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In vivo reflectance confocal microscopy for early diagnosis of nonmelanoma skin cancer
La microscopía confocal de reflectancia in vivo para el diagnóstico precoz del cáncer de piel no melanoma
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(A) Clinical image showing a flat erythematous plaque on the neck with brown pigmentation around the periphery of the lesion. (B) Dermoscopy reveals fine telangiectasias in the center and brown pigmentation at the border of the lesion. (C) RCM mosaic obtained at the level of the superficial dermis (4<span class="elsevierStyleHsp" style=""></span>mm<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>4<span class="elsevierStyleHsp" style=""></span>mm) shows multiple hyporefractile tumors islands in the upper dermis (red arrowheads). (D) On a single RCM image (0.5<span class="elsevierStyleHsp" style=""></span>mm<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>0.5<span class="elsevierStyleHsp" style=""></span>mm) these tumor islands display elongated nuclei with peripheral palisading (black arrowheads) and are separated from the surrounding stroma by dark, cleft-like spaces (white asterisk). (E) Hematoxylin–eosin histology shows tumor nodules comprising basaloid tumor cells with peripheral palisading and surrounding fibrous stroma.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "M. Ulrich, S. Lange-Asschenfeldt, S. González" "autores" => array:3 [ 0 => array:2 [ "nombre" => "M." "apellidos" => "Ulrich" ] 1 => array:2 [ "nombre" => "S." "apellidos" => "Lange-Asschenfeldt" ] 2 => array:2 [ "nombre" => "S." 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Ballester, V. Oliver, J. Bañuls, M. Moragón, F. Valcuende, R. Botella-Estrada, E. Nagore" "autores" => array:7 [ 0 => array:2 [ "nombre" => "I." "apellidos" => "Ballester" ] 1 => array:2 [ "nombre" => "V." "apellidos" => "Oliver" ] 2 => array:2 [ "nombre" => "J." "apellidos" => "Bañuls" ] 3 => array:2 [ "nombre" => "M." "apellidos" => "Moragón" ] 4 => array:2 [ "nombre" => "F." "apellidos" => "Valcuende" ] 5 => array:2 [ "nombre" => "R." "apellidos" => "Botella-Estrada" ] 6 => array:2 [ "nombre" => "E." 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Pereiro Ferreirós, F.J. García-Martínez, J. Alonso-González" "autores" => array:3 [ 0 => array:3 [ "nombre" => "M." "apellidos" => "Pereiro Ferreirós" "sufijo" => "Jr." ] 1 => array:2 [ "nombre" => "F.J." "apellidos" => "García-Martínez" ] 2 => array:2 [ "nombre" => "J." "apellidos" => "Alonso-González" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1578219012002752?idApp=UINPBA000044" "url" => "/15782190/0000010300000009/v1_201304241357/S1578219012002752/v1_201304241357/en/main.assets" ] "en" => array:19 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Review</span>" "titulo" => "In vivo reflectance confocal microscopy for early diagnosis of nonmelanoma skin cancer" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "784" "paginaFinal" => "789" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "M. Ulrich, S. Lange-Asschenfeldt, S. González" "autores" => array:3 [ 0 => array:4 [ "nombre" => "M." "apellidos" => "Ulrich" "email" => array:1 [ 0 => "martina.ulrich@charite.de" ] "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" => "S." "apellidos" => "Lange-Asschenfeldt" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 2 => array:3 [ "nombre" => "S." "apellidos" => "González" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Skin Cancer Center Charité, Department of Dermatology, Charité Universitätsmedizin, Berlin, Germany" "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Servicio de Dermatología, Hospital Ramon y Cajal, Madrid, Spain" "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Dermatology Service, Memorial Sloan Kettering Cancer Center, New York, USA" "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" => "La microscopía confocal de reflectancia in vivo para el diagnóstico precoz del cáncer de piel no melanoma" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2277 "Ancho" => 1667 "Tamanyo" => 461559 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Correlation of clinical, dermoscopic, and reflectance confocal microscopy (RCM) images of a cystic basal cell carcinoma (BCC). (A) Clinical image of the lesion showing severe actinic damage with multiple actinic keratoses. On the right cheek a small skin-colored papule is observed (white arrow). (B) Dermatoscopic image of the lesion showing some telangiectasias around the papule. (C) RCM horizontal mosaic (4<span class="elsevierStyleHsp" style=""></span>mm<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>4<span class="elsevierStyleHsp" style=""></span>mm) obtained at the level of the superficial dermis showing multiple, round hyporefractile and non-refractile areas in a lobular arrangement (red circle). (D) Single RCM image (0.5<span class="elsevierStyleHsp" style=""></span>mm<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>0.5<span class="elsevierStyleHsp" style=""></span>mm) showing tumor islands with bright homogeneous centers surrounded by large dark clefts (white asterisk). (E) Histopathologic correlate showing a cystic variant of a BCC with basaloid tumor cells arranged in nests. Areas of mucin deposition (white asterisk) can be observed surrounding the tumor islands and forming cystic spaces (black asterisk).</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Nonmelanoma skin cancers (NMSC) are the most common tumors in the white population, with rising incidence rates reported in recent decades.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1–4</span></a> While the term NMSC encompasses a wide variety of cutaneous malignancies, the most frequent subtypes are basal cell carcinoma (BCC), actinic keratosis (AK), Bowen disease, and invasive squamous cell carcinoma. Overall, most NMSC have an excellent prognosis when diagnosed and treated at an early stage. In routine practice, diagnosis is based on clinical evaluation plus histologic examination of a biopsy specimen. Whereas surgical excision represents the treatment of choice for invasive NMSC, novel noninvasive treatments may be applied in the case of AK and superficial variants of BCC.</p><p id="par0010" class="elsevierStylePara elsevierViewall">Clinical diagnosis of a fully developed BCC or squamous cell carcinoma usually poses no major problem for an experienced dermatologist. However, diagnosis can be complicated in patients with multiple or very small lesions and in the presence of extensive sun-damage. Furthermore, cases in immunosuppressed patients, particularly those receiving systemic immunosuppression therapy after solid organ transplantation, may pose a significant challenge for the clinician as such patients often develop multiple NMSC in addition to wart-like lesions and sebaceous hyperplasia.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> Wart-like lesions in organ transplant recipients can correspond histologically to flat viral warts, seborrheic keratosis, or AK, but are often clinically indistinguishable.</p><p id="par0015" class="elsevierStylePara elsevierViewall">In the past decade, several noninvasive diagnostic tools for the diagnosis of malignant melanoma and NMSC have been developed and studied.<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6–9</span></a> Among these, reflectance confocal microscopy (RCM) offers the possibility of obtaining real-time images of the skin at high resolution, thereby facilitating in vivo assessment of cellular morphology. Consequently, it has been proposed that RCM represents an excellent tool for the early diagnosis and subsequent monitoring of NMSC.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Materials and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Patients and clinical evaluation</span><p id="par0020" class="elsevierStylePara elsevierViewall">Patients were recruited from an outpatient clinic for NMSC at the Skin Cancer Center Charité (Charité – Universitätsmedizin Berlin). Informed consent was obtained from the patients and all research was conducted according to the principles of the Declaration of Helsinki.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">In vivo reflectance confocal microscopy</span><p id="par0025" class="elsevierStylePara elsevierViewall">In vivo RCM was performed with a commercially available device (Vivascope 1500, Lucid Inc, Rochester NY, USA; Mavig GmbH, München, Germany). A detailed description of this device and the technique used has previously been published.<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9–11</span></a> Briefly, the device is equipped with an 830<span class="elsevierStyleHsp" style=""></span>nm diode laser operating at low power (<20<span class="elsevierStyleHsp" style=""></span>mW) for tissue illumination. The optical principle of this device is based on the detection of reflected and backscattered light from the skin site under investigation. Images are presented in grayscale and image brightness corresponds to the variable degree of reflection (different refraction indices) of each skin component. Reflected light is collected via a small pinhole enabling high-resolution images with a lateral resolution of approximately 1<span class="elsevierStyleHsp" style=""></span>μm and an axial resolution of approximately 3–5<span class="elsevierStyleHsp" style=""></span>μm. Vertical displacement of the lens changes the depth of the image within the tissue, and the system software facilitates the collection of sequential <span class="elsevierStyleItalic">XY</span> planes of the sample. In this way, thin sections of horizontal tissue can be assessed in vivo and the results can then be used to create a three-dimensional reconstruction of the entire area under study.</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">RCM evaluation protocol</span><p id="par0030" class="elsevierStylePara elsevierViewall">For the purpose of this report, RCM was used to systematically evaluate lesions found to be suspicious for NMSC on clinical examination. The Vivablock horizontal mapping function was used at the level of the stratum spinosum and the superficial dermis (4<span class="elsevierStyleHsp" style=""></span>mm<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>4<span class="elsevierStyleHsp" style=""></span>mm to 6<span class="elsevierStyleHsp" style=""></span>mm<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>6<span class="elsevierStyleHsp" style=""></span>mm). In addition, vertical mapping using the Vivastack function was performed in 5<span class="elsevierStyleHsp" style=""></span>μm steps to a maximum depth of 200<span class="elsevierStyleHsp" style=""></span>μm, beginning at the stratum corneum and continuing throughout the entire epidermis and into the papillary dermis. At areas of special interest individual images were captured and stored during the imaging process.</p></span></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">RCM features of NMSC</span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Basal cell carcinoma</span><p id="par0035" class="elsevierStylePara elsevierViewall">Various studies have described the main features of BCC on RCM evaluation, and a large multicenter study has shown high sensitivity and specificity rates for selected RCM parameters.<a class="elsevierStyleCrossRef" href="#bib12"><span class="elsevierStyleSup">12</span></a> Although different subtypes of BCC can show varying morphology on RCM, a phenomenon also observed in histology, they share certain common findings that easily allow for the diagnosis of BCC. These include the presence of a uniform population of tumor cells with elongated nuclei oriented along a common axis, a phenomenon that has also been described as nuclear polarization or streaming.<a class="elsevierStyleCrossRefs" href="#bib13"><span class="elsevierStyleSup">13,14</span></a> Tumor islands in the dermis visualized as areas appearing less bright than the surrounding stroma have been referred to as hyporefractile tumor islands. Cells on the periphery of the tumor islands show elongated nuclei with peripheral palisading. The overlying epidermis of the BCC often displays a disarranged keratinocyte pattern, probably the result of chronic actinic damage.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">15</span></a> Abnormal blood flow characterized by an increase in the number and diameter of blood vessels may also be observed in BCC; the blood vessels are frequently observed to branch and intertwine between the tumor aggregates and are probably the result of neoplastic angiogenesis. On RCM, blood vessels can easily be identified as parallel arrays and blood flow can be observed during in vivo examination. Another feature seen is the rolling of small round cells along the vessel walls, a phenomenon sometimes referred to as leukocyte rolling. The area surrounding the neoplastic aggregates consists of collagen and inflammatory cells and appears bright on RCM evaluation. The characteristics of pigmented BCC are similar to those of the nonpigmented form. However, in the case of the pigmented subtype, hyperrefractile dendritic cells may be observed in the tumor islands (corresponding to melanocytes) and plump bright cells may be seen in the tumoral stroma (corresponding to melanophages) (<a class="elsevierStyleCrossRefs" href="#fig0005">Figs. 1 and 2</a>) (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">16</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Actinic keratosis and actinic cheilitis</span><p id="par0040" class="elsevierStylePara elsevierViewall">Actinic keratoses (AK) represent a proliferation of a typical keratinocytes limited to the epidermis. Depending on the extent of the atypia present, 3 different grades of AK have been described.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">17</span></a> On RCM evaluation, AK displays several features that facilitate a noninvasive diagnosis. Superficial disruption of the stratum corneum with detached keratinocytes is observed; these cells, unlike those found in normal skin, often contain nuclei that correspond histologically to parakeratosis. At the level of the stratum granulosum and spinosum, keratinocyte atypia appears as pleomorphism of single cells with variation in their size and shape. On RCM images this results in a characteristic appearance often called an atypical honeycomb pattern. At the level of the superficial dermis, small round-to-slightly elongated blood vessels may be observed. RCM also visualizes changes in the dermal stroma in the form of thickened fibers, which on histologic examination correspond to solar elastosis (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>).</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0045" class="elsevierStylePara elsevierViewall">Actinic cheilitis, which is the equivalent of AK on the lip, shows similar findings on RCM evaluation. A recent study showed the usefulness of RCM for distinguishing actinic cheilitis from inflammatory forms of cheilitis and also for in vivo monitoring of response to treatment in these patients<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">18</span></a> (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>).</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Bowen disease</span><p id="par0050" class="elsevierStylePara elsevierViewall">RCM findings in Bowen disease are similar to those observed in AK, including superficial disruption, an atypical honeycomb pattern, and solar elastosis. However, in Bowen disease atypia and pleomorphism is usually more severe, involving the entire epidermis. Furthermore, large cells with bright centers, which correspond to histologically dyskeratotic cells, are commonly seen in Bowen disease. Multinucleated cells may also be observed. The vasculature in Bowen disease shows characteristic round to S-shaped vessels in the papillary dermis (<a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>).<a class="elsevierStyleCrossRef" href="#bib19"><span class="elsevierStyleSup">19</span></a></p><elsevierMultimedia ident="fig0020"></elsevierMultimedia></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Invasive squamous cell carcinoma</span><p id="par0055" class="elsevierStylePara elsevierViewall">The RCM evaluation of invasive squamous cell carcinoma may be challenging even for an experienced operator as the hyperkeratosis in these tumors limits the visualization of the deeper layers. In lesions with severe hyperkeratosis, a significant part of the light is backscattered due to the high refractive index of keratin. This results in fuzzy images and impaired visualization of deeper structures. In contrast to AK, in which the superficial hyperkeratosis can easily be removed, the hyperkeratosis in squamous cell carcinomas is usually adherent and attempts to remove the keratotic scale may result in bleeding or pain. However, particularly small evolving squamous cell carcinoma lesions may be evaluated and distinguished from AK by RCM. At the level of the stratum corneum, hyperkeratosis and impetiginization associated with the presence of neutrophils are commonly present. Possible findings in the granular and spinous layers include a variable degree of atypical keratinocytes seen as an atypical honeycomb pattern and, in some cases, the presence of dyskeratotic cells with targetoid appearance. At the level of the superficial dermis, RCM images may visualize tumor islands lacking the features typical of BCC, in particular palisading with elongated cells. Large bright structures corresponding to keratin pearls may be observed within tumor islands and elongated blood vessels are present in the surrounding areas.</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Monitoring treatment of NMSC</span><p id="par0060" class="elsevierStylePara elsevierViewall">RCM offers the possibility of in vivo monitoring of a skin lesion over time because no tissue is removed or altered during the process. This makes the technique useful for assessing treatment efficacy and for evaluating treatment effects such as necrosis, apoptosis, and the induction of inflammatory infiltrate. In a previous study by our group, RCM was used to monitor the treatment of AK with the topical immune modulator imiquimod. In that study we detected the presence of dendritic-shaped Langerhans cells and other inflammatory cells within AK lesions 2 weeks after start of treatment.<a class="elsevierStyleCrossRef" href="#bib20"><span class="elsevierStyleSup">20</span></a> Re-arrangement of the epidermal structure was observed 4 weeks after cessation of treatment. Similar findings have also been reported for imiquimod treatment in BCC.<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">21,22</span></a> The technique may also help to identify nonresponders at an early stage and guide treatment selection because RCM can detect the presence of an inflammatory infiltrate in vivo.</p><p id="par0065" class="elsevierStylePara elsevierViewall">Clinical applications of RCM include the determination of surgical margins in clinically ill-defined lesions, such as amelanotic lentigo maligna of the face.<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">23,24</span></a> A recent study has also demonstrated the feasibility of using RCM imaging to identify residual tumor in shave biopsy wounds<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">25</span></a> and Ahlgrimm-Siess et al. studied the usefulness of this novel technique for monitoring treatment efficacy after cryotherapy of BCC.<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">26</span></a></p></span></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Discussion</span><p id="par0070" class="elsevierStylePara elsevierViewall">In vivo RCM is an emerging technology in dermatology that allows rapid in vivo diagnosis of skin cancer and differentiation between benign and malignant lesions. RCM enables high-resolution skin analysis with visualization of morphological details on a cellular level. In this regard, RCM is particularly useful for evaluating suspicious lesions that do not clearly fulfil clinical criteria for nonmelanoma skin cancer on physical examination or have the characteristic dermoscopic features. As a completely noninvasive device, RCM is an excellent tool for the detection of skin cancer in cosmetically sensitive areas of the face and it can also facilitate differentiation between malignant tumors and benign lesions such as sebaceous hyperplasia and seborrheic keratosis.<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">27</span></a> However, RCM evaluation of hyperkeratotic lesions, such as warts and squamous cell carcinoma, is limited because of the high refractive index of keratin and the consequent backscattering of light and reduced resolution. Moreover, RCM is more useful in the evaluation of selected lesions which are suspicious on clinical examination because the assessment of multiple lesions would be quite time consuming.</p><p id="par0075" class="elsevierStylePara elsevierViewall">The most obvious advantage of the technique is that diagnoses can be obtained in vivo during the course of the examination. Based on RCM findings, a decision for further management and therapy can be made without delay while at the same time avoiding unnecessary biopsies.</p><p id="par0080" class="elsevierStylePara elsevierViewall">In the context of novel therapeutic modalities for the treatment of NMSC, RCM allows noninvasive monitoring of photodynamic therapy and of topical therapies, such as imiquimod and diclofenac plus hyaluronic acid. RCM can be used to obtain a diagnosis prior to the start of therapy and to verify treatment efficacy during treatment and follow-up. This approach may ultimately decrease the number of procedural complications and increase complete clearance rates compared to clinical evaluation alone.</p><p id="par0085" class="elsevierStylePara elsevierViewall">On the basis of the available evidence, in vivo RCM is a promising and innovative technology for the early diagnosis of skin cancer, which may ultimately play an important role in skin cancer screening and prevention as well as in the early detection of progression or recurrence after therapy.</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conflicts of interest</span><p id="par0090" 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" => "xres96640" "titulo" => "Abstract" ] 1 => array:2 [ "identificador" => "xpalclavsec83797" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xres96641" "titulo" => "Resumen" ] 3 => array:2 [ "identificador" => "xpalclavsec83798" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Materials and methods" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Patients and clinical evaluation" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "In vivo reflectance confocal microscopy" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "RCM evaluation protocol" ] ] ] 6 => array:3 [ "identificador" => "sec0030" "titulo" => "RCM features of NMSC" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0035" "titulo" => "Basal cell carcinoma" ] 1 => array:2 [ "identificador" => "sec0040" "titulo" => "Actinic keratosis and actinic cheilitis" ] 2 => array:2 [ "identificador" => "sec0045" "titulo" => "Bowen disease" ] 3 => array:2 [ "identificador" => "sec0050" "titulo" => "Invasive squamous cell carcinoma" ] 4 => array:2 [ "identificador" => "sec0055" "titulo" => "Monitoring treatment of NMSC" ] ] ] 7 => array:2 [ "identificador" => "sec0060" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0065" "titulo" => "Conflicts of interest" ] 9 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2011-07-12" "fechaAceptado" => "2011-10-29" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec83797" "palabras" => array:5 [ 0 => "Actinic keratosis" 1 => "Squamous cell carcinoma" 2 => "Basal cell carcinoma" 3 => "Diagnosis" 4 => "Monitoring" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec83798" "palabras" => array:5 [ 0 => "queratosis actínica" 1 => "carcinoma epidermoide" 2 => "carcinomas basocelulares" 3 => "Diagnosis" 4 => "Monitorizar" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Reflectance confocal microscopy (RCM) is a novel tool for noninvasive in vivo diagnosis of nonmelanoma skin cancer at high resolution. Given the excellent correlation that has been demonstrated between RCM findings and routine histology, clinicians using this imaging technique can establish an immediate diagnosis. Multiple studies have evaluated the use of RCM in melanoma and nonmelanoma skin cancer and have demonstrated high sensitivity and specificity rates. We discuss the applicability of RCM for the early diagnosis of NMSC and discuss other clinical applications of this emerging technique.</p>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La microscopía confocal de reflectancia (MCR) es un herramienta novedosa para el diagnóstico precoz in vivo del cáncer de piel no melanoma (CPNM) con alta resolución. Dada la excelente correlación demostrada entre los hallazgos de la MCR y la histología de rutina, los clínicos que utilizan esta técnica de imágenes pueden establecer un diagnóstico inmediato. Múltiples estudios han evaluado el uso de la MCR en cáncer de piel melanoma y no melanoma, demostrando altas tasas de sensibilidad y especificad. Hablamos de la aplicabilidad de la MCR para el diagnóstico temprano de CPNM, comentando otros aplicaciones clínicas de esta técnica emergente.</p>" ] ] "multimedia" => array:6 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2277 "Ancho" => 1667 "Tamanyo" => 461559 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Correlation of clinical, dermoscopic, and reflectance confocal microscopy (RCM) images of a cystic basal cell carcinoma (BCC). (A) Clinical image of the lesion showing severe actinic damage with multiple actinic keratoses. On the right cheek a small skin-colored papule is observed (white arrow). (B) Dermatoscopic image of the lesion showing some telangiectasias around the papule. (C) RCM horizontal mosaic (4<span class="elsevierStyleHsp" style=""></span>mm<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>4<span class="elsevierStyleHsp" style=""></span>mm) obtained at the level of the superficial dermis showing multiple, round hyporefractile and non-refractile areas in a lobular arrangement (red circle). (D) Single RCM image (0.5<span class="elsevierStyleHsp" style=""></span>mm<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>0.5<span class="elsevierStyleHsp" style=""></span>mm) showing tumor islands with bright homogeneous centers surrounded by large dark clefts (white asterisk). (E) Histopathologic correlate showing a cystic variant of a BCC with basaloid tumor cells arranged in nests. Areas of mucin deposition (white asterisk) can be observed surrounding the tumor islands and forming cystic spaces (black asterisk).</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" => 2193 "Ancho" => 1667 "Tamanyo" => 437581 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Correlation of clinical, dermoscopic, and reflectance confocal microscopy (RCM) images of a pigmented basal cell carcinoma (BCC) in an immunosuppressed patient after kidney transplantation. (A) Clinical image showing a flat erythematous plaque on the neck with brown pigmentation around the periphery of the lesion. (B) Dermoscopy reveals fine telangiectasias in the center and brown pigmentation at the border of the lesion. (C) RCM mosaic obtained at the level of the superficial dermis (4<span class="elsevierStyleHsp" style=""></span>mm<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>4<span class="elsevierStyleHsp" style=""></span>mm) shows multiple hyporefractile tumors islands in the upper dermis (red arrowheads). (D) On a single RCM image (0.5<span class="elsevierStyleHsp" style=""></span>mm<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>0.5<span class="elsevierStyleHsp" style=""></span>mm) these tumor islands display elongated nuclei with peripheral palisading (black arrowheads) and are separated from the surrounding stroma by dark, cleft-like spaces (white asterisk). (E) Hematoxylin–eosin histology shows tumor nodules comprising basaloid tumor cells with peripheral palisading and surrounding fibrous stroma.</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" => 2270 "Ancho" => 1667 "Tamanyo" => 464100 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Correlation of clinical, dermoscopic, and reflectance confocal microscopy (RCM) images of an actinic keratosis (AK). (A) Clinical image reveals multiple erythematous to brown hyperkeratotic plaques on the scalp. (B) Dermoscopy reveals a brownish erythematous plaque with central scale lacking the classical strawberry pattern typical of AK. (C) RCM mosaic of the lesions obtained at the granular and spinous layer shows a central area of hyperkeratosis with amorphous material of medium to high reflectance. (D) RCM single image obtained at the periphery of the lesion demonstrates a broadened (black asterisk) and generally atypical honeycomb pattern with variations in cell and nuclei sizes and shapes. (E) Corresponding hematoxylin–eosin histology illustrates overlying hyperparakeratosis (black arrow) and epidermal proliferation of atypical keratinocytes.</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" => 2192 "Ancho" => 1667 "Tamanyo" => 452230 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Correlation of clinical, dermoscopic, and reflectance confocal microscopy (RCM) images of Bowen's disease. (A) Clinical image showing a single small erythematous plaque on the forearm in a kidney transplant patient. (B) Dermoscopic examination reveals the presence of glomerular vessels and areas of erosion. (C) RCM mosaic illustrates correlation between erosion and superficial disruption and crusting seen as deposits of low refractile amorphous material (white arrowheads). (D) RCM single images obtained at the level of the stratum spinosum showing complete architectural disruption with atypical honeycomb pattern and broadened honeycomb pattern (black asterisk). Single large cells with bright centers can be observed (red arrowhead), probably corresponding to dyskeratotic cells. Also visualized are small round bright structures that correspond to inflammatory cells. The dilated round-to-oval blood vessels are the RCM equivalent of the glomerular vessels seen on dermoscopy. (E) Corresponding hematoxylin–eosin histology showing marked keratinocyte atypia with large atypical cells, multinucleated cells (white arrowhead) and dyskeratotic cells (red arrowhead). Keratin pearls (white dashed circle) and dilated blood vessels are also visualized.</p>" ] ] 4 => 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">RCM features of BCC \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"><span class="elsevierStyleBold">Stratum corneum</span> \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"><span class="elsevierStyleHsp" style=""></span>• Superficial disruption \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"><span class="elsevierStyleHsp" style=""></span>• Amorphous grey material (crusting/bleeding) \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"><span class="elsevierStyleHsp" style=""></span>• Neutrophils and/or impetiginization \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"><span class="elsevierStyleVsp" style="height:0.5px"></span> \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"><span class="elsevierStyleBold">Stratum granulosum/spinosum</span> \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"><span class="elsevierStyleHsp" style=""></span>• Mild keratinocyte atypia (atypical <span class="elsevierStyleHsp" style=""></span>honeycomb pattern) \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"><span class="elsevierStyleHsp" style=""></span>• Presence of dendritic cells \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"><span class="elsevierStyleVsp" style="height:0.5px"></span> \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"><span class="elsevierStyleBold">Dermoepidermal junction</span> \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"><span class="elsevierStyleHsp" style=""></span>• Elongated keratinocytes and nuclei \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"><span class="elsevierStyleHsp" style=""></span>• Orientation of nuclei along the same axis (polarization) \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"><span class="elsevierStyleVsp" style="height:0.5px"></span> \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"><span class="elsevierStyleBold">Dermis</span> \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"><span class="elsevierStyleHsp" style=""></span>• Homogeneous tumor islands of lower reflectance than the surrounding stroma \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"><span class="elsevierStyleHsp" style=""></span>• Palisading of elongated cells at the periphery of the tumor nodules \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"><span class="elsevierStyleHsp" style=""></span>• Dark clefts between tumor islands and surrounding fibrous stroma (corresponding to mucin deposition) \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"><span class="elsevierStyleHsp" style=""></span>• Small bright cells and dendritic cells/inflammatory infiltrate \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"><span class="elsevierStyleHsp" style=""></span>• Increased vascularity: \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"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>- increase in the number and tortuosity of <span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>blood vessels \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"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>- large caliber blood vessels \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"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>- leukocyte trafficking \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab182599.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Key features of basal cell carcinoma (BCC) on reflectance confocal microscopy (RCM).</p>" ] ] 5 => array:7 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "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">RCM features of actinic keratosis \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"><span class="elsevierStyleBold">Stratum corneum:</span> \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"><span class="elsevierStyleHsp" style=""></span>• Superficial disruption with large single keratinocytes \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"><span class="elsevierStyleHsp" style=""></span>• Nucleated cells (parakeratosis) \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"><span class="elsevierStyleHsp" style=""></span>• Small bright cells with dark centers (neutrophils/impetiginization) \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"><span class="elsevierStyleVsp" style="height:0.5px"></span> \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"><span class="elsevierStyleBold">Stratum granulosum/spinosum:</span> \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"><span class="elsevierStyleHsp" style=""></span>• Atypical honeycomb pattern: variations in cell size and morphology \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"><span class="elsevierStyleHsp" style=""></span>• Broadened honeycomb pattern: areas with broadened and blurred intercellular connections \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"><span class="elsevierStyleHsp" style=""></span>• Loss of regular epidermal architecture \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"><span class="elsevierStyleVsp" style="height:0.5px"></span> \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"><span class="elsevierStyleBold">Dermis</span> \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"><span class="elsevierStyleHsp" style=""></span>• Slightly dilated blood vessels \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"><span class="elsevierStyleHsp" style=""></span>• Solar elastosis: moderately refractive lace-like material adjacent to collagen bundles \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab182598.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Key features of actinic keratosis on reflectance confocal microscopy (RCM).</p>" ] ] ] 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 11 | 8 | 19 |
| 2024 October | 74 | 47 | 121 |
| 2024 September | 93 | 32 | 125 |
| 2024 August | 120 | 59 | 179 |
| 2024 July | 84 | 23 | 107 |
| 2024 June | 102 | 47 | 149 |
| 2024 May | 88 | 34 | 122 |
| 2024 April | 87 | 28 | 115 |
| 2024 March | 109 | 31 | 140 |
| 2024 February | 67 | 40 | 107 |
| 2024 January | 60 | 34 | 94 |
| 2023 December | 76 | 40 | 116 |
| 2023 November | 107 | 36 | 143 |
| 2023 October | 82 | 21 | 103 |
| 2023 September | 93 | 38 | 131 |
| 2023 August | 58 | 13 | 71 |
| 2023 July | 91 | 36 | 127 |
| 2023 June | 69 | 25 | 94 |
| 2023 May | 85 | 26 | 111 |
| 2023 April | 58 | 23 | 81 |
| 2023 March | 53 | 23 | 76 |
| 2023 February | 45 | 25 | 70 |
| 2023 January | 49 | 33 | 82 |
| 2022 December | 48 | 48 | 96 |
| 2022 November | 29 | 31 | 60 |
| 2022 October | 22 | 34 | 56 |
| 2022 September | 18 | 37 | 55 |
| 2022 August | 26 | 23 | 49 |
| 2022 July | 22 | 36 | 58 |
| 2022 June | 30 | 26 | 56 |
| 2022 May | 32 | 37 | 69 |
| 2022 April | 46 | 45 | 91 |
| 2022 March | 51 | 57 | 108 |
| 2022 February | 34 | 32 | 66 |
| 2022 January | 55 | 45 | 100 |
| 2021 December | 46 | 49 | 95 |
| 2021 November | 51 | 43 | 94 |
| 2021 October | 44 | 46 | 90 |
| 2021 September | 30 | 44 | 74 |
| 2021 August | 42 | 36 | 78 |
| 2021 July | 44 | 29 | 73 |
| 2021 June | 49 | 38 | 87 |
| 2021 May | 56 | 26 | 82 |
| 2021 April | 150 | 45 | 195 |
| 2021 March | 71 | 20 | 91 |
| 2021 February | 48 | 27 | 75 |
| 2021 January | 42 | 17 | 59 |
| 2020 December | 33 | 11 | 44 |
| 2020 November | 40 | 21 | 61 |
| 2020 October | 38 | 15 | 53 |
| 2020 September | 35 | 20 | 55 |
| 2020 August | 23 | 15 | 38 |
| 2020 July | 21 | 18 | 39 |
| 2020 June | 28 | 26 | 54 |
| 2020 May | 44 | 18 | 62 |
| 2020 April | 23 | 18 | 41 |
| 2020 March | 28 | 20 | 48 |
| 2020 February | 1 | 2 | 3 |
| 2020 January | 4 | 8 | 12 |
| 2019 December | 8 | 8 | 16 |
| 2019 November | 6 | 9 | 15 |
| 2019 October | 0 | 4 | 4 |
| 2019 September | 8 | 9 | 17 |
| 2019 August | 4 | 6 | 10 |
| 2019 July | 4 | 12 | 16 |
| 2019 June | 6 | 15 | 21 |
| 2019 May | 4 | 31 | 35 |
| 2019 April | 2 | 16 | 18 |
| 2019 March | 2 | 9 | 11 |
| 2019 February | 2 | 2 | 4 |
| 2019 January | 2 | 1 | 3 |
| 2018 December | 3 | 5 | 8 |
| 2018 November | 2 | 0 | 2 |
| 2018 October | 2 | 0 | 2 |
| 2018 September | 4 | 0 | 4 |
| 2018 June | 0 | 1 | 1 |
| 2018 May | 0 | 3 | 3 |
| 2018 April | 0 | 3 | 3 |
| 2018 March | 4 | 2 | 6 |
| 2018 February | 35 | 8 | 43 |
| 2018 January | 35 | 8 | 43 |
| 2017 December | 53 | 6 | 59 |
| 2017 November | 49 | 19 | 68 |
| 2017 October | 39 | 5 | 44 |
| 2017 September | 43 | 17 | 60 |
| 2017 August | 50 | 22 | 72 |
| 2017 July | 55 | 13 | 68 |
| 2017 June | 56 | 26 | 82 |
| 2017 May | 49 | 16 | 65 |
| 2017 April | 34 | 11 | 45 |
| 2017 March | 54 | 38 | 92 |
| 2017 February | 33 | 12 | 45 |
| 2017 January | 25 | 11 | 36 |
| 2016 December | 50 | 18 | 68 |
| 2016 November | 65 | 7 | 72 |
| 2016 October | 90 | 20 | 110 |
| 2016 September | 166 | 17 | 183 |
| 2016 August | 59 | 14 | 73 |
| 2016 July | 32 | 16 | 48 |
| 2016 June | 10 | 19 | 29 |
| 2016 May | 14 | 11 | 25 |
| 2016 April | 6 | 14 | 20 |
| 2016 March | 6 | 7 | 13 |
| 2016 February | 6 | 12 | 18 |
| 2016 January | 4 | 10 | 14 |
| 2015 December | 12 | 12 | 24 |
| 2015 November | 16 | 10 | 26 |
| 2015 October | 17 | 15 | 32 |
| 2015 September | 7 | 8 | 15 |
| 2015 August | 15 | 8 | 23 |
| 2015 July | 28 | 1 | 29 |
| 2015 June | 32 | 9 | 41 |
| 2015 May | 44 | 17 | 61 |
| 2015 April | 54 | 10 | 64 |
| 2015 March | 33 | 6 | 39 |
| 2015 February | 42 | 7 | 49 |
| 2015 January | 24 | 11 | 35 |
| 2014 December | 45 | 4 | 49 |
| 2014 November | 32 | 13 | 45 |
| 2014 October | 34 | 1 | 35 |
| 2014 September | 14 | 3 | 17 |
| 2014 August | 14 | 3 | 17 |
| 2014 July | 21 | 4 | 25 |
| 2014 June | 36 | 2 | 38 |
| 2014 May | 33 | 7 | 40 |
| 2014 April | 23 | 6 | 29 |
| 2014 March | 42 | 6 | 48 |
| 2014 February | 17 | 13 | 30 |
| 2014 January | 20 | 6 | 26 |
| 2013 December | 19 | 2 | 21 |
| 2013 November | 12 | 7 | 19 |
| 2013 October | 9 | 5 | 14 |
| 2013 September | 6 | 3 | 9 |
| 2013 August | 9 | 11 | 20 |
| 2013 July | 10 | 21 | 31 |
| 2013 June | 5 | 15 | 20 |
| 2013 May | 7 | 18 | 25 |
| 2013 April | 6 | 16 | 22 |
| 2013 March | 10 | 8 | 18 |
| 2013 February | 32 | 3 | 35 |
| 2013 January | 20 | 4 | 24 |
| 2012 December | 12 | 8 | 20 |
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