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o que corresponde a uma taxa de incid&#234;ncia semelhante a&#160;0&#44;7&#47;100&#46;000&#160;pessoas&#8208;ano&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">6</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Maior incid&#234;ncia de CCM foi observada em estudo australiano&#44; com taxa de&#160;1&#44;6&#47;100&#46;000&#160;habitantes no estado de Queensland entre&#160;2006&#160;e&#160;2010&#44; mais frequente no sexo masculino &#40;2&#44;5&#47;100&#46;000&#41; do que no feminino &#40;0&#44;9&#47;100&#46;000&#41; e com expectativa de vida m&#233;dia de&#160;75&#44;5&#160;anos para homens e&#160;78&#160;anos para mulheres no momento do diagn&#243;stico&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">7</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Embora rara&#44; a incid&#234;ncia de CCM cresceu drasticamente&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">8</span></a> Em&#160;2018&#44; Paulson et al&#46; relataram que a quantidade de casos aumentou&#160;95&#37; entre&#160;2000&#160;e&#160;2013 nos EUA&#44; em compara&#231;&#227;o com um aumento de&#160;57&#37; para melanoma e&#160;15&#37; para todos os demais tumores s&#243;lidos&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">6</span></a> Na Austr&#225;lia&#44; a incid&#234;ncia geral de CCM aumentou em m&#233;dia&#160;2&#44;6&#37; ao ano entre&#160;1993&#160;e&#160;2010 &#40;95&#37;IC&#160;1&#44;1&#37;&#8208;4&#44;2&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">7</span></a> O CCM &#233; frequentemente subdiagnosticado&#44; e acredita&#8208;se que parte de sua incid&#234;ncia aumentada seja decorrente de patologistas mais bem treinados e tamb&#233;m do desenvolvimento de biomarcadores que melhoraram a detec&#231;&#227;o da doen&#231;a&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">6</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">No que diz respeito &#224; epidemiologia do CCM no Brasil&#44; Melo et al&#46; publicaram um estudo com dados coletados dos Registros de C&#226;ncer de Base Populacional &#40;2000&#8208;2015&#41; e de Base Hospitalar &#40;2000&#8208;2017&#41;&#46; Foram analisados&#160;881&#160;pacientes com a doen&#231;a&#59; a maioria era do sexo feminino &#40;51&#44;2&#37;&#41;&#44; com idade maior que&#160;60&#160;anos&#160;&#40;82&#44;2&#37;&#41;&#44; de cor branca&#160;&#40;67&#44;6&#37;&#41; e com diagn&#243;stico predominantemente nos est&#225;dios&#160;III ou&#160;IV &#40;50&#44;5&#37;&#41;&#46; Al&#233;m disso&#44; constatou&#8208;se que as taxas m&#233;dias de incid&#234;ncia padronizadas por idade aumentaram significantemente em homens entre os anos de&#160;2000 &#40;0&#44;31&#47;1&#46;000&#46;000&#41; e 2015 &#40;1&#44;21&#47;1&#46;000&#46;000&#41;&#44; com varia&#231;&#227;o percentual anual de&#160;9&#44;4 &#40;95&#37;IC&#160;4&#44;7&#37;&#8208;14&#44;4&#37;&#59; p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#41;&#46; Nas mulheres&#44; as taxas de incid&#234;ncia n&#227;o aumentaram significantemente no per&#237;odo&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">9</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">Carneiro et al&#46; avaliaram retrospectivamente&#160;32&#160;pacientes atendidos no Instituto Nacional de C&#226;ncer com CCM entre&#160;2002&#160;e&#160;2012&#44; e a m&#233;dia de idade ao diagn&#243;stico foi de&#160;72&#160;anos&#46; No entanto&#44; diferentemente dos dados internacionais&#44; a maioria dos pacientes era do sexo feminino&#160;&#40;69&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">10</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Fatores de risco</span><p id="par0035" class="elsevierStylePara elsevierViewall">V&#225;rios estudos sugerem que m&#250;ltiplos fatores podem contribuir para o desenvolvimento do CCM&#46;<a class="elsevierStyleCrossRefs" href="#bib0330"><span class="elsevierStyleSup">7&#44;8&#44;11&#8211;13</span></a> A exposi&#231;&#227;o solar &#233; importante fator de risco&#44;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">13&#44;14</span></a> corroborado pela maior incid&#234;ncia de CCM em regi&#245;es com maior &#237;ndice de radia&#231;&#227;o ultravioleta<a class="elsevierStyleCrossRefs" href="#bib0330"><span class="elsevierStyleSup">7&#44;8</span></a> e pela maior tend&#234;ncia a ocorrer em &#225;reas fotoexpostas&#44; como regi&#227;o de cabe&#231;a e pesco&#231;o&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">15</span></a> Lunder et al&#46; tamb&#233;m mostraram maior ocorr&#234;ncia de CCM em pacientes com hist&#243;ria de uso de psoralenos e exposi&#231;&#227;o da pele &#224; radia&#231;&#227;o ultravioleta de ondas longas&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">16</span></a> O CCM &#233; mais frequente em pacientes caucasianos em compara&#231;&#227;o com outras etnias&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">8</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">A imunossupress&#227;o tamb&#233;m &#233; fator de risco&#59;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">13</span></a> portanto&#44; o CCM &#233; mais comum em pacientes transplantados&#44; com diagn&#243;stico de neoplasias linfoproliferativas &#40;como a leucemia linfoc&#237;tica cr&#244;nica&#41; ou em portadores do v&#237;rus HIV&#46;<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">8&#44;14</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">Al&#233;m disso&#44; idade avan&#231;ada tamb&#233;m &#233; considerada fator de risco&#46;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">13&#44;15</span></a> Em uma s&#233;rie dos EUA&#44; 90&#37;&#160;de todos os pacientes com CCM estavam acima de&#160;50&#160;anos&#44; 76&#37;&#160;acima de&#160;65&#160;anos e 49&#37;&#160;acima de&#160;75&#160;anos&#46;<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">8&#44;15</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">Em&#160;2008&#44; Feng et al&#46; descreveram pela primeira vez a associa&#231;&#227;o entre um novo poliomav&#237;rus e o CCM&#44; identificando o DNA do v&#237;rus em&#160;8&#160;de&#160;10&#160;tumores de Merkel&#44; sugerindo que a infec&#231;&#227;o viral poderia ser um evento precoce na patog&#234;nese&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">11</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Poliomav&#237;rus associado ao carcinoma de c&#233;lulas de Merkel</span><p id="par0055" class="elsevierStylePara elsevierViewall">A descoberta do poliomav&#237;rus associado ao CCM&#44; em&#160;2008&#44; revolucionou os conhecimentos sobre a patog&#234;nese desse tumor&#44; ent&#227;o denominado <span class="elsevierStyleItalic">Merkel cell polyomavirus</span> &#40;MCPyV&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">11</span></a> A associa&#231;&#227;o foi identificada usando&#8208;se t&#233;cnica de subtra&#231;&#227;o de transcriptoma digital&#44; que &#233; um m&#233;todo de bioinform&#225;tica para detectar a presen&#231;a de novos transcritos de pat&#243;genos por meio da remo&#231;&#227;o computacional das sequ&#234;ncias do hospedeiro&#46; Ent&#227;o&#44; nesse caso&#44; sequ&#234;ncias humanas conhecidas foram filtradas para identificar potenciais transcritos virais&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">3</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">Os casos de infec&#231;&#227;o subcl&#237;nica por MCPyV aumentam de acordo com a senesc&#234;ncia&#44; atingindo preval&#234;ncia de&#160;60&#37;&#160;a&#160;80&#37; em adultos&#46; No entanto&#44; isso pode diferir significantemente em outras regi&#245;es geogr&#225;ficas&#44; como a Austr&#225;lia&#44; onde foi relatada associa&#231;&#227;o muito menor com infec&#231;&#227;o viral&#44; em torno de&#160;25&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">17</span></a> A pele constitui o maior s&#237;tio da infec&#231;&#227;o viral&#44; apesar de o v&#237;rus ter sido detectado tamb&#233;m no sangue perif&#233;rico e em outros &#243;rg&#227;os&#46; A infec&#231;&#227;o pelo MCPyV parece ser assintom&#225;tica&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">3</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">A fam&#237;lia Polyomaviridae&#44; a qual o MCPyV pertence&#44; &#233; composta por pequenos v&#237;rus de DNA dupla&#8208;h&#233;lice&#46; Ela inclui outros poliomav&#237;rus associados com infec&#231;&#227;o cut&#226;nea em humanos &#40;poliomav&#237;rus da Tricodisplasia Spinulosa&#44; poliomav&#237;rus humano&#160;6 e poliomav&#237;rus humano&#160;7&#41; ou doen&#231;as em outros &#243;rg&#227;os e sistemas &#40;como o v&#237;rus JC&#44; um poliomav&#237;rus humano ub&#237;quo que causa doen&#231;as do sistema nervoso central em pacientes imunocomprometidos&#44; incluindo leucoencefalopatia multifocal progressiva&#44; neuropatia de c&#233;lulas granulares e encefalopatia pelo v&#237;rus JC&#41;&#46; At&#233; a presente data&#44; o MCPyV &#233; o &#250;nico oncov&#237;rus humano da fam&#237;lia Polyomaviridae&#44; mas o motivo desse <span class="elsevierStyleItalic">status</span> distinto ainda n&#227;o &#233; conhecido&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">3</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">O tipo espec&#237;fico de c&#233;lula hospedeira para a infec&#231;&#227;o por esse poliomav&#237;rus ainda permanece incerto&#46; Acredita&#8208;se que as c&#233;lulas de Merkel n&#227;o sejam suficientemente numerosas para explicar a carga viral normalmente detectada na pele&#44; e os mon&#243;citos no sangue perif&#233;rico t&#234;m sido apontados como poss&#237;vel reservat&#243;rio de c&#233;lulas infectadas&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">3</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">O genoma viral epissomal apresenta regi&#245;es precoces e tardias&#46; As primeiras t&#234;m genes que codificam prote&#237;nas respons&#225;veis por coordenar a replica&#231;&#227;o viral&#44; enquanto as regi&#245;es tardias est&#227;o ligadas &#224;s prote&#237;nas do caps&#237;deo viral&#46; Parece que a integra&#231;&#227;o do DNA do MCPyV no genoma do hospedeiro ocorre logo ap&#243;s a infec&#231;&#227;o&#46;<a class="elsevierStyleCrossRefs" href="#bib0310"><span class="elsevierStyleSup">3&#44;18</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">Imuno&#8208;histoqu&#237;mica&#44; PCR&#44; hibridiza&#231;&#227;o <span class="elsevierStyleItalic">in situ</span> de DNA ou tecnologias de sequenciamento de nova gera&#231;&#227;o s&#227;o m&#233;todos dispon&#237;veis para detectar MCPyV em tumores&#44; mas esses testes variam muito em sensibilidade e especificidade&#46; O desenvolvimento de um anticorpo monoclonal usado para detec&#231;&#227;o espec&#237;fica do ant&#237;geno T grande &#40;LT&#41; por meio da imuno&#8208;histoqu&#237;mica &#8208; exclusivo para o MCPyV &#40;o clone CM2B4&#41; &#8208; possibilitou a detec&#231;&#227;o e visualiza&#231;&#227;o de MCPyV <span class="elsevierStyleItalic">in situ</span>&#46; Esse m&#233;todo est&#225; dispon&#237;vel comercialmente e tem aproximadamente 88&#37; de sensibilidade e 94&#37; de especificidade&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">3</span></a> A <a class="elsevierStyleCrossRef" href="#fig0005">figura 1</a> demonstra exemplos de resultados de imuno&#8208;histoqu&#237;mica positivo e negativo para o poliomav&#237;rus de c&#233;lulas de Merkel realizada utilizando o anticorpo anti&#8208;MCPyV large T&#8208;antigen &#40;CM2B4&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Caracter&#237;sticas cl&#237;nicas</span><p id="par0085" class="elsevierStylePara elsevierViewall">Clinicamente&#44; o CCM pode se apresentar como n&#243;dulo cut&#226;neo ou subcut&#226;neo&#44; e at&#233; mesmo ter aspecto c&#237;stico&#46; A cor pode variar entre vermelho&#44; rosa&#44; azul&#44; violeta ou cor da pele&#46; Inicialmente&#44; as les&#245;es s&#227;o geralmente indolores e solit&#225;rias&#44; mas tamb&#233;m podem ulcerar ou ser circundadas por les&#245;es sat&#233;lites&#46; No diagn&#243;stico&#44; as dimens&#245;es podem variar em tamanho&#44; mas costumam ser menores que&#160;20&#160;mm&#44; e a maioria dos casos apresenta crescimento r&#225;pido do tumor em poucos meses &#40;<a class="elsevierStyleCrossRef" href="#fig0010">fig&#46; 2</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">15</span></a></p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0090" class="elsevierStylePara elsevierViewall">As les&#245;es geralmente aparecem em &#225;reas fotoexpostas&#44; enquanto&#160;19&#37; aparecem nas n&#225;degas ou em &#225;reas minimamente expostas ao sol&#46; Os s&#237;tios anat&#244;micos prim&#225;rios mais frequentes s&#227;o cabe&#231;a e pesco&#231;o&#160;&#40;29&#37;&#41;&#44; seguidos por membros inferiores&#160;&#40;24&#37;&#41; e membros superiores&#160;&#40;21&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">15</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">Heath et al&#46;&#44; em&#160;2008&#44; propuseram a regra mnem&#244;nica &#8220;AEIOU&#8221; &#40;<span class="elsevierStyleItalic">Assintomatic&#47;lack of tenderness&#44; Expandig rapidly&#44; Immune suppression&#44; Older than&#160;50&#160;years&#44; and Ultraviolet exposed site</span>&#41; a partir da an&#225;lise de&#160;195&#160;casos&#44; na tentativa de auxiliar o diagn&#243;stico&#46; Nessa coorte&#44; 89&#37;&#160;dos pacientes com diagn&#243;stico de CCM preencheram&#160;tr&#234;s&#160;ou mais crit&#233;rios&#44; 52&#37;&#160;dos pacientes preencheram&#160;quatro&#160;ou mais crit&#233;rios e 7&#37;&#160;dos pacientes preencheram todos os&#160;cinco&#160;crit&#233;rios&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">15</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">No momento do diagn&#243;stico&#44; at&#233;&#160;37&#37; dos pacientes apresentam doen&#231;a nodal e&#160;6&#37;&#8208;12&#37; apresentam&#8208;se com doen&#231;a metast&#225;tica&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">19</span></a> Cerca de&#160;15&#37; dos pacientes t&#234;m um linfonodo acometido pela doen&#231;a sem identificar les&#227;o cut&#226;nea&#44; provavelmente refletindo a regress&#227;o do s&#237;tio prim&#225;rio&#46;<a class="elsevierStyleCrossRefs" href="#bib0310"><span class="elsevierStyleSup">3&#44;15</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">As met&#225;stases a dist&#226;ncia aparecem com mais frequ&#234;ncia em linfonodos n&#227;o regionais&#44; pele&#44; ossos&#44; pulm&#245;es e pleura ou f&#237;gado e&#44; menos comumente&#44; p&#226;ncreas&#44; gl&#226;ndulas suprarrenais&#44; c&#233;rebro&#44; rins&#44; tecido subcut&#226;neo ou m&#250;sculo&#46; Os locais raros de met&#225;stases incluem mama&#44; trato gastrintestinal&#44; test&#237;culos&#44; cora&#231;&#227;o&#44; retroperit&#244;nio e perit&#244;nio&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">14</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Diagn&#243;stico</span><p id="par0110" class="elsevierStylePara elsevierViewall">Em decorr&#234;ncia da falta de caracter&#237;sticas e de sintomas espec&#237;ficos&#44; o diagn&#243;stico torna&#8208;se um desafio&#46; Assim&#44; o exame histopatol&#243;gico por patologista experiente e a colora&#231;&#227;o com marcadores imuno&#8208;histoqu&#237;micos espec&#237;ficos s&#227;o essenciais nesse processo&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">3</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">A organiza&#231;&#227;o americana National Comprehensive Cancer Network &#40;NCCN&#41; prop&#244;s algoritmos espec&#237;ficos para o diagn&#243;stico de CCM&#44; que incluem as seguintes estrat&#233;gias&#58; 1&#41;&#160;exame completo de pele e linfonodos&#59; 2&#41;&#160;bi&#243;psia para an&#225;lise histopatol&#243;gica e imuno&#8208;histoqu&#237;mica&#59; 3&#41;&#160;bi&#243;psia de linfonodo sentinela &#40;BLS&#41; para pacientes sem linfonodos clinicamente positivos&#44; precedendo a excis&#227;o&#44; se poss&#237;vel&#59; 4&#41;&#160;aspira&#231;&#227;o por agulha fina ou bi&#243;psia linfonodal para pacientes com linfonodos clinicamente positivos&#59; considerar bi&#243;psia aberta&#59; 5&#41;&#160;exames de imagem para estadiamento&#44; conforme indica&#231;&#227;o cl&#237;nica&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">14</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">A dermatoscopia &#233; um exame complementar que pode ser &#250;til em alguns casos&#44; mas ainda faltam descri&#231;&#245;es dermatosc&#243;picas mais completas na literatura&#46; O CCM geralmente exibe uma variedade de padr&#245;es vasculares dermatosc&#243;picos&#44; mais comumente &#225;reas&#47;gl&#243;bulos vermelho&#8208;leitosos&#44; vasos polim&#243;rficos e vasos lineares irregulares&#44;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">20</span></a> refletindo o r&#225;pido crescimento do tumor&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">A colora&#231;&#227;o com hematoxilina &#38; eosina revela a prolifera&#231;&#227;o de pequenas c&#233;lulas tumorais basof&#237;licas na derme e&#47;ou hipoderme&#44;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">21</span></a> com citoplasma escasso&#44; mitoses abundantes e gr&#226;nulos citoplasm&#225;ticos densos&#46; C&#233;lulas necr&#243;ticas tamb&#233;m s&#227;o comuns&#46;<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">8&#44;20</span></a> Exemplos da histopatologia est&#227;o representados na <a class="elsevierStyleCrossRef" href="#fig0015">figura 3</a>&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0130" class="elsevierStylePara elsevierViewall">A citoqueratina&#160;20 &#40;CK20&#41; e marcadores neuroend&#243;crinos&#44; como cromogranina A&#44; sinaptofisina&#44; CD56&#44; enolase neur&#244;nio&#8208;espec&#237;fica e neurofilamento s&#227;o expressos no CCM&#46;<span class="elsevierStyleSup">3&#44;14&#44;21</span> A imunopositividade paranuclear semelhante a pontos para CK20 &#233; altamente sugestiva&#44; enquanto os marcadores neuroend&#243;crinos n&#227;o s&#227;o espec&#237;ficos&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">3</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">Para pacientes com linfonodos clinicamente negativos&#44; a BLS deve ser realizada e sua taxa de positividade varia de&#160;30&#37;&#160;a&#160;38&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">14</span></a> Quando negativo&#44; menor risco de recorr&#234;ncia&#44;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">22</span></a> melhor sobrevida livre de doen&#231;a &#40;SLD&#41; e sobrevida global &#40;SG&#41; s&#227;o observados&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">14</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall">O uso de exames de imagens para investiga&#231;&#227;o diagn&#243;stica de pacientes com CCM ainda est&#225; em discuss&#227;o&#46; O NCCN n&#227;o recomenda exames de imagem em pacientes sem suspeita cl&#237;nica de linfonodos acometidos&#46; A BLS &#233; considerada o teste mais confi&#225;vel para identificar met&#225;stases em linfonodos n&#227;o clinicamente suspeitos&#46; A resson&#226;ncia magn&#233;tica cerebral&#44; as tomografias computadorizadas &#40;TC&#41; de pesco&#231;o&#44; t&#243;rax&#44; abdome e pelve ou PET&#8208;CT s&#227;o indicadas para planejamento cir&#250;rgico ou quando houver suspeita de tumor irressec&#225;vel ou met&#225;stases a dist&#226;ncia&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">14</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">Gupta et al&#46; mostraram que a TC tem baixa sensibilidade &#40;em torno de&#160;20&#37;&#41; para detec&#231;&#227;o de met&#225;stases linfonodais e baixa especificidade para met&#225;stases a dist&#226;ncia&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">22</span></a> Portanto&#44; embora a TC tenha sido usada como ferramenta de triagem para met&#225;stases regionais ou a dist&#226;ncia em CCM&#44; os dados que suportam sua aplica&#231;&#227;o s&#227;o limitados&#46;<a class="elsevierStyleCrossRefs" href="#bib0365"><span class="elsevierStyleSup">14&#44;22</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">O PET&#8208;CT tem sido amplamente estudado em pacientes com CCM&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">14</span></a> Colgan et al&#46; avaliaram retrospectivamente&#160;36&#160;pacientes com CCM que realizaram exames de PET&#8208;CT antes da BLS e observaram&#160;83&#37;&#160;e&#160;95&#37;&#160;de sensibilidade e especificidade&#44; respectivamente&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">23</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Diagn&#243;stico diferencial</span><p id="par0155" class="elsevierStylePara elsevierViewall">Clinicamente&#44; os diagn&#243;sticos diferenciais para CCM s&#227;o les&#245;es benignas da pele&#44; como cisto acneiforme&#44; lipoma&#44; dermatofibroma ou fibroma e les&#227;o vascular&#46; Les&#245;es malignas representadas por c&#226;ncer de pele n&#227;o melanoma&#44; linfoma cut&#226;neo&#44; carcinoma metast&#225;tico e sarcoma tamb&#233;m devem ser consideradas diagn&#243;sticos diferenciais&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">15</span></a></p><p id="par0160" class="elsevierStylePara elsevierViewall">Histologicamente&#44; o diagn&#243;stico tamb&#233;m pode ser um desafio&#44; pois o CCM &#233; semelhante a uma variedade de outros tumores que t&#234;m c&#233;lulas azuis pequenas e arredondadas&#44; incluindo linfomas&#44; melanoma amelan&#243;tico&#44; met&#225;stases cut&#226;neas de carcinoma de c&#233;lulas pequenas de pulm&#227;o<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">3</span></a> e outros carcinomas metast&#225;ticos &#40;neuroblastoma&#44; rabdomiossarcoma&#44; tumor desmopl&#225;sico de pequenas c&#233;lulas&#44; condrossarcoma mesenquimal&#44; sarcoma de <span class="elsevierStyleItalic">Ewing</span> e osteossarcoma&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">8</span></a> O CCM <span class="elsevierStyleItalic">in situ</span>&#44; no qual as c&#233;lulas neopl&#225;sicas s&#227;o limitadas &#224; epiderme e&#47;ou epit&#233;lio folicular&#44; pode ser confundido com carcinoma de c&#233;lulas escamosas <span class="elsevierStyleItalic">in situ</span>&#44; melanoma <span class="elsevierStyleItalic">in situ</span> ou outra neoplasia intraepid&#233;rmica pagetoide&#46;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">20</span></a></p><p id="par0165" class="elsevierStylePara elsevierViewall">Em decorr&#234;ncia dos aspectos morfol&#243;gicos similares&#44; o diagn&#243;stico diferencial mais desafiador &#233; o c&#226;ncer de pulm&#227;o de pequenas c&#233;lulas metast&#225;tico<a class="elsevierStyleCrossRefs" href="#bib0310"><span class="elsevierStyleSup">3&#44;8</span></a> que exige painel de marcadores imuno&#8208;histoqu&#237;micos para definir o diagn&#243;stico&#46; CK20 e o fator de transcri&#231;&#227;o da tireoide&#160;1 &#40;TTF&#8208;1&#41; t&#234;m maior sensibilidade e especificidade para excluir c&#226;ncer de pulm&#227;o de pequenas c&#233;lulas&#59;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">8</span></a> CK20 &#233; positivo em&#160;70&#37;&#160;a&#160;100&#37; do CCM e negativo em c&#226;ncer de pulm&#227;o de pequenas c&#233;lulas&#44; enquanto TTF&#8208;1 &#233; sempre negativo em CCM e positivo em mais de&#160;80&#37; dos c&#226;nceres de pulm&#227;o de pequenas c&#233;lulas&#46;<span class="elsevierStyleSup">3&#44;8&#44;14</span></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Estadiamento</span><p id="par0170" class="elsevierStylePara elsevierViewall">A atual&#160;8&#170;&#160;edi&#231;&#227;o do sistema de estadiamento do American Joint Committee on Cancer &#40;AJCC&#41; &#233; baseada em uma an&#225;lise atualizada de 9&#46;387&#160;casos de CCM do National Cancer Database&#44; com acompanhamento m&#233;dio de 28&#44;2 meses &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">tabela 1</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">24</span></a> De acordo com o AJCC&#44; os seguintes par&#226;metros s&#227;o necess&#225;rios para o estadiamento do CCM T&#58; 1&#41;&#160;di&#226;metro m&#225;ximo do tumor medido clinicamente&#44; antes da ressec&#231;&#227;o e 2&#41;&#160;extens&#227;o do tumor &#40;f&#225;scia&#44; m&#250;sculo&#44; cartilagem ou invas&#227;o &#243;ssea&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">24</span></a> O di&#226;metro do tumor tem valor progn&#243;stico&#44; estando significantemente associado ao envolvimento de linfonodos&#44; sobrevida doen&#231;a&#8208;espec&#237;fica &#40;SDE&#41; e SG&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">14</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0175" class="elsevierStylePara elsevierViewall">O CCM &#233; caracteristicamente um tumor agressivo e localmente invasivo&#44; com alta incid&#234;ncia de recorr&#234;ncia local e envolvimento de linfonodos regionais&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">1</span></a> A BLS &#233; importante ferramenta de estadiamento recomendada para todos os pacientes com linfonodo clinicamente negativo&#44; sempre que poss&#237;vel&#44; para realizar o estadiamento nodal patol&#243;gico&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">14</span></a></p><p id="par0180" class="elsevierStylePara elsevierViewall">De acordo com a&#160;8&#170;&#160;edi&#231;&#227;o do sistema de estadiamento AJCC&#44; as estimativas de SG de cinco anos para o estadiamento cl&#237;nico e patol&#243;gico da doen&#231;a local foram&#160;45&#44;0&#37;&#160;e&#160;62&#44;8&#37; para o est&#225;dio&#160;I&#59; 30&#44;9&#37;&#160;e&#160;54&#44;6&#37; para o est&#225;dio IIA e 27&#44;3&#37;&#160;e&#160;34&#44;8&#37; para o est&#225;dio&#160;IIB&#44; respectivamente&#46; A SG de&#160;cinco&#160;anos para o est&#225;dio&#160;IIIA revisado foi de 40&#44;3&#37;&#44; enquanto para o est&#225;dio&#160;IIIB foi de&#160;26&#44;8&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">24</span></a> Na doen&#231;a em est&#225;dio&#160;IV&#44; a taxa de sobrevida de&#160;dois&#160;anos &#233; de&#160;apenas&#160;26&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">1</span></a></p><p id="par0185" class="elsevierStylePara elsevierViewall">Sihto et al&#46;&#44; em&#160;2009&#44; relataram que os CCM positivos para o poliomav&#237;rus apresentaram maior taxa de sobrevida em compara&#231;&#227;o com os tumores negativos para esse v&#237;rus&#59; a sobrevida em cinco anos foi de&#160;45&#37;&#160;<span class="elsevierStyleItalic">vs</span>&#46;&#160;13&#37; &#40;p&#8208;valor<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;01&#41;&#44; respectivamente&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">12</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Tratamento</span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Cirurgia para o tumor prim&#225;rio</span><p id="par0190" class="elsevierStylePara elsevierViewall">A cirurgia &#233; a modalidade de tratamento inicial para a maioria dos casos de CCM&#46; A defini&#231;&#227;o das margens cir&#250;rgicas ainda &#233; um tema controverso&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">14</span></a> O objetivo do tratamento cir&#250;rgico &#233; uma margem histol&#243;gica negativa e&#44; em geral&#44; a excis&#227;o cir&#250;rgica com margens de&#160;1&#160;cm&#160;a&#160;2&#160;cm continua a ser o primeiro passo no manejo do tumor&#46;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">25</span></a> Boyer et al&#46; analisaram&#160;45&#160;pacientes com CCM em est&#225;dio&#160;I e relataram margem mediana de&#160;16&#44;7&#160;mm de pele clinicamente normal necess&#225;ria para a aus&#234;ncia de envolvimento histol&#243;gico&#46;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">26</span></a></p><p id="par0195" class="elsevierStylePara elsevierViewall">Um estudo de&#160;1&#46;795&#160;pacientes com CCM est&#225;dios&#160;I&#160;e&#160;II n&#227;o mostrou diferen&#231;as entre a excis&#227;o cir&#250;rgica ampla e a cirurgia microgr&#225;fica de Mohs em rela&#231;&#227;o &#224; presen&#231;a de tumor residual nas margens cir&#250;rgicas&#44; e nenhuma diferen&#231;a na SG entre as duas modalidades de tratamento foi encontrada&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">27</span></a> As margens histologicamente negativas est&#227;o relacionadas ao melhor controle local e sobrevida&#44; principalmente nos casos de doen&#231;a localizada tratada apenas com cirurgia&#46; Em todos os casos de tratamento cir&#250;rgico&#44; a BLS deve ser planejada antes da excis&#227;o definitiva&#44; pois a cirurgia pode alterar a drenagem linf&#225;tica&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">14</span></a></p><p id="par0200" class="elsevierStylePara elsevierViewall">Santamaria&#8208;Barria et al&#46; elucidaram o papel da BLS no manejo do CCM em uma revis&#227;o de&#160;161&#160;pacientes&#44; tendo identificado micromet&#225;stases em 1&#47;3 deles&#46;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">28</span></a> Assim&#44; ap&#243;s verifica&#231;&#227;o de margens livres e&#44; se indicado BLS&#44; o desafio &#233; determinar se deve ou n&#227;o oferecer tratamento adjuvante&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Radioterapia</span><p id="par0205" class="elsevierStylePara elsevierViewall">A radioterapia &#40;RT&#41; tem papel importante no tratamento do CCM&#46; O CCM &#233; uma neoplasia radiossens&#237;vel&#44; e a RT pode ser considerada terapia prim&#225;ria em pacientes que n&#227;o s&#227;o candidatos &#224; cirurgia&#46;<a class="elsevierStyleCrossRefs" href="#bib0440"><span class="elsevierStyleSup">29&#44;30</span></a> Embora a RT por si s&#243; seja inferior &#224; ressec&#231;&#227;o cir&#250;rgica em raz&#227;o do risco de recorr&#234;ncia de CCM a dist&#226;ncia&#44; ela pode ser usada quando a cirurgia &#233; contraindicada<a class="elsevierStyleCrossRefs" href="#bib0450"><span class="elsevierStyleSup">31&#8211;33</span></a> com bom controle locorregional e SG em&#160;cinco&#160;anos de at&#233;&#160;40&#37;&#160;a&#160;60&#37; em pacientes com met&#225;stases macrosc&#243;picas prim&#225;rias e&#47;ou nodais&#46;<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">33</span></a></p><p id="par0210" class="elsevierStylePara elsevierViewall">Em rela&#231;&#227;o a seu uso como terapia adjuvante&#44; os dados s&#227;o conflitantes&#46; A RT adjuvante p&#243;s&#8208;operat&#243;ria parece aumentar o controle local do tumor&#44; mas n&#227;o tem impacto significante na sobrevida global relacionada ao tumor&#46;<a class="elsevierStyleCrossRefs" href="#bib0465"><span class="elsevierStyleSup">34&#44;35</span></a> Em uma revis&#227;o com casos de CCM apenas de cabe&#231;a e pesco&#231;o&#44; a RT adjuvante apresentou benef&#237;cio significante na sobrevida em rela&#231;&#227;o &#224; cirurgia sozinha&#44; e a quimioterapia &#40;QT&#41; associada &#224; RT ofereceu vantagem sobre a RT sozinha em casos de tumores grandes &#40;&#62; 3&#160;cm&#41; ou margens positivas&#46;<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">36</span></a> Uma an&#225;lise retrospectiva de CCM est&#225;dios&#160;I&#160;a&#160;III mostrou baixa taxa de recorr&#234;ncia &#40;3&#37;&#41; em pacientes com linfonodo clinicamente negativo tratados com cirurgia adequada &#40;incluindo BLS&#41; e o uso seletivo de RT adjuvante para tumores de alto risco&#44; incluindo invas&#227;o linfovascular&#59; segunda malignidade &#40;leucemia&#47;linfoma&#41; no momento do diagn&#243;stico&#44; m&#250;ltiplos linfonodos positivos e extens&#227;o extracapsular&#59; tumores&#160;&#62;<span class="elsevierStyleHsp" style=""></span>2&#160;cm&#46; Os autores tamb&#233;m concluem que&#44; com cirurgia adequada&#44; &#233; improv&#225;vel que o uso rotineiro de RT local adjuvante seja ben&#233;fico para a grande maioria dos pacientes&#46;<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">37</span></a> Al&#233;m disso&#44; alguns dados sugeriram que a RT adjuvante pode ser omitida para aqueles com pequenos tumores prim&#225;rios &#40;&#60; 1&#160;cm&#41;&#44; margens cir&#250;rgicas livres&#44; BLS negativa e aus&#234;ncia de fatores de mau progn&#243;stico&#44; como invas&#227;o linfovascular e imunodefici&#234;ncia&#46;<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">38</span></a></p><p id="par0215" class="elsevierStylePara elsevierViewall">Uma an&#225;lise retrospectiva de&#160;46&#160;casos de CCM de cabe&#231;a e pesco&#231;o de baixo risco tratados entre&#160;2006&#160;e&#160;2015 demonstrou que a n&#227;o realiza&#231;&#227;o da RT p&#243;s&#8208;operat&#243;ria foi associada a risco significantemente maior de recorr&#234;ncia local &#40;recorr&#234;ncia local em&#160;cinco&#160;anos de&#160;26&#37; no grupo tratado sem RT adjuvante <span class="elsevierStyleItalic">versus</span>&#160;0&#37; no grupo que recebeu RT adjuvante&#59; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;02&#41;&#46; Os pacientes foram considerados de baixo risco em caso de tumor prim&#225;rio&#160;&#8804; 2&#44;0&#160;cm de di&#226;metro&#44; margens microscopicamente negativas na excis&#227;o cir&#250;rgica&#44; BLS negativa e aus&#234;ncia de imunossupress&#227;o cr&#244;nica&#46;<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">39</span></a></p><p id="par0220" class="elsevierStylePara elsevierViewall">Jouary Y et al&#46; mostraram redu&#231;&#227;o significante na recorr&#234;ncia local sem melhora da sobrevida global com RT adjuvante em estudo realizado antes da introdu&#231;&#227;o da BLS no tratamento do CCM&#46;<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">40</span></a></p><p id="par0225" class="elsevierStylePara elsevierViewall">Em uma coorte retrospectiva e n&#227;o randomizada de&#160;6&#46;908&#160;casos do National Cancer Database dos EUA&#44; a RT adjuvante foi associada a melhora da sobrevida em pacientes com CCM localizado &#40;est&#225;dios&#160;I&#160;e&#160;II&#41; em compara&#231;&#227;o com pacientes que passaram apenas pelo tratamento cir&#250;rgico &#40;est&#225;dio&#160;I&#58; <span class="elsevierStyleItalic">hazard ratio</span> &#91;HR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;71&#93;&#59; 95&#37;IC 0&#44;64&#37;&#8208;0&#44;80&#37;&#59; p &#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#59; est&#225;dio&#160;II&#58; HR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;77&#59; 95&#37;IC&#160;0&#44;66&#37;&#8208;0&#44;89&#37;&#59; p &#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#41;&#46; No entanto&#44; em pacientes com envolvimento nodal &#40;est&#225;dio&#160;III&#41;&#44; n&#227;o houve diferen&#231;a estatisticamente significante na SG entre os pacientes que tiveram cirurgia seguida de RT em compara&#231;&#227;o com a cirurgia isolada &#40;HR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;98&#59; 95&#37;IC 0&#44;86&#37;&#8208;1&#44;12&#59; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;80&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">41</span></a></p><p id="par0230" class="elsevierStylePara elsevierViewall">Em contraste&#44; um estudo retrospectivo do Moffitt Cancer Center&#44; avaliando&#160;171&#160;pacientes&#44; encontrou melhora no controle locorregional e SG entre pacientes com linfonodos patologicamente ou clinicamente positivos tratados com RT p&#243;s&#8208;operat&#243;ria&#46; Nessa publica&#231;&#227;o&#44; os pacientes foram tratados com excis&#227;o local ampla &#40;margens de&#160;1&#8208;2&#160;cm&#41; e todos realizaram estadiamento nodal&#46;<a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">42</span></a></p><p id="par0235" class="elsevierStylePara elsevierViewall">Assim&#44; o NCCN incluiu a RT como op&#231;&#227;o de tratamento adjuvante para todos os est&#225;dios do CCM e&#44; idealmente&#44; deve ser realizada em&#160;quatro&#160;a&#160;seis&#160;semanas ap&#243;s a cirurgia&#44; pois o atraso tem sido associado a piores desfechos&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">14</span></a></p></span></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Tratamento sist&#234;mico</span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Quimioterapia</span><p id="par0240" class="elsevierStylePara elsevierViewall">O papel da QT adjuvante para o CCM &#233; menos definido&#46; Hasan et al&#46; realizaram uma grande revis&#227;o sistem&#225;tica e notaram que a RT adjuvante resultou em taxas de controle local em&#160;tr&#234;s&#160;anos significantemente maiores&#44; taxas de recorr&#234;ncia diminu&#237;das e taxas de SG melhores em&#160;tr&#234;s&#160;anos&#44; enquanto a QT adjuvante n&#227;o ofereceu nenhum benef&#237;cio&#46;<a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">43</span></a> Al&#233;m disso&#44; estudos adicionais sugerem que o efeito da QT adjuvante na recorr&#234;ncia n&#227;o &#233; claro ou que n&#227;o h&#225; melhora significante na sobrevida quando comparada &#224; RT adjuvante isolada&#46;<a class="elsevierStyleCrossRefs" href="#bib0440"><span class="elsevierStyleSup">29&#44;44&#44;45</span></a></p><p id="par0245" class="elsevierStylePara elsevierViewall">Por muitos anos&#44; a QT foi a &#250;nica op&#231;&#227;o dispon&#237;vel como tratamento para a doen&#231;a avan&#231;ada&#46; O CCM &#233; considerado tumor quimiossens&#237;vel&#44; e esquemas de platina com etopos&#237;deo ou taxanos e antraciclinas isoladas ou em combina&#231;&#227;o s&#227;o inicialmente eficazes&#44; com taxa de resposta de at&#233;&#160;75&#37;&#44; mas geralmente a dura&#231;&#227;o da resposta &#233; curta&#44; n&#227;o resultando em benef&#237;cio de sobrevida&#46; A sobrevida livre de progress&#227;o &#40;SLP&#41; mediana varia de&#160;tr&#234;s&#160;a&#160;oito&#160;meses&#44; e a dura&#231;&#227;o da resposta parcial &#233; de apenas&#160;tr&#234;s&#160;meses para a terapia de primeira linha&#46;<a class="elsevierStyleCrossRefs" href="#bib0420"><span class="elsevierStyleSup">25&#44;46</span></a> Dada a idade avan&#231;ada de muitos pacientes e suas comorbidades&#44; a toxicidade da QT pode afetar gravemente a qualidade de vida&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Imunoterapia</span><p id="par0250" class="elsevierStylePara elsevierViewall">As imunoterapias est&#227;o atualmente em foco&#44; uma vez que foi descrita a import&#226;ncia do sistema imunol&#243;gico no controle do CCM&#59; os inibidores de PD&#8208;1 &#40;<span class="elsevierStyleItalic">programmed cell death&#160;1</span>&#41; e PD&#8208;L1 &#40;<span class="elsevierStyleItalic">programmed cell death protein ligand&#160;1</span>&#41; s&#227;o op&#231;&#245;es promissoras nos casos de doen&#231;a metast&#225;tica&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">21</span></a></p><p id="par0255" class="elsevierStylePara elsevierViewall">As vias PD&#8208;1 e PD&#8208;L1&#47;PD&#8208;L2 formam um sistema complexo de receptores e ligantes envolvidos no controle da ativa&#231;&#227;o de c&#233;lulas&#160;T&#46; Na maioria dos tumores&#44; PD&#8208;L1 &#233; predominantemente expresso em c&#233;lulas tumorais e PD&#8208;1 nos linf&#243;citos que se infiltram no tumor&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">1</span></a> No entanto&#44; o PD&#8208;1 pode ser expresso n&#227;o apenas por linf&#243;citos T CD8<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>&#44; mas tamb&#233;m pelas c&#233;lulas CD4<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>&#44; CD20<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>&#44; Treg e c&#233;lulas NK&#46;<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">47</span></a> A liga&#231;&#227;o entre PD&#8208;1 e seu ligante PD&#8208;L1 leva &#224; inativa&#231;&#227;o e diminui&#231;&#227;o da prolifera&#231;&#227;o de c&#233;lulas&#160;T&#46; Esse processo parece ser um mecanismo importante para a inibi&#231;&#227;o da resposta imune pelo tumor&#46;<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">48</span></a></p><p id="par0260" class="elsevierStylePara elsevierViewall">A associa&#231;&#227;o da imunossupress&#227;o com o maior risco de CCM&#44; al&#233;m de alguns dados que mostram melhor progn&#243;stico em tumores com alta infiltra&#231;&#227;o de linf&#243;citos&#160;T CD8<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>&#44; tornou&#8208;se uma justificativa para o uso da imunoterapia&#46;<a class="elsevierStyleCrossRefs" href="#bib0370"><span class="elsevierStyleSup">15&#44;49</span></a> Al&#233;m disso&#44; Lipson et al&#46;&#44; em&#160;2013&#44; relataram associa&#231;&#227;o significante entre a presen&#231;a do MCPyV e a express&#227;o de PD&#8208;L1 no tumor e entre a presen&#231;a do MCPyV com um infiltrado inflamat&#243;rio moderado a intenso&#46; Esses achados sugerem a hip&#243;tese de que uma resposta imune a ant&#237;genos virais cria um ambiente pr&#243;&#8208;inflamat&#243;rio local que estimula a express&#227;o de PD&#8208;L1 no tumor&#46;<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">50</span></a> Essas descobertas abriram caminho para o uso de inibidores de <span class="elsevierStyleItalic">checkpoint</span> imunes no MCC metast&#225;tico&#46;</p><p id="par0265" class="elsevierStylePara elsevierViewall">O primeiro estudo nesse cen&#225;rio foi o JAVELIN Merkel&#160;200&#44; um ensaio cl&#237;nico multic&#234;ntrico de fase&#160;II&#44; aberto&#44; que investigou a atividade cl&#237;nica e a seguran&#231;a de avelumabe&#44; um anticorpo anti&#8208;PD&#8208;L1&#46; O estudo apresenta parte&#160;A&#44; realizado em pacientes com CCM previamente expostos &#224; QT&#44;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">51</span></a> e parte&#160;B&#44; realizado em pacientes que n&#227;o haviam recebido tratamento sist&#234;mico pr&#233;vio para doen&#231;a metast&#225;tica&#46;<a class="elsevierStyleCrossRef" href="#bib0555"><span class="elsevierStyleSup">52</span></a> Na parte&#160;A&#44; 88&#160;pacientes foram tratados com avelumabe e a taxa de resposta global confirmada &#40;ORR&#41; foi de&#160;33&#37; &#40;incluindo&#160;10&#160;respostas completas&#41; e com&#160;26&#37; dos pacientes sem progress&#227;o em&#160;dois&#160;anos&#46; A dura&#231;&#227;o mediana da resposta n&#227;o foi alcan&#231;ada&#44; e a SG mediana foi de&#160;12&#44;6&#160;meses&#46;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">51</span></a> Uma resposta objetiva de&#160;34&#44;5&#37; foi encontrada em PD&#8208;L1 positivo contra apenas&#160;18&#44;8&#37; em pacientes PDL&#8208;1 negativos &#40;express&#227;o&#160;&#60;<span class="elsevierStyleHsp" style=""></span>1&#37;&#46;&#41; Considerando o corte na express&#227;o de PD&#8208;L1 em&#160;5&#37;&#44; 52&#44;6&#37; dos pacientes PD&#8208;L1 positivos <span class="elsevierStyleItalic">versus</span>&#160;23&#44;6&#37; dos pacientes PD&#8208;L1 negativos tiveram resposta objetiva&#46; Al&#233;m disso&#44; 26&#44;1&#37;&#160;dos pacientes com tumores MCPyV&#8208;positivos em compara&#231;&#227;o com&#160;35&#44;5&#37; nos tumores MCPyV&#8208;negativos tiveram resposta&#46;<a class="elsevierStyleCrossRef" href="#bib0560"><span class="elsevierStyleSup">53</span></a> Outra an&#225;lise de subgrupo sugeriu maior probabilidade de resposta em pacientes que receberam menos terapias sist&#234;micas pr&#233;vias&#44; o que foi confirmado na parte&#160;B do ensaio Javelin Merkel&#160;200&#46; A resposta objetiva entre os&#160;29&#160;pacientes inclu&#237;dos no cen&#225;rio de primeira linha foi de&#160;62&#37;&#44; com propor&#231;&#227;o de respostas com dura&#231;&#227;o de&#160;seis&#160;meses ou mais de&#160;83&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0555"><span class="elsevierStyleSup">52</span></a></p><p id="par0270" class="elsevierStylePara elsevierViewall">Munhoz et al&#46;&#44; em&#160;2020&#44; descreveram a experi&#234;ncia com avelumabe como tratamento de segunda linha &#40;ou primeira linha em pacientes n&#227;o candidatos ao uso de QT&#41; em um subconjunto de&#160;46&#160;pacientes latino&#8208;americanos &#40;idade m&#233;dia&#160;71&#44;6&#160;anos&#59; 60&#44;9&#37;&#160;homens&#59; dura&#231;&#227;o m&#233;dia do tratamento&#160;7&#44;9&#160;meses&#41;&#46; Respostas objetivas foram observadas em&#160;19&#160;pacientes &#40;resposta objetiva&#160;57&#44;9&#37;&#59; resposta completa&#160;15&#44;8&#37;&#59; resposta parcial&#160;42&#44;1&#37;&#59; e doen&#231;a est&#225;vel&#160;10&#44;5&#37;&#41; e seguran&#231;a consistente com dados globais&#46;<a class="elsevierStyleCrossRef" href="#bib0565"><span class="elsevierStyleSup">54</span></a></p><p id="par0275" class="elsevierStylePara elsevierViewall">Outro estudo com caracter&#237;sticas semelhantes demonstrou a efic&#225;cia do pembrolizumabe no CCM&#44; um anticorpo monoclonal anti&#8208;PD&#8208;1&#46; Um total de&#160;50&#160;pacientes com CCM avan&#231;ado foram tratados com resposta objetiva de&#160;56&#37; e taxa de SLP em&#160;seis&#160;meses de&#160;67&#37;&#46; Em contraste com o estudo com avelumabe&#44; uma taxa de resposta mais alta foi observada nos tumores positivos para MCPyV&#160;&#40;62&#37;&#41; do que nos tumores negativos para MCPyV&#160;&#40;44&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">55</span></a></p><p id="par0280" class="elsevierStylePara elsevierViewall">No estudo CheckMate&#160;358&#44; o nivolumabe&#44; outro anti&#8208;PD&#8208;1&#44; foi avaliado em&#160;25&#160;pacientes com CCM avan&#231;ado&#44; uma resposta objetiva de&#160;64&#37;&#46; As respostas ocorreram em pacientes virgens de tratamento&#160;&#40;71&#37;&#41;&#44; bem como naqueles com pelo menos uma terapia sist&#234;mica anterior&#160;&#40;63&#37;&#41;&#44; com tempo m&#233;dio curto para resposta &#40;75&#37; dos pacientes responderam em&#160;dois&#160;meses&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">56</span></a></p><p id="par0285" class="elsevierStylePara elsevierViewall">O resumo dos recentes estudos com imunoterapia para o tratamento do MCC metast&#225;tico pode ser visto na <a class="elsevierStyleCrossRef" href="#tbl0010">tabela 2</a>&#46;<a class="elsevierStyleCrossRefs" href="#bib0555"><span class="elsevierStyleSup">52&#44;56&#8211;58</span></a></p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0290" class="elsevierStylePara elsevierViewall">Dada a efic&#225;cia da imunoterapia para CCM metast&#225;tico&#44; o pr&#243;ximo desafio consiste em avaliar tais tratamentos no cen&#225;rio adjuvante&#46; Em raz&#227;o do alto risco de recorr&#234;ncia do CCM&#44; apesar do tratamento inicial e da falta de benef&#237;cio do tratamento citot&#243;xico&#44; sua investiga&#231;&#227;o &#233; altamente relevante&#44; cobrindo uma necessidade m&#233;dica n&#227;o atendida&#46; Dois estudos de fase&#160;II com nivolumabe e avelumabe est&#227;o avaliando o uso de inibidores de <span class="elsevierStyleItalic">checkpoints</span> imunes para pacientes de alto risco&#44; ainda sem os resultados oficialmente publicados&#46; O cen&#225;rio neoadjuvante com o estudo CheckMate&#160;358&#44; envolvendo&#160;39&#160;pacientes com CCM ressec&#225;vel est&#225;gio&#160;IIA&#160;a&#160;IV&#44; avaliou o uso do nivolumabe &#40;&#8805; 1&#160;dose&#41; cerca de&#160;quatro&#160;semanas antes da cirurgia&#46; Tr&#234;s pacientes n&#227;o foram operados por progress&#227;o tumoral e 36&#160;pacientes foram operados&#44; dentre os quais&#160;17&#160;&#40;42&#44;2&#37;&#41; obtiveram resposta patol&#243;gica completa&#46; Entre&#160;33&#160;pacientes avali&#225;veis radiograficamente submetidos &#224; cirurgia&#44; 18&#160;&#40;54&#44;5&#37;&#41; tiveram redu&#231;&#227;o tumoral&#160;&#8805; 30&#37;&#46; Nenhum paciente com resposta patol&#243;gica completa teve recidiva tumoral durante a observa&#231;&#227;o&#46;<a class="elsevierStyleCrossRef" href="#bib0590"><span class="elsevierStyleSup">59</span></a></p></span></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Conclus&#227;o</span><p id="par0295" class="elsevierStylePara elsevierViewall">O CCM &#233; doen&#231;a rara e agressiva&#44; cuja incid&#234;ncia est&#225; aumentando&#46; Nas &#250;ltimas d&#233;cadas&#44; muitos avan&#231;os foram feitos no conhecimento da biologia&#44; diagn&#243;stico e tratamento do CCM&#44; mas grandes desafios ainda permanecem&#46; Os tumores prim&#225;rios devem ser tratados com excis&#227;o cir&#250;rgica completa&#44; com margens cir&#250;rgicas adequadas&#46; RT adjuvante deve ser considerada&#46; Em rela&#231;&#227;o ao CCM avan&#231;ado&#44; a imunoterapia mudou drasticamente o padr&#227;o de tratamento&#44; uma vez que &#233; superior &#224; QT&#46; Not&#225;veis respostas foram observadas em pacientes com CCM tratados com inibidores do eixo PD&#8208;1&#47;PD&#8208;L1 e parece ser maneira promissora de mudar o progn&#243;stico desse c&#226;ncer de pele grave&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Suporte financeiro</span><p id="par0300" class="elsevierStylePara elsevierViewall">Nenhum&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Contribui&#231;&#227;o dos autores</span><p id="par0305" class="elsevierStylePara elsevierViewall">Stella Meireles Siqueira&#58; An&#225;lise estat&#237;stica&#59; elabora&#231;&#227;o e reda&#231;&#227;o do manuscrito&#59; obten&#231;&#227;o&#44; an&#225;lise e interpreta&#231;&#227;o dos dados&#59; participa&#231;&#227;o intelectual em conduta proped&#234;utica e&#47;ou terap&#234;utica de casos estudados&#59; revis&#227;o cr&#237;tica da literatura&#46;</p><p id="par0310" class="elsevierStylePara elsevierViewall">Gabriella Campos&#8208;do&#8208;Carmo&#58; An&#225;lise estat&#237;stica&#59; elabora&#231;&#227;o e reda&#231;&#227;o do manuscrito&#59; obten&#231;&#227;o&#44; an&#225;lise e interpreta&#231;&#227;o dos dados&#59; participa&#231;&#227;o intelectual em conduta proped&#234;utica e&#47;ou terap&#234;utica de casos estudados&#46;</p><p id="par0315" class="elsevierStylePara elsevierViewall">Alexssandra Lima Siqueira dos Santos&#58; An&#225;lise estat&#237;stica&#59; elabora&#231;&#227;o e reda&#231;&#227;o do manuscrito&#59; obten&#231;&#227;o&#44; an&#225;lise e interpreta&#231;&#227;o dos dados&#59; participa&#231;&#227;o intelectual em conduta proped&#234;utica e&#47;ou terap&#234;utica de casos estudados&#59; revis&#227;o cr&#237;tica da literatura&#46;</p><p id="par0320" class="elsevierStylePara elsevierViewall">C&#237;cero Martins&#58; An&#225;lise estat&#237;stica&#59; elabora&#231;&#227;o e reda&#231;&#227;o do manuscrito&#59; obten&#231;&#227;o&#44; an&#225;lise e interpreta&#231;&#227;o dos dados&#59; participa&#231;&#227;o intelectual em conduta proped&#234;utica e&#47;ou terap&#234;utica de casos estudados&#59; revis&#227;o cr&#237;tica da literatura&#46;</p><p id="par0325" class="elsevierStylePara elsevierViewall">Andreia Cristina de Melo&#58; An&#225;lise estat&#237;stica&#59; aprova&#231;&#227;o da vers&#227;o final do manuscrito&#59; concep&#231;&#227;o e planejamento do estudo&#59; elabora&#231;&#227;o e reda&#231;&#227;o do manuscrito&#59; obten&#231;&#227;o&#44; an&#225;lise e interpreta&#231;&#227;o dos dados&#59; participa&#231;&#227;o efetiva na orienta&#231;&#227;o da pesquisa&#59; participa&#231;&#227;o intelectual em conduta proped&#234;utica e&#47;ou terap&#234;utica de casos estudados&#59; 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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">O carcinoma de c&#233;lulas de Merkel &#233; c&#226;ncer de pele raro com diferencia&#231;&#227;o neuroend&#243;crina&#46; Os fatores de risco incluem exposi&#231;&#227;o solar&#44; idade avan&#231;ada&#44; imunossupress&#227;o &#40;como pacientes transplantados&#44; pacientes com neoplasias linfoproliferativas ou portadores do v&#237;rus HIV&#41; e infec&#231;&#227;o pelo poliomav&#237;rus de c&#233;lulas de Merkel&#46; Clinicamente&#44; o carcinoma de c&#233;lulas de Merkel aparece como placa ou n&#243;dulo cut&#226;neo ou subcut&#226;neo&#44; mas o diagn&#243;stico desse tumor raramente &#233; feito clinicamente&#46; Assim&#44; a histopatologia e a imuno&#8208;histoqu&#237;mica costumam ser necess&#225;rias&#46; Tumores prim&#225;rios sem evid&#234;ncia de met&#225;stases s&#227;o tratados com excis&#227;o cir&#250;rgica completa com margens cir&#250;rgicas apropriadas&#46; A presen&#231;a de met&#225;stase oculta em linfonodo &#233; frequente&#44; e a bi&#243;psia do linfonodo sentinela deve ser realizada&#46; A radioterapia adjuvante p&#243;s&#8208;operat&#243;ria aumenta o controle local do tumor&#46; Recentemente&#44; agentes que bloqueiam a via PD&#8208;1&#47;PD&#8208;L1 mostraram regress&#245;es tumorais objetivas e dur&#225;veis em pacientes com neoplasias s&#243;lidas avan&#231;adas&#46; O primeiro anticorpo anti&#8208;PD&#8208;L1 usado em pacientes com carcinoma de c&#233;lulas de Merkel foi o avelumabe&#44; mas pembrolizumabe e nivolumabe tamb&#233;m demonstraram efic&#225;cia&#46; Neste artigo&#44; o estado atual do conhecimento da epidemiologia&#44; diagn&#243;stico&#44; estadiamento e as novas estrat&#233;gias de tratamento sist&#234;mico do carcinoma de c&#233;lulas de Merkel s&#227;o descritos&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Como citar este artigo&#58; Siqueira SM&#44; Campos&#8208;do&#8208;Carmo G&#44; Santos ALS&#44; Martins C&#44; Melo AC&#46; Merkel cell carcinoma&#58; epidemiology&#44; clinical features&#44; diagnosis and treatment of a rare disease&#46; An Bras Dermatol&#46; 2023&#59;98&#58;277&#8211;86&#46;</p>"
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          "pt" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Imuno&#8208;histoqu&#237;mica para MCPyV realizada em l&#226;minas de carcinoma de c&#233;lulas de Merkel&#46; &#40;A&#41; L&#226;mina de imuno&#8208;histoqu&#237;mica de paciente apresentando resultado positivo para MCPyV &#40;aumento de&#160;400<span class="elsevierStyleHsp" style=""></span>&#215;&#41;&#46; &#40;B&#41; L&#226;mina de imuno&#8208;histoqu&#237;mica de paciente apresentando resultado negativo para MCPyV &#40;aumento de&#160;400<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>&#41;&#46;</p>"
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          "pt" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Carcinoma de c&#233;lulas de Merkel localizado na coxa esquerda de paciente do sexo masculino&#46; &#40;A&#41; Ao diagn&#243;stico&#44; les&#227;o tumoral com aspecto cupuliforme&#44; com eritema e discreta descama&#231;&#227;o&#46; &#40;B&#41; Evolu&#231;&#227;o do tumor com crescimento e ulcera&#231;&#227;o em toda a les&#227;o&#46;</p> <p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Fonte&#58; Cortesia da Dra&#46; Gabriella Campos&#8208;do&#8208;Carmo&#46; O paciente consentiu com o uso das imagens para fins educacionais&#46;</p>"
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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">Est&#225;dio&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">Tumor Prim&#225;rio&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">Linfonodos&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">Met&#225;stases&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><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">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"><span class="elsevierStyleItalic">In situ</span> &#40;restrito &#224; epiderme&#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">Sem met&#225;stase para linfonodo regional&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">Sem met&#225;stase a dist&#226;ncia&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">I&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  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Di&#226;metro cl&#237;nico m&#225;ximo do tumor &#8804;&#160;2&#160;cm</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">cN0&#44; sem met&#225;stase para linfonodo regional na avalia&#231;&#227;o cl&#237;nica ou radiol&#243;gica&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">Sem met&#225;stase a dist&#226;ncia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" 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><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">pN0&#44; sem met&#225;stase para linfonodo regional detectada na avalia&#231;&#227;o histopatol&#243;gica&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">IIA&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  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Di&#226;metro cl&#237;nico m&#225;ximo do tumor<span class="elsevierStyleHsp" style=""></span>&#62; 2&#160;cm</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">cN0&#44; sem met&#225;stase para linfonodo regional na avalia&#231;&#227;o cl&#237;nica ou radiol&#243;gica&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">Sem met&#225;stase a dist&#226;ncia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" 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><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">pN0&#44; sem met&#225;stase para linfonodo regional detectada na avalia&#231;&#227;o histopatol&#243;gica&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">IIB&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  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tumor prim&#225;rio invade f&#225;scia&#44; m&#250;sculo&#44; cartilagem ou osso</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">cN0&#44; sem met&#225;stase para linfonodo regional na avalia&#231;&#227;o cl&#237;nica ou radiol&#243;gica&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">Sem met&#225;stase a dist&#226;ncia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" 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><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">pN0&#44; sem met&#225;stase para linfonodo regional detectada na avalia&#231;&#227;o histopatol&#243;gica&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">III &#40;cl&#237;nico&#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">Tumor de qualquer tamanho&#44; incluindo tumores invasivos e tumor prim&#225;rio desconhecido&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">Met&#225;stase nodal regional clinicamente detectada&#44; met&#225;stase em tr&#226;nsito com ou sem met&#225;stase linfonodal&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">Sem met&#225;stase a dist&#226;ncia&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">IIIA &#40;patol&#243;gico&#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  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tumor de qualquer tamanho&#44; incluindo tumores invasivos e tumor prim&#225;rio desconhecido</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">Met&#225;stase nodal clinicamente oculta identificada apenas por BLS ou dissec&#231;&#227;o de linfonodo&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">Sem met&#225;stase a dist&#226;ncia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" 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><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">Met&#225;stase em linfonodo regional detectada cl&#237;nica ou radiologicamente&#44; confirmada patologicamente&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">IIIB &#40;patol&#243;gico&#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">Tumor de qualquer tamanho&#44; incluindo tumores invasivos&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">Met&#225;stase linfonodal regional detectada cl&#237;nica ou radiologicamente&#44; confirmada patologicamente&#44; met&#225;stase em tr&#226;nsito<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> com ou sem met&#225;stase linfonodal&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">IV&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">Tumor de qualquer tamanho&#44; incluindo tumores invasivos e tumor prim&#225;rio desconhecido&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">Qualquer N&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">Met&#225;stase al&#233;m dos linfonodos regionais&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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            0 => array:3 [
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              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Met&#225;stase em tr&#226;nsito&#58; tumor distinto da les&#227;o prim&#225;ria e localizado entre a les&#227;o prim&#225;ria e os linfonodos regionais ou distal &#224; les&#227;o prim&#225;ria&#46;</p>"
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          ]
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          "pt" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Estadiamento do carcinoma de c&#233;lulas de Merkel &#8211; AJCC 8&#170;&#160;edi&#231;&#227;o</p>"
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        "etiqueta" => "Tabela 2"
        "tipo" => "MULTIMEDIATABLA"
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          0 => array:3 [
            "identificador" => "at2"
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            "rol" => "short"
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        "tabla" => array:2 [
          "leyenda" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">TRG&#44; taxa de resposta global&#59; SLP&#44; sobrevida livre de progress&#227;o&#59; SG&#44; sobrevida global&#59; NR&#44; n&#227;o relatado&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&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">Nome do estudo&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">Classe de f&#225;rmacos&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">Tipo de estudo&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">N&#250;mero de pacientes&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">TRG &#40;&#37;&#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">SLP aos 24m &#40;&#37;&#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">SG aos 24m &#40;&#37;&#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">Refer&#234;ncias&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><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">Avelumabe&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">Javelin&#160;200 &#8208; Parte A&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">Anti&#8208;PD&#8208;L1&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<span class="elsevierStyleSup">a</span> linha ou linhas subsequentes&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&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">26&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">36&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">Kaufman 2018<a class="elsevierStyleCrossRef" href="#bib0580"><span class="elsevierStyleSup">57</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">Avelumabe&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">Javelin&#160;200 &#8208; Parte B&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">Anti&#8208;PD&#8208;L1&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<span class="elsevierStyleSup">a</span> linha&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">29&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&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">NR&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">NR&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">D&#8217;Angelo&#44; 2018<a class="elsevierStyleCrossRef" href="#bib0555"><span class="elsevierStyleSup">52</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">Pembrolizumabe&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">Keynote &#8208; 017&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">Anti&#8208;PD&#8208;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<span class="elsevierStyleSup">a</span> linha&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">50&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">56&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">48&#44;3&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">68&#44;7&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">Nghiem&#44; 2019<a class="elsevierStyleCrossRef" href="#bib0585"><span class="elsevierStyleSup">58</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">Nivolumabe&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">CheckMate 358&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">Anti&#8208;PD&#8208;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<span class="elsevierStyleSup">a</span> linha&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">15&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">71&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">NR&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">NR&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">Topalian&#44; 2017<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">56</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" 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><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><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><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<span class="elsevierStyleSup">a</span> linha&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">10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">63&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><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><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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              "imagenFichero" => array:1 [
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        "descripcion" => array:1 [
          "pt" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Dados importantes de ensaios cl&#237;nicos recentes envolvendo imunoterapia<a class="elsevierStyleCrossRefs" href="#bib0555"><span class="elsevierStyleSup">52&#44;56&#8211;58</span></a></p>"
        ]
      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "Refer&#234;ncias"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0015"
          "bibliografiaReferencia" => array:59 [
            0 => array:3 [
              "identificador" => "bib0300"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Co&#8208;expression of NGF and PD&#8208;L1 on tumor&#8208;associated immune cells in the microenvironment of Merkel cell carcinoma"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "U&#46; Wehkamp"
                            1 => "S&#46; Stern"
                            2 => "S&#46; Kr&#252;ger"
                            3 => "M&#46; Weichenthal"
                            4 => "A&#46; Hauschild"
                            5 => "C&#46; R&#246;cken"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Cancer Res Clin Oncol&#46;"
                        "fecha" => "2018"
                        "volumen" => "144"
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                        "itemHostRev" => array:3 [
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                          "issn" => "01406736"
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                  ]
                ]
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              "identificador" => "bib0305"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
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                      "autores" => array:1 [
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                          "etal" => false
                          "autores" => array:1 [
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                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
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                        "fecha" => "1972"
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                ]
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            2 => array:3 [
              "identificador" => "bib0310"
              "etiqueta" => "3"
              "referencia" => array:1 [
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                  "contribucion" => array:1 [
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                      "titulo" => "The biology and treatment of Merkel cell carcinoma&#58; current understanding and research priorities"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "P&#46;W&#46; Harms"
                            1 => "K&#46;L&#46; Harms"
                            2 => "P&#46;S&#46; Moore"
                            3 => "J&#46;A&#46; DeCaprio"
                            4 => "P&#46; Nghiem"
                            5 => "M&#46;K&#46;K&#46; Wong"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Nat Ver Clin Oncol&#46;"
                        "fecha" => "2018"
                        "volumen" => "15"
                        "paginaInicial" => "763"
                        "paginaFinal" => "766"
                      ]
                    ]
                  ]
                ]
              ]
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            3 => array:3 [
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              "etiqueta" => "4"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
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                      "titulo" => "Rare neuroendocrine tumours&#58; results of the surveillance of rare cancers in Europe project"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "J&#46;M&#46; Van der Zwan"
                            1 => "A&#46; Trama"
                            2 => "R&#46; Otter"
                            3 => "N&#46; Larra&#241;aga"
                            4 => "A&#46; Tavilla"
                            5 => "R&#46; Marcos-Gragera"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Eur J Cancer&#46;"
                        "fecha" => "2013"
                        "volumen" => "49"
                        "paginaInicial" => "2565"
                        "paginaFinal" => "2578"
                        "itemHostRev" => array:3 [
                          "pii" => "S0016508513002916"
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            4 => array:3 [
              "identificador" => "bib0320"
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              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Dramatic Increase in the Incidence and Mortality from Merkel Cell Carcinoma in the United States"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "T&#46;L&#46; Fitzgerald"
                            1 => "S&#46; Dennis"
                            2 => "S&#46;D&#46; Kachare"
                            3 => "N&#46;A&#46; Vohra"
                            4 => "J&#46;H&#46; Wong"
                            5 => "E&#46;E&#46; Zervos"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1177/000313481508100819"
                      "Revista" => array:6 [
                        "tituloSerie" => "The American Surgeon&#46;"
                        "fecha" => "2015"
                        "volumen" => "81"
                        "paginaInicial" => "802"
                        "paginaFinal" => "806"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26215243"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            5 => array:3 [
              "identificador" => "bib0325"
              "etiqueta" => "6"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Merkel cell carcinoma&#58; Current US incidence and projected increases based on changing demographics"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "K&#46;G&#46; Paulson"
                            1 => "S&#46;Y&#46; Park"
                            2 => "N&#46;A&#46; Vandeven"
                            3 => "K&#46; Lachance"
                            4 => "H&#46; Thomas"
                            5 => "A&#46;G&#46; Chapuis"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "J Am Acad Dermatol&#46;"
                        "fecha" => "2018"
                        "volumen" => "78"
                        "paginaInicial" => "457"
                        "paginaFinal" => "463"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            6 => array:3 [
              "identificador" => "bib0330"
              "etiqueta" => "7"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Incidence and survival for Merkel cell carcinoma in Queensland"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "D&#46;R&#46; Youlden"
                            1 => "H&#46;P&#46; Soyer"
                            2 => "P&#46;H&#46; Youl"
                            3 => "L&#46; Fritschi"
                            4 => "P&#46;D&#46; Baade"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Australia&#44; 1993&#8208;2010&#46; JAMA Dermatol&#46;"
                        "fecha" => "2014"
                        "volumen" => "150"
                        "paginaInicial" => "864"
                        "paginaFinal" => "872"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            7 => array:3 [
              "identificador" => "bib0335"
              "etiqueta" => "8"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Merkel Cell Carcinoma&#44; Version 1&#46;2018"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "C&#46;K&#46; Bichakjian"
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Educação médica continuada
Carcinoma de células de Merkel: epidemiologia, características clínicas, diagnóstico e tratamento de doença rara
Stella Meireles Siqueiraa,
Corresponding author
stellamsiqueira@gmail.com

Autor para correspondência.
, Gabriella Campos‐do‐Carmob, Alexssandra Lima Siqueira dos Santosa, Cícero Martinsc, Andreia Cristina de Meloa
a Divisão de Pesquisa Clínica, Instituto Nacional de Câncer, Rio de Janeiro, RJ, Brasil
b Gávea Medical Center, Rio de Janeiro, RJ, Brasil
c Serviço de Oncologia, Instituto Nacional de Câncer, Rio de Janeiro, RJ, Brasil
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o que corresponde a uma taxa de incid&#234;ncia semelhante a&#160;0&#44;7&#47;100&#46;000&#160;pessoas&#8208;ano&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">6</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Maior incid&#234;ncia de CCM foi observada em estudo australiano&#44; com taxa de&#160;1&#44;6&#47;100&#46;000&#160;habitantes no estado de Queensland entre&#160;2006&#160;e&#160;2010&#44; mais frequente no sexo masculino &#40;2&#44;5&#47;100&#46;000&#41; do que no feminino &#40;0&#44;9&#47;100&#46;000&#41; e com expectativa de vida m&#233;dia de&#160;75&#44;5&#160;anos para homens e&#160;78&#160;anos para mulheres no momento do diagn&#243;stico&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">7</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Embora rara&#44; a incid&#234;ncia de CCM cresceu drasticamente&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">8</span></a> Em&#160;2018&#44; 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epidemiologia do CCM no Brasil&#44; Melo et al&#46; publicaram um estudo com dados coletados dos Registros de C&#226;ncer de Base Populacional &#40;2000&#8208;2015&#41; e de Base Hospitalar &#40;2000&#8208;2017&#41;&#46; Foram analisados&#160;881&#160;pacientes com a doen&#231;a&#59; a maioria era do sexo feminino &#40;51&#44;2&#37;&#41;&#44; com idade maior que&#160;60&#160;anos&#160;&#40;82&#44;2&#37;&#41;&#44; de cor branca&#160;&#40;67&#44;6&#37;&#41; e com diagn&#243;stico predominantemente nos est&#225;dios&#160;III ou&#160;IV &#40;50&#44;5&#37;&#41;&#46; Al&#233;m disso&#44; constatou&#8208;se que as taxas m&#233;dias de incid&#234;ncia padronizadas por idade aumentaram significantemente em homens entre os anos de&#160;2000 &#40;0&#44;31&#47;1&#46;000&#46;000&#41; e 2015 &#40;1&#44;21&#47;1&#46;000&#46;000&#41;&#44; com varia&#231;&#227;o percentual anual de&#160;9&#44;4 &#40;95&#37;IC&#160;4&#44;7&#37;&#8208;14&#44;4&#37;&#59; p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#41;&#46; 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importante fator de risco&#44;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">13&#44;14</span></a> corroborado pela maior incid&#234;ncia de CCM em regi&#245;es com maior &#237;ndice de radia&#231;&#227;o ultravioleta<a class="elsevierStyleCrossRefs" href="#bib0330"><span class="elsevierStyleSup">7&#44;8</span></a> e pela maior tend&#234;ncia a ocorrer em &#225;reas fotoexpostas&#44; como regi&#227;o de cabe&#231;a e pesco&#231;o&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">15</span></a> Lunder et al&#46; tamb&#233;m mostraram maior ocorr&#234;ncia de CCM em pacientes com hist&#243;ria de uso de psoralenos e exposi&#231;&#227;o da pele &#224; radia&#231;&#227;o ultravioleta de ondas longas&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">16</span></a> O CCM &#233; mais frequente em pacientes caucasianos em compara&#231;&#227;o com outras etnias&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">8</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">A imunossupress&#227;o tamb&#233;m &#233; fator de risco&#59;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">13</span></a> portanto&#44; o CCM &#233; mais comum em pacientes transplantados&#44; com diagn&#243;stico de neoplasias linfoproliferativas &#40;como a leucemia linfoc&#237;tica cr&#244;nica&#41; ou em portadores do v&#237;rus HIV&#46;<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">8&#44;14</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">Al&#233;m disso&#44; idade avan&#231;ada tamb&#233;m &#233; considerada fator de risco&#46;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">13&#44;15</span></a> Em uma s&#233;rie dos EUA&#44; 90&#37;&#160;de todos os pacientes com CCM estavam acima de&#160;50&#160;anos&#44; 76&#37;&#160;acima de&#160;65&#160;anos e 49&#37;&#160;acima de&#160;75&#160;anos&#46;<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">8&#44;15</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">Em&#160;2008&#44; Feng et al&#46; descreveram pela primeira vez a associa&#231;&#227;o entre um novo poliomav&#237;rus e o CCM&#44; identificando o DNA do v&#237;rus em&#160;8&#160;de&#160;10&#160;tumores de Merkel&#44; sugerindo que a infec&#231;&#227;o viral poderia ser um evento precoce na patog&#234;nese&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">11</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Poliomav&#237;rus associado ao carcinoma de c&#233;lulas de Merkel</span><p id="par0055" class="elsevierStylePara elsevierViewall">A descoberta do poliomav&#237;rus associado ao CCM&#44; em&#160;2008&#44; revolucionou os conhecimentos sobre a patog&#234;nese desse tumor&#44; ent&#227;o denominado <span class="elsevierStyleItalic">Merkel cell polyomavirus</span> &#40;MCPyV&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">11</span></a> A associa&#231;&#227;o foi identificada usando&#8208;se t&#233;cnica de subtra&#231;&#227;o de transcriptoma digital&#44; que &#233; um m&#233;todo de bioinform&#225;tica para detectar a presen&#231;a de novos transcritos de pat&#243;genos por meio da remo&#231;&#227;o computacional das sequ&#234;ncias do hospedeiro&#46; Ent&#227;o&#44; nesse caso&#44; sequ&#234;ncias humanas conhecidas foram filtradas para identificar potenciais transcritos virais&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">3</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">Os casos de infec&#231;&#227;o subcl&#237;nica por MCPyV aumentam de acordo com a senesc&#234;ncia&#44; atingindo preval&#234;ncia de&#160;60&#37;&#160;a&#160;80&#37; em adultos&#46; No entanto&#44; isso pode diferir significantemente em outras regi&#245;es geogr&#225;ficas&#44; como a Austr&#225;lia&#44; onde foi relatada associa&#231;&#227;o muito menor com infec&#231;&#227;o viral&#44; em torno de&#160;25&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">17</span></a> A pele constitui o maior s&#237;tio da infec&#231;&#227;o viral&#44; apesar de o v&#237;rus ter sido detectado tamb&#233;m no sangue perif&#233;rico e em outros &#243;rg&#227;os&#46; A infec&#231;&#227;o pelo MCPyV parece ser assintom&#225;tica&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">3</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">A fam&#237;lia Polyomaviridae&#44; a qual o MCPyV pertence&#44; &#233; composta por pequenos v&#237;rus de DNA dupla&#8208;h&#233;lice&#46; Ela inclui outros poliomav&#237;rus associados com infec&#231;&#227;o cut&#226;nea em humanos &#40;poliomav&#237;rus da Tricodisplasia Spinulosa&#44; poliomav&#237;rus humano&#160;6 e poliomav&#237;rus humano&#160;7&#41; ou doen&#231;as em outros &#243;rg&#227;os e sistemas &#40;como o v&#237;rus JC&#44; um poliomav&#237;rus humano ub&#237;quo que causa doen&#231;as do sistema nervoso central em pacientes imunocomprometidos&#44; incluindo leucoencefalopatia multifocal progressiva&#44; neuropatia de c&#233;lulas granulares e encefalopatia pelo v&#237;rus JC&#41;&#46; At&#233; a presente data&#44; o MCPyV &#233; o &#250;nico oncov&#237;rus humano da fam&#237;lia Polyomaviridae&#44; mas o motivo desse <span class="elsevierStyleItalic">status</span> distinto ainda n&#227;o &#233; conhecido&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">3</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">O tipo espec&#237;fico de c&#233;lula hospedeira para a infec&#231;&#227;o por esse poliomav&#237;rus ainda permanece incerto&#46; Acredita&#8208;se que as c&#233;lulas de Merkel n&#227;o sejam suficientemente numerosas para explicar a carga viral normalmente detectada na pele&#44; e os mon&#243;citos no sangue perif&#233;rico t&#234;m sido apontados como poss&#237;vel reservat&#243;rio de c&#233;lulas infectadas&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">3</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">O genoma viral epissomal apresenta regi&#245;es precoces e tardias&#46; As primeiras t&#234;m genes que codificam prote&#237;nas respons&#225;veis por coordenar a replica&#231;&#227;o viral&#44; enquanto as regi&#245;es tardias est&#227;o ligadas &#224;s prote&#237;nas do caps&#237;deo viral&#46; Parece que a integra&#231;&#227;o do DNA do MCPyV no genoma do hospedeiro ocorre logo ap&#243;s a infec&#231;&#227;o&#46;<a class="elsevierStyleCrossRefs" href="#bib0310"><span class="elsevierStyleSup">3&#44;18</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">Imuno&#8208;histoqu&#237;mica&#44; PCR&#44; hibridiza&#231;&#227;o <span class="elsevierStyleItalic">in situ</span> de DNA ou tecnologias de sequenciamento de nova gera&#231;&#227;o s&#227;o m&#233;todos dispon&#237;veis para detectar MCPyV em tumores&#44; mas esses testes variam muito em sensibilidade e especificidade&#46; O desenvolvimento de um anticorpo monoclonal usado para detec&#231;&#227;o espec&#237;fica do ant&#237;geno T grande &#40;LT&#41; por meio da imuno&#8208;histoqu&#237;mica &#8208; exclusivo para o MCPyV &#40;o clone CM2B4&#41; &#8208; possibilitou a detec&#231;&#227;o e visualiza&#231;&#227;o de MCPyV <span class="elsevierStyleItalic">in situ</span>&#46; Esse m&#233;todo est&#225; dispon&#237;vel comercialmente e tem aproximadamente 88&#37; de sensibilidade e 94&#37; de especificidade&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">3</span></a> A <a class="elsevierStyleCrossRef" href="#fig0005">figura 1</a> demonstra exemplos de resultados de imuno&#8208;histoqu&#237;mica positivo e negativo para o poliomav&#237;rus de c&#233;lulas de Merkel realizada utilizando o anticorpo anti&#8208;MCPyV large T&#8208;antigen &#40;CM2B4&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Caracter&#237;sticas cl&#237;nicas</span><p id="par0085" class="elsevierStylePara elsevierViewall">Clinicamente&#44; o CCM pode se apresentar como n&#243;dulo cut&#226;neo ou subcut&#226;neo&#44; e at&#233; mesmo ter aspecto c&#237;stico&#46; A cor pode variar entre vermelho&#44; rosa&#44; azul&#44; violeta ou cor da pele&#46; Inicialmente&#44; as les&#245;es s&#227;o geralmente indolores e solit&#225;rias&#44; mas tamb&#233;m podem ulcerar ou ser circundadas por les&#245;es sat&#233;lites&#46; No diagn&#243;stico&#44; as dimens&#245;es podem variar em tamanho&#44; mas costumam ser menores que&#160;20&#160;mm&#44; e a maioria dos casos apresenta crescimento r&#225;pido do tumor em poucos meses &#40;<a class="elsevierStyleCrossRef" href="#fig0010">fig&#46; 2</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">15</span></a></p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0090" class="elsevierStylePara elsevierViewall">As les&#245;es geralmente aparecem em &#225;reas fotoexpostas&#44; enquanto&#160;19&#37; aparecem nas n&#225;degas ou em &#225;reas minimamente expostas ao sol&#46; Os s&#237;tios anat&#244;micos prim&#225;rios mais frequentes s&#227;o cabe&#231;a e pesco&#231;o&#160;&#40;29&#37;&#41;&#44; seguidos por membros inferiores&#160;&#40;24&#37;&#41; e membros superiores&#160;&#40;21&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">15</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">Heath et al&#46;&#44; em&#160;2008&#44; propuseram a regra mnem&#244;nica &#8220;AEIOU&#8221; &#40;<span class="elsevierStyleItalic">Assintomatic&#47;lack of tenderness&#44; Expandig rapidly&#44; Immune suppression&#44; Older than&#160;50&#160;years&#44; and Ultraviolet exposed site</span>&#41; a partir da an&#225;lise de&#160;195&#160;casos&#44; na tentativa de auxiliar o diagn&#243;stico&#46; Nessa coorte&#44; 89&#37;&#160;dos pacientes com diagn&#243;stico de CCM preencheram&#160;tr&#234;s&#160;ou mais crit&#233;rios&#44; 52&#37;&#160;dos pacientes preencheram&#160;quatro&#160;ou mais crit&#233;rios e 7&#37;&#160;dos pacientes preencheram todos os&#160;cinco&#160;crit&#233;rios&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">15</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">No momento do diagn&#243;stico&#44; at&#233;&#160;37&#37; dos pacientes apresentam doen&#231;a nodal e&#160;6&#37;&#8208;12&#37; apresentam&#8208;se com doen&#231;a metast&#225;tica&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">19</span></a> Cerca de&#160;15&#37; dos pacientes t&#234;m um linfonodo acometido pela doen&#231;a sem identificar les&#227;o cut&#226;nea&#44; provavelmente refletindo a regress&#227;o do s&#237;tio prim&#225;rio&#46;<a class="elsevierStyleCrossRefs" href="#bib0310"><span class="elsevierStyleSup">3&#44;15</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">As met&#225;stases a dist&#226;ncia aparecem com mais frequ&#234;ncia em linfonodos n&#227;o regionais&#44; pele&#44; ossos&#44; pulm&#245;es e pleura ou f&#237;gado e&#44; menos comumente&#44; p&#226;ncreas&#44; gl&#226;ndulas suprarrenais&#44; c&#233;rebro&#44; rins&#44; tecido subcut&#226;neo ou m&#250;sculo&#46; Os locais raros de met&#225;stases incluem mama&#44; trato gastrintestinal&#44; test&#237;culos&#44; cora&#231;&#227;o&#44; retroperit&#244;nio e perit&#244;nio&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">14</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Diagn&#243;stico</span><p id="par0110" class="elsevierStylePara elsevierViewall">Em decorr&#234;ncia da falta de caracter&#237;sticas e de sintomas espec&#237;ficos&#44; o diagn&#243;stico torna&#8208;se um desafio&#46; Assim&#44; o exame histopatol&#243;gico por patologista experiente e a colora&#231;&#227;o com marcadores imuno&#8208;histoqu&#237;micos espec&#237;ficos s&#227;o essenciais nesse processo&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">3</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">A organiza&#231;&#227;o americana National Comprehensive Cancer Network &#40;NCCN&#41; prop&#244;s algoritmos espec&#237;ficos para o diagn&#243;stico de CCM&#44; que incluem as seguintes estrat&#233;gias&#58; 1&#41;&#160;exame completo de pele e linfonodos&#59; 2&#41;&#160;bi&#243;psia para an&#225;lise histopatol&#243;gica e imuno&#8208;histoqu&#237;mica&#59; 3&#41;&#160;bi&#243;psia de linfonodo sentinela &#40;BLS&#41; para pacientes sem linfonodos clinicamente positivos&#44; precedendo a excis&#227;o&#44; se poss&#237;vel&#59; 4&#41;&#160;aspira&#231;&#227;o por agulha fina ou bi&#243;psia linfonodal para pacientes com linfonodos clinicamente positivos&#59; considerar bi&#243;psia aberta&#59; 5&#41;&#160;exames de imagem para estadiamento&#44; conforme indica&#231;&#227;o cl&#237;nica&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">14</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">A dermatoscopia &#233; um exame complementar que pode ser &#250;til em alguns casos&#44; mas ainda faltam descri&#231;&#245;es dermatosc&#243;picas mais completas na literatura&#46; O CCM geralmente exibe uma variedade de padr&#245;es vasculares dermatosc&#243;picos&#44; mais comumente &#225;reas&#47;gl&#243;bulos vermelho&#8208;leitosos&#44; vasos polim&#243;rficos e vasos lineares irregulares&#44;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">20</span></a> refletindo o r&#225;pido crescimento do tumor&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">A colora&#231;&#227;o com hematoxilina &#38; eosina revela a prolifera&#231;&#227;o de pequenas c&#233;lulas tumorais basof&#237;licas na derme e&#47;ou hipoderme&#44;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">21</span></a> com citoplasma escasso&#44; mitoses abundantes e gr&#226;nulos citoplasm&#225;ticos densos&#46; C&#233;lulas necr&#243;ticas tamb&#233;m s&#227;o comuns&#46;<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">8&#44;20</span></a> Exemplos da histopatologia est&#227;o representados na <a class="elsevierStyleCrossRef" href="#fig0015">figura 3</a>&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0130" class="elsevierStylePara elsevierViewall">A citoqueratina&#160;20 &#40;CK20&#41; e marcadores neuroend&#243;crinos&#44; como cromogranina A&#44; sinaptofisina&#44; CD56&#44; enolase neur&#244;nio&#8208;espec&#237;fica e neurofilamento s&#227;o expressos no CCM&#46;<span class="elsevierStyleSup">3&#44;14&#44;21</span> A imunopositividade paranuclear semelhante a pontos para CK20 &#233; altamente sugestiva&#44; enquanto os marcadores neuroend&#243;crinos n&#227;o s&#227;o espec&#237;ficos&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">3</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">Para pacientes com linfonodos clinicamente negativos&#44; a BLS deve ser realizada e sua taxa de positividade varia de&#160;30&#37;&#160;a&#160;38&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">14</span></a> Quando negativo&#44; menor risco de recorr&#234;ncia&#44;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">22</span></a> melhor sobrevida livre de doen&#231;a &#40;SLD&#41; e sobrevida global &#40;SG&#41; s&#227;o observados&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">14</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall">O uso de exames de imagens para investiga&#231;&#227;o diagn&#243;stica de pacientes com CCM ainda est&#225; em discuss&#227;o&#46; O NCCN n&#227;o recomenda exames de imagem em pacientes sem suspeita cl&#237;nica de linfonodos acometidos&#46; A BLS &#233; considerada o teste mais confi&#225;vel para identificar met&#225;stases em linfonodos n&#227;o clinicamente suspeitos&#46; A resson&#226;ncia magn&#233;tica cerebral&#44; as tomografias computadorizadas &#40;TC&#41; de pesco&#231;o&#44; t&#243;rax&#44; abdome e pelve ou PET&#8208;CT s&#227;o indicadas para planejamento cir&#250;rgico ou quando houver suspeita de tumor irressec&#225;vel ou met&#225;stases a dist&#226;ncia&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">14</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">Gupta et al&#46; mostraram que a TC tem baixa sensibilidade &#40;em torno de&#160;20&#37;&#41; para detec&#231;&#227;o de met&#225;stases linfonodais e baixa especificidade para met&#225;stases a dist&#226;ncia&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">22</span></a> Portanto&#44; embora a TC tenha sido usada como ferramenta de triagem para met&#225;stases regionais ou a dist&#226;ncia em CCM&#44; os dados que suportam sua aplica&#231;&#227;o s&#227;o limitados&#46;<a class="elsevierStyleCrossRefs" href="#bib0365"><span class="elsevierStyleSup">14&#44;22</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">O PET&#8208;CT tem sido amplamente estudado em pacientes com CCM&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">14</span></a> Colgan et al&#46; avaliaram retrospectivamente&#160;36&#160;pacientes com CCM que realizaram exames de PET&#8208;CT antes da BLS e observaram&#160;83&#37;&#160;e&#160;95&#37;&#160;de sensibilidade e especificidade&#44; respectivamente&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">23</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Diagn&#243;stico diferencial</span><p id="par0155" class="elsevierStylePara elsevierViewall">Clinicamente&#44; os diagn&#243;sticos diferenciais para CCM s&#227;o les&#245;es benignas da pele&#44; como cisto acneiforme&#44; lipoma&#44; dermatofibroma ou fibroma e les&#227;o vascular&#46; Les&#245;es malignas representadas por c&#226;ncer de pele n&#227;o melanoma&#44; linfoma cut&#226;neo&#44; carcinoma metast&#225;tico e sarcoma tamb&#233;m devem ser consideradas diagn&#243;sticos diferenciais&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">15</span></a></p><p id="par0160" class="elsevierStylePara elsevierViewall">Histologicamente&#44; o diagn&#243;stico tamb&#233;m pode ser um desafio&#44; pois o CCM &#233; semelhante a uma variedade de outros tumores que t&#234;m c&#233;lulas azuis pequenas e arredondadas&#44; incluindo linfomas&#44; melanoma amelan&#243;tico&#44; met&#225;stases cut&#226;neas de carcinoma de c&#233;lulas pequenas de pulm&#227;o<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">3</span></a> e outros carcinomas metast&#225;ticos &#40;neuroblastoma&#44; rabdomiossarcoma&#44; tumor desmopl&#225;sico de pequenas c&#233;lulas&#44; condrossarcoma mesenquimal&#44; sarcoma de <span class="elsevierStyleItalic">Ewing</span> e osteossarcoma&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">8</span></a> O CCM <span class="elsevierStyleItalic">in situ</span>&#44; no qual as c&#233;lulas neopl&#225;sicas s&#227;o limitadas &#224; epiderme e&#47;ou epit&#233;lio folicular&#44; pode ser confundido com carcinoma de c&#233;lulas escamosas <span class="elsevierStyleItalic">in situ</span>&#44; melanoma <span class="elsevierStyleItalic">in situ</span> ou outra neoplasia intraepid&#233;rmica pagetoide&#46;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">20</span></a></p><p id="par0165" class="elsevierStylePara elsevierViewall">Em decorr&#234;ncia dos aspectos morfol&#243;gicos similares&#44; o diagn&#243;stico diferencial mais desafiador &#233; o c&#226;ncer de pulm&#227;o de pequenas c&#233;lulas metast&#225;tico<a class="elsevierStyleCrossRefs" href="#bib0310"><span class="elsevierStyleSup">3&#44;8</span></a> que exige painel de marcadores imuno&#8208;histoqu&#237;micos para definir o diagn&#243;stico&#46; CK20 e o fator de transcri&#231;&#227;o da tireoide&#160;1 &#40;TTF&#8208;1&#41; t&#234;m maior sensibilidade e especificidade para excluir c&#226;ncer de pulm&#227;o de pequenas c&#233;lulas&#59;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">8</span></a> CK20 &#233; positivo em&#160;70&#37;&#160;a&#160;100&#37; do CCM e negativo em c&#226;ncer de pulm&#227;o de pequenas c&#233;lulas&#44; enquanto TTF&#8208;1 &#233; sempre negativo em CCM e positivo em mais de&#160;80&#37; dos c&#226;nceres de pulm&#227;o de pequenas c&#233;lulas&#46;<span class="elsevierStyleSup">3&#44;8&#44;14</span></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Estadiamento</span><p id="par0170" class="elsevierStylePara elsevierViewall">A atual&#160;8&#170;&#160;edi&#231;&#227;o do sistema de estadiamento do American Joint Committee on Cancer &#40;AJCC&#41; &#233; baseada em uma an&#225;lise atualizada de 9&#46;387&#160;casos de CCM do National Cancer Database&#44; com acompanhamento m&#233;dio de 28&#44;2 meses &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">tabela 1</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">24</span></a> De acordo com o AJCC&#44; os seguintes par&#226;metros s&#227;o necess&#225;rios para o estadiamento do CCM T&#58; 1&#41;&#160;di&#226;metro m&#225;ximo do tumor medido clinicamente&#44; antes da ressec&#231;&#227;o e 2&#41;&#160;extens&#227;o do tumor &#40;f&#225;scia&#44; m&#250;sculo&#44; cartilagem ou invas&#227;o &#243;ssea&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">24</span></a> O di&#226;metro do tumor tem valor progn&#243;stico&#44; estando significantemente associado ao envolvimento de linfonodos&#44; sobrevida doen&#231;a&#8208;espec&#237;fica &#40;SDE&#41; e SG&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">14</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0175" class="elsevierStylePara elsevierViewall">O CCM &#233; caracteristicamente um tumor agressivo e localmente invasivo&#44; com alta incid&#234;ncia de recorr&#234;ncia local e envolvimento de linfonodos regionais&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">1</span></a> A BLS &#233; importante ferramenta de estadiamento recomendada para todos os pacientes com linfonodo clinicamente negativo&#44; sempre que poss&#237;vel&#44; para realizar o estadiamento nodal patol&#243;gico&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">14</span></a></p><p id="par0180" class="elsevierStylePara elsevierViewall">De acordo com a&#160;8&#170;&#160;edi&#231;&#227;o do sistema de estadiamento AJCC&#44; as estimativas de SG de cinco anos para o estadiamento cl&#237;nico e patol&#243;gico da doen&#231;a local foram&#160;45&#44;0&#37;&#160;e&#160;62&#44;8&#37; para o est&#225;dio&#160;I&#59; 30&#44;9&#37;&#160;e&#160;54&#44;6&#37; para o est&#225;dio IIA e 27&#44;3&#37;&#160;e&#160;34&#44;8&#37; para o est&#225;dio&#160;IIB&#44; respectivamente&#46; A SG de&#160;cinco&#160;anos para o est&#225;dio&#160;IIIA revisado foi de 40&#44;3&#37;&#44; enquanto para o est&#225;dio&#160;IIIB foi de&#160;26&#44;8&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">24</span></a> Na doen&#231;a em est&#225;dio&#160;IV&#44; a taxa de sobrevida de&#160;dois&#160;anos &#233; de&#160;apenas&#160;26&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">1</span></a></p><p id="par0185" class="elsevierStylePara elsevierViewall">Sihto et al&#46;&#44; em&#160;2009&#44; relataram que os CCM positivos para o poliomav&#237;rus apresentaram maior taxa de sobrevida em compara&#231;&#227;o com os tumores negativos para esse v&#237;rus&#59; a sobrevida em cinco anos foi de&#160;45&#37;&#160;<span class="elsevierStyleItalic">vs</span>&#46;&#160;13&#37; &#40;p&#8208;valor<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;01&#41;&#44; respectivamente&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">12</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Tratamento</span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Cirurgia para o tumor prim&#225;rio</span><p id="par0190" class="elsevierStylePara elsevierViewall">A cirurgia &#233; a modalidade de tratamento inicial para a maioria dos casos de CCM&#46; A defini&#231;&#227;o das margens cir&#250;rgicas ainda &#233; um tema controverso&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">14</span></a> O objetivo do tratamento cir&#250;rgico &#233; uma margem histol&#243;gica negativa e&#44; em geral&#44; a excis&#227;o cir&#250;rgica com margens de&#160;1&#160;cm&#160;a&#160;2&#160;cm continua a ser o primeiro passo no manejo do tumor&#46;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">25</span></a> Boyer et al&#46; analisaram&#160;45&#160;pacientes com CCM em est&#225;dio&#160;I e relataram margem mediana de&#160;16&#44;7&#160;mm de pele clinicamente normal necess&#225;ria para a aus&#234;ncia de envolvimento histol&#243;gico&#46;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">26</span></a></p><p id="par0195" class="elsevierStylePara elsevierViewall">Um estudo de&#160;1&#46;795&#160;pacientes com CCM est&#225;dios&#160;I&#160;e&#160;II n&#227;o mostrou diferen&#231;as entre a excis&#227;o cir&#250;rgica ampla e a cirurgia microgr&#225;fica de Mohs em rela&#231;&#227;o &#224; presen&#231;a de tumor residual nas margens cir&#250;rgicas&#44; e nenhuma diferen&#231;a na SG entre as duas modalidades de tratamento foi encontrada&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">27</span></a> As margens histologicamente negativas est&#227;o relacionadas ao melhor controle local e sobrevida&#44; principalmente nos casos de doen&#231;a localizada tratada apenas com cirurgia&#46; Em todos os casos de tratamento cir&#250;rgico&#44; a BLS deve ser planejada antes da excis&#227;o definitiva&#44; pois a cirurgia pode alterar a drenagem linf&#225;tica&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">14</span></a></p><p id="par0200" class="elsevierStylePara elsevierViewall">Santamaria&#8208;Barria et al&#46; elucidaram o papel da BLS no manejo do CCM em uma revis&#227;o de&#160;161&#160;pacientes&#44; tendo identificado micromet&#225;stases em 1&#47;3 deles&#46;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">28</span></a> Assim&#44; ap&#243;s verifica&#231;&#227;o de margens livres e&#44; se indicado BLS&#44; o desafio &#233; determinar se deve ou n&#227;o oferecer tratamento adjuvante&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Radioterapia</span><p id="par0205" class="elsevierStylePara elsevierViewall">A radioterapia &#40;RT&#41; tem papel importante no tratamento do CCM&#46; O CCM &#233; uma neoplasia radiossens&#237;vel&#44; e a RT pode ser considerada terapia prim&#225;ria em pacientes que n&#227;o s&#227;o candidatos &#224; cirurgia&#46;<a class="elsevierStyleCrossRefs" href="#bib0440"><span class="elsevierStyleSup">29&#44;30</span></a> Embora a RT por si s&#243; seja inferior &#224; ressec&#231;&#227;o cir&#250;rgica em raz&#227;o do risco de recorr&#234;ncia de CCM a dist&#226;ncia&#44; ela pode ser usada quando a cirurgia &#233; contraindicada<a class="elsevierStyleCrossRefs" href="#bib0450"><span class="elsevierStyleSup">31&#8211;33</span></a> com bom controle locorregional e SG em&#160;cinco&#160;anos de at&#233;&#160;40&#37;&#160;a&#160;60&#37; em pacientes com met&#225;stases macrosc&#243;picas prim&#225;rias e&#47;ou nodais&#46;<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">33</span></a></p><p id="par0210" class="elsevierStylePara elsevierViewall">Em rela&#231;&#227;o a seu uso como terapia adjuvante&#44; os dados s&#227;o conflitantes&#46; A RT adjuvante p&#243;s&#8208;operat&#243;ria parece aumentar o controle local do tumor&#44; mas n&#227;o tem impacto significante na sobrevida global relacionada ao tumor&#46;<a class="elsevierStyleCrossRefs" href="#bib0465"><span class="elsevierStyleSup">34&#44;35</span></a> Em uma revis&#227;o com casos de CCM apenas de cabe&#231;a e pesco&#231;o&#44; a RT adjuvante apresentou benef&#237;cio significante na sobrevida em rela&#231;&#227;o &#224; cirurgia sozinha&#44; e a quimioterapia &#40;QT&#41; associada &#224; RT ofereceu vantagem sobre a RT sozinha em casos de tumores grandes &#40;&#62; 3&#160;cm&#41; ou margens positivas&#46;<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">36</span></a> Uma an&#225;lise retrospectiva de CCM est&#225;dios&#160;I&#160;a&#160;III mostrou baixa taxa de recorr&#234;ncia &#40;3&#37;&#41; em pacientes com linfonodo clinicamente negativo tratados com cirurgia adequada &#40;incluindo BLS&#41; e o uso seletivo de RT adjuvante para tumores de alto risco&#44; incluindo invas&#227;o linfovascular&#59; segunda malignidade &#40;leucemia&#47;linfoma&#41; no momento do diagn&#243;stico&#44; m&#250;ltiplos linfonodos positivos e extens&#227;o extracapsular&#59; tumores&#160;&#62;<span class="elsevierStyleHsp" style=""></span>2&#160;cm&#46; Os autores tamb&#233;m concluem que&#44; com cirurgia adequada&#44; &#233; improv&#225;vel que o uso rotineiro de RT local adjuvante seja ben&#233;fico para a grande maioria dos pacientes&#46;<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">37</span></a> Al&#233;m disso&#44; alguns dados sugeriram que a RT adjuvante pode ser omitida para aqueles com pequenos tumores prim&#225;rios &#40;&#60; 1&#160;cm&#41;&#44; margens cir&#250;rgicas livres&#44; BLS negativa e aus&#234;ncia de fatores de mau progn&#243;stico&#44; como invas&#227;o linfovascular e imunodefici&#234;ncia&#46;<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">38</span></a></p><p id="par0215" class="elsevierStylePara elsevierViewall">Uma an&#225;lise retrospectiva de&#160;46&#160;casos de CCM de cabe&#231;a e pesco&#231;o de baixo risco tratados entre&#160;2006&#160;e&#160;2015 demonstrou que a n&#227;o realiza&#231;&#227;o da RT p&#243;s&#8208;operat&#243;ria foi associada a risco significantemente maior de recorr&#234;ncia local &#40;recorr&#234;ncia local em&#160;cinco&#160;anos de&#160;26&#37; no grupo tratado sem RT adjuvante <span class="elsevierStyleItalic">versus</span>&#160;0&#37; no grupo que recebeu RT adjuvante&#59; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;02&#41;&#46; Os pacientes foram considerados de baixo risco em caso de tumor prim&#225;rio&#160;&#8804; 2&#44;0&#160;cm de di&#226;metro&#44; margens microscopicamente negativas na excis&#227;o cir&#250;rgica&#44; BLS negativa e aus&#234;ncia de imunossupress&#227;o cr&#244;nica&#46;<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">39</span></a></p><p id="par0220" class="elsevierStylePara elsevierViewall">Jouary Y et al&#46; mostraram redu&#231;&#227;o significante na recorr&#234;ncia local sem melhora da sobrevida global com RT adjuvante em estudo realizado antes da introdu&#231;&#227;o da BLS no tratamento do CCM&#46;<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">40</span></a></p><p id="par0225" class="elsevierStylePara elsevierViewall">Em uma coorte retrospectiva e n&#227;o randomizada de&#160;6&#46;908&#160;casos do National Cancer Database dos EUA&#44; a RT adjuvante foi associada a melhora da sobrevida em pacientes com CCM localizado &#40;est&#225;dios&#160;I&#160;e&#160;II&#41; em compara&#231;&#227;o com pacientes que passaram apenas pelo tratamento cir&#250;rgico &#40;est&#225;dio&#160;I&#58; <span class="elsevierStyleItalic">hazard ratio</span> &#91;HR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;71&#93;&#59; 95&#37;IC 0&#44;64&#37;&#8208;0&#44;80&#37;&#59; p &#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#59; est&#225;dio&#160;II&#58; HR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;77&#59; 95&#37;IC&#160;0&#44;66&#37;&#8208;0&#44;89&#37;&#59; p &#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#41;&#46; No entanto&#44; em pacientes com envolvimento nodal &#40;est&#225;dio&#160;III&#41;&#44; n&#227;o houve diferen&#231;a estatisticamente significante na SG entre os pacientes que tiveram cirurgia seguida de RT em compara&#231;&#227;o com a cirurgia isolada &#40;HR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;98&#59; 95&#37;IC 0&#44;86&#37;&#8208;1&#44;12&#59; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;80&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">41</span></a></p><p id="par0230" class="elsevierStylePara elsevierViewall">Em contraste&#44; um estudo retrospectivo do Moffitt Cancer Center&#44; avaliando&#160;171&#160;pacientes&#44; encontrou melhora no controle locorregional e SG entre pacientes com linfonodos patologicamente ou clinicamente positivos tratados com RT p&#243;s&#8208;operat&#243;ria&#46; Nessa publica&#231;&#227;o&#44; os pacientes foram tratados com excis&#227;o local ampla &#40;margens de&#160;1&#8208;2&#160;cm&#41; e todos realizaram estadiamento nodal&#46;<a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">42</span></a></p><p id="par0235" class="elsevierStylePara elsevierViewall">Assim&#44; o NCCN incluiu a RT como op&#231;&#227;o de tratamento adjuvante para todos os est&#225;dios do CCM e&#44; idealmente&#44; deve ser realizada em&#160;quatro&#160;a&#160;seis&#160;semanas ap&#243;s a cirurgia&#44; pois o atraso tem sido associado a piores desfechos&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">14</span></a></p></span></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Tratamento sist&#234;mico</span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Quimioterapia</span><p id="par0240" class="elsevierStylePara elsevierViewall">O papel da QT adjuvante para o CCM &#233; menos definido&#46; Hasan et al&#46; realizaram uma grande revis&#227;o sistem&#225;tica e notaram que a RT adjuvante resultou em taxas de controle local em&#160;tr&#234;s&#160;anos significantemente maiores&#44; taxas de recorr&#234;ncia diminu&#237;das e taxas de SG melhores em&#160;tr&#234;s&#160;anos&#44; enquanto a QT adjuvante n&#227;o ofereceu nenhum benef&#237;cio&#46;<a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">43</span></a> Al&#233;m disso&#44; estudos adicionais sugerem que o efeito da QT adjuvante na recorr&#234;ncia n&#227;o &#233; claro ou que n&#227;o h&#225; melhora significante na sobrevida quando comparada &#224; RT adjuvante isolada&#46;<a class="elsevierStyleCrossRefs" href="#bib0440"><span class="elsevierStyleSup">29&#44;44&#44;45</span></a></p><p id="par0245" class="elsevierStylePara elsevierViewall">Por muitos anos&#44; a QT foi a &#250;nica op&#231;&#227;o dispon&#237;vel como tratamento para a doen&#231;a avan&#231;ada&#46; O CCM &#233; considerado tumor quimiossens&#237;vel&#44; e esquemas de platina com etopos&#237;deo ou taxanos e antraciclinas isoladas ou em combina&#231;&#227;o s&#227;o inicialmente eficazes&#44; com taxa de resposta de at&#233;&#160;75&#37;&#44; mas geralmente a dura&#231;&#227;o da resposta &#233; curta&#44; n&#227;o resultando em benef&#237;cio de sobrevida&#46; A sobrevida livre de progress&#227;o &#40;SLP&#41; mediana varia de&#160;tr&#234;s&#160;a&#160;oito&#160;meses&#44; e a dura&#231;&#227;o da resposta parcial &#233; de apenas&#160;tr&#234;s&#160;meses para a terapia de primeira linha&#46;<a class="elsevierStyleCrossRefs" href="#bib0420"><span class="elsevierStyleSup">25&#44;46</span></a> Dada a idade avan&#231;ada de muitos pacientes e suas comorbidades&#44; a toxicidade da QT pode afetar gravemente a qualidade de vida&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Imunoterapia</span><p id="par0250" class="elsevierStylePara elsevierViewall">As imunoterapias est&#227;o atualmente em foco&#44; uma vez que foi descrita a import&#226;ncia do sistema imunol&#243;gico no controle do CCM&#59; os inibidores de PD&#8208;1 &#40;<span class="elsevierStyleItalic">programmed cell death&#160;1</span>&#41; e PD&#8208;L1 &#40;<span class="elsevierStyleItalic">programmed cell death protein ligand&#160;1</span>&#41; s&#227;o op&#231;&#245;es promissoras nos casos de doen&#231;a metast&#225;tica&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">21</span></a></p><p id="par0255" class="elsevierStylePara elsevierViewall">As vias PD&#8208;1 e PD&#8208;L1&#47;PD&#8208;L2 formam um sistema complexo de receptores e ligantes envolvidos no controle da ativa&#231;&#227;o de c&#233;lulas&#160;T&#46; Na maioria dos tumores&#44; PD&#8208;L1 &#233; predominantemente expresso em c&#233;lulas tumorais e PD&#8208;1 nos linf&#243;citos que se infiltram no tumor&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">1</span></a> No entanto&#44; o PD&#8208;1 pode ser expresso n&#227;o apenas por linf&#243;citos T CD8<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>&#44; mas tamb&#233;m pelas c&#233;lulas CD4<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>&#44; CD20<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>&#44; Treg e c&#233;lulas NK&#46;<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">47</span></a> A liga&#231;&#227;o entre PD&#8208;1 e seu ligante PD&#8208;L1 leva &#224; inativa&#231;&#227;o e diminui&#231;&#227;o da prolifera&#231;&#227;o de c&#233;lulas&#160;T&#46; Esse processo parece ser um mecanismo importante para a inibi&#231;&#227;o da resposta imune pelo tumor&#46;<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">48</span></a></p><p id="par0260" class="elsevierStylePara elsevierViewall">A associa&#231;&#227;o da imunossupress&#227;o com o maior risco de CCM&#44; al&#233;m de alguns dados que mostram melhor progn&#243;stico em tumores com alta infiltra&#231;&#227;o de linf&#243;citos&#160;T CD8<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>&#44; tornou&#8208;se uma justificativa para o uso da imunoterapia&#46;<a class="elsevierStyleCrossRefs" href="#bib0370"><span class="elsevierStyleSup">15&#44;49</span></a> Al&#233;m disso&#44; Lipson et al&#46;&#44; em&#160;2013&#44; relataram associa&#231;&#227;o significante entre a presen&#231;a do MCPyV e a express&#227;o de PD&#8208;L1 no tumor e entre a presen&#231;a do MCPyV com um infiltrado inflamat&#243;rio moderado a intenso&#46; Esses achados sugerem a hip&#243;tese de que uma resposta imune a ant&#237;genos virais cria um ambiente pr&#243;&#8208;inflamat&#243;rio local que estimula a express&#227;o de PD&#8208;L1 no tumor&#46;<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">50</span></a> Essas descobertas abriram caminho para o uso de inibidores de <span class="elsevierStyleItalic">checkpoint</span> imunes no MCC metast&#225;tico&#46;</p><p id="par0265" class="elsevierStylePara elsevierViewall">O primeiro estudo nesse cen&#225;rio foi o JAVELIN Merkel&#160;200&#44; um ensaio cl&#237;nico multic&#234;ntrico de fase&#160;II&#44; aberto&#44; que investigou a atividade cl&#237;nica e a seguran&#231;a de avelumabe&#44; um anticorpo anti&#8208;PD&#8208;L1&#46; O estudo apresenta parte&#160;A&#44; realizado em pacientes com CCM previamente expostos &#224; QT&#44;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">51</span></a> e parte&#160;B&#44; realizado em pacientes que n&#227;o haviam recebido tratamento sist&#234;mico pr&#233;vio para doen&#231;a metast&#225;tica&#46;<a class="elsevierStyleCrossRef" href="#bib0555"><span class="elsevierStyleSup">52</span></a> Na parte&#160;A&#44; 88&#160;pacientes foram tratados com avelumabe e a taxa de resposta global confirmada &#40;ORR&#41; foi de&#160;33&#37; &#40;incluindo&#160;10&#160;respostas completas&#41; e com&#160;26&#37; dos pacientes sem progress&#227;o em&#160;dois&#160;anos&#46; A dura&#231;&#227;o mediana da resposta n&#227;o foi alcan&#231;ada&#44; e a SG mediana foi de&#160;12&#44;6&#160;meses&#46;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">51</span></a> Uma resposta objetiva de&#160;34&#44;5&#37; foi encontrada em PD&#8208;L1 positivo contra apenas&#160;18&#44;8&#37; em pacientes PDL&#8208;1 negativos &#40;express&#227;o&#160;&#60;<span class="elsevierStyleHsp" style=""></span>1&#37;&#46;&#41; Considerando o corte na express&#227;o de PD&#8208;L1 em&#160;5&#37;&#44; 52&#44;6&#37; dos pacientes PD&#8208;L1 positivos <span class="elsevierStyleItalic">versus</span>&#160;23&#44;6&#37; dos pacientes PD&#8208;L1 negativos tiveram resposta objetiva&#46; Al&#233;m disso&#44; 26&#44;1&#37;&#160;dos pacientes com tumores MCPyV&#8208;positivos em compara&#231;&#227;o com&#160;35&#44;5&#37; nos tumores MCPyV&#8208;negativos tiveram resposta&#46;<a class="elsevierStyleCrossRef" href="#bib0560"><span class="elsevierStyleSup">53</span></a> Outra an&#225;lise de subgrupo sugeriu maior probabilidade de resposta em pacientes que receberam menos terapias sist&#234;micas pr&#233;vias&#44; o que foi confirmado na parte&#160;B do ensaio Javelin Merkel&#160;200&#46; A resposta objetiva entre os&#160;29&#160;pacientes inclu&#237;dos no cen&#225;rio de primeira linha foi de&#160;62&#37;&#44; com propor&#231;&#227;o de respostas com dura&#231;&#227;o de&#160;seis&#160;meses ou mais de&#160;83&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0555"><span class="elsevierStyleSup">52</span></a></p><p id="par0270" class="elsevierStylePara elsevierViewall">Munhoz et al&#46;&#44; em&#160;2020&#44; descreveram a experi&#234;ncia com avelumabe como tratamento de segunda linha &#40;ou primeira linha em pacientes n&#227;o candidatos ao uso de QT&#41; em um subconjunto de&#160;46&#160;pacientes latino&#8208;americanos &#40;idade m&#233;dia&#160;71&#44;6&#160;anos&#59; 60&#44;9&#37;&#160;homens&#59; dura&#231;&#227;o m&#233;dia do tratamento&#160;7&#44;9&#160;meses&#41;&#46; Respostas objetivas foram observadas em&#160;19&#160;pacientes &#40;resposta objetiva&#160;57&#44;9&#37;&#59; resposta completa&#160;15&#44;8&#37;&#59; resposta parcial&#160;42&#44;1&#37;&#59; e doen&#231;a est&#225;vel&#160;10&#44;5&#37;&#41; e seguran&#231;a consistente com dados globais&#46;<a class="elsevierStyleCrossRef" href="#bib0565"><span class="elsevierStyleSup">54</span></a></p><p id="par0275" class="elsevierStylePara elsevierViewall">Outro estudo com caracter&#237;sticas semelhantes demonstrou a efic&#225;cia do pembrolizumabe no CCM&#44; um anticorpo monoclonal anti&#8208;PD&#8208;1&#46; Um total de&#160;50&#160;pacientes com CCM avan&#231;ado foram tratados com resposta objetiva de&#160;56&#37; e taxa de SLP em&#160;seis&#160;meses de&#160;67&#37;&#46; Em contraste com o estudo com avelumabe&#44; uma taxa de resposta mais alta foi observada nos tumores positivos para MCPyV&#160;&#40;62&#37;&#41; do que nos tumores negativos para MCPyV&#160;&#40;44&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">55</span></a></p><p id="par0280" class="elsevierStylePara elsevierViewall">No estudo CheckMate&#160;358&#44; o nivolumabe&#44; outro anti&#8208;PD&#8208;1&#44; foi avaliado em&#160;25&#160;pacientes com CCM avan&#231;ado&#44; uma resposta objetiva de&#160;64&#37;&#46; As respostas ocorreram em pacientes virgens de tratamento&#160;&#40;71&#37;&#41;&#44; bem como naqueles com pelo menos uma terapia sist&#234;mica anterior&#160;&#40;63&#37;&#41;&#44; com tempo m&#233;dio curto para resposta &#40;75&#37; dos pacientes responderam em&#160;dois&#160;meses&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">56</span></a></p><p id="par0285" class="elsevierStylePara elsevierViewall">O resumo dos recentes estudos com imunoterapia para o tratamento do MCC metast&#225;tico pode ser visto na <a class="elsevierStyleCrossRef" href="#tbl0010">tabela 2</a>&#46;<a class="elsevierStyleCrossRefs" href="#bib0555"><span class="elsevierStyleSup">52&#44;56&#8211;58</span></a></p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0290" class="elsevierStylePara elsevierViewall">Dada a efic&#225;cia da imunoterapia para CCM metast&#225;tico&#44; o pr&#243;ximo desafio consiste em avaliar tais tratamentos no cen&#225;rio adjuvante&#46; Em raz&#227;o do alto risco de recorr&#234;ncia do CCM&#44; apesar do tratamento inicial e da falta de benef&#237;cio do tratamento citot&#243;xico&#44; sua investiga&#231;&#227;o &#233; altamente relevante&#44; cobrindo uma necessidade m&#233;dica n&#227;o atendida&#46; Dois estudos de fase&#160;II com nivolumabe e avelumabe est&#227;o avaliando o uso de inibidores de <span class="elsevierStyleItalic">checkpoints</span> imunes para pacientes de alto risco&#44; ainda sem os resultados oficialmente publicados&#46; O cen&#225;rio neoadjuvante com o estudo CheckMate&#160;358&#44; envolvendo&#160;39&#160;pacientes com CCM ressec&#225;vel est&#225;gio&#160;IIA&#160;a&#160;IV&#44; avaliou o uso do nivolumabe &#40;&#8805; 1&#160;dose&#41; cerca de&#160;quatro&#160;semanas antes da cirurgia&#46; Tr&#234;s pacientes n&#227;o foram operados por progress&#227;o tumoral e 36&#160;pacientes foram operados&#44; dentre os quais&#160;17&#160;&#40;42&#44;2&#37;&#41; obtiveram resposta patol&#243;gica completa&#46; Entre&#160;33&#160;pacientes avali&#225;veis radiograficamente submetidos &#224; cirurgia&#44; 18&#160;&#40;54&#44;5&#37;&#41; tiveram redu&#231;&#227;o tumoral&#160;&#8805; 30&#37;&#46; Nenhum paciente com resposta patol&#243;gica completa teve recidiva tumoral durante a observa&#231;&#227;o&#46;<a class="elsevierStyleCrossRef" href="#bib0590"><span class="elsevierStyleSup">59</span></a></p></span></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Conclus&#227;o</span><p id="par0295" class="elsevierStylePara elsevierViewall">O CCM &#233; doen&#231;a rara e agressiva&#44; cuja incid&#234;ncia est&#225; aumentando&#46; Nas &#250;ltimas d&#233;cadas&#44; muitos avan&#231;os foram feitos no conhecimento da biologia&#44; diagn&#243;stico e tratamento do CCM&#44; mas grandes desafios ainda permanecem&#46; Os tumores prim&#225;rios devem ser tratados com excis&#227;o cir&#250;rgica completa&#44; com margens cir&#250;rgicas adequadas&#46; RT adjuvante deve ser considerada&#46; Em rela&#231;&#227;o ao CCM avan&#231;ado&#44; a imunoterapia mudou drasticamente o padr&#227;o de tratamento&#44; uma vez que &#233; superior &#224; QT&#46; Not&#225;veis respostas foram observadas em pacientes com CCM tratados com inibidores do eixo PD&#8208;1&#47;PD&#8208;L1 e parece ser maneira promissora de mudar o progn&#243;stico desse c&#226;ncer de pele grave&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Suporte financeiro</span><p id="par0300" class="elsevierStylePara elsevierViewall">Nenhum&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Contribui&#231;&#227;o dos autores</span><p id="par0305" class="elsevierStylePara elsevierViewall">Stella Meireles Siqueira&#58; An&#225;lise estat&#237;stica&#59; elabora&#231;&#227;o e reda&#231;&#227;o do manuscrito&#59; obten&#231;&#227;o&#44; an&#225;lise e interpreta&#231;&#227;o dos dados&#59; participa&#231;&#227;o intelectual em conduta proped&#234;utica e&#47;ou terap&#234;utica de casos estudados&#59; revis&#227;o cr&#237;tica da literatura&#46;</p><p id="par0310" class="elsevierStylePara elsevierViewall">Gabriella Campos&#8208;do&#8208;Carmo&#58; An&#225;lise estat&#237;stica&#59; elabora&#231;&#227;o e reda&#231;&#227;o do manuscrito&#59; obten&#231;&#227;o&#44; an&#225;lise e interpreta&#231;&#227;o dos dados&#59; participa&#231;&#227;o intelectual em conduta proped&#234;utica e&#47;ou terap&#234;utica de casos estudados&#46;</p><p id="par0315" class="elsevierStylePara elsevierViewall">Alexssandra Lima Siqueira dos Santos&#58; An&#225;lise estat&#237;stica&#59; elabora&#231;&#227;o e reda&#231;&#227;o do manuscrito&#59; obten&#231;&#227;o&#44; an&#225;lise e interpreta&#231;&#227;o dos dados&#59; participa&#231;&#227;o intelectual em conduta proped&#234;utica e&#47;ou terap&#234;utica de casos estudados&#59; revis&#227;o cr&#237;tica da literatura&#46;</p><p id="par0320" class="elsevierStylePara elsevierViewall">C&#237;cero Martins&#58; An&#225;lise estat&#237;stica&#59; elabora&#231;&#227;o e reda&#231;&#227;o do manuscrito&#59; obten&#231;&#227;o&#44; an&#225;lise e interpreta&#231;&#227;o dos dados&#59; participa&#231;&#227;o intelectual em conduta proped&#234;utica e&#47;ou terap&#234;utica de casos estudados&#59; revis&#227;o cr&#237;tica da literatura&#46;</p><p id="par0325" class="elsevierStylePara elsevierViewall">Andreia Cristina de Melo&#58; An&#225;lise estat&#237;stica&#59; aprova&#231;&#227;o da vers&#227;o final do manuscrito&#59; concep&#231;&#227;o e planejamento do estudo&#59; elabora&#231;&#227;o e reda&#231;&#227;o do manuscrito&#59; obten&#231;&#227;o&#44; an&#225;lise e interpreta&#231;&#227;o dos dados&#59; participa&#231;&#227;o efetiva na orienta&#231;&#227;o da pesquisa&#59; participa&#231;&#227;o intelectual em conduta proped&#234;utica e&#47;ou terap&#234;utica de casos estudados&#59; revis&#227;o cr&#237;tica do manuscrito&#46;</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Conflito de interesses</span><p id="par0330" class="elsevierStylePara elsevierViewall">Nenhum&#46;</p></span></span>"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">O carcinoma de c&#233;lulas de Merkel &#233; c&#226;ncer de pele raro com diferencia&#231;&#227;o neuroend&#243;crina&#46; Os fatores de risco incluem exposi&#231;&#227;o solar&#44; idade avan&#231;ada&#44; imunossupress&#227;o &#40;como pacientes transplantados&#44; pacientes com neoplasias linfoproliferativas ou portadores do v&#237;rus HIV&#41; e infec&#231;&#227;o pelo poliomav&#237;rus de c&#233;lulas de Merkel&#46; Clinicamente&#44; o carcinoma de c&#233;lulas de Merkel aparece como placa ou n&#243;dulo cut&#226;neo ou subcut&#226;neo&#44; mas o diagn&#243;stico desse tumor raramente &#233; feito clinicamente&#46; Assim&#44; a histopatologia e a imuno&#8208;histoqu&#237;mica costumam ser necess&#225;rias&#46; Tumores prim&#225;rios sem evid&#234;ncia de met&#225;stases s&#227;o tratados com excis&#227;o cir&#250;rgica completa com margens cir&#250;rgicas apropriadas&#46; A presen&#231;a de met&#225;stase oculta em linfonodo &#233; frequente&#44; e a bi&#243;psia do linfonodo sentinela deve ser realizada&#46; A radioterapia adjuvante p&#243;s&#8208;operat&#243;ria aumenta o controle local do tumor&#46; Recentemente&#44; agentes que bloqueiam a via PD&#8208;1&#47;PD&#8208;L1 mostraram regress&#245;es tumorais objetivas e dur&#225;veis em pacientes com neoplasias s&#243;lidas avan&#231;adas&#46; O primeiro anticorpo anti&#8208;PD&#8208;L1 usado em pacientes com carcinoma de c&#233;lulas de Merkel foi o avelumabe&#44; mas pembrolizumabe e nivolumabe tamb&#233;m demonstraram efic&#225;cia&#46; Neste artigo&#44; o estado atual do conhecimento da epidemiologia&#44; diagn&#243;stico&#44; estadiamento e as novas estrat&#233;gias de tratamento sist&#234;mico do carcinoma de c&#233;lulas de Merkel s&#227;o descritos&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Como citar este artigo&#58; Siqueira SM&#44; Campos&#8208;do&#8208;Carmo G&#44; Santos ALS&#44; Martins C&#44; Melo AC&#46; Merkel cell carcinoma&#58; epidemiology&#44; clinical features&#44; diagnosis and treatment of a rare disease&#46; An Bras Dermatol&#46; 2023&#59;98&#58;277&#8211;86&#46;</p>"
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          "pt" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Imuno&#8208;histoqu&#237;mica para MCPyV realizada em l&#226;minas de carcinoma de c&#233;lulas de Merkel&#46; &#40;A&#41; L&#226;mina de imuno&#8208;histoqu&#237;mica de paciente apresentando resultado positivo para MCPyV &#40;aumento de&#160;400<span class="elsevierStyleHsp" style=""></span>&#215;&#41;&#46; &#40;B&#41; L&#226;mina de imuno&#8208;histoqu&#237;mica de paciente apresentando resultado negativo para MCPyV &#40;aumento de&#160;400<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>&#41;&#46;</p>"
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          "pt" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Carcinoma de c&#233;lulas de Merkel localizado na coxa esquerda de paciente do sexo masculino&#46; &#40;A&#41; Ao diagn&#243;stico&#44; les&#227;o tumoral com aspecto cupuliforme&#44; com eritema e discreta descama&#231;&#227;o&#46; &#40;B&#41; Evolu&#231;&#227;o do tumor com crescimento e ulcera&#231;&#227;o em toda a les&#227;o&#46;</p> <p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Fonte&#58; Cortesia da Dra&#46; Gabriella Campos&#8208;do&#8208;Carmo&#46; O paciente consentiu com o uso das imagens para fins educacionais&#46;</p>"
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          "leyenda" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Fonte adaptada&#58; Harms KL et al&#46;&#44; 2016&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">24</span></a>&#46;</p>"
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                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Met&#225;stases&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><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">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"><span class="elsevierStyleItalic">In situ</span> &#40;restrito &#224; epiderme&#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">Sem met&#225;stase para linfonodo regional&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">Sem met&#225;stase a dist&#226;ncia&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">I&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  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Di&#226;metro cl&#237;nico m&#225;ximo do tumor &#8804;&#160;2&#160;cm</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">cN0&#44; sem met&#225;stase para linfonodo regional na avalia&#231;&#227;o cl&#237;nica ou radiol&#243;gica&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">Sem met&#225;stase a dist&#226;ncia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" 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><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">pN0&#44; sem met&#225;stase para linfonodo regional detectada na avalia&#231;&#227;o histopatol&#243;gica&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">IIA&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  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Di&#226;metro cl&#237;nico m&#225;ximo do tumor<span class="elsevierStyleHsp" style=""></span>&#62; 2&#160;cm</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">cN0&#44; sem met&#225;stase para linfonodo regional na avalia&#231;&#227;o cl&#237;nica ou radiol&#243;gica&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">Sem met&#225;stase a dist&#226;ncia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" 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><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">pN0&#44; sem met&#225;stase para linfonodo regional detectada na avalia&#231;&#227;o histopatol&#243;gica&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">IIB&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  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tumor prim&#225;rio invade f&#225;scia&#44; m&#250;sculo&#44; cartilagem ou osso</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">cN0&#44; sem met&#225;stase para linfonodo regional na avalia&#231;&#227;o cl&#237;nica ou radiol&#243;gica&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">Sem met&#225;stase a dist&#226;ncia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" 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><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">pN0&#44; sem met&#225;stase para linfonodo regional detectada na avalia&#231;&#227;o histopatol&#243;gica&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">III &#40;cl&#237;nico&#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">Tumor de qualquer tamanho&#44; incluindo tumores invasivos e tumor prim&#225;rio desconhecido&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">Met&#225;stase nodal regional clinicamente detectada&#44; met&#225;stase em tr&#226;nsito com ou sem met&#225;stase linfonodal&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">Sem met&#225;stase a dist&#226;ncia&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">IIIA &#40;patol&#243;gico&#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  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tumor de qualquer tamanho&#44; incluindo tumores invasivos e tumor prim&#225;rio desconhecido</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">Met&#225;stase nodal clinicamente oculta identificada apenas por BLS ou dissec&#231;&#227;o de linfonodo&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">Sem met&#225;stase a dist&#226;ncia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" 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><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">Met&#225;stase em linfonodo regional detectada cl&#237;nica ou radiologicamente&#44; confirmada patologicamente&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">IIIB &#40;patol&#243;gico&#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">Tumor de qualquer tamanho&#44; incluindo tumores invasivos&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">Met&#225;stase linfonodal regional detectada cl&#237;nica ou radiologicamente&#44; confirmada patologicamente&#44; met&#225;stase em tr&#226;nsito<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> com ou sem met&#225;stase linfonodal&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">IV&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">Tumor de qualquer tamanho&#44; incluindo tumores invasivos e tumor prim&#225;rio desconhecido&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">Qualquer N&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">Met&#225;stase al&#233;m dos linfonodos regionais&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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            0 => array:3 [
              "identificador" => "tblfn0005"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Met&#225;stase em tr&#226;nsito&#58; tumor distinto da les&#227;o prim&#225;ria e localizado entre a les&#227;o prim&#225;ria e os linfonodos regionais ou distal &#224; les&#227;o prim&#225;ria&#46;</p>"
            ]
          ]
        ]
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          "pt" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Estadiamento do carcinoma de c&#233;lulas de Merkel &#8211; AJCC 8&#170;&#160;edi&#231;&#227;o</p>"
        ]
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        "etiqueta" => "Tabela 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
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        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at2"
            "detalle" => "Tabela "
            "rol" => "short"
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        "tabla" => array:2 [
          "leyenda" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">TRG&#44; taxa de resposta global&#59; SLP&#44; sobrevida livre de progress&#227;o&#59; SG&#44; sobrevida global&#59; NR&#44; n&#227;o relatado&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&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">Nome do estudo&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">Classe de f&#225;rmacos&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">Tipo de estudo&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">N&#250;mero de pacientes&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">TRG &#40;&#37;&#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">SLP aos 24m &#40;&#37;&#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">SG aos 24m &#40;&#37;&#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">Refer&#234;ncias&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><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">Avelumabe&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">Javelin&#160;200 &#8208; Parte A&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">Anti&#8208;PD&#8208;L1&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<span class="elsevierStyleSup">a</span> linha ou linhas subsequentes&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&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">26&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">36&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">Kaufman 2018<a class="elsevierStyleCrossRef" href="#bib0580"><span class="elsevierStyleSup">57</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">Avelumabe&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">Javelin&#160;200 &#8208; Parte B&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">Anti&#8208;PD&#8208;L1&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<span class="elsevierStyleSup">a</span> linha&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">29&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&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">NR&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">NR&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">D&#8217;Angelo&#44; 2018<a class="elsevierStyleCrossRef" href="#bib0555"><span class="elsevierStyleSup">52</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">Pembrolizumabe&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">Keynote &#8208; 017&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">Anti&#8208;PD&#8208;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<span class="elsevierStyleSup">a</span> linha&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">50&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">56&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">48&#44;3&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">68&#44;7&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">Nghiem&#44; 2019<a class="elsevierStyleCrossRef" href="#bib0585"><span class="elsevierStyleSup">58</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">Nivolumabe&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">CheckMate 358&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">Anti&#8208;PD&#8208;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<span class="elsevierStyleSup">a</span> linha&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">15&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">71&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">NR&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">NR&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">Topalian&#44; 2017<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">56</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" 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><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><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><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">2<span class="elsevierStyleSup">a</span> linha&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">10&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">63&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><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><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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          "pt" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Dados importantes de ensaios cl&#237;nicos recentes envolvendo imunoterapia<a class="elsevierStyleCrossRefs" href="#bib0555"><span class="elsevierStyleSup">52&#44;56&#8211;58</span></a></p>"
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      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "Refer&#234;ncias"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0015"
          "bibliografiaReferencia" => array:59 [
            0 => array:3 [
              "identificador" => "bib0300"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Co&#8208;expression of NGF and PD&#8208;L1 on tumor&#8208;associated immune cells in the microenvironment of Merkel cell carcinoma"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "U&#46; Wehkamp"
                            1 => "S&#46; Stern"
                            2 => "S&#46; Kr&#252;ger"
                            3 => "M&#46; Weichenthal"
                            4 => "A&#46; Hauschild"
                            5 => "C&#46; R&#246;cken"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
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                      ]
                    ]
                  ]
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                            1 => "K&#46;L&#46; Harms"
                            2 => "P&#46;S&#46; Moore"
                            3 => "J&#46;A&#46; DeCaprio"
                            4 => "P&#46; Nghiem"
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                  ]
                  "host" => array:1 [
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                          "etal" => true
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                            0 => "J&#46;M&#46; Van der Zwan"
                            1 => "A&#46; Trama"
                            2 => "R&#46; Otter"
                            3 => "N&#46; Larra&#241;aga"
                            4 => "A&#46; Tavilla"
                            5 => "R&#46; Marcos-Gragera"
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                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
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            4 => array:3 [
              "identificador" => "bib0320"
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                  "contribucion" => array:1 [
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                      "titulo" => "Dramatic Increase in the Incidence and Mortality from Merkel Cell Carcinoma in the United States"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "T&#46;L&#46; Fitzgerald"
                            1 => "S&#46; Dennis"
                            2 => "S&#46;D&#46; Kachare"
                            3 => "N&#46;A&#46; Vohra"
                            4 => "J&#46;H&#46; Wong"
                            5 => "E&#46;E&#46; Zervos"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1177/000313481508100819"
                      "Revista" => array:6 [
                        "tituloSerie" => "The American Surgeon&#46;"
                        "fecha" => "2015"
                        "volumen" => "81"
                        "paginaInicial" => "802"
                        "paginaFinal" => "806"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26215243"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
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              ]
            ]
            5 => array:3 [
              "identificador" => "bib0325"
              "etiqueta" => "6"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Merkel cell carcinoma&#58; Current US incidence and projected increases based on changing demographics"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "K&#46;G&#46; Paulson"
                            1 => "S&#46;Y&#46; Park"
                            2 => "N&#46;A&#46; Vandeven"
                            3 => "K&#46; Lachance"
                            4 => "H&#46; Thomas"
                            5 => "A&#46;G&#46; Chapuis"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "J Am Acad Dermatol&#46;"
                        "fecha" => "2018"
                        "volumen" => "78"
                        "paginaInicial" => "457"
                        "paginaFinal" => "463"
                      ]
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                  ]
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            6 => array:3 [
              "identificador" => "bib0330"
              "etiqueta" => "7"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Incidence and survival for Merkel cell carcinoma in Queensland"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "D&#46;R&#46; Youlden"
                            1 => "H&#46;P&#46; Soyer"
                            2 => "P&#46;H&#46; Youl"
                            3 => "L&#46; Fritschi"
                            4 => "P&#46;D&#46; Baade"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
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                        "volumen" => "150"
                        "paginaInicial" => "864"
                        "paginaFinal" => "872"
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            ]
            7 => array:3 [
              "identificador" => "bib0335"
              "etiqueta" => "8"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Merkel Cell Carcinoma&#44; Version 1&#46;2018"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "C&#46;K&#46; Bichakjian"
                            1 => "T&#46; Olencki"
                            2 => "S&#46;Z&#46; Aasi"
                            3 => "M&#46; Alam"
                            4 => "J&#46;S&#46; Anderson"
                            5 => "R&#46; Blitzblau"
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                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "NCCN Clinical Practice Guidelines in Oncology&#46; J Natl Compr Canc Netw&#46;"
                        "fecha" => "2018"
                        "volumen" => "16"
                        "paginaInicial" => "742"
                        "paginaFinal" => "774"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            8 => array:3 [
              "identificador" => "bib0340"
              "etiqueta" => "9"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Trends in the incidence and morbidity of Merkel cell carcinoma in Brazil"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "A&#46;C&#46; Melo"
                            1 => "L&#46;S&#46; Thuler"
                          ]
                        ]
                      ]
                    ]
                  ]
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ISSN: 26662752
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