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inflamat&#243;ria&#44; sist&#234;mica e fibr&#243;tica que pode afetar quase todos os &#243;rg&#227;os&#46; Foi encontrado um relato de que alguns casos de DRD exibiam caracter&#237;sticas de DR&#8208;IgG4&#44; mas a rela&#231;&#227;o entre DRDC e DR&#8208;IgG4 n&#227;o foi estudada&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">10</span></a> Para investigar melhor a rela&#231;&#227;o entre DRDC e DR&#8208;IgG4&#44; foram avaliadas as manifesta&#231;&#245;es cl&#237;nicas e caracter&#237;sticas histopatol&#243;gicas de 23 casos de DRDC e detectada a express&#227;o de IgG e IgG4&#44; que podem fornecer novos biomarcadores &#40;IgG4&#44; IgG e a raz&#227;o IgG4&#47;IgG&#41; para a identifica&#231;&#227;o de DRDC e ajudar a esclarecer sua patogenia&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Materiais e m&#233;todos</span><p id="par0010" class="elsevierStylePara elsevierViewall">Foram avaliados 23 casos em dois hospitais diferentes&#44; durante o per&#237;odo de agosto de 2009 a agosto de 2018&#46; Todos os casos foram diagnosticados por dois patologistas experientes&#44; de acordo com os crit&#233;rios de diagn&#243;stico mais recentes da Organiza&#231;&#227;o Mundial da Sa&#250;de &#40;OMS&#41;&#46; O presente estudo foi autorizado pelo Comit&#234; de &#201;tica e conduzido sob os princ&#237;pios &#233;ticos da Declara&#231;&#227;o de Direitos Humanos adotada em Helsinque e estava de acordo com as Regras de Boas Pr&#225;ticas Cl&#237;nicas&#46; Todos os pacientes receberam esclarecimentos sobre consentimento informado&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">As biopsias de pele foram fixadas em solu&#231;&#227;o tamponada de formol a 10&#37;&#44; processadas e emblocadas em parafina&#46; Os blocos de parafina foram seccionados com micr&#243;tomo para obter cortes histol&#243;gicos de 4&#8208;5<span class="elsevierStyleHsp" style=""></span>&#956;m colocados em l&#226;minas de vidro&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">A colora&#231;&#227;o pela hematoxilina &#38; eosina &#40;HE&#41; foi utilizada para histopatologia cl&#225;ssica&#44; e a IHQ foi realizada no mesmo material biol&#243;gico emblocado em parafina&#46; Cada rea&#231;&#227;o imuno&#8208;histoqu&#237;mica incluiu um controle negativo &#40;sem incuba&#231;&#227;o com o anticorpo prim&#225;rio&#41;&#46; Os anticorpos IgG4 e IgG &#40;comercialmente dispon&#237;veis&#41; foram adquiridos da Zhongshan Golden Bridge Biological Technology Company&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">As c&#233;lulas IgG4&#40;&#43;&#41; e IgG&#40;&#43;&#41; foram contadas separadamente utilizando microsc&#243;pio Olympus BX40 e o <span class="elsevierStyleItalic">software</span> Image J 1&#46;52a para computador&#46; Tr&#234;s campos de grande aumento com o n&#250;mero m&#225;ximo de c&#233;lulas positivas foram contados&#44; e um n&#250;mero m&#233;dio por campo de grande aumento foi calculado&#46; Um campo de grande aumento representa uma &#225;rea de 0&#44;24<span class="elsevierStyleHsp" style=""></span>mm<span class="elsevierStyleSup">2</span>&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Resultados</span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Caracter&#237;sticas cl&#237;nicas</span><p id="par0030" class="elsevierStylePara elsevierViewall">A idade dos 23 pacientes com DRDC &#40;14 do sexo masculino e nove do sexo feminino&#41; variou de 17 a 68 anos &#40;m&#233;dia de 47&#44;91<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>14&#44;16&#41;&#46; Dentre eles&#44; 16 pacientes apresentavam les&#245;es &#250;nicas&#44; enquanto os outros sete apresentavam les&#245;es m&#250;ltiplas&#46; Dez pacientes apresentavam placas&#44; 12 tinham manchas e um paciente apresentava massa subaxilar&#46; Na maioria dos casos de DRDC&#44; as les&#245;es distribu&#237;ram&#8208;se pela face e pelo t&#243;rax&#46; Em nove casos&#44; a les&#227;o estava em outro local&#44; como membro&#44; dorso ou coxa&#46; As caracter&#237;sticas cl&#237;nicas de todos os pacientes est&#227;o descritas na <a class="elsevierStyleCrossRef" href="#fig0005">figura 1</a> e na <a class="elsevierStyleCrossRef" href="#fig0010">figura 2</a> e resumidas na <a class="elsevierStyleCrossRef" href="#tbl0005">tabela 1</a>&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Caracter&#237;sticas histopatol&#243;gicas</span><p id="par0035" class="elsevierStylePara elsevierViewall">Foi observada infiltra&#231;&#227;o difusa de grandes histi&#243;citos e plasm&#243;citos com neutr&#243;filos e linf&#243;citos dispersos em todos os cortes histol&#243;gicos &#40;<a class="elsevierStyleCrossRef" href="#fig0015">fig&#46; 3</a>A&#41;&#46; Na maioria dos casos&#44; os histi&#243;citos eram grandes&#44; com citoplasma amplo e p&#225;lido e n&#250;cleos arredondados evidentes&#46; Entretanto&#44; os histi&#243;citos apresentavam aspecto espumoso ou multinuclea&#231;&#227;o em quatro casos&#46; Foram observadas fibrose difusa e deposi&#231;&#227;o de col&#225;geno sem infiltra&#231;&#227;o de fibroblastos em um caso&#46; Emperipolese foi encontrada na maioria dos casos de DRDC&#46; Al&#233;m disso&#44; foram observadas hem&#225;cias engolfadas por histi&#243;citos em um caso&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0040" class="elsevierStylePara elsevierViewall">As caracter&#237;sticas IHQ s&#227;o mostradas na <a class="elsevierStyleCrossRef" href="#fig0015">figura 3</a>B e 3C e est&#227;o resumidas na <a class="elsevierStyleCrossRef" href="#tbl0010">tabela 2</a>&#46; Os resultados revelaram express&#227;o significante de IgG4 em seis pacientes &#40;&#62; 50 c&#233;lulas&#47; campo de grande aumento&#41;&#44; express&#227;o moderada de IgG4 em tr&#234;s pacientes &#40;30&#8208;50 c&#233;lulas&#47; campo de grande aumento&#41;&#44; express&#227;o leve em nove pacientes &#40;10&#8208;29 c&#233;lulas&#47; campo de grande aumento&#41; e infiltra&#231;&#227;o negativa em cinco pacientes &#40;&#60; 10 c&#233;lulas&#47; campo de grande aumento&#41;&#46; A raz&#227;o IgG4&#47;IgG variou de 1&#44;7 a 85&#44;7&#37; &#40;m&#233;dia de 29&#44;5&#37;&#44; mediana de 20&#44;8&#37;&#41; em todos os casos positivos&#44; e a raz&#227;o IgG4&#47;IgG foi superior a 40&#37; em sete casos&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Discuss&#227;o</span><p id="par0045" class="elsevierStylePara elsevierViewall">Em compara&#231;&#227;o com a DRD sist&#234;mica cl&#225;ssica&#44; a DRDC parece ocorrer com mais frequ&#234;ncia em asi&#225;ticos e predomina no sexo feminino&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">11</span></a> A doen&#231;a geralmente afeta indiv&#237;duos de meia&#8208;idade&#44; de 40 a 60 anos&#46; Dos 23 pacientes inclu&#237;dos no presente estudo&#44; 65&#37; tinham mais de 50 anos&#44; idade em que a predomin&#226;ncia feminina &#233; menos evidente&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">Em contraste com a DRD cl&#225;ssica com sintomas sist&#234;micos evidentes&#44; a DRDC geralmente &#233; limitada &#224; pele&#46; As les&#245;es na pele em DRDC variam em morfologia&#44; tamanho&#44; cor e localiza&#231;&#227;o&#46; As manifesta&#231;&#245;es cl&#237;nicas incluem p&#225;pulas&#44; placas&#44; n&#243;dulos e p&#250;stulas&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">12</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">Emperipolese &#233; fen&#244;meno de linf&#243;citos que mant&#234;m sua estrutura e fun&#231;&#227;o&#44; enquanto aprisionados no citoplasma de histi&#243;citos&#46; N&#227;o &#233; caracter&#237;stica exclusiva da DRDC e tamb&#233;m pode ser observada em casos de linfoma de Hodgkin&#44; melanoma e em alguns outros tumores malignos&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">13</span></a> Os crit&#233;rios diagn&#243;sticos mais reconhecidos da DRDC s&#227;o IHQ positiva para prote&#237;nas CD68 e S&#8208;100 e negativa para CD1a&#46; Apesar disso&#44; o diagn&#243;stico de DRD ainda permanece um desafio&#44; provavelmente pela sobreposi&#231;&#227;o de suas manifesta&#231;&#245;es cl&#237;nicas&#44; morfologia e caracter&#237;sticas de IHQ com as de outras doen&#231;as&#46; &#201; prov&#225;vel que a DRD seja confundida com DR&#8208;IgG4 em termos de manifesta&#231;&#245;es cl&#237;nicas&#46; Aumento do n&#250;mero de plasm&#243;citos IgG4&#43; foi encontrado em 70 casos nodais e extranodais de DRD&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">14</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">Os padr&#245;es diagn&#243;sticos mais reconhecidos para DR&#8208;IgG4 com base em sua histopatologia e IHQ s&#227;o os seguintes&#58; aumento difuso ou caracter&#237;stico&#44; tumores&#44; n&#243;dulos ou hipertrofia de um ou mais &#243;rg&#227;os&#59; n&#237;veis s&#233;ricos de IgG4 aumentados &#8805; 1&#44;350<span class="elsevierStyleHsp" style=""></span>mg&#47;L&#59; e histopatologia mostrando infiltra&#231;&#227;o de linf&#243;citos e plasm&#243;citos&#44; e fibrose evidente&#44; ou infiltra&#231;&#227;o de plasm&#243;citos IgG4&#43; com raz&#227;o de plasm&#243;citos IgG4&#47;IgG&#43; superior a 40&#37; e quantidade de c&#233;lulas IgG4&#43;<span class="elsevierStyleHsp" style=""></span>&#62; 200&#47; campo de grande aumento na pele&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">15</span></a> Zhang et al&#46; especularam que DR&#8208;IgG4 e DRD podem compartilhar uma patog&#234;nese comum&#44; ou que as caracter&#237;sticas da DR&#8208;IgG4 podem ocorrer em algum est&#225;gio da DRD&#44;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">10</span></a> o que torna a identifica&#231;&#227;o mais dif&#237;cil&#46; No presente estudo&#44; quatro pacientes diagnosticados com DRDC tamb&#233;m preenchem os crit&#233;rios diagn&#243;sticos para DR&#8208;IgG4&#44; com raz&#227;o de plasm&#243;citos IgG4&#47;IgG&#43;<span class="elsevierStyleHsp" style=""></span>&#62; 40&#37;&#46; Esses resultados mostraram que DRD e DR&#8208;IgG4 n&#227;o eram completamente distintas uma da outra&#46; Entretanto&#44; no total de 23 casos de DRDC&#44; a quantidade de c&#233;lulas IgG4&#43; foi &#60; 200&#47; campo de grande aumento&#46; &#201; poss&#237;vel&#44; portanto&#44; determinar se o paciente tem DRD&#44; DR&#8208;IgG4 ou uma sobreposi&#231;&#227;o das duas com base na avalia&#231;&#227;o IHQ de IgG&#44; IgG4 e da raz&#227;o de plasm&#243;citos IgG4&#47;IgG combinadas com as altera&#231;&#245;es histopatol&#243;gicas e os resultados da IHQ para S&#8208;100&#44; CD68 e CD1a&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">Em geral&#44; a DRDC &#233; doen&#231;a autolimitada e autocur&#225;vel&#46; Entretanto&#44; na minoria dos casos&#44; as les&#245;es cut&#226;neas apresentam crescimento invasivo que deve ser tratado com excis&#227;o&#44; crioterapia&#44; metotrexato&#44; retinoides&#44; corticosteroides e&#47;ou talidomida&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Conclus&#227;o</span><p id="par0070" class="elsevierStylePara elsevierViewall">A DRD cut&#226;nea &#233; doen&#231;a rara&#44; benigna&#44; caracterizada por certas caracter&#237;sticas cl&#237;nicas e histopatol&#243;gicas&#46; A presen&#231;a de emperipolese e padr&#227;o de IHQ S100&#40;&#43;&#41;&#47;CD68&#40;&#43;&#41;&#47;CD1a&#40;&#8722;&#41; nos histi&#243;citos continua sendo o principal crit&#233;rio diagn&#243;stico&#46; A imunomarca&#231;&#227;o positiva para IgG4 e IgG e a raz&#227;o IgG4&#47;IgG podem ser importantes para diferenciar DRD de DR&#8208;IgG4&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Suporte financeiro</span><p id="par0080" class="elsevierStylePara elsevierViewall">Este estudo recebeu suporte financeiro da National Natural Science Foundation of China &#40;n&#176; 81500187&#44; n&#176; 81502710&#41;&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Contribui&#231;&#227;o dos autores</span><p id="par0085" class="elsevierStylePara elsevierViewall">Puyu Zou&#58; Contribuiu com a revis&#227;o cr&#237;tica da literatura e concep&#231;&#227;o e planejamento do estudo&#59; reda&#231;&#227;o do manuscrito&#59; an&#225;lise estat&#237;stica&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">Yu Liu&#58; Contribuiu com a revis&#227;o cr&#237;tica da literatura e concep&#231;&#227;o e planejamento do estudo&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">Yi Zhan&#58; Conduziu a obten&#231;&#227;o&#44; an&#225;lise e interpreta&#231;&#227;o dos dados&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">Xueru Zeng&#58; Participa&#231;&#227;o efetiva na orienta&#231;&#227;o da pesquisa&#44; na conduta proped&#234;utica e&#47;ou terap&#234;utica de casos estudados&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">Guiying Zhang&#58; Realizou a revis&#227;o cr&#237;tica do manuscrito&#44; da literatura e aprovou a vers&#227;o final do manuscrito&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Conflito de interesses</span><p id="par0110" class="elsevierStylePara elsevierViewall">Nenhum&#46;</p></span></span>"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Objetivo</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Investigar a express&#227;o de IgG4 e IgG na doen&#231;a de Rosai&#8208;Dorfman &#40;DRD&#41; cut&#226;nea para melhorar ainda mais a compreens&#227;o dessa doen&#231;a&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">M&#233;todos</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">As caracter&#237;sticas clinicopatol&#243;gicas de 23 pacientes com DRD cut&#226;nea &#40;DRDC&#41; foram revisadas retrospectivamente&#46; DRDC foi diagnosticada pela presen&#231;a de emperipolese e identifica&#231;&#227;o imuno&#8208;histoqu&#237;mica &#40;IHQ&#41; de histi&#243;citos S&#8208;100&#40;&#43;&#41;&#47;CD68&#40;&#43;&#41;&#47;CD1a&#40;&#8722;&#41;&#46; As express&#245;es de IgG e IgG4 em tecido cut&#226;neo foram avaliadas por IHQ &#40;EnVision&#41; com avalia&#231;&#227;o quantitativa por meio de um sistema de an&#225;lise de imagens m&#233;dicas&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Resultados</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Foi confirmado que todos os 23 pacientes &#40;14 do sexo masculino e nove do sexo feminino&#41; tinham DRDC&#46; A idade variou de 17 a 68 anos &#40;m&#233;dia de 47&#44;91<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>14&#44;16&#41;&#46; A regi&#227;o cut&#226;nea mais acometida foi a face&#44; seguida do tronco&#44; pavilh&#245;es auriculares&#44; regi&#227;o cervical&#44; membros e genit&#225;lia&#46; Em 16 desses casos&#44; a doen&#231;a se apresentou como les&#227;o &#250;nica&#46; A avalia&#231;&#227;o IHQ das amostras demonstrou imunorreatividade com IgG &#40;&#8805; 10 c&#233;lulas&#47;campo de grande aumento&#41; em 22 casos&#44; enquanto imunorreatividade com IgG4 foi observada &#40;&#8805; 10 c&#233;lulas&#47;campo de grande aumento&#41; em 18 casos&#46; Al&#233;m disso&#44; a raz&#227;o IgG4&#47;IgG variou de 1&#44;7&#37; a 85&#44;7&#37; &#40;m&#233;dia 29&#44;50<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>24&#44;67&#37;&#44; mediana 18&#44;4&#37;&#41; nos 18 casos&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Limita&#231;&#245;es do estudo</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Como na maioria dos trabalhos&#44; o desenho do presente estudo est&#225; sujeito a limita&#231;&#245;es&#46; A DRDC &#233; doen&#231;a rara&#44; ent&#227;o o tamanho da amostra &#233; pequeno&#46; Nos pr&#243;ximos trabalhos&#44; os autores pretendem ampliar a amostra para verifica&#231;&#227;o multic&#234;ntrica e aprofundamento do estudo&#46;</p></span> <span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Conclus&#227;o</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">As taxas positivas de IgG4 e IgG e a rela&#231;&#227;o IgG4&#47;IgG na avalia&#231;&#227;o IHQ podem ser importantes na compreens&#227;o da patog&#234;nese da DRDC&#46;</p></span>"
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                  \t\t\t\t">1<span class="elsevierStyleHsp" style=""></span>cm &#215; 1<span class="elsevierStyleHsp" style=""></span>cm Placa vermelha no l&#225;bio superior direito&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">N&#227;o&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Nenhuma&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">2&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">23&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">F&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">6m&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">3&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
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                  \t\t\t\t">53&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">M&nbsp;\t\t\t\t\t\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">1a&nbsp;\t\t\t\t\t\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">1<span class="elsevierStyleHsp" style=""></span>cm &#215; 1<span class="elsevierStyleHsp" style=""></span>cm Mancha vermelha opaca na regi&#227;o direita do t&#243;rax&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">1&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">N&#227;o&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">Nenhuma&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
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                  \t\t\t\t">4&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">59&nbsp;\t\t\t\t\t\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">F&nbsp;\t\t\t\t\t\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">1a&nbsp;\t\t\t\t\t\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">10<span class="elsevierStyleHsp" style=""></span>cm &#215; 10<span class="elsevierStyleHsp" style=""></span>cm Placa vermelha na regi&#227;o direita do t&#243;rax&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">N&#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">Nenhuma&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">5&nbsp;\t\t\t\t\t\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">28&nbsp;\t\t\t\t\t\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">F&nbsp;\t\t\t\t\t\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">6m&nbsp;\t\t\t\t\t\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
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                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Sim&nbsp;\t\t\t\t\t\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
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                  \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
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                  \t\t\t\t">6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">52&nbsp;\t\t\t\t\t\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">M&nbsp;\t\t\t\t\t\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">6m&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Sim&nbsp;\t\t\t\t\t\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">Nenhuma&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">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">17&nbsp;\t\t\t\t\t\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">M&nbsp;\t\t\t\t\t\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">6a&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3<span class="elsevierStyleHsp" style=""></span>cm &#215; 2<span class="elsevierStyleHsp" style=""></span>cm Placa vermelha do membro superior esquerdo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#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">Nenhuma&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">8&nbsp;\t\t\t\t\t\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">M&nbsp;\t\t\t\t\t\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">3m&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3<span class="elsevierStyleHsp" style=""></span>cm &#215; 2&#44;5<span class="elsevierStyleHsp" style=""></span>cm Mancha vermelha na regi&#227;o bucinadora esquerda&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#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">Nenhuma&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">9&nbsp;\t\t\t\t\t\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">61&nbsp;\t\t\t\t\t\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">M&nbsp;\t\t\t\t\t\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">1a&nbsp;\t\t\t\t\t\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">Erup&#231;&#227;o cut&#226;nea generalizada com p&#225;pula em mancha vermelha&nbsp;\t\t\t\t\t\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">Muitas&nbsp;\t\t\t\t\t\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">N&#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">Nenhuma&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">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">57&nbsp;\t\t\t\t\t\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">F&nbsp;\t\t\t\t\t\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">6m&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;5<span class="elsevierStyleHsp" style=""></span>cm &#215; 0&#44;4<span class="elsevierStyleHsp" style=""></span>cm P&#225;pula marrom na regi&#227;o direita do t&#243;rax&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#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">Nenhuma&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">11&nbsp;\t\t\t\t\t\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">38&nbsp;\t\t\t\t\t\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">F&nbsp;\t\t\t\t\t\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">2m&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;8<span class="elsevierStyleHsp" style=""></span>cm &#215; 0&#44;8<span class="elsevierStyleHsp" style=""></span>cm P&#225;pula vermelha opaca na panturrilha esquerda&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#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">Nenhuma&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">12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">57&nbsp;\t\t\t\t\t\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">M&nbsp;\t\t\t\t\t\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">4m&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;7<span class="elsevierStyleHsp" style=""></span>cm &#215; 0&#44;6<span class="elsevierStyleHsp" style=""></span>cm P&#225;pula vermelha na regi&#227;o esquerda do t&#243;rax&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#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">Nenhuma&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">13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">68&nbsp;\t\t\t\t\t\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">M&nbsp;\t\t\t\t\t\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">1a&nbsp;\t\t\t\t\t\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="elsevierStyleHsp" style=""></span>cm &#215; 1<span class="elsevierStyleHsp" style=""></span>cm Placa vermelha na regi&#227;o temporal esquerda&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#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">Nenhuma&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">14&nbsp;\t\t\t\t\t\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">61&nbsp;\t\t\t\t\t\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">M&nbsp;\t\t\t\t\t\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">1m&nbsp;\t\t\t\t\t\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="elsevierStyleHsp" style=""></span>cm &#215; 2<span class="elsevierStyleHsp" style=""></span>cm Placa no t&#243;rax e abd&#244;men&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&nbsp;\t\t\t\t\t\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">N&#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">Nenhuma&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">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">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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">F&nbsp;\t\t\t\t\t\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">2a&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3<span class="elsevierStyleHsp" style=""></span>cm &#215; 3<span class="elsevierStyleHsp" style=""></span>cm Mancha vermelha opaca na coxa esquerda&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#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">Nenhuma&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">16&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">20&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">M&nbsp;\t\t\t\t\t\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">50d&nbsp;\t\t\t\t\t\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="elsevierStyleHsp" style=""></span>cm &#215; 1<span class="elsevierStyleHsp" style=""></span>cm Placas no t&#243;rax e abd&#244;men&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&nbsp;\t\t\t\t\t\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">N&#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">Nenhuma&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">17&nbsp;\t\t\t\t\t\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">59&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">F&nbsp;\t\t\t\t\t\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">7m&nbsp;\t\t\t\t\t\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="elsevierStyleHsp" style=""></span>cm &#215; 1<span class="elsevierStyleHsp" style=""></span>cm Placa vermelha na regi&#227;o bucinadora esquerda&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#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">Nenhuma&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
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">18&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">40&nbsp;\t\t\t\t\t\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">M&nbsp;\t\t\t\t\t\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">2a&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3<span class="elsevierStyleHsp" style=""></span>cm &#215; 3<span class="elsevierStyleHsp" style=""></span>cm Mancha marrom escura na coxa direita&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#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">Nenhuma&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">19&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">54&nbsp;\t\t\t\t\t\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">M&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2a&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">Erup&#231;&#227;o cut&#226;nea generalizada com p&#225;pulas marrons&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Nenhuma&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
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                  \t\t\t\t">20&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">39&nbsp;\t\t\t\t\t\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">F&nbsp;\t\t\t\t\t\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">2m&nbsp;\t\t\t\t\t\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="elsevierStyleHsp" style=""></span>cm &#215; 1&#44;5<span class="elsevierStyleHsp" style=""></span>cm Placa vermelha na regi&#227;o bucinadora esquerda&nbsp;\t\t\t\t\t\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">Muitas&nbsp;\t\t\t\t\t\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">N&#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">Nenhuma&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
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">21&nbsp;\t\t\t\t\t\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">42&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">F&nbsp;\t\t\t\t\t\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">6m&nbsp;\t\t\t\t\t\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="elsevierStyleHsp" style=""></span>cm &#215; 1<span class="elsevierStyleHsp" style=""></span>cm Placa vermelha na regi&#227;o bucinadora esquerda&nbsp;\t\t\t\t\t\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&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#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">Nenhuma&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">22&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">52&nbsp;\t\t\t\t\t\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">M&nbsp;\t\t\t\t\t\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">6m&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;3<span class="elsevierStyleHsp" style=""></span>cm &#215; 0&#44;3<span class="elsevierStyleHsp" style=""></span>cm P&#225;pulas na coxa direita&nbsp;\t\t\t\t\t\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&nbsp;\t\t\t\t\t\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">N&#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">Nenhuma&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">23&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">52&nbsp;\t\t\t\t\t\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">M&nbsp;\t\t\t\t\t\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">1a&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3<span class="elsevierStyleHsp" style=""></span>cm &#215; 3<span class="elsevierStyleHsp" style=""></span>cm Massa subaxilar esquerda&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">2&nbsp;\t\t\t\t\t\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">N&#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">Nenhuma&nbsp;\t\t\t\t\t\t\n
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                  """
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              "nota" => "<p class="elsevierStyleNotepara" id="npar0010">M&#44; Masculino&#59; F&#44; Feminino&#46;</p>"
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              "nota" => "<p class="elsevierStyleNotepara" id="npar0015">a&#44; Anos&#59; m&#44; Meses&#59; d&#44; Dias&#46;</p>"
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          "pt" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Dados demogr&#225;ficos e cl&#237;nicos</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td-with-role" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t" scope="col">Caso<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " colspan="3" align="center" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Caracter&#237;sticas especificas de DRD</th><th class="td" title="\n
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                  \t\t\t\t  " colspan="3" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Anticorpos avaliados podem contribuir para o diagn&#243;stico</th></tr><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">S100<a class="elsevierStyleCrossRef" href="#tblfn0025"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">CD68<a class="elsevierStyleCrossRef" href="#tblfn0025"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">CD1a<a class="elsevierStyleCrossRef" href="#tblfn0025"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">IgG4&#43;&#47;HPF<a class="elsevierStyleCrossRef" href="#tblfn0030"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">IgG&#43;&#47;HPF<a class="elsevierStyleCrossRef" href="#tblfn0030"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">IgG4&#47;IgG&#37;<a class="elsevierStyleCrossRef" href="#tblfn0030"><span class="elsevierStyleSup">c</span></a>&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
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">56&#44;8&#37;&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
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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</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\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
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&#8722;&nbsp;\t\t\t\t\t\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\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">16&#44;9&#37;&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
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                  \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">&#43;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">38&#44;9&#37;&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
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                  \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  " align="left" valign="\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
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Vol. 98. Núm. 5.
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Vol. 98. Núm. 5.
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Avaliação da expressão de IgG4 e IgG na doença de Rosai‐Dorfman cutânea
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Puyu Zoua, Yi Zhana, Ruzeng Xueb, Yu Liua, Guiying Zhanga,
Autor para correspondência
lindazgy@csu.edu.cn

Autor para correspondência.
a Departamento de Dermatologia, Second Xiangya Hospital, Central South University, Changsha, China
b Dermatology Hospital, Southern Medical University, Guangzhou, China
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Estatísticas
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Tabela 1. Dados demográficos e clínicos
Tabela 2. Características imuno‐histoquímicas das amostras
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Resumo
Objetivo

Investigar a expressão de IgG4 e IgG na doença de Rosai‐Dorfman (DRD) cutânea para melhorar ainda mais a compreensão dessa doença.

Métodos

As características clinicopatológicas de 23 pacientes com DRD cutânea (DRDC) foram revisadas retrospectivamente. DRDC foi diagnosticada pela presença de emperipolese e identificação imuno‐histoquímica (IHQ) de histiócitos S‐100(+)/CD68(+)/CD1a(−). As expressões de IgG e IgG4 em tecido cutâneo foram avaliadas por IHQ (EnVision) com avaliação quantitativa por meio de um sistema de análise de imagens médicas.

Resultados

Foi confirmado que todos os 23 pacientes (14 do sexo masculino e nove do sexo feminino) tinham DRDC. A idade variou de 17 a 68 anos (média de 47,91±14,16). A região cutânea mais acometida foi a face, seguida do tronco, pavilhões auriculares, região cervical, membros e genitália. Em 16 desses casos, a doença se apresentou como lesão única. A avaliação IHQ das amostras demonstrou imunorreatividade com IgG (≥ 10 células/campo de grande aumento) em 22 casos, enquanto imunorreatividade com IgG4 foi observada (≥ 10 células/campo de grande aumento) em 18 casos. Além disso, a razão IgG4/IgG variou de 1,7% a 85,7% (média 29,50±24,67%, mediana 18,4%) nos 18 casos.

Limitações do estudo

Como na maioria dos trabalhos, o desenho do presente estudo está sujeito a limitações. A DRDC é doença rara, então o tamanho da amostra é pequeno. Nos próximos trabalhos, os autores pretendem ampliar a amostra para verificação multicêntrica e aprofundamento do estudo.

Conclusão

As taxas positivas de IgG4 e IgG e a relação IgG4/IgG na avaliação IHQ podem ser importantes na compreensão da patogênese da DRDC.

Palavras‐chave:
Doença relacionada à imunoglobulina G4
Histiocitose
Imunoglobulina G
Pele
Texto Completo
Introdução

A doença de Rosai‐Dorfman (RDD) é forma rara de histiocitose não maligna, anteriormente denominada histiocitose sinusal, com grande número de linfadenopatias. Foi nomeada em homenagem a Rosai e Dorfman, que definiram a doença em dois relatos iniciais, em 1969 e 1972.1,2 Mutações em KRAS e MAP2K1 podem estar relacionadas à patogênese da DRD.3 A DRD geralmente ocorre em crianças e adultos jovens, com leve predominância masculina de 58% e maior incidência em pacientes de ascendência africana.1,4 Estima‐se que até 43% dos pacientes com DRD tenham envolvimento extranodal, especialmente no trato respiratório superior, pele e ossos.5 A DRD cutânea (DRDC) é a forma da doença limitada à pele, sem envolvimento sistêmico.1,6,7 Na histopatologia, os histiócitos são grandes e têm aspecto espumoso, com citoplasma abundante e núcleo vesicular.8 Emperipolese (histiócitos contendo células intactas, especialmente linfócitos e plasmócitos) é característica histopatológica típica, mas não exclusiva, da DRD.9 A presença de histiócitos imunorreativos com S100 e CD68 e negativos com CD1a na avaliação imuno‐histoquímica (IHQ) é importante para o diagnóstico de DRD. Muitos outros marcadores também foram relatados como positivos em DRDC, como CD14, CD15, CD163 e fator XIIIa.8 Entretanto, as expressões de IgG4 e IgG em DRDC ainda não foram investigadas. Acredita‐se que o número aumentado de plasmócitos IgG4+ em lesões cutâneas indique doença relacionada a IgG4 (DR‐IgG4). A DR‐IgG4 é doença crônica, inflamatória, sistêmica e fibrótica que pode afetar quase todos os órgãos. Foi encontrado um relato de que alguns casos de DRD exibiam características de DR‐IgG4, mas a relação entre DRDC e DR‐IgG4 não foi estudada.10 Para investigar melhor a relação entre DRDC e DR‐IgG4, foram avaliadas as manifestações clínicas e características histopatológicas de 23 casos de DRDC e detectada a expressão de IgG e IgG4, que podem fornecer novos biomarcadores (IgG4, IgG e a razão IgG4/IgG) para a identificação de DRDC e ajudar a esclarecer sua patogenia.

Materiais e métodos

Foram avaliados 23 casos em dois hospitais diferentes, durante o período de agosto de 2009 a agosto de 2018. Todos os casos foram diagnosticados por dois patologistas experientes, de acordo com os critérios de diagnóstico mais recentes da Organização Mundial da Saúde (OMS). O presente estudo foi autorizado pelo Comitê de Ética e conduzido sob os princípios éticos da Declaração de Direitos Humanos adotada em Helsinque e estava de acordo com as Regras de Boas Práticas Clínicas. Todos os pacientes receberam esclarecimentos sobre consentimento informado.

As biopsias de pele foram fixadas em solução tamponada de formol a 10%, processadas e emblocadas em parafina. Os blocos de parafina foram seccionados com micrótomo para obter cortes histológicos de 4‐5μm colocados em lâminas de vidro.

A coloração pela hematoxilina & eosina (HE) foi utilizada para histopatologia clássica, e a IHQ foi realizada no mesmo material biológico emblocado em parafina. Cada reação imuno‐histoquímica incluiu um controle negativo (sem incubação com o anticorpo primário). Os anticorpos IgG4 e IgG (comercialmente disponíveis) foram adquiridos da Zhongshan Golden Bridge Biological Technology Company.

As células IgG4(+) e IgG(+) foram contadas separadamente utilizando microscópio Olympus BX40 e o software Image J 1.52a para computador. Três campos de grande aumento com o número máximo de células positivas foram contados, e um número médio por campo de grande aumento foi calculado. Um campo de grande aumento representa uma área de 0,24mm2.

ResultadosCaracterísticas clínicas

A idade dos 23 pacientes com DRDC (14 do sexo masculino e nove do sexo feminino) variou de 17 a 68 anos (média de 47,91±14,16). Dentre eles, 16 pacientes apresentavam lesões únicas, enquanto os outros sete apresentavam lesões múltiplas. Dez pacientes apresentavam placas, 12 tinham manchas e um paciente apresentava massa subaxilar. Na maioria dos casos de DRDC, as lesões distribuíram‐se pela face e pelo tórax. Em nove casos, a lesão estava em outro local, como membro, dorso ou coxa. As características clínicas de todos os pacientes estão descritas na figura 1 e na figura 2 e resumidas na tabela 1.

Figura 1.

(A) Placa infiltrada eritêmato-acastanhada, com superfície irregular, e múltiplos nódulos vermelho‐escuros de diferentes tamanhos na borda. (B) Lesão do tipo pápulo‐nodular: múltiplas pápulas eritematosas medindo 0,2‐0,5cm agrupadas sobre área de eritema pálido, apresentando‐se isoladas, ou seja, sem fusionamento

(0.27MB).
Figura 2.

Lesão tumoral em base infiltrada eritêmato-acastanhada do tamanho da palma da mão na superfície flexora da coxa esquerda, com evidente elevação central e múltiplos nódulos vermelho‐escuros na área circundante

(0.12MB).
Tabela 1.

Dados demográficos e clínicos

Casoa  Idade  Sexob  Duraçãoc  Descrição da lesão cutânea  Quantidade  Dor  Comorbidade 
57  20d  1cm × 1cm Placa vermelha no lábio superior direito  Não  Nenhuma 
23  6m  5cm × 4cm Mancha marrom no membro superior direito  Não  Nenhuma 
53  1a  1cm × 1cm Mancha vermelha opaca na região direita do tórax  Não  Nenhuma 
59  1a  10cm × 10cm Placa vermelha na região direita do tórax  Não  Nenhuma 
28  6m  0,3cm × 0,2cm Pápula vermelha na mama direita  Sim  Nenhuma 
52  6m  15cm × 10cm Placa vermelha na parte inferior direita do dorso  Sim  Nenhuma 
17  6a  3cm × 2cm Placa vermelha do membro superior esquerdo  Não  Nenhuma 
50  3m  3cm × 2,5cm Mancha vermelha na região bucinadora esquerda  Não  Nenhuma 
61  1a  Erupção cutânea generalizada com pápula em mancha vermelha  Muitas  Não  Nenhuma 
10  57  6m  0,5cm × 0,4cm Pápula marrom na região direita do tórax  Não  Nenhuma 
11  38  2m  0,8cm × 0,8cm Pápula vermelha opaca na panturrilha esquerda  Não  Nenhuma 
12  57  4m  0,7cm × 0,6cm Pápula vermelha na região esquerda do tórax  Não  Nenhuma 
13  68  1a  2cm × 1cm Placa vermelha na região temporal esquerda  Não  Nenhuma 
14  61  1m  2cm × 2cm Placa no tórax e abdômen  Não  Nenhuma 
15  63  2a  3cm × 3cm Mancha vermelha opaca na coxa esquerda  Não  Nenhuma 
16  20  50d  1cm × 1cm Placas no tórax e abdômen  Não  Nenhuma 
17  59  7m  1cm × 1cm Placa vermelha na região bucinadora esquerda  Não  Nenhuma 
18  40  2a  3cm × 3cm Mancha marrom escura na coxa direita  Não  Nenhuma 
19  54  2a  Erupção cutânea generalizada com pápulas marrons  Não  Nenhuma 
20  39  2m  1cm × 1,5cm Placa vermelha na região bucinadora esquerda  Muitas  Não  Nenhuma 
21  42  6m  2cm × 1cm Placa vermelha na região bucinadora esquerda  Não  Nenhuma 
22  52  6m  0,3cm × 0,3cm Pápulas na coxa direita  Não  Nenhuma 
23  52  1a  3cm × 3cm Massa subaxilar esquerda  Não  Nenhuma 
a

Caso 1 ao caso 12 eram do Second Xiangya Hospital of Central South University e caso 13 ao caso 23 do Dermatology Hospital of Southern Medical University.

b

M, Masculino; F, Feminino.

c

a, Anos; m, Meses; d, Dias.

Características histopatológicas

Foi observada infiltração difusa de grandes histiócitos e plasmócitos com neutrófilos e linfócitos dispersos em todos os cortes histológicos (fig. 3A). Na maioria dos casos, os histiócitos eram grandes, com citoplasma amplo e pálido e núcleos arredondados evidentes. Entretanto, os histiócitos apresentavam aspecto espumoso ou multinucleação em quatro casos. Foram observadas fibrose difusa e deposição de colágeno sem infiltração de fibroblastos em um caso. Emperipolese foi encontrada na maioria dos casos de DRDC. Além disso, foram observadas hemácias engolfadas por histiócitos em um caso.

Figura 3.

(A) Infiltração difusa de grandes histiócitos, linfócitos e plasmócitos com neutrófilos dispersos. (B) Expressão de IgG. (C) Expressão de IgG4

(0.53MB).

As características IHQ são mostradas na figura 3B e 3C e estão resumidas na tabela 2. Os resultados revelaram expressão significante de IgG4 em seis pacientes (> 50 células/ campo de grande aumento), expressão moderada de IgG4 em três pacientes (30‐50 células/ campo de grande aumento), expressão leve em nove pacientes (10‐29 células/ campo de grande aumento) e infiltração negativa em cinco pacientes (< 10 células/ campo de grande aumento). A razão IgG4/IgG variou de 1,7 a 85,7% (média de 29,5%, mediana de 20,8%) em todos os casos positivos, e a razão IgG4/IgG foi superior a 40% em sete casos.

Tabela 2.

Características imuno‐histoquímicas das amostras

Casoa  Características especificas de DRDAnticorpos avaliados podem contribuir para o diagnóstico
  S100b  CD68b  CD1ab  IgG4+/HPFc  IgG+/HPFc  IgG4/IgG%c 
−  46  81  56,8% 
−  33  40  82,5% 
−  11  65  16,9% 
−  35  90  38,9% 
−  20  220  9,1% 
−  101  213  47,4% 
−  72  84  85,7% 
−  10  265  3,8% 
−  25% 
10  −  49  18,4% 
11  −  46  2,2% 
12  −  12  12  13,3% 
13  −  10  190  5,3% 
14  −  71  160  44,3% 
15  −  69  116  59,5% 
16  −  19  79  24,1% 
17  −  178  3,4% 
18  −  18  182  9,9% 
19  −  65  118  55,1% 
20  −  120  1,7% 
21  −  78  218  35,8% 
22  −  10  48  20,8% 
23  −  21  117  17,9% 
a

Caso 1 ao caso 12 eram do Second Xiangya Hospital of Central South University e caso 13 ao caso 23 do Dermatology Hospital of Southern Medical University.

b

As expressões imuno‐histoquímicas de S100, CD68 e CD1a foram coletadas de relatos patológicos existentes.

c

Três campos de alta potência (HPF, do inglês high power field; 400×) com o número máximo de células positivas foram contados e um número médio por HPF foi calculado e apresentado na tabela 2.

Discussão

Em comparação com a DRD sistêmica clássica, a DRDC parece ocorrer com mais frequência em asiáticos e predomina no sexo feminino.11 A doença geralmente afeta indivíduos de meia‐idade, de 40 a 60 anos. Dos 23 pacientes incluídos no presente estudo, 65% tinham mais de 50 anos, idade em que a predominância feminina é menos evidente.

Em contraste com a DRD clássica com sintomas sistêmicos evidentes, a DRDC geralmente é limitada à pele. As lesões na pele em DRDC variam em morfologia, tamanho, cor e localização. As manifestações clínicas incluem pápulas, placas, nódulos e pústulas.12

Emperipolese é fenômeno de linfócitos que mantêm sua estrutura e função, enquanto aprisionados no citoplasma de histiócitos. Não é característica exclusiva da DRDC e também pode ser observada em casos de linfoma de Hodgkin, melanoma e em alguns outros tumores malignos.13 Os critérios diagnósticos mais reconhecidos da DRDC são IHQ positiva para proteínas CD68 e S‐100 e negativa para CD1a. Apesar disso, o diagnóstico de DRD ainda permanece um desafio, provavelmente pela sobreposição de suas manifestações clínicas, morfologia e características de IHQ com as de outras doenças. É provável que a DRD seja confundida com DR‐IgG4 em termos de manifestações clínicas. Aumento do número de plasmócitos IgG4+ foi encontrado em 70 casos nodais e extranodais de DRD.14

Os padrões diagnósticos mais reconhecidos para DR‐IgG4 com base em sua histopatologia e IHQ são os seguintes: aumento difuso ou característico, tumores, nódulos ou hipertrofia de um ou mais órgãos; níveis séricos de IgG4 aumentados ≥ 1,350mg/L; e histopatologia mostrando infiltração de linfócitos e plasmócitos, e fibrose evidente, ou infiltração de plasmócitos IgG4+ com razão de plasmócitos IgG4/IgG+ superior a 40% e quantidade de células IgG4+> 200/ campo de grande aumento na pele.15 Zhang et al. especularam que DR‐IgG4 e DRD podem compartilhar uma patogênese comum, ou que as características da DR‐IgG4 podem ocorrer em algum estágio da DRD,10 o que torna a identificação mais difícil. No presente estudo, quatro pacientes diagnosticados com DRDC também preenchem os critérios diagnósticos para DR‐IgG4, com razão de plasmócitos IgG4/IgG+> 40%. Esses resultados mostraram que DRD e DR‐IgG4 não eram completamente distintas uma da outra. Entretanto, no total de 23 casos de DRDC, a quantidade de células IgG4+ foi < 200/ campo de grande aumento. É possível, portanto, determinar se o paciente tem DRD, DR‐IgG4 ou uma sobreposição das duas com base na avaliação IHQ de IgG, IgG4 e da razão de plasmócitos IgG4/IgG combinadas com as alterações histopatológicas e os resultados da IHQ para S‐100, CD68 e CD1a.

Em geral, a DRDC é doença autolimitada e autocurável. Entretanto, na minoria dos casos, as lesões cutâneas apresentam crescimento invasivo que deve ser tratado com excisão, crioterapia, metotrexato, retinoides, corticosteroides e/ou talidomida.

Conclusão

A DRD cutânea é doença rara, benigna, caracterizada por certas características clínicas e histopatológicas. A presença de emperipolese e padrão de IHQ S100(+)/CD68(+)/CD1a(−) nos histiócitos continua sendo o principal critério diagnóstico. A imunomarcação positiva para IgG4 e IgG e a razão IgG4/IgG podem ser importantes para diferenciar DRD de DR‐IgG4.

Suporte financeiro

Este estudo recebeu suporte financeiro da National Natural Science Foundation of China (n° 81500187, n° 81502710).

Contribuição dos autores

Puyu Zou: Contribuiu com a revisão crítica da literatura e concepção e planejamento do estudo; redação do manuscrito; análise estatística.

Yu Liu: Contribuiu com a revisão crítica da literatura e concepção e planejamento do estudo.

Yi Zhan: Conduziu a obtenção, análise e interpretação dos dados.

Xueru Zeng: Participação efetiva na orientação da pesquisa, na conduta propedêutica e/ou terapêutica de casos estudados.

Guiying Zhang: Realizou a revisão crítica do manuscrito, da literatura e aprovou a versão final do manuscrito.

Conflito de interesses

Nenhum.

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Como citar este artigo: Zou P, Zhan Y, Xue R, Liu Y, Zhang G. The evaluation of IgG4 and IgG expression in cutaneous Rosai‐Dorfman disease. An Bras Dermatol. 2023;98:651–5.

Trabalho realizado no Departamento de Dermatologia, Second Xiangya Hospital, Central South University, Changsha, China.

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