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REVIEW
A review of the epidemiology and treatment of Merkel cell carcinoma
João Pedreira DupratI,
Corresponding author
jduprat@uol.com.br

Tel.: 55 11 2189-5135
, Gilles LandmanII,IV, João Victor SalvajoliIII, Eduard Rene BrechtbühlI
I Hospital do Câncer AC Camargo, Department of Skin Câncer, São Paulo/SP, Brazil.
II Hospital AC Camargo - Post Graduation, São Paulo/SP, Brazil.
III Instituto do Câncer do Estado de São Paulo Octavio Frias de Oliveira (ICESP), Radio-Oncology, São Paulo, SP, Brazil.
IV Federal University of São Paulo, Department of Pathology, São Paulo/SP, Brazil.
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="cesec10" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle20">INTRODUCTION</span><p id="para10" class="elsevierStylePara elsevierViewall">Merkel Cell Carcinoma &#40;MCC&#41; is a very rare and aggressive neoplasm&#46; Due to its rarity&#44; therapeutic guidelines are not well established&#44; especially for regionally advanced cases&#46;</p></span><span id="cesec20" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle30">METHOD</span><p id="para20" class="elsevierStylePara elsevierViewall">The MEDLINE database was searched for articles written in English&#44; French&#44; Italian&#44; Portuguese&#44; and Spanish&#46; The key word &#8220;Merkel&#8221; was used as the basis for these searches&#46; Relevant articles were selected&#44; and their references were also evaluated&#46;</p></span><span id="cesec30" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle40">DISCUSSION</span><span id="cesec40" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle50">Epidemiology and Etiopathology</span><p id="para30" class="elsevierStylePara elsevierViewall">Merkel Cell Carcinoma &#40;MCC&#41; is a rare and aggressive neoplasia that was first described in 1972 by Toker&#46;<a class="elsevierStyleCrossRef" href="#bib1">1</a> This tumor likely originates from a cutaneous mechanoreceptor cell &#40;Merkel cell&#41; located in the basal layer of the epidermis&#46; In the last decade&#44; reports on Merkel cell carcinoma have increased significantly&#44; primarily due to the advent of new and specific immunohistochemical staining methods&#46; This unusual cutaneous neuroendocrine neoplasia has many synonyms including &#8220;cutaneous neuroendocrine carcinoma&#44;&#8221; &#8220;cutaneous trabecular carcinoma&#44;&#8221; and &#8220;small cell primary cutaneous carcinoma&#8221;&#46;<a class="elsevierStyleCrossRefs" href="#bib1">1&#44;2</a> Currently&#44; 950 to 1&#44;300 cases of MCC are diagnosed per year in the United States&#46; This number appears to be increasing due to the advancing age of the population&#44; the higher incidence of damaging sun exposure&#44; and increasing numbers of immunocompromised individuals&#46;<a class="elsevierStyleCrossRefs" href="#bib3">3&#8211;7</a> Feng et al&#46; recently described a polyomavirus isolated from MCC specimens&#44; which may explain why MCC is more frequently observed in immunocompromised patients&#46; These authors studied ten tumors and detected the virus in eight cases&#46; In six of the eight positive tumors&#44; the virus was integrated into the tumor genome&#46; In non-MCC patients&#44; integration was observed in 16&#37; of cases&#46;<a class="elsevierStyleCrossRef" href="#bib8">8</a></p><p id="para40" class="elsevierStylePara elsevierViewall">The estimated annual incidence of MCC is 0&#46;23 per 100&#44;000 individuals for Caucasians&#44; whereas the incidence in those of African descent is 0&#46;01 per 100&#44;000 and appears to be even lower in Polynesians&#46; Merkel cell carcinoma occurs predominantly in elderly persons&#44; with a mean of 69 years-old at diagnosis&#46;<a class="elsevierStyleCrossRefs" href="#bib9">9&#8211;11</a> Males are affected more commonly than females &#40;61&#37; male vs&#46; 39&#37; female&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib12">12</a> Other tumors&#44; such as squamous cell carcinoma and chronic lymphocytic leukemia&#44; are also common in this population&#46;<a class="elsevierStyleCrossRef" href="#bib11">11</a></p><p id="para50" class="elsevierStylePara elsevierViewall">Angiogenesis has been described by many authors in this rare tumor&#46; Gaudin and Rosai described a vascular distribution pattern common to Merkel and other neural and neuroendocrine neoplasms characterized by tufts of vessels&#44; similar to a glomeruloid pattern&#44; or long cords of vessels&#46;<a class="elsevierStyleCrossRef" href="#bib13">13</a> They proposed that this characteristic pattern may be caused by angiogenic factors produced by these tumors&#46; Furthermore&#44; Kukko et al&#46; analyzed the expression of vascular endothelial growth factor receptor-2 &#40;VEGFR-2&#41; in Merkel tumors and found a strong positive correlation between the presence of VEGFR-2&#44; tumor size and metastatic potential&#46;<a class="elsevierStyleCrossRef" href="#bib14">14</a> In that study&#44; the authors suggested that antiangiogenic therapy could help control the tumor&#44; but this was not analyzed experimentally&#46; It has been shown in experimental models of MCC that inhibitors of the mTor pathways result in reduced VEGF production and angiogenesis&#46;<a class="elsevierStyleCrossRef" href="#bib15">15</a></p><p id="para60" class="elsevierStylePara elsevierViewall">Recently&#44; an interesting study was conducted by Vazmitel et al&#46;<a class="elsevierStyleCrossRef" href="#bib16">16</a> involving 92 cases of MCC&#46; They found prominent vascular alterations in 18 cases &#40;20&#37;&#41;&#46; Pericyte hyperplasia was observed in ten cases &#40;11&#37;&#41; among others six different patterns&#46; In this interesting study&#44; the presence of HHV-8 was analyzed because this virus is known to stimulate angiogenesis&#46; However&#44; HHV-8 was not detected with the polymerase chain reaction&#46;</p><p id="para70" class="elsevierStylePara elsevierViewall">Studies have been conducted on many tumors&#44; including MCC&#44; involving mTor receptors and the AKT&#47;PI3C pathway&#46; mTor &#40;Mammalian Target of Rapamycin&#41; is a protein kinase and a member of the PIKK family that controls cell growth&#46; mTor is regulated by many factors&#44; such as growth factors&#44; hormones &#40;insulin&#41;&#44; and the PI3K&#47;Akt pathway&#46; This pathway is initiated by growth factor receptors&#44; such as IGFR &#40;Insulin-like Growth Factor Receptor&#41;&#44; PDGFR &#40;Platelet-Derived Growth Factor Receptor&#41;&#44; EGFR &#40;Epidermal Growth Factor Receptor&#41;&#44; and the HER family&#46;<a class="elsevierStyleCrossRefs" href="#bib17">17&#44;18</a> In this particular pathway&#44; inactivation of PTEN&#44; which commonly occurs in human tumors&#44; is antagonistic to PI3K and results in increases in PIP3&#46; PI3K activation and accumulation of PIP3 causes translocation of Akt to the plasma membrane&#44; where Akt is activated&#46; These steps initiate anti-apoptotic pathways and stimulate the cell cycle via a series of factors&#44; including mTOR&#46; Akt&#47;mTOR can regulate suppression of p53&#44; and Akt can activate mdm2 and promote p53 degradation&#46; In models of MCC&#44; inhibition of Ras causes apoptosis with p53 degradation&#44; so it is very likely that this pathway is involved in MCC&#46;<a class="elsevierStyleCrossRefs" href="#bib19">19&#44;20</a></p><p id="para80" class="elsevierStylePara elsevierViewall">It is well accepted that Merkel carcinoma commonly occurs in immunocompromised patients&#44; and in this population&#44; changing the immunosuppression regimen from calcineurin inhibitors &#40;azathioprine and cyclosporine&#41; to serolimus results in better cure rates and regression of tumors&#46;<a class="elsevierStyleCrossRef" href="#bib21">21</a> Serolimus &#40;rapamycin&#41; acts both via the inhibition of the mTOR pathway and by diminishing angiogenesis&#46;<a class="elsevierStyleCrossRef" href="#bib22">22</a> It has been tested prospectively after transplants&#44; and there was a significant reduction of skin and non-skin cancers&#46;<a class="elsevierStyleCrossRef" href="#bib23">23</a> Furthermore&#44; serolimus has been tested for MCC&#46;<a class="elsevierStyleCrossRef" href="#bib19">19</a></p><p id="para90" class="elsevierStylePara elsevierViewall">In an experimental model of MCC&#44; the use of imatinib has been tested&#46; It has been suggested that an autocrine and paracrine activation of KIT receptors in MCC cell lines occurs via stem cell factor &#40;SCF&#41; and induces the MAPK pathway and AKT activation&#46; Although MCC cells display some response to imatinib&#44; a high dose is necessary to obtain cell death&#46; However&#44; relapse has been observed and is most likely due to direct activation of MEK1 and AKT&#44; which induces further proliferation and anti-apoptosis effects&#44; respectively&#46; This pathway is promising as a novel therapeutic option for this tumor&#46;<a class="elsevierStyleCrossRef" href="#bib24">24</a></p></span><span id="cesec50" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle60">Diagnosis</span><p id="para100" class="elsevierStylePara elsevierViewall">MCC occurs predominantly in the head and neck &#40;41 to 50&#37;&#41;&#44; followed by the extremities &#40;32 to 38&#37;&#41; and trunk &#40;12 to 14&#37;&#41;&#46; Typically&#44; this neoplasm presents as a rapidly growing&#44; dome-shaped red or bluish nodule&#46;<a class="elsevierStyleCrossRefs" href="#bib10">10&#44;12&#44;25</a> In addition&#44; the tumor may sometimes have a plaque-like appearance with small satellite lesions&#46;<a class="elsevierStyleCrossRef" href="#bib3">3</a></p><p id="para110" class="elsevierStylePara elsevierViewall">Diagnosis is usually established only after biopsy&#46; Similar to other neuroendocrine tumors&#44; small round to ovoid cells with hyperchromatic nuclei and frequent mitosis or apoptosis are commonly observed&#46; The architecture is often variable and includes trabecular&#44; nodular and diffuse patterns&#46; Sometimes&#44; it is difficult to differentiate MCC from other small cell tumors&#44; and in these cases&#44; immunohistochemical staining and&#47;or electron microscopy must be used&#46; MCC stains positively for neuron-specific enolase&#44; synaptophysin&#44; chromogranin&#44; cytokeratin 20 &#40;in a characteristic dot-like pattern&#41; and CAM 5&#46;2 and is negative for S100&#44; desmin and common leukocyte antigens&#46;<a class="elsevierStyleCrossRef" href="#bib10">10</a> Cytokeratin-20 expression is detected in 89 to 100&#37; of MCC cases as well as in 30&#37; of small-cell lung tumors&#46;<a class="elsevierStyleCrossRef" href="#bib26">26</a></p></span><span id="cesec60" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle70">Stage Classification</span><p id="para120" class="elsevierStylePara elsevierViewall">Yiengpruksawan<a class="elsevierStyleCrossRef" href="#bib27">27</a> proposed a stage classification for MCC as follows&#58; stage I would be restricted to the skin&#44; stage II would include nodal metastasis&#44; and stage III would be characterized by distant metastasis&#46; Later&#44; stage I disease was classified as IA &#40;&#8804;2 cm&#41; or IB &#40;&#62;2 cm&#41; based on publications by Yiengpruksawan and Allen&#46;<a class="elsevierStyleCrossRefs" href="#bib25">25&#44;27&#44;28</a> However&#44; that study was not able to show any statistical differences in the prognosis between tumor size groups&#46; In a study of 251 patients&#44; Allen et al&#46; showed that the proposed stage system with the division of IA and IB resulted in a different prognosis&#59; thus&#44; they used a four-stage system defined as follows&#58; Stage I T &#40;tumor size&#41; &#60;2 cm&#44; Stage II T &#8805;2 cm with no evidence of regional or distant disease&#44; Stage III with positive lymph nodes in the drainage basin&#44; and Stage IV with distant metastasis&#46; After a forty-month average follow-up&#44; the survival rates were 81&#37; for Stage I&#44; 67&#37; for Stage II&#44; 52&#37; for Stage III&#44; and 11&#37; for Stage IV&#46;<a class="elsevierStyleCrossRef" href="#bib29">29</a> Pitale et al&#46; did not observe any influence of the tumor size on the prognosis of 306 patients&#44; but their meta-analysis was a summary of the literature and did not represent data from a single institution&#46;<a class="elsevierStyleCrossRef" href="#bib30">30</a> Lemos et al&#46; evaluated 2&#44;856 patients and were able to analyze the impact of tumor size with 1-cm increments&#46; They found that the most important difference was between &#8804;2 cm and more than 2 cm &#40;five-year survival rate of 66&#37; vs&#46; 51&#37;&#44; respectively&#59; <span class="elsevierStyleItalic">p</span>&#60;0&#46;0001&#41;&#46; Interestingly&#44; tumors that are &#60;1 cm are associated with only minimal improvement in survival when compared with those that are 1 to 2 cm in diameter &#40;69&#37; vs&#46; 61&#37;&#44; respectively&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib12">12</a></p><p id="para130" class="elsevierStylePara elsevierViewall">Nodal disease is an important negative prognostic factor for this type of tumor&#46; Clinical versus pathological staging seems to be important in prognosis and treatment&#59; patients with a clinically enlarged node had a worse prognosis than those whose nodes were evaluated histopathologically by sentinel lymph node biopsy&#44; fine needle aspiration or elective lymphadenectomy&#46;<a class="elsevierStyleCrossRef" href="#bib12">12</a> Even in the tumor &#40;T&#41; category&#44; the authors categorized the tumors as pathologically negative or clinically negative nodes&#44; with different prognoses &#40;<a class="elsevierStyleCrossRefs" href="#tbl1">Tables 1 and 2</a>&#41;&#46; It is noteworthy that approximately 50 to 70&#37; of all patients will develop lymph node metastases&#44; and of these patients&#44; 33 to 70&#37; will develop distant disease&#46;<a class="elsevierStyleCrossRefs" href="#bib1">1&#44;2&#44;30&#8211;35</a> The most frequent sites of metastasis are liver &#40;13&#37;&#41;&#44; bone &#40;10-15&#37;&#41;&#44; lung &#40;10-23&#37;&#41;&#44; brain &#40;18&#37;&#41;&#44; distant skin &#40;9-30&#37;&#41; and distant lymph nodes &#40;9&#37;&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib29">29&#44;36&#8211;38</a></p><elsevierMultimedia ident="tbl1"></elsevierMultimedia><elsevierMultimedia ident="tbl2"></elsevierMultimedia><p id="para140" class="elsevierStylePara elsevierViewall">In the largest patient cohort of patients from the American National Cancer Database&#44; Lemos et al&#46; evaluated the mortality of each clinical presentation and adjusted for age&#46; For the overall population&#44; the 5-year survival was 54&#37;&#59; for those with local&#44; nodal and distant disease at presentation&#44; these values were 64&#44; 39&#44; and 18&#37;&#44; respectively&#46;<a class="elsevierStyleCrossRef" href="#bib12">12</a></p><p id="para150" class="elsevierStylePara elsevierViewall">The Seventh Edition of AJCC<a class="elsevierStyleCrossRef" href="#bib39">39</a> integrates Lemos et al&#46;&#39;s findings&#44; as summarized in <a class="elsevierStyleCrossRef" href="#tbl2">Table 2</a> &#40;excluded Tx and T0&#41;&#46;</p><p id="para160" class="elsevierStylePara elsevierViewall">It was possible&#44; with a greater cohort of patients&#44; to show that in the nodal-negative group clinically evaluated&#44; relative survival was worse when compared to pathologyical proof&#44; such as sentinel&#44; fine-needle or elective lymph node biopsy &#40;HR 1&#46;80&#44; 95&#37; confidence interval 1&#46;4-2&#46;4&#44; <span class="elsevierStyleItalic">p</span>&#60;0&#46;0001&#41;&#46; For the positive nodal group&#44; the survival was worse when a node was clinically detected &#40;HR 1&#46;48&#44; 95&#37; confidence interval 1&#46;1-1&#46;9&#44; <span class="elsevierStyleItalic">p</span> &#61; 0&#46;004&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib12">12</a></p></span><span id="cesec70" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle80">Treatment</span><p id="para170" class="elsevierStylePara elsevierViewall">Due to its rare incidence&#44; there is currently a lack of standard therapeutic procedures ascribed for the treatment of MCC&#44; especially when the disease is locally advanced&#46; Surgical excision and radiotherapy remain the mainstays of therapy in the initial stages&#46;<a class="elsevierStyleCrossRefs" href="#bib2">2&#44;10&#44;25&#44;27&#44;31&#44;32</a></p></span><span id="cesec80" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle90">Primary Lesion</span><p id="para180" class="elsevierStylePara elsevierViewall">Following a confirmatory biopsy of a suspected lesion that confirms the diagnosis&#44; surgery is the usual treatment choice&#46;<a class="elsevierStyleCrossRefs" href="#bib2">2&#44;10&#44;27&#44;31&#44;32&#44;36</a> Depending on the physician&#39;s and patient&#39;s preference&#44; a wide local excision made deep into the muscle fascia or Mohs micrographic surgery can be performed&#46; Both are successful in achieving tumor-free margins and an acceptable level of disease-free survival&#46; Of note&#44; at our institution&#44; the wide margin resection was preferred&#46; If Mohs micrographic surgery &#40;MMC&#41; is performed&#44; adjuvant radiotherapy seems to be essential&#46; In support of this&#44; Boyer et al&#46; conducted a study among patients who underwent Mohs surgery&#46; Twenty patients had radiotherapy as adjuvant treatment&#44; and 25 did not receive any adjuvant radiotherapy&#46; In the adjuvant radiotherapy group&#44; there was no recurrence&#44; but in the Mohs surgery-only group&#44; recurrence was detected in four cases&#46; Given the small study numbers&#44; this difference was not statistically significant&#46;<a class="elsevierStyleCrossRef" href="#bib40">40</a> Since adjuvant radiotherapy is typically performed regardless of a tumor&#39;s margins&#44; it is not reasonable to compare wide local excision and MMC&#46; Wide local excision for MCC is often performed as it is performed for melanoma&#44; with 2 cm margins&#44; if feasible&#46; Unfortunately&#44; there are no prospective studies on the ideal margin&#46; Allen et al&#46;&#44; in a study of 251 patients from a single institution&#44; found that obtaining a surgical margin of more than 1 cm was not associated with decreased local recurrence &#40;&#60;1 cm 9&#37; vs&#46; &#8805;1 cm 10&#37;&#44; <span class="elsevierStyleItalic">p</span> &#61; 0&#46;8&#41;&#46; Local recurrence occurred in 18&#37; of patients with positive margins&#59; if the margins were negative&#44; recurrence occurred in 8&#37;&#44; and this difference was not statistically significant &#40;<span class="elsevierStyleItalic">p</span> &#61; 0&#46;31&#41;&#46; In addition&#44; in their study&#44; the use of radiotherapy as opposed to surgery did not decrease the local recurrence rate &#40;radiotherapy 10&#37; vs&#46; no radiotherapy 8&#37;&#44; <span class="elsevierStyleItalic">p</span> &#61; 0&#46;76&#41;&#46; Unfortunately&#44; this was not a randomized study&#44; so patients with tumors &#8805;2 cm received additional adjuvant radiotherapy &#40;&#60;2 cm 10&#37; vs&#46; &#8805;2 cm 23&#37;&#44; <span class="elsevierStyleItalic">p</span> &#61; 0&#46;02&#41;&#46; It is also worth noting that radiotherapy was given only to 12&#37; of patients&#44; who generally represented the most severe cases&#59; this could have influenced the outcome in patients with positive margins who received adjuvant treatment&#46;<a class="elsevierStyleCrossRef" href="#bib29">29</a> Jabbour et al&#46;<a class="elsevierStyleCrossRef" href="#bib41">41</a> reinforced previous evidence that&#44; if adjuvant radiotherapy is associated&#44; the margin does not interfere with recurrence or survival&#46; Thus&#44; those authors emphasized the benefit of adjuvant radiotherapy administered either locally or regionally&#46;</p><p id="para190" class="elsevierStylePara elsevierViewall">There are some authors who advocate the use of adjuvant radiotherapy based on histological features&#44; such as thickness and angiolymphatic invasion&#46;<a class="elsevierStyleCrossRef" href="#bib42">42</a> Comparison is very difficult because each study&#39;s design and characteristics are different&#59; some compare positive margins&#44; some treat exclusively with radiotherapy&#44; and some add the evaluation of the draining lymph node basin&#46; Various protocols reported in reviews are applied to a large number of patients&#46; <a class="elsevierStyleCrossRef" href="#tbl3">Table 3</a> is an effort to compile these trends&#46;</p><elsevierMultimedia ident="tbl3"></elsevierMultimedia><p id="para200" class="elsevierStylePara elsevierViewall">In a study of 17 patients&#44; Warner et al&#46; did not observe a significant impact of a positive sentinel node on the prediction of regional recurrence&#46; However&#44; they did find that radiotherapy had an impact on local and regional control&#46;<a class="elsevierStyleCrossRef" href="#bib43">43</a></p><p id="para210" class="elsevierStylePara elsevierViewall">Adjuvant radiotherapy is often suggested for large tumors and for cases in which regional disease is present&#46;<a class="elsevierStyleCrossRefs" href="#bib30">30&#44;32&#44;33&#44;35&#44;36&#44;44&#44;45</a> In a meta-analysis by Lewis et al&#46;<a class="elsevierStyleCrossRef" href="#bib46">46</a> who compared surgery alone to surgery plus adjuvant radiation&#44; the authors showed a reduction in local and regional recurrence in the combined therapy group&#46; That study encompassed 1&#44;254 patients&#44; and if local radiotherapy was performed&#44; a decrease in local &#40;88 vs&#46; 61&#37;&#44; respectively&#59; <span class="elsevierStyleItalic">p</span>&#60;0&#46;001&#41; and regional &#40;77 vs&#46; 44&#37;&#44; respectively&#59; <span class="elsevierStyleItalic">p</span>&#60;0&#46;001&#41; recurrence was observed&#44; as was an increase in survival &#40;HR 0&#46;63&#44; <span class="elsevierStyleItalic">p</span> &#61; 0&#46;02&#41;&#46; It is very important to note that the group with primary tumors &#8804;2 cm benefitted the most from radiotherapy&#46; Gillenwater et al&#46; found a statistically significant difference in local recurrence in the head and neck region with radiotherapy &#40;12&#37; with vs&#46; 44&#37; without&#59; <span class="elsevierStyleItalic">p</span>&#60;0&#46;01&#41; and regional therapy &#40;27 vs&#46; 85&#37;&#59; <span class="elsevierStyleItalic">p</span>&#60;0&#46;01&#41; but did not find a difference in overall survival&#46;<a class="elsevierStyleCrossRef" href="#bib47">47</a> In a retrospective study&#44; Meeuwissen et al&#46; showed that all 38 patients treated with surgery alone relapsed&#44; whereas only 10 in 34 patients treated with surgery plus radiotherapy relapsed&#46;<a class="elsevierStyleCrossRef" href="#bib48">48</a> In that study&#44; the patients treated with surgery plus radiotherapy were treated at a referred radiotherapy facility&#44; therefore attending mostly the recurrences&#46; It was not clear whether the surgeons who referred patients had the skills to treat the disease&#46;<a class="elsevierStyleCrossRef" href="#bib3">3</a></p><p id="para220" class="elsevierStylePara elsevierViewall">A primary lesion that is not resectable can be treated with radiotherapy as an isolated treatment&#46; The usual dose is 45-70 Gy&#46;<a class="elsevierStyleCrossRef" href="#bib49">49</a> Mortier et al&#46; treated nine cases of primary lesions that could not be treated surgically&#46; After a median follow-up of three years&#44; there was no recurrence&#46;<a class="elsevierStyleCrossRef" href="#bib50">50</a> In a larger series of 43 patients&#44; Veness et al&#46; treated patients who were non-operable because of clinical or local reasons&#59; 77&#37; of patients had nodal metastasis&#46; In this particularly bad prognosis group&#44; they had only 60&#37; relapse&#44; which commonly occurred out-of-field&#46; The in-field control was 75&#37;&#46; The overall survival after two and five years was 58 and 37&#37;&#44; respectively&#46;<a class="elsevierStyleCrossRef" href="#bib51">51</a></p><p id="para230" class="elsevierStylePara elsevierViewall">The Peter MacCallum Cancer Centre in Australia collected robust data on 176 patients&#46; In that cohort&#44; 94&#37; of patients received radiotherapy&#46; In the multivariate analysis&#44; the dose of radiotherapy was significantly different for locoregional control&#46; They divided their cohort into three groups&#58; a&#41; no radiotherapy&#44; b&#41; radiotherapy &#60;45 Gy and c&#41; radiotherapy &#8805;45 Gy&#59; Comparing the control achieved in the groups&#44; respectively was 51 vs&#46; 71 vs&#46; 80 months <span class="elsevierStyleItalic">p</span> &#61; 0&#46;044 and overall survival&#44; <span class="elsevierStyleItalic">p</span> &#61; 0&#46;005&#41;&#46; However&#44; only 11 patients received no radiotherapy&#46;<a class="elsevierStyleCrossRef" href="#bib52">52</a></p></span><span id="cesec90" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle100">Regional Treatment</span><p id="para240" class="elsevierStylePara elsevierViewall">In the absence of clinically positive lymph nodes&#44; most centers will perform a sentinel lymph node biopsy &#40;SLNB&#41; to obtain accurate nodal staging&#46; As stated previously&#44; this is an important prognostic factor&#46;<a class="elsevierStyleCrossRefs" href="#bib3">3&#44;6&#44;43&#44;53</a> The SLNB technique is conducted in the same manner as in melanoma patients&#46; Immunohistochemistry for CK-20 is a valuable tool in identifying micrometastases&#46; Allen et al&#46; found 23&#37; positivity of lymph nodes in patients who underwent pathologic staging of a clinically negative nodal basin &#40;17 patients underwent elective lymph node dissection and 54 had sentinel lymph node biopsy&#41;&#46; Paradoxically&#44; if the primary lesion was less than 2 cm&#44; the rate of positive nodes was 24&#37;&#44; and if the tumor was &#8805;2 cm&#44; the rate of positive nodes was 20&#37; &#40;<span class="elsevierStyleItalic">p</span> &#61; 0&#46;71&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib29">29</a> Gupta et al&#46; reviewed 122 patients with MCC who underwent SLNB and observed that 60&#37; of those patients with a positive sentinel node recurred in three years &#40;compared to a recurrence rate of 20&#37; in those with negative SLNB&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib6">6</a> Warner et al&#46; analyzed 22 papers involving the use of SLNB for MCC and found that among 241 patients&#44; 31&#37; had metastases&#46; This group experienced recurrence in 19&#37; of cases&#46; In the negative sentinel node group&#44; the recurrence was 7&#46;5&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib42">42</a> A positive node&#44; either clinically or pathologically detected&#44; requires the complete removal of all drainage basin lymph nodes&#46; Patients who underwent a lymphadenectomy had longer disease-free survival &#40;28&#46;5 vs&#46; 11&#46;8 months&#44; <span class="elsevierStyleItalic">p</span> &#61; 0&#46;04&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib41">41</a> Follow-up in small groups of patients reinforces this observation&#46;<a class="elsevierStyleCrossRefs" href="#bib36">36&#44;38&#44;53&#44;54</a> Mehrany et al&#46; performed a meta-analysis and showed that 15 of 20 patients with positive sentinel lymph nodes subsequently underwent a lymphadenectomy and had no regional recurrence after nine months&#46; In contrast&#44; three of four patients with positive nodes who did not subsequently undergo lymphadenectomy had regional recurrences&#44; with one patient absent from follow-up&#46;<a class="elsevierStyleCrossRef" href="#bib53">53</a> Gupta et al&#46; showed that a sentinel lymph node biopsy is not only important as a prognostic procedure but can also guide therapy&#46; Data from Lemos et al&#46; have shown that there is also a survival benefit in performing SLNB&#44; as already shown in the stage chapter&#46;<a class="elsevierStyleCrossRef" href="#bib12">12</a></p><p id="para250" class="elsevierStylePara elsevierViewall">There are some questions about false-negative sentinel nodes in MCC because compared to melanoma patients&#44; the mean age is older&#44; and there is a higher incidence in the head and neck region&#46; In both situations&#44; higher numbers of false-negatives have been obtained during the sentinel node biopsy evaluation&#46; MCC more frequently invades deep into the tissues&#44; such as deep dermis and subcutaneous layers&#44; affecting different sentinel nodes than those of the melanoma patients&#46;<a class="elsevierStyleCrossRef" href="#bib42">42</a> However&#44; data from AJCC 2010<a class="elsevierStyleCrossRef" href="#bib39">39</a> have shown that the value of the procedure is easily demonstrated&#46; Patients with positive sentinel lymph nodes who received adjuvant therapy localized to the nodal positive basin &#40;surgery&#44; radio-&#44; or chemotherapy&#41; had 50&#37; disease-free survival at three years&#44; but this was decreased to 0&#37; if adjuvant therapy was not administered&#46;<a class="elsevierStyleCrossRef" href="#bib6">6</a> As adjuvant therapy&#44; a dose of 40 to 50 Gy is administered in 2-Gy daily fractions to the primary or regional basin&#46;<a class="elsevierStyleCrossRefs" href="#bib34">34&#44;41&#44;43</a></p><p id="para260" class="elsevierStylePara elsevierViewall">A major discussion in the literature refers to management after a positive node is detected&#58; is it better to perform a complete node dissection&#44; radiotherapy only&#44; or both&#63;<a class="elsevierStyleCrossRef" href="#bib42">42</a> The answer remains unclear&#46; Lymphadenectomy associated with radiotherapy in axillary and inguinal regions can lead to substantial lymphedema&#46; In older patients with micrometastases&#44; isolated radiotherapy seems to be a good option&#46; For good performance status&#44; in patients with larger tumors&#44; macrometastases&#44; or extra-nodal invasion&#44; combined therapy is a reasonable option&#46; For patients with less-than-optimal margins&#44; especially in the head-neck region where adjuvant radiotherapy is planned&#44; it is reasonable to excise lymph nodes close to the positive node basin &#40;if micrometastasis has minimal disease&#41; without performing a complete lymph node dissection&#46; Extrapolating from studies of the primary lesion&#44; there are enough data to support that radiotherapy only applied to the positive sentinel node basin can be a reasonable option&#44;<a class="elsevierStyleCrossRefs" href="#bib50">50&#44;51</a> but the data for positive sentinel nodes remain limited&#46; Bichakjian et al&#46; suggested that with the limited available data&#44; radical lymphadenectomy should be considered the first-line treatment for sentinel node positive patients&#46; In cases where surgery is a high-risk procedure for the patient&#44; radiotherapy without surgery should be considered&#46;<a class="elsevierStyleCrossRef" href="#bib36">36</a></p><p id="para270" class="elsevierStylePara elsevierViewall">If an enlarged regional node is present&#44; lymphadenectomy and adjuvant radiotherapy are often performed&#46;<a class="elsevierStyleCrossRefs" href="#bib30">30&#44;32&#44;33&#44;35&#44;41&#44;44&#44;45</a> As previously mentioned&#44; in the head and neck region&#44; Gillenwater et al&#46; found that local and regional recurrence differed significantly when patients received radiotherapy&#44; but they did not find differences in overall survival&#46;<a class="elsevierStyleCrossRef" href="#bib47">47</a> Patients receiving radiotherapy had a regional recurrence rate of 27 vs&#46; 85&#37; compared to those who did not&#46; Disease-free survival increased from eight to twenty-four months if any radiotherapy was applied&#46;<a class="elsevierStyleCrossRef" href="#bib41">41</a> In summary&#44; it seems that adjuvant radiotherapy is beneficial both locally and regionally&#46;</p><p id="para280" class="elsevierStylePara elsevierViewall">Distant disease occurs in 36&#37; of patients&#44; regardless of the adjuvant therapy applied&#46;<a class="elsevierStyleCrossRef" href="#bib47">47</a> In addition&#44; adjuvant chemotherapy failed to provide any benefit&#46; Garneski et al&#46; showed that the chemotherapeutic regimen is toxic&#44; and the target population is elderly&#44; leading to a treatment-related death rate of approximately 16&#37; in patients older than 65 years&#46; Morbidity is also high in these cases&#44; and the chemotherapeutic regimen is adapted from that used for small-cell lung carcinoma&#46; Without evidence of improved outcomes&#44; it does not seem reasonable to take on the risk of such a toxic treatment&#46;<a class="elsevierStyleCrossRefs" href="#bib29">29&#44;41&#44;55&#44;56</a></p></span><span id="cesec100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle110">Distant metastasis</span><p id="para290" class="elsevierStylePara elsevierViewall">Chemotherapy plays a role in the treatment of distant metastatic disease&#46; The preferred therapeutic regimen consists of platinum-based components&#44; such as cisplatin or carboplatin&#44; plus etoposide or doxorubicin&#46; Response rates of up to 40&#37; were observed in some studies&#59; however&#44; those who responded did so only for a short time&#46;<a class="elsevierStyleCrossRefs" href="#bib33">33&#44;35&#44;44</a></p><p id="para300" class="elsevierStylePara elsevierViewall">In recurrent disease&#44; the choice of treatment becomes a matter of debate&#46; Many investigators defend radiotherapy as an important part of the treatment for such patients&#44;<a class="elsevierStyleCrossRefs" href="#bib27">27&#44;31&#44;45&#44;57&#44;58</a> whereas others believe that chemotherapy should play a role in recurrent disease&#46; However&#44; the results obtained with this therapy have been disappointing&#46;<a class="elsevierStyleCrossRefs" href="#bib58">58&#44;59</a></p></span><span id="cesec110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle120">Treatment of in-transit metastasis</span><p id="para310" class="elsevierStylePara elsevierViewall">In-transit disease is a common phenomenon in cutaneous melanoma&#44; as well as in MCC patients&#46;<a class="elsevierStyleCrossRefs" href="#bib46">46&#44;60</a> For selected patients with in-transit disease or for whom limb amputation would be indicated&#44; local control of the tumor and limb preservation have been achieved with the increased use of hyperthermic isolated limb perfusion with melphalan&#46;<a class="elsevierStyleCrossRefs" href="#bib60">60&#8211;64</a></p><p id="para320" class="elsevierStylePara elsevierViewall">Alternative treatment options&#44; such as radiotherapy and chemotherapy&#44; have been reported&#46; For extensive but localized lesions&#44; radiotherapy can be a good option&#46; Mortier et al&#46; treated nine cases of primary lesions that were not eligible for surgical treatment&#46; After a median follow-up of three years&#44; there was no recurrence&#46;<a class="elsevierStyleCrossRef" href="#bib49">49</a></p><p id="para330" class="elsevierStylePara elsevierViewall">Selected cases with in-transit metastasis may be successfully treated with isolated perfusion of chemotherapeutic agents as an alternative to radical surgery&#46;</p><p id="para340" class="elsevierStylePara elsevierViewall">We recently published a review of the literature on hyperthermic isolated limb perfusion in MCC&#44; which covered a series of nine cases&#44; including one case in which we performed the operation&#46; Five patients were treated with melphalan alone&#44; and four were treated with melphalan and TNF-&#945;&#46; All patients treated with melphalan alone had a complete response&#44; whereas in the melphalan and TNF-&#945; treatment groups there were two complete responses&#44; one partial response&#44; and one patient with no response&#46;<a class="elsevierStyleCrossRef" href="#bib63">63</a></p></span></span><span id="cesec120" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle130">CONCLUSION</span><p id="para350" class="elsevierStylePara elsevierViewall">The incidence of MCC is increasing due to the advancing age of the population&#44; a higher incidence of damaging sun exposure&#44; and an increase in the number of immunocompromised individuals&#46; Regarding its etiology of MCC&#44; the recently described Merkel cell polyomavirus must be considered&#46; While local or regional surgical treatment remains the standard of care&#44; adjuvant radiotherapy or radiotherapy alone have been shown to be reasonable therapeutic options&#46;</p></span></span>"
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    "fechaAceptado" => "2011-05-30"
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            0 => "Carcinoma&#44; Merkel CELL"
            1 => "Literature review"
            2 => "Radiotherapy"
            3 => "Polyomavirus"
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        "resumen" => "<span id="ceabs10" class="elsevierStyleSection elsevierViewall"><p id="spara40" class="elsevierStyleSimplePara elsevierViewall">Merkel cell carcinoma is a very rare and aggressive neoplasm&#46; Due to its rarity&#44; therapeutic guidelines are not well established&#44; especially for regionally advanced disease&#46; Articles in English&#44; French&#44; Italian&#44; Portuguese&#44; and Spanish from the last 20 years were identified in MEDLINE and reviewed&#46; The key word &#8220;Merkel&#8221; was used for the search&#44; relevant articles were selected&#44; and their references were examined&#46; The most important articles related to epidemiology&#44; genesis and treatment were reviewed&#46; The incidence of Merkel cell carcinoma is increasing due to the advancing age of the population&#44; higher rates of sun exposure and an increasing number of immunocompromised individuals&#46; With regard to etiology&#44; the recently described Merkel Cell polyomavirus is thought to play a role&#46; Either local or regional surgical intervention remains the standard of care&#44; but adjuvant radiotherapy or radiotherapy as a primary treatment have been discussed as reasonable therapeutic options&#46; An update on this rare neoplasia is essential because of its increasing incidence and changing treatment options&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="cenpara10">No potential conflict of interest was reported&#46;</p>"
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              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">&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="center" valign="top" scope="col">Tumor &#40;T&#41;&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" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">T1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">&#8804;2 cm tumor size&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">T2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">&#62;2 cm but no more than 5 cm&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">T3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">&#62;5 cm&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">T4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">invasion of bone&#44; muscle&#44; fascia or cartilage&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">Nodal &#40;N&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">cN0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">node negative by clinical exam &#40;clinical or imaging exam&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">pN0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">node negative by pathologic exam&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">N1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">metastasis in regional node&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">N1a&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">micrometastasis &#40;sentinel node or elective lymphadenectomy&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">N1b&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">macrometastasis &#40;clinically detectable&#44; confirmed by surgery or fine-needle aspiration&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">N2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">in-transit metastasis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">Metastasis &#40;M&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">M0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">no distant metastasis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">M1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">metastasis beyond regional lymph nodes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">M1a&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">metastasis to skin&#44; subcutaneous tissues or distant lymph nodes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">M1b&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">metastasis to lung&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top" style="border-bottom: 2px solid black">M1c&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top" style="border-bottom: 2px solid black">metastasis to all other visceral sites&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spara10" class="elsevierStyleSimplePara elsevierViewall">TNM Classification&#46;</p>"
        ]
      ]
      1 => array:7 [
        "identificador" => "tbl2"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:2 [
          "tablatextoimagen" => array:1 [
            0 => array:1 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="top" scope="col">Stage&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">&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="center" valign="top" scope="col">Five-yearSurvival &#40;&#37;&#41;<a class="elsevierStyleCrossRef" href="#tfn1">&#42;</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" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">Tis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">N0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">M0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">IA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">T1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">pN0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">M0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">79&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">IB&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">T1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">cN0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">M0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">60&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">IIA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">T2&#47;T3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">pN0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">M0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">58&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">IIB&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">T2&#47;T3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">cN0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">M0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">49&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">IIC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">T4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">N0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">M0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">47&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">IIIA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">Any T&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">N1a&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">M0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">45&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">IIIB&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">Any T&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">N1b&#47;N2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">M0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">30&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top" style="border-bottom: 2px solid black">IV&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top" style="border-bottom: 2px solid black">Any T&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top" style="border-bottom: 2px solid black">Any N&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top" style="border-bottom: 2px solid black">M1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top" style="border-bottom: 2px solid black">18&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
            ]
          ]
          "notaPie" => array:1 [
            0 => array:3 [
              "identificador" => "tfn1"
              "etiqueta" => "&#42;"
              "nota" => "<p class="elsevierStyleNotepara" id="cenpara20">&#40;Lemos&#41;&#46;</p>"
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spara20" class="elsevierStyleSimplePara elsevierViewall">Staging System&#46;</p>"
        ]
      ]
      2 => array:7 [
        "identificador" => "tbl3"
        "etiqueta" => "Table 3"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:2 [
          "tablatextoimagen" => array:1 [
            0 => array:1 [
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                      "titulo" => "Trabecular carcinoma of the skin"
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                          "autores" => array:1 [
                            0 => """
                              C Toker \n
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                          "autores" => array:3 [
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                            1 => """
                              LF Glass \n
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                              NA Fenske \n
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                        "tituloSerie" => "Diagnosis and treatment&#46; Dermatol Surg"
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                              MG Boersma \n
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                              M Joyner \n
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