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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">In 1990&#44; Anhalt et al&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">1</span></a> reported a new clinical entity named as &#8220;Paraneoplastic pemphigus&#8221;&#44; fulfilling five diagnostic criteria&#46; Subsequently&#44; their findings were confirmed by several studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0435"><span class="elsevierStyleSup">2&#8211;9</span></a> Nguyen et al&#46;<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">10</span></a> described PNP as a heterogeneous autoimmune syndrome that affects several internal organs&#44; and that its pathophysiology is not limited to antibodies targeting adhesion molecules like other subtypes of pemphigus&#46; In 2001&#44; they proposed the term &#8220;Paraneoplastic autoimmune multi-organ syndrome&#8221; instead of PNP&#46; This is because the autoantibodies in the disease bind to the kidney&#44; smooth and striated muscle&#44; as well as the epithelium of the small intestine&#44; colon and thyroid&#46;<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">3</span></a> The term more widely used in most reports and reviews&#44; including the present paper&#44; is PNP&#46; About the position of PNP among skin disorders&#44; some studies<a class="elsevierStyleCrossRefs" href="#bib0480"><span class="elsevierStyleSup">11&#8211;13</span></a> propose to include it as a type of pemphigus with an associated tumor&#44; whereas others<a class="elsevierStyleCrossRefs" href="#bib0495"><span class="elsevierStyleSup">14&#8211;16</span></a> describe it as an independent autoimmune disorder&#59; moreover&#44; PNP does not fully meet Curth&#39;s criteria for cutaneous paraneoplastic syndrome &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0010" class="elsevierStylePara elsevierViewall">Paraneoplastic pemphigus is closely related to benign or malignant tumors&#46; The most often reported malignancies are lymphomatoid and hematologic &#40;B-cell lymphoma&#44; chronic lymphocytic leukemia&#44; Castleman&#39;s disease&#44; Waldenstrom&#39;s macroglobulinemia&#44; and thymoma&#44; with or without myasthenia gravis&#41;&#46; Interactions between the immune system and concomitant neoplasm seem to be key pathogenic steps with autoantibodies directed against both desmosomal and hemidesmosomal antigens&#46; In PNP&#44; most patients develop autoantibodies against periplakins and envoplakins&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">In 1990&#44; Anhalt et al&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">1</span></a> first described five cases of patients with a rare form of atypical pemphigus that were all associated with lymphoproliferative diseases&#46; PNP mostly affects adults between 45 and 70 years old&#44; but it may also be found in younger patients&#44; in whom Castleman&#39;s disease is more commonly seen&#46; There is no known correlation between incidence of the disease and specific gender&#44; race&#44; or geographical distribution&#46;<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">3</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Based on its very unique clinical pictures&#44; as well as its histologic and immunologic features&#44; and most of all its elevated mortality &#40;90&#37; if untreated&#41;&#44; diagnosis should be stated promptly&#46;<a class="elsevierStyleCrossRefs" href="#bib0440"><span class="elsevierStyleSup">3&#44;17&#8211;20</span></a> Prognosis depends on the nature of the associated tumor&#46; Some patients experience rapid improvement after excision of a benign tumor&#44; such as PNP associated to Castleman&#39;s disease&#46; However&#44; malignant tumors are often accompanied not only by higher mortality from the associated malignancy but also because the PNP can be severe and often recalcitrant&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Epidemiology</span><p id="par0025" class="elsevierStylePara elsevierViewall">The exact incidence of PNP is unknown but it is less common than pemphigus vulgaris or pemphigus foliaceus&#46; There appears to be no age preference&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">4</span></a> Although PNP presents most often in older patients aged between 45 and 70 years&#44; it also occurs in younger patients&#46; The disease has been reported in patients ranging from 7 to 83 years-old&#46;<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">5</span></a> Ogawa et al&#46;<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">21</span></a> studied 496 patients with malignancy and recorded 25 cases of pemphigus &#40;5&#37;&#41;&#44; an elevated number when compared with controls&#46; There was a positive correlation with advancing age&#46; The mean age of pemphigus patients with malignancy was 64&#46;7 years&#46;<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">21</span></a> It appears to be no gender predilection&#46;<a class="elsevierStyleCrossRefs" href="#bib0435"><span class="elsevierStyleSup">2&#44;22</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">The associated malignant or benign neoplasm may be occult or already diagnosed at the point of PNP presentation&#46; PNP may also develop after the tumor has been treated&#46;<a class="elsevierStyleCrossRefs" href="#bib0455"><span class="elsevierStyleSup">6&#44;7</span></a> The most commonly associated tumors are hematological&#44; accounting for nearly 84&#37; of all cases&#44; these include non-Hodgkin&#39;s lymphoma &#40;38&#46;6&#37;&#41;&#44; chronic lymphocytic leukemia &#40;18&#46;4&#37;&#41;&#44; Castleman&#39;s disease &#40;18&#46;4&#37;&#41;&#44; thymoma &#40;5&#46;5&#37;&#41;&#44; Waldenstr&#246;m macroglobulinemia &#40;1&#46;2&#37;&#41;&#44; Hodgkin&#39;s lymphoma &#40;0&#46;6&#37;&#41; and monoclonal gammopathy &#40;0&#46;6&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">4</span></a> Non-hematological neoplasms include carcinomas &#40;8&#46;6&#37;&#41;&#44; sarcomas &#40;6&#46;2&#37;&#41;<a class="elsevierStyleCrossRef" href="#bib0540"><span class="elsevierStyleSup">23</span></a> and melanoma &#40;0&#46;6&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">4</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">In children and adolescents&#44; PNP is most commonly associated with Castleman&#39;s disease<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">8</span></a> and PNP is often the presenting sign of Castleman&#39;s disease&#46;<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">9</span></a> This tumor is rare in the general population but is the third most common neoplasm associated with PNP&#46;<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">24</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Etiopathogenesis</span><p id="par0040" class="elsevierStylePara elsevierViewall">PNP is an autoimmune disorder launched by an underlying neoplasm &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; Etiopathogenesis of PNP is not fully described&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">4</span></a> Skin lesions are thought to be originated by an antibody-mediated autoimmune response to tumor antigens that cross-react with epithelial antigens&#46; Tumor autoantibodies produce and release cytokines &#40;such as interleukin-6&#41; that enhance B-cells differentiation<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">5</span></a> and foster to develop the humoral response&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0045" class="elsevierStylePara elsevierViewall">PNP is often a clinical marker of benign and malignant neoplasms&#44; most commonly malignancies of the lymphatic system&#46;<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">6</span></a> Ohzono et al&#46;<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">7</span></a> described the associated tumors in 104 PNP cases&#46; Their clinical and histopathological findings were similar to those in previous reports&#46;<a class="elsevierStyleCrossRefs" href="#bib0440"><span class="elsevierStyleSup">3&#44;4&#44;6</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">Some patients have tumors that are difficult to diagnose&#44; such as follicular dendritic cell sarcomas located in the retroperitoneal space&#46;<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">8</span></a> Studies of patients with non-Hodgkin lymphoma revealed that most severe lesions during the PNP occur 2&#8211;3 years after diagnosis of lymphoma&#46;<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">6</span></a> Castleman&#39;s disease&#44; also known as giant lymph node hyperplasia&#44; occurs most commonly in children&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">Previous studies have shown that HLA-DR4 and DR14 alleles confer strong susceptibility to pemphigus vulgaris and foliaceous&#59; however&#44; PNP is not associated with these alleles&#46; HLA-DRB1&#42;03 in Caucasian patients<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">24</span></a> and Cw&#42;14 in Chinese patients have been reported in PNP&#46;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">25</span></a> These findings indicate that people with different racial backgrounds have a different susceptibility to PNP&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">It is hypothesized that tumor antigens evoke not only a humoral response but a cellular one&#46;<a class="elsevierStyleCrossRefs" href="#bib0445"><span class="elsevierStyleSup">4&#44;5</span></a> While direct immunofluorescence findings of autoantibodies bound to the cell surface of affected epithelium support a humoral response&#44; histopathological findings of individual keratinocyte necrosis with lymphocyte exocytosis support the role of cell-mediated immunity&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">In order to explain such hypothesis&#44; several explanations have been proposed&#44; like production of autoantibodies to epithelial proteins by tumors&#44; supported by finding B-cells-producing IgG antibodies directed to epidermal antigens in Castleman&#39;s disease<a class="elsevierStyleCrossRef" href="#bib0555"><span class="elsevierStyleSup">26</span></a>&#59; cross-reactivity of tumor antigens and epidermal antigens&#59; high levels of interleukin-6&#44; which promotes B-cell differentiation and immunoglobulin production&#46;<a class="elsevierStyleCrossRef" href="#bib0560"><span class="elsevierStyleSup">27</span></a> Anti-IL-6 monoclonal antibody inhibitors &#40;Tocilizumab&#41; have been successfully used for treating Castleman&#39;s disease<a class="elsevierStyleCrossRefs" href="#bib0565"><span class="elsevierStyleSup">28&#8211;30</span></a>&#59; epitope spreading and cellular immunity-mediated processes have been reported in previous studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0580"><span class="elsevierStyleSup">31&#44;32</span></a> Cummins et al&#46;<a class="elsevierStyleCrossRef" href="#bib0585"><span class="elsevierStyleSup">32</span></a> reported a series of four patients with a lichenoid variant of PNP without detectable autoantibodies&#46; They inferred that these patients had disease mainly mediated by cytotoxic T lymphocytes rather than autoantibodies&#46; Nguyen et al&#46;<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">10</span></a> also showed the presence of cytotoxic T lymphocytes&#44; macrophages&#44; and natural killer cells in tissues affected by PNP&#46; These theories support that both cellular and humoral immunity are implicated in the pathogenesis of PNP&#46;<a class="elsevierStyleCrossRef" href="#bib0590"><span class="elsevierStyleSup">33</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Clinical</span><p id="par0070" class="elsevierStylePara elsevierViewall">Various lesions may occur in patients with PNP&#46; Although characterized by severe oral mucositis &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#44; a generalized polymorphous cutaneous eruption and pulmonary involvement may develop&#46; Typically&#44; the first symptoms are usually florid&#44; painful as well as intractable stomatitis&#44; and also&#44; it can involve the vermilion of the lips&#44; oro and nasopharynx&#44; the nose &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#44; tongue&#44; esophagus&#44; stomach&#59; duodenum&#44; intestines and the pulmonary epithelium&#44; as well as the conjunctiva<a class="elsevierStyleCrossRef" href="#bib0595"><span class="elsevierStyleSup">34</span></a> and anogenital region &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41; are also affected&#46;<a class="elsevierStyleCrossRefs" href="#bib0435"><span class="elsevierStyleSup">2&#44;3&#44;35&#8211;38</span></a></p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0075" class="elsevierStylePara elsevierViewall">The lesions are polymorphic&#44; and symptoms include blisters&#44; erosions&#44; spots&#44; papules&#44; and plaques&#46; Nikolsky sign can be present&#46; Cutaneous lesions usually appear after the onset of mucosal lesions and may involve any site&#44; mostly the upper body&#46; Nguyen et al&#46;<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">10</span></a> proposed a classification including several clinical presentations of PNP&#46; It is believed that each category occurs with nearly equal incidence&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">PNP cutaneous lesions can be classified into several groups according to the types of changes&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">-</span><p id="par0085" class="elsevierStylePara elsevierViewall">Pemphigus-like&#58; flaccid blisters&#44; erosions&#44; crust&#44; and erythema&#46;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">-</span><p id="par0090" class="elsevierStylePara elsevierViewall">Bullous pemphigoid-like&#58; scaly erythematous papules and stretched vesicles&#46; These are more commonly seen on the extremities&#46;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">-</span><p id="par0095" class="elsevierStylePara elsevierViewall">Erythema multiforme-like&#58; polymorphic changes&#44; mainly erythematous peeling pellets with erosions and sometimes even with recalcitrant ulcerations &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>&#41;&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">-</span><p id="par0100" class="elsevierStylePara elsevierViewall">Graft-versus-host disease&#58; scattered dusky red scaly papules&#46;</p></li><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">-</span><p id="par0105" class="elsevierStylePara elsevierViewall">Lichen planus-like&#58; the presenting picture consists in flat&#44; red-brown scaly papules and plaques&#44; as well as intense mucous membrane involvement&#44; more commonly seen in children on the trunk and extremities &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#44; and rapidly extending to the face and neck&#46;<a class="elsevierStyleCrossRef" href="#bib0615"><span class="elsevierStyleSup">38</span></a> Scaly lesions on the palms and soles may accompany the lichenoid lesions&#46;</p></li></ul></p><p id="par0110" class="elsevierStylePara elsevierViewall">Patients with PNP can develop life-threatening restrictive bronchiolitis obliterans&#46; The frequency of the involvement of the respiratory system and its pathological mechanisms are unknown&#46;<a class="elsevierStyleCrossRef" href="#bib0620"><span class="elsevierStyleSup">39</span></a> In a study of 17 patients with PNP&#44; restrictive bronchiolitis was found only in three patients&#46; However&#44; in another analysis where 28 patients with PNP and concomitant Castleman&#39;s disease were examined&#44; the respiratory system was affected in 26 cases&#46;<a class="elsevierStyleCrossRefs" href="#bib0625"><span class="elsevierStyleSup">40&#44;41</span></a> Pulmonary disease&#44; when present&#44; is irreversible despite aggressive therapy&#46;<a class="elsevierStyleCrossRefs" href="#bib0435"><span class="elsevierStyleSup">2&#44;3&#44;42</span></a> The recently discovered autoantigen&#44; epiplakin&#44; has demonstrated correlation with development of bronchiolitis obliterans in Japanese patients&#46;<a class="elsevierStyleCrossRef" href="#bib0640"><span class="elsevierStyleSup">43</span></a> Epiplakin is present in the respiratory bronchiole&#44; and mice injected with epiplakin autoantibody showed abnormal changes in the histopathology of their pulmonary epithelia&#46; While more research is needed&#44; these early results indicate that epiplakin may represent a specific autoantigen in PNP-related bronchiolitis obliterans&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">Differential diagnosis of PNP is extensive &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#44; and includes pemphigus vulgaris&#44; mucous membrane pemphigoid&#44; erythema multiforme&#44; Stevens&#8211;Johnson syndrome&#44; lichen planus&#44; graft-versus-host disease&#44; and herpes simplex virus infection&#46; When PNP is suspected&#44; an extensive baseline workup should be conducted&#44; including&#58; blood cell count&#44; lactate dehydrogenase&#44; flow cytometry&#44; as well as chest&#44; abdomen&#44; and pelvis CT scan&#46; The existence of a neoplasm is often recognized prior to PNP &#40;30&#37; of cases approximately&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">22</span></a></p><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Histology</span><p id="par0120" class="elsevierStylePara elsevierViewall">The disease often require several biopsies to achieve diagnosis&#46;<a class="elsevierStyleCrossRef" href="#bib0645"><span class="elsevierStyleSup">44</span></a> Horn and Anhalt<a class="elsevierStyleCrossRef" href="#bib0650"><span class="elsevierStyleSup">45</span></a> examined 16 skin and oral mucous membrane biopsy specimens from six patients with PNP&#44; and observed epidermal acantholysis&#44; suprabasal cleft formation&#44; dyskeratotic keratinocytes and vacuolar changes in the basal epidermis&#44; and epidermal exocytosis of inflammatory cells&#46; According to the morphology of the clinical lesions&#44; the histopathology may reveal a different spectrum from minor inflammatory bullous lesions to a dense lichenoid reaction&#46;<a class="elsevierStyleCrossRef" href="#bib0650"><span class="elsevierStyleSup">45</span></a> Additionally&#44; there might be vacuolar degeneration of the basal layer associated with band-like infiltrate of lymphocytes in the dermis &#40;lichenoid features&#41;&#46; Prompt clinic-pathologic correlation is recommended in these patients&#44; as well as evaluations for neoplasm&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Immunology</span><p id="par0125" class="elsevierStylePara elsevierViewall">Immunopathology plays an important role in the diagnosis of PNP&#46; The variety of possible autoantigens and the combination in which they occur&#44; account for the diverse nature of this disorder&#44; and thus for the conflicting findings&#46;<a class="elsevierStyleCrossRefs" href="#bib0655"><span class="elsevierStyleSup">46&#8211;48</span></a> DIF performed on a perilesional biopsy may reveal intercellular deposits of IgG and C3 autoantibodies&#46; In addition&#44; linear deposits of IgG or C3 in the basement membrane zone&#44; due to autoantibody binding to BPAG1-2&#44; may be present&#46; This helps distinguish PNP from other types of pemphigus&#44; in which immunoglobulin deposits are found between keratinocytes but not on the basement membrane&#46;<a class="elsevierStyleCrossRefs" href="#bib0440"><span class="elsevierStyleSup">3&#44;5</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">Direct immunofluorescence can be negative in a few PNP patients&#44; however&#44; most cases exhibit positive DIF and thus&#44; it is necessary for diagnosing PNP&#46; False negatives on DIF are common in PNP for mucosal biopsies when necrotic tissue is predominant&#46;<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">5</span></a> Another reason is that a significant proportion of lesions are lichenoid&#44; with predominant cellular immunity instead of humoral immunity&#46;<a class="elsevierStyleCrossRefs" href="#bib0450"><span class="elsevierStyleSup">5&#44;32</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">The autoantibody profile of PNP has been recently studied&#46;<a class="elsevierStyleCrossRefs" href="#bib0655"><span class="elsevierStyleSup">46&#44;47&#44;49</span></a> Elegant studies<a class="elsevierStyleCrossRefs" href="#bib0675"><span class="elsevierStyleSup">50&#8211;53</span></a> have suggested that patients with PNP have autoantibodies against the plakin family &#40;e&#46;g&#46; envoplakin and periplakin&#41;&#46; Antibodies against desmoglein 1 and 3 &#40;antigens for classic pemphigus&#41;&#44; however&#44; these antibodies may play a role in the initial stages of the development of PNP&#46;<a class="elsevierStyleCrossRefs" href="#bib0695"><span class="elsevierStyleSup">54&#44;55</span></a> The presence of autoantibodies to plakins is a characteristic feature of PNP&#46; Envoplakin and periplakin antibody levels are most specific&#44;<a class="elsevierStyleCrossRef" href="#bib0705"><span class="elsevierStyleSup">56</span></a> followed by desmoplakin I and II&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">Paraneoplastic pemphigus is the result of either a humoral or cell-mediated responses&#46; This combined pathogenesis is clinically expressed in the varied pictures of PNP in contrast with those of pemphigus vulgaris&#46; Auto-reactive cellular toxicity&#44; mediated by cluster differentiating T lymphocytes &#40;CD8&#43; cytotoxic T lymphocytes&#41;&#44; CD56&#43; natural killer cells&#44; and CD68&#43; macrophages&#44; has also been implicated&#46;<a class="elsevierStyleCrossRefs" href="#bib0705"><span class="elsevierStyleSup">56&#44;50</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">Indirect immunofluorescence shows that IgG antibodies bind to the stratified epithelium in the esophagus and other tissues from monkeys&#46; In contrast to pemphigus vulgaris and foliaceus&#44; these antibodies also bind with the transitional and cylindrical epithelium of the urinary bladder&#44; bronchi&#44; small intestine&#44; and colon&#44; as well as&#44; to a lesser extent&#44; with myocardium and skeletal muscles and thyroid epithelium&#46;<a class="elsevierStyleCrossRef" href="#bib0675"><span class="elsevierStyleSup">50</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">In a previous study&#44; Anhalt et al&#46; showed that rat bladder immunofluorescence testing technique has a sensitivity of 75&#37; and a specificity of 83&#37; for diagnosing PNP&#46; This can be explained because the transitional epithelium of the rat bladder contains desmoplakin but not envoplakin&#44; periplakin and desmoglein&#44;<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">5</span></a> and not all patients with PNP have antibodies against all the antigens of the plakin complex&#46;<a class="elsevierStyleCrossRefs" href="#bib0675"><span class="elsevierStyleSup">50&#44;57</span></a> Plakin autoantibodies have been found in specific diseases&#58; anti-desmoplakin antibodies in pemphigus vulgaris and erythema multiforme&#44; anti-periplakin antibodies in pemphigus foliaceous and toxic epidermal necrolysis and rarely&#44; anti-envoplakin antibodies in pemphigus foliaceous and vulgaris&#46;<a class="elsevierStyleCrossRefs" href="#bib0705"><span class="elsevierStyleSup">56&#8211;58</span></a></p><p id="par0155" class="elsevierStylePara elsevierViewall">Poot et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0720"><span class="elsevierStyleSup">59</span></a> in a previous study&#44; showed that indirect immunofluorescence with salt-split skin&#44; showing a cytoplasmic staining of all layers of the epithelium&#44; was a highly specific pattern of PNP&#44; similarly as positive rat bladder indirect immunofluorescence&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">Immunoprecipitation is the most sensitive and specific test for measuring anti-plakin antibodies in PNP&#46;<a class="elsevierStyleCrossRef" href="#bib0720"><span class="elsevierStyleSup">59</span></a> A positive immunoprecipitation test qualifies as a major criterion for the diagnosis of PNP&#44;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">2</span></a> however&#44; it has limited availability&#46; Alternatives for the detection of plakin autoantibodies include immunoblotting and ELISA&#46; Immunoblotting can be performed using an extract of cultured human keratinocytes to detect all desmosomal proteins&#58; desmoglein 3 &#40;130<span class="elsevierStyleHsp" style=""></span>kDa&#41;&#44; desmoplakin 1 &#40;250<span class="elsevierStyleHsp" style=""></span>kDa&#41;&#44; BP230&#44; desmoplakin 2 &#40;210<span class="elsevierStyleHsp" style=""></span>kDa&#41;&#44; envoplakin &#40;210<span class="elsevierStyleHsp" style=""></span>kDa&#41;&#44; plectin &#40;&#62;400<span class="elsevierStyleHsp" style=""></span>kDa&#41;&#44; periplakin &#40;190<span class="elsevierStyleHsp" style=""></span>kDa&#41;&#44; epiplakin&#44;<a class="elsevierStyleCrossRef" href="#bib0640"><span class="elsevierStyleSup">43</span></a> and occasionally desmoglein 1 &#40;160<span class="elsevierStyleHsp" style=""></span>kDa&#41;&#46; Immunoblotting and ELISA may also be performed using recombinant fragments of periplakin and envoplakin&#46;<a class="elsevierStyleCrossRefs" href="#bib0725"><span class="elsevierStyleSup">60&#44;61</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Diagnosis</span><p id="par0165" class="elsevierStylePara elsevierViewall">Even when there is no consensus about the diagnostic criteria for PNP&#59; the diagnosis is based on the criteria of Anhalt et al&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">1</span></a> mostly on clinical and histologic observations&#44; direct immunofluorescence&#44; indirect immunofluorescence&#44; and immunoprecipitation tests &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#44; furthermore&#44; Camisa and Helm<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">14</span></a> have classified these criteria into major and minor signs&#46; Three major or two major and two minor signs are required to make a diagnosis of PNP&#46; The most common laboratory finding is the immunoprecipitation pattern which is characteristic<a class="elsevierStyleCrossRefs" href="#bib0430"><span class="elsevierStyleSup">1&#44;62</span></a> and may allow prompt diagnosis and active management of PNP&#46;<a class="elsevierStyleCrossRefs" href="#bib0740"><span class="elsevierStyleSup">63&#44;64</span></a></p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0170" class="elsevierStylePara elsevierViewall">The first diagnostic criteria made by Anhalt et al&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">1</span></a> include &#40;1&#41; characteristic clinical appearance and histopathology and&#44; &#40;2&#41; detection of tissue bound&#44; circulating autoantibodies via direct immunofluorescence&#44; indirect immunofluorescence and immunoprecipitation studies&#46;</p><p id="par0175" class="elsevierStylePara elsevierViewall">Anhalt further described other characteristics of PNP such as painful stomatitis&#44; a polymorphous skin eruption with histological findings showing lichenoid or acantholytic changes&#44; supportive immunofluorescence findings showing intercellular and basement membrane binding&#44; serum antibodies that bind simple&#44; columnar&#44; and transitional epithelium&#44; coexistence of lymphoproliferative disorders&#44; and the presence of anti-dsg&#44; desmoplakin I and II&#44; envoplakin&#44; periplakin&#44; bullous pemphigoid antigen 1&#44; and plectin antibodies&#46;<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">9</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Extension work-up</span><p id="par0180" class="elsevierStylePara elsevierViewall">In patients suspected of PNP&#44; an extensive work-up for an underlying associated malignancy must be performed if no tumor has been diagnosed so far&#46; This should include a chest&#44; abdomen and pelvis computed tomography scan&#46;<a class="elsevierStyleCrossRef" href="#bib0750"><span class="elsevierStyleSup">65</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Treatment</span><p id="par0185" class="elsevierStylePara elsevierViewall">To date&#44; PNP treatment has been rather disappointing&#46; It is vital to define and treat the associated neoplasm in PNP&#46; In patients with an operable tumor&#44; a surgical cure is often the best chance of inducing remission of PNP&#46;<a class="elsevierStyleCrossRef" href="#bib0755"><span class="elsevierStyleSup">66</span></a> The skin and mucosal eruptions cause severe morbidity and are often recalcitrant&#46;<a class="elsevierStyleCrossRefs" href="#bib0750"><span class="elsevierStyleSup">65&#44;66</span></a> The response to therapy is generally poor&#46; Firstly&#44; treatment is aimed at decreasing the production of autoantibodies&#46;<a class="elsevierStyleCrossRefs" href="#bib0760"><span class="elsevierStyleSup">67&#8211;69</span></a> A better prognosis can be expected when the neoplasm is less aggressive &#40;e&#46;g&#46; thymoma and Castleman&#39;s disease&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0755"><span class="elsevierStyleSup">66&#44;70&#8211;75</span></a></p><p id="par0190" class="elsevierStylePara elsevierViewall">Concurrent to a medical workup in patients without operable neoplasms&#44; several non-surgical treatments have proven effective in reducing symptoms in these patients&#46;<a class="elsevierStyleCrossRef" href="#bib0805"><span class="elsevierStyleSup">76</span></a> Initially&#44; glucocorticosteroid therapy should be added &#40;prednisone &#40;0&#46;5&#8211;1&#46;0<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#41;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0810"><span class="elsevierStyleSup">77</span></a> Cutaneous lesions tend to crust over and heal faster than mucosal&#46; Steroid-sparing agents can be added to glucocorticoid therapy to reduce the total steroid burden&#46; The addition of steroid-sparing agents&#44; such as azathioprine&#44; cyclosporine A&#44;<a class="elsevierStyleCrossRefs" href="#bib0810"><span class="elsevierStyleSup">77&#44;78</span></a> and mycophenolate mofetil&#44;<a class="elsevierStyleCrossRef" href="#bib0795"><span class="elsevierStyleSup">74</span></a> may reduce steroid intake and thus limit potential side-effects&#59; however&#44; a high level of caution is advised in patients with PNP and confirmed malignancy&#44; where immunosuppression is paramount and dictates the mainstay of treatment options&#46; Stem cell ablation therapy using high-dose cyclophosphamide without skin cell rescue has been used in some cases&#44;<a class="elsevierStyleCrossRefs" href="#bib0775"><span class="elsevierStyleSup">70&#44;79</span></a> but this is hazardous&#46;</p><p id="par0195" class="elsevierStylePara elsevierViewall">Less conventional therapies may be considered when the first-choice therapy fails&#59; when the patient is severely ill or when prompt intervention is required&#46; While results with plasmapheresis and intravenous immunoglobulin have been disappointing&#44;<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">5</span></a> rituximab&#44; a monoclonal antibody to CD20 on B-cells&#44; has shown promising results in patients with underlying B-cell lymphoma&#46;<a class="elsevierStyleCrossRefs" href="#bib0780"><span class="elsevierStyleSup">71&#44;80</span></a> Patients can be treated with the lymphoma protocol at a dose of 375<span class="elsevierStyleHsp" style=""></span>mg&#47;m<span class="elsevierStyleSup">2</span> weekly for 4 weeks&#44; or the rheumatologic protocol of 1<span class="elsevierStyleHsp" style=""></span>g once and repeated in 2 weeks&#46; Additional cycles may be administered every 6&#8211;12 months depending on clinical response and recovery of the B-cell &#40;CD20-CD19&#41; population&#46; Rituximab is usually well tolerated&#44; but notable adverse effects of treatment include infusion and allergic reactions&#46; Severe&#44; life-threatening anaphylactic reactions have occurred&#46; For this reason&#44; rituximab is infused in a monitored setting such as an infusion center where an allergy can be rapidly identified and treated&#46;<a class="elsevierStyleCrossRef" href="#bib0825"><span class="elsevierStyleSup">80</span></a> In addition&#44; progressive multifocal leukoencephalopathy&#44; a fatal and untreatable reactivation of Creutzfeldt Jakob virus in the brain&#44; has been reported in association with rituximab&#46;<a class="elsevierStyleCrossRef" href="#bib0830"><span class="elsevierStyleSup">81</span></a> This reactivation occurs only in the setting of severe immunosuppression&#46; Alemtuzumab&#44; a humanized monoclonal antibody against CD52&#44; has also been successfully when used to induce long-term remission in a patient with underlying B-cell chronic lymphocytic leukemia&#46;<a class="elsevierStyleCrossRefs" href="#bib0800"><span class="elsevierStyleSup">75&#44;82</span></a></p><p id="par0200" class="elsevierStylePara elsevierViewall">The concomitant use of rituximab with intravenous immunoglobulin has proven successful in patients who do not respond to conventional therapy or using rituximab as monotherapy&#46; Intravenous immunoglobulin at 2<span class="elsevierStyleHsp" style=""></span>g&#47;kg per monthly cycle is usually dosed&#46; Intravenous immunoglobulin is well tolerated and it has shown to be effective&#44; rapidly reducing pathogenic autoantibodies in patients with autoimmune bullous diseases&#46; Another benefit of intravenous immunoglobulin is the fact that it can be added into the patient&#39;s existing treatment regimen without added concern of additional immunosuppression&#44; becoming a popular approach among clinicians who treat PNP&#46; Intravenous immunoglobulin&#39;s favorable safety profile makes it an obvious choice in patients who are often on complicated treatments for PNP and an underlying malignancy&#46; However&#44; the considerable high cost has limited its extensive use&#46;<a class="elsevierStyleCrossRef" href="#bib0810"><span class="elsevierStyleSup">77</span></a></p><p id="par0205" class="elsevierStylePara elsevierViewall">Patients with PNP have an increased susceptibility to skin infections related to the loss of skin integrity and the use of potent immunosuppressant&#46; Early treatment of secondary infections with proper systemic antimicrobial therapy is of significant relevance to prevent sepsis and death&#46;<a class="elsevierStyleCrossRef" href="#bib0840"><span class="elsevierStyleSup">83</span></a></p><p id="par0210" class="elsevierStylePara elsevierViewall">Adequate analgesia should be provided as the lesions can be painful&#46; Oropharyngeal ulcerations may also interfere with proper feeding&#44; and a nasogastric tube may be required&#46;<a class="elsevierStyleCrossRef" href="#bib0810"><span class="elsevierStyleSup">77</span></a></p><p id="par0215" class="elsevierStylePara elsevierViewall">Importantly&#44; involvement of the respiratory tract epithelium can lead to bronchiolitis obliterans&#44; respiratory insufficiency and subsequent death&#46; A perioperative infusion of high-dose intravenous immunoglobulin during the surgical removal of Castleman&#39;s disease has been suggested to reduce the risk of bronchiolitis obliterans&#44; which is the most common cause of death in PNP patients with Castleman&#39;s disease&#46;<a class="elsevierStyleCrossRefs" href="#bib0730"><span class="elsevierStyleSup">61&#44;65&#44;66</span></a> Lung transplantation has been reported in managing progressive respiratory insufficiency caused by constrictive bronchiolitis in a 14 year-old patient with PNP and Castleman&#39;s disease&#46;<a class="elsevierStyleCrossRef" href="#bib0845"><span class="elsevierStyleSup">84</span></a></p></span></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Prognosis</span><p id="par0220" class="elsevierStylePara elsevierViewall">The overall prognosis of PNP is poor&#46; The mortality rate ranges from 75&#37; to 90&#37;&#44; being respiratory failure the main cause of death&#46;<a class="elsevierStyleCrossRef" href="#bib0830"><span class="elsevierStyleSup">81</span></a> The prognosis is better when the disease is associated with benign tumors and may even remit when tumors are excised&#46;</p><p id="par0225" class="elsevierStylePara elsevierViewall">The outcome of PNP&#44; however&#44; does not simply parallel the course of the underlying malignancy&#46; Complications resulting from PNP and its treatment contribute significantly to morbidity and mortality&#46; These include sepsis&#44; multi-organ failure&#44; gastrointestinal hemorrhage and respiratory failure related to bronchiolitis obliterans&#46;<a class="elsevierStyleCrossRef" href="#bib0840"><span class="elsevierStyleSup">83</span></a></p><p id="par0230" class="elsevierStylePara elsevierViewall">Ohzono et al&#46;<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">7</span></a> in a study of 104 PNP patients&#44; of whom 40 died&#59; the main cause of death in these patients was bronchiolitis obliterans &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>16&#47;40&#44; 40&#37;&#41;&#44; while the second cause &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>24&#47;40&#44; 60&#37;&#41; was infection &#40;mainly pneumonia&#41; and the third cause related to the associated tumor&#46;</p><p id="par0235" class="elsevierStylePara elsevierViewall">Bronchiolitis obliterans correlates with poor prognosis&#46; Pulmonary involvement occurs in 30&#8211;92&#46;8&#37; of patients and it is estimated that one-third of the deaths in PNP are due to pulmonary insufficiency&#46; It is known that constrictive bronchiolitis can continue to worsen despite improvement in muco-cutaneous manifestations after immunosuppressive therapy and resection of tumor&#46;<a class="elsevierStyleCrossRef" href="#bib0850"><span class="elsevierStyleSup">85</span></a> A prompt diagnosis and early introduction of treatment are mandatory&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Conclusions</span><p id="par0240" class="elsevierStylePara elsevierViewall">Through this literature review&#44; we acquired a global context of paraneoplastic pemphigus&#46; We present the main clinical features&#44; the fundamental principles of its etiopathogeny&#44; review the diagnostic aspects that integrate criteria distinguishing the entity from others such as pemphigus vulgaris&#59; the main associated tumors&#44; where we share part of the experience obtained in these almost 20 years studying autoimmune bullous diseases&#59; finally the main treatment options and the prognostic factors of the disease are discussed&#46; We emphasize the importance of making a timely diagnosis and choosing the most appropriate treatment option for each specific case&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Ethical disclosures</span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Protection of human and animal subjects</span><p id="par0245" class="elsevierStylePara elsevierViewall">The authors declare that no experiments were performed on humans or animals for this study&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Confidentiality of data</span><p id="par0250" class="elsevierStylePara elsevierViewall">The authors declare that no patient data appear in this article&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Right to privacy and informed consent</span><p id="par0255" class="elsevierStylePara elsevierViewall">The authors declare that no patient data appear in this article&#46;</p></span></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Conflict of interests</span><p id="par0260" class="elsevierStylePara elsevierViewall">The authors declare no conflict of interests&#46;</p></span></span>"
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          "titulo" => "Introduction"
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              "titulo" => "Protection of human and animal subjects"
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          "titulo" => "References"
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    "fechaRecibido" => "2016-11-26"
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            0 => "P&#233;nfigo paraneopl&#225;sico"
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            2 => "Producci&#243;n de anticuerpos"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Paraneoplastic pemphigus &#40;PNP&#41;&#44; a subset of pemphigus&#44; is a unique autoimmune blistering condition that can affect multiple organs other than the skin&#46; It is a life-threatening disease associated with an underlying malignancy&#44; most commonly of lymphoproliferative origin&#46; The clinical picture may resemble pemphigus&#44; pemphigoid&#44; erythema multiforme&#44; graft-versus-host disease&#44; or lichen planus&#46; The earliest and most consistent finding is a painful&#44; severe&#44; chronic and often recalcitrant stomatitis&#46; Treatment of PNP is difficult&#46; Immunosuppressive agents are required to decrease blistering&#44; and treating the underlying tumor may control autoantibody production&#46; In this review&#44; we included essential diagnostic aspects of PNP and the most useful treatment options in the dermatologist practice&#46;</p></span>"
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        "resumen" => "<span id="abst0015" class="elsevierStyleSection elsevierViewall"><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">El p&#233;nfigo paraneopl&#225;sico &#40;PNP&#41;&#44; una variedad de p&#233;nfigo&#44; es una enfermedad ampollosa autoinmune que puede afectar a m&#250;ltiples &#243;rganos distintos de la piel&#46; Es una enfermedad grave asociada con una malignidad subyacente&#44; com&#250;nmente de origen linfoproliferativo&#46; Las lesiones cl&#237;nicas pueden parecerse al p&#233;nfigo&#44; penfigoide&#44; eritema multiforme&#44; enfermedad de injerto contra hu&#233;sped o liquen plano&#46; El hallazgo m&#225;s temprano y m&#225;s consistente es una estomatitis dolorosa&#44; grave&#44; cr&#243;nica y&#44; a menudo&#44; recalcitrante&#46; El tratamiento del PNP es dif&#237;cil&#46; Se requieren agentes inmunosupresores para disminuir la formaci&#243;n de ampollas y el tratamiento del tumor subyacente puede controlar la producci&#243;n de autoanticuerpos&#46; En esta revisi&#243;n se incluyeron los aspectos diagn&#243;sticos m&#225;s esenciales del PNP y las opciones de tratamiento m&#225;s &#250;tiles en la pr&#225;ctica dermatol&#243;gica&#46;</p></span>"
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          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Pathogenesis of paraneoplastic pemphigus&#46; Neoplasms develop immune dysregulation and therefore the production of autoantibodies against self-antigens&#46; Antigen-processing cells assimilate antigens that are cross-reactive with several skin antigens&#44; presenting them to CD4&#43; T cells&#44; and therefore to the known immune cascade that ends in the formation of autoantibodies against different substrates&#46; The tumor itself can develop an immune process with the release of proinflammatory cytokines &#40;IL-12 and IFN&#41;&#46; This mechanism can be enhanced by the epitope spreading creating secondary epitopes&#44; increasing antibody production&#59; this mechanism contributes to epidermal and subepidermal lesions &#40;pemphigus and pemphigoid-like lesions&#41;&#46; Cell-mediated immune activation &#40;mainly CD8&#43; T cells&#41; also develops and contributes to several skin lesions &#40;lichenoid and graft-versus-host disease-like&#41;&#46;</p>"
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          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Severe oral mucositis&#44; also involving the nose&#46;</p>"
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          "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Erosions affecting the glans of penis&#46; It is evident the lichenoid lesions on the hands&#46;</p>"
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          "leyenda" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">PNP&#58; paraneoplastic pemphigus&#46;</p>"
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                  <table border="0" frame="\n
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                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Criteria&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Both conditions began simultaneously &#40;neoplasia and paraneoplasia&#41;&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Development of a parallel course &#40;treatment of the neoplasia results in regression of the skin lesion&#59; recurrence of the neoplasia implies recurrence of the skin lesion&#41;&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">The skin lesion is not associated with a genetic syndrome&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">There is a specific type of neoplasia that occurs with paraneoplasia&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">The dermatosis is rare in the general population&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">There is a high frequency of association between both conditions&#46;&nbsp;\t\t\t\t\t\t\n
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          "en" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Curth&#39;s criteria for the diagnosis of cutaneous paraneoplastic syndrome&#46;</p>"
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          "leyenda" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">PNP&#58; paraneoplastic pemphigus&#59; DIF&#58; direct immunofluorescence&#59; IIF&#58; indirect immunofluorescence&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Characteristic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Features&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Clinical&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Painful mucosal erosions with a polymorphous skin eruption culminating in vesicles&#47;bullae in the context of an occult&#47;confirmed neoplasm&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Histopathology&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Suprabasal acantholysis with clefting and suprabasal acantholysis resembling pemphigus vulgaris&#59; interface dermatitis and exocytosis of inflammatory cells into the epidermis resembling lupus erythematosus&#59; dyskeratosis &#40;keratinocyte necrosis&#41; with suprabasal acantholysis is a clue to PNP&#59; may resemble changes seen in erythema multiforme or graft versus host disease&#59; a lichenoid band may be seen along the dermal-epidermal junction resembling lichen planus&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">DIF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Deposition of complement and IgG in intracellular epidermal spaces and in the basement membrane zone in linear granular lesions&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">IIF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">IIF of patient serum with rat bladder epithelia shows intercellular staining&#46; Confirmation of autoantibodies to periplakin and&#47;or envoplakin&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Neoplasm&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Association with neoplasms &#40;in order of frequency&#58; non-Hodgkin lymphoma&#41;&#59; chronic lymphocytic leukemia&#59; Castleman disease&#59; carcinoma&#59; thymoma&#59; sarcoma &#40;liposarcoma&#44; leiomyosarcoma&#44; reticulum cell sarcoma&#44; malignant nerve sheath tumor&#41;&#59; Waldenstr&#246;m&#39;s macroglobulinemia&#59; Hodgkin lymphoma&#44; monoclonal gammopathy&#59; melanoma&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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        "descripcion" => array:1 [
          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Characteristics of paraneoplastic pemphigus&#47;paraneoplastic autoimmune multiorgan syndrome&#46;</p>"
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