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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Cutaneous squamous cell carcinoma &#40;cSCC&#41; is a relatively indolent malignant tumor compared to other types of cancer and rarely causes metastasis if treated promptly&#44; with a 5-year cure rate &#62; 90&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">1</span></a> Curative treatment is usually surgery and less frequently radiotherapy&#44; which is of particular interest in frail patients and&#47;or large tumors&#46; Surgery can be conventional or Mohs micrographic surgery &#40;MMS&#41;&#44; which achieves lower recurrence rates&#58; 3&#46;1&#37; up to 8&#37; vs 0&#37; up to 4&#37;&#44; respectively&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">2</span></a> Some cases respond poorly to these treatments or may not be the best therapeutic option due to the characteristics associated with the patient or tumor&#46; Alternative treatments&#8212;mainly systemic or palliative&#8212;are often considered&#46; Immunotherapy with anti-PD-1 has been a therapeutic revolution in the management of advanced and metastatic cSCC&#46; However&#44; approximately 50&#37; of patients will eventually not respond to this therapy&#44; and it is not a good option for transplanted patients&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">3</span></a> New intralesional therapies could represent another therapeutic revolution&#44; potentially solving some situations described in this article&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">The objective of this article&#44; resulting from reflection and routine clinical practice&#44; is to identify and analyze the various scenarios in which conventional local treatments such as surgery and radiotherapy are difficult to apply or offer limited curative options&#46; These situations are not always optimally addressed in clinical practice guidelines &#40;National Comprehensive Cancer Network &#91;NCCN&#93; Guidelines<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">4</span></a> and European Association of Dermato Oncology &#91;EADO&#93; Guidelines<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">5</span></a>&#41;&#44; or in the staging systems &#40;American Joint Committee on Cancer &#91;AJCC&#93; 8<span class="elsevierStyleSup">th</span> edition<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">6</span></a> and Brigham and Women&#39;s Hospital &#91;BWH&#93; system<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">7</span></a>&#41; that are currently widely used&#46; They are challenging regarding management and treatment and overlap with concepts of high-risk&#44; locally advanced&#44; and metastatic cSCC&#46; These scenarios are &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#58;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Invasion of deep structures or cavities</span><p id="par0015" class="elsevierStylePara elsevierViewall">Some tumors compromise deep structures or cavities such as the orbit<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">8</span></a> or the ear&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">9</span></a> Surgery in these cases&#44; beyond posing a higher rate of recurrence due to its complexity&#44; can be so mutilating that it is contraindicated or not feasible&#46; Sometimes&#44; adequate surgical margins are not achieved&#46; Radiotherapy is often contraindicated in these cases&#46; Similarly&#44; tumors in limbs or other locations invading deep structures such as tendons&#44; leading to excessively mutilating surgeries such as amputation&#44; represent a similar scenario&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">Discussing these cases with ophthalmologists&#44; otolaryngologists&#44; and other specialists is of paramount importance to give the patient our best clinical judgement&#46; Preoperative imaging modalities and the patient&#39;s general condition should be taken into consideration across the entire decision-making process&#46; If surgery is decided upon&#44; MMS should be the treatment of choice&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Bone involvement and beyond</span><p id="par0025" class="elsevierStylePara elsevierViewall">Bone involvement is a recognized poor prognostic factor in major staging systems&#44; being a risk factor for recurrence&#44; disease progression&#44; and mortality&#46; Bone involvement alone is a T4 stage in the AJCC<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">6</span></a> and a T3 in the BWH&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">7</span></a> Beyond this&#44; bone resection or irradiation is sometimes not possible&#46; As a matter of fact&#44; in some cases&#8212;such as scalp tumors&#8212;they can be invasive and lead to intracranial invasion&#44; making curative surgical or radiotherapeutic treatment very difficult or nearly impossible&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">10</span></a> In these cases&#44; curative options are very limited&#44; and a multidisciplinary approach is required &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Perineural invasion</span><p id="par0030" class="elsevierStylePara elsevierViewall">Perineural invasion is a known poor prognostic factor for recurrence and mortality&#44; especially when it invades large-diameter nerves &#40;&#62; 0&#46;1<span class="elsevierStyleHsp" style=""></span>mm&#41; or nerves that run deeper than the dermis&#46; Perineural invasion is not a type of lymphatic or hematogenous invasion but a direct spread of the primary tumor&#46; It is often subclinical&#44; though it sometimes causes neurological symptoms such as paresthesias&#44; pain&#44; paralysis&#46;&#46;&#46; In such cases&#44; performing a preoperative magnetic resonance imaging is advised&#46; The trigeminal nerve&#44; the facial nerve&#44; and their branches are most frequently affected&#46; Despite being considered in staging systems&#44; it often goes unnoticed and is therapeutically challenging&#46; Due to perineural spread&#44; resection is often incomplete&#44; either because surgery cannot proceed to a certain depth or because of undetected spread&#46; Therefore&#44; options such as adding a surgical safety margin despite negative margins in MMS or administering adjuvant radiotherapy are often discussed in the management of this entity&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">11</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Complex anatomical locations</span><p id="par0035" class="elsevierStylePara elsevierViewall">The anatomical location of the tumor is a risk factor for recurrence and metastasis&#46; Low-risk areas include the trunk and extremities&#46; In contrast&#44; high-risk areas include the head and neck &#40;especially the H-zone of the face&#41;&#44; genitals&#44; mucous membranes&#44; ears&#44; pre-tibial region&#44; hands&#44; and feet&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">4</span></a> Although MMS can reduce the rate of recurrence there are locations in which achieving a cure with a single surgical treatment remains challenging&#46; An example is the nail&#46; In this location&#44; the rates of recurrence described&#8212;despite treated with MMS&#8212;exceed 20&#37;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">12</span></a> &#40;much higher than the 0&#37;-4&#37; reported in other locations&#41;&#46; This high rate of recurrence could be explained by 2 non-exclusive hypotheses&#58; 1&#41; the anatomical difficulty of this specific area&#44; 2&#41; the etiology behind these tumors being human papillomavirus infection and the persistence of non-tumor cells infected by this virus causing their recurrence&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">12</span></a> Therefore&#44; studies are needed to confirm the possible role of human papillomavirus and propose new prevention and treatment strategies&#46; Penile squamous cell carcinoma also presents particular etiological features such as phimosis&#44; smoking&#44; human papillomavirus&#44; chronic inflammatory diseases such as lichen sclerosus&#44;&#46;&#46;&#46; impacting its recurrence and determining the therapeutic and prophylactic strategies that should be used&#46; This location has a high rate of regional recurrence and progression&#46; MMS would avoid mutilating surgeries without affecting the outcomes&#59; however&#44; a joint approach with urology is essential&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">13</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Hidradenitis suppurativa concomitant with other chronic inflammatory diseases</span><p id="par0040" class="elsevierStylePara elsevierViewall">cSCCs developing in areas touches by chronic inflammatory diseases such as hidradenitis suppurativa &#40;other examples include conditions such as lichen planus or tumors arising in irradiated zones&#44; ostomies&#44; or patients with congenital epidermolysis bullosa&#41; often present a therapeutic challenge&#46; Firstly&#44; there is often a diagnostic delay&#44; making it not uncommon to encounter locally advanced tumors&#46; Secondly&#44; they occur on skin damaged by the underlying disease&#44; leading to more frequent postoperative complications such as wound dehiscence&#46; The skin is usually less elastic and may exhibit fibrosis&#44; making closures and flaps difficult&#46; Furthermore&#44; this skin is often unsuitable for irradiation&#46; This inflamed skin acts as a field of cancerization&#44; and recurrences can occur despite proper tumor treatment&#46; Finally&#44; hidradenitis suppurativa causes fistulous tracts where the tumor finds an ideal plane for progression&#44; often resulting in greater local tumor spread than anticipated&#44; complicating its excision&#46; These fistulas can run deep and be associated with anorectal and urogenital structures&#44; which may be compromised by the tumor or surgery&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">To address this scenario&#44; it is essential to maintain a high level of suspicion during the screening of these patients for the earliest possible detection and optimize the treatment of the underlying disease to prevent new tumors from appearing&#46; Secondly&#44; once faced with a tumor of this type&#44; it is essential to perform imaging modalities to plan surgery and approach it along with the corresponding specialist &#40;general surgeon&#44; urologist&#44; gynecologist&#46;&#46;&#46;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">14</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Incomplete excisions or recurrences in flaps</span><p id="par0050" class="elsevierStylePara elsevierViewall">The occurrence of a recurrence in a flap or the excision with a tumor affected margins whose defect has been reconstructed with a flap remains a relatively frequent and difficult scenario to manage&#46; Firstly&#44; recurrence <span class="elsevierStyleItalic">per se</span> is a poor prognostic factor&#44; and incomplete excision may be due to a tumor of difficult clinical delineation&#46; Secondly&#44; it is challenging to determine where the tumor persists in cases of affected margins&#44; and in cases of recurrence&#44; the tumor often finds a plane of dissemination through the flap scars and&#47;or has a long progression time due to deep recurrences that go clinically unnoticed&#46; Finally&#44; reconstructions can be challenging as we have &#8220;used up&#8221; other reconstructive options before&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">In the authors&#8217; opinion&#44; to prevent this from happening&#44; MMS should be performed to analyze 100&#37; of the tumor margins whenever a flap is to be used to reconstruct a tumor excision defect&#46; Even so&#44; some cases &#40;not many&#41; treated with MMS will present recurrences on flaps&#46; These cases should always be approached with another MMS&#44; preferably delayed&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Satellite lesions or in-transit metastasis</span><p id="par0060" class="elsevierStylePara elsevierViewall">Satellite lesions or in-transit metastasis are one of the long-forgotten scenarios in the management of cSCC&#46; These are non-epidermal lesions originating between the primary tumor and the first draining lymph nodes&#46; It has been confirmed that satellite lesions are an independent risk factor for poor prognosis in cSCC and that&#44; in terms of recurrence and disease-specific survival&#44; the clinical outcomes of patients with cSCC-induced satellite lesions are similar to those of nodal metastases&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">15</span></a> Although rare&#44; encountering a patient with satellite lesions in the routine clinical practice is a diagnostic and therapeutic challenge since they are often omitted from the main currently used staging systems and clinical practice guidelines&#46;<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">4&#8211;7</span></a> Recently&#44; it has been demonstrated that not all satellite lesions are the same and that sizes &#8805; 2<span class="elsevierStyleHsp" style=""></span>cm and the presence of &#62; 5 lesions confer an increased risk of tumor recurrence and specific mortality&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">16</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">Incorporating satellite lesions into upcoming staging systems and clinical practice guidelines&#8212;as it has already been the case with melanoma and Merkel cell carcinoma&#8212;would be a first step toward initiating clinical trials and other studies to determine the optimal therapeutic strategy in each case &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>b&#41;&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Multiple simultaneous tumors</span><p id="par0070" class="elsevierStylePara elsevierViewall">The presence of multiple simultaneous tumors does not indicate widespread or metastatic disease like satellite lesions but just shares with the fact of exhibiting multiple lesions too&#46; In some cases&#44; due to the number&#44; size&#44; location&#44; or rapid emergence of new tumors&#44; treatment with conventional therapies becomes difficult or nearly impossible&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Parotid metastasis</span><p id="par0075" class="elsevierStylePara elsevierViewall">In countries with a high incidence of skin cancer&#44; such as Australia&#44; cSCC-induced metastasis is the leading cause of malignancy in this salivary gland&#46; However&#44; this situation has not been included in the main staging systems&#46; While gland involvement can occur through local invasion&#44; it is mostly affected by intraparotid nodal metastases&#46; In the most widely used staging systems&#44;<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">6&#44;7</span></a> parotid metastasis is often equated with cervical lymph node metastasis&#44; despite several studies propose alternative staging systems that classify this scenario separately due to its unique prognostic characteristics&#46; The most well-known is the study conducted by O&#8217;Brien&#44;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">17</span></a> which differentiates parotid metastases from cervical lymph node metastases and establishes 3 levels of prognosis-related severity&#46; Despite a few controversial results&#44; this classification has been corroborated by other studies throughout the years&#46; However&#44; current staging systems still do not provide the distinction and particularity this situation deserves&#44; leading to suboptimal management and treatment of these patients&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Extensive nodal metastasis</span><p id="par0080" class="elsevierStylePara elsevierViewall">Patients with nodal metastasis exhibit&#44; by definition&#44; advanced disease&#46; Surgical treatment of nodal metastasis can be curative but often fails when metastases are large&#44; involve numerous nodes&#44; or show extracapsular extension&#44; which is why radiotherapy is usually added in these cases&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">6</span></a> Lymphadenectomies are associated with postoperative complications in &#62; 55&#37; of cases&#44; including infections&#44; seromas&#44; dehiscence&#44; or lymphedema&#46; Despite undergoing surgery and radiotherapy&#44; as recommended by the guidelines&#44; in these cases&#44; the rates of recurrence are generally between 20&#37; and 35&#37;&#44; while the 5-year disease-free survival and disease-specific survival rates are 59&#37;-83&#37; and 63&#37;-83&#37;&#44; respectively&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">4</span></a></p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Very elderly or frail patients</span><p id="par0085" class="elsevierStylePara elsevierViewall">cSCC predominantly occurs in elderly patients&#44; making it a common finding in the routine clinical practice to encounter frail patients or those with comorbidities contraindicating surgery&#44; in whom radiotherapy is considered palliative&#46; Aging is associated with increased frailty&#44; risk of dependence&#44; and reduced autonomy&#46; Frail patients have worse survival and tolerate standard treatments less well&#46; Some geriatric oncology societies recommend that elderly cancer patients should undergo geriatric assessments to detect problems that may go unnoticed in routine physical examinations or in the patient&#39;s medical history to predict survival and help in therapeutic decision-making&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">18</span></a> Geriatric assessment is a multidimensional and interdisciplinary tool that identifies functional&#44; nutritional&#44; cognitive&#44; psychological&#44; social support&#44; and comorbidity factors&#46; Although comprehensive geriatric assessment can be useful in oncology&#44; it requires complex and long visits and tests&#46; In this regard&#44; there are rapid geriatric screening tools currently available beyond ECOG&#44; such as the G8 and the Vulnerable Elders Survey-13&#44; which have proven useful in identifying patients requiring further evaluation&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">19</span></a> In cases in which frailty is indicated by the score&#44; comprehensive geriatric assessments evaluating physical&#44; mental&#44; nutritional&#44; comorbidity&#44; and social function are advised&#46; If frailty is confirmed&#44; interventions to revert to non-frail states and consideration of non-surgical or minimally aggressive treatments are advised&#46; Additionally&#44; the Charlson Comorbidity Index can predict short- or long-term mortality based on the patient&#39;s comorbidities and has&#44; also&#44; been validated in some cancer populations&#46; Its results should be validated in cSCC patients&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">20</span></a></p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Conclusions</span><p id="par0090" class="elsevierStylePara elsevierViewall">The present article identifies and analyzes the main scenarios in which cSCC is difficult to treat with conventional local therapies&#46; Therefore&#44; there is no clear consensus on what their therapeutic management should be&#46; Preoperative imaging modalities&#44; MMS&#44; multidisciplinary committee discussions&#44; and individualized therapies are common elements for the optimal management of various scenarios&#46; The scientific community should focus on including these scenarios in the routine clinical guidelines&#44; conducting studies to optimize their management&#44; and including these patients in clinical trials &#40;especially now that we lieve in the new era of intralesional therapies&#41; to offer the best therapeutic options to these patients&#46;</p></span></span>"
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          "titulo" => "Invasion of deep structures or cavities"
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        1 => array:2 [
          "identificador" => "sec0010"
          "titulo" => "Bone involvement and beyond"
        ]
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          "identificador" => "sec0015"
          "titulo" => "Perineural invasion"
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        3 => array:2 [
          "identificador" => "sec0020"
          "titulo" => "Complex anatomical locations"
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        4 => array:2 [
          "identificador" => "sec0025"
          "titulo" => "Hidradenitis suppurativa concomitant with other chronic inflammatory diseases"
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          "titulo" => "Incomplete excisions or recurrences in flaps"
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          "titulo" => "Satellite lesions or in-transit metastasis"
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          "titulo" => "Multiple simultaneous tumors"
        ]
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          "identificador" => "sec0045"
          "titulo" => "Parotid metastasis"
        ]
        9 => array:2 [
          "identificador" => "sec0050"
          "titulo" => "Extensive nodal metastasis"
        ]
        10 => array:2 [
          "identificador" => "sec0055"
          "titulo" => "Very elderly or frail patients"
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        11 => array:2 [
          "identificador" => "sec0060"
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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">a&#41; 98-year-old male with a large cutaneous squamous cell carcinoma&#44; affecting the entire scalp with bone invasion involving the entire cranial vault&#46;</p> <p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">b&#41; Woman with cutaneous squamous cell carcinoma operated on the left forehead &#40;see the scar&#41; who developed satellite lesions in the form of a dermal tumor nodule on the left temple a few weeks after surgery&#46;</p>"
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                  \t\t\t\t">Perineural invasion&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Complex anatomical locations&#58; nail and penis&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Satellite lesions or in-transit metastasis&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Multiple simultaneous tumors&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t">Parotid metastasis&nbsp;\t\t\t\t\t\t\n
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                            0 => "N&#46;D&#46;L&#46;S&#46; Brougham"
                            1 => "E&#46;R&#46; Dennett"
                            2 => "R&#46; Cameron"
                            3 => "S&#46;T&#46; Tan"
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                      "doi" => "10.1002/jso.23155"
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                          "autores" => array:3 [
                            0 => "G&#46; Marrazzo"
                            1 => "J&#46;A&#46; Zitelli"
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                      "doi" => "10.1016/j.jaad.2018.09.015"
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                      "titulo" => "Systemic Immunotherapy for Advanced Cutaneous Squamous Cell Carcinoma"
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                            0 => "D&#46; Ogata"
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                  "contribucion" => array:1 [
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                      "titulo" => "European interdisciplinary guideline on invasive squamous cell carcinoma of the skin&#58; Part 2 Treatment"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "A&#46;J&#46; Stratigos"
                            1 => "C&#46; Garbe"
                            2 => "C&#46; Dessinioti"
                            3 => "C&#46; Lebbe"
                            4 => "V&#46; Bataille"
                            5 => "L&#46; Bastholt"
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                      "doi" => "10.1016/j.ejca.2020.01.008"
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                        "tituloSerie" => "Eur J Cancer&#46;"
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                      "titulo" => "AJCC cancer staging manual"
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Artículo de opinión
Cutaneous squamous cell carcinoma that are difficult-to-manage with conventional local treatments
Carcinoma escamoso cutáneo: escenarios de difícil manejo con tratamientos locales convencionales
I. Marti-Marti
Autor para correspondencia
ignasi.marti.marti@gmail.com

Autor para correspondencia.
, A. Toll
Servicio de Dermatología, Hospital Clínic de Barcelona, Universitat de Barcelona, Barcelona, Spain
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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Cutaneous squamous cell carcinoma &#40;cSCC&#41; is a relatively indolent malignant tumor compared to other types of cancer and rarely causes metastasis if treated promptly&#44; with a 5-year cure rate &#62; 90&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">1</span></a> Curative treatment is usually surgery and less frequently radiotherapy&#44; which is of particular interest in frail patients and&#47;or large tumors&#46; Surgery can be conventional or Mohs micrographic surgery &#40;MMS&#41;&#44; which achieves lower recurrence rates&#58; 3&#46;1&#37; up to 8&#37; vs 0&#37; up to 4&#37;&#44; respectively&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">2</span></a> Some cases respond poorly to these treatments or may not be the best therapeutic option due to the characteristics associated with the patient or tumor&#46; Alternative treatments&#8212;mainly systemic or palliative&#8212;are often considered&#46; Immunotherapy with anti-PD-1 has been a therapeutic revolution in the management of advanced and metastatic cSCC&#46; However&#44; approximately 50&#37; of patients will eventually not respond to this therapy&#44; and it is not a good option for transplanted patients&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">3</span></a> New intralesional therapies could represent another therapeutic revolution&#44; potentially solving some situations described in this article&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">The objective of this article&#44; resulting from reflection and routine clinical practice&#44; is to identify and analyze the various scenarios in which conventional local treatments such as surgery and radiotherapy are difficult to apply or offer limited curative options&#46; These situations are not always optimally addressed in clinical practice guidelines &#40;National Comprehensive Cancer Network &#91;NCCN&#93; Guidelines<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">4</span></a> and European Association of Dermato Oncology &#91;EADO&#93; Guidelines<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">5</span></a>&#41;&#44; or in the staging systems &#40;American Joint Committee on Cancer &#91;AJCC&#93; 8<span class="elsevierStyleSup">th</span> edition<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">6</span></a> and Brigham and Women&#39;s Hospital &#91;BWH&#93; system<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">7</span></a>&#41; that are currently widely used&#46; They are challenging regarding management and treatment and overlap with concepts of high-risk&#44; locally advanced&#44; and metastatic cSCC&#46; These scenarios are &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#58;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Invasion of deep structures or cavities</span><p id="par0015" class="elsevierStylePara elsevierViewall">Some tumors compromise deep structures or cavities such as the orbit<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">8</span></a> or the ear&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">9</span></a> Surgery in these cases&#44; beyond posing a higher rate of recurrence due to its complexity&#44; can be so mutilating that it is contraindicated or not feasible&#46; Sometimes&#44; adequate surgical margins are not achieved&#46; Radiotherapy is often contraindicated in these cases&#46; Similarly&#44; tumors in limbs or other locations invading deep structures such as tendons&#44; leading to excessively mutilating surgeries such as amputation&#44; represent a similar scenario&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">Discussing these cases with ophthalmologists&#44; otolaryngologists&#44; and other specialists is of paramount importance to give the patient our best clinical judgement&#46; Preoperative imaging modalities and the patient&#39;s general condition should be taken into consideration across the entire decision-making process&#46; If surgery is decided upon&#44; MMS should be the treatment of choice&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Bone involvement and beyond</span><p id="par0025" class="elsevierStylePara elsevierViewall">Bone involvement is a recognized poor prognostic factor in major staging systems&#44; being a risk factor for recurrence&#44; disease progression&#44; and mortality&#46; Bone involvement alone is a T4 stage in the AJCC<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">6</span></a> and a T3 in the BWH&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">7</span></a> Beyond this&#44; bone resection or irradiation is sometimes not possible&#46; As a matter of fact&#44; in some cases&#8212;such as scalp tumors&#8212;they can be invasive and lead to intracranial invasion&#44; making curative surgical or radiotherapeutic treatment very difficult or nearly impossible&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">10</span></a> In these cases&#44; curative options are very limited&#44; and a multidisciplinary approach is required &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Perineural invasion</span><p id="par0030" class="elsevierStylePara elsevierViewall">Perineural invasion is a known poor prognostic factor for recurrence and mortality&#44; especially when it invades large-diameter nerves &#40;&#62; 0&#46;1<span class="elsevierStyleHsp" style=""></span>mm&#41; or nerves that run deeper than the dermis&#46; Perineural invasion is not a type of lymphatic or hematogenous invasion but a direct spread of the primary tumor&#46; It is often subclinical&#44; though it sometimes causes neurological symptoms such as paresthesias&#44; pain&#44; paralysis&#46;&#46;&#46; In such cases&#44; performing a preoperative magnetic resonance imaging is advised&#46; The trigeminal nerve&#44; the facial nerve&#44; and their branches are most frequently affected&#46; Despite being considered in staging systems&#44; it often goes unnoticed and is therapeutically challenging&#46; Due to perineural spread&#44; resection is often incomplete&#44; either because surgery cannot proceed to a certain depth or because of undetected spread&#46; Therefore&#44; options such as adding a surgical safety margin despite negative margins in MMS or administering adjuvant radiotherapy are often discussed in the management of this entity&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">11</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Complex anatomical locations</span><p id="par0035" class="elsevierStylePara elsevierViewall">The anatomical location of the tumor is a risk factor for recurrence and metastasis&#46; Low-risk areas include the trunk and extremities&#46; In contrast&#44; high-risk areas include the head and neck &#40;especially the H-zone of the face&#41;&#44; genitals&#44; mucous membranes&#44; ears&#44; pre-tibial region&#44; hands&#44; and feet&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">4</span></a> Although MMS can reduce the rate of recurrence there are locations in which achieving a cure with a single surgical treatment remains challenging&#46; An example is the nail&#46; In this location&#44; the rates of recurrence described&#8212;despite treated with MMS&#8212;exceed 20&#37;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">12</span></a> &#40;much higher than the 0&#37;-4&#37; reported in other locations&#41;&#46; This high rate of recurrence could be explained by 2 non-exclusive hypotheses&#58; 1&#41; the anatomical difficulty of this specific area&#44; 2&#41; the etiology behind these tumors being human papillomavirus infection and the persistence of non-tumor cells infected by this virus causing their recurrence&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">12</span></a> Therefore&#44; studies are needed to confirm the possible role of human papillomavirus and propose new prevention and treatment strategies&#46; Penile squamous cell carcinoma also presents particular etiological features such as phimosis&#44; smoking&#44; human papillomavirus&#44; chronic inflammatory diseases such as lichen sclerosus&#44;&#46;&#46;&#46; impacting its recurrence and determining the therapeutic and prophylactic strategies that should be used&#46; This location has a high rate of regional recurrence and progression&#46; MMS would avoid mutilating surgeries without affecting the outcomes&#59; however&#44; a joint approach with urology is essential&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">13</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Hidradenitis suppurativa concomitant with other chronic inflammatory diseases</span><p id="par0040" class="elsevierStylePara elsevierViewall">cSCCs developing in areas touches by chronic inflammatory diseases such as hidradenitis suppurativa &#40;other examples include conditions such as lichen planus or tumors arising in irradiated zones&#44; ostomies&#44; or patients with congenital epidermolysis bullosa&#41; often present a therapeutic challenge&#46; Firstly&#44; there is often a diagnostic delay&#44; making it not uncommon to encounter locally advanced tumors&#46; Secondly&#44; they occur on skin damaged by the underlying disease&#44; leading to more frequent postoperative complications such as wound dehiscence&#46; The skin is usually less elastic and may exhibit fibrosis&#44; making closures and flaps difficult&#46; Furthermore&#44; this skin is often unsuitable for irradiation&#46; This inflamed skin acts as a field of cancerization&#44; and recurrences can occur despite proper tumor treatment&#46; Finally&#44; hidradenitis suppurativa causes fistulous tracts where the tumor finds an ideal plane for progression&#44; often resulting in greater local tumor spread than anticipated&#44; complicating its excision&#46; These fistulas can run deep and be associated with anorectal and urogenital structures&#44; which may be compromised by the tumor or surgery&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">To address this scenario&#44; it is essential to maintain a high level of suspicion during the screening of these patients for the earliest possible detection and optimize the treatment of the underlying disease to prevent new tumors from appearing&#46; Secondly&#44; once faced with a tumor of this type&#44; it is essential to perform imaging modalities to plan surgery and approach it along with the corresponding specialist &#40;general surgeon&#44; urologist&#44; gynecologist&#46;&#46;&#46;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">14</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Incomplete excisions or recurrences in flaps</span><p id="par0050" class="elsevierStylePara elsevierViewall">The occurrence of a recurrence in a flap or the excision with a tumor affected margins whose defect has been reconstructed with a flap remains a relatively frequent and difficult scenario to manage&#46; Firstly&#44; recurrence <span class="elsevierStyleItalic">per se</span> is a poor prognostic factor&#44; and incomplete excision may be due to a tumor of difficult clinical delineation&#46; Secondly&#44; it is challenging to determine where the tumor persists in cases of affected margins&#44; and in cases of recurrence&#44; the tumor often finds a plane of dissemination through the flap scars and&#47;or has a long progression time due to deep recurrences that go clinically unnoticed&#46; Finally&#44; reconstructions can be challenging as we have &#8220;used up&#8221; other reconstructive options before&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">In the authors&#8217; opinion&#44; to prevent this from happening&#44; MMS should be performed to analyze 100&#37; of the tumor margins whenever a flap is to be used to reconstruct a tumor excision defect&#46; Even so&#44; some cases &#40;not many&#41; treated with MMS will present recurrences on flaps&#46; These cases should always be approached with another MMS&#44; preferably delayed&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Satellite lesions or in-transit metastasis</span><p id="par0060" class="elsevierStylePara elsevierViewall">Satellite lesions or in-transit metastasis are one of the long-forgotten scenarios in the management of cSCC&#46; These are non-epidermal lesions originating between the primary tumor and the first draining lymph nodes&#46; It has been confirmed that satellite lesions are an independent risk factor for poor prognosis in cSCC and that&#44; in terms of recurrence and disease-specific survival&#44; the clinical outcomes of patients with cSCC-induced satellite lesions are similar to those of nodal metastases&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">15</span></a> Although rare&#44; encountering a patient with satellite lesions in the routine clinical practice is a diagnostic and therapeutic challenge since they are often omitted from the main currently used staging systems and clinical practice guidelines&#46;<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">4&#8211;7</span></a> Recently&#44; it has been demonstrated that not all satellite lesions are the same and that sizes &#8805; 2<span class="elsevierStyleHsp" style=""></span>cm and the presence of &#62; 5 lesions confer an increased risk of tumor recurrence and specific mortality&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">16</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">Incorporating satellite lesions into upcoming staging systems and clinical practice guidelines&#8212;as it has already been the case with melanoma and Merkel cell carcinoma&#8212;would be a first step toward initiating clinical trials and other studies to determine the optimal therapeutic strategy in each case &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>b&#41;&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Multiple simultaneous tumors</span><p id="par0070" class="elsevierStylePara elsevierViewall">The presence of multiple simultaneous tumors does not indicate widespread or metastatic disease like satellite lesions but just shares with the fact of exhibiting multiple lesions too&#46; In some cases&#44; due to the number&#44; size&#44; location&#44; or rapid emergence of new tumors&#44; treatment with conventional therapies becomes difficult or nearly impossible&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Parotid metastasis</span><p id="par0075" class="elsevierStylePara elsevierViewall">In countries with a high incidence of skin cancer&#44; such as Australia&#44; cSCC-induced metastasis is the leading cause of malignancy in this salivary gland&#46; However&#44; this situation has not been included in the main staging systems&#46; While gland involvement can occur through local invasion&#44; it is mostly affected by intraparotid nodal metastases&#46; In the most widely used staging systems&#44;<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">6&#44;7</span></a> parotid metastasis is often equated with cervical lymph node metastasis&#44; despite several studies propose alternative staging systems that classify this scenario separately due to its unique prognostic characteristics&#46; The most well-known is the study conducted by O&#8217;Brien&#44;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">17</span></a> which differentiates parotid metastases from cervical lymph node metastases and establishes 3 levels of prognosis-related severity&#46; Despite a few controversial results&#44; this classification has been corroborated by other studies throughout the years&#46; However&#44; current staging systems still do not provide the distinction and particularity this situation deserves&#44; leading to suboptimal management and treatment of these patients&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Extensive nodal metastasis</span><p id="par0080" class="elsevierStylePara elsevierViewall">Patients with nodal metastasis exhibit&#44; by definition&#44; advanced disease&#46; Surgical treatment of nodal metastasis can be curative but often fails when metastases are large&#44; involve numerous nodes&#44; or show extracapsular extension&#44; which is why radiotherapy is usually added in these cases&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">6</span></a> Lymphadenectomies are associated with postoperative complications in &#62; 55&#37; of cases&#44; including infections&#44; seromas&#44; dehiscence&#44; or lymphedema&#46; Despite undergoing surgery and radiotherapy&#44; as recommended by the guidelines&#44; in these cases&#44; the rates of recurrence are generally between 20&#37; and 35&#37;&#44; while the 5-year disease-free survival and disease-specific survival rates are 59&#37;-83&#37; and 63&#37;-83&#37;&#44; respectively&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">4</span></a></p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Very elderly or frail patients</span><p id="par0085" class="elsevierStylePara elsevierViewall">cSCC predominantly occurs in elderly patients&#44; making it a common finding in the routine clinical practice to encounter frail patients or those with comorbidities contraindicating surgery&#44; in whom radiotherapy is considered palliative&#46; Aging is associated with increased frailty&#44; risk of dependence&#44; and reduced autonomy&#46; Frail patients have worse survival and tolerate standard treatments less well&#46; Some geriatric oncology societies recommend that elderly cancer patients should undergo geriatric assessments to detect problems that may go unnoticed in routine physical examinations or in the patient&#39;s medical history to predict survival and help in therapeutic decision-making&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">18</span></a> Geriatric assessment is a multidimensional and interdisciplinary tool that identifies functional&#44; nutritional&#44; cognitive&#44; psychological&#44; social support&#44; and comorbidity factors&#46; Although comprehensive geriatric assessment can be useful in oncology&#44; it requires complex and long visits and tests&#46; In this regard&#44; there are rapid geriatric screening tools currently available beyond ECOG&#44; such as the G8 and the Vulnerable Elders Survey-13&#44; which have proven useful in identifying patients requiring further evaluation&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">19</span></a> In cases in which frailty is indicated by the score&#44; comprehensive geriatric assessments evaluating physical&#44; mental&#44; nutritional&#44; comorbidity&#44; and social function are advised&#46; If frailty is confirmed&#44; interventions to revert to non-frail states and consideration of non-surgical or minimally aggressive treatments are advised&#46; Additionally&#44; the Charlson Comorbidity Index can predict short- or long-term mortality based on the patient&#39;s comorbidities and has&#44; also&#44; been validated in some cancer populations&#46; Its results should be validated in cSCC patients&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">20</span></a></p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Conclusions</span><p id="par0090" class="elsevierStylePara elsevierViewall">The present article identifies and analyzes the main scenarios in which cSCC is difficult to treat with conventional local therapies&#46; Therefore&#44; there is no clear consensus on what their therapeutic management should be&#46; Preoperative imaging modalities&#44; MMS&#44; multidisciplinary committee discussions&#44; and individualized therapies are common elements for the optimal management of various scenarios&#46; The scientific community should focus on including these scenarios in the routine clinical guidelines&#44; conducting studies to optimize their management&#44; and including these patients in clinical trials &#40;especially now that we lieve in the new era of intralesional therapies&#41; to offer the best therapeutic options to these patients&#46;</p></span></span>"
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          "titulo" => "Invasion of deep structures or cavities"
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          "identificador" => "sec0010"
          "titulo" => "Bone involvement and beyond"
        ]
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          "identificador" => "sec0015"
          "titulo" => "Perineural invasion"
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          "identificador" => "sec0020"
          "titulo" => "Complex anatomical locations"
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        4 => array:2 [
          "identificador" => "sec0025"
          "titulo" => "Hidradenitis suppurativa concomitant with other chronic inflammatory diseases"
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          "titulo" => "Incomplete excisions or recurrences in flaps"
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          "titulo" => "Satellite lesions or in-transit metastasis"
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          "titulo" => "Multiple simultaneous tumors"
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          "identificador" => "sec0045"
          "titulo" => "Parotid metastasis"
        ]
        9 => array:2 [
          "identificador" => "sec0050"
          "titulo" => "Extensive nodal metastasis"
        ]
        10 => array:2 [
          "identificador" => "sec0055"
          "titulo" => "Very elderly or frail patients"
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        11 => array:2 [
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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">a&#41; 98-year-old male with a large cutaneous squamous cell carcinoma&#44; affecting the entire scalp with bone invasion involving the entire cranial vault&#46;</p> <p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">b&#41; Woman with cutaneous squamous cell carcinoma operated on the left forehead &#40;see the scar&#41; who developed satellite lesions in the form of a dermal tumor nodule on the left temple a few weeks after surgery&#46;</p>"
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                            1 => "E&#46;R&#46; Dennett"
                            2 => "R&#46; Cameron"
                            3 => "S&#46;T&#46; Tan"
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                          "etal" => true
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                            1 => "C&#46; Garbe"
                            2 => "C&#46; Dessinioti"
                            3 => "C&#46; Lebbe"
                            4 => "V&#46; Bataille"
                            5 => "L&#46; Bastholt"
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                            2 => "F&#46;L&#46; Greene"
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