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            "entidad" => "Servicio de Dermatolog&#237;a&#44; Instituto Valenciano de Oncolog&#237;a&#44; Valencia&#44; Spain"
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        "titulo" => "Estudio longitudinal de los diferentes patrones de progresi&#243;n en el carcinoma cut&#225;neo de c&#233;lulas escamosas de alto riesgo"
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          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Temporal course of the different progression pathways for patients who finally died from high-risk cSCC&#46; d&#44; death&#59; L&#44; regional lymphatic recurrence&#59; LR&#44; local recurrence&#59; M&#44; systemic metastasis&#59; S&#44; satellitosis&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Cutaneous squamous cell carcinoma &#40;cSCC&#41; is the second most frequent malignant cutaneous neoplasm in Spain&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">1</span></a> cSCC is also the second leading cause of skin cancer mortality after melanoma&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">1</span></a> This tumor has low metastatic potential&#46; cSCC preferentially metastasizes via the lymphatic route in 3&#37; up to 5&#37; of cases&#44; depending on the location&#44; size&#44; depth of invasion&#44; perineural invasion&#44; or bone involvement&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">On the other hand&#44; selective sentinel lymph node biopsy &#40;SLNB&#41; is a surgical technique widely developed in other types of tumors&#44; such as melanoma&#44; based on its propensity for regional lymphatic metastases&#44; without an impact on the survival of these patients&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">3</span></a> In the case of cSCC&#44; the utility of SLNB is unknown to this date&#44; with a positivity rate of 8&#37; up to 10&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">4</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Very few studies have been published on the natural history in terms of cSCC progression&#44;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">5</span></a> or on the clinical course of various relapse forms in this tumor progression&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">Understanding and analyzing how cSCC progresses would help design diagnostic&#44; therapeutic&#44; and follow-up strategies for these patients&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">The primary endpoint of this study is to analyze the different pathways of cSCC progression &#40;local recurrence&#44; satellitosis&#44; regional lymphatic recurrence&#44; or distant metastasis&#41;&#44; along with the time course of these progressions&#46; Secondary endpoints include analyzing the relationship of different clinical and pathological variables with the different forms of progression&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Material and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Participants and study design</span><p id="par0030" class="elsevierStylePara elsevierViewall">We conducted a retrospective&#44; multicenter&#44; and observational study&#44; including patients from 8 reference hospitals participating in the SQUAMATA project&#46; This project focuses on studying prognostic factors of cSCC and has been previously described&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">6</span></a> Participant hospitals are Hospital Universitario de Salamanca&#44; Salamanca&#44; Spain&#44; Instituto Valenciano de Oncolog&#237;a&#44; Valencia&#44; Spain&#44; Hospital Germans Trias i Pujol&#44; Badalona&#44; Spain&#44; Hospital Cl&#237;nic&#44; Barcelona&#44; Spain&#44; Hospital Universitari Vall d&#8217;Hebron&#44; Barcelona&#44; Spain&#44; Hospital Universitario Central de Asturias&#44; Oviedo&#44; Spain&#59; Hospital San Cecilio&#44; Granada&#44; Spain&#44; and University Hospital Citt&#224; della Salute e della Scienza di Torino&#44; Turin&#44; Italy&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">Patients diagnosed with high-risk cSCC from January 1<span class="elsevierStyleSup">st</span>&#44; 2000 through December 31<span class="elsevierStyleSup">st</span>&#44; 2020&#44; were included&#46; Tumors with a diameter &#8805; 2<span class="elsevierStyleHsp" style=""></span>cm&#44; tumor thickness &#8805; 6<span class="elsevierStyleHsp" style=""></span>mm&#44; presence of perineural or lymphovascular invasion&#44; poor histological differentiation&#44; invasion beyond subcutaneous fat&#44; location in the ear or lip&#44; and patient immunosuppression &#40;solid organ transplantation&#44; chronic lymphocytic leukemia&#44; chronic immunosuppressive treatment&#44; or chronic kidney disease&#41; were considered high-risk cSCC&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">In cases of multiple cSCC&#44; only the tumor with the highest-risk characteristics was included in the database&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">The study was approved by Hospital Universitario Reina Sof&#237;a research and ethics committee in C&#243;rdoba&#44; Spain &#40;registration No&#46; 3958&#41;&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">The follow-up of the different centers is similar and is fundamentally based on NCCN guidelines&#44;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">7</span></a> with patient follow-up every 3 to 6 months within the first 2 years and then every 6-12 months from the 3<span class="elsevierStyleSup">rd</span> year onwards&#44; becoming annual from the 5<span class="elsevierStyleSup">th</span> year&#46; In the case of regional disease&#44; controls are every 2-3 months within the 1<span class="elsevierStyleSup">st</span> year&#44; every 4-6 months up to year 3&#44; and every 6-12 months from year 4&#46; The imaging modalities used in the follow-ups are ultrasound&#44; computed tomography &#40;CT&#41;&#44; and&#44; in cases in which local spread of tissues needed to be assessed&#44; magnetic resonance imaging &#40;MRI&#41; was used&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">The first progression pathway was described for the purpose of the study&#46; Based on this progression&#44; 4 groups were defined&#58; local recurrence &#40;LR&#41;&#44; regional lymphatic recurrence &#40;L&#41;&#44; satellitosis&#47;transit metastasis &#40;S&#41;&#44; and distant metastasis &#40;M&#41;&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">The involvement of these 4 progression pathways can lead to various dissemination patterns&#44; which is similar to those classically described for melanoma&#46;<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">8&#44;9</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">For patients who ended up dying of this disease&#44; 7 patterns or routes of dissemination were described&#58; LR-d pattern&#44; development of LR and the dead &#40;d&#41;&#59; LR-M-d pattern&#44; development of LR and then M and d&#59; LR-L-d pattern&#44; development of LR&#44; and then L&#44; and eventually d&#59; LR-L-M-d pattern&#44; development of LR and then L&#44; M&#44; and eventually d&#59; LR-d pattern&#44; development of L and then d&#59; L-M-d pattern&#44; development of L&#44; then M&#44; and eventually d&#59; and finally&#44; S-d pattern&#44; with the development of S and eventually d&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">The chi-square test was used to compare differences between different metastatic pathways &#40;LR&#44; L&#44; S&#44; and M&#41; and several categorical clinical and pathological variables &#40;gender&#44; immunosuppression&#44; location on head&#47;neck&#44; trunk&#47;extremities&#44; and hands&#47;feet&#44; diameter &#8804; 20<span class="elsevierStyleHsp" style=""></span>mm vs &#62;<span class="elsevierStyleHsp" style=""></span>20<span class="elsevierStyleHsp" style=""></span>mm&#44; tumor thickness &#8804; 6 vs &#62;<span class="elsevierStyleHsp" style=""></span>6<span class="elsevierStyleHsp" style=""></span>mm&#44; perineural invasion&#44; lymphovascular invasion&#44; histological grading&#44; American Joint Committee on Cancer &#40;AJCC&#41; classification&#44;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">10</span></a> and Brigham and Women&#39;s Hospital &#40;BWH&#41; classification&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">11</span></a> Age was evaluated using the Kruskal-Wallis test&#46; Significant tests were evaluated with post hoc analyses&#44; and with adjusted p-values using the Holm method&#46; Kaplan-Meier &#40;KM&#41; curves and the log-rank test were used to compare the time elapsed until different forms of progression were reported&#46; Similarly&#44; KM curves were compared for regional lymphatic metastases as first recurrence or after local recurrence&#44; as well as the same regional lymphatic metastases depending on whether they progressed regionally to systemic metastases or whether the patient remained alive&#46; Finally&#44; the time until progression was assessed based on the type of local&#44; regional&#44; or distant recurrence&#46; P values &#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05 were considered statistically significant&#46; IBM SPSS Statistics software &#40;IBM Corp&#46; Released 2011&#46; IBM SPSS Statistics for Windows&#44; Version 20&#46;0&#46; Armonk&#44; NY&#58; IBM Corp&#46;&#41; was used for statistical analysis&#46;</p></span></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Results</span><p id="par0075" class="elsevierStylePara elsevierViewall">A total of 1346 patients with primary high-risk cSCC were included&#44; 16&#46;5&#37; of whom &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>222&#41; experienced some form of recurrence during follow-up&#46; The median follow-up was 33 months&#46; <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> shows the clinical and pathological characteristics of the population based on the different progression pathways&#46; Statistically significant differences were found only in terms of immunosuppression status&#44; tumor diameter&#44; and the probability of mortality both from the neoplasm and from any other causes&#46; The most common dissemination pathway in both immunocompetent and immunocompromised patients was lymphatic spread &#40;71&#46;8&#37; and 51&#37;&#44; respectively&#41;&#44; while local recurrences and dissemination via satellitosis were relatively more frequent in immunocompromised patients &#40;40&#37; vs 24&#46;6&#37; in immunocompetent&#41;&#46; Lymphatic recurrences were somewhat more frequent in immunocompetent patients &#40;71&#46;8&#37; vs 51&#46;1&#37;&#41;&#46; Tumors that spread via lymphatic system were&#44; on average&#44; 5<span class="elsevierStyleHsp" style=""></span>mm larger in diameter than those that recurred locally &#40;25<span class="elsevierStyleHsp" style=""></span>mm vs 20<span class="elsevierStyleHsp" style=""></span>mm&#44; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;01&#41;&#46; Regarding tumors that spread via satellitosis as the primary dissemination pathway&#44; we observed that most were tumors &#8804; 20<span class="elsevierStyleHsp" style=""></span>mm &#40;77&#46;8&#37;&#41;&#44; unlike those that recurred lymphatically&#44; which were mostly &#62;<span class="elsevierStyleHsp" style=""></span>2<span class="elsevierStyleHsp" style=""></span>cm &#40;61&#46;0&#37;&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0080" class="elsevierStylePara elsevierViewall">Regarding staging&#44; we should mention that&#44; all T4 tumors according to AJCC and all T3 tumors according to BWH preferentially spread to lymph nodes &#40;100&#37;&#41;&#46; On the other hand&#44; low-risk T1 tumors that progressed did so almost equally as local recurrences or lymph node metastases &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">table 1</a>&#41;&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">Regarding mortality according to pathways&#44; tumors that presented with a local recurrence had a lower specific mortality rate than those presenting in lymph nodes &#40;23&#37; vs 47&#46;5&#37;&#44; p &#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#44; and a lower overall mortality rate too &#40;44&#46;6&#37; vs 68&#46;3&#37;&#44; p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;005&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">table 1</a>&#41;&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">Of note that neither age&#44; sex&#44; location&#44; differentiation grade&#44; tumor thickness&#44; perineural or lymphovascular invasion&#44; nor staging were significantly differentially distributed among the different dissemination pathways&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#fig0005">Figure 1</a> illustrates the different metastatic pathways in the progression of primary cSCC&#46; The most frequent progression pathway was lymphatic &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>139 &#91;62&#46;6&#37;&#93;&#41;&#44; followed by local recurrences &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>74 &#91;33&#46;3&#37;&#93;&#41; and satellitosis &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>9 &#91;4&#46;4&#37;&#93;&#41;&#46; In 12 cases of local recurrence &#40;16&#46;2&#37; of LR&#41;&#44; subsequent lymphatic progression was reported&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0100" class="elsevierStylePara elsevierViewall">Overall&#44; 31 cases &#40;20&#46;5&#37; of L&#41; out of all cases with regional lymphatic recurrence progressed into systemic metastases&#46; Only 1 case of local recurrence was described&#44; which directly developed systemic metastases&#46; Systemic metastases were not found as the first progression pathway&#44; nor were lymphatic metastases following satellitosis&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">The deaths of patients with cSCC were most due to the regional lymphatic progression of their disease &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>47 &#91;54&#46;6&#37; of deaths&#93;&#41;&#44; followed by systemic metastases &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>27 &#91;31&#46;4&#37; of deaths&#93;&#41;&#46; Local progressions were the cause of death in 11&#46;6&#37; &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>10&#41; of all reported deaths&#46; Finally&#44; 2 deaths due to satellitosis were reported &#40;2&#46;3&#37; of all reported deaths&#41;&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">The different metastatic and progression pathways of cSCC cases resulting in death are depicted in <a class="elsevierStyleCrossRef" href="#fig0010">Figure 2</a>&#46; The most frequent metastatic pathway was the L-d route &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>42 &#91;49&#46;4&#37;&#93;&#41;&#44; followed by the L-M-d route &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>24 &#91;28&#46;2&#37;&#93;&#41;&#46; The next most frequent route was the LR-d route &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>9 &#91;10&#46;6&#37;&#93;&#41;&#46; The remaining metastatic and progression pathways occurred in 5 or fewer cases&#46; Of note that&#44; regardless of the metastatic pathway involved&#44; all regional lymphatic recurrences appeared&#44; on average&#44; between the 13- and 18-month follow-up&#44; while disease-related deaths occurred&#44; on average&#44; between the 26- and 35-month follow-up from diagnosis for the most frequent metastatic pathways&#46; Interestingly&#44; there was a trend toward longer time to death in cases with L metastasis followed by development of systemic metastases &#40;L-M-d route&#41; compared with cases that only had local progression &#40;LR-d route&#41;&#44; via satellitosis &#40;S-d route&#41;&#44; or regionally &#40;L-d route&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0115" class="elsevierStylePara elsevierViewall">Survival analysis until recurrence based on the type of pathway &#40;LR&#44; L&#44; and S&#41; showed no differences among them &#40;<a class="elsevierStyleCrossRef" href="#fig0015">figure 3</a>&#41;&#46; No differences in survival time were reported either until the appearance of lymphatic metastases based on whether they were the first recurrence or followed local recurrence &#40;<a class="elsevierStyleCrossRef" href="#fig0020">figure 4</a>&#41;&#46; Finally&#44; the time elapsed until the appearance of lymphatic metastases was not associated with prognosis&#44; which was determined as the absence of further progressions vs progression to systemic metastases or regional progression until the patient&#39;s death &#40;<a class="elsevierStyleCrossRef" href="#fig0025">figure 5</a>&#41;&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><elsevierMultimedia ident="fig0020"></elsevierMultimedia><elsevierMultimedia ident="fig0025"></elsevierMultimedia></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Discussion</span><p id="par0120" class="elsevierStylePara elsevierViewall">The present study shows that the most frequent progression for high-risk cSCCs is the lymphatic pathway&#44; and that this pathway is virtually mandatory before systemic metastases develop&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">The metastatic process is a complex process in which genetically unstable cells adapt to a tissue microenvironment&#44; which is different from their own tissue of origin&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">12</span></a> This process is not random&#59; tumor cells generally have a certain affinity for specific tissues depending on the tumor lineage in a dissemination model originally termed &#8220;seed and soil&#8221; by Paget back in the 19<span class="elsevierStyleSup">th</span> century&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">13</span></a> This model explains why certain tumors&#44; such as breast cancer&#44; frequently metastasize to the lung&#44; bone&#44; liver&#44; or brain&#44; while others&#44; such as prostate cancer&#44; are more prone to bone metastasis&#46; Similarly&#44; uveal melanoma characteristically metastasizes more to the liver&#44; while sarcomas metastasize to the lung&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">12</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">In the case of cSCCs&#44; the most important implication of these findings would be the locoregional management of the disease&#46; More than half of the patients in the study die from progression of regional lymphatic metastases&#44; which raises the question of whether elective lymph node dissection could benefit these patients&#44; as in the case of oral cavity squamous cell carcinoma&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">14</span></a> However&#44; available observational studies present conflicting results&#46; Amit et al&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">15</span></a> did not demonstrate the benefit of elective lymph node dissection in cSCC patients compared with observation&#46; Conversely&#44; in a different observational study&#44; Xiao et al&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">16</span></a> did observe improved survival in patients undergoing elective lymph node dissection and superficial parotidectomy&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">The ordered and gradual progression of cSCC from the primary tumor to the regional lymph node and from there to metastatic dissemination is the ideal theoretical basis supporting the therapeutic use of sentinel lymph node biopsy &#40;SLNB&#41;&#46; This is was decades ago was called the &#8220;incubator hypothesis&#8221;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">17</span></a> by SLNB advocates in melanoma&#44; compared to the &#8220;marker hypothesis&#44;&#8221; which hypothesized that the presence of metastases in regional lymph nodes is not a preceding step&#44; but a marker that the tumor has already spread to other organs&#46;<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">18&#44;19</span></a> The observation that the median survival time is longer for metastatic pathways involving the appearance of systemic metastases &#40;<a class="elsevierStyleCrossRef" href="#fig0010">figure 2</a>&#41; vs the same pathways without systemic dissemination to some extent supports this &#8220;incubator hypothesis&#44;&#8221; an unseen phenomenon in similar studies for melanoma&#46;<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">8&#44;9</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall">Paradoxically&#44; while a clinical trial has evaluated the role of SLNB in melanoma&#44;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">3</span></a> showing no survival benefit&#44; no clinical trial has ever been conducted evaluating the role of SLNB in cSCC&#46; However&#44; observational studies have been conducted comparing cSCC patients undergoing SLNB with patients under observation alone without any survival differences being reported&#46; In this line&#44; our group has found differences in a recent observational trial when stratified by patient immune status&#44; with a clear advantage in progression-free survival seen only in immunocompetent patients undergoing SLNB &#40;unpublished data&#41;&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">The problem with the indication of this technique&#44; and the overall prediction of lymphatic and systemic metastases&#44; is far from resolved&#44; as only 4&#37; to 5&#37; of patients will develop lymphatic metastases&#44; and of those&#44; only a quarter will develop systemic metastases&#46; In a recent systematic review&#44; SLNB positivity in cSCC was 8&#37;&#44; without clear predictors of involvement identified just yet&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">4</span></a> Current evidence on genetic changes in cell cycle regulation&#44; tumor suppression&#44; tissue invasion&#44; microenvironment&#44; and immune system interaction is still far from offering specific targets that can more accurately predict which patients will progress&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">20</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">In our series&#44; 11&#46;6&#37; of specific deaths were due to local progression&#46; These data demonstrate the importance of local control of cSCC&#46; In a recent systematic review&#44; deep invasion beyond fat&#44; or to a lesser extent&#44; desmoplasia&#44; are the histological factors that most predict this recurrence&#44;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">21</span></a> with Mohs surgery being the preferred option for local control of cSCC&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">21</span></a> In a recent review&#44; the success of SLNB in cSCC was not affected whether performed synchronously or asynchronously with surgery&#44; including Mohs surgery&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">22</span></a> This is important in the current context&#44; in which Mohs surgery is becoming increasingly common&#44; and the SLNB would be required after the procedure&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">23</span></a></p><p id="par0155" class="elsevierStylePara elsevierViewall">In conclusion&#44; the most frequent metastatic dissemination pathway for cSCC is the lymphatic pathway&#46; This pathway is virtually necessary for systemic dissemination&#46; Regional progression of lymphatic metastases is also the main cause of death&#46; Measures aimed at regional control of this tumor&#44; such as SLNB&#44; elective lymph node dissection&#44; or adjuvant radiotherapy&#44; could play a role in improving survival in this disease&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Funding</span><p id="par0160" class="elsevierStylePara elsevierViewall">This study was funded by Fundaci&#243;n Piel Sana of the Spanish Academy of Dermatology and Venereology&#46; JC&#39;s research has been partially funded by Instituto de Salud Carlos III&#44; Madrid&#44; Spain &#40;and co-funded by the European Union&#41; through project PI21&#47;1207&#44; by the Regional Health Management of Castilla y Le&#243;n&#44; Spain &#40;GRS2549&#47;A&#47;22&#41;&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Conflicts of interest</span><p id="par0165" class="elsevierStylePara elsevierViewall">None declared&#46;</p></span></span>"
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          "titulo" => "Material and methods"
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            0 => array:2 [
              "identificador" => "sec0015"
              "titulo" => "Participants and study design"
            ]
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          "identificador" => "sec0020"
          "titulo" => "Results"
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          "titulo" => "Discussion"
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          "titulo" => "References"
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    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2023-09-15"
    "fechaAceptado" => "2024-03-11"
    "PalabrasClave" => array:2 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec1843108"
          "palabras" => array:5 [
            0 => "Cutaneous squamous cell carcinoma"
            1 => "Prognosis"
            2 => "Neoplastic metastasis"
            3 => "Lymphatic metastasis"
            4 => "Disease progression"
          ]
        ]
      ]
      "es" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec1843109"
          "palabras" => array:5 [
            0 => "Carcinoma cut&#225;neo de c&#233;lulas escamosas"
            1 => "Pron&#243;stico"
            2 => "Met&#225;stasis neopl&#225;sica"
            3 => "Met&#225;stasis linf&#225;tica"
            4 => "Progresi&#243;n de la enfermedad"
          ]
        ]
      ]
    ]
    "tieneResumen" => true
    "resumen" => array:2 [
      "en" => array:3 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Background and objective</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Cutaneous squamous cell carcinoma &#40;cSCC&#41; is the second leading cause of skin cancer mortality in Europe&#46; Few studies have analyzed the different pathways of this tumor progression in its natural history&#46; The main objective of this study was to analyze the different metastatic and progression pathways and their temporal occurrence in the evolution of cSCC&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Material and method</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">We conducted a multicenter&#44; retrospective&#44; and observational study of consecutive high-risk sSCCs included in the SQUAMATA project&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">A total of 222 out of the 1346 patients included relapsed&#46; The most frequent route of progression was the lymphatic one &#40;62&#46;6&#37;&#41;&#46; A total of 20&#46;2&#37; of the cases with lymphatic progression developed distant metastases&#46; Only 1 case &#40;3&#46;1&#37;&#41; of distant metastasis followed local recurrence without previous lymphatic metastasis&#46; The median time to disease-related mortality was longer in patients who developed systemic metastases than in those who died of locoregional progression&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">The mortality of patients with cSCC is mostly due to the regional progression of their lymphatic metastases&#46; The appearance of distant metastases is practically always &#40;96&#46;9&#37;&#41; associated with previous lymphatic metastatic progression&#46; Therefore&#44; in the future&#44; new studies will be needed to assess the regional management of cSCC in both surgical and adjuvant therapies&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
            "identificador" => "abst0005"
            "titulo" => "Background and objective"
          ]
          1 => array:2 [
            "identificador" => "abst0010"
            "titulo" => "Material and method"
          ]
          2 => array:2 [
            "identificador" => "abst0015"
            "titulo" => "Results"
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          3 => array:2 [
            "identificador" => "abst0020"
            "titulo" => "Conclusions"
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      ]
      "es" => array:3 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Antecedentes y objetivo</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">El carcinoma cut&#225;neo de c&#233;lulas escamosas &#40;CEC&#41; es la segunda causa de fallecimientos por c&#225;ncer de piel en Europa&#46; Existen pocos estudios que hayan analizado las distintas v&#237;as de progresi&#243;n de este tumor en su historia natural&#46; El objetivo principal del presente estudio ha sido analizar las diferentes v&#237;as metast&#225;sicas&#44; as&#237; como de progresi&#243;n&#44; y su aparici&#243;n temporal en la evoluci&#243;n del CEC&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Material y m&#233;todo</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Estudio observacional retrospectivo multic&#233;ntrico de los CEC consecutivos de alto riesgo englobados en el proyecto SQUAMATA&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">De los 1&#46;346 pacientes incluidos&#44; tuvieron reca&#237;da 222 pacientes&#46; La v&#237;a de progresi&#243;n m&#225;s frecuente fue la v&#237;a linf&#225;tica &#40;62&#44;6&#37;&#41;&#46; El 20&#44;2&#37; de los casos con progresi&#243;n linf&#225;tica desarrollaron met&#225;stasis a distancia&#46; Un solo caso &#40;3&#44;1&#37;&#41; de met&#225;stasis a distancia fue tras recidiva local sin met&#225;stasis linf&#225;ticas previas&#46; La mediana del tiempo hasta el exitus por la enfermedad fue mayor en los pacientes que desarrollaron met&#225;stasis sist&#233;micas que en aquellos fallecidos por progresi&#243;n locorregional&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">El fallecimiento de los pacientes con CEC es mayoritariamente por progresi&#243;n regional de sus met&#225;stasis linf&#225;ticas&#46; La aparici&#243;n de met&#225;stasis a distancia se asocia pr&#225;cticamente siempre &#40;96&#44;9&#37;&#41; a la progresi&#243;n metast&#225;sica linf&#225;tica previa&#46; En el futuro&#44; por tanto&#44; se hacen necesarios nuevos estudios que valoren el manejo regional del CEC tanto en su manejo quir&#250;rgico como adyuvante&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
            "identificador" => "abst0025"
            "titulo" => "Antecedentes y objetivo"
          ]
          1 => array:2 [
            "identificador" => "abst0030"
            "titulo" => "Material y m&#233;todo"
          ]
          2 => array:2 [
            "identificador" => "abst0035"
            "titulo" => "Resultados"
          ]
          3 => array:2 [
            "identificador" => "abst0040"
            "titulo" => "Conclusiones"
          ]
        ]
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    "multimedia" => array:6 [
      0 => array:7 [
        "identificador" => "fig0005"
        "etiqueta" => "Figure 1"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr1.jpeg"
            "Alto" => 1951
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        "descripcion" => array:1 [
          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Type of relapse and different metastatic pathways of the 222 patients with high-risk cSCC with relapses at their follow-up&#46; &#40;&#42;&#41; indicates percentage &#40;&#37;&#41; of patients&#44; in nodes it is the &#37; over the total number of patients with recurrence&#44; and in the arrows it indicates the &#37; over the upper node&#46;</p>"
        ]
      ]
      1 => array:7 [
        "identificador" => "fig0010"
        "etiqueta" => "Figure 2"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr2.jpeg"
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        "descripcion" => array:1 [
          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Temporal course of the different progression pathways for patients who finally died from high-risk cSCC&#46; d&#44; death&#59; L&#44; regional lymphatic recurrence&#59; LR&#44; local recurrence&#59; M&#44; systemic metastasis&#59; S&#44; satellitosis&#46;</p>"
        ]
      ]
      2 => array:7 [
        "identificador" => "fig0015"
        "etiqueta" => "Figure 3"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr3.jpeg"
            "Alto" => 1636
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        "descripcion" => array:1 [
          "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Survival until the appearance of the first recurrence in high-risk cSCC &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>222&#41;&#46;</p>"
        ]
      ]
      3 => array:7 [
        "identificador" => "fig0020"
        "etiqueta" => "Figure 4"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr4.jpeg"
            "Alto" => 1693
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        "descripcion" => array:1 [
          "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Survival until regional lymphatic recurrence as the first recurrence vs regional lymphatic recurrence after local recurrence &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>152&#41;&#46;</p>"
        ]
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      4 => array:7 [
        "identificador" => "fig0025"
        "etiqueta" => "Figure 5"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr5.jpeg"
            "Alto" => 1689
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            "Tamanyo" => 165463
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        "descripcion" => array:1 [
          "en" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Survival until lymphatic recurrence depending on whether patients remained disease-free&#44; died from regional progression of their disease&#44; or progressed to systemic metastases &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>152&#41;&#46;</p>"
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          "leyenda" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">AJCC-8&#44; American Joint Committee on Cancer VIII edition&#59; BWH&#44; Brigham and Women&#39;s Hospital classification&#59; L&#44; lymphatic&#59; LR&#44; local recurrence&#59; NA&#44; not available&#59; NS&#44; nonstatistically significant&#59; Q1&#44; Q2&#44; 1<span class="elsevierStyleSup">st</span> and 3<span class="elsevierStyleSup">rd</span> quartiles&#59; S&#44; satellitosis&#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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Characteristics of the sample<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Local recurrence &#40;LR&#41; dissemination pathway &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>74&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Satellitosis dissemination pathway &#40;S&#41; &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Lymphatic &#40;L&#41; dissemination pathway &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>139&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Total &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>222&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">p-value<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Age at diagnosis</span></td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;615&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Median &#40;Q1&#44; Q3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">80&#46;0 &#40;72&#46;0&#44; 86&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">79&#46;0 &#40;73&#46;0&#44; 80&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">78&#46;0 &#40;72&#46;0&#44; 83&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">78&#46;0 &#40;72&#46;0&#44; 84&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" 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  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Sex</span></td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;090&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Male&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">52 &#40;70&#46;3&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5 &#40;55&#46;6&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">77 &#40;55&#46;4&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">134 &#40;60&#46;4&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Female&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">22 &#40;29&#46;7&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4 &#40;44&#46;4&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">62 &#40;44&#46;6&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">88 &#40;39&#46;6&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" 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  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Immunosuppression</span></td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleBold">0&#46;024</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>No&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">35 &#40;64&#46;8&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">5 &#40;55&#46;6&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">102 &#40;81&#46;0&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">142 &#40;75&#46;1&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NS<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Yes&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">19 &#40;35&#46;2&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">4 &#40;44&#46;4&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">24 &#40;19&#46;0&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
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                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>NA&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">20&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">33&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \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
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                  \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
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;839&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Head and neck&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">63 &#40;85&#46;1&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8 &#40;88&#46;9&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">109 &#40;78&#46;4&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">180 &#40;81&#46;1&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Trunk&#47;Extremities&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9 &#40;12&#46;2&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1 &#40;11&#46;1&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">24 &#40;17&#46;3&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">34 &#40;15&#46;3&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Hands&#47;Feet&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2 &#40;2&#46;7&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6 &#40;4&#46;3&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8 &#40;3&#46;6&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Tumor diameter &#40;mm&#41;</span></td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">0&#46;005</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Median &#40;Q1&#44;Q3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">20&#46;0 &#40;10&#46;0&#44; 30&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">18&#46;0 &#40;15&#46;0&#44; 20&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">25&#46;0 &#40;16&#46;5&#44; 37&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">22&#46;0 &#40;15&#46;0&#44; 34&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;01c LR vs L&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" 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  " colspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Tumor diameter &#40;mm&#41;</span></td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">0&#46;027</span>&nbsp;\t\t\t\t\t\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
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>&#8804; 20&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">38 &#40;51&#46;4&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7 &#40;77&#46;8&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">53 &#40;39&#46;0&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">98 &#40;44&#46;7&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NS<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>20&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">36 &#40;48&#46;6&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2 &#40;22&#46;2&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">83 &#40;61&#46;0&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">121 &#40;55&#46;3&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Tumor thickness &#40;mm&#41;</span></td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;438&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>&#8804; 6&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">31 &#40;48&#46;4&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">2 &#40;28&#46;6&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">52 &#40;40&#46;6&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">85 &#40;42&#46;7&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">33 &#40;51&#46;6&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">5 &#40;71&#46;4&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">76 &#40;59&#46;4&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">114 &#40;57&#46;3&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">23&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Perineural invasion</span></td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;538&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Absent&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">40 &#40;80&#46;0&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6 &#40;66&#46;7&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">92 &#40;74&#46;8&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">138 &#40;75&#46;8&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Present&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">10 &#40;20&#46;0&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
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                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">44 &#40;24&#46;2&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">24&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">16&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">40&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Lymphovascular invasion</span></td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Absent&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
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                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">126 &#40;90&#46;6&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">201 &#40;91&#46;0&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Present&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5 &#40;6&#46;8&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2 &#40;22&#46;2&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">13 &#40;9&#46;4&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">20 &#40;9&#46;0&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" 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  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Differentiation degree</span></td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;291&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>T2b&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">31 &#40;41&#46;9&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4 &#40;44&#46;4&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">46 &#40;33&#46;3&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">81 &#40;36&#46;7&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" 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  " colspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Disease-related death</span></td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">&#60;</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">0&#46;001</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">57 &#40;77&#46;0&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7 &#40;77&#46;8&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">73 &#40;52&#46;5&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">137 &#40;61&#46;7&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">17 &#40;23&#46;0&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2 &#40;22&#46;2&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">66 &#40;47&#46;5&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">85 &#40;38&#46;3&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">LR vs Lc&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Death for any other causes</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;280&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;280&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">37 &#40;68&#46;5&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5 &#40;55&#46;6&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">96 &#40;76&#46;2&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">138 &#40;73&#46;0&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">17 &#40;31&#46;5&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4 &#40;44&#46;4&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">30 &#40;23&#46;8&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">51 &#40;27&#46;0&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">20&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">33&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" 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  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Death for any other causes</span></td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">0&#46;001</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">41 &#40;55&#46;4&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3 &#40;33&#46;3&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">44 &#40;31&#46;7&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">88 &#40;39&#46;6&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;005&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">33 &#40;44&#46;6&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6 &#40;66&#46;7&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">95 &#40;68&#46;3&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">134 &#40;60&#46;4&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Incidencia y mortalidad del c&#225;ncer cut&#225;neo en Espa&#241;a&#58; revisi&#243;n sistem&#225;tica y metaan&#225;lisis"
                      "autores" => array:1 [
                        0 => array:2 [
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                            1 => "M&#46;A&#46; Descalzo-Gallego"
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                            3 => "C&#46; Posada-Garc&#237;a"
                            4 => "L&#46; Rodr&#237;guez-Pazos"
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                          ]
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                        "tituloSerie" => "Actas Dermosifiliogr&#46;"
                        "fecha" => "2016"
                        "volumen" => "107"
                        "paginaInicial" => "318"
                        "paginaFinal" => "328"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26852370"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "bib0125"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Los nuevos sistemas de estadificaci&#243;n del AJCC incorporan novedades en el c&#225;ncer cut&#225;neo"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "J&#46; Ca&#241;ueto"
                            1 => "C&#46; Rom&#225;n-Curto"
                          ]
                        ]
                      ]
                    ]
                  ]
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                    0 => array:2 [
                      "doi" => "10.1016/j.ad.2017.05.012"
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                        "tituloSerie" => "Actas Dermosifiliogr&#46;"
                        "fecha" => "2017"
                        "volumen" => "108"
                        "paginaInicial" => "818"
                        "paginaFinal" => "826"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28732551"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0130"
              "etiqueta" => "3"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Final trial report of sentinel-node biopsy versus nodal observation in melanoma"
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                          "autores" => array:6 [
                            0 => "D&#46;L&#46; Morton"
                            1 => "J&#46;F&#46; Thompson"
                            2 => "A&#46;J&#46; Cochran"
                            3 => "N&#46; Mozzillo"
                            4 => "O&#46;E&#46; Nieweg"
                            5 => "D&#46;F&#46; Roses"
                          ]
                        ]
                      ]
                    ]
                  ]
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                        "tituloSerie" => "N Engl J Med&#46;"
                        "fecha" => "2014"
                        "volumen" => "370"
                        "paginaInicial" => "599"
                        "paginaFinal" => "609"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24521106"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            3 => array:3 [
              "identificador" => "bib0135"
              "etiqueta" => "4"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Systematic review of the prevalence of nodal metastases and the prognostic utility of sentinel lymph node biopsy in cutaneous squamous cell carcinoma"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
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                            1 => "I&#46; Garc&#237;a-Doval"
                            2 => "B&#46; Llombart"
                            3 => "J&#46; Ca&#241;ueto"
                            4 => "A&#46; Martorell-Calatayud"
                            5 => "M&#46;A&#46; Descalzo-Gallego"
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                        ]
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                        "fecha" => "2018"
                        "volumen" => "45"
                        "paginaInicial" => "781"
                        "paginaFinal" => "790"
                        "link" => array:1 [
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                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29701281"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            4 => array:3 [
              "identificador" => "bib0140"
              "etiqueta" => "5"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Analysis of risk factors determining prognosis of cutaneous squamous-cell carcinoma&#58; A prospective study"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "K&#46;D&#46; Brantsch"
                            1 => "C&#46; Meisner"
                            2 => "B&#46; Sch&#246;nfisch"
                            3 => "B&#46; Trilling"
                            4 => "J&#46; Wehner-Caroli"
                            5 => "J&#46; R&#246;cken"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/S1470-2045(08)70178-5"
                      "Revista" => array:6 [
                        "tituloSerie" => "Lancet Oncol&#46;"
                        "fecha" => "2008"
                        "volumen" => "9"
                        "paginaInicial" => "713"
                        "paginaFinal" => "720"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18617440"
                            "web" => "Medline"
                          ]
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                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0145"
              "etiqueta" => "6"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Estimated effect of COVID-19 lockdown on skin tumor size and survival&#58; An exponential growth model"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "A&#46; Tejera-Vaquerizo"
                            1 => "J&#46; Ca&#241;ueto"
                            2 => "A&#46; Toll"
                            3 => "J&#46; Santos-Juanes"
                            4 => "A&#46; Jaka"
                            5 => "C&#46; Ferrandiz"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.adengl.2020.09.008"
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                        "tituloSerie" => "Actas Dermosifiliogr &#40;Engl Ed&#41;&#46;"
                        "fecha" => "2020"
                        "volumen" => "111"
                        "paginaInicial" => "629"
                        "paginaFinal" => "638"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/32513393"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0150"
              "etiqueta" => "7"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "NCCN Guidelines&#174; Insights&#58; Squamous Cell Skin Cancer&#44; Version 1&#46;2022&#58; Featured Updates to the NCCN Guidelines"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "C&#46;D&#46; Schmults"
                            1 => "R&#46; Blitzblau"
                            2 => "S&#46;Z&#46; Aasi"
                            3 => "M&#46; Alam"
                            4 => "J&#46;S&#46; Andersen"
                            5 => "B&#46;C&#46; Baumann"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.6004/JNCCN. 2021.0059"
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                        "tituloSerie" => "J Natl Compr Cancer Netw&#46;"
                        "fecha" => "2021"
                        "volumen" => "19"
                        "paginaInicial" => "1382"
                        "paginaFinal" => "1394"
                      ]
                    ]
                  ]
                ]
              ]
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              "identificador" => "bib0155"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Estudio temporal de los diferentes patrones metast&#225;sicos en la progresi&#243;n del melanoma cut&#225;neo"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
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                            1 => "M&#46; Mendiola-Fern&#225;ndez"
                            2 => "A&#46; Fern&#225;ndez-Orland"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/S0001-7310(07)70128-X"
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                        "tituloSerie" => "Actas Dermosifiliogr&#46;"
                        "fecha" => "2007"
                        "volumen" => "98"
                        "paginaInicial" => "531"
                        "paginaFinal" => "538"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17919427"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0160"
              "etiqueta" => "9"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Metastatic pathways and time courses in the orderly progression of cutaneous melanoma"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "F&#46; Meier"
                            1 => "S&#46; Will"
                            2 => "U&#46; Ellwanger"
                            3 => "B&#46; Schlagenhauff"
                            4 => "B&#46; Schittek"
                            5 => "G&#46; Rassner"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1046/j.1365-2133.2002.04867.x"
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                        "tituloSerie" => "Br J Dermatol&#46;"
                        "fecha" => "2002"
                        "volumen" => "147"
                        "paginaInicial" => "62"
                        "paginaFinal" => "70"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12100186"
                            "web" => "Medline"
                          ]
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                          "pii" => "S0959289X15000862"
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                          "issn" => "0959289X"
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                  ]
                ]
              ]
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              "identificador" => "bib0165"
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                    0 => array:2 [
                      "titulo" => "AJCC Cancer Staging Manual"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "M&#46; Amin"
                            1 => "S&#46; Edge"
                            2 => "F&#46; Greene"
                            3 => "C&#46;C&#46; Compton"
                            4 => "J&#46;E&#46; Gershenwald"
                            5 => "R&#46;K&#46; Brookland"
                          ]
                        ]
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                    ]
                  ]
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                    0 => array:1 [
                      "Libro" => array:4 [
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                        "editorialLocalizacion" => "New York"
                      ]
                    ]
                  ]
                ]
              ]
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              "identificador" => "bib0170"
              "etiqueta" => "11"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Evaluation of AJCC tumor staging for cutaneous squamous cell carcinoma and a proposed alternative tumor staging system"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "A&#46; Jambusaria-Pahlajani"
                            1 => "P&#46;A&#46; Kanetsky"
                            2 => "P&#46;S&#46; Karia"
                            3 => "W&#46;T&#46; Hwang"
                            4 => "J&#46;M&#46; Gelfand"
                            5 => "F&#46;M&#46; Whalen"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1001/jamadermatol.2013.2456"
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                        "tituloSerie" => "JAMA Dermatol&#46;"
                        "fecha" => "2013"
                        "volumen" => "149"
                        "paginaInicial" => "402"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23325457"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
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              "identificador" => "bib0175"
              "etiqueta" => "12"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Cancer metastasis&#58; Building a framework"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "G&#46;P&#46; Gupta"
                            1 => "J&#46; Massagu&#233;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.cell.2006.11.001"
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                        "tituloSerie" => "Cell&#46;"
                        "fecha" => "2006"
                        "volumen" => "127"
                        "paginaInicial" => "679"
                        "paginaFinal" => "695"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17110329"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0180"
              "etiqueta" => "13"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The pathogenesis of cancer metastasis&#58; The &#171;seed and soil&#187; hypothesis revisited"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "I&#46;J&#46; Fidler"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/nrc1098"
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                        "tituloSerie" => "Nat Rev Cancer&#46;"
                        "fecha" => "2003"
                        "volumen" => "3"
                        "paginaInicial" => "453"
                        "paginaFinal" => "458"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12778135"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
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              "identificador" => "bib0185"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Elective versus therapeutic neck dissection in node-negative oral cancer"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "A&#46;K&#46; D&#8217;Cruz"
                            1 => "R&#46; Vaish"
                            2 => "N&#46; Kapre"
                            3 => "M&#46; Dandekar"
                            4 => "S&#46; Gupta"
                            5 => "R&#46; Hawaldar"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
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                        "fecha" => "2015"
                        "volumen" => "373"
                        "paginaInicial" => "521"
                        "paginaFinal" => "529"
                      ]
                    ]
                  ]
                ]
              ]
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              "identificador" => "bib0190"
              "etiqueta" => "15"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Elective neck dissection versus observation in patients with head and neck cutaneous squamous cell carcinoma"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "M&#46; Amit"
                            1 => "C&#46; Liu"
                            2 => "J&#46; Mansour"
                            3 => "F&#46;O&#46; Gleber-Netto"
                            4 => "S&#46; Tam"
                            5 => "E&#46;N&#46; Baruch"
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                        ]
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                    ]
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                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/34358340"
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                        ]
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                    ]
                  ]
                ]
              ]
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              "identificador" => "bib0195"
              "etiqueta" => "16"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Comparison between wait-and-see policy and elective neck dissection in clinically N0 cutaneous squamous cell carcinoma of head and neck"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "Y&#46; Xiao"
                            1 => "S&#46; Yuan"
                            2 => "F&#46; Liu"
                            3 => "B&#46; Liu"
                            4 => "J&#46; Zhu"
                            5 => "W&#46; He"
                          ]
                        ]
                      ]
                    ]
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                        "tituloSerie" => "Medicine &#40;Baltimore&#41;&#46;"
                        "fecha" => "2018"
                        "volumen" => "97"
                        "paginaInicial" => "e10782"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29851784"
                            "web" => "Medline"
                          ]
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                      ]
                    ]
                  ]
                ]
              ]
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              "identificador" => "bib0200"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The case for lymphatic mapping and sentinel lymphadenectomy in the management of primary melanoma"
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                        "volumen" => "106"
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                        "link" => array:1 [
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                      "titulo" => "Molecular prediction of metastasis in cutaneous squamous cell carcinoma"
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                            3 => "M&#46;L&#46; Stevenson"
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                      "titulo" => "Timing of sentinel lymph node biopsy in cutaneous squamous cell carcinoma"
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Vol. 115. Issue 7.
Pages T670-T678 (July - August 2024)
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Vol. 115. Issue 7.
Pages T670-T678 (July - August 2024)
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Longitudinal Study of Different Progression Patterns in High-Risk Cutaneous Squamous Cell Carcinoma
Estudio longitudinal de los diferentes patrones de progresión en el carcinoma cutáneo de células escamosas de alto riesgo
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A. Tejera-Vaquerizoa,b,
Corresponding author
antoniotejera@aedv.es

Corresponding author.
, J. Cañuetoc, A. Gómez-Tomásd, J. Santos-Juanese, S. Riberof, G. Avallonef, A. Jakag, C. Ferrandiz-Pulidod, A. Tollh, O. Sanmartíni
a Unidad de Oncología Cutánea, Hospital San Juan de Dios, Córdoba, Spain
b Servicio de Dermatología, Instituto Dermatológico GlobalDerm, Palma del Río, Córdoba, Spain
c Servicio de Dermatología, Complejo Asistencial Universitario de Salamanca, Salamanca, Spain
d Servicio de Dermatología, Hospital Universitari Vall d’Hebron, Universidad Autónoma de Barcelona, Barcelona, Spain
e Servicio de Dermatología, Hospital Central de Asturias e Instituto de Investigación Sanitaria del Principado de Asturias, IUOPA, Universidad de Oviedo, Oviedo, Spain
f Medical Sciences Department, Section of Dermatology, University of Turin, Turin, Italy
g Servicio de Dermatología, Hospital Universitari Germans Trials i Pujol, Institut d’Investigació Germans Trias i Pujol, Universitat Autónoma de Barcelona, Badalona, Barcelona, Spain
h Servicio de Dermatología, Hospital Clínic, Universitat de Barcelona, Barcelona, Spain
i Servicio de Dermatología, Instituto Valenciano de Oncología, Valencia, Spain
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A. Tejera-Vaquerizo, J. Cañueto, A. Gómez-Tomás, J. Santos-Juanes, S. Ribero, G. Avallone, A. Jaka, C. Ferrandiz-Pulido, A. Toll, O. Sanmartín
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Table 1. Clinical and pathological characteristics of high-risk skin carcinomas based on various dissemination pathways (n=222).
Abstract
Background and objective

Cutaneous squamous cell carcinoma (cSCC) is the second leading cause of skin cancer mortality in Europe. Few studies have analyzed the different pathways of this tumor progression in its natural history. The main objective of this study was to analyze the different metastatic and progression pathways and their temporal occurrence in the evolution of cSCC.

Material and method

We conducted a multicenter, retrospective, and observational study of consecutive high-risk sSCCs included in the SQUAMATA project.

Results

A total of 222 out of the 1346 patients included relapsed. The most frequent route of progression was the lymphatic one (62.6%). A total of 20.2% of the cases with lymphatic progression developed distant metastases. Only 1 case (3.1%) of distant metastasis followed local recurrence without previous lymphatic metastasis. The median time to disease-related mortality was longer in patients who developed systemic metastases than in those who died of locoregional progression.

Conclusions

The mortality of patients with cSCC is mostly due to the regional progression of their lymphatic metastases. The appearance of distant metastases is practically always (96.9%) associated with previous lymphatic metastatic progression. Therefore, in the future, new studies will be needed to assess the regional management of cSCC in both surgical and adjuvant therapies.

Keywords:
Cutaneous squamous cell carcinoma
Prognosis
Neoplastic metastasis
Lymphatic metastasis
Disease progression
Resumen
Antecedentes y objetivo

El carcinoma cutáneo de células escamosas (CEC) es la segunda causa de fallecimientos por cáncer de piel en Europa. Existen pocos estudios que hayan analizado las distintas vías de progresión de este tumor en su historia natural. El objetivo principal del presente estudio ha sido analizar las diferentes vías metastásicas, así como de progresión, y su aparición temporal en la evolución del CEC.

Material y método

Estudio observacional retrospectivo multicéntrico de los CEC consecutivos de alto riesgo englobados en el proyecto SQUAMATA.

Resultados

De los 1.346 pacientes incluidos, tuvieron recaída 222 pacientes. La vía de progresión más frecuente fue la vía linfática (62,6%). El 20,2% de los casos con progresión linfática desarrollaron metástasis a distancia. Un solo caso (3,1%) de metástasis a distancia fue tras recidiva local sin metástasis linfáticas previas. La mediana del tiempo hasta el exitus por la enfermedad fue mayor en los pacientes que desarrollaron metástasis sistémicas que en aquellos fallecidos por progresión locorregional.

Conclusiones

El fallecimiento de los pacientes con CEC es mayoritariamente por progresión regional de sus metástasis linfáticas. La aparición de metástasis a distancia se asocia prácticamente siempre (96,9%) a la progresión metastásica linfática previa. En el futuro, por tanto, se hacen necesarios nuevos estudios que valoren el manejo regional del CEC tanto en su manejo quirúrgico como adyuvante.

Palabras clave:
Carcinoma cutáneo de células escamosas
Pronóstico
Metástasis neoplásica
Metástasis linfática
Progresión de la enfermedad
Full Text
Introduction

Cutaneous squamous cell carcinoma (cSCC) is the second most frequent malignant cutaneous neoplasm in Spain.1 cSCC is also the second leading cause of skin cancer mortality after melanoma.1 This tumor has low metastatic potential. cSCC preferentially metastasizes via the lymphatic route in 3% up to 5% of cases, depending on the location, size, depth of invasion, perineural invasion, or bone involvement.2

On the other hand, selective sentinel lymph node biopsy (SLNB) is a surgical technique widely developed in other types of tumors, such as melanoma, based on its propensity for regional lymphatic metastases, without an impact on the survival of these patients.3 In the case of cSCC, the utility of SLNB is unknown to this date, with a positivity rate of 8% up to 10%.4

Very few studies have been published on the natural history in terms of cSCC progression,5 or on the clinical course of various relapse forms in this tumor progression.

Understanding and analyzing how cSCC progresses would help design diagnostic, therapeutic, and follow-up strategies for these patients.

The primary endpoint of this study is to analyze the different pathways of cSCC progression (local recurrence, satellitosis, regional lymphatic recurrence, or distant metastasis), along with the time course of these progressions. Secondary endpoints include analyzing the relationship of different clinical and pathological variables with the different forms of progression.

Material and methodsParticipants and study design

We conducted a retrospective, multicenter, and observational study, including patients from 8 reference hospitals participating in the SQUAMATA project. This project focuses on studying prognostic factors of cSCC and has been previously described.6 Participant hospitals are Hospital Universitario de Salamanca, Salamanca, Spain, Instituto Valenciano de Oncología, Valencia, Spain, Hospital Germans Trias i Pujol, Badalona, Spain, Hospital Clínic, Barcelona, Spain, Hospital Universitari Vall d’Hebron, Barcelona, Spain, Hospital Universitario Central de Asturias, Oviedo, Spain; Hospital San Cecilio, Granada, Spain, and University Hospital Città della Salute e della Scienza di Torino, Turin, Italy.

Patients diagnosed with high-risk cSCC from January 1st, 2000 through December 31st, 2020, were included. Tumors with a diameter ≥ 2cm, tumor thickness ≥ 6mm, presence of perineural or lymphovascular invasion, poor histological differentiation, invasion beyond subcutaneous fat, location in the ear or lip, and patient immunosuppression (solid organ transplantation, chronic lymphocytic leukemia, chronic immunosuppressive treatment, or chronic kidney disease) were considered high-risk cSCC.

In cases of multiple cSCC, only the tumor with the highest-risk characteristics was included in the database.

The study was approved by Hospital Universitario Reina Sofía research and ethics committee in Córdoba, Spain (registration No. 3958).

The follow-up of the different centers is similar and is fundamentally based on NCCN guidelines,7 with patient follow-up every 3 to 6 months within the first 2 years and then every 6-12 months from the 3rd year onwards, becoming annual from the 5th year. In the case of regional disease, controls are every 2-3 months within the 1st year, every 4-6 months up to year 3, and every 6-12 months from year 4. The imaging modalities used in the follow-ups are ultrasound, computed tomography (CT), and, in cases in which local spread of tissues needed to be assessed, magnetic resonance imaging (MRI) was used.

The first progression pathway was described for the purpose of the study. Based on this progression, 4 groups were defined: local recurrence (LR), regional lymphatic recurrence (L), satellitosis/transit metastasis (S), and distant metastasis (M).

The involvement of these 4 progression pathways can lead to various dissemination patterns, which is similar to those classically described for melanoma.8,9

For patients who ended up dying of this disease, 7 patterns or routes of dissemination were described: LR-d pattern, development of LR and the dead (d); LR-M-d pattern, development of LR and then M and d; LR-L-d pattern, development of LR, and then L, and eventually d; LR-L-M-d pattern, development of LR and then L, M, and eventually d; LR-d pattern, development of L and then d; L-M-d pattern, development of L, then M, and eventually d; and finally, S-d pattern, with the development of S and eventually d.

The chi-square test was used to compare differences between different metastatic pathways (LR, L, S, and M) and several categorical clinical and pathological variables (gender, immunosuppression, location on head/neck, trunk/extremities, and hands/feet, diameter ≤ 20mm vs >20mm, tumor thickness ≤ 6 vs >6mm, perineural invasion, lymphovascular invasion, histological grading, American Joint Committee on Cancer (AJCC) classification,10 and Brigham and Women's Hospital (BWH) classification.11 Age was evaluated using the Kruskal-Wallis test. Significant tests were evaluated with post hoc analyses, and with adjusted p-values using the Holm method. Kaplan-Meier (KM) curves and the log-rank test were used to compare the time elapsed until different forms of progression were reported. Similarly, KM curves were compared for regional lymphatic metastases as first recurrence or after local recurrence, as well as the same regional lymphatic metastases depending on whether they progressed regionally to systemic metastases or whether the patient remained alive. Finally, the time until progression was assessed based on the type of local, regional, or distant recurrence. P values <0.05 were considered statistically significant. IBM SPSS Statistics software (IBM Corp. Released 2011. IBM SPSS Statistics for Windows, Version 20.0. Armonk, NY: IBM Corp.) was used for statistical analysis.

Results

A total of 1346 patients with primary high-risk cSCC were included, 16.5% of whom (n=222) experienced some form of recurrence during follow-up. The median follow-up was 33 months. Table 1 shows the clinical and pathological characteristics of the population based on the different progression pathways. Statistically significant differences were found only in terms of immunosuppression status, tumor diameter, and the probability of mortality both from the neoplasm and from any other causes. The most common dissemination pathway in both immunocompetent and immunocompromised patients was lymphatic spread (71.8% and 51%, respectively), while local recurrences and dissemination via satellitosis were relatively more frequent in immunocompromised patients (40% vs 24.6% in immunocompetent). Lymphatic recurrences were somewhat more frequent in immunocompetent patients (71.8% vs 51.1%). Tumors that spread via lymphatic system were, on average, 5mm larger in diameter than those that recurred locally (25mm vs 20mm, p=0.01). Regarding tumors that spread via satellitosis as the primary dissemination pathway, we observed that most were tumors ≤ 20mm (77.8%), unlike those that recurred lymphatically, which were mostly >2cm (61.0%).

Table 1.

Clinical and pathological characteristics of high-risk skin carcinomas based on various dissemination pathways (n=222).

Characteristics of the samplea  Local recurrence (LR) dissemination pathway (n=74)  Satellitosis dissemination pathway (S) (n=9)  Lymphatic (L) dissemination pathway (n=139)  Total (n=222)  p-valueb 
Age at diagnosis0.615 
Median (Q1, Q3)  80.0 (72.0, 86.0)  79.0 (73.0, 80.0)  78.0 (72.0, 83.0)  78.0 (72.0, 84.0)   
Sex0.090 
Male  52 (70.3%)  5 (55.6%)  77 (55.4%)  134 (60.4%)   
Female  22 (29.7%)  4 (44.4%)  62 (44.6%)  88 (39.6%)   
Immunosuppression0.024 
No  35 (64.8%)  5 (55.6%)  102 (81.0%)  142 (75.1%)  NSc 
Yes  19 (35.2%)  4 (44.4%)  24 (19.0%)  47 (24.9%)   
NA  20  13  33   
Location          0.839 
Head and neck  63 (85.1%)  8 (88.9%)  109 (78.4%)  180 (81.1%)   
Trunk/Extremities  9 (12.2%)  1 (11.1%)  24 (17.3%)  34 (15.3%)   
Hands/Feet  2 (2.7%)  6 (4.3%)  8 (3.6%)   
Tumor diameter (mm)0.005 
Median (Q1,Q3)  20.0 (10.0, 30.0)  18.0 (15.0, 20.0)  25.0 (16.5, 37.0)  22.0 (15.0, 34.0)  0.01c LR vs L 
NA   
Tumor diameter (mm)0.027   
≤ 20  38 (51.4%)  7 (77.8%)  53 (39.0%)  98 (44.7%)  NSc 
>20  36 (48.6%)  2 (22.2%)  83 (61.0%)  121 (55.3%)   
NA   
Tumor thickness (mm)0.438 
≤ 6  31 (48.4%)  2 (28.6%)  52 (40.6%)  85 (42.7%)   
>33 (51.6%)  5 (71.4%)  76 (59.4%)  114 (57.3%)   
NA  10  11  23   
Perineural invasion0.538 
Absent  40 (80.0%)  6 (66.7%)  92 (74.8%)  138 (75.8%)   
Present  10 (20.0%)  3 (33.3%)  31 (25.2%)  44 (24.2%)   
NA  24  16  40   
Lymphovascular invasion0.240 
Absent  68 (93.2%)  7 (77.8%)  126 (90.6%)  201 (91.0%)   
Present  5 (6.8%)  2 (22.2%)  13 (9.4%)  20 (9.0%)   
NA   
Differentiation degree0.291 
Well  9 (15.0%)  24 (18.2%)  33 (16.5%)   
Moderate  31 (51.7%)  7 (87.5%)  78 (59.1%)  116 (58.0%)   
Poor  20 (33.3%)  1 (12.5%)  30 (22.7%)  51 (25.5%)   
NA  14  22   
AJCC8 Staging0.121 
T1  18 (24.3%)  1 (11.1%)  19 (13.8%)  38 (17.2%)   
T2  4 (5.4%)  0 (0%)  13 (9.4%)  17 (7.7%)   
T3  52 (70.3%)  8 (88.9%)  98 (71.0%)  158 (71.5%)   
T4  8 (5.8%)  8 (3.6%)   
NA   
BWH Staging0.424 
T1  21 (28.4%)  2 (22.2%)  27 (19.6%)  50 (22.6%)   
T2a  22 (29.7%)  3 (33.3%)  54 (39.1%)  79 (35.7%)   
T2b  31 (41.9%)  4 (44.4%)  46 (33.3%)  81 (36.7%)   
T3         
NA   
Disease-related death<0.001   
No  57 (77.0%)  7 (77.8%)  73 (52.5%)  137 (61.7%)  <0.001 
Yes  17 (23.0%)  2 (22.2%)  66 (47.5%)  85 (38.3%)  LR vs Lc 
Death for any other causes  0.280        0.280 
No  37 (68.5%)  5 (55.6%)  96 (76.2%)  138 (73.0%)   
Yes  17 (31.5%)  4 (44.4%)  30 (23.8%)  51 (27.0%)   
NA  20  13  33   
Death for any other causes0.001 
No  41 (55.4%)  3 (33.3%)  44 (31.7%)  88 (39.6%)  <0.005 
Yes  33 (44.6%)  6 (66.7%)  95 (68.3%)  134 (60.4%)  LR vs Lc 

AJCC-8, American Joint Committee on Cancer VIII edition; BWH, Brigham and Women's Hospital classification; L, lymphatic; LR, local recurrence; NA, not available; NS, nonstatistically significant; Q1, Q2, 1st and 3rd quartiles; S, satellitosis.

a

Expressed as n (% column) | (% row), unless otherwise specified.

b

Fisher's exact test p-values for categorical variables, trend test for ordinal variables, and Kruskal-Wallis test for continuous variables.

c

When the above-mentioned tests were statistically significant, post hoc tests were conducted with adjusted p-values using the Holm method.

Regarding staging, we should mention that, all T4 tumors according to AJCC and all T3 tumors according to BWH preferentially spread to lymph nodes (100%). On the other hand, low-risk T1 tumors that progressed did so almost equally as local recurrences or lymph node metastases (table 1).

Regarding mortality according to pathways, tumors that presented with a local recurrence had a lower specific mortality rate than those presenting in lymph nodes (23% vs 47.5%, p <0.001), and a lower overall mortality rate too (44.6% vs 68.3%, p<0.005) (table 1).

Of note that neither age, sex, location, differentiation grade, tumor thickness, perineural or lymphovascular invasion, nor staging were significantly differentially distributed among the different dissemination pathways.

Figure 1 illustrates the different metastatic pathways in the progression of primary cSCC. The most frequent progression pathway was lymphatic (n=139 [62.6%]), followed by local recurrences (n=74 [33.3%]) and satellitosis (n=9 [4.4%]). In 12 cases of local recurrence (16.2% of LR), subsequent lymphatic progression was reported.

Figure 1.

Type of relapse and different metastatic pathways of the 222 patients with high-risk cSCC with relapses at their follow-up. (*) indicates percentage (%) of patients, in nodes it is the % over the total number of patients with recurrence, and in the arrows it indicates the % over the upper node.

(0.25MB).

Overall, 31 cases (20.5% of L) out of all cases with regional lymphatic recurrence progressed into systemic metastases. Only 1 case of local recurrence was described, which directly developed systemic metastases. Systemic metastases were not found as the first progression pathway, nor were lymphatic metastases following satellitosis.

The deaths of patients with cSCC were most due to the regional lymphatic progression of their disease (n=47 [54.6% of deaths]), followed by systemic metastases (n=27 [31.4% of deaths]). Local progressions were the cause of death in 11.6% (n=10) of all reported deaths. Finally, 2 deaths due to satellitosis were reported (2.3% of all reported deaths).

The different metastatic and progression pathways of cSCC cases resulting in death are depicted in Figure 2. The most frequent metastatic pathway was the L-d route (n=42 [49.4%]), followed by the L-M-d route (n=24 [28.2%]). The next most frequent route was the LR-d route (n=9 [10.6%]). The remaining metastatic and progression pathways occurred in 5 or fewer cases. Of note that, regardless of the metastatic pathway involved, all regional lymphatic recurrences appeared, on average, between the 13- and 18-month follow-up, while disease-related deaths occurred, on average, between the 26- and 35-month follow-up from diagnosis for the most frequent metastatic pathways. Interestingly, there was a trend toward longer time to death in cases with L metastasis followed by development of systemic metastases (L-M-d route) compared with cases that only had local progression (LR-d route), via satellitosis (S-d route), or regionally (L-d route).

Figure 2.

Temporal course of the different progression pathways for patients who finally died from high-risk cSCC. d, death; L, regional lymphatic recurrence; LR, local recurrence; M, systemic metastasis; S, satellitosis.

(0.16MB).

Survival analysis until recurrence based on the type of pathway (LR, L, and S) showed no differences among them (figure 3). No differences in survival time were reported either until the appearance of lymphatic metastases based on whether they were the first recurrence or followed local recurrence (figure 4). Finally, the time elapsed until the appearance of lymphatic metastases was not associated with prognosis, which was determined as the absence of further progressions vs progression to systemic metastases or regional progression until the patient's death (figure 5).

Figure 3.

Survival until the appearance of the first recurrence in high-risk cSCC (n=222).

(0.14MB).
Figure 4.

Survival until regional lymphatic recurrence as the first recurrence vs regional lymphatic recurrence after local recurrence (n=152).

(0.14MB).
Figure 5.

Survival until lymphatic recurrence depending on whether patients remained disease-free, died from regional progression of their disease, or progressed to systemic metastases (n=152).

(0.16MB).
Discussion

The present study shows that the most frequent progression for high-risk cSCCs is the lymphatic pathway, and that this pathway is virtually mandatory before systemic metastases develop.

The metastatic process is a complex process in which genetically unstable cells adapt to a tissue microenvironment, which is different from their own tissue of origin.12 This process is not random; tumor cells generally have a certain affinity for specific tissues depending on the tumor lineage in a dissemination model originally termed “seed and soil” by Paget back in the 19th century.13 This model explains why certain tumors, such as breast cancer, frequently metastasize to the lung, bone, liver, or brain, while others, such as prostate cancer, are more prone to bone metastasis. Similarly, uveal melanoma characteristically metastasizes more to the liver, while sarcomas metastasize to the lung.12

In the case of cSCCs, the most important implication of these findings would be the locoregional management of the disease. More than half of the patients in the study die from progression of regional lymphatic metastases, which raises the question of whether elective lymph node dissection could benefit these patients, as in the case of oral cavity squamous cell carcinoma.14 However, available observational studies present conflicting results. Amit et al.15 did not demonstrate the benefit of elective lymph node dissection in cSCC patients compared with observation. Conversely, in a different observational study, Xiao et al.16 did observe improved survival in patients undergoing elective lymph node dissection and superficial parotidectomy.

The ordered and gradual progression of cSCC from the primary tumor to the regional lymph node and from there to metastatic dissemination is the ideal theoretical basis supporting the therapeutic use of sentinel lymph node biopsy (SLNB). This is was decades ago was called the “incubator hypothesis”17 by SLNB advocates in melanoma, compared to the “marker hypothesis,” which hypothesized that the presence of metastases in regional lymph nodes is not a preceding step, but a marker that the tumor has already spread to other organs.18,19 The observation that the median survival time is longer for metastatic pathways involving the appearance of systemic metastases (figure 2) vs the same pathways without systemic dissemination to some extent supports this “incubator hypothesis,” an unseen phenomenon in similar studies for melanoma.8,9

Paradoxically, while a clinical trial has evaluated the role of SLNB in melanoma,3 showing no survival benefit, no clinical trial has ever been conducted evaluating the role of SLNB in cSCC. However, observational studies have been conducted comparing cSCC patients undergoing SLNB with patients under observation alone without any survival differences being reported. In this line, our group has found differences in a recent observational trial when stratified by patient immune status, with a clear advantage in progression-free survival seen only in immunocompetent patients undergoing SLNB (unpublished data).

The problem with the indication of this technique, and the overall prediction of lymphatic and systemic metastases, is far from resolved, as only 4% to 5% of patients will develop lymphatic metastases, and of those, only a quarter will develop systemic metastases. In a recent systematic review, SLNB positivity in cSCC was 8%, without clear predictors of involvement identified just yet.4 Current evidence on genetic changes in cell cycle regulation, tumor suppression, tissue invasion, microenvironment, and immune system interaction is still far from offering specific targets that can more accurately predict which patients will progress.20

In our series, 11.6% of specific deaths were due to local progression. These data demonstrate the importance of local control of cSCC. In a recent systematic review, deep invasion beyond fat, or to a lesser extent, desmoplasia, are the histological factors that most predict this recurrence,21 with Mohs surgery being the preferred option for local control of cSCC.21 In a recent review, the success of SLNB in cSCC was not affected whether performed synchronously or asynchronously with surgery, including Mohs surgery.22 This is important in the current context, in which Mohs surgery is becoming increasingly common, and the SLNB would be required after the procedure.23

In conclusion, the most frequent metastatic dissemination pathway for cSCC is the lymphatic pathway. This pathway is virtually necessary for systemic dissemination. Regional progression of lymphatic metastases is also the main cause of death. Measures aimed at regional control of this tumor, such as SLNB, elective lymph node dissection, or adjuvant radiotherapy, could play a role in improving survival in this disease.

Funding

This study was funded by Fundación Piel Sana of the Spanish Academy of Dermatology and Venereology. JC's research has been partially funded by Instituto de Salud Carlos III, Madrid, Spain (and co-funded by the European Union) through project PI21/1207, by the Regional Health Management of Castilla y León, Spain (GRS2549/A/22).

Conflicts of interest

None declared.

References
[1]
A. Tejera-Vaquerizo, M.A. Descalzo-Gallego, M.M. Otero-Rivas, C. Posada-García, L. Rodríguez-Pazos, I. Pastushenko, et al.
Incidencia y mortalidad del cáncer cutáneo en España: revisión sistemática y metaanálisis.
Actas Dermosifiliogr., 107 (2016), pp. 318-328
[2]
J. Cañueto, C. Román-Curto.
Los nuevos sistemas de estadificación del AJCC incorporan novedades en el cáncer cutáneo.
Actas Dermosifiliogr., 108 (2017), pp. 818-826
[3]
D.L. Morton, J.F. Thompson, A.J. Cochran, N. Mozzillo, O.E. Nieweg, D.F. Roses, et al.
Final trial report of sentinel-node biopsy versus nodal observation in melanoma.
N Engl J Med., 370 (2014), pp. 599-609
[4]
A. Tejera-Vaquerizo, I. García-Doval, B. Llombart, J. Cañueto, A. Martorell-Calatayud, M.A. Descalzo-Gallego, et al.
Systematic review of the prevalence of nodal metastases and the prognostic utility of sentinel lymph node biopsy in cutaneous squamous cell carcinoma.
J Dermatol., 45 (2018), pp. 781-790
[5]
K.D. Brantsch, C. Meisner, B. Schönfisch, B. Trilling, J. Wehner-Caroli, J. Röcken, et al.
Analysis of risk factors determining prognosis of cutaneous squamous-cell carcinoma: A prospective study.
Lancet Oncol., 9 (2008), pp. 713-720
[6]
A. Tejera-Vaquerizo, J. Cañueto, A. Toll, J. Santos-Juanes, A. Jaka, C. Ferrandiz, et al.
Estimated effect of COVID-19 lockdown on skin tumor size and survival: An exponential growth model.
Actas Dermosifiliogr (Engl Ed)., 111 (2020), pp. 629-638
[7]
C.D. Schmults, R. Blitzblau, S.Z. Aasi, M. Alam, J.S. Andersen, B.C. Baumann, et al.
NCCN Guidelines® Insights: Squamous Cell Skin Cancer, Version 1.2022: Featured Updates to the NCCN Guidelines.
J Natl Compr Cancer Netw., 19 (2021), pp. 1382-1394
[8]
N. Blázquez-Sánchez, M. Mendiola-Fernández, A. Fernández-Orland, et al.
Estudio temporal de los diferentes patrones metastásicos en la progresión del melanoma cutáneo.
Actas Dermosifiliogr., 98 (2007), pp. 531-538
[9]
F. Meier, S. Will, U. Ellwanger, B. Schlagenhauff, B. Schittek, G. Rassner, et al.
Metastatic pathways and time courses in the orderly progression of cutaneous melanoma.
Br J Dermatol., 147 (2002), pp. 62-70
[10]
M. Amin, S. Edge, F. Greene, C.C. Compton, J.E. Gershenwald, R.K. Brookland, et al.
AJCC Cancer Staging Manual.
8th Ed., Springle, ed., (2017),
[11]
A. Jambusaria-Pahlajani, P.A. Kanetsky, P.S. Karia, W.T. Hwang, J.M. Gelfand, F.M. Whalen, et al.
Evaluation of AJCC tumor staging for cutaneous squamous cell carcinoma and a proposed alternative tumor staging system.
JAMA Dermatol., 149 (2013), pp. 402
[12]
G.P. Gupta, J. Massagué.
Cancer metastasis: Building a framework.
Cell., 127 (2006), pp. 679-695
[13]
I.J. Fidler.
The pathogenesis of cancer metastasis: The «seed and soil» hypothesis revisited.
Nat Rev Cancer., 3 (2003), pp. 453-458
[14]
A.K. D’Cruz, R. Vaish, N. Kapre, M. Dandekar, S. Gupta, R. Hawaldar, et al.
Elective versus therapeutic neck dissection in node-negative oral cancer.
N Engl J Med., 373 (2015), pp. 521-529
[15]
M. Amit, C. Liu, J. Mansour, F.O. Gleber-Netto, S. Tam, E.N. Baruch, et al.
Elective neck dissection versus observation in patients with head and neck cutaneous squamous cell carcinoma.
Cancer., 127 (2021), pp. 4413-4420
[16]
Y. Xiao, S. Yuan, F. Liu, B. Liu, J. Zhu, W. He, et al.
Comparison between wait-and-see policy and elective neck dissection in clinically N0 cutaneous squamous cell carcinoma of head and neck.
Medicine (Baltimore)., 97 (2018), pp. e10782
[17]
D.L. Morton, A.J. Cochran.
The case for lymphatic mapping and sentinel lymphadenectomy in the management of primary melanoma.
Br J Dermatol., 151 (2004), pp. 308-319
[18]
N.S. Medalie, A.B. Ackerman.
Sentinel lymph node biopsy has no benefit for patients with primary cutaneous melanoma metastatic to a lymph node: An assertion based on comprehensive, critical analysis: part II.
Am J Dermatopathol., 25 (2003), pp. 473-484
[19]
A. Pizarro.
Modelos de diseminación del melanoma y resultado final del multicenter selective lymphadenectomy trial-I.
Actas Dermosifiliogr., 106 (2015), pp. 82-85
[20]
P.M. Mulvaney, C.D. Schmults.
Molecular prediction of metastasis in cutaneous squamous cell carcinoma.
Curr Opin Oncol., 32 (2020), pp. 129-136
[21]
G.A. Zakhem, A.N. Pulavarty, J. Carucci, M.L. Stevenson.
Association of patient risk factors, tumor characteristics, and treatment modality with poor outcomes in primary cutaneous squamous cell carcinoma: A systematic review and meta-analysis.
JAMA Dermatol., 159 (2023), pp. 160-171
[22]
T.D. Walker, A. Cusick, K.T. Shahwan, D.R. Carr.
Timing of sentinel lymph node biopsy in cutaneous squamous cell carcinoma.
J Am Acad Dermatol., 88 (2023), pp. 249-251
[23]
G. Marrazzo, J.A. Zitelli, D. Brodland.
Clinical outcomes in high-risk squamous cell carcinoma patients treated with Mohs micrographic surgery alone.
J Am Acad Dermatol., 80 (2019), pp. 633-638
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