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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Introdu&#231;&#227;o</span><p id="par0005" class="elsevierStylePara elsevierViewall">As met&#225;stases cut&#226;neas de tumores s&#243;lidos s&#227;o eventos pouco frequentes na pr&#225;tica cl&#237;nica&#46; Estima&#8208;se que entre 0&#44;7&#160;e&#160;9&#37; das met&#225;stases desses tumores tenham a pele como destino&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">1</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Na maioria das vezes&#44; o paciente j&#225; tem o diagn&#243;stico de neoplasia maligna quando a met&#225;stase cut&#226;nea &#233; detectada&#46; No entanto&#44; em at&#233; um ter&#231;o dos casos a met&#225;stase cut&#226;nea &#233; identificada antes do tumor prim&#225;rio&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">2</span></a> Em alguns casos&#44; a identifica&#231;&#227;o da met&#225;stase cut&#226;nea indica a recidiva do c&#226;ncer&#44; e em&#160;79&#37; das vezes h&#225; concomitantemente met&#225;stases viscerais&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">3</span></a> A apresenta&#231;&#227;o cl&#237;nica &#233; diversa e pode simular doen&#231;as inflamat&#243;rias&#44; tumores benignos ou at&#233; mesmo tumores cut&#226;neos malignos&#46; Nesta revis&#227;o&#44; discutimos o paradigma atual dos mecanismos de met&#225;stase e expomos as principais formas cl&#237;nicas de sua apresenta&#231;&#227;o&#46; Por quest&#245;es did&#225;ticas&#44; discutiremos as apresenta&#231;&#245;es cl&#237;nicas de acordo com o s&#237;tio do tumor prim&#225;rio&#44; incluindo aqueles originalmente cut&#226;neos&#46; As manifesta&#231;&#245;es paraneopl&#225;sicas e as neoplasias hematol&#243;gicas n&#227;o ser&#227;o revisadas neste artigo&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Etiopatogenia</span><p id="par0015" class="elsevierStylePara elsevierViewall">Met&#225;stase &#233; definida como o desenvolvimento de um tumor a dist&#226;ncia do s&#237;tio prim&#225;rio&#46; A met&#225;stase desenvolve&#8208;se predominantemente por invas&#227;o vascular &#40;linf&#225;tica ou hematog&#234;nica&#41;&#46; Discute&#8208;se na literatura se os implantes por contiguidade ou de forma iatrog&#234;nica devem ser considerados met&#225;stases de fato&#46; Atualmente&#44; entendemos o processo de met&#225;stase como um fen&#244;meno complexo que ocorre paralelamente ao desenvolvimento do tumor prim&#225;rio&#46; Pela maior import&#226;ncia&#44; discutiremos com mais detalhes a met&#225;stase por invas&#227;o vascular&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">A fisiopatologia da met&#225;stase &#233; dividida em seis etapas&#58; invas&#227;o local&#59; intravasamento&#59; sobreviv&#234;ncia na circula&#231;&#227;o&#59; parada em &#243;rg&#227;o distante&#59; extravasamento&#59; forma&#231;&#227;o de micromet&#225;stase e coloniza&#231;&#227;o metast&#225;tica&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">4</span></a></p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Invas&#227;o local</span><p id="par0025" class="elsevierStylePara elsevierViewall">Ap&#243;s o desenvolvimento do tumor maligno no s&#237;tio prim&#225;rio&#44; h&#225; a invas&#227;o local&#46; Tal evento consiste na entrada das c&#233;lulas malignas no estroma adjacente ao tumor&#46; Para que isso ocorra&#44; &#233; necess&#225;rio o rompimento da membrana basal secund&#225;rio &#224; a&#231;&#227;o de metaloproteinases de matriz&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">4</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Intravasamento</span><p id="par0030" class="elsevierStylePara elsevierViewall">O intravasamento &#233; o fen&#244;meno complexo que possibilita a entrada das c&#233;lulas malignas nos vasos sangu&#237;neos ou linf&#225;ticos&#46; Esse processo &#233; fundamental para que as c&#233;lulas malignas atinjam o s&#237;tio distante e continuem o processo de met&#225;stase&#46; &#201; bem descrito que os tumores malignos t&#234;m a capacidade de produzir neoangiog&#234;nese&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">5</span></a> O que ocorre &#233; que tais vasos neoformados apresentam pouca cobertura de pericitos e c&#233;lulas endoteliais com pouca ades&#227;o celular&#44; o que facilita a entrada das c&#233;lulas malignas &#40;intravasamento&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0330"><span class="elsevierStyleSup">4&#44;5</span></a> De maneira intrigante&#44; evid&#234;ncias mais recentes demonstram que esse fen&#244;meno ocorre predominantemente durante o sono&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">6</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Sobreviv&#234;ncia na circula&#231;&#227;o</span><p id="par0035" class="elsevierStylePara elsevierViewall">Uma vez dentro dos vasos&#44; as c&#233;lulas malignas precisam sobreviver&#46; Elas est&#227;o sujeitas ao trauma decorrente das for&#231;as hemodin&#226;micas e &#224; a&#231;&#227;o do sistema imunol&#243;gico&#46; A principal forma adaptativa para evadir&#8208;se desses mecanismos &#233; a forma&#231;&#227;o de microtrombos plaquet&#225;rios ao redor das c&#233;lulas neopl&#225;sicas&#44; que as protegem desses fen&#244;menos&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">4</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Parada em &#243;rg&#227;o distante</span><p id="par0040" class="elsevierStylePara elsevierViewall">Por meio da circula&#231;&#227;o sangu&#237;nea ou linf&#225;tica&#44; os tumores podem atingir virtualmente qualquer tecido do corpo&#46; O grande questionamento &#233; o motivo de alguns tumores apresentarem s&#237;tios preferenciais de met&#225;stase&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">7</span></a> Por exemplo&#44; h&#225; n&#237;tida prefer&#234;ncia &#243;ssea nas met&#225;stases prost&#225;ticas ou&#44; nos casos de tumores do c&#243;lon&#44; para o f&#237;gado&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">8</span></a> Acredita&#8208;se que seja necess&#225;ria uma forte intera&#231;&#227;o entre o tumor prim&#225;rio e o estroma do s&#237;tio alvo&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">4</span></a> Apesar de a pele ser um &#243;rg&#227;o altamente vascularizado&#44; poucos tumores como o melanoma t&#234;m predile&#231;&#227;o evidente&#46; Talvez isso ocorra por uma boa prote&#231;&#227;o imunol&#243;gica ou baixa intera&#231;&#227;o estroma&#8208;tumor maligno&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Extravasamento</span><p id="par0045" class="elsevierStylePara elsevierViewall">Ap&#243;s atingir a circula&#231;&#227;o do &#243;rg&#227;o alvo&#44; as c&#233;lulas malignas precisam sair dos vasos para atingir o estroma&#46; Esse processo pode ocorrer pela ruptura mec&#226;nica vascular ou por um processo mais complexo&#46; Nesse &#250;ltimo caso&#44; as c&#233;lulas tumorais poderiam induzir a hiperpermeabilidade vascular secund&#225;ria &#224; libera&#231;&#227;o de prote&#237;nas como epiregulina &#40;EREG&#41;&#44; cicloxigenase&#160;2 &#40;COX&#8208;2&#41;&#44; metaloproteinase&#160;1&#160;e&#160;2 &#40;MMP&#8208;1 e MMP&#8208;2&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">9</span></a> &#201; importante frisar que cada prote&#237;na tem a&#231;&#227;o espec&#237;fica sobre a vasculariza&#231;&#227;o de cada &#243;rg&#227;o alvo&#44; refor&#231;ando a ideia de que cada tumor maligno apresenta um ou mais s&#237;tios preferenciais de met&#225;stase&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">4</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Forma&#231;&#227;o de micromet&#225;stase e coloniza&#231;&#227;o metast&#225;tica</span><p id="par0050" class="elsevierStylePara elsevierViewall">O &#250;ltimo passo &#233; o tumor sobreviver no estroma do s&#237;tio alvo&#46; Para isso&#44; o tumor precisa ter capacidade de autorrenova&#231;&#227;o e prolifera&#231;&#227;o&#46; Ademais&#44; o tumor libera subst&#226;ncias que tornam o estroma adjacente mais receptivo para sua multiplica&#231;&#227;o&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">4</span></a> As micromet&#225;stases podem persistir em estado de lat&#234;ncia por meses ou anos&#46; Nesse per&#237;odo&#44; aquelas micromet&#225;stases que adquirem altera&#231;&#227;o gen&#233;ticas ou epigen&#233;ticas e que conseguem tornar o microambiente mais favor&#225;vel ao seu desenvolvimento evoluir&#227;o com a forma&#231;&#227;o de met&#225;stases macrosc&#243;picas com potencial letal significante&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">4</span></a></p></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Epidemiologia</span><p id="par0055" class="elsevierStylePara elsevierViewall">H&#225; diverg&#234;ncia na literatura sobre quais tumores mais frequentemente metastatizam para a pele&#46; Estudos mais recentes indicam que o melanoma &#233; o mais frequente&#44; por&#233;m em alguns estudos cl&#225;ssicos essa neoplasia aparece apenas em quarto lugar&#46;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">10&#44;11</span></a> Uma metan&#225;lise de 2002 identificou que os tumores de mama s&#227;o os mais frequentes &#40;24&#37;&#41;&#44; seguidos de c&#226;ncer renal &#40;4&#37;&#41;&#44; ov&#225;rios &#40;3&#44;8&#37;&#41;&#44; bexiga &#40;3&#44;6&#37;&#41;&#44; pulm&#227;o &#40;3&#44;4&#37;&#41;&#44; colorretal &#40;3&#44;4&#37;&#41; e de pr&#243;stata &#40;0&#44;7&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">12</span></a> Por&#233;m&#44; nesse estudo foram exclu&#237;dos os casos de melanoma&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">H&#225; uma diferen&#231;a epidemiol&#243;gica de acordo com o sexo&#46; Um estudo brasileiro com 209 casos de met&#225;stases cut&#226;neas identificou que nas mulheres as met&#225;stases cut&#226;neas mais frequentes tiveram origem de c&#226;ncer de mama &#40;63&#44;19&#37;&#41;&#44; intestino grosso &#40;10&#44;41&#37;&#41; e pulm&#227;o &#40;4&#44;16&#37;&#41;&#44; enquanto nos homens a ordem de frequ&#234;ncia foi pulm&#227;o&#44; est&#244;mago e laringe &#40;33&#44;84&#37;&#44; 12&#44;3&#37; e 7&#44;69&#37;&#44; respectivamente&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">13</span></a> Quando analisamos especificamente a popula&#231;&#227;o pedi&#225;trica&#44; os tumores prim&#225;rios mais frequentes s&#227;o rabdomiosarcoma e neuroblastoma&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">14</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">&#201; fato not&#243;rio que h&#225; alguns locais da pele nos quais &#233; mais frequente o surgimento das les&#245;es metast&#225;ticas&#46; O t&#243;rax anterior &#233; o local mais comum&#44; seguindo de abdome&#44; cabe&#231;a e pesco&#231;o &#40;incluindo couro cabeludo&#41; e membros&#46;<a class="elsevierStyleCrossRefs" href="#bib0365"><span class="elsevierStyleSup">11&#8211;13</span></a> H&#225; nitidamente uma predile&#231;&#227;o de s&#237;tio acometido de acordo com o tumor prim&#225;rio&#44; por isso o local da met&#225;stase cut&#226;nea pode indicar a poss&#237;vel origem neopl&#225;sica&#46; Por exemplo&#44; o c&#226;ncer de mama metastatiza mais frequentemente para o t&#243;rax anterior&#44; enquanto os tumores do trato gastrintestinal acometem secundariamente mais frequentemente o abdome&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">15</span></a> A <a class="elsevierStyleCrossRef" href="#tbl0005">tabela 1</a> resume os locais preferenciais de met&#225;stases cut&#226;neas&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Apresenta&#231;&#227;o cl&#237;nica</span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Pele</span><p id="par0070" class="elsevierStylePara elsevierViewall">Diversas neoplasias malignas originalmente cut&#226;neas podem evoluir com met&#225;stases para a pele&#46; Desses&#44; o mais frequente &#233; o melanoma e&#44; por essa raz&#227;o&#44; discutiremos de modo mais aprofundado&#46; Por&#233;m&#44; &#233; importante salientar que carcinoma espinocelular&#44; carcinoma de c&#233;lulas de Merkel e at&#233; pilomatricoma maligno podem desenvolver met&#225;stases cut&#226;neas&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">11</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">Um estudo norte&#8208;americano demonstrou que o n&#250;mero de met&#225;stases cut&#226;neas por melanoma vem aumentando nos &#250;ltimos anos&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">16</span></a> Esse n&#227;o &#233; um evento infrequente na hist&#243;ria natural da doen&#231;a&#46; O envolvimento secund&#225;rio da pele surge em&#160;10&#8208;17&#37; dos pacientes com melanoma e est&#225; presente em at&#233;&#160;50&#37; dos indiv&#237;duos com doen&#231;a disseminada&#46;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">17</span></a> A pele &#233; o primeiro s&#237;tio de envolvimento metast&#225;tico na maioria dos casos&#44; e em cerca de&#160;30&#37; das vezes ocorre ap&#243;s a met&#225;stase linfonodal&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">18</span></a> Achado concomitante de met&#225;stase cut&#226;nea&#44; nodal e visceral ocorre em aproximadamente 10&#37;&#160;dos casos&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">18</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">As met&#225;stases cut&#226;neas do melanoma s&#227;o divididas em microssat&#233;lites&#44; sat&#233;lites&#44; em tr&#226;nsito ou a dist&#226;ncia&#46; As primeiras s&#227;o met&#225;stases microsc&#243;picas &#40;cut&#226;neas ou subcut&#226;neas&#41; descont&#237;nuas do tumor prim&#225;rio &#8211; logo&#44; n&#227;o &#233; percebida no exame cl&#237;nico&#46; A met&#225;stase sat&#233;lite &#233; aquele tumor metast&#225;tico vis&#237;vel at&#233; 2<span class="elsevierStyleHsp" style=""></span>cm do s&#237;tio do tumor prim&#225;rio&#46; Met&#225;stase em tr&#226;nsito &#233; definida como qualquer met&#225;stase cut&#226;nea ou subcut&#226;neas que esteja a mais de 2<span class="elsevierStyleHsp" style=""></span>cm da les&#227;o prim&#225;ria&#44; mas dentro da drenagem linf&#225;tica regional&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">19</span></a> Apesar dessa distin&#231;&#227;o&#44; tanto as les&#245;es sat&#233;lites quanto a met&#225;stase em tr&#226;nsito correspondem &#224; dissemina&#231;&#227;o intralinf&#225;tica e apresentam implica&#231;&#245;es terap&#234;uticas e progn&#243;sticas semelhantes&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">20</span></a> &#201; importante&#44; ainda&#44; diferenciar as met&#225;stases linf&#225;ticas da recorr&#234;ncia local que ocorre como resultado de uma ressec&#231;&#227;o incompleta do tumor prim&#225;rio&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">J&#225; a met&#225;stase a dist&#226;ncia est&#225; relacionada &#224; dissemina&#231;&#227;o hematog&#234;nica e ocorre quando o s&#237;tio metast&#225;tico cut&#226;neo est&#225; longe do foco de drenagem linf&#225;tica do tumor prim&#225;rio&#46; Essa distin&#231;&#227;o &#233; importante pois nos dois primeiros cen&#225;rios considera&#8208;se o paciente com doen&#231;a locorregional&#44; enquanto no &#250;ltimo h&#225; met&#225;stase a dist&#226;ncia piorando consideravelmente o progn&#243;stico do paciente&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">19</span></a> O estadiamento do melanoma foge do escopo deste artigo e&#44; portanto&#44; n&#227;o ser&#225; discutido&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">As met&#225;stases cut&#226;neas do melanoma s&#227;o mais comumente encontradas no dorso em homens e nos membros inferiores em mulheres&#46; O fato de as localiza&#231;&#245;es cut&#226;neas secund&#225;rias ocorrerem na mesma localiza&#231;&#227;o anat&#244;mica das localiza&#231;&#245;es cut&#226;neas iniciais em mais de&#160;30&#37; dos casos explica os padr&#245;es distintos das met&#225;stases entre os sexos&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">18</span></a> Clinicamente&#44; h&#225; p&#225;pulas ou n&#243;dulos d&#233;rmicos ou subcut&#226;neos geralmente pretos ou amarronzados que podem ulcerar &#40;<a class="elsevierStyleCrossRef" href="#fig0005">fig&#46; 1</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">21</span></a> Eventualmente&#44; podem ser amelan&#243;ticos e atingir grandes dimens&#245;es levando &#224; morbidade significante&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">16</span></a> No caso das met&#225;stases em tr&#226;nsito&#44; geralmente est&#227;o localizadas entre o s&#237;tio do tumor prim&#225;rio e o linfonodo regional&#46; Por&#233;m&#44; em algumas situa&#231;&#245;es pode surgir do lado oposto&#44; em decorr&#234;ncia de uma altera&#231;&#227;o do fluxo linf&#225;tico secund&#225;rio &#224; presen&#231;a do tumor&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">20</span></a> Casos mais at&#237;picos&#44; como placas eritematosas &#40;erisipela&#8208;s&#237;mile&#41;&#44; les&#245;es esclerodermiformes &#40;em coura&#231;a&#41;&#44; purp&#250;ricas e telangiect&#225;sicas&#44; j&#225; foram descritas&#46;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">22</span></a> H&#225; ainda relatos de met&#225;stases zosteriformes com les&#245;es vesicobolhosas e n&#243;dulos distribu&#237;dos por um derm&#225;tomo&#46;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">23</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Mama</span><p id="par0095" class="elsevierStylePara elsevierViewall">A maioria dos casos de met&#225;stase cut&#226;nea do c&#226;ncer de mama decorre de adenocarcinomas &#40;77&#8208;82&#37;&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0395"><span class="elsevierStyleSup">17&#44;24</span></a> Em geral&#44; surge no t&#243;rax anterior em decorr&#234;ncia da dissemina&#231;&#227;o linf&#225;tica regional&#46;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">25</span></a> Clinicamente&#44; a forma mais comum de apresenta&#231;&#227;o s&#227;o p&#225;pulas ou n&#243;dulos normocr&#244;micos&#46; Por&#233;m&#44; s&#227;o descritas algumas apresenta&#231;&#245;es bem caracterizadas&#44; a saber&#58; carcinoma telangiectoide&#44; carcinoma erisipeloide&#44; carcinoma em coura&#231;a &#40;<span class="elsevierStyleItalic">en courasse</span>&#41; e alopecia neopl&#225;sica&#46;<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">26</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">O carcinoma telangiectoide se apresenta com p&#225;pulas viol&#225;ceas sobre superf&#237;cie telangiect&#225;sica surgindo pr&#243;ximo &#224; cicatriz da mastectomia pr&#233;via&#46; De maneira menos comum&#44; surgem les&#245;es papulovesiculares semelhante ao linfangioma circunscrito&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">27</span></a> O carcinoma erisipeloide &#40;ou inflamat&#243;rio&#41; surge como placas eritematosas&#44; quentes e com bordas bem delimitadas afetando a pele da mama e adjacente &#40;<a class="elsevierStyleCrossRef" href="#fig0010">fig&#46; 2</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">26</span></a> Marneros et al&#46; demonstraram que a dissemina&#231;&#227;o no carcinoma telangiectoide ocorre predominantemente por vasos sangu&#237;neos&#44; enquanto no carcinoma erisipeloide a dissemina&#231;&#227;o &#233; linf&#225;tica&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">27</span></a> No carcinoma em coura&#231;a&#44; a pele adquire aspecto infiltrado e endurecido semelhante &#224; esclerodermia&#46; Por fim&#44; na alopecia neopl&#225;sica h&#225; n&#243;dulos ou placas endurecidas no couro cabeludo que resultam em alopecia&#46;<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">26</span></a> A alopecia pode ser cicatricial e irrevers&#237;vel&#44; j&#225; que as c&#233;lulas neopl&#225;sicas podem destruir os fol&#237;culos pilosos e induzir fibroplasia&#46;<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">28</span></a> Assim como no melanoma&#44; tamb&#233;m j&#225; foram descritos casos com p&#225;pulas dispostas em aspecto zosteriforme&#46;<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">26</span></a> &#201; importante salientar que apresenta&#231;&#245;es semelhantes ao carcinoma telangiect&#225;sico&#44; em coura&#231;a&#44; erisipeloide e alopecia mucinosa j&#225; foram descritas em met&#225;stases de outros tumores&#44; por&#233;m s&#227;o mais comuns secund&#225;rias ao adenocarcinoma de mama&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">21</span></a></p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0105" class="elsevierStylePara elsevierViewall">Quanto ao progn&#243;stico&#44; Hu et al&#46; demonstraram que a sobrevida m&#233;dia de pacientes com c&#226;ncer de mama e met&#225;stase cut&#226;nea &#233; de 57 meses&#44; e de apenas 25 meses entre aqueles com met&#225;stase visceral concomitantemente&#46;<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">29</span></a></p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Pulm&#227;o</span><p id="par0110" class="elsevierStylePara elsevierViewall">As met&#225;stases de c&#226;ncer de pulm&#227;o ocorrem mais frequentemente para o f&#237;gado&#44; ossos&#44; sistema nervoso central&#44; gl&#226;ndulas adrenais e linfonodos mediastinais&#59; a met&#225;stase cut&#226;nea &#233; pouco frequente&#46;<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">30</span></a> Estima&#8208;se que entre&#160;1&#160;a&#160;12&#37; dos pacientes com c&#226;ncer de pulm&#227;o cursem com met&#225;stases para a pele&#46;<a class="elsevierStyleCrossRefs" href="#bib0460"><span class="elsevierStyleSup">30&#44;31</span></a> Quando analisados todos os tipos de met&#225;stases cut&#226;neas&#44; os pacientes com met&#225;stases por c&#226;ncer de pulm&#227;o apresentaram o pior progn&#243;stico&#46;<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">32</span></a> Embora possam afetar qualquer s&#237;tio da pele&#44; acometem preferencialmente a regi&#227;o da cabe&#231;a e pesco&#231;o&#44; t&#243;rax anterior e abdome&#46; Assim como no c&#226;ncer de mama&#44; o adenocarcinoma &#233; o tipo metast&#225;tico mais comum&#44; seguido pelo carcinoma de c&#233;lulas escamosas&#59; o c&#226;ncer de pulm&#227;o de pequenas c&#233;lulas &#233; o menos frequente&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">21</span></a> Em geral&#44; o tumor prim&#225;rio est&#225; localizado nos lobos pulmonares superiores&#46;<a class="elsevierStyleCrossRefs" href="#bib0460"><span class="elsevierStyleSup">30&#44;31</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">Clinicamente&#44; as met&#225;stases de c&#226;ncer de pulm&#227;o s&#227;o indistingu&#237;veis de met&#225;stases de tumores de outras origens&#46; Em geral&#44; apresentam&#8208;se como n&#243;dulos subcut&#226;neos normocr&#244;micos ou levemente eritematosos&#44; endurecidos e aderidos a planos profundos &#40;<a class="elsevierStyleCrossRef" href="#fig0015">fig&#46; 3</a>&#41;&#46; Na maior parte das vezes&#44; surgem de maneira solit&#225;ria&#44; mas posteriormente podem surgir m&#250;ltiplas les&#245;es&#46; H&#225; relatos de met&#225;stases simulando ceratoacantomas&#44;<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">33</span></a> n&#243;dulos eritematosos localizados na ponta do nariz &#40;&#8220;nariz de palha&#231;o&#8221;&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">34</span></a> com distribui&#231;&#227;o zosteriforme ou simulando erisipela&#46;<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">35</span></a> Um acometimento pouco conhecido &#233; o subungueal&#46; Uma revis&#227;o de literatura demonstrou que a met&#225;stase subungueal ocorre mais frequentemente em pacientes com c&#226;ncer de pulm&#227;o&#160;&#40;41&#37;&#41;&#44; &#243;rg&#227;os genitourin&#225;rios&#160;&#40;17&#37;&#41; e mama&#160;&#40;9&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">36</span></a> Essas met&#225;stases se manifestam como n&#243;dulos eritematoviol&#225;ceos subungueais ou com edema&#44; eritema e dor das falanges distais simulando um quadro infeccioso&#46;<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">36</span></a></p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0120" class="elsevierStylePara elsevierViewall">&#201; importante salientar que&#44; na maioria das vezes&#44; quando h&#225; met&#225;stase cut&#226;nea&#44; outros s&#237;tios extrapulmonares tamb&#233;m est&#227;o acometidos&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">21</span></a></p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Trato gastrintestinal</span><p id="par0125" class="elsevierStylePara elsevierViewall">Dentre as neoplasias malignas do trato gastrintestinal&#44; o adenocarcinoma colorretal &#233; o que mais leva a met&#225;stases cut&#226;neas&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">12</span></a> No momento do diagn&#243;stico&#44; cerca de&#160;10&#37; dos casos j&#225; apresentam met&#225;stase a dist&#226;ncia&#59; os locais mais comumente acometidos s&#227;o o f&#237;gado&#44; os pulm&#245;es e o sistema nervoso central&#46;<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">37</span></a> Estima&#8208;se que cerca de&#160;4&#37; de pacientes com c&#226;ncer colorretal evoluam com alguma met&#225;stase para a pele&#44; e o tempo m&#233;dio do diagn&#243;stico at&#233; a met&#225;stase &#233; de&#160;25&#160;meses&#46;<a class="elsevierStyleCrossRefs" href="#bib0395"><span class="elsevierStyleSup">17&#44;38</span></a> A idade m&#233;dia no momento do diagn&#243;stico da met&#225;stase &#233; de&#160;55&#160;anos&#46;<a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">39</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">O acometimento da pele pode se dar por contiguidade&#44; por dissemina&#231;&#227;o linf&#225;tica ou hematog&#234;nica ou&#44; ainda por dissemina&#231;&#227;o ao longo dos remanescentes embrion&#225;rios&#44; como o &#250;raco&#46;<a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">40</span></a> Por isso&#44; a pele do abdome &#233; o s&#237;tio do tegumento mais frequentemente afetado&#44; seguido pela regi&#227;o pr&#233;&#8208;sacral e perineal&#44; esta &#250;ltima mais relacionada ao c&#226;ncer retal&#46;<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">38</span></a> Num estudo&#44; a maioria das met&#225;stases cut&#226;neas surgiu nos locais da incis&#227;o cir&#250;rgica da colectomia&#46;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">17</span></a> Apesar disso&#44; h&#225; relatos de dissemina&#231;&#227;o para as mais diversas localidades&#44; como t&#243;rax&#44; membros superiores e regi&#227;o de cabe&#231;a e pesco&#231;o&#46;<a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">40</span></a> Quando a met&#225;stase acomete a regi&#227;o umbilical&#44; &#233; denominada n&#243;dulo da irm&#227; Mary Joseph&#46;<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">41</span></a> Esse achado n&#227;o &#233; patognom&#244;nico de tumores colorretais&#44; j&#225; que foi relatado em outras malignidades como est&#244;mago&#44; ov&#225;rio&#44; p&#226;ncreas e at&#233; mesmo de colo uterino&#44; ves&#237;cula biliar e intestino delgado&#46;<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">41</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">N&#227;o h&#225; uma apresenta&#231;&#227;o cl&#237;nica caracter&#237;stica&#59; a maioria surge como les&#245;es nodulares firmes de colora&#231;&#227;o r&#243;sea ou avermelhada que pode ulcerar&#46;<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">38</span></a> Outras apresenta&#231;&#245;es descritas s&#227;o les&#245;es semelhantes a cistos epid&#233;rmicos&#44; neurofibromas&#44; eritema anular&#44; condilomas&#44; elefant&#237;ase nostra verrucosa e &#225;reas de alopecia&#46;<a class="elsevierStyleCrossRefs" href="#bib0395"><span class="elsevierStyleSup">17&#44;40</span></a> No caso do n&#243;dulo da irm&#227; Mary Joseph&#44; tipicamente h&#225; n&#243;dulos firmes medindo de 0&#44;5 a 2<span class="elsevierStyleHsp" style=""></span>cm&#44; que podem eventualmente drenar secre&#231;&#227;o purulenta&#44; serosa ou sangue&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">21</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall">No caso de tumores g&#225;stricos&#44; o que mais se metastatiza para a pele &#233; o carcinoma de c&#233;lulas de anel de sinete&#46;<a class="elsevierStyleCrossRef" href="#bib0520"><span class="elsevierStyleSup">42</span></a> Assim como o adenocarcinoma colorretal&#44; o abdome &#233; o local mais comumente acometido e clinicamente podem se apresentar como n&#243;dulos&#44; les&#245;es do tipo erisipela&#8208;s&#237;mile&#44; ou semelhantes a cistos epid&#233;rmicos&#46;<a class="elsevierStyleCrossRef" href="#bib0520"><span class="elsevierStyleSup">42</span></a> O progn&#243;stico &#233; muito ruim em ambas as met&#225;stases&#44; com sobrevida m&#233;dia de poucos meses&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">Por fim&#44; h&#225; raros relatos de met&#225;stases cut&#226;neas oriundas de neoplasias malignas do es&#244;fago&#44; p&#226;ncreas e f&#237;gado&#46;<a class="elsevierStyleCrossRef" href="#bib0525"><span class="elsevierStyleSup">43</span></a> Nesses casos&#44; as les&#245;es foram identificadas em diferentes s&#237;tios como couro cabeludo&#44; abdome e dorso&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Sistema genitourin&#225;rio</span><p id="par0150" class="elsevierStylePara elsevierViewall">Dos c&#226;nceres do sistema urin&#225;rio&#44; o renal &#233; o mais comum&#46; Como o carcinoma de c&#233;lulas renais produz poucos sinais e sintomas&#44; a maioria &#233; diagnosticada em fases tardias&#44; quando j&#225; h&#225; met&#225;stases&#46;<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">44</span></a> Desses casos metast&#225;ticos&#44; em menos de 2&#37; das vezes o s&#237;tio da met&#225;stase &#233; a pele&#59; o carcinoma renal de c&#233;lulas claras &#233; o subtipo histol&#243;gico mais comum&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">21</span></a> Na maioria dos casos&#44; o paciente j&#225; tem o diagn&#243;stico de c&#226;ncer renal quando a met&#225;stase cut&#226;nea &#233; identificada &#40;seis a cinco anos ap&#243;s o diagn&#243;stico&#41;&#44; por&#233;m em at&#233; 20&#37; dos casos a les&#227;o cut&#226;nea surge antes da identifica&#231;&#227;o do tumor renal prim&#225;rio&#46;<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">45</span></a></p><p id="par0155" class="elsevierStylePara elsevierViewall">A regi&#227;o da cabe&#231;a e pesco&#231;o &#233; frequentemente acometida pelas met&#225;stases do carcinoma de c&#233;lulas renais&#46; A teoria vigente explica que as veias renais apresentam anastomoses com os plexos vertebrais&#44; que por sua vez t&#234;m conex&#227;o com a vasculariza&#231;&#227;o cef&#225;lica&#46; Isso tornaria poss&#237;vel a dissemina&#231;&#227;o hematog&#234;nica das c&#233;lulas neopl&#225;sicas renais para a regi&#227;o da cabe&#231;a e pesco&#231;o&#46;<a class="elsevierStyleCrossRef" href="#bib0540"><span class="elsevierStyleSup">46</span></a> &#201; importante frisar que o carcinoma de c&#233;lulas renais&#44; bem como o carcinoma folicular de tireoide e o carcinoma hepatocelular&#44; se disseminam preferencialmente por via hematog&#234;nica&#46;<a class="elsevierStyleCrossRef" href="#bib0540"><span class="elsevierStyleSup">46</span></a></p><p id="par0160" class="elsevierStylePara elsevierViewall">As met&#225;stases cut&#226;neas do carcinoma de c&#233;lulas renais se apresentam como n&#243;dulos de crescimento r&#225;pido&#44; que podem ser normocr&#244;micos ou mais caracteristicamente avermelhados&#46; Isso ocorre pela alta vasculariza&#231;&#227;o do tumor e&#44; por isso&#44; podem ser confundidos com hemangiomas&#44; angiomas rubis ou granuloma piog&#234;nico&#46;<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">47</span></a> A presen&#231;a de met&#225;stase &#233; um marcador de pior progn&#243;stico&#44; e a expectativa de vida &#233; de aproximadamente seis meses&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">Mais raramente s&#227;o descritos casos de met&#225;stase cut&#226;nea de carcinoma urotelial da bexiga com sobrevida m&#233;dia de menos de 12 meses&#46; Na maioria das vezes o envolvimento cut&#226;neo ocorre por invas&#227;o tumoral direta&#44; mas tamb&#233;m pode ser secund&#225;rio a dissemina&#231;&#227;o vascular &#40;linf&#225;tica ou hematog&#234;nica&#41; ou implante iatrog&#234;nico &#40;p&#243;s&#8208;procedimentos&#44; como cistectomia&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">48</span></a> Por isso&#44; na maioria das vezes a les&#227;o se localiza no abdome inferior&#44; pelve ou escroto&#46; A apresenta&#231;&#227;o cl&#237;nica &#233; inespec&#237;fica e pode ser &#250;nica ou m&#250;ltipla&#44; surgindo como n&#243;dulos&#44; placas infiltradas ou at&#233; mesmo com aspecto esclerodermiforme&#46;<a class="elsevierStyleCrossRef" href="#bib0555"><span class="elsevierStyleSup">49</span></a> Por fim&#44; Savell et al&#46; descreveram um caso de carcinoma urotelial se manifestando como livedo racemosa em decorr&#234;ncia de oclus&#227;o vascular&#46;<a class="elsevierStyleCrossRef" href="#bib0560"><span class="elsevierStyleSup">50</span></a></p><p id="par0170" class="elsevierStylePara elsevierViewall">As met&#225;stases cut&#226;neas de tumores ginecol&#243;gicos &#40;excluindo mama&#41; podem corresponder a at&#233; 8&#44;5&#37; dos implantes secund&#225;rios em pacientes do sexo feminino&#46;<a class="elsevierStyleCrossRef" href="#bib0525"><span class="elsevierStyleSup">43</span></a> A maioria dos casos &#233; derivada de neoplasias malignas do ov&#225;rio&#44; mas tamb&#233;m pode ser oriunda de c&#226;ncer do colo uterino&#46; Por quest&#245;es anat&#244;micas&#44; o abdome &#40;principalmente cicatriz umbilical&#41; &#233; o local mais comumente atingido&#46;<a class="elsevierStyleCrossRef" href="#bib0525"><span class="elsevierStyleSup">43</span></a> Quanto ao sexo masculino&#44; sabe&#8208;se que o c&#226;ncer de pr&#243;stata raramente cursa com met&#225;stase cut&#226;nea&#44; embora seja muito frequente&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">11</span></a></p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Cabe&#231;a e pesco&#231;o</span><p id="par0175" class="elsevierStylePara elsevierViewall">Os carcinomas espinocelulares de cabe&#231;a e pesco&#231;o t&#234;m como s&#237;tio mais comum de met&#225;stase a dist&#226;ncia o pulm&#227;o e os ossos&#46; Pitman et al&#46;&#44; em uma coorte de 2&#46;491 pacientes com carcinoma espinocelular de cabe&#231;a e pesco&#231;o&#44; identificaram apenas 19 &#40;0&#44;763&#37;&#41; com met&#225;stase cut&#226;nea&#46;<a class="elsevierStyleCrossRef" href="#bib0565"><span class="elsevierStyleSup">51</span></a> J&#225; Yoskovitch et al&#46; identificaram 19 casos &#40;2&#44;4&#37;&#41; de met&#225;stases cut&#226;neas entre 798 carcinomas espinocelulares de cabe&#231;a e pesco&#231;o&#46;<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">52</span></a> &#201; importante notar que nesses estudos foram exclu&#237;dos os casos de acometimento cut&#226;neo por contiguidade tumoral&#44; inclu&#237;dos apenas aqueles com met&#225;stase a dist&#226;ncia&#46;</p><p id="par0180" class="elsevierStylePara elsevierViewall">Os carcinomas espinocelulares da cavidade oral&#44; principalmente do assoalho&#44; s&#227;o os que mais levam a met&#225;stases cut&#226;neas&#46;<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">52</span></a> O pesco&#231;o&#44; couro cabeludo e t&#243;rax anterior s&#227;o os s&#237;tios acometidos em 63&#37;&#44; 15&#37; e 10&#37;&#44; respectivamente e&#44; na maioria dos casos&#44; as les&#245;es s&#227;o m&#250;ltiplas&#46;<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">52</span></a> A sobrevida m&#233;dia ap&#243;s o surgimento da met&#225;stase &#233; de apenas tr&#234;s meses&#46;<a class="elsevierStyleCrossRef" href="#bib0565"><span class="elsevierStyleSup">51</span></a></p><p id="par0185" class="elsevierStylePara elsevierViewall">Outro tumor maligno frequente do pesco&#231;o &#233; carcinoma de tireoide&#44; a malignidade endocrinol&#243;gica mais comum&#46;<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">53</span></a> Os dois principais tipos histol&#243;gicos &#40;papilar e folicular&#41; s&#227;o os que mais frequentemente acometem a pele secundariamente&#44; com incid&#234;ncia estimada de menos de&#160;1&#160;para&#160;1&#46;000&#160;casos&#46;<a class="elsevierStyleCrossRefs" href="#bib0580"><span class="elsevierStyleSup">54&#44;55</span></a> H&#225; rar&#237;ssimos casos de met&#225;stase cut&#226;nea de carcinomas anapl&#225;sicos ou medulares&#59;<a class="elsevierStyleCrossRef" href="#bib0590"><span class="elsevierStyleSup">56</span></a> a ocorr&#234;ncia em homens e mulheres se d&#225; na mesma propor&#231;&#227;o&#44; com m&#233;dia de idade de 50 anos&#46;<a class="elsevierStyleCrossRef" href="#bib0580"><span class="elsevierStyleSup">54</span></a> Na maioria dos casos&#44; o couro cabeludo &#233; a regi&#227;o da pele envolvida&#44; embora outras &#225;reas como tronco &#40;anterior e posterior&#41;&#44; face e pesco&#231;o tamb&#233;m tenham sido relatados &#40;<a class="elsevierStyleCrossRef" href="#fig0020">fig&#46; 4</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0580"><span class="elsevierStyleSup">54&#44;57</span></a> H&#225; uma apresenta&#231;&#227;o cl&#237;nica caracter&#237;stica&#44; j&#225; que a maioria dos relatos da literatura descrevem n&#243;dulos eritematosos&#44; pruriginosos ou ulcerados&#44; localizados no couro cabeludo&#46;<a class="elsevierStyleCrossRefs" href="#bib0575"><span class="elsevierStyleSup">53&#44;57</span></a> A sobrevida m&#233;dia ap&#243;s o diagn&#243;stico da met&#225;stase cut&#226;nea &#233; de 19 meses&#46;<a class="elsevierStyleCrossRef" href="#bib0580"><span class="elsevierStyleSup">54</span></a></p><elsevierMultimedia ident="fig0020"></elsevierMultimedia></span></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Diagn&#243;stico</span><p id="par0190" class="elsevierStylePara elsevierViewall">O diagn&#243;stico definitivo depende de exame cl&#237;nico minucioso&#44; exames de imagem e an&#225;lise histopatol&#243;gica&#46; A <a class="elsevierStyleCrossRef" href="#tbl0010">tabela 2</a> resume ind&#237;cios histopatol&#243;gicos para a suspeita de met&#225;stases cut&#226;neas&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0195" class="elsevierStylePara elsevierViewall">As caracter&#237;sticas histopatol&#243;gicas e imuno&#8208;histoqu&#237;micas da met&#225;stase cut&#226;nea tendem a ser semelhantes ao do tumor prim&#225;rio&#44; por&#233;m as c&#233;lulas metast&#225;ticas tendem a ser mais anapl&#225;sicas e menos diferenciadas&#46;<a class="elsevierStyleCrossRef" href="#bib0600"><span class="elsevierStyleSup">58</span></a> Hussein recomenda que um painel imuno&#8208;histoqu&#237;mico b&#225;sico inclua CD45 &#40;para malignidades linfoides&#41;&#44; panqueratinas AE1&#47;AE3 &#40;para a maioria dos carcinomas&#41;&#44; S100 &#40;melanomas&#41; e CD34 &#40;neoplasias vasculares e leucemias&#41;&#46; A partir da&#237; &#233; realizado um segundo painel&#44; que pode incluir marcados linfoides &#40;CD3 e CD20 para linf&#243;citos T e B&#44; respectivamente&#41;&#44; marcadores epiteliais &#40;EMA e CEA&#41;&#44; cromogranina &#40;tumores neuroend&#243;crinos&#41;&#44; fator de transcri&#231;&#227;o tiroidiano &#40;c&#226;ncer de pulm&#227;o&#41;&#44; WT1 &#40;carcinoma de ov&#225;rio&#41;&#44; ant&#237;geno espec&#237;fico da pr&#243;stata e fosfatase &#225;cida &#40;carcinoma de pr&#243;stata&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0600"><span class="elsevierStyleSup">58</span></a> A <a class="elsevierStyleCrossRef" href="#tbl0015">tabela 3</a> resume os imunofen&#243;tipos dos principais tumores que sofrem met&#225;stases para a pele&#44; e as <a class="elsevierStyleCrossRefs" href="#fig0025">figuras 5 e 6</a> exemplificam&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><elsevierMultimedia ident="fig0025"></elsevierMultimedia><elsevierMultimedia ident="fig0030"></elsevierMultimedia><p id="par0200" class="elsevierStylePara elsevierViewall">Mesmo ap&#243;s a avalia&#231;&#227;o imuno&#8208;histoqu&#237;mica&#44; por vezes o patologista n&#227;o consegue determinar com exatid&#227;o o tumor prim&#225;rio e apenas classifica em classes gen&#233;ticas como adenocarcinoma&#44; carcinoma de c&#233;lulas escamosas ou carcinoma indiferenciado&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">15</span></a> Em alguns casos&#44; ap&#243;s a avalia&#231;&#227;o inicial&#44; n&#227;o se consegue determinar a origem prim&#225;ria do tumor e s&#227;o classificados como c&#226;ncer de s&#237;tio prim&#225;rio desconhecido&#46;<a class="elsevierStyleCrossRef" href="#bib0605"><span class="elsevierStyleSup">59</span></a> Nesses casos&#44; &#233; preciso uma avalia&#231;&#227;o mais aprofundada&#46; Os primeiros exames radiol&#243;gicos s&#227;o a tomografia computadorizada &#40;TC&#41; e&#47;ou resson&#226;ncia magn&#233;tica &#40;RM&#41; de v&#225;rios segmentos do corpo&#44; associado &#224; mamografia quando h&#225; suspeita de c&#226;ncer de mama&#46; Se esses exames forem inconclusivos&#44; o pr&#243;ximo passo &#233; uma tomografia por emiss&#227;o de p&#243;sitrons &#40;PET&#41; e TC &#40;PET&#8208;CT&#41; combinadas&#46;<a class="elsevierStyleCrossRef" href="#bib0605"><span class="elsevierStyleSup">59</span></a></p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Tratamento</span><p id="par0205" class="elsevierStylePara elsevierViewall">De modo geral&#44; o tratamento deve ser direcionado ao tumor prim&#225;rio&#46; Como na maioria das vezes a presen&#231;a de met&#225;stase cut&#226;nea indica doen&#231;a avan&#231;ada&#44; a terapia sist&#234;mica antineopl&#225;sica usualmente &#233; a op&#231;&#227;o terap&#234;utica escolhida&#46; Por&#233;m&#44; a terapia sist&#234;mica pode ter efic&#225;cia reduzida nas les&#245;es cut&#226;neas&#44; e terapias dirigidas &#224; pele t&#234;m fun&#231;&#227;o adjuvante&#46;</p><p id="par0210" class="elsevierStylePara elsevierViewall">Uma metan&#225;lise que incluiu 47 estudos e 4&#46;313 met&#225;stases cut&#226;neas avaliou cinco terapias dirigidas &#224; pele&#58; eletroquimioterapia&#44; terapia fotodin&#226;mica&#44; radioterapia&#44; terapia intralesional e terapia t&#243;pica&#46;<a class="elsevierStyleCrossRef" href="#bib0610"><span class="elsevierStyleSup">60</span></a> Os pesquisadores encontraram taxa de resposta completa e taxa de resposta objetiva de 35&#44;5&#37; e 60&#44;2&#37;&#44; respectivamente&#46; A eletroquimioterapia para met&#225;stases cut&#226;neas usa pulsos el&#233;tricos curtos direcionados ao tumor para permeabilizar as membranas celulares a fim de aumentar a absor&#231;&#227;o da quimioterapia intralesional ou intravenosa&#46;</p><p id="par0215" class="elsevierStylePara elsevierViewall">Quanto &#224;s terapias intralesionais&#44; h&#225; estudos com inje&#231;&#245;es de anticorpos recombinantes direcionados para ErbB2&#47;HER2 em casos de c&#226;ncer de colo e de mama e de interferona e interleucina&#8208;2 em melanoma&#46;<a class="elsevierStyleCrossRef" href="#bib0615"><span class="elsevierStyleSup">61</span></a> &#201; poss&#237;vel&#44; ainda&#44; realizar tratamento com imunoterapia t&#243;pica para alguns tumores&#46; Um estudo brasileiro demonstrou que a difenciprona pode levar a at&#233; 37&#37; de resposta completa em casos de met&#225;stases de melanoma cut&#226;neo&#46;<a class="elsevierStyleCrossRef" href="#bib0620"><span class="elsevierStyleSup">62</span></a></p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Conclus&#227;o</span><p id="par0220" class="elsevierStylePara elsevierViewall">Apesar de infrequente&#44; a met&#225;stase cut&#226;nea pode ser o primeiro sinal de uma neoplasia maligna ou indicar sua recidiva&#46; O dermatologista deve saber identificar as les&#245;es suspeitas e realizar a biopsia de maneira adequada&#46; O diagn&#243;stico depender&#225; da an&#225;lise cl&#237;nica&#44; histopatol&#243;gica e imuno&#8208;histoqu&#237;mica&#46; Por vezes&#44; a identifica&#231;&#227;o do s&#237;tio prim&#225;rio &#233; dif&#237;cil&#44; por&#233;m &#233; importante a an&#225;lise minuciosa por meio de exames de imagem e constante vigil&#226;ncia&#46;</p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Suporte financeiro</span><p id="par0225" class="elsevierStylePara elsevierViewall">Nenhum&#46;</p></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Contribui&#231;&#227;o dos autores</span><p id="par0230" class="elsevierStylePara elsevierViewall">Bruno de Castro e Souza&#58; Elabora&#231;&#227;o e reda&#231;&#227;o do manuscrito&#59; revis&#227;o cr&#237;tica da literatura&#46;</p><p id="par0235" class="elsevierStylePara elsevierViewall">Denis Miyashiro&#58; Obten&#231;&#227;o&#44; an&#225;lise e interpreta&#231;&#227;o de dados&#59; elabora&#231;&#227;o e reda&#231;&#227;o do manuscrito&#59; revis&#227;o cr&#237;tica da literatura&#46;</p><p id="par0240" class="elsevierStylePara elsevierViewall">Marcella Soares Pincelli&#58; Concep&#231;&#227;o e planejamento do estudo&#44; elabora&#231;&#227;o e reda&#231;&#227;o do manuscrito&#59; revis&#227;o cr&#237;tica da literatura&#46;</p><p id="par0245" class="elsevierStylePara elsevierViewall">Jos&#233; Antonio Sanches&#58; Concep&#231;&#227;o e planejamento do estudo&#44; elabora&#231;&#227;o e reda&#231;&#227;o do manuscrito&#59; revis&#227;o cr&#237;tica da literatura&#46;</p></span><span id="sec0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Conflito de interesses</span><p id="par0250" 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">As met&#225;stases cut&#226;neas de tumores s&#243;lidos s&#227;o eventos pouco frequentes na pr&#225;tica cl&#237;nica&#46; Na maioria das vezes&#44; o paciente j&#225; tem o diagn&#243;stico de neoplasia maligna quando a met&#225;stase cut&#226;nea &#233; detectada&#46; No entanto&#44; em at&#233; um ter&#231;o dos casos a met&#225;stase cut&#226;nea &#233; identificada antes do tumor prim&#225;rio &#8211; portanto&#44; seu reconhecimento pode ser fundamental para o in&#237;cio do tratamento&#44; embora geralmente seja indicativo de progn&#243;stico ruim&#46; O diagn&#243;stico depender&#225; da an&#225;lise cl&#237;nica&#44; histopatol&#243;gica e imuno&#8208;histoqu&#237;mica&#46; A identifica&#231;&#227;o do s&#237;tio prim&#225;rio pode ser dif&#237;cil&#59; assim&#44; &#233; importante uma an&#225;lise minuciosa por meio de exames de imagem e constante vigil&#226;ncia&#46;</p></span>"
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          "pt" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">&#40;A&#41; Prolifera&#231;&#227;o nodular at&#237;pica na derme profunda em paciente com met&#225;stase cut&#226;nea de adenocarcinoma de c&#243;lon &#40;Hematoxilina &#38; eosina&#44; 100<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>&#41;&#46; CK7 &#40;B&#41; CDX2 &#40;C&#41; e EMA &#40;D&#41; positivos corroboram o diagn&#243;stico</p>"
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                  \t\t\t\t">Face e pesco&#231;o&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Mama&#44; pulm&#227;o&#44; melanoma&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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          "pt" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Principais localiza&#231;&#245;es das met&#225;stases cut&#226;neas de acordo com o tumor prim&#225;rio<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">15</span></a></p>"
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                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">Presen&#231;a de c&#233;lulas neopl&#225;sicas alinhadas entre as fibras de col&#225;geno &#40;&#8220;filas indianas&#8221;&#41;&nbsp;\t\t\t\t\t\t\n
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          "pt" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Ind&#237;cios histopatol&#243;gicos para a suspeita de met&#225;stases cut&#226;neas<a class="elsevierStyleCrossRef" href="#bib0600"><span class="elsevierStyleSup">58</span></a></p>"
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
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                  \t\t\t\t">CK20&#44; CK7&#44; CEA&#44; CDX2&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">CK7 &#40;alguns casos podem ser positivos&#41;&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">Adenocarcinoma de pulm&#227;o&nbsp;\t\t\t\t\t\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">FTT&#8208;1&#44; CK7&#44; CEA&#44; EMA&nbsp;\t\t\t\t\t\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">CK5&#47;6&#44; CK20&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">C&#226;ncer de pulm&#227;o de pequenas c&#233;lulas&nbsp;\t\t\t\t\t\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">FTT&#8208;1&#44; enolase neuronal espec&#237;fica &#40;NSE&#41;&#44; cromogranina&#44; sinaptofisina&nbsp;\t\t\t\t\t\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">CK7&#44; CK20&#44; CD99&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">Carcinoma renal de c&#233;lulas claras&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">CAM5&#46;2&#44; EMA&#44; CD10&#44; RCC&#8208;Ma&#44; vimentina&#44; S100&nbsp;\t\t\t\t\t\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">melan&#8208;A&#44; TTF&#8208;1&#44; CK7&#44; CK20&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">Melanoma&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">Vimentina&#44; S100&#44; tirosinase&#44; melan&#8208;A&#44; HMB45&#44; MITF&nbsp;\t\t\t\t\t\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">&#8208;&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">Bexiga&#47;urotelial&nbsp;\t\t\t\t\t\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">P63&#44; CK5&#47;6&#44; CK7&#44; CK20&#44; uroplaquina III&nbsp;\t\t\t\t\t\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">&#8208;&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">Pr&#243;stata&nbsp;\t\t\t\t\t\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">PSA&#44; fosfatase &#225;cida prost&#225;tica&#44;&nbsp;\t\t\t\t\t\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">CK7&#44; CK20&#44; trombomodulina&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">Ov&#225;rio&nbsp;\t\t\t\t\t\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">CA&#46;125&#44; CK7&#44; PAX8&nbsp;\t\t\t\t\t\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">CK20 &#40;exceto algumas variantes mucinosas&#41;&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">Carcinoma espinocelular de cabe&#231;a e pesco&#231;o&nbsp;\t\t\t\t\t\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">CK5&#47;6&#44; p63&#44; CK903&nbsp;\t\t\t\t\t\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">&#8208;&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">Tireoide&nbsp;\t\t\t\t\t\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">FTT&#8208;1&#44; tiroglobulina&#44; PAX8&nbsp;\t\t\t\t\t\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">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "pt" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Resumo de imunofen&#243;tipos dos principais tumores que metastatizam para a pele<a class="elsevierStyleCrossRef" href="#bib0600"><span class="elsevierStyleSup">58</span></a></p>"
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      "titulo" => "Refer&#234;ncias"
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        0 => array:2 [
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                  "host" => array:1 [
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                  "host" => array:1 [
                    0 => array:2 [
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                          "etal" => true
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                            1 => "F&#46; Castro-Giner"
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                            4 => "M&#46; Saini"
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                  ]
                  "host" => array:1 [
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            8 => array:3 [
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                            1 => "X&#46;H&#46; Zhang"
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                  "host" => array:1 [
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "M&#46;H&#46; Brownstein"
                            1 => "E&#46;B&#46; Helwig"
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                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
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                  "contribucion" => array:1 [
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                          "etal" => false
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                            2 => "L&#46; Soares de Almeida"
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/jdv.16120"
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                        "tituloSerie" => "J Eur Acad Dermatol Venereol&#46;"
                        "fecha" => "2020"
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