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">V&#237;a diseminaci&#243;n linf&#225;tica &#40;L&#41; &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>139&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Total &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>222&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">p<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Edad al diagn&#243;stico</span></td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">0&#44;615&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Mediana &#40;Q1&#44; Q3&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">80&#44;0 &#40;72&#44;0&#44; 86&#44;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">79&#44;0 &#40;73&#44;0&#44; 80&#44;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">78&#44;0 &#40;72&#44;0&#44; 83&#44;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">78&#44;0 &#40;72&#44;0&#44; 84&#44;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Sexo</span></td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;090&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Hombre&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">52 &#40;70&#44;3&#37;&#41; &#124; &#40;38&#44;8&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5 &#40;55&#44;6&#37;&#41; &#124; &#40;3&#44;7&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">77 &#40;55&#44;4&#37;&#41; &#124; &#40;57&#44;5&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">134 &#40;60&#44;4&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Mujer&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">22 &#40;29&#44;7&#37;&#41; &#124; &#40;25&#44;0&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4 &#40;44&#44;4&#37;&#41; &#124; &#40;4&#44;5&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">62 &#40;44&#44;6&#37;&#41; &#124; &#40;70&#44;5&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">88 &#40;39&#44;6&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Inmunosupresi&#243;n</span></td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">0&#44;024</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">35 &#40;64&#44;8&#37;&#41; &#124; &#40;24&#44;6&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5 &#40;55&#44;6&#37;&#41; &#124; &#40;3&#44;5&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">102 &#40;81&#44;0&#37;&#41; &#124; &#40;71&#44;8&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">142 &#40;75&#44;1&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NS<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>S&#237;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">19 &#40;35&#44;2&#37;&#41; &#124; &#40;40&#44;4&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4 &#40;44&#44;4&#37;&#41; &#124; &#40;8&#44;5&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">24 &#40;19&#44;0&#37;&#41; &#124; &#40;51&#44;1&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">47 &#40;24&#44;9&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">20&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">33&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Localizaci&#243;n</span></td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;839&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Cabeza y cuello&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">63 &#40;85&#44;1&#37;&#41; &#124; &#40;35&#44;0&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8 &#40;88&#44;9&#37;&#41; &#124; &#40;4&#44;4&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">109 &#40;78&#44;4&#37;&#41; &#124; &#40;60&#44;6&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">180 &#40;81&#44;1&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Di&#225;metro tumoral &#40;mm&#41;</span></td><td class="td" title="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Mediana &#40;Q1&#44;Q3&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#44;01<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a> RL vs L&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Grosor tumoral &#40;mm&#41;</span></td><td class="td" title="\n
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                  \t\t\t\t"><span class="elsevierStyleBold">&#60;</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">0&#44;001</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">57 &#40;77&#44;0&#37;&#41; &#124; &#40;41&#44;6&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7 &#40;77&#44;8&#37;&#41; &#124; &#40;5&#44;1&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">73 &#40;52&#44;5&#37;&#41; &#124; &#40;53&#44;3&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">137 &#40;61&#44;7&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001 RL vs L<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>S&#237;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">17 &#40;23&#44;0&#37;&#41; &#124; &#40;20&#44;0&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2 &#40;22&#44;2&#37;&#41; &#124; &#40;2&#44;4&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">66 &#40;47&#44;5&#37;&#41; &#124; &#40;77&#44;6&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">85 &#40;38&#44;3&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Exitus por otras causas</span></td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;280&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">37 &#40;68&#44;5&#37;&#41; &#124; &#40;26&#44;8&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5 &#40;55&#44;6&#37;&#41; &#124; &#40;3&#44;6&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">96 &#40;76&#44;2&#37;&#41; &#124; &#40;69&#44;6&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">138 &#40;73&#44;0&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>S&#237;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">17 &#40;31&#44;5&#37;&#41; &#124; &#40;33&#44;3&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4 &#40;44&#44;4&#37;&#41; &#124; &#40;7&#44;8&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">30 &#40;23&#44;8&#37;&#41; &#124; &#40;58&#44;8&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">51 &#40;27&#44;0&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">20&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">33&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Exitus por cualquier causa</span></td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">0&#44;001</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">41 &#40;55&#44;4&#37;&#41; &#124; &#40;46&#44;6&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3 &#40;33&#44;3&#37;&#41; &#124; &#40;3&#44;4&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">44 &#40;31&#44;7&#37;&#41; &#124; &#40;50&#44;0&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">88 &#40;39&#44;6&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;005 RL vs L<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>S&#237;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">33 &#40;44&#44;6&#37;&#41; &#124; &#40;24&#44;6&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6 &#40;66&#44;7&#37;&#41; &#124; &#40;4&#44;5&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">95 &#40;68&#44;3&#37;&#41; &#124; &#40;70&#44;9&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">134 &#40;60&#44;4&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Reportadas como n &#40;&#37; columna&#41; &#124; &#40;&#37; fila&#41;&#44; salvo que se especifique lo contrario&#46;</p>"
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              "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Valores de p de la prueba exacta de Fisher para variables categ&#243;ricas&#44; test de tendencias para variables ordinales y test de Kruskall Wallis para variables continuas&#46;</p>"
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              "nota" => "<p class="elsevierStyleNotepara" id="npar0015">Si las anteriores pruebas resultaron estad&#237;sticamente significativas se llevaron a cabo pruebas <span class="elsevierStyleItalic">post hoc</span> con valores de p ajustados por el m&#233;todo de Holm&#46;</p>"
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          "es" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Caracter&#237;sticas cl&#237;nicas y patol&#243;gicas de los carcinomas cut&#225;neos de alto riesgo en funci&#243;n de las distintas v&#237;as de diseminaci&#243;n &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>222&#41;</p>"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Incidencia y mortalidad del c&#225;ncer cut&#225;neo en Espa&#241;a&#58; revisi&#243;n sistem&#225;tica y metaan&#225;lisis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "A&#46; Tejera-Vaquerizo"
                            1 => "M&#46;A&#46; Descalzo-Gallego"
                            2 => "M&#46;M&#46; Otero-Rivas"
                            3 => "C&#46; Posada-Garc&#237;a"
                            4 => "L&#46; Rodr&#237;guez-Pazos"
                            5 => "I&#46; Pastushenko"
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                      "doi" => "10.1016/j.ad.2015.12.008"
                      "Revista" => array:6 [
                        "tituloSerie" => "Actas Dermosifiliogr&#46;"
                        "fecha" => "2016"
                        "volumen" => "107"
                        "paginaInicial" => "318"
                        "paginaFinal" => "328"
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                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26852370"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Los nuevos sistemas de estadificaci&#243;n del AJCC incorporan novedades en el c&#225;ncer cut&#225;neo"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "J&#46; Ca&#241;ueto"
                            1 => "C&#46; Rom&#225;n-Curto"
                          ]
                        ]
                      ]
                    ]
                  ]
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                    0 => array:2 [
                      "doi" => "10.1016/j.ad.2017.05.012"
                      "Revista" => array:5 [
                        "tituloSerie" => "Actas Dermosifiliogr&#46;"
                        "fecha" => "2017"
                        "volumen" => "108"
                        "paginaInicial" => "818"
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Final trial report of sentinel-node biopsy versus nodal observation in melanoma"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "D&#46;L&#46; Morton"
                            1 => "J&#46;F&#46; Thompson"
                            2 => "A&#46;J&#46; Cochran"
                            3 => "N&#46; Mozzillo"
                            4 => "O&#46;E&#46; Nieweg"
                            5 => "D&#46;F&#46; Roses"
                          ]
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                    0 => array:2 [
                      "doi" => "10.1056/NEJMoa1310460"
                      "Revista" => array:6 [
                        "tituloSerie" => "N Engl J Med&#46;"
                        "fecha" => "2014"
                        "volumen" => "370"
                        "paginaInicial" => "599"
                        "paginaFinal" => "609"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24521106"
                            "web" => "Medline"
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Original
Estudio longitudinal de los diferentes patrones de progresión en el carcinoma cutáneo de células escamosas de alto riesgo
Longitudinal Study of Different Progression Patterns in High-Risk Cutaneous Squamous Cell Carcinoma
A. Tejera-Vaquerizoa,b,
Corresponding author
antoniotejera@aedv.es

Autor para correspondencia.
, J. Cañuetoc, A. Gómez-Tomásd, J. Santos-Juanese, S. Riberof, G. Avallonef, A. Jakag, C. Ferrandiz-Pulidod, A. Tollh, O. Sanmartíni
a Unidad de Oncología Cutánea, Hospital San Juan de Dios, Córdoba, España
b Servicio de Dermatología, Instituto Dermatológico GlobalDerm, Palma del Río, Córdoba, España
c Servicio de Dermatología, Complejo Asistencial Universitario de Salamanca, Salamanca, España
d Servicio de Dermatología, Hospital Universitari Vall d’Hebron, Universidad Autónoma de Barcelona, Barcelona, España
e Servicio de Dermatología, Hospital Central de Asturias e Instituto de Investigación Sanitaria del Principado de Asturias, IUOPA, Universidad de Oviedo, Oviedo, España
f Medical Sciences Department, Section of Dermatology, University of Turin, Turín, Italia
g Servicio de Dermatología, Hospital Universitari Germans Trials i Pujol, Institut d’Investigació GermansTrias i Pujol, Universitat Autònoma de Barcelona, Badalona, Barcelona, España
h Servicio de Dermatología, Hospital Clínic, Universitat de Barcelona, Barcelona, España
i Servicio de Dermatología, Instituto Valenciano de Oncología, Valencia, España
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          "es" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Supervivencia hasta la aparici&#243;n de la primera recurrencia en los carcinomas cut&#225;neos de c&#233;lulas escamosas de alto riesgo &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>222&#41;&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introducci&#243;n</span><p id="par0005" class="elsevierStylePara elsevierViewall">El carcinoma epidermoide cut&#225;neo &#40;CEC&#41; es la segunda neoplasia cut&#225;nea maligna en frecuencia tras el carcinoma basocelular en nuestro pa&#237;s<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">1</span></a>&#46; Tambi&#233;n es la segunda causa de mortalidad por c&#225;ncer de piel tras el melanoma<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">1</span></a>&#46; Es un tumor con un bajo potencial metast&#225;sico&#46; El CEC metastatiza preferentemente por v&#237;a linf&#225;tica en el 3-5&#37; de los casos&#44; dependiendo de la localizaci&#243;n&#44; del tama&#241;o&#44; de la invasi&#243;n en profundidad&#44; de la invasi&#243;n perineural o de la afectaci&#243;n &#243;sea<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">2</span></a>&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">Por otro lado&#44; la biopsia selectiva del ganglio centinela &#40;BSGC&#41; es una t&#233;cnica quir&#250;rgica que se desarroll&#243; ampliamente en otros tumores&#44; como el melanoma&#44; en base a su propensi&#243;n a las met&#225;stasis regionales linf&#225;ticas&#44; sin que tuviera un impacto en la supervivencia de estos pacientes<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">3</span></a>&#46; En el caso del CEC&#44; la utilidad de la BSGC es a&#250;n desconocida&#44; siendo su porcentaje de positividad del 8-10&#37;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">4</span></a>&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Existen pocos estudios publicados sobre la historia natural en t&#233;rminos de progresi&#243;n del CEC<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">5</span></a>&#44; o bien que se hayan focalizado en el tiempo de evoluci&#243;n de las distintas formas de recidiva en la progresi&#243;n de este tumor&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">Comprender y analizar c&#243;mo progresan los CEC ayudar&#237;a a dise&#241;ar estrategias diagn&#243;sticas&#44; terap&#233;uticas y de seguimiento de estos pacientes&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">El objetivo primario de este estudio es analizar las diferentes v&#237;as de progresi&#243;n del CEC &#40;recurrencia local&#44; satelitosis&#44; recurrencia linf&#225;tica regional o met&#225;stasis a distancia&#41; junto con el tiempo de evoluci&#243;n de estas&#46; Como objetivos secundarios se analiza la relaci&#243;n de las distintas variables cl&#237;nicas y patol&#243;gicas con las diferentes formas de progresi&#243;n&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Material y m&#233;todo</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Participantes y dise&#241;o del estudio</span><p id="par0030" class="elsevierStylePara elsevierViewall">Se dise&#241;&#243; un estudio multic&#233;ntrico observacional retrospectivo incluyendo pacientes de ocho hospitales de referencia que participan en el proyecto SQUAMATA&#46; Este proyecto se focaliza en el estudio de factores pron&#243;sticos del CEC y ha sido descrito previamente<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">6</span></a>&#46; Los hospitales participantes son el Hospital Universitario de Salamanca&#44; Salamanca &#40;Espa&#241;a&#41;&#59; el Instituto Valenciano de Oncolog&#237;a&#44; Valencia &#40;Espa&#241;a&#41;&#59; el Hospital Germans Trias i Pujol&#44; Badalona &#40;Espa&#241;a&#41;&#59; el Hospital Cl&#237;nic&#44; Barcelona &#40;Espa&#241;a&#41;&#59; el Hospital Universitari Vall d&#8217;Hebron&#44; Barcelona &#40;Espa&#241;a&#41;&#59; el Hospital Universitario Central de Asturias&#44; Oviedo &#40;Espa&#241;a&#41;&#59; el Hospital San Cecilio&#44; Granada &#40;Espa&#241;a&#41;&#44; y la University Hospital Citt&#224; della Salute e della Scienza di Torino&#44; Tur&#237;n &#40;Italia&#41;&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">Se incluy&#243; a los pacientes diagnosticados de un CEC de alto riesgo entre el 1 de enero de 2000 y el 31 de diciembre de 2020&#46; Se consider&#243; como un CEC de alto riesgo aquel tumor con di&#225;metro &#8805;<span class="elsevierStyleHsp" style=""></span>2<span class="elsevierStyleHsp" style=""></span>cm&#44; un grosor tumoral &#8805;<span class="elsevierStyleHsp" style=""></span>6<span class="elsevierStyleHsp" style=""></span>mm&#44; la presencia de invasi&#243;n perineural o linfovascular&#44; una mala diferenciaci&#243;n histol&#243;gica&#44; la invasi&#243;n m&#225;s all&#225; de la grasa subcut&#225;nea&#44; la localizaci&#243;n en oreja o labio y la inmunosupresi&#243;n del paciente &#40;trasplante de &#243;rgano s&#243;lido&#44; leucemia linfoc&#237;tica cr&#243;nica&#44; tratamiento inmunosupresor cr&#243;nico o insuficiencia renal cr&#243;nica&#41;&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">En el caso de la presencia de m&#250;ltiples CEC&#44; solo el tumor con caracter&#237;sticas de mayor riesgo fue incluido en la base de datos&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">El estudio fue aprobado por el comit&#233; &#233;tico del Hospital Universitario Reina Sof&#237;a de C&#243;rdoba &#40;registro n&#46;&#176; 3958&#41;&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">El seguimiento de los distintos centros es similar y se basa fundamentalmente en las gu&#237;as de la NCCN<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">7</span></a>&#44; con un seguimiento de los pacientes cada 3-6<span class="elsevierStyleHsp" style=""></span>meses los dos primeros a&#241;os y cada 6-12<span class="elsevierStyleHsp" style=""></span>meses a partir del tercer a&#241;o&#44; siendo anual a partir del quinto a&#241;o&#46; En caso de enfermedad regional&#44; los controles son cada 2-3<span class="elsevierStyleHsp" style=""></span>meses el primer a&#241;o&#44; cada 4-6<span class="elsevierStyleHsp" style=""></span>meses hasta el tercer a&#241;o y cada 6-12<span class="elsevierStyleHsp" style=""></span>meses a partir del cuarto a&#241;o&#46; Las pruebas de imagen usadas en los controles son la ecograf&#237;a&#44; la tomograf&#237;a axial computarizada &#40;TAC&#41; y&#44; en casos donde se quer&#237;a valorar la extensi&#243;n local de tejidos&#44; la resonancia magn&#233;tica &#40;RM&#41;&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">Para el prop&#243;sito del estudio se registr&#243; la primera v&#237;a de progresi&#243;n&#46; En funci&#243;n de esta se definieron cuatro grupos&#58; recurrencia local &#40;RL&#41;&#44; recurrencia linf&#225;tica regional &#40;L&#41;&#44; satelitosis&#47;met&#225;stasis en tr&#225;nsito &#40;S&#41; y met&#225;stasis a distancia &#40;M&#41;&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">La implicaci&#243;n de estas cuatro v&#237;as de progresi&#243;n puede definir distintos patrones de diseminaci&#243;n&#44; similar a como se han descrito cl&#225;sicamente para el melanoma<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">8&#44;9</span></a>&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">Para aquellos pacientes que terminaron en exitus por la enfermedad&#44; se describieron siete patrones o rutas de diseminaci&#243;n&#58; patr&#243;n RL-Ex&#44; desarrollo de RL y exitus &#40;Ex&#41;&#59; patr&#243;n RL-M-EX&#44; desarrollo de RL&#44; posteriormente M y Ex&#59; patr&#243;n RL-L-Ex&#44; desarrollo de RL&#44; posteriormente L y posterior Ex&#59; patr&#243;n RL-L-M-EX&#44; desarrollo de RL&#44; posteriormente L&#44; M y finalmente Ex&#59; patr&#243;n L-Ex&#44; desarrollo directamente de L y posterior Ex&#59; patr&#243;n L-M-Ex&#44; desarrollo de L&#44; posteriormente M y posterior Ex&#44; y finamente patr&#243;n S-Ex&#44; con el desarrollo de S y posterior Ex&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">Se us&#243; el test de chi-cuadrado para comparar las diferencias entre las distintas v&#237;as metast&#225;sicas &#40;RL&#44; L&#44; S y M&#41; y las distintas variables cl&#237;nicas y patol&#243;gicas categ&#243;ricas &#40;g&#233;nero&#44; inmunosupresi&#243;n&#44; localizaci&#243;n en cabeza&#47;cuello&#44; tronco&#47;extremidades y manos&#47;pies&#44; di&#225;metro &#8804;<span class="elsevierStyleHsp" style=""></span>20<span class="elsevierStyleHsp" style=""></span>mm vs&#46; &#62;<span class="elsevierStyleHsp" style=""></span>20<span class="elsevierStyleHsp" style=""></span>mm&#44; grosor tumoral &#8804;<span class="elsevierStyleHsp" style=""></span>6 vs&#46; &#62;<span class="elsevierStyleHsp" style=""></span>6<span class="elsevierStyleHsp" style=""></span>mm&#44; invasi&#243;n perineural&#44; invasi&#243;n linfovascular&#44; grado de diferenciaci&#243;n&#44; clasificaci&#243;n de la <span class="elsevierStyleItalic">American Joint Committee on Cancer</span> &#40;AJCC&#41;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">10</span></a> y clasificaci&#243;n del Brigham and Woman Hospital &#40;BWH&#41;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">11</span></a>&#46; La edad fue evaluada con la prueba de Kruskas-Wallis&#46; Las pruebas significativas fueron evaluadas con an&#225;lisis <span class="elsevierStyleItalic">post hoc</span>&#44; con valores de p ajustados mediante el m&#233;todo de Holm&#46; Se compar&#243; mediante las curvas de Kaplan-Meier &#40;KM&#41; y la prueba del logaritmo de los rangos el tiempo hasta la observaci&#243;n de las diferentes formas de progresi&#243;n&#46; De forma similar&#44; se compararon las curvas de KM para las met&#225;stasis linf&#225;ticas regionales como primera recidiva o tras recurrencia local por un lado&#44; y las mismas met&#225;stasis linf&#225;ticas regionales en funci&#243;n de si progresaban regionalmente a met&#225;stasis sist&#233;micas o bien si permanec&#237;a vivo el paciente&#46; Por &#250;ltimo&#44; se valor&#243; el tiempo hasta progresi&#243;n en funci&#243;n del tipo de recidiva local&#44; regional o a distancia&#46; Se consider&#243; un nivel de significaci&#243;n de p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;05&#46; Se utiliz&#243; el programa estad&#237;stico SPSS &#40;IBM Corp&#46; Released 2011&#46; IBM SPSS Statistics for Windows&#44; Version 20&#46;0&#46; Armonk&#44; NY&#58; IBM Corp&#46;&#41;&#46;</p></span></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Resultados</span><p id="par0075" class="elsevierStylePara elsevierViewall">Se incluyeron un total de 1&#46;346 pacientes con CEC primario de alto riesgo&#44; de los cuales el 16&#44;5&#37; &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>222&#41; experiment&#243; alg&#250;n tipo de reca&#237;da en su seguimiento&#46; La mediana de seguimiento fue de 33<span class="elsevierStyleHsp" style=""></span>meses&#46; La <a class="elsevierStyleCrossRef" href="#tbl0005">tabla 1</a> refleja las caracter&#237;sticas cl&#237;nicas y patol&#243;gicas de la poblaci&#243;n en funci&#243;n de las distintas v&#237;as de progresi&#243;n&#46; &#218;nicamente se hallaron diferencias estad&#237;sticamente significativas en cuanto al estado de inmunosupresi&#243;n&#44; el di&#225;metro tumoral y la probabilidad de exitus tanto por la neoplasia como por cualquier causa&#46; La v&#237;a de diseminaci&#243;n m&#225;s frecuente tanto en inmunocompetentes como en inmunodeprimidos fue la diseminaci&#243;n linf&#225;tica &#40;71&#44;8&#37; y 51&#37;&#44; respectivamente&#41;&#44; mientras que las recurrencias locales y la diseminaci&#243;n mediante satelitosis fueron relativamente m&#225;s frecuentes en los pacientes inmunodeprimidos &#40;40&#37; vs&#46; 24&#44;6&#37; en inmunocompetentes&#41;&#46; Las recidivas linf&#225;ticas fueron algo m&#225;s frecuentes en los pacientes inmunocompetentes &#40;71&#44;8&#37; vs&#46; 51&#44;1&#37;&#41;&#46; Los tumores que hicieron diseminaci&#243;n linf&#225;tica fueron de mediana 5<span class="elsevierStyleHsp" style=""></span>mm mayores en su di&#225;metro que los que recurrieron localmente &#40;25<span class="elsevierStyleHsp" style=""></span>mm vs 20<span class="elsevierStyleHsp" style=""></span>mm&#44; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;01&#41;&#46; En cuanto a los tumores que hicieron satelitosis como primera v&#237;a de diseminaci&#243;n&#44; se observ&#243; que la mayor&#237;a fueron tumores &#8804;<span class="elsevierStyleHsp" style=""></span>20<span class="elsevierStyleHsp" style=""></span>mm &#40;77&#44;8&#37;&#41;&#44; a diferencia de los que hicieron recidiva linf&#225;tica&#44; que en su mayor&#237;a fueron superiores a los 2<span class="elsevierStyleHsp" style=""></span>cm &#40;61&#44;0&#37;&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0080" class="elsevierStylePara elsevierViewall">En referencia a la estadificaci&#243;n&#44; destaca como la totalidad de los tumores T4 de la AJCC y T3 de la BWH se diseminaron de forma preferente a los ganglios linf&#225;ticos &#40;100&#37;&#41;&#46; Por otra parte&#44; los tumores de bajo riesgo T1 que progresaron lo hicieron casi en igual medida en forma de recurrencias locales o bien ganglionares &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">tabla 1</a>&#41;&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">En cuanto a mortalidad seg&#250;n las v&#237;as&#44; se observ&#243; que los tumores que debutaron con una recidiva local presentaban menor porcentaje de mortalidad espec&#237;fica que los que lo hicieron en los ganglios &#40;23&#37; vs 47&#44;5&#37;&#44; p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#41; y tambi&#233;n una menor mortalidad global &#40;44&#46;6&#37; vs 68&#44;3&#37;&#44; p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;005&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">tabla 1</a>&#41;&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">Es de remarcar que ni la edad&#44; el sexo&#44; la localizaci&#243;n&#44; el grado de diferenciaci&#243;n&#44; el grosor tumoral&#44; la invasi&#243;n perineural o linfovascular ni la estadificaci&#243;n se distribuyeron de forma significativamente distinta entre las distintas v&#237;as de diseminaci&#243;n&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">La <a class="elsevierStyleCrossRef" href="#fig0005">figura 1</a> refleja las distintas v&#237;as metast&#225;sicas en la progresi&#243;n del CEC primario&#46; La v&#237;a de progresi&#243;n m&#225;s frecuente fue la linf&#225;tica &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>139 &#91;62&#44;6&#37;&#93;&#41;&#44; seguida de las recurrencias locales &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>74 &#91;33&#44;3&#37;&#93;&#41; y las satelitosis &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>9 &#91;4&#44;4&#37;&#93;&#41;&#46; En 12 casos de recurrencia local &#40;16&#44;2&#37; de RL&#41; hubo progresi&#243;n linf&#225;tica posterior&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0100" class="elsevierStylePara elsevierViewall">En conjunto&#44; de todos los casos con recidiva regional linf&#225;tica&#44; en 31 casos &#40;20&#44;5&#37; de L&#41; progresaron a met&#225;stasis sist&#233;micas&#46; Solo se describi&#243; un caso de recurrencia local y que desarroll&#243; met&#225;stasis sist&#233;micas directamente&#46; No se hallaron met&#225;stasis sist&#233;micas como primera v&#237;a de progresi&#243;n&#44; ni met&#225;stasis linf&#225;ticas tras satelitosis&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">Los exitus de los pacientes con CEC fueron en su mayor&#237;a debidos a progresi&#243;n regional linf&#225;tica de su enfermedad &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>47 &#91;54&#44;6&#37; de los exitus&#93;&#41; seguido de las met&#225;stasis sist&#233;micas &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>27 &#91;31&#44;4&#37; de los exitus&#93;&#41;&#46; Las progresiones locales fueron el motivo de exitus en el 11&#44;6&#37; &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>10&#41; de los exitus&#46; Finalmente&#44; se registraron 2 fallecimientos por satelitosis &#40;2&#44;3&#37; de los exitus&#41;&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">Las distintas v&#237;as metast&#225;sicas y de progresi&#243;n del CEC de los casos con resultado de exitus se representan en la <a class="elsevierStyleCrossRef" href="#fig0010">figura 2</a>&#46; La v&#237;a metast&#225;sica m&#225;s frecuente fue la ruta L-Ex &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>42 &#91;49&#44;4&#37;&#93;&#41;&#44; seguida por la L-M-Ex &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>24 &#91;28&#44;2&#37;&#93;&#41;&#46; La siguiente en frecuencia es la ruta RL-Ex &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>9 &#91;10&#44;6&#37;&#93;&#41;&#46; El resto de las v&#237;as metast&#225;sicas y de progresi&#243;n fueron de 5 o menos casos&#46; Llama la atenci&#243;n que&#44; con independencia de la v&#237;a metast&#225;sica&#44; todas las recidivas regionales linf&#225;ticas aparecieron de media entre los 13 y los 18<span class="elsevierStyleHsp" style=""></span>meses de seguimiento&#44; as&#237; como los exitus por la enfermedad ocurrieron entre los 26 y 35<span class="elsevierStyleHsp" style=""></span>meses de media desde el diagn&#243;stico para las distintas v&#237;as metast&#225;sicas m&#225;s frecuentes&#46; Curiosamente&#44; se observ&#243; una tendencia a un mayor tiempo hasta exitus en aquellos casos con met&#225;stasis<span class="elsevierStyleHsp" style=""></span>L y posterior desarrollo de met&#225;stasis sist&#233;micas &#40;ruta L-M-Ex&#41; con respecto a aquellos casos que &#250;nicamente progresaron a nivel local &#40;ruta RL-Ex&#41;&#44; por satelitosis &#40;ruta S-Ex&#41; o a nivel regional &#40;ruta L-Ex&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0115" class="elsevierStylePara elsevierViewall">El an&#225;lisis de supervivencia hasta la reca&#237;da en funci&#243;n del tipo de v&#237;a &#40;RL&#44; L y S&#41; no mostr&#243; diferencias entre estas &#40;<a class="elsevierStyleCrossRef" href="#fig0020">fig&#46; 3</a>&#41;&#46; Tampoco se apreciaron diferencias en el tiempo de supervivencia hasta la aparici&#243;n de met&#225;stasis linf&#225;ticas en funci&#243;n de si eran la primera recidiva o bien tras recidiva local &#40;<a class="elsevierStyleCrossRef" href="#fig0025">fig&#46; 4</a>&#41;&#46; Por &#250;ltimo&#44; el tiempo transcurrido hasta la aparici&#243;n de las met&#225;stasis linf&#225;ticas no se correlacion&#243; con el pron&#243;stico&#44; determinado como ausencia de posteriores progresiones respecto a progresi&#243;n a met&#225;stasis sist&#233;micas o progresi&#243;n regional hasta el fallecimiento del paciente &#40;<a class="elsevierStyleCrossRef" href="#fig0030">fig&#46; 5</a>&#41;&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia><elsevierMultimedia ident="fig0025"></elsevierMultimedia><elsevierMultimedia ident="fig0030"></elsevierMultimedia></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Discusi&#243;n</span><p id="par0120" class="elsevierStylePara elsevierViewall">El presente estudio muestra que la progresi&#243;n m&#225;s frecuente para los CEC de alto riesgo es la v&#237;a linf&#225;tica&#44; y que esta v&#237;a es pr&#225;cticamente obligatoria antes del desarrollo de met&#225;stasis sist&#233;micas&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">El proceso metast&#225;sico es un complejo proceso en el que unas c&#233;lulas gen&#233;ticamente inestables se adaptan a un microambiente tisular diferente a su tejido de origen<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">12</span></a>&#46; Este proceso no es aleatorio&#44; sino que las c&#233;lulas tumorales generalmente tienen cierta apetencia por tejidos determinados en funci&#243;n de la estirpe tumoral en un modelo de diseminaci&#243;n denominado originalmente &#171;semilla y terreno&#187; por Paget en el siglo<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleSmallCaps">xix</span><a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">13</span></a>&#46; Este modelo explica por qu&#233; ciertos tumores como el c&#225;ncer de mama frecuentemente metastatizan en pulm&#243;n&#44; hueso&#44; h&#237;gado o cerebro&#44; mientras que otros&#44; como el c&#225;ncer de pr&#243;stata&#44; lo hace m&#225;s en hueso&#46; O bien que el melanoma uveal caracter&#237;sticamente metastatice m&#225;s a h&#237;gado&#44; o bien los sarcomas a pulm&#243;n<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">12</span></a>&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">En el caso de los CEC&#44; la implicaci&#243;n m&#225;s importante de estos hallazgos ser&#237;a el manejo locorregional de la enfermedad&#46; M&#225;s de la mitad de los pacientes en el estudio fallecen por progresi&#243;n de las met&#225;stasis regionales linf&#225;ticas&#44; lo que plantea si una disecci&#243;n linf&#225;tica electiva podr&#237;a beneficiar a estos pacientes&#44; como en el caso del carcinoma de c&#233;lulas escamosas de la cavidad oral<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">14</span></a>&#46; Sin embargo&#44; los estudios observacionales disponibles presentan resultados contrapuestos&#46; Amit et al&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">15</span></a> no demostraron en un estudio observacional beneficio de la disecci&#243;n ganglionar electiva en pacientes con CEC frente a la observaci&#243;n&#46; Por el contrario&#44; Xiao et al&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">16</span></a>&#44; en otro estudio observacional&#44; s&#237; observaron mejor&#237;a en la supervivencia en los pacientes sometidos a una disecci&#243;n ganglionar electiva y parotidectom&#237;a superficial&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">Esta progresi&#243;n ordenada y gradual que muestra el CEC desde el tumor primario al ganglio linf&#225;tico regional y de aqu&#237; a la diseminaci&#243;n metast&#225;sica es la base te&#243;rica ideal que avala la utilizaci&#243;n terap&#233;utica de la biopsia selectiva del ganglio centinela &#40;BSGC&#41;&#46; Es precisamente lo que hace d&#233;cadas se denomin&#243; &#171;hip&#243;tesis de la incubadora&#187;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">17</span></a> por los defensores de la BSGC en el melanoma&#44; en contraposici&#243;n con la &#171;hip&#243;tesis del marcador&#187;&#44; que establec&#237;a que la presencia de met&#225;stasis en los ganglios linf&#225;ticos regionales constituye no un paso previo&#44; sino un marcador de que el tumor ya se habr&#237;a diseminado a otros &#243;rganos<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">18&#44;19</span></a>&#46; La observaci&#243;n de que el tiempo medio de supervivencia es mayor para las v&#237;as metast&#225;sicas que implican la aparici&#243;n de met&#225;stasis sist&#233;micas &#40;<a class="elsevierStyleCrossRef" href="#fig0010">fig&#46; 2</a>&#41; con respecto a las mismas v&#237;as pero sin la diseminaci&#243;n sist&#233;mica apoya en cierta medida esta &#171;hip&#243;tesis de la incubadora&#187;&#44; hecho que no se observa en estudios similares para el melanoma<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">8&#44;9</span></a>&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">De forma parad&#243;jica&#44; mientras que en el melanoma se dispone de un ensayo cl&#237;nico que ha evaluado el papel de la BSGC<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">3</span></a>&#44; sin que este haya demostrado un beneficio en la supervivencia&#44; no se dispone a&#250;n de un ensayo que haya evaluado lo mismo en el CEC&#46; Existen&#44; no obstante&#44; algunos estudios observacionales que han comparado a pacientes con CEC sometidos a BSGC con pacientes solo con observaci&#243;n sin que se haya observado diferencia en la supervivencia&#46; En esta l&#237;nea&#44; nuestro grupo ha encontrado diferencias en un reciente estudio observacional cuando se ha estratificado por estado inmunol&#243;gico del paciente&#44; observ&#225;ndose una clara ventaja en la supervivencia libre de progresi&#243;n &#250;nicamente en pacientes inmunocompetentes sometidos a BSGC &#40;datos no publicados&#41;&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">El problema para la indicaci&#243;n de esta t&#233;cnica&#44; as&#237; como la predicci&#243;n en general de met&#225;stasis linf&#225;ticas y sist&#233;micas&#44; est&#225; lejos de ser resuelto&#44; ya que solo el 4-5&#37; de los pacientes desarrollar&#225;n met&#225;stasis linf&#225;ticas&#44; y de ellos solo una cuarta parte&#44; met&#225;stasis sist&#233;micas&#46; En una revisi&#243;n sistem&#225;tica reciente&#44; la positividad de la BSGC en el CEC ronda el 8&#37;&#44; sin que se hayan identificado a&#250;n claros factores predictores de afectaci&#243;n<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">4</span></a>&#46; La evidencia actual sobre las alteraciones gen&#233;ticas en la regulaci&#243;n del ciclo celular&#44; la supresi&#243;n tumoral&#44; la invasi&#243;n tisular y microambiente y la interacci&#243;n con el sistema inmune est&#225; a&#250;n lejos de ofrecer dianas concretas que puedan predecir con m&#225;s exactitud los pacientes que van a progresar<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">20</span></a>&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">En nuestra serie&#44; el 11&#44;6&#37; de las muertes espec&#237;ficas fueron por progresi&#243;n local&#46; Estos datos muestran la importancia del control local de CEC&#46; En una reciente revisi&#243;n sistem&#225;tica&#44; la invasi&#243;n profunda m&#225;s all&#225; de la grasa&#44; o bien&#44; y en menor medida&#44; la desmoplasia son los factores histol&#243;gicos que m&#225;s predicen esta recurrencia<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">21</span></a>&#44; siendo la cirug&#237;a de Mohs la opci&#243;n preferida para el control local del CEC<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">21</span></a>&#46; En una reciente revisi&#243;n&#44; el &#233;xito de la BSGC en el CEC cut&#225;neo no se vio afectada tanto si se hizo de forma sincr&#243;nica como asincr&#243;nica con la cirug&#237;a&#44; incluyendo cirug&#237;a de Mohs<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">22</span></a>&#46; Esto es importante en el contexto actual&#44; en el que la cirug&#237;a de Mohs es un procedimiento cada vez m&#225;s frecuente y la realizaci&#243;n de la BSGC tendr&#237;a que ser llevada a cabo tras el procedimiento<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">23</span></a>&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">Como conclusi&#243;n&#44; la v&#237;a metast&#225;sica m&#225;s frecuente de diseminaci&#243;n para el CEC es la v&#237;a linf&#225;tica&#46; Esta v&#237;a es pr&#225;cticamente necesaria para la diseminaci&#243;n sist&#233;mica&#46; La progresi&#243;n regional de las met&#225;stasis linf&#225;ticas es tambi&#233;n la causa principal de fallecimiento&#46; Las medidas enfocadas al control regional de este tumor&#44; como la BSGC&#44; la disecci&#243;n ganglionar electiva o la radioterapia adyuvante&#44; podr&#237;an tener un papel en la mejora de la supervivencia en esta enfermedad&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Financiaci&#243;n</span><p id="par0160" class="elsevierStylePara elsevierViewall">Este estudio ha sido financiado por la Fundaci&#243;n Piel Sana de la Academia Espa&#241;ola de Dermatolog&#237;a y Venereolog&#237;a&#46; La investigaci&#243;n de JC est&#225; parcialmente financiada por el Instituto de Salud Carlos<span class="elsevierStyleHsp" style=""></span>III &#40;cofinanciado por la Uni&#243;n Europea&#41; a trav&#233;s del proyecto PI21&#47;1207&#44; por la Gerencia Regional de Salud de Castilla y Le&#243;n &#40;GRS2549&#47;A&#47;22&#41;&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Conflicto de intereses</span><p id="par0165" class="elsevierStylePara elsevierViewall">Los autores declaran no tener ning&#250;n conflicto de intereses&#46;</p></span></span>"
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            0 => "Carcinoma cut&#225;neo de c&#233;lulas escamosas"
            1 => "Pron&#243;stico"
            2 => "Met&#225;stasis neopl&#225;sica"
            3 => "Met&#225;stasis linf&#225;tica"
            4 => "Progresi&#243;n de la enfermedad"
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            0 => "Cutaneous squamous cell carcinoma"
            1 => "Prognosis"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Antecedentes y objetivo</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">El carcinoma cut&#225;neo de c&#233;lulas escamosas &#40;CEC&#41; es la segunda causa de fallecimientos por c&#225;ncer de piel en Europa&#46; Existen pocos estudios que hayan analizado las distintas v&#237;as de progresi&#243;n de este tumor en su historia natural&#46; El objetivo principal del presente estudio ha sido analizar las diferentes v&#237;as metast&#225;sicas&#44; as&#237; como de progresi&#243;n&#44; y su aparici&#243;n temporal en la evoluci&#243;n del CEC&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Material y m&#233;todo</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Estudio observacional retrospectivo multic&#233;ntrico de los CEC consecutivos de alto riesgo englobados en el proyecto SQUAMATA&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Resultados</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">De los 1&#46;346 pacientes incluidos&#44; tuvieron reca&#237;da 222 pacientes&#46; La v&#237;a de progresi&#243;n m&#225;s frecuente fue la v&#237;a linf&#225;tica &#40;62&#44;6&#37;&#41;&#46; El 20&#44;2&#37; de los casos con progresi&#243;n linf&#225;tica desarrollaron met&#225;stasis a distancia&#46; Un solo caso &#40;3&#44;1&#37;&#41; de met&#225;stasis a distancia fue tras recidiva local sin met&#225;stasis linf&#225;ticas previas&#46; La mediana del tiempo hasta el exitus por la enfermedad fue mayor en los pacientes que desarrollaron met&#225;stasis sist&#233;micas que en aquellos fallecidos por progresi&#243;n locorregional&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusiones</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">El fallecimiento de los pacientes con CEC es mayoritariamente por progresi&#243;n regional de sus met&#225;stasis linf&#225;ticas&#46; La aparici&#243;n de met&#225;stasis a distancia se asocia pr&#225;cticamente siempre &#40;96&#44;9&#37;&#41; a la progresi&#243;n metast&#225;sica linf&#225;tica previa&#46; En el futuro&#44; por tanto&#44; se hacen necesarios nuevos estudios que valoren el manejo regional del CEC tanto en su manejo quir&#250;rgico como adyuvante&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
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        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Background and objective</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Cutaneous squamous cell carcinoma &#40;cSCC&#41; is the second leading cause of skin cancer mortality in Europe&#46; Few studies have analyzed the different pathways of this tumor progression in its natural history&#46; The main objective of this study was to analyze the different metastatic and progression pathways and their temporal occurrence in the evolution of cSCC&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Material and method</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">We conducted a multicenter&#44; retrospective&#44; and observational study of consecutive high-risk sSCCs included in the SQUAMATA project&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Results</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">A total of 222 out of the 1346 patients included relapsed&#46; The most frequent route of progression was the lymphatic one &#40;62&#46;6&#37;&#41;&#46; A total of 20&#46;2&#37; of the cases with lymphatic progression developed distant metastases&#46; Only 1 case &#40;3&#46;1&#37;&#41; of distant metastasis followed local recurrence without previous lymphatic metastasis&#46; The median time to disease-related mortality was longer in patients who developed systemic metastases than in those who died of locoregional progression&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusions</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">The mortality of patients with cSCC is mostly due to the regional progression of their lymphatic metastases&#46; The appearance of distant metastases is practically always &#40;96&#46;9&#37;&#41; associated with previous lymphatic metastatic progression&#46; Therefore&#44; in the future&#44; new studies will be needed to assess the regional management of cSCC in both surgical and adjuvant therapies&#46;</p></span>"
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          "es" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Curso temporal de las diferentes v&#237;as de progresi&#243;n para los pacientes que finalmente fallecieron por carcinoma cut&#225;neo de c&#233;lulas escamosas de alto riesgo&#46;Ex&#58; exitus&#59; L&#58; recurrencia linf&#225;tica regional&#59; M&#58; met&#225;stasis sist&#233;mica&#59; RL&#58; recurrencia local&#59; S&#58; satelitosis&#46;</p>"
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          "es" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Supervivencia hasta la aparici&#243;n de la primera recurrencia en los carcinomas cut&#225;neos de c&#233;lulas escamosas de alto riesgo &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>222&#41;&#46;</p>"
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          "leyenda" => "<p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">AJCC-8&#58; 8&#46;<span class="elsevierStyleSup">a</span> Clasificaci&#243;n del <span class="elsevierStyleItalic">American Joint Committee on Cancer</span>&#59; BWH&#58; clasificaci&#243;n del <span class="elsevierStyleItalic">Brigham and Woman Hospital</span>&#59; L&#58; linf&#225;tica&#59; ND&#58; no disponible&#59; NS&#58; no estad&#237;sticamente significativo&#59; Q1&#44;Q2&#58; primer y tercer cuartiles&#59; RL&#58; recurrencia local&#59; S&#58; satelitosis&#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" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Caracter&#237;sticas de la muestra<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">V&#237;a diseminaci&#243;n recurrencia local &#40;RL&#41; &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>74&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">V&#237;a diseminaci&#243;n satelitosis &#40;S&#41; &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">V&#237;a diseminaci&#243;n linf&#225;tica &#40;L&#41; &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>139&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Total &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>222&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">p<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Edad al diagn&#243;stico</span></td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;615&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Mediana &#40;Q1&#44; Q3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">80&#44;0 &#40;72&#44;0&#44; 86&#44;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">79&#44;0 &#40;73&#44;0&#44; 80&#44;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">78&#44;0 &#40;72&#44;0&#44; 83&#44;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">78&#44;0 &#40;72&#44;0&#44; 84&#44;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Sexo</span></td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;090&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Hombre&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">52 &#40;70&#44;3&#37;&#41; &#124; &#40;38&#44;8&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5 &#40;55&#44;6&#37;&#41; &#124; &#40;3&#44;7&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">77 &#40;55&#44;4&#37;&#41; &#124; &#40;57&#44;5&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">134 &#40;60&#44;4&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Mujer&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">22 &#40;29&#44;7&#37;&#41; &#124; &#40;25&#44;0&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4 &#40;44&#44;4&#37;&#41; &#124; &#40;4&#44;5&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">62 &#40;44&#44;6&#37;&#41; &#124; &#40;70&#44;5&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">88 &#40;39&#44;6&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Inmunosupresi&#243;n</span></td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">0&#44;024</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">35 &#40;64&#44;8&#37;&#41; &#124; &#40;24&#44;6&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5 &#40;55&#44;6&#37;&#41; &#124; &#40;3&#44;5&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">102 &#40;81&#44;0&#37;&#41; &#124; &#40;71&#44;8&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">142 &#40;75&#44;1&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NS<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>S&#237;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">19 &#40;35&#44;2&#37;&#41; &#124; &#40;40&#44;4&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4 &#40;44&#44;4&#37;&#41; &#124; &#40;8&#44;5&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">24 &#40;19&#44;0&#37;&#41; &#124; &#40;51&#44;1&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">47 &#40;24&#44;9&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>ND&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">20&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Cabeza y cuello&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Tronco&#47;Extremidades&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Manos&#47;Pies&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Di&#225;metro tumoral &#40;mm&#41;</span></td><td class="td" title="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Mediana &#40;Q1&#44;Q3&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#44;01<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a> RL vs L&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Di&#225;metro tumoral &#40;mm&#41;</span></td><td class="td" title="\n
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                  \t\t\t\t">NS<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>&#62; 20&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Grosor tumoral &#40;mm&#41;</span></td><td class="td" title="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>&#8804;<span class="elsevierStyleHsp" style=""></span>6&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>&#62; 6&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">11 &#40;8&#44;0&#37;&#41; &#124; &#40;100&#44;0&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">11 &#40;5&#44;0&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Exitus por la enfermedad</span></td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">&#60;</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">0&#44;001</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">57 &#40;77&#44;0&#37;&#41; &#124; &#40;41&#44;6&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7 &#40;77&#44;8&#37;&#41; &#124; &#40;5&#44;1&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">73 &#40;52&#44;5&#37;&#41; &#124; &#40;53&#44;3&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">137 &#40;61&#44;7&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001 RL vs L<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>S&#237;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">17 &#40;23&#44;0&#37;&#41; &#124; &#40;20&#44;0&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2 &#40;22&#44;2&#37;&#41; &#124; &#40;2&#44;4&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">66 &#40;47&#44;5&#37;&#41; &#124; &#40;77&#44;6&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">85 &#40;38&#44;3&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Exitus por otras causas</span></td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;280&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">37 &#40;68&#44;5&#37;&#41; &#124; &#40;26&#44;8&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5 &#40;55&#44;6&#37;&#41; &#124; &#40;3&#44;6&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">96 &#40;76&#44;2&#37;&#41; &#124; &#40;69&#44;6&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">138 &#40;73&#44;0&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>S&#237;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">17 &#40;31&#44;5&#37;&#41; &#124; &#40;33&#44;3&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4 &#40;44&#44;4&#37;&#41; &#124; &#40;7&#44;8&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">30 &#40;23&#44;8&#37;&#41; &#124; &#40;58&#44;8&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">51 &#40;27&#44;0&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">20&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">33&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Exitus por cualquier causa</span></td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">0&#44;001</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">41 &#40;55&#44;4&#37;&#41; &#124; &#40;46&#44;6&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3 &#40;33&#44;3&#37;&#41; &#124; &#40;3&#44;4&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">44 &#40;31&#44;7&#37;&#41; &#124; &#40;50&#44;0&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">88 &#40;39&#44;6&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;005 RL vs L<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>S&#237;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">33 &#40;44&#44;6&#37;&#41; &#124; &#40;24&#44;6&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6 &#40;66&#44;7&#37;&#41; &#124; &#40;4&#44;5&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">95 &#40;68&#44;3&#37;&#41; &#124; &#40;70&#44;9&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">134 &#40;60&#44;4&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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                0 => "xTab3580546.png"
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            0 => array:3 [
              "identificador" => "tblfn0005"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Reportadas como n &#40;&#37; columna&#41; &#124; &#40;&#37; fila&#41;&#44; salvo que se especifique lo contrario&#46;</p>"
            ]
            1 => array:3 [
              "identificador" => "tblfn0010"
              "etiqueta" => "b"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Valores de p de la prueba exacta de Fisher para variables categ&#243;ricas&#44; test de tendencias para variables ordinales y test de Kruskall Wallis para variables continuas&#46;</p>"
            ]
            2 => array:3 [
              "identificador" => "tblfn0015"
              "etiqueta" => "c"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0015">Si las anteriores pruebas resultaron estad&#237;sticamente significativas se llevaron a cabo pruebas <span class="elsevierStyleItalic">post hoc</span> con valores de p ajustados por el m&#233;todo de Holm&#46;</p>"
            ]
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        "descripcion" => array:1 [
          "es" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Caracter&#237;sticas cl&#237;nicas y patol&#243;gicas de los carcinomas cut&#225;neos de alto riesgo en funci&#243;n de las distintas v&#237;as de diseminaci&#243;n &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>222&#41;</p>"
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    "bibliografia" => array:2 [
      "titulo" => "Bibliograf&#237;a"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0015"
          "bibliografiaReferencia" => array:23 [
            0 => array:3 [
              "identificador" => "bib0120"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Incidencia y mortalidad del c&#225;ncer cut&#225;neo en Espa&#241;a&#58; revisi&#243;n sistem&#225;tica y metaan&#225;lisis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "A&#46; Tejera-Vaquerizo"
                            1 => "M&#46;A&#46; Descalzo-Gallego"
                            2 => "M&#46;M&#46; Otero-Rivas"
                            3 => "C&#46; Posada-Garc&#237;a"
                            4 => "L&#46; Rodr&#237;guez-Pazos"
                            5 => "I&#46; Pastushenko"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
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Article information
ISSN: 00017310
Original language: Spanish
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