Review
Cutaneous Squamous Cell Carcinoma: Defining the High-Risk Variant
Carcinoma epidermoide cutáneo: definendo la variante de alto riesgo
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Paciente de 70 años con carcinoma epidermoide cutáneo en el pabellón auricular. B. Tumoración carnosa que infiltra el conducto auricular externo. C y D. Histológicamente se caracteriza por una tumoración de células escamosas mal diferenciado con invasión linfovascular (B: hematoxilina-eosina x40; C: Inmunotinción CD31<span class="elsevierStyleHsp" style=""></span>×100) E. Glándula parótida que presenta una tumoración nodular. F. La tumoración parotídea está formada por una proliferación de células escamosas mal diferenciadas, siguiendo un patrón similar a la tumoración primaria (hematoxilina-eosina, x40).</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "A. Martorell-Calatayud, O. Sanmartín Jimenez, J. Cruz Mojarrieta, C. Guillén Barona" "autores" => array:4 [ 0 => array:2 [ "nombre" => "A." "apellidos" => "Martorell-Calatayud" ] 1 => array:2 [ "nombre" => "O." "apellidos" => "Sanmartín Jimenez" ] 2 => array:2 [ "nombre" => "J." 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The primary or most important reference centers, working on a national level, would be located in the more populous autonomous communities (red squares), and the secondary reference centers (blue squares), serving a considerable number of patients, would be located in the less populous autonomous communities. The patients in the other Spanish autonomous communities could choose the most appropriate primary or secondary centers depending on geographical distance or personal considerations.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "A. Hernández-Martin, R. de Lucas, A. Vicente, E. Baselga, E. Morcillo-Makow, M.I. Arroyo Manzanal, I. Abaitua, A. Torrelo" "autores" => array:8 [ 0 => array:2 [ "nombre" => "A." "apellidos" => "Hernández-Martin" ] 1 => array:2 [ "nombre" => "R." "apellidos" => "de Lucas" ] 2 => array:2 [ "nombre" => "A." "apellidos" => "Vicente" ] 3 => array:2 [ "nombre" => "E." "apellidos" => "Baselga" ] 4 => array:2 [ "nombre" => "E." 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Martorell-Calatayud, O. Sanmartín Jimenez, J. Cruz Mojarrieta, C. Guillén Barona" "autores" => array:4 [ 0 => array:4 [ "nombre" => "A." "apellidos" => "Martorell-Calatayud" "email" => array:1 [ 0 => "antmarto@hotmail.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "O." "apellidos" => "Sanmartín Jimenez" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "J." "apellidos" => "Cruz Mojarrieta" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] 3 => array:3 [ "nombre" => "C." "apellidos" => "Guillén Barona" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Departamento de Dermatología, Hospital de Manises, Valencia, Spain" "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Departamento de Dermatología, Instituto Valenciano de Oncología, Valencia, Spain" "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Departamento de Anatomía Patológica, Instituto Valenciano de Oncología, Valencia, Spain" "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "*" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Carcinoma epidermoide cutáneo: definendo la variante de alto riesgo" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0020" "etiqueta" => "Figure 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 461 "Ancho" => 1500 "Tamanyo" => 196218 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">A, Perineural invasion detected incidentally during surgery. B, Histology showing invasion of the nerve trunk (diameter, ><span class="elsevierStyleHsp" style=""></span>0.1<span class="elsevierStyleHsp" style=""></span>mm) by atypical squamous cells (hematoxylin-eosin, original magnification x40). C, Magnetic resonance image showing intracranial invasion of the tumor along the nerve pathway.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Cutaneous squamous cell carcinoma (CSCC) has a lifetime incidence of between 7% and 11%. It accounts for 20% to 25% of all nonmelanoma skin cancers, and is second only to basal cell carcinoma in terms of prevalence.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1–5</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Most CSCCs are benign and can be completely eradicated by surgery and other dermatological procedures. Accordingly, 5-year survival rates after surgical excision are in excess of 90%,<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> and mortality is around 1%.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> Nevertheless, there is a subgroup of CSCC associated with a higher frequency of lymph node metastasis and with high morbidity and mortality (<a class="elsevierStyleCrossRefs" href="#fig0005">Figs. 1-6</a>).<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7–10</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia><elsevierMultimedia ident="fig0020"></elsevierMultimedia><elsevierMultimedia ident="fig0025"></elsevierMultimedia><elsevierMultimedia ident="fig0030"></elsevierMultimedia><p id="par0015" class="elsevierStylePara elsevierViewall">The main aim of this article is to accurately define this subgroup of CSCC, which is known as high-risk CSCC. A clear definition will help to refine prognosis and improve the individualized care of patients with high-risk CSCC.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Definition of High-Risk CSCC</span><p id="par0020" class="elsevierStylePara elsevierViewall">In recent years, several authors have focused their research on analyzing differences between nonmetastatic and metastatic CSCC. The ultimate aim of such research was to predict which forms of CSCC are associated with an increased risk of locoregional and/or distant complications in order to be able to intervene promptly in patients at risk.</p><p id="par0025" class="elsevierStylePara elsevierViewall">The findings led to the concept of high-risk CSCC, which is defined as a squamous cell carcinoma lesion, clinically staged as N0, that extends through the basement membrane and is associated with a high risk of subclinical metastasis. CSCCs that do not this meet this definition are classified as low-risk.</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Defining Features of High-Risk CSCC</span><p id="par0030" class="elsevierStylePara elsevierViewall">The factors that define high-risk CSCC can be divided into 3 subgroups: clinical factors, histologic factors, and molecular factors.</p><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Clinical Factors</span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Personal History</span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Genetic Disorders</span><p id="par0035" class="elsevierStylePara elsevierViewall">Patients with genetic disorders associated with an increased risk of CSCC typically develop tumors with a high risk of malignant transformation. Examples of these disorders are xeroderma pigmentosum, epidermodysplasia verruciformis, oculocutaneous albinism, dyskeratosis congenita, and recessive dystrophic epidermolysis bullosa. This last condition is associated with the highest mortality in patients with concomitant CSCC, with 5-year survival rates of just 80% after a diagnosis of the skin tumor.<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4,11–13</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">CSCC Arising at the Site of a Pre-existing Lesion</span><p id="par0040" class="elsevierStylePara elsevierViewall">CSCCs that arise at the site of chronic skin damage, such as scars, slow-growing ulcers, burn sites, and chronic radiation dermatitis, have an increased risk of metastatic spread. This risk appears to be associated with a reduction in E-cadherin levels, which would favor the spread of atypical keratinocytes through the epidermis and into the dermis.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Immunosuppression and Transplantation</span><p id="par0045" class="elsevierStylePara elsevierViewall">Immune status is a predictor of prognosis in many neoplastic conditions. Immune system alterations, for example, play an important role in the development of skin cancers, such as Merkel cell carcinoma.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">Patients who undergo solid organ transplantation (SOT) have a 65-fold higher risk of developing CSCC than the general population; furthermore, CSCC is the most common nonmelanoma skin cancer in SOT recipients and is 3 times more common than basal cell carcinoma.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">Recurrence rates, locoregional metastasis, and survival in transplant recipients with CSCC vary depending on the organ transplanted. In the field of SOT, heart transplantation is considered to carry the highest risk of CSCC and its high-risk variant,<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> followed by, in decreasing order, lung, kidney, and liver transplantation. In the case of hematologic malignancies, the highest risk of both types of CSCC has been observed in patients with chronic lymphatic leukemia and small lymphocytic lymphoma.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">The cumulative incidence of CSCC increases progressively with the duration of immunosuppression, with observed rates of 7% after a year, 45% after 11 years, and 70% after 20 years. Furthermore, up to 66% of transplant recipients have been reported to develop a second CSCC after the first squamous cell carcinoma.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">CSCC recurs more frequently in immunosuppressed than in immunocompetent individuals (39% vs 15% in 5 years of follow-up),<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> and mortality is also higher (5% in transplant recipients vs 1% in immunocompetent individuals).<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> Organ transplant recipients with metastatic CSCC have a 3-year survival rate of 56%, which is similar to rates reported for patients with noncutaneous SCC of the head and neck.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">The fact that metastatic CSCC often has similar clinical characteristics (horizontal diameter of <<span class="elsevierStyleHsp" style=""></span>2<span class="elsevierStyleHsp" style=""></span>cm and vertical histologic thickness of <<span class="elsevierStyleHsp" style=""></span>2<span class="elsevierStyleHsp" style=""></span>mm) and favorable outcomes in immunosuppressed and immunocompetent individuals suggests that as yet unknown molecular alterations have a role in the high malignant potential of CSCC in immunosuppressed individuals.</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Human Immunodeficiency Virus Infection</span><p id="par0075" class="elsevierStylePara elsevierViewall">Human immunodeficiency virus (HIV) infection, regardless of disease stage or immune status, appears to be a marker of poor prognosis in CSCC. This possibility was suggested by Nguyen et al.<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> in a retrospective study of 10 consecutively recruited HIV-positive patients aged between 31 and 54 years with high-risk CSCC. Five of the 10 patients died within 7 years of the initial diagnosis, and local recurrence, metastasis, and survival were not correlated with the number of opportunistic infections or with CD4<span class="elsevierStyleSup">+</span> T cell count.</p></span></span></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Clinical Characteristics of CSCC</span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Lesion Size</span><p id="par0080" class="elsevierStylePara elsevierViewall">The size of primary lesions in CSCC has been described by many authors as being an important predictor of lymph node metastasis.<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">12,22–25</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">Data from the first prospective study of CSCC, involving over 1000 patients, showed that horizontal tumor size was an independent risk factor for metastasis. Specifically, the risk of metastatic spread was 0.01% in lesions measuring 2<span class="elsevierStyleHsp" style=""></span>cm or less in diameter and 10% in larger lesions. In the second group, 7% of patients with a tumor size of between 2 and 5<span class="elsevierStyleHsp" style=""></span>cm developed metastasis compared with 20% of those with a tumor size of over 5<span class="elsevierStyleHsp" style=""></span>cm.<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">26–29</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">Based on our experience and on data from the literature, we consider a horizontal size of 2<span class="elsevierStyleHsp" style=""></span>cm to be the cutoff for increased risk of lymph node metastasis in CSCC. A smaller size, by contrast, would exert a protective effect, meaning that there would not be a risk of distant metastasis in immunocompetent patients with a tumor diameter of less than 2<span class="elsevierStyleHsp" style=""></span>cm.</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Lesion Site</span><p id="par0095" class="elsevierStylePara elsevierViewall">Lesion sites with the highest incidence (20%-30%) of metastatic CSCC are the external ear (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>) and the nonglabrous lip (<a class="elsevierStyleCrossRef" href="#fig0030">Fig. 6</a>).<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">19,30</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">Middle-risk sites include the scalp (mainly the temple), the perineal and genital areas, and acral sites (hands and feet).<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6,31</span></a> It is also important to consider that areas not exposed to sunlight, such as the perineum, the sacral region, and the soles of the feet, have a proportionally higher rate of metastasis than chronically sun-exposed areas.<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a></p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Recurrence</span><p id="par0105" class="elsevierStylePara elsevierViewall">Tumor recurrence tends to be associated with poor prognosis in skin cancers.</p><p id="par0110" class="elsevierStylePara elsevierViewall">Comparative analysis of lymph node metastasis in recurrent CSCC (15%) and nonrecurrent CSCC (2%) (<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>.001) has led to the conclusion that tumor recurrence is an important risk factor in CSCC.<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">Clayman et al.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> observed an association between CSCC recurrence and tumor size, and reported that large tumors were associated with a significantly higher rate of recurrence (2.4<span class="elsevierStyleHsp" style=""></span>vs 1.5<span class="elsevierStyleHsp" style=""></span>cm, <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>.0001). They also found recurrent lesions to be associated with a higher rate of perineural invasion (PNI) (24% vs 10%), lymphovascular invasion (17% vs 8%), and subcutaneous tissue invasion (30% vs 10%).<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">Recurrence has also been significantly associated with positive margins in surgically excised CSCC, with recurrent tumors—and consequently increased risk of metastasis—observed in up to 50% of patients with positive margins.<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a></p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Human Papillomavirus Infection</span><p id="par0125" class="elsevierStylePara elsevierViewall">β-Human papillomaviruses (HPVs) are the most common type of HPVs involved in CSCC. Numerous studies have demonstrated a relationship between β-HPVs and CSCC, above all in immunosuppressed patients, although these viruses may also act as a cofactor with UV radiation in immunocompetent patients. Nevertheless, because β-HPVs appear to be involved in the etiology and pathogenesis of CSCC and not in metastatic spread, they are not considered prognostic factors.α-HPVs associated with CSCC of the genital region, the head and the neck, and acral sites might be associated with a higher risk of metastasis as they alter regulatory mechanisms, such as p53 and the retinoblastoma gene/<span class="elsevierStyleItalic">p16</span>. Most studies of <span class="elsevierStyleItalic">p16</span> in CSCC have reported loss of <span class="elsevierStyleItalic">p16</span> expression to be associated with the transformation of in situ CSCC to invasive CSCC but not with a higher risk of metastatic spread. As mentioned previously, only <span class="elsevierStyleItalic">p16</span>-positive cases associated with the presence of α-HPVs would carry an increased risk of metastasis.<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">34–39</span></a></p></span></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Histologic Features of CSCC</span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Tumor Thickness and Clark Level</span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Tumor Thickness</span><p id="par0130" class="elsevierStylePara elsevierViewall">Tumor thickness is currently considered to be the most important independent predictor of metastasis in CSCC, with greater thickness associated with higher risk.<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">26,32</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">Based on data from the largest prospective series of CSCC to date, conducted by Brantsch et al.,<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> CSCC can be divided into 3 risk groups (low-risk, middle-risk, and high-risk) based on tumor thickness. Patients in the low-risk group have tumors with a thickness of 2<span class="elsevierStyleHsp" style=""></span>mm or less, and have virtually no risk of distant metastasis. Those in the middle-risk group have a tumor thickness of between 2 and 6<span class="elsevierStyleHsp" style=""></span>mm, which is associated with a 4% increased risk of metastasis in 5 years of follow-up. Finally, those in the high-risk group have tumors with a thickness of 6<span class="elsevierStyleHsp" style=""></span>mm or more and a 16% increased risk of metastasis.</p><p id="par0140" class="elsevierStylePara elsevierViewall">Based on data from later studies and on our own experience, we believe that a cutoff a 4<span class="elsevierStyleHsp" style=""></span>mm provides the best sensitivity for separating low-risk CSCC from CSCC with a high risk of metastatic spread. Tumors with a thickness of less than 2<span class="elsevierStyleHsp" style=""></span>mm, by contrast, would be associated with virtually no risk of distant disease.</p></span></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Degree of Tumor Differentiation</span><p id="par0145" class="elsevierStylePara elsevierViewall">Degree of tumor differentiation is another important prognostic factor in CSCC and other neoplastic diseases.</p><p id="par0150" class="elsevierStylePara elsevierViewall">In a study of 571 patients with CSCC, a significant difference was observed for the rate of metastasis between lesions with a high degree of differentiation and other lesions (17% vs 4%, <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>.004),<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> and in another study involving a large number of patients, high-grade CSSS was associated with a greater risk of malignant transformation than other types of CSCC (44% vs 5%, <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>.01).<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a></p><p id="par0155" class="elsevierStylePara elsevierViewall">Tumor differentiation is also associated with an increased risk of early recurrence. Poorly differentiated CSCCs have a 2.9-fold increased risk of distant metastasis and death compared with well-differentiated CSCCs, although well-differentiated tumors may also be associated with the development of advanced disease.<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">12,40</span></a></p><p id="par0160" class="elsevierStylePara elsevierViewall">Finally certain histologic subtypes of CSCC (acantholytic, adenoid, isolated cell pattern) should be considered as a risk factor in combination with tumor differentiation (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>).</p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Histologically Positive Surgical Margins</span><p id="par0165" class="elsevierStylePara elsevierViewall">Incomplete tumor excision—and consequently—disease persistence, is a predictor of poor prognosis in CSCC. Disease, and with it an increased risk of metastasis, recurs in up to 50% of patients with histologically positive margins following surgical excision.<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a> Recurrence following tumor excision appears to be related to a risk of subclinical tumor progression, which would, in turn, favor metastasis.<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a></p><p id="par0170" class="elsevierStylePara elsevierViewall">The decision to take a watch and wait approach with patients with incompletely excised CSCCs, i.e., with a pathology report showing the involvement of 1 or more margins, should be weighed up carefully given the high rate of lymph node disease in recurrent CSCC. Several studies have shown a history of disease recurrence in between 45% and 51% of patients with CSCC and lymph node involvement.<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">12,22,42,43</span></a></p><p id="par0175" class="elsevierStylePara elsevierViewall">Consequently, all patients with CSCC should undergo surgery until disease-free margins are achieved,<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">44</span></a> and if this is not possible, other treatments, mainly radiation therapy, should be considered.</p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Perineural Invasion</span><p id="par0180" class="elsevierStylePara elsevierViewall">PNI occurs in approximately 5% to 10% of patients with CSCC and is usually detected as an incidental finding.<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6,45</span></a> Nonetheless, histologic evidence of PNI appears to be associated with a significant increase in disease recurrence and distant metastasis rates.<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6,45</span></a> A study performed at the Anderson clinic in Texas, United States, showed that compared with CSCC patients without PNI, those with PNI had a significantly increased frequency of regional metastasis (35% vs 15%, <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>.005) and distant metastasis (15% vs 3.3%, <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>.005).<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">46</span></a>PNI is important not only because of the risk of locoregional spread, but also because of disease caused by perineural spread through the cranial nerves, mostly the facial and the trigeminal nerves (<a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>) and because PNI is associated with worse 3-year survival in CSCC (64% in patients with PNI vs 91% in those without, <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>.002).<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">47–49</span></a></p><p id="par0185" class="elsevierStylePara elsevierViewall">The evaluation of PNI risk in CSCC should vary depending on the thickness of the nerves affected and the presence of clinical and/or radiologic signs of invasion. Infiltration of nerves with a diameter of less than 0.1<span class="elsevierStyleHsp" style=""></span>mm, for instance, is associated with a low risk of local or distant complications, while invasion of nerves measuring more than 0.1<span class="elsevierStyleHsp" style=""></span>mm in diameter has been associated with poor short-term and long-term prognosis (CSCC-specific death of 0% in individuals with PNI of nerves<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.1<span class="elsevierStyleHsp" style=""></span>mm vs 32% in those with PNI of nerves<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>0.1<span class="elsevierStyleHsp" style=""></span>mm, <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>.003).<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">50</span></a></p><p id="par0190" class="elsevierStylePara elsevierViewall">PNI can manifest as an incidental finding on histology, with or without accompanying symptoms. Symptoms include pain on palpation, regional paresthesia, and acute intermittent or shooting pain. Based on data from the University of Florida College of Medicine in the United States, it has been suggested that patients with asymptomatic PNI not visible on radiography have a better prognosis than those with clinical or radiological evidence of PNI (5-year local control rate of 87% vs 55%, <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>.006).<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">51</span></a></p></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Lymphovascular Invasion</span><p id="par0195" class="elsevierStylePara elsevierViewall">Recent studies have suggested that lymphovascular invasion may increase the risk of metastasis in CSCC. Moore et al.<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a> defined lymphovascular invasion as an independent predictor of lymph node metastasis in a multivariate analysis (OR, 7.54, <span class="elsevierStyleItalic">P</span>.<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>.00001), and reported that 40% of patients with metastasis had lymphovascular invasion, compared with just 8% of those without. The prognostic significance of lymphovascular invasion, however, has been questioned by some authors.<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">12,50</span></a></p><p id="par0200" class="elsevierStylePara elsevierViewall">The implications of CSCC in dermal lymph vessels, which has been rarely described, are unknown, but it may increase the risk of recurrence and explain in-transit metastasis (<a class="elsevierStyleCrossRef" href="#fig0025">Fig. 5</a>).</p></span><span id="sec0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Other Factors</span><p id="par0205" class="elsevierStylePara elsevierViewall">Other factors that have been proposed as possible prognostic factors in CSCC are peritumoral actinic keratosis,<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">37–39</span></a> Clark level,<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">37–39</span></a> Ki67 expression, desmoplasia,<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">26,38</span></a> and the presence of a tumor inflammatory response with mainly eosinophils and plasma cells. The true prognostic value, however, of these factors, is still a matter of debate and needs to be investigated in further studies.</p></span></span><span id="sec0115" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Molecular Markers in CSCC</span><p id="par0210" class="elsevierStylePara elsevierViewall">Seventy percent of patients with metastatic CSCC have 1 or more of the defining features of high-risk CSCC described above. However, between 20% and 30% do not (those with thin, small CSCCs), suggesting that other, as yet unknown variables, probably have an important role in the pathogenesis of high-risk CSCC.<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">12,51</span></a> Of relevance in this group are certain molecular alterations that appear to be associated with a subgroup of CSCCs with more aggressive behavior. Specifically, it has been suggested that mutations in genes expressing the epidermal growth factor receptor (EFGR), and to a lesser extent, <span class="elsevierStyleItalic">p16</span> and <span class="elsevierStyleItalic">CKS1B</span> mutations, are the main molecular alterations involved in high-risk CSCC; confirmation of this would have important therapeutic implications.<a class="elsevierStyleCrossRefs" href="#bib0260"><span class="elsevierStyleSup">52–56</span></a></p><span id="sec0120" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Epidermal Growth Factor Receptor</span><p id="par0215" class="elsevierStylePara elsevierViewall">Tumors that overexpress EGFR tend to be associated with more advanced disease, a greater risk of lymph node metastasis, and higher rates of early recurrence and shorter survival in various malignant disorders, including squamous cell carcinoma of the mucosa of the upper aerodigestive tract.<a class="elsevierStyleCrossRefs" href="#bib0285"><span class="elsevierStyleSup">57–62</span></a></p><p id="par0220" class="elsevierStylePara elsevierViewall">Just 1 small study has analyzed the importance of <span class="elsevierStyleItalic">EFGR</span> mutations in the prognosis of CSCC. In an analysis of 15 cases of metastatic CSCC in the head and neck region, EGFR overexpression was significantly associated with metastatic potential, with strong overexpression found in 79% of patients with metastatic disease and in just 36% of those without.<a class="elsevierStyleCrossRefs" href="#bib0310"><span class="elsevierStyleSup">62,63</span></a> Overexpression was independent of gene amplification. Alternative mechanisms that would explain the increase in EGFR expression include increased messenger RNA (mRNA) transcription, activating receptor mutations, increased levels of receptor ligands, and increased expression of heterologous receptors, such as Her-2.<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">62</span></a> With respect to Her-2, abnormal Her-2 expression and alterations in the gene encoding Her-2 (chromosome 17) have been analyzed in patients with EGFR overexpression.<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">63</span></a> While the authors did not observe Her-2 overexpression in any of the 27 cases they analyzed, they did detect Her-2 polysomy, which, like in breast cancer, was not associated with increased overexpression. The absence of overexpression leads to treatment failure with anti-Her2 drugs, such as trastuzumab.<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">64</span></a> Although the significance of this last finding has not yet been clarified, the detection of Her-2 polysomy may have an impact on predicting therapeutic response to tyrosine kinase inhibitors.<a class="elsevierStyleCrossRefs" href="#bib0305"><span class="elsevierStyleSup">61,62</span></a> Nevertheless, EGFR overexpression has only been observed in up 65% to 75% of metastatic CSCCs, adding strength to the hypothesis that multiple factors are involved in the etiology of this form of CSCC.<a class="elsevierStyleCrossRefs" href="#bib0310"><span class="elsevierStyleSup">62,63</span></a></p></span><span id="sec0125" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145"><span class="elsevierStyleItalic">p16</span></span><p id="par0225" class="elsevierStylePara elsevierViewall">Data from several studies support a correlation between <span class="elsevierStyleItalic">p16</span> overexpression and degree of malignancy, suggesting that <span class="elsevierStyleItalic">p16</span> expression (like <span class="elsevierStyleItalic">p53</span> expression) might be a biomarker of tumor progression.<a class="elsevierStyleCrossRefs" href="#bib0320"><span class="elsevierStyleSup">64,65</span></a> Other authors, however, have reported a correlation between loss of <span class="elsevierStyleItalic">p16</span> expression and high-risk CSCC.<a class="elsevierStyleCrossRefs" href="#bib0330"><span class="elsevierStyleSup">66,67</span></a> In 1 of these studies, Chang et al.<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">67</span></a> detected a correlation between loss of <span class="elsevierStyleItalic">p16</span> expression and the development of metastasis, suggesting that loss of this protein might be a predictor of poor prognosis.</p><p id="par0230" class="elsevierStylePara elsevierViewall">The explanation behind why elevated levels of p16 might be associated with poor prognosis could be related to the coexistence of HPV infection. However, with the exception of epidermodysplasia verruciformis in immunocompromised individuals and CSCC in areas other than the head and neck, the role of HPV in the development of CSCC is still a matter of debate.</p><p id="par0235" class="elsevierStylePara elsevierViewall">Another possible explanation for increased <span class="elsevierStyleItalic">p16</span> levels might be <span class="elsevierStyleItalic">p16</span> UV-induced changes. The presence of a mutated <span class="elsevierStyleItalic">p16</span>, with a long half-life but with a loss of anti-oncogenic function, would explain the increased risk of malignancy.</p></span><span id="sec0130" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150"><span class="elsevierStyleItalic">CSK1B</span></span><p id="par0240" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">CKS1B</span> gene encodes the cyclin-dependent kinases regulatory subunit 1. The protein binds to the catalytic subunit of cyclin-dependent kinases and play an essential role in their biologic function. <span class="elsevierStyleItalic">CKS1B</span> mRNA appears to be expressed in different patterns throughout the cell cycle of HeLa cells, indicating a specific role for the encoded protein. The peptide plays a role in cell-cycle regulation by interacting with other proteins, mainly SKP2 and CDKN1B.<a class="elsevierStyleCrossRefs" href="#bib0340"><span class="elsevierStyleSup">68,69</span></a></p><p id="par0245" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">CKS1B</span> appears to have a critical role in tumor progression in CSCC. In a study of 43 CSCCs and 26 actinic keratoses, Salgado et al.<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">70</span></a> analyzed CKS1B gene and protein status using fluorescence in situ hybridization and immunohistochemical analysis, and reported that chromosome 1 polysomy was a frequent event in both CSCC (30 of 43 cases) and actinic keratosis (13 of 23 cases). <span class="elsevierStyleItalic">CKS1B</span> amplification, observed in 4 cases (9.3%), was associated in all cases with aggressive tumor behavior (PNI, lymph node spread, and CSCC in transplant recipients).</p><p id="par0250" class="elsevierStylePara elsevierViewall">In conclusion, <span class="elsevierStyleItalic">CKS1B</span> amplifications might be a marker of high-risk CSCC.</p></span><span id="sec0135" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0155">Towards a New Prognostic Classification of CSCC</span><p id="par0255" class="elsevierStylePara elsevierViewall">CSCC is one of the most common cancers in the world and, as such, responsible for many deaths.</p><p id="par0260" class="elsevierStylePara elsevierViewall">The ability to clearly differentiate between high-risk and low-risk CSCC would appear to be key in improving survival and optimizing management of the disease according to risk.</p><p id="par0265" class="elsevierStylePara elsevierViewall">The American Joint Committee on Cancer (AJCC) recently modified its staging system for CSCC.<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">71</span></a> The main changes are summarized in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>. One of the most significant changes was the introduction of a list of high-risk clinical and histologic features that modify the T designation, regardless of tumor size. These features include a tumor thickness of more than 2<span class="elsevierStyleHsp" style=""></span>mm, a Clark level of IV or more, location on the external ear or nonglabrous lip, PNI, bone involvement, and poor tumor differentiation.<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">71</span></a> Based on our experience, however, this list is not sufficient to accurately define high-risk CSCC. While anatomic location and PNI are good prognostic predictors, the situation with tumor differentiation and Clark level is less clear. Furthermore, the establishment of a cutoff of 2<span class="elsevierStyleHsp" style=""></span>mm for differentiating between low-risk and high-risk CSCC deserves special mention. A high proportion of CSCCs are thicker than 2<span class="elsevierStyleHsp" style=""></span>mm, meaning that this cutoff has high sensitivity but very poor specificity in terms of predicting risk. Finally, the new AJCC staging system does not include important factors such as immune system status, tumor recurrence, or lymphovascular invasion.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0270" class="elsevierStylePara elsevierViewall">In its latest update, published in 2010, the National Comprehensive Cancer Network (NCNN) proposed that the treatment of CSCC should be guided by a series of variables. It lists a set of risk factors and considers 2 possible scenarios. First, it recommends that all CSCCs with any of the risk factors shown in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> should be surgically excised with safety margins of 10<span class="elsevierStyleHsp" style=""></span>mm or with Mohs micrographic surgery. And second, it recommends that patients with 3 or more of these factors should receive special attention. In our opinion, the NCCN guidelines also have shortcomings. A high percentage of patients have at least 1 of the factors shown in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>, meaning that suggesting treatment modifications based on this alone would appear to be quite a broad recommendation. The second scenario is even more confusing, as the NCNN considers that patients with 3 or more of the risk factors shown in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> should receive special treatment. However, there is no mention of exactly how treatment or follow-up should be modified.</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0140" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0160">Proposal for Defining and Managing High-Risk CSCC</span><span id="sec0145" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0165">Defining High-Risk CSCC</span><p id="par0275" class="elsevierStylePara elsevierViewall">In our opinion, the main difficulty with attempts to define high-risk CSCC to date is the fact that most studies have identified the risk factors discussed in this article in isolation. There have been no analyses of their cumulative effects.</p><p id="par0280" class="elsevierStylePara elsevierViewall">Based on data systematically stored in a database at our hospital, a specialist skin cancer center, and data from the literature, we designed a system to identify the cumulative value of each of the prognostic factors that define high-risk CSCC. We divided risk factors into major and minor criteria and created a scoring system to differentiate between low risk and high-risk CSCC (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>). We then considered high-risk CSCC to be any CSCC with <span class="elsevierStyleItalic">a)</span> 3 major criteria, <span class="elsevierStyleItalic">b)</span> 2 major and 2 minor criteria, and <span class="elsevierStyleItalic">c)</span> 1 major criterion and 4 minor criteria. Our proposed definition of high-risk CSCC, which has important prognostic and therapeutic implications, needs to be corroborated in prospective studies that analyze the different prognostic factors for CSCC from a global perspective.</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></span><span id="sec0150" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0170">Optimizing the Management of High-Risk CSCC</span><p id="par0285" class="elsevierStylePara elsevierViewall">Our provisional definition of high-risk CSCC would lead to a more aggressive treatment approach and much closer follow-up<span class="elsevierStyleItalic">.</span></p></span><span id="sec0155" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0175">Treating High-Risk CSCC</span><p id="par0290" class="elsevierStylePara elsevierViewall">The treatment of choice for high-risk CSCC is surgical excision. In conventional excision, safety margins should range from 4<span class="elsevierStyleHsp" style=""></span>mm for tumors measuring 2<span class="elsevierStyleHsp" style=""></span>cm or less to 6<span class="elsevierStyleHsp" style=""></span>mm for larger tumors. Mohs micrographic surgery is the treatment of choice for tumors in locations with a risk of cosmetic or functional sequelae and for recurrent tumors<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">42,71–75</span></a> (<a class="elsevierStyleCrossRef" href="#fig0035">Fig. 7</a>).</p><elsevierMultimedia ident="fig0035"></elsevierMultimedia><p id="par0295" class="elsevierStylePara elsevierViewall">Radiation therapy, which is considered by several authors to be a first-line treatment for high-risk CSCC, produces poorer outcomes than surgical excision and is associated with a high percentage of earlier and more aggressive recurrence and considerable direct and indirect costs. Furthermore, it can cause iatrogenic carcinogenesis in the irradiated area. Radiation therapy, thus, should be reserved for patients who are not candidates for surgery, either because of poor general health status or the inability to achieve disease-free margins by surgical techniques.<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">42,71–73</span></a></p></span></span><span id="sec0160" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0180">Additional Strategies for the Management of High-Risk CSCC</span><p id="par0300" class="elsevierStylePara elsevierViewall">Additional management strategies are necessary in patients with high-risk CSCC given the high associated risk of lymph node invasion and mortality.</p></span><span id="sec0165" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0185">Sentinel Lymph Node Biopsy</span><p id="par0305" class="elsevierStylePara elsevierViewall">In 2006, Ross et al.<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">74</span></a> concluded that sentinel lymph node biopsy (SLNB) was associated with a reliable diagnosis of locoregional invasion and with low morbidity in CSCC provided that the surgeon had sufficient experience. This is also the case with cutaneous melanoma.</p><p id="par0310" class="elsevierStylePara elsevierViewall">Indeed, SLNB provides better results in CSCC than in melanoma as the early detection of lymph node involvement in high-risk CSCC leads to a significant reduction in mortality.</p><p id="par0315" class="elsevierStylePara elsevierViewall">We therefore believe that SLNB is justified in CSCCs defined as high-risk according to our provisional definition (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a> and <a class="elsevierStyleCrossRef" href="#fig0030">Fig. 6</a>).</p></span><span id="sec0170" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0190">Follow-up in Patients With a History of High-Risk CSCC</span><p id="par0320" class="elsevierStylePara elsevierViewall">High-risk CSCC is associated with a higher risk of recurrence and lymph node metastasis than low-risk CSCC in the first 5 years after treatment. The early detection of recurrence and lymph node metastasis is of supreme importance, as has been shown in multiple studies. Of particular relevance in this respect is a study by Ebrahimi et al.<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">75</span></a> that showed that in patients with CSCC and lymph node involvement, a single diseased lymph node measuring 3<span class="elsevierStyleHsp" style=""></span>cm or less in diameter without extracapsular nodal spread had a low risk of distant metastasis and mortality.</p><p id="par0325" class="elsevierStylePara elsevierViewall">We therefore propose a follow-up approach based on risk (<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>), whereby patients with high-risk CSCC should be followed very closely during the first 5 years after surgery. Close monitoring is particularly important during the first 24 months, which is when the risk of lymph node invasion is highest.</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia></span></span></span><span id="sec0175" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0195">Conclusions</span><p id="par0330" class="elsevierStylePara elsevierViewall">The incidence of CSCC has increased considerably in recent years. CSCC is the second most common nonmelanocytic skin tumor in the general population and causes a similar number of deaths as melanoma.</p><p id="par0335" class="elsevierStylePara elsevierViewall">A clear definition of epidemiological, clinical, and histologic factors of CSCCs with high rates of systemic spread (high-risk CSCC) will lead to a different management approach when dealing with this subgroup of patients. Such an approach should include more exhaustive staging at the time of diagnosis, more aggressive treatment, including SLNB, and closer follow-up. Individualized care will help to reduce the mortality associated with this malignant tumor.</p><p id="par0340" class="elsevierStylePara elsevierViewall">In the not-so-distant future, the characterization of the molecular biology of high-risk CSCC and the analysis of genetic differences with respect to low-risk CSCC will probably help to define the malignant potential of this high-risk variant and allow the optimization of treatment via drugs that act on key molecular targets in the pathogenesis of squamous cell carcinoma.</p></span><span id="sec0180" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0200">Conflicts of Interest</span><p id="par0345" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:10 [ 0 => array:2 [ "identificador" => "xres197913" "titulo" => "Abstract" ] 1 => array:2 [ "identificador" => "xpalclavsec184663" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xres197914" "titulo" => "Resumen" ] 3 => array:2 [ "identificador" => "xpalclavsec184664" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Definition of High-Risk CSCC" ] 6 => array:3 [ "identificador" => "sec0015" "titulo" => "Defining Features of High-Risk CSCC" "secciones" => array:4 [ 0 => array:3 [ "identificador" => "sec0020" "titulo" => "Clinical Factors" "secciones" => array:1 [ 0 => array:3 [ "identificador" => "sec0025" "titulo" => "Personal History" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0030" "titulo" => "Genetic Disorders" ] 1 => array:2 [ "identificador" => "sec0035" "titulo" => "CSCC Arising at the Site of a Pre-existing Lesion" ] 2 => array:2 [ "identificador" => "sec0040" "titulo" => "Immunosuppression and Transplantation" ] 3 => array:2 [ "identificador" => "sec0045" "titulo" => "Human Immunodeficiency Virus Infection" ] ] ] ] ] 1 => array:3 [ "identificador" => "sec0050" "titulo" => "Clinical Characteristics of CSCC" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0055" "titulo" => "Lesion Size" ] 1 => array:2 [ "identificador" => "sec0060" "titulo" => "Lesion Site" ] 2 => array:2 [ "identificador" => "sec0065" "titulo" => "Recurrence" ] 3 => array:2 [ "identificador" => "sec0070" "titulo" => "Human Papillomavirus Infection" ] ] ] 2 => array:3 [ "identificador" => "sec0075" "titulo" => "Histologic Features of CSCC" "secciones" => array:6 [ 0 => array:3 [ "identificador" => "sec0080" "titulo" => "Tumor Thickness and Clark Level" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "sec0085" "titulo" => "Tumor Thickness" ] ] ] 1 => array:2 [ "identificador" => "sec0090" "titulo" => "Degree of Tumor Differentiation" ] 2 => array:2 [ "identificador" => "sec0095" "titulo" => "Histologically Positive Surgical Margins" ] 3 => array:2 [ "identificador" => "sec0100" "titulo" => "Perineural Invasion" ] 4 => array:2 [ "identificador" => "sec0105" "titulo" => "Lymphovascular Invasion" ] 5 => array:2 [ "identificador" => "sec0110" "titulo" => "Other Factors" ] ] ] 3 => array:3 [ "identificador" => "sec0115" "titulo" => "Molecular Markers in CSCC" "secciones" => array:8 [ 0 => array:2 [ "identificador" => "sec0120" "titulo" => "Epidermal Growth Factor Receptor" ] 1 => array:2 [ "identificador" => "sec0125" "titulo" => "p16" ] 2 => array:2 [ "identificador" => "sec0130" "titulo" => "CSK1B" ] 3 => array:2 [ "identificador" => "sec0135" "titulo" => "Towards a New Prognostic Classification of CSCC" ] 4 => array:3 [ "identificador" => "sec0140" "titulo" => "Proposal for Defining and Managing High-Risk CSCC" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0145" "titulo" => "Defining High-Risk CSCC" ] 1 => array:2 [ "identificador" => "sec0150" "titulo" => "Optimizing the Management of High-Risk CSCC" ] 2 => array:2 [ "identificador" => "sec0155" "titulo" => "Treating High-Risk CSCC" ] ] ] 5 => array:2 [ "identificador" => "sec0160" "titulo" => "Additional Strategies for the Management of High-Risk CSCC" ] 6 => array:2 [ "identificador" => "sec0165" "titulo" => "Sentinel Lymph Node Biopsy" ] 7 => array:2 [ "identificador" => "sec0170" "titulo" => "Follow-up in Patients With a History of High-Risk CSCC" ] ] ] ] ] 7 => array:2 [ "identificador" => "sec0175" "titulo" => "Conclusions" ] 8 => array:2 [ "identificador" => "sec0180" "titulo" => "Conflicts of Interest" ] 9 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2011-07-12" "fechaAceptado" => "2011-12-04" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec184663" "palabras" => array:2 [ 0 => "Cutaneous squamous cell carcinoma" 1 => "High-risk cutaneous squamous cell carcinoma" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec184664" "palabras" => array:2 [ 0 => "Carcinoma epidermoide cutáneo" 1 => "Carcinoma epidermoide cutáneo de alto riesgo" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">With a lifetime incidence of approximately 10% in the general population, cutaneous squamous cell carcinoma (CSCC) is the second most common type of nonmelanoma skin cancer.</p><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Most CSCCs are benign and can be completely eradicated by surgery or other dermatological procedures. There is, however, a subgroup associated with an increased likelihood of lymph node metastases and, therefore, with high morbidity and mortality.</p><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">This article analyzes the various factors that define aggressive CSCC. We propose a method for defining high-risk SCC on the basis of a series of major and minor criteria. This method will allow better prognostic evaluation and enable personalized management of patients with high-risk SCC, possibly leading to improved overall survival.</p>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">El carcinoma epidermoide cutáneo, con una incidencia en la población general de aproximadamente un 10% a lo largo de la vida, es la segunda neoplasia más frecuente dentro del grupo del cáncer cutáneo no melanoma.</p><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">La mayoría de los carcinomas epidermoides cutáneos muestran un comportamiento benigno y pueden ser completamente erradicados mediante cirugía y otros procedimientos dermatológicos. Sin embargo, existe un subgrupo de esta entidad que se asocia con una mayor capacidad de desarrollar metástasis nodal y, por tanto, con una elevada morbimortalidad.</p><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">En el presente artículo se analizan los diferentes factores que definen al carcinoma epidermoide cutáneo de comportamiento agresivo. Proponemos un método de definición del carcinoma epidermoide de alto riesgo basado en el establecimiento de una serie de criterios mayores y menores. Este hecho supondrá una mejor evaluación pronóstica y un manejo personalizado de este grupo de enfermos, que puede resultar en un aumento de la supervivencia global.</p>" ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0030">Please cite this article as: Please cite this article as: Martorell-Calatayud A, et al. Carcinoma epidermoide cutáneo: definiendo la variante de alto riesgo. Actas Dermosifiliogr. 2013;104:367-79.</p>" ] ] "multimedia" => array:11 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 899 "Ancho" => 1600 "Tamanyo" => 278389 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">A, Cutaneous squamous cell carcinoma on the external ear of a 70-year-old patient. B, Fleshy tumor invading the external auditory canal. C and D, Histology showing a poorly differentiated squamous cell tumor with lymphovascular invasion (C, hematoxylin-eosin, original magnification x40; D, Immunostaining with CD31, original magnification x100); E, Parotid gland with nodular tumor. F, The parotid tumor is formed by a proliferation of poorly differentiated squamous cells in a pattern similar to that of the primary tumor (original magnification, hematoxylin-eosin, x40).</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 883 "Ancho" => 1400 "Tamanyo" => 172364 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">A and B, Two patients, aged 67 and 69 years, respectively, treated for high-risk squamous cell carcinoma on the scalp (A) and the temple (B). The 2 patients developed invasion of the upper cervical lymph nodes in the second year of follow-up.</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" => 841 "Ancho" => 1600 "Tamanyo" => 437692 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Different histologic subtypes associated with high-risk cutaneous squamous cell carcinoma. A, Isolated-cell pattern (hematoxylin-eosin, original magnification x40). B and C, Squamous cell carcinoma with perineural invasion (nerves ><span class="elsevierStyleHsp" style=""></span>0.1<span class="elsevierStyleHsp" style=""></span>mm) (hematoxylin-eosin, original magnification x40 [B] and x100 [C]). D, Squamous cell carcinoma with marked lymphovascular invasion (hematoxylin-eosin, original magnification x100). E, Adenoid squamous cell carcinoma (hematoxylin-eosin, original magnification x40). F, Acantholytic squamous cell carcinoma (hematoxylin-eosin, original magnification x40).</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" => 461 "Ancho" => 1500 "Tamanyo" => 196218 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">A, Perineural invasion detected incidentally during surgery. B, Histology showing invasion of the nerve trunk (diameter, ><span class="elsevierStyleHsp" style=""></span>0.1<span class="elsevierStyleHsp" style=""></span>mm) by atypical squamous cells (hematoxylin-eosin, original magnification x40). C, Magnetic resonance image showing intracranial invasion of the tumor along the nerve pathway.</p>" ] ] 4 => array:7 [ "identificador" => "fig0025" "etiqueta" => "Figure 5" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr5.jpeg" "Alto" => 611 "Ancho" => 1500 "Tamanyo" => 222811 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Carcinomatous lymphangitis secondary to squamous cell carcinoma previously excised from the left temple. A, Multiple papulous vesicles on the left temple. B and C, Invasion of lymph vessels by atypical squamous cells (B, Hematoxylin-eosin, original magnification x40; C, Immunostaining with D2-40, original magnification x40).</p>" ] ] 5 => array:7 [ "identificador" => "fig0030" "etiqueta" => "Figure 6" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr6.jpeg" "Alto" => 896 "Ancho" => 1600 "Tamanyo" => 325081 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">High-risk squamous cell carcinoma studied by sentinel lymph node biopsy. A, Squamous cell carcinoma of the lower lip in a 65-year-old man. B and C, Atypical squamous cell proliferation with acantholysis and perineural invasion. D-F, Invasion of sentinel lymph node by atypical squamous cells (hematoxylin-eosin, original magnification x40 [D] and x100 [E]; immunostaining with pankeratin, original magnification x100 [F]).</p>" ] ] 6 => array:7 [ "identificador" => "fig0035" "etiqueta" => "Figure 7" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr7.jpeg" "Alto" => 1608 "Ancho" => 2167 "Tamanyo" => 251729 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Treatment algorithm for high-risk squamous cell carcinoma; CT indicates computed tomography; MMS, Mohs micrographic surgery; MRI, magnetic resonance imaging; PNI, perineural invasion.</p>" ] ] 7 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "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"><td 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" style="border-bottom: 2px solid black">Factor \t\t\t\t\t\t\n \t\t\t\t</td><td 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" style="border-bottom: 2px solid black">6th Edition \t\t\t\t\t\t\n \t\t\t\t</td><td 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" style="border-bottom: 2px solid black">7th Edition \t\t\t\t\t\t\n \t\t\t\t</td><td 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" style="border-bottom: 2px solid black">Comment \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">T category \t\t\t\t\t\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">T1:<span class="elsevierStyleHsp" style=""></span>≤<span class="elsevierStyleHsp" style=""></span>2<span class="elsevierStyleHsp" style=""></span>cmT2:<span class="elsevierStyleHsp" style=""></span> 2-5<span class="elsevierStyleHsp" style=""></span>cmT3:<span class="elsevierStyleHsp" style=""></span> ><span class="elsevierStyleHsp" style=""></span>5<span class="elsevierStyleHsp" style=""></span>cm \t\t\t\t\t\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">T1:<span class="elsevierStyleHsp" style=""></span>≤<span class="elsevierStyleHsp" style=""></span>2<span class="elsevierStyleHsp" style=""></span>cmT2:<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>2<span class="elsevierStyleHsp" style=""></span>cm \t\t\t\t\t\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">No evidence regarding usefulness of cutoff of 5<span class="elsevierStyleHsp" style=""></span>cm \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Histologic grade \t\t\t\t\t\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">Not included \t\t\t\t\t\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">Risk factor (poorly differentiated tumor) \t\t\t\t\t\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">Degree of differentiation described as a risk feature in CSCC \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">High-risk factors \t\t\t\t\t\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">Not included \t\t\t\t\t\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">Inclusion of risk factors that modify the T designation (elevated by 1 level in patients with ≥<span class="elsevierStyleHsp" style=""></span>2 factors) \t\t\t\t\t\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">Factors include:- Histologic grade-Location on the ear or in area of the chin and lip-Thickness ><span class="elsevierStyleHsp" style=""></span>2<span class="elsevierStyleHsp" style=""></span>mm-Clark level ≥<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleSmallCaps">iv</span>-Perineural invasion \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Extradermal invasion (histologic) \t\t\t\t\t\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">Used to determine T4 \t\t\t\t\t\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">Removed \t\t\t\t\t\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">Lack of data showing clear prognostic value \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Anatomic site \t\t\t\t\t\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">Not included \t\t\t\t\t\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">Included as high risk factor \t\t\t\t\t\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">Location of CSCC on the ear or in the area of the chin and lip associated with worse prognosis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Facial/cranial bone invasion \t\t\t\t\t\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">Included in T4 as invasion of extradermal structures \t\t\t\t\t\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">Invasion of maxilla, mandible, orbit, and temporal bone, defined as T3 \t\t\t\t\t\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">Correlated with stage of SSC of the head and neck \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">N category \t\t\t\t\t\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">Based on presence (N1) or absence (N0) of nodal disease \t\t\t\t\t\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">Disease staged as N0-N3 based on the size and number of involved nodes \t\t\t\t\t\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">Correlated with stage of SCC of the head and neck, and with recently published data \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">M category \t\t\t\t\t\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">Based on presence (M1) or absence (M0) of distant metastasis \t\t\t\t\t\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">No changes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">M, only TNM category not modified \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab333436.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Comparison Between the 6th and 7th Editions of the American Joint Committee on Cancer Staging Manuals.</p>" ] ] 8 => array:7 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "<p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">Special attention should be paid to patients with 3 or more of the above risk factors.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "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"><td 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" style="border-bottom: 2px solid black">The presence of any of the following risk factors is sufficient to justify excision with a safety margin of 10<span class="elsevierStyleHsp" style=""></span>mm or complete assessment of all margins (Mohs micrographic surgery) \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Tumor size ≥<span class="elsevierStyleHsp" style=""></span>2<span class="elsevierStyleHsp" style=""></span>cm (or 1<span class="elsevierStyleHsp" style=""></span>cm on the head and 6<span class="elsevierStyleHsp" style=""></span>mm on the genitals, hands, and feet) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Tumor thickness <span class="elsevierStyleHsp" style=""></span>≥<span class="elsevierStyleHsp" style=""></span>4<span class="elsevierStyleHsp" style=""></span>mm \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Poorly defined borders \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Recurrent tumor \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Immunosuppression \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Previous radiation \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Chronic inflammation \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Rapid growth \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Perineural or vascular invasion \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Moderate or poor differentiation \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab333437.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Factors Considered by the National Comprehensive Cancer Network for the Definition of Risk in Cutaneous Squamous Cell Carcinoma.</p>" ] ] 9 => array:7 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "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"><td 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" style="border-bottom: 2px solid black">Major Criteria \t\t\t\t\t\t\n \t\t\t\t</td><td 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" style="border-bottom: 2px solid black">Clinical Features \t\t\t\t\t\t\n \t\t\t\t</td><td 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" style="border-bottom: 2px solid black">Histologic Features \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\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">Personal history of:dystrophic epidermolysis bullosaepidermodysplasia verruciformisdyskeratosis congenitaxeroderma pigmentosumoculocutaneous albinism \t\t\t\t\t\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">Tumor thickness <span class="elsevierStyleMonospace">></span><span class="elsevierStyleHsp" style=""></span>6 mm \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\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">Immunosuppression due to:solid organ transplantation (heart and lung)hematologic disease (chronic lymphatic leukemia, small lymphocytic lymphoma) \t\t\t\t\t\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">Perineural invasion (nerves with a diameter ≥<span class="elsevierStyleHsp" style=""></span>0.1<span class="elsevierStyleHsp" style=""></span>mm) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\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">Tumor site (lip, anogenital region, external ear) \t\t\t\t\t\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">Bony involvement \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\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">Tumor recurrence \t\t\t\t\t\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"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\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">Tumor diameter ><span class="elsevierStyleHsp" style=""></span>5<span class="elsevierStyleHsp" style=""></span>cm \t\t\t\t\t\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"> \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="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Minor Criteria \t\t\t\t\t\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">Clinical Features \t\t\t\t\t\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">Histologic Features \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\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">Immunosuppression due to:solid organ transplantation (kidney and liver) \t\t\t\t\t\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">Tumor thickness 2-6<span class="elsevierStyleHsp" style=""></span>mm \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\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">Lesion arising on preexisting lesion (scar, radiation dermatitis area) \t\t\t\t\t\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">Poorly differentiated tumor \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\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">Tumor diameter 2-5<span class="elsevierStyleHsp" style=""></span>cm<a class="elsevierStyleCrossRef" href="#tblfn0025"><span class="elsevierStyleSup">b</span></a> \t\t\t\t\t\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">Certain CSCC variants (acantholytic, isolated cell, basosquamous) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\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">Infection with human immunodeficiency virus \t\t\t\t\t\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"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\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"> \t\t\t\t\t\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">Human papillomavirus infection in histologic section from immunosuppressed patient \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\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"> \t\t\t\t\t\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">Lymphovascular invasion \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab333434.png" ] ] ] "notaPie" => array:2 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">A CSCC is considered high risk if the tumor meets: a) 3 minor criteria, b) 2 major criteria and 2 minor criteria, and c) 1 major criterion and 4 minor criteria.</p>" ] 1 => array:3 [ "identificador" => "tblfn0025" "etiqueta" => "b" "nota" => "<p class="elsevierStyleNotepara" id="npar0010">><span class="elsevierStyleHsp" style=""></span>1.5<span class="elsevierStyleHsp" style=""></span>cm on lip and ear.</p>" ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">Major and Minor Criteria That Define High-Risk Cutaneous Squamous Cell Carcinoma (CSCC).<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a></p>" ] ] 10 => array:7 [ "identificador" => "tbl0020" "etiqueta" => "Table 4" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:3 [ "leyenda" => "<p id="spar0095" class="elsevierStyleSimplePara elsevierViewall">Abbreviations: CT; computed tomography; MRI, magnetic resonance imaging.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "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"><td 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" style="border-bottom: 2px solid black">Period<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">a</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td 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" style="border-bottom: 2px solid black">Check-up Frequency \t\t\t\t\t\t\n \t\t\t\t</td><td 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" style="border-bottom: 2px solid black">Physical Examination \t\t\t\t\t\t\n \t\t\t\t</td><td 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" style="border-bottom: 2px solid black">Additional Tests \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Years 1 and 2 \t\t\t\t\t\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">Every 3 mo \t\t\t\t\t\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">Yes \t\t\t\t\t\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">Ultrasound every 3 mo<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">b</span></a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CT/MRI every 6 mo<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">c</span></a> \t\t\t\t\t\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"> \t\t\t\t\t\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"> \t\t\t\t\t\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"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Years 3-5 \t\t\t\t\t\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">Every 6 mo \t\t\t\t\t\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">Yes \t\t\t\t\t\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">Ultrasound every 6 mo<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">b</span></a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Annual CT/MRI<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">c</span></a> \t\t\t\t\t\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"> \t\t\t\t\t\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"> \t\t\t\t\t\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"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">After fifth year \t\t\t\t\t\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">Annually \t\t\t\t\t\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">Yes \t\t\t\t\t\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">No \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab333435.png" ] ] ] "notaPie" => array:3 [ 0 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "a" "nota" => "<p class="elsevierStyleNotepara" id="npar0015">Ninety-five percent of recurrences and metastasis are observed in the first 5 years.</p>" ] 1 => array:3 [ "identificador" => "tblfn0015" "etiqueta" => "b" "nota" => "<p class="elsevierStyleNotepara" id="npar0020">Ultrasound of lymph node regions in the area of the tumor.</p>" ] 2 => array:3 [ "identificador" => "tblfn0020" "etiqueta" => "c" "nota" => "<p class="elsevierStyleNotepara" id="npar0025">In immunosuppressed patients or patients with perineural invasion of the main nerve trunk.</p>" ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0090" class="elsevierStyleSimplePara elsevierViewall">Follow-up Protocol for Squamous Cell Carcinoma Based on Risk.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:75 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Skin cancer as an occupational disease: the effect of ultraviolet and other forms of radiation" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "C.C. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 28 | 12 | 40 |
| 2024 October | 276 | 119 | 395 |
| 2024 September | 309 | 106 | 415 |
| 2024 August | 298 | 127 | 425 |
| 2024 July | 316 | 74 | 390 |
| 2024 June | 280 | 62 | 342 |
| 2024 May | 275 | 59 | 334 |
| 2024 April | 247 | 61 | 308 |
| 2024 March | 313 | 44 | 357 |
| 2024 February | 386 | 48 | 434 |
| 2024 January | 310 | 60 | 370 |
| 2023 December | 329 | 59 | 388 |
| 2023 November | 403 | 63 | 466 |
| 2023 October | 361 | 55 | 416 |
| 2023 September | 350 | 40 | 390 |
| 2023 August | 193 | 31 | 224 |
| 2023 July | 182 | 64 | 246 |
| 2023 June | 193 | 47 | 240 |
| 2023 May | 260 | 36 | 296 |
| 2023 April | 219 | 31 | 250 |
| 2023 March | 200 | 21 | 221 |
| 2023 February | 173 | 32 | 205 |
| 2023 January | 225 | 71 | 296 |
| 2022 December | 192 | 45 | 237 |
| 2022 November | 152 | 50 | 202 |
| 2022 October | 111 | 36 | 147 |
| 2022 September | 120 | 42 | 162 |
| 2022 August | 50 | 43 | 93 |
| 2022 July | 128 | 45 | 173 |
| 2022 June | 85 | 44 | 129 |
| 2022 May | 245 | 72 | 317 |
| 2022 April | 332 | 53 | 385 |
| 2022 March | 398 | 76 | 474 |
| 2022 February | 354 | 69 | 423 |
| 2022 January | 335 | 81 | 416 |
| 2021 December | 189 | 50 | 239 |
| 2021 November | 255 | 53 | 308 |
| 2021 October | 133 | 64 | 197 |
| 2021 September | 153 | 47 | 200 |
| 2021 August | 148 | 45 | 193 |
| 2021 July | 167 | 29 | 196 |
| 2021 June | 129 | 38 | 167 |
| 2021 May | 145 | 52 | 197 |
| 2021 April | 322 | 61 | 383 |
| 2021 March | 172 | 43 | 215 |
| 2021 February | 206 | 36 | 242 |
| 2021 January | 112 | 34 | 146 |
| 2020 December | 108 | 19 | 127 |
| 2020 November | 74 | 31 | 105 |
| 2020 October | 52 | 22 | 74 |
| 2020 September | 63 | 15 | 78 |
| 2020 August | 61 | 35 | 96 |
| 2020 July | 58 | 15 | 73 |
| 2020 June | 69 | 31 | 100 |
| 2020 May | 67 | 40 | 107 |
| 2020 April | 58 | 30 | 88 |
| 2020 March | 40 | 25 | 65 |
| 2020 February | 9 | 5 | 14 |
| 2020 January | 4 | 10 | 14 |
| 2019 December | 8 | 7 | 15 |
| 2019 November | 4 | 7 | 11 |
| 2019 October | 0 | 5 | 5 |
| 2019 September | 4 | 0 | 4 |
| 2019 August | 4 | 3 | 7 |
| 2019 July | 4 | 0 | 4 |
| 2019 June | 4 | 3 | 7 |
| 2019 May | 7 | 41 | 48 |
| 2019 April | 3 | 2 | 5 |
| 2019 March | 4 | 6 | 10 |
| 2019 February | 2 | 0 | 2 |
| 2019 January | 4 | 0 | 4 |
| 2018 December | 2 | 0 | 2 |
| 2018 November | 1 | 0 | 1 |
| 2018 October | 3 | 0 | 3 |
| 2018 September | 2 | 0 | 2 |
| 2018 March | 45 | 2 | 47 |
| 2018 February | 230 | 5 | 235 |
| 2018 January | 197 | 4 | 201 |
| 2017 December | 241 | 10 | 251 |
| 2017 November | 214 | 6 | 220 |
| 2017 October | 260 | 3 | 263 |
| 2017 September | 252 | 8 | 260 |
| 2017 August | 206 | 13 | 219 |
| 2017 July | 205 | 14 | 219 |
| 2017 June | 257 | 12 | 269 |
| 2017 May | 150 | 9 | 159 |
| 2017 April | 160 | 9 | 169 |
| 2017 March | 206 | 6 | 212 |
| 2017 February | 411 | 11 | 422 |
| 2017 January | 207 | 10 | 217 |
| 2016 December | 232 | 15 | 247 |
| 2016 November | 333 | 26 | 359 |
| 2016 October | 336 | 26 | 362 |
| 2016 September | 366 | 24 | 390 |
| 2016 August | 363 | 12 | 375 |
| 2016 July | 164 | 14 | 178 |
| 2016 June | 9 | 14 | 23 |
| 2016 May | 10 | 15 | 25 |
| 2016 April | 4 | 3 | 7 |
| 2016 March | 6 | 3 | 9 |
| 2016 February | 7 | 8 | 15 |
| 2016 January | 8 | 3 | 11 |
| 2015 December | 10 | 1 | 11 |
| 2015 November | 20 | 9 | 29 |
| 2015 October | 13 | 4 | 17 |
| 2015 September | 14 | 1 | 15 |
| 2015 August | 12 | 3 | 15 |
| 2015 July | 228 | 10 | 238 |
| 2015 June | 170 | 24 | 194 |
| 2015 May | 163 | 16 | 179 |
| 2015 April | 160 | 17 | 177 |
| 2015 March | 189 | 7 | 196 |
| 2015 February | 183 | 12 | 195 |
| 2015 January | 108 | 4 | 112 |
| 2014 December | 105 | 6 | 111 |
| 2014 November | 95 | 7 | 102 |
| 2014 October | 101 | 9 | 110 |
| 2014 September | 74 | 8 | 82 |
| 2014 August | 128 | 10 | 138 |
| 2014 July | 134 | 12 | 146 |
| 2014 June | 133 | 15 | 148 |
| 2014 May | 119 | 17 | 136 |
| 2014 April | 93 | 11 | 104 |
| 2014 March | 128 | 13 | 141 |
| 2014 February | 113 | 19 | 132 |
| 2014 January | 73 | 16 | 89 |
| 2013 December | 71 | 9 | 80 |
| 2013 November | 63 | 10 | 73 |
| 2013 October | 58 | 5 | 63 |
| 2013 September | 62 | 17 | 79 |
| 2013 August | 30 | 9 | 39 |
| 2013 July | 18 | 19 | 37 |
| 2013 June | 9 | 14 | 23 |
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