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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Cutaneous metastases from solid tumors are uncommon events in clinical practice&#46; It is estimated that between 0&#46;7&#37; and 9&#37; of metastases from these tumors occur in the skin&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Most of the time&#44; the patient already has a diagnosis of malignant neoplasm when the cutaneous metastasis is detected&#46; However&#44; in up to one-third of cases&#44; skin metastasis is identified before the primary tumor&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> In some cases&#44; the identification of the cutaneous metastasis indicates cancer recurrence&#44; and in 79&#37; of cases&#44; there are concurrent visceral metastases&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> The clinical presentation is diverse and can simulate inflammatory diseases&#44; benign tumors&#44; or even malignant skin tumors&#46; This review discusses the current paradigm of metastasis mechanisms and displays the main clinical presentations&#46; For didactic reasons&#44; clinical presentations will be discussed according to the primary tumor site&#44; including the ones originally from the skin&#46; Paraneoplastic manifestations and hematological malignancies will not be reviewed in this article&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Etiopathogenesis</span><p id="par0015" class="elsevierStylePara elsevierViewall">Metastasis is defined as the development of a tumor at some distance from the primary site&#46; It develops predominantly by vascular invasion &#40;lymphatic or hematogenous&#41;&#46; There is a discussion in the literature whether implants should be considered as actual metastases either by contiguity or iatrogenically&#46; Currently&#44; the metastatic process is understood as a complex phenomenon that occurs in parallel with the development of the primary tumor&#46; Due to its greater importance&#44; metastases through vascular invasion will be discussed in more detail&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">The pathophysiology of metastasis is divided into six stages&#58; &#40;1&#41; local invasion&#44; &#40;2&#41; intravasation&#44; &#40;3&#41; survival in the circulation&#44; &#40;4&#41; arrest in a distant organ&#44; &#40;5&#41; extravasation&#44; &#40;6&#41; micrometastasis formation and metastatic colonization&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Local invasion</span><p id="par0025" class="elsevierStylePara elsevierViewall">After the development of the malignant tumor in the primary site&#44; local invasion occurs&#46; This event consists of the entry of malignant cells into the soft tissue adjacent to the tumor&#46; For this to occur&#44; disruption of the basement membrane secondary to the action of matrix metalloproteinases is necessary&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Intravasation</span><p id="par0030" class="elsevierStylePara elsevierViewall">Intravasation is a complex phenomenon that allows malignant cells to enter the blood or lymphatic vessels&#46; This process is essential for malignant cells to reach distant sites and continue the metastatic process&#46; It has been well-described that malignant tumors have the ability to produce neoangiogenesis&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> What happens is that the neoformed vessels have little coverage of pericytes and endothelial cells with little cell adhesion&#44; facilitating the entry of malignant cells &#40;intravasation&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;5</span></a> Curiously&#44; more recent evidence demonstrates that this phenomenon occurs predominantly during sleep&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Survival in circulation</span><p id="par0035" class="elsevierStylePara elsevierViewall">Once inside the vessels&#44; the malignant cells need to survive&#46; They are subject to trauma resulting from hemodynamic forces and&#44; in addition&#44; are subject to the immune system action&#46; The main adaptive way to evade these mechanisms is the formation of platelet microthrombi around the neoplastic cells&#44; which protect them from these phenomena&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Arrest in a distant organ</span><p id="par0040" class="elsevierStylePara elsevierViewall">Tumors can reach virtually any tissue in the body through blood or lymphatic circulation&#46; The major question is why some tumors have preferential metastasis sites&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> For instance&#44; there is a clear preference for bone in prostate cancer metastases or&#44; in cases of colon tumors&#44; metastases to the liver&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> A strong interaction between the primary tumor and the target site soft tissue is believed to be necessary&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> Although the skin is a highly vascularized organ&#44; few tumors&#44; such as melanoma&#44; have an obvious predilection for it&#46; Perhaps this is due to good immunological protection or low soft tissue-malignant tumor interaction&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Extravasation</span><p id="par0045" class="elsevierStylePara elsevierViewall">After reaching the target organ circulation&#44; malignant cells must exit the vessels to reach the soft tissue&#46; This process may occur due to mechanical vascular rupture or a more complex process&#46; In the latter case&#44; tumor cells might induce vascular hyperpermeability secondary to the release of proteins such as epiregulin &#40;EREG&#41;&#44; cyclooxygenase 2 &#40;COX-2&#41;&#44; metalloproteinase 1 and 2 &#40;MMP-1 and MMP-2&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> It is important to emphasize that each protein has a specific action on the vascularization of each target organ&#44; reinforcing the idea that each malignant tumor has one or more preferential metastasis sites&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Micrometastasis formation and metastatic colonization</span><p id="par0050" class="elsevierStylePara elsevierViewall">The last step is tumor survival in the target site soft tissue&#46; For this to occur&#44; the tumor needs to have a self-renewal and proliferation capacity&#46; Additionally&#44; it releases substances that make the adjacent soft tissue more receptive to its multiplication&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> Micrometastases may persist in a latent state for months or years&#46; During this period&#44; micrometastases that acquire genetic or epigenetic alterations and can make the microenvironment more favorable to their development with the formation of macroscopic metastases with significant lethal potential&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Epidemiology</span><p id="par0055" class="elsevierStylePara elsevierViewall">There is divergence in the literature about which tumors most frequently metastasize to the skin&#46; More recent studies indicate that melanoma is the most frequent one&#44; but in some classic studies&#44; this neoplasm appears only in the fourth place&#46;<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10&#44;11</span></a> A 2002 meta-analysis identified that breast tumors are the most frequent ones &#40;24&#37;&#41; followed by kidney &#40;4&#37;&#41;&#44; ovary &#40;3&#46;8&#37;&#41;&#44; bladder &#40;3&#46;6&#37;&#41;&#44; lung &#40;3&#46;4&#37;&#41;&#44; colorectal &#40;3&#46;4&#37;&#41;&#44; and prostate &#40;0&#46;7&#37;&#41; cancer&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> However&#44; cases of melanoma were excluded from this study&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">There is an epidemiological difference according to sex&#46; A Brazilian study with 209 cases of cutaneous metastases identified that the most frequent cutaneous metastases in women originated from breast &#40;63&#46;19&#37;&#41;&#44; large intestine &#40;10&#46;41&#37;&#41;&#44; and lung cancer &#40;4&#46;16&#37;&#41; whereas in men&#44; the order of frequency was lung&#44; stomach&#44; and larynx &#40;33&#46;84&#37;&#44; 12&#46;3&#37;&#44; and 7&#46;69&#37;&#44; respectively&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> When specifically analyzing the pediatric population&#44; the most frequent primary tumors are rhabdomyosarcoma and neuroblastoma&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">It is a well-known fact that there are some areas of the skin where the appearance of metastatic lesions is more frequent&#46; The anterior thorax is the most common site&#44; followed by the abdomen&#44; head and neck &#40;including the scalp&#41;&#44; and limbs&#46;<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11&#8211;13</span></a> There is a clear predilection for the affected site according to the primary tumor&#59; therefore&#44; the cutaneous metastasis site may indicate a possible neoplastic origin&#46; For instance&#44; breast cancer most often metastasizes to the anterior thorax&#44; whereas gastrointestinal tract tumors secondarily most often affect the abdomen&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a><a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> summarizes the preferred sites of skin metastases&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Clinical presentation</span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Skin</span><p id="par0070" class="elsevierStylePara elsevierViewall">Several originally cutaneous malignant neoplasms can develop metastases to the skin&#46; Of these&#44; the most frequent is melanoma and&#44; for that reason&#44; it will be discussed in more detail&#46; However&#44; it is important to emphasize that squamous cell carcinoma&#44; Merkel cell carcinoma&#44; and even malignant pilomatricoma can develop skin metastases&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">A North-American study has shown that the number of cutaneous metastases from melanoma has been increasing in recent years&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> This is not a rare event in the natural history of the disease&#46; Secondary skin involvement occurs in 10&#37; to 17&#37; of patients with melanoma and is present in up to 50&#37; of individuals with disseminated disease&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> In most cases&#44; the skin is the first site of metastatic involvement and&#44; in about 30&#37; of cases&#44; it occurs after lymph node metastasis&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> The concomitant finding of cutaneous&#44; nodal&#44; and visceral metastasis occurs in approximately 10&#37; of cases&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">Cutaneous melanoma metastases are divided into microsatellite&#44; satellite&#44; in-transit or distant metastases&#46; The first is microscopic metastasis &#40;cutaneous or subcutaneous&#41; disconnected from the primary tumor&#44; therefore&#44; it is not perceived in the clinical examination&#46; A satellite metastasis is a metastatic tumor visible up to 2&#8239;cm from the primary tumor site&#46; In-transit metastasis is defined as any cutaneous or subcutaneous metastasis that is more than 2&#8239;cm away from the primary lesion but within the regional lymphatic drainage&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> Despite this differentiation&#44; both satellite lesions and in-transit metastasis correspond to intralymphatic spread and have similar therapeutic and prognostic implications&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> It is also important to differentiate lymph node metastases from local recurrence that occurs as a result of incomplete resection of the primary tumor&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">Distant metastasis is related to hematogenous spread and occurs when the cutaneous metastatic site is far from the lymphatic drainage focus of the primary tumor&#46; This differentiation is important&#44; as in the first two scenarios the patient is considered to have locoregional disease&#44; whereas&#44; in the latter&#44; the patient has distant metastasis&#44; which considerably worsens the patient&#8217;s prognosis&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> Melanoma staging is beyond the scope of this article and therefore will not be discussed&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">Cutaneous metastases from melanoma are most commonly found on the back in men and on the lower limbs in women&#46; The fact that secondary cutaneous locations occur in the same anatomical location as the initial cutaneous location in more than 30&#37; of cases explain the distinct patterns of metastases between sexes&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> Clinically&#44; there are generally black or brownish dermal or subcutaneous papules or nodules that may ulcerate &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> Eventually&#44; they can be amelanotic and reach large dimensions&#44; leading to significant morbidity&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> In the case of in-transit metastases&#44; they are usually located between the primary tumor site and the regional lymph node&#46; However&#44; in some situations&#44; they may arise on the opposite side&#44; due to a change in lymphatic flow secondary to the tumor presence&#46; <a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> More atypical cases&#44; such as erythematous plaques &#40;erysipela-like&#41;&#44; sclerosing &#40;<span class="elsevierStyleItalic">en cuirasse</span>&#41;&#44; purpuric&#44; and telangiectatic lesions have been described&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> There are also reports of zosteriform metastases with vesiculobullous lesions and nodules distributed across a dermatome&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Breast</span><p id="par0095" class="elsevierStylePara elsevierViewall">Most cases of breast cancer cutaneous metastasis are due to adenocarcinomas &#40;77&#37;&#8211;82&#37;&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">17&#44;24</span></a> They usually arise in the anterior thorax due to regional lymphatic spread&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> Clinically&#44; the most common form of presentation comprises normochromic papules or nodules&#46; However&#44; some well-characterized presentations are described&#44; namely&#58; telangiectatic carcinoma&#44; erysipeloid carcinoma&#44; carcinoma <span class="elsevierStyleItalic">en cuirasse</span> and neoplastic alopecia&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">Telangiectatic carcinoma presents with violaceous papules on a telangiectatic surface&#44; arising close to the previous mastectomy scar&#46; Less commonly&#44; papulovesicular lesions similar to circumscribed lymphangioma appear&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> Erysipeloid &#40;or inflammatory&#41; carcinoma appears as erythematous&#44; warm&#44; plaques with well-demarcated borders&#44; affecting the breast and adjacent skin &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> Marneros et&#46; al&#46; have shown that telangiectatic carcinoma spread occurs predominantly via blood vessels&#44; whereas in erysipeloid carcinoma the spread is lymphatic&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> In carcinoma <span class="elsevierStyleItalic">en cuirasse</span>&#44; the skin acquires an infiltrated hardened appearance&#44; similar to scleroderma&#46; Finally&#44; in neoplastic alopecia&#44; there are nodules or hardened plaques on the scalp&#44; which result in alopecia&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> The alopecia can be cicatricial and irreversible&#44; as neoplastic cells can destroy hair follicles and induce fibroplasia&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> As with melanoma&#44; cases with papules arranged in a zosteriform pattern have also been described&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> It is noteworthy that presentations similar to telangiectatic&#44; <span class="elsevierStyleItalic">en cuirasse</span>&#44; erysipeloid carcinoma&#44; and mucinous alopecia have been described in metastases from other tumors&#44; but are more commonly secondary to breast adenocarcinoma&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a></p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0105" class="elsevierStylePara elsevierViewall">As for prognosis&#44; Hu et&#46; al&#46; demonstrated that the mean survival of patients with breast cancer and cutaneous metastasis is 57 months&#44; and only 25 months among those with concomitant visceral metastasis&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a></p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Lung</span><p id="par0110" class="elsevierStylePara elsevierViewall">Lung cancer metastases are most often seen in the liver&#44; bones&#44; central nervous system&#44; adrenal glands&#44; and mediastinal lymph nodes&#44; with cutaneous metastasis being rare&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> It is estimated that between 1&#37; to 12&#37; of patients with lung cancer have cutaneous metastases&#46;<a class="elsevierStyleCrossRefs" href="#bib0150"><span class="elsevierStyleSup">30&#44;31</span></a> When analyzing all types of cutaneous metastases&#44; patients with lung cancer metastases have the worst prognosis&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> Although they can affect any site on the skin&#44; they preferentially affect the head and neck&#44; anterior thorax&#44; and abdomen&#46; As with breast cancer&#44; adenocarcinoma is the most common metastatic type&#44; followed by squamous cell carcinoma&#44; while small cell lung cancer is the least frequent one&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> The primary tumor is usually located in the upper pulmonary lobes&#46;<a class="elsevierStyleCrossRefs" href="#bib0150"><span class="elsevierStyleSup">30&#44;31</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">Clinically&#44; they are indistinguishable from metastases from tumors with other origins&#46; They usually present as normochromic or slightly erythematous subcutaneous nodules&#44; hardened and adhered to deep planes &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46; Most of the time they appear as solitary lesions&#44; but multiple lesions can appear subsequently&#46; There are reports of metastases simulating keratoacanthomas&#44;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a> erythematous nodules located at the tip of the nose &#40;&#8220;clown nose&#8221;&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> with a zosteriform pattern of distribution or simulating erysipelas&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a> A little-known involvement is the subungual type&#46; A literature review showed that subungual metastasis occurs more frequently in patients with lung &#40;41&#37;&#41;&#44; genitourinary &#40;17&#37;&#41;&#44; and breast &#40;9&#37;&#41; cancer&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a> These metastases manifest as subungual erythematous-violaceous nodules or as edema&#44; erythema&#44; and pain in the distal phalanges simulating an infectious condition&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a></p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0120" class="elsevierStylePara elsevierViewall">It is noteworthy that most of the time when there is cutaneous metastasis&#44; other extrapulmonary sites are often also detected&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a></p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Gastrointestinal tract</span><p id="par0125" class="elsevierStylePara elsevierViewall">Among the malignant neoplasms of the gastrointestinal tract&#44; colorectal adenocarcinoma is the one that most often leads to cutaneous metastases&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> At the time of the diagnosis&#44; about 10&#37; of the cases already have distant metastasis&#44; and the most commonly affected sites are the liver&#44; lungs and central nervous system&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a> It is estimated that about 4&#37; of patients with colorectal cancer progress to cutaneous metastasis&#44; and the mean time from the diagnosis to metastasis onset is 25 months&#46;<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">17&#44;38</span></a> The mean age at the metastasis diagnosis is 55 years&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">Skin involvement can occur either by contiguity&#44; lymphatic or hematogenous spread&#44; or by spread along embryonic remnants&#44; such as the urachus&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a> For this reason&#44; the skin of the abdomen is the most frequently affected cutaneous site&#44; followed by the presacral and perineal region&#44; with the latter being more often related to rectal cancer&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> In one study&#44; most cutaneous metastases arose from the colectomy surgical incision sites&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> Nonetheless&#44; there are reports of spread to the most diverse locations&#44; such as the thorax&#44; upper limbs&#44; and head and neck region&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a> When the metastasis affects the umbilical region&#44; it is called Sister Mary Joseph&#8217;s nodule&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a> This finding is not pathognomonic of colorectal tumors&#44; as it has been reported in other malignant tumors such as stomach&#44; ovary&#44; pancreas&#44; and even uterine cervix&#44; gallbladder&#44; and small bowel cancer&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">There is no characteristic clinical presentation&#44; with most appearing as pink or reddish&#44; firm nodular lesions that may ulcerate&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> Other described presentations are epidermal cyst-like lesions&#44; neurofibromas&#44; annular erythema&#44; condylomas&#44; elephantiasis nostra verrucosa&#44; and areas of alopecia&#46;<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">17&#44;40</span></a> In the case of Sister Mary Joseph&#8217;s nodule&#44; there are typically firm nodules measuring 0&#46;5 to 2&#8239;cm&#44; which may eventually show purulent&#44; serous&#44; or bloody secretion&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall">In the case of gastric tumors&#44; signet-ring cell carcinoma is the most common to show cutaneous metastasis&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a> As with colorectal adenocarcinoma&#44; the abdomen is the most commonly affected site and clinically may present as nodules&#44; erysipela-like lesions&#44; or epidermal cyst-like lesions&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a> The prognosis is very poor in both metastases&#44; with a mean survival of a few months&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">Finally&#44; there have been rare reports of cutaneous metastases from malignant neoplasms of the esophagus&#44; pancreas&#44; and liver&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a> In these cases&#44; the lesions were identified in different sites&#44; such as the scalp&#44; abdomen&#44; and dorsum region&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Genitourinary system</span><p id="par0150" class="elsevierStylePara elsevierViewall">Of the cancers of the urinary system&#44; renal cancer is the most common one&#46; As renal cell carcinoma displays few signs and symptoms&#44; most are diagnosed in later stages when metastases already exist&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">44</span></a> In these metastatic cases&#44; the skin is the site of the metastasis less than 2&#37; of the time&#44; with clear cell renal carcinoma being the most common histopathological subtype&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> In most cases&#44; the patient already has a diagnosis of renal cancer when the cutaneous metastasis is identified &#40;six to five years after the diagnosis&#41;&#44; but in up to 20&#37; of cases&#44; the cutaneous lesion appears before the identification of the primary renal tumor&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a></p><p id="par0155" class="elsevierStylePara elsevierViewall">The head and neck region is frequently affected by metastases from renal cell carcinoma&#46; The current theory explains that renal veins have anastomoses with the vertebral plexuses&#44; which in turn are connected to the cephalic vasculature&#46; This would allow the hematogenous spread of renal neoplastic cells to the head and neck region&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">46</span></a> It is important to emphasize that renal cell carcinoma&#44; as well as follicular thyroid carcinoma and hepatocellular carcinoma preferentially show hematogenous spread&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">46</span></a></p><p id="par0160" class="elsevierStylePara elsevierViewall">Cutaneous metastases from renal cell carcinoma present as rapidly growing nodules that may be normochromic or more characteristically reddish&#46; This is due to high tumor vascularity and therefore can be confused with hemangiomas&#44; ruby angiomas&#44; or pyogenic granulomas&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">47</span></a> The presence of metastasis is a marker of worse prognosis and survival expectancy is about six months&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">More rarely&#44; cases of cutaneous metastasis of bladder urothelial carcinoma are described with a mean survival of fewer than 12 months&#46; In most cases&#44; cutaneous involvement occurs through direct tumor invasion&#44; but it may also be secondary to vascular spread &#40;lymphatic or hematogenous&#41; or iatrogenic implantation &#40;following procedures such as cystectomy&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a> Therefore&#44; in most cases&#44; the lesion is located in the lower abdomen&#44; pelvis or scrotum&#46; The clinical presentation is non-specific and may be as single or multiple nodules&#44; infiltrated plaques&#44; or even showing a sclerosing appearance&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">49</span></a> Finally&#44; Savell et&#46; al&#46; described a case of urothelial carcinoma manifesting as livedo racemosa due to vascular occlusion&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">50</span></a></p><p id="par0170" class="elsevierStylePara elsevierViewall">Cutaneous metastases from gynecological &#40;excluding breast&#41; tumors may account for up to 8&#46;5&#37; of secondary implants in female patients&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a> Most cases are derived from malignant ovarian neoplasms&#44; but they can also originate from uterine cervix cancer&#46; For anatomical reasons&#44; the abdomen &#40;especially the umbilicus&#41; is the most commonly affected site&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a> As for males&#44; it is known that prostate cancer&#44; which is very frequent&#44; rarely courses with cutaneous metastases&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a></p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Head and neck</span><p id="par0175" class="elsevierStylePara elsevierViewall">Head and neck squamous cell carcinomas have the lung and bones as the most common sites of distant metastasis&#46; Pitman et&#46; al&#46;&#44; in a cohort of 2&#44;491 patients with head and neck squamous cell carcinoma&#44; identified only 19 &#40;0&#46;763&#37;&#41; with cutaneous metastasis&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">51</span></a> Yoskovitch et al&#46; al&#46; identified 19 cases &#40;2&#46;4&#37;&#41; of cutaneous metastases among 798 cases of head and neck squamous cell carcinoma&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">52</span></a> It is important to note that in these studies&#44; cases of cutaneous involvement due to tumor contiguity were excluded&#44; and only those with distant metastasis were included&#46;</p><p id="par0180" class="elsevierStylePara elsevierViewall">Squamous cell carcinomas of the oral cavity&#44; particularly the mouth floor&#44; are the ones that most often lead to cutaneous metastases&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">52</span></a> The neck&#44; scalp&#44; and anterior thorax are the sites affected in 63&#37;&#44; 15&#37;&#44; and 10&#37; of cases&#44; respectively&#44; and the lesions are multiple in most cases&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">52</span></a> The mean survival after the onset of metastasis is only three months&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">51</span></a></p><p id="par0185" class="elsevierStylePara elsevierViewall">Another frequent malignant tumor of the neck is thyroid carcinoma&#44; the most common endocrinological malignancy&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">53</span></a> The two main histopathological types &#40;papillary and follicular&#41; most frequently affect the skin secondarily&#44; with an estimated incidence of less than one in 1&#44;000 cases&#46;<a class="elsevierStyleCrossRefs" href="#bib0270"><span class="elsevierStyleSup">54&#44;55</span></a> There are very rare cases of cutaneous metastasis from anaplastic or medullary carcinomas&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">56</span></a> It occurs in men and women in equal proportions&#44; with a mean age of 50 years&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a> The scalp is involved in most cases&#44; although the involvement of other areas such as the trunk &#40;anterior and posterior&#41;&#44; face&#44; and neck have also been reported &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0270"><span class="elsevierStyleSup">54&#44;57</span></a> There is a characteristic clinical presentation since most reports in the literature describe erythematous&#44; pruritic&#44; or ulcerated nodules located on the scalp&#46;<a class="elsevierStyleCrossRefs" href="#bib0265"><span class="elsevierStyleSup">53&#44;57</span></a> The mean survival after the diagnosis of cutaneous metastasis is 19 months&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a></p><elsevierMultimedia ident="fig0020"></elsevierMultimedia></span></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Diagnosis</span><p id="par0190" class="elsevierStylePara elsevierViewall">Definitive diagnosis depends on a thorough clinical examination&#44; imaging tests&#44; and histopathological analysis&#46; <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> summarizes histopathological evidence for suspected skin metastases&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0195" class="elsevierStylePara elsevierViewall">Histopathological and immunohistochemical characteristics of cutaneous metastases tend to be similar to that of the primary tumor&#59; however&#44; metastatic cells tend to be more anaplastic&#44; that is less differentiated&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">58</span></a> Hussein recommends a basic immunohistochemical panel including CD45 &#40;for lymphoid malignancies&#41;&#44; AE1&#47;AE3 pankeratins &#40;for most carcinomas&#41;&#44; S100 &#40;melanomas&#41;&#44; and CD34 &#40;vascular neoplasms and leukemias&#41;&#46; Subsequently&#44; a second panel may be performed including lymphoid markers &#40;CD3 and CD20 for T and B lymphocytes&#44; respectively&#41;&#44; epithelial markers &#40;EMA and CEA&#41;&#44; chromogranin &#40;neuroendocrine tumors&#41;&#44; thyroid transcription factor &#40;lung cancer&#41;&#44; WT1 &#40;ovarian carcinoma&#41;&#44; prostate-specific antigen and acid phosphatase &#40;prostate carcinoma&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">58</span></a><a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a> summarizes the immunophenotypes of the main tumors that metastasize to the skin and <a class="elsevierStyleCrossRefs" href="#fig0025">Figs&#46; 5 and 6</a> exemplify them&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><elsevierMultimedia ident="fig0025"></elsevierMultimedia><elsevierMultimedia ident="fig0030"></elsevierMultimedia><p id="par0200" class="elsevierStylePara elsevierViewall">Even after immunohistochemical evaluation&#44; sometimes the pathologist cannot accurately determine the primary tumor and only classifies it into general classes&#44; such as adenocarcinoma&#44; squamous cell carcinoma&#44; or undifferentiated carcinoma&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> In some cases&#44; after the initial evaluation&#44; the primary origin of the tumor cannot be determined and it is then classified as cancer of an unknown primary site&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">59</span></a> In these cases&#44; a more in-depth assessment is required&#46; The first radiological exams to be performed are computed tomography &#40;CT&#41; and&#47;or magnetic resonance imaging &#40;MRI&#41; of different segments of the body&#44; associated with mammography when breast cancer is suspected&#46; If these are inconclusive&#44; the next step is the combined positron emission tomography &#40;PET&#41; and CT &#40;PET-CT&#41; imaging test&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">59</span></a></p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Treatment</span><p id="par0205" class="elsevierStylePara elsevierViewall">Overall&#44; treatment should be directed at the primary tumor&#46; As in most cases&#44; the presence of cutaneous metastasis indicates advanced disease&#44; systemic antineoplastic therapy is usually the chosen therapeutic option&#46; However&#44; systemic therapy may have reduced efficacy in cutaneous lesions&#44; and skin-directed therapies have an adjuvant function&#46;</p><p id="par0210" class="elsevierStylePara elsevierViewall">A meta-analysis including 47 studies and 4&#44;313 skin metastases evaluated five skin-directed therapies&#58; electrochemotherapy&#44; photodynamic therapy&#44; radiotherapy&#44; intralesional therapy&#44; and topical therapy&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">60</span></a> The researchers found a complete response rate and an objective response rate of 35&#46;5&#37; and 60&#46;2&#37;&#44; respectively&#46; Electrochemotherapy for cutaneous metastases uses short electrical pulses directed at the tumor to permeabilize cell membranes aiming to increase the absorption of intralesional or intravenous chemotherapy&#46;</p><p id="par0215" class="elsevierStylePara elsevierViewall">As for intralesional therapies&#44; there have been studies with injections of recombinant antibodies directed at ErbB2&#47;HER2 in cases of uterine cervix and breast cancer and interferon and interleukin-2 in cases of melanoma&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">61</span></a> It is also possible to perform treatment with topical immunotherapy for some tumors&#46; A Brazilian study showed that diphencyprone can lead to up to 37&#37; of complete response in cases of cutaneous melanoma metastases&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">62</span></a></p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Conclusion</span><p id="par0220" class="elsevierStylePara elsevierViewall">Although infrequent&#44; cutaneous metastasis can be the first sign of a malignant neoplasm or indicate its recurrence&#46; The dermatologist must know how to identify suspicious lesions and perform an adequate biopsy&#46; The diagnosis will depend on the clinical&#44; histopathological&#44; and immunohistochemical analysis&#46; Sometimes the identification of the primary site is difficult&#44; but a thorough evaluation using imaging tests and constant surveillance is important&#46;</p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Financial support</span><p id="par0225" class="elsevierStylePara elsevierViewall">None declared&#46;</p></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Authors&#8217; contributions</span><p id="par0230" class="elsevierStylePara elsevierViewall">Bruno de Castro e Souza&#58; Drafting and editing of the manuscript&#59; critical review of the literature&#46;</p><p id="par0235" class="elsevierStylePara elsevierViewall">Denis Miyashiro&#58; Collection&#44; analysis and interpretation of data&#59; drafting and editing of the manuscript&#59; critical review of the literature&#46;</p><p id="par0240" class="elsevierStylePara elsevierViewall">Marcella Soares Pincelli&#58; Design and planning of the study&#44; drafting and editing of the manuscript&#59; critical review of the literature&#46;</p><p id="par0245" class="elsevierStylePara elsevierViewall">Jos&#233; Antonio Sanches&#58; Design and planning of the study&#44; drafting and editing of the manuscript&#59; critical review of the literature&#46;</p></span><span id="sec0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Conflicts of interest</span><p id="par0250" class="elsevierStylePara elsevierViewall">None declared&#46;</p></span></span>"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Cutaneous metastases from solid tumors are uncommon events in clinical practice&#46; Most of the time&#44; the patient already has the diagnosis of a malignant neoplasm when the cutaneous metastasis is detected&#46; However&#44; in up to one-third of cases&#44; cutaneous metastasis is identified before the primary tumor&#46; Therefore&#44; its identification may be essential for starting treatment&#44; although it is usually indicative of poor prognosis&#46; The diagnosis will depend on clinical&#44; histopathological&#44; and immunohistochemical analysis&#46; Sometimes the identification of the primary site is difficult&#59; however&#44; a thorough analysis using imaging tests and constant surveillance is important&#46;</p></span>"
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">CK7&#44; Estrogen and Progesterone Receptor&#44; Ber-EP4&#44; GATA3&#44; Mammaglobin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CK20&#44; CK5&#47;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Colon adenocarcinoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CK20&#44; CDX2&#44; CEA&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CK7 &#40;some cases may be positive&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Stomach adenocarcinoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CK20&#44; CK7&#44; CEA&#44; CDX2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CK7 &#40;some cases may be positive&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Lung adenocarcinoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">FTT-1&#44; CK7&#44; CEA&#44; EMA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CK5&#47;6&#44; CK20&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Small-cell lung cancer&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">FTT-1&#44; neuron-specific enolase &#40;NSE&#41;&#44; chromogranin&#44; synaptophysin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CK7&#44; CK20&#44; CD99&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Clear cell renal carcinoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CAM5&#46;2&#44; EMA&#44; CD10&#44; RCC-Ma&#44; vimentin&#44; S100&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Melan-A&#44; TTF-1&#44; CK7&#44; CK20&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Melanoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Vimentin&#44; S100&#44; tyrosinase&#44; Melan-A&#44; HMB45&#44; MITF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Bladder&#47;urothelial&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">P63&#44; CK5&#47;6&#44; CK7&#44; CK20&#44; uroplakin III&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Prostate&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">PSA&#44; prostatic acid phosphatase&#44;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CK7&#44; CK20&#44; thrombomodulin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ovary&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CA&#46;125&#44; CK7&#44; PAX8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CK20 &#40;except some mucinous variants&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Head and neck squamous cell carcinoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CK5&#47;6&#44; p63&#44; CK903&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Thyroid&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">FTT-1&#44; thyroglobulin&#44; PAX8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Summary of immunophenotypes of the main tumors that metastasize to the skin&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">58</span></a></p>"
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      "titulo" => "References"
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        0 => array:2 [
          "identificador" => "bibs0005"
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                0 => array:2 [
                  "contribucion" => array:1 [
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                        0 => array:2 [
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                            1 => "R&#46; Guti&#233;rrez"
                            2 => "O&#46; Paiva"
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                      ]
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                  ]
                  "host" => array:1 [
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                            "web" => "Medline"
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                      "titulo" => "Cutaneous metastatic disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "R&#46;A&#46; Schwartz"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
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                      "Revista" => array:7 [
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                        0 => array:2 [
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                  "contribucion" => array:1 [
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                          "etal" => false
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                  "host" => array:1 [
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                        0 => array:2 [
                          "etal" => false
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                            1 => "R&#46;K&#46; Jain"
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                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/nrd3455"
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                  "contribucion" => array:1 [
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "Z&#46; Diamantopoulou"
                            1 => "F&#46; Castro-Giner"
                            2 => "F&#46;D&#46; Schwab"
                            3 => "C&#46; Foerster"
                            4 => "M&#46; Saini"
                            5 => "S&#46; Budinjas"
                          ]
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                      ]
                    ]
                  ]
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                    0 => array:2 [
                      "doi" => "10.1038/s41586-022-04875-y"
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                      "titulo" => "Tumour-cell invasion and migration&#58; diversity and escape mechanisms"
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                          "etal" => false
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                            0 => "P&#46; Friedl"
                            1 => "K&#46; Wolf"
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                    0 => array:2 [
                      "doi" => "10.1038/nrc1075"
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                        "tituloSerie" => "Nat Rev Cancer"
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            7 => array:3 [
              "identificador" => "bib0040"
              "etiqueta" => "8"
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                0 => array:2 [
                  "contribucion" => array:1 [
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                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "P&#46; Auguste"
                            1 => "L&#46; Fallavollita"
                            2 => "N&#46; Wang"
                            3 => "J&#46; Burnier"
                            4 => "A&#46; Bikfalvi"
                            5 => "P&#46; Brodt"
                          ]
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                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.2353/ajpath.2007.060886"
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                        "fecha" => "2007"
                        "volumen" => "170"
                        "paginaInicial" => "1781"
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                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17456781"
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            8 => array:3 [
              "identificador" => "bib0045"
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                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "TGFbeta primes breast tumors for lung metastasis seeding through angiopoietin-like 4"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "D&#46; Padua"
                            1 => "X&#46;H&#46; Zhang"
                            2 => "Q&#46; Wang"
                            3 => "C&#46; Nadal"
                            4 => "W&#46;L&#46; Gerald"
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Continuing Medical Education
Cutaneous metastases from solid neoplasms – Literature review
Bruno de Castro e Souza
Autor para correspondência
bruno.csouza@hc.fm.usp.br

Corresponding author.
, Denis Miyashiro, Marcella Soares Pincelli, José Antonio Sanches
Department of Dermatology, Hospital das Clínicas, Universidade de São Paulo, São Paulo, SP, Brazil
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Cutaneous metastases from solid tumors are uncommon events in clinical practice&#46; It is estimated that between 0&#46;7&#37; and 9&#37; of metastases from these tumors occur in the skin&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Most of the time&#44; the patient already has a diagnosis of malignant neoplasm when the cutaneous metastasis is detected&#46; However&#44; in up to one-third of cases&#44; skin metastasis is identified before the primary tumor&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> In some cases&#44; the identification of the cutaneous metastasis indicates cancer recurrence&#44; and in 79&#37; of cases&#44; there are concurrent visceral metastases&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> The clinical presentation is diverse and can simulate inflammatory diseases&#44; benign tumors&#44; or even malignant skin tumors&#46; This review discusses the current paradigm of metastasis mechanisms and displays the main clinical presentations&#46; For didactic reasons&#44; clinical presentations will be discussed according to the primary tumor site&#44; including the ones originally from the skin&#46; Paraneoplastic manifestations and hematological malignancies will not be reviewed in this article&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Etiopathogenesis</span><p id="par0015" class="elsevierStylePara elsevierViewall">Metastasis is defined as the development of a tumor at some distance from the primary site&#46; It develops predominantly by vascular invasion &#40;lymphatic or hematogenous&#41;&#46; There is a discussion in the literature whether implants should be considered as actual metastases either by contiguity or iatrogenically&#46; Currently&#44; the metastatic process is understood as a complex phenomenon that occurs in parallel with the development of the primary tumor&#46; Due to its greater importance&#44; metastases through vascular invasion will be discussed in more detail&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">The pathophysiology of metastasis is divided into six stages&#58; &#40;1&#41; local invasion&#44; &#40;2&#41; intravasation&#44; &#40;3&#41; survival in the circulation&#44; &#40;4&#41; arrest in a distant organ&#44; &#40;5&#41; extravasation&#44; &#40;6&#41; micrometastasis formation and metastatic colonization&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Local invasion</span><p id="par0025" class="elsevierStylePara elsevierViewall">After the development of the malignant tumor in the primary site&#44; local invasion occurs&#46; This event consists of the entry of malignant cells into the soft tissue adjacent to the tumor&#46; For this to occur&#44; disruption of the basement membrane secondary to the action of matrix metalloproteinases is necessary&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Intravasation</span><p id="par0030" class="elsevierStylePara elsevierViewall">Intravasation is a complex phenomenon that allows malignant cells to enter the blood or lymphatic vessels&#46; This process is essential for malignant cells to reach distant sites and continue the metastatic process&#46; It has been well-described that malignant tumors have the ability to produce neoangiogenesis&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> What happens is that the neoformed vessels have little coverage of pericytes and endothelial cells with little cell adhesion&#44; facilitating the entry of malignant cells &#40;intravasation&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;5</span></a> Curiously&#44; more recent evidence demonstrates that this phenomenon occurs predominantly during sleep&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Survival in circulation</span><p id="par0035" class="elsevierStylePara elsevierViewall">Once inside the vessels&#44; the malignant cells need to survive&#46; They are subject to trauma resulting from hemodynamic forces and&#44; in addition&#44; are subject to the immune system action&#46; The main adaptive way to evade these mechanisms is the formation of platelet microthrombi around the neoplastic cells&#44; which protect them from these phenomena&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Arrest in a distant organ</span><p id="par0040" class="elsevierStylePara elsevierViewall">Tumors can reach virtually any tissue in the body through blood or lymphatic circulation&#46; The major question is why some tumors have preferential metastasis sites&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> For instance&#44; there is a clear preference for bone in prostate cancer metastases or&#44; in cases of colon tumors&#44; metastases to the liver&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> A strong interaction between the primary tumor and the target site soft tissue is believed to be necessary&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> Although the skin is a highly vascularized organ&#44; few tumors&#44; such as melanoma&#44; have an obvious predilection for it&#46; Perhaps this is due to good immunological protection or low soft tissue-malignant tumor interaction&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Extravasation</span><p id="par0045" class="elsevierStylePara elsevierViewall">After reaching the target organ circulation&#44; malignant cells must exit the vessels to reach the soft tissue&#46; This process may occur due to mechanical vascular rupture or a more complex process&#46; In the latter case&#44; tumor cells might induce vascular hyperpermeability secondary to the release of proteins such as epiregulin &#40;EREG&#41;&#44; cyclooxygenase 2 &#40;COX-2&#41;&#44; metalloproteinase 1 and 2 &#40;MMP-1 and MMP-2&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> It is important to emphasize that each protein has a specific action on the vascularization of each target organ&#44; reinforcing the idea that each malignant tumor has one or more preferential metastasis sites&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Micrometastasis formation and metastatic colonization</span><p id="par0050" class="elsevierStylePara elsevierViewall">The last step is tumor survival in the target site soft tissue&#46; For this to occur&#44; the tumor needs to have a self-renewal and proliferation capacity&#46; Additionally&#44; it releases substances that make the adjacent soft tissue more receptive to its multiplication&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> Micrometastases may persist in a latent state for months or years&#46; During this period&#44; micrometastases that acquire genetic or epigenetic alterations and can make the microenvironment more favorable to their development with the formation of macroscopic metastases with significant lethal potential&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Epidemiology</span><p id="par0055" class="elsevierStylePara elsevierViewall">There is divergence in the literature about which tumors most frequently metastasize to the skin&#46; More recent studies indicate that melanoma is the most frequent one&#44; but in some classic studies&#44; this neoplasm appears only in the fourth place&#46;<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10&#44;11</span></a> A 2002 meta-analysis identified that breast tumors are the most frequent ones &#40;24&#37;&#41; followed by kidney &#40;4&#37;&#41;&#44; ovary &#40;3&#46;8&#37;&#41;&#44; bladder &#40;3&#46;6&#37;&#41;&#44; lung &#40;3&#46;4&#37;&#41;&#44; colorectal &#40;3&#46;4&#37;&#41;&#44; and prostate &#40;0&#46;7&#37;&#41; cancer&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> However&#44; cases of melanoma were excluded from this study&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">There is an epidemiological difference according to sex&#46; A Brazilian study with 209 cases of cutaneous metastases identified that the most frequent cutaneous metastases in women originated from breast &#40;63&#46;19&#37;&#41;&#44; large intestine &#40;10&#46;41&#37;&#41;&#44; and lung cancer &#40;4&#46;16&#37;&#41; whereas in men&#44; the order of frequency was lung&#44; stomach&#44; and larynx &#40;33&#46;84&#37;&#44; 12&#46;3&#37;&#44; and 7&#46;69&#37;&#44; respectively&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> When specifically analyzing the pediatric population&#44; the most frequent primary tumors are rhabdomyosarcoma and neuroblastoma&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">It is a well-known fact that there are some areas of the skin where the appearance of metastatic lesions is more frequent&#46; The anterior thorax is the most common site&#44; followed by the abdomen&#44; head and neck &#40;including the scalp&#41;&#44; and limbs&#46;<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11&#8211;13</span></a> There is a clear predilection for the affected site according to the primary tumor&#59; therefore&#44; the cutaneous metastasis site may indicate a possible neoplastic origin&#46; For instance&#44; breast cancer most often metastasizes to the anterior thorax&#44; whereas gastrointestinal tract tumors secondarily most often affect the abdomen&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a><a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> summarizes the preferred sites of skin metastases&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Clinical presentation</span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Skin</span><p id="par0070" class="elsevierStylePara elsevierViewall">Several originally cutaneous malignant neoplasms can develop metastases to the skin&#46; Of these&#44; the most frequent is melanoma and&#44; for that reason&#44; it will be discussed in more detail&#46; However&#44; it is important to emphasize that squamous cell carcinoma&#44; Merkel cell carcinoma&#44; and even malignant pilomatricoma can develop skin metastases&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">A North-American study has shown that the number of cutaneous metastases from melanoma has been increasing in recent years&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> This is not a rare event in the natural history of the disease&#46; Secondary skin involvement occurs in 10&#37; to 17&#37; of patients with melanoma and is present in up to 50&#37; of individuals with disseminated disease&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> In most cases&#44; the skin is the first site of metastatic involvement and&#44; in about 30&#37; of cases&#44; it occurs after lymph node metastasis&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> The concomitant finding of cutaneous&#44; nodal&#44; and visceral metastasis occurs in approximately 10&#37; of cases&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">Cutaneous melanoma metastases are divided into microsatellite&#44; satellite&#44; in-transit or distant metastases&#46; The first is microscopic metastasis &#40;cutaneous or subcutaneous&#41; disconnected from the primary tumor&#44; therefore&#44; it is not perceived in the clinical examination&#46; A satellite metastasis is a metastatic tumor visible up to 2&#8239;cm from the primary tumor site&#46; In-transit metastasis is defined as any cutaneous or subcutaneous metastasis that is more than 2&#8239;cm away from the primary lesion but within the regional lymphatic drainage&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> Despite this differentiation&#44; both satellite lesions and in-transit metastasis correspond to intralymphatic spread and have similar therapeutic and prognostic implications&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> It is also important to differentiate lymph node metastases from local recurrence that occurs as a result of incomplete resection of the primary tumor&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">Distant metastasis is related to hematogenous spread and occurs when the cutaneous metastatic site is far from the lymphatic drainage focus of the primary tumor&#46; This differentiation is important&#44; as in the first two scenarios the patient is considered to have locoregional disease&#44; whereas&#44; in the latter&#44; the patient has distant metastasis&#44; which considerably worsens the patient&#8217;s prognosis&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> Melanoma staging is beyond the scope of this article and therefore will not be discussed&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">Cutaneous metastases from melanoma are most commonly found on the back in men and on the lower limbs in women&#46; The fact that secondary cutaneous locations occur in the same anatomical location as the initial cutaneous location in more than 30&#37; of cases explain the distinct patterns of metastases between sexes&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> Clinically&#44; there are generally black or brownish dermal or subcutaneous papules or nodules that may ulcerate &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> Eventually&#44; they can be amelanotic and reach large dimensions&#44; leading to significant morbidity&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> In the case of in-transit metastases&#44; they are usually located between the primary tumor site and the regional lymph node&#46; However&#44; in some situations&#44; they may arise on the opposite side&#44; due to a change in lymphatic flow secondary to the tumor presence&#46; <a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> More atypical cases&#44; such as erythematous plaques &#40;erysipela-like&#41;&#44; sclerosing &#40;<span class="elsevierStyleItalic">en cuirasse</span>&#41;&#44; purpuric&#44; and telangiectatic lesions have been described&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> There are also reports of zosteriform metastases with vesiculobullous lesions and nodules distributed across a dermatome&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Breast</span><p id="par0095" class="elsevierStylePara elsevierViewall">Most cases of breast cancer cutaneous metastasis are due to adenocarcinomas &#40;77&#37;&#8211;82&#37;&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">17&#44;24</span></a> They usually arise in the anterior thorax due to regional lymphatic spread&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> Clinically&#44; the most common form of presentation comprises normochromic papules or nodules&#46; However&#44; some well-characterized presentations are described&#44; namely&#58; telangiectatic carcinoma&#44; erysipeloid carcinoma&#44; carcinoma <span class="elsevierStyleItalic">en cuirasse</span> and neoplastic alopecia&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">Telangiectatic carcinoma presents with violaceous papules on a telangiectatic surface&#44; arising close to the previous mastectomy scar&#46; Less commonly&#44; papulovesicular lesions similar to circumscribed lymphangioma appear&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> Erysipeloid &#40;or inflammatory&#41; carcinoma appears as erythematous&#44; warm&#44; plaques with well-demarcated borders&#44; affecting the breast and adjacent skin &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> Marneros et&#46; al&#46; have shown that telangiectatic carcinoma spread occurs predominantly via blood vessels&#44; whereas in erysipeloid carcinoma the spread is lymphatic&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> In carcinoma <span class="elsevierStyleItalic">en cuirasse</span>&#44; the skin acquires an infiltrated hardened appearance&#44; similar to scleroderma&#46; Finally&#44; in neoplastic alopecia&#44; there are nodules or hardened plaques on the scalp&#44; which result in alopecia&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> The alopecia can be cicatricial and irreversible&#44; as neoplastic cells can destroy hair follicles and induce fibroplasia&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> As with melanoma&#44; cases with papules arranged in a zosteriform pattern have also been described&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> It is noteworthy that presentations similar to telangiectatic&#44; <span class="elsevierStyleItalic">en cuirasse</span>&#44; erysipeloid carcinoma&#44; and mucinous alopecia have been described in metastases from other tumors&#44; but are more commonly secondary to breast adenocarcinoma&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a></p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0105" class="elsevierStylePara elsevierViewall">As for prognosis&#44; Hu et&#46; al&#46; demonstrated that the mean survival of patients with breast cancer and cutaneous metastasis is 57 months&#44; and only 25 months among those with concomitant visceral metastasis&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a></p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Lung</span><p id="par0110" class="elsevierStylePara elsevierViewall">Lung cancer metastases are most often seen in the liver&#44; bones&#44; central nervous system&#44; adrenal glands&#44; and mediastinal lymph nodes&#44; with cutaneous metastasis being rare&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> It is estimated that between 1&#37; to 12&#37; of patients with lung cancer have cutaneous metastases&#46;<a class="elsevierStyleCrossRefs" href="#bib0150"><span class="elsevierStyleSup">30&#44;31</span></a> When analyzing all types of cutaneous metastases&#44; patients with lung cancer metastases have the worst prognosis&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> Although they can affect any site on the skin&#44; they preferentially affect the head and neck&#44; anterior thorax&#44; and abdomen&#46; As with breast cancer&#44; adenocarcinoma is the most common metastatic type&#44; followed by squamous cell carcinoma&#44; while small cell lung cancer is the least frequent one&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> The primary tumor is usually located in the upper pulmonary lobes&#46;<a class="elsevierStyleCrossRefs" href="#bib0150"><span class="elsevierStyleSup">30&#44;31</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">Clinically&#44; they are indistinguishable from metastases from tumors with other origins&#46; They usually present as normochromic or slightly erythematous subcutaneous nodules&#44; hardened and adhered to deep planes &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46; Most of the time they appear as solitary lesions&#44; but multiple lesions can appear subsequently&#46; There are reports of metastases simulating keratoacanthomas&#44;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a> erythematous nodules located at the tip of the nose &#40;&#8220;clown nose&#8221;&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> with a zosteriform pattern of distribution or simulating erysipelas&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a> A little-known involvement is the subungual type&#46; A literature review showed that subungual metastasis occurs more frequently in patients with lung &#40;41&#37;&#41;&#44; genitourinary &#40;17&#37;&#41;&#44; and breast &#40;9&#37;&#41; cancer&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a> These metastases manifest as subungual erythematous-violaceous nodules or as edema&#44; erythema&#44; and pain in the distal phalanges simulating an infectious condition&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a></p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0120" class="elsevierStylePara elsevierViewall">It is noteworthy that most of the time when there is cutaneous metastasis&#44; other extrapulmonary sites are often also detected&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a></p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Gastrointestinal tract</span><p id="par0125" class="elsevierStylePara elsevierViewall">Among the malignant neoplasms of the gastrointestinal tract&#44; colorectal adenocarcinoma is the one that most often leads to cutaneous metastases&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> At the time of the diagnosis&#44; about 10&#37; of the cases already have distant metastasis&#44; and the most commonly affected sites are the liver&#44; lungs and central nervous system&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a> It is estimated that about 4&#37; of patients with colorectal cancer progress to cutaneous metastasis&#44; and the mean time from the diagnosis to metastasis onset is 25 months&#46;<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">17&#44;38</span></a> The mean age at the metastasis diagnosis is 55 years&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">Skin involvement can occur either by contiguity&#44; lymphatic or hematogenous spread&#44; or by spread along embryonic remnants&#44; such as the urachus&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a> For this reason&#44; the skin of the abdomen is the most frequently affected cutaneous site&#44; followed by the presacral and perineal region&#44; with the latter being more often related to rectal cancer&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> In one study&#44; most cutaneous metastases arose from the colectomy surgical incision sites&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> Nonetheless&#44; there are reports of spread to the most diverse locations&#44; such as the thorax&#44; upper limbs&#44; and head and neck region&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a> When the metastasis affects the umbilical region&#44; it is called Sister Mary Joseph&#8217;s nodule&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a> This finding is not pathognomonic of colorectal tumors&#44; as it has been reported in other malignant tumors such as stomach&#44; ovary&#44; pancreas&#44; and even uterine cervix&#44; gallbladder&#44; and small bowel cancer&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">There is no characteristic clinical presentation&#44; with most appearing as pink or reddish&#44; firm nodular lesions that may ulcerate&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> Other described presentations are epidermal cyst-like lesions&#44; neurofibromas&#44; annular erythema&#44; condylomas&#44; elephantiasis nostra verrucosa&#44; and areas of alopecia&#46;<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">17&#44;40</span></a> In the case of Sister Mary Joseph&#8217;s nodule&#44; there are typically firm nodules measuring 0&#46;5 to 2&#8239;cm&#44; which may eventually show purulent&#44; serous&#44; or bloody secretion&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall">In the case of gastric tumors&#44; signet-ring cell carcinoma is the most common to show cutaneous metastasis&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a> As with colorectal adenocarcinoma&#44; the abdomen is the most commonly affected site and clinically may present as nodules&#44; erysipela-like lesions&#44; or epidermal cyst-like lesions&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a> The prognosis is very poor in both metastases&#44; with a mean survival of a few months&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">Finally&#44; there have been rare reports of cutaneous metastases from malignant neoplasms of the esophagus&#44; pancreas&#44; and liver&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a> In these cases&#44; the lesions were identified in different sites&#44; such as the scalp&#44; abdomen&#44; and dorsum region&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Genitourinary system</span><p id="par0150" class="elsevierStylePara elsevierViewall">Of the cancers of the urinary system&#44; renal cancer is the most common one&#46; As renal cell carcinoma displays few signs and symptoms&#44; most are diagnosed in later stages when metastases already exist&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">44</span></a> In these metastatic cases&#44; the skin is the site of the metastasis less than 2&#37; of the time&#44; with clear cell renal carcinoma being the most common histopathological subtype&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> In most cases&#44; the patient already has a diagnosis of renal cancer when the cutaneous metastasis is identified &#40;six to five years after the diagnosis&#41;&#44; but in up to 20&#37; of cases&#44; the cutaneous lesion appears before the identification of the primary renal tumor&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a></p><p id="par0155" class="elsevierStylePara elsevierViewall">The head and neck region is frequently affected by metastases from renal cell carcinoma&#46; The current theory explains that renal veins have anastomoses with the vertebral plexuses&#44; which in turn are connected to the cephalic vasculature&#46; This would allow the hematogenous spread of renal neoplastic cells to the head and neck region&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">46</span></a> It is important to emphasize that renal cell carcinoma&#44; as well as follicular thyroid carcinoma and hepatocellular carcinoma preferentially show hematogenous spread&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">46</span></a></p><p id="par0160" class="elsevierStylePara elsevierViewall">Cutaneous metastases from renal cell carcinoma present as rapidly growing nodules that may be normochromic or more characteristically reddish&#46; This is due to high tumor vascularity and therefore can be confused with hemangiomas&#44; ruby angiomas&#44; or pyogenic granulomas&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">47</span></a> The presence of metastasis is a marker of worse prognosis and survival expectancy is about six months&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">More rarely&#44; cases of cutaneous metastasis of bladder urothelial carcinoma are described with a mean survival of fewer than 12 months&#46; In most cases&#44; cutaneous involvement occurs through direct tumor invasion&#44; but it may also be secondary to vascular spread &#40;lymphatic or hematogenous&#41; or iatrogenic implantation &#40;following procedures such as cystectomy&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a> Therefore&#44; in most cases&#44; the lesion is located in the lower abdomen&#44; pelvis or scrotum&#46; The clinical presentation is non-specific and may be as single or multiple nodules&#44; infiltrated plaques&#44; or even showing a sclerosing appearance&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">49</span></a> Finally&#44; Savell et&#46; al&#46; described a case of urothelial carcinoma manifesting as livedo racemosa due to vascular occlusion&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">50</span></a></p><p id="par0170" class="elsevierStylePara elsevierViewall">Cutaneous metastases from gynecological &#40;excluding breast&#41; tumors may account for up to 8&#46;5&#37; of secondary implants in female patients&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a> Most cases are derived from malignant ovarian neoplasms&#44; but they can also originate from uterine cervix cancer&#46; For anatomical reasons&#44; the abdomen &#40;especially the umbilicus&#41; is the most commonly affected site&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a> As for males&#44; it is known that prostate cancer&#44; which is very frequent&#44; rarely courses with cutaneous metastases&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a></p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Head and neck</span><p id="par0175" class="elsevierStylePara elsevierViewall">Head and neck squamous cell carcinomas have the lung and bones as the most common sites of distant metastasis&#46; Pitman et&#46; al&#46;&#44; in a cohort of 2&#44;491 patients with head and neck squamous cell carcinoma&#44; identified only 19 &#40;0&#46;763&#37;&#41; with cutaneous metastasis&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">51</span></a> Yoskovitch et al&#46; al&#46; identified 19 cases &#40;2&#46;4&#37;&#41; of cutaneous metastases among 798 cases of head and neck squamous cell carcinoma&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">52</span></a> It is important to note that in these studies&#44; cases of cutaneous involvement due to tumor contiguity were excluded&#44; and only those with distant metastasis were included&#46;</p><p id="par0180" class="elsevierStylePara elsevierViewall">Squamous cell carcinomas of the oral cavity&#44; particularly the mouth floor&#44; are the ones that most often lead to cutaneous metastases&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">52</span></a> The neck&#44; scalp&#44; and anterior thorax are the sites affected in 63&#37;&#44; 15&#37;&#44; and 10&#37; of cases&#44; respectively&#44; and the lesions are multiple in most cases&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">52</span></a> The mean survival after the onset of metastasis is only three months&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">51</span></a></p><p id="par0185" class="elsevierStylePara elsevierViewall">Another frequent malignant tumor of the neck is thyroid carcinoma&#44; the most common endocrinological malignancy&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">53</span></a> The two main histopathological types &#40;papillary and follicular&#41; most frequently affect the skin secondarily&#44; with an estimated incidence of less than one in 1&#44;000 cases&#46;<a class="elsevierStyleCrossRefs" href="#bib0270"><span class="elsevierStyleSup">54&#44;55</span></a> There are very rare cases of cutaneous metastasis from anaplastic or medullary carcinomas&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">56</span></a> It occurs in men and women in equal proportions&#44; with a mean age of 50 years&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a> The scalp is involved in most cases&#44; although the involvement of other areas such as the trunk &#40;anterior and posterior&#41;&#44; face&#44; and neck have also been reported &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0270"><span class="elsevierStyleSup">54&#44;57</span></a> There is a characteristic clinical presentation since most reports in the literature describe erythematous&#44; pruritic&#44; or ulcerated nodules located on the scalp&#46;<a class="elsevierStyleCrossRefs" href="#bib0265"><span class="elsevierStyleSup">53&#44;57</span></a> The mean survival after the diagnosis of cutaneous metastasis is 19 months&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a></p><elsevierMultimedia ident="fig0020"></elsevierMultimedia></span></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Diagnosis</span><p id="par0190" class="elsevierStylePara elsevierViewall">Definitive diagnosis depends on a thorough clinical examination&#44; imaging tests&#44; and histopathological analysis&#46; <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> summarizes histopathological evidence for suspected skin metastases&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0195" class="elsevierStylePara elsevierViewall">Histopathological and immunohistochemical characteristics of cutaneous metastases tend to be similar to that of the primary tumor&#59; however&#44; metastatic cells tend to be more anaplastic&#44; that is less differentiated&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">58</span></a> Hussein recommends a basic immunohistochemical panel including CD45 &#40;for lymphoid malignancies&#41;&#44; AE1&#47;AE3 pankeratins &#40;for most carcinomas&#41;&#44; S100 &#40;melanomas&#41;&#44; and CD34 &#40;vascular neoplasms and leukemias&#41;&#46; Subsequently&#44; a second panel may be performed including lymphoid markers &#40;CD3 and CD20 for T and B lymphocytes&#44; respectively&#41;&#44; epithelial markers &#40;EMA and CEA&#41;&#44; chromogranin &#40;neuroendocrine tumors&#41;&#44; thyroid transcription factor &#40;lung cancer&#41;&#44; WT1 &#40;ovarian carcinoma&#41;&#44; prostate-specific antigen and acid phosphatase &#40;prostate carcinoma&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">58</span></a><a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a> summarizes the immunophenotypes of the main tumors that metastasize to the skin and <a class="elsevierStyleCrossRefs" href="#fig0025">Figs&#46; 5 and 6</a> exemplify them&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><elsevierMultimedia ident="fig0025"></elsevierMultimedia><elsevierMultimedia ident="fig0030"></elsevierMultimedia><p id="par0200" class="elsevierStylePara elsevierViewall">Even after immunohistochemical evaluation&#44; sometimes the pathologist cannot accurately determine the primary tumor and only classifies it into general classes&#44; such as adenocarcinoma&#44; squamous cell carcinoma&#44; or undifferentiated carcinoma&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> In some cases&#44; after the initial evaluation&#44; the primary origin of the tumor cannot be determined and it is then classified as cancer of an unknown primary site&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">59</span></a> In these cases&#44; a more in-depth assessment is required&#46; The first radiological exams to be performed are computed tomography &#40;CT&#41; and&#47;or magnetic resonance imaging &#40;MRI&#41; of different segments of the body&#44; associated with mammography when breast cancer is suspected&#46; If these are inconclusive&#44; the next step is the combined positron emission tomography &#40;PET&#41; and CT &#40;PET-CT&#41; imaging test&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">59</span></a></p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Treatment</span><p id="par0205" class="elsevierStylePara elsevierViewall">Overall&#44; treatment should be directed at the primary tumor&#46; As in most cases&#44; the presence of cutaneous metastasis indicates advanced disease&#44; systemic antineoplastic therapy is usually the chosen therapeutic option&#46; However&#44; systemic therapy may have reduced efficacy in cutaneous lesions&#44; and skin-directed therapies have an adjuvant function&#46;</p><p id="par0210" class="elsevierStylePara elsevierViewall">A meta-analysis including 47 studies and 4&#44;313 skin metastases evaluated five skin-directed therapies&#58; electrochemotherapy&#44; photodynamic therapy&#44; radiotherapy&#44; intralesional therapy&#44; and topical therapy&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">60</span></a> The researchers found a complete response rate and an objective response rate of 35&#46;5&#37; and 60&#46;2&#37;&#44; respectively&#46; Electrochemotherapy for cutaneous metastases uses short electrical pulses directed at the tumor to permeabilize cell membranes aiming to increase the absorption of intralesional or intravenous chemotherapy&#46;</p><p id="par0215" class="elsevierStylePara elsevierViewall">As for intralesional therapies&#44; there have been studies with injections of recombinant antibodies directed at ErbB2&#47;HER2 in cases of uterine cervix and breast cancer and interferon and interleukin-2 in cases of melanoma&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">61</span></a> It is also possible to perform treatment with topical immunotherapy for some tumors&#46; A Brazilian study showed that diphencyprone can lead to up to 37&#37; of complete response in cases of cutaneous melanoma metastases&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">62</span></a></p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Conclusion</span><p id="par0220" class="elsevierStylePara elsevierViewall">Although infrequent&#44; cutaneous metastasis can be the first sign of a malignant neoplasm or indicate its recurrence&#46; The dermatologist must know how to identify suspicious lesions and perform an adequate biopsy&#46; The diagnosis will depend on the clinical&#44; histopathological&#44; and immunohistochemical analysis&#46; Sometimes the identification of the primary site is difficult&#44; but a thorough evaluation using imaging tests and constant surveillance is important&#46;</p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Financial support</span><p id="par0225" class="elsevierStylePara elsevierViewall">None declared&#46;</p></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Authors&#8217; contributions</span><p id="par0230" class="elsevierStylePara elsevierViewall">Bruno de Castro e Souza&#58; Drafting and editing of the manuscript&#59; critical review of the literature&#46;</p><p id="par0235" class="elsevierStylePara elsevierViewall">Denis Miyashiro&#58; Collection&#44; analysis and interpretation of data&#59; drafting and editing of the manuscript&#59; critical review of the literature&#46;</p><p id="par0240" class="elsevierStylePara elsevierViewall">Marcella Soares Pincelli&#58; Design and planning of the study&#44; drafting and editing of the manuscript&#59; critical review of the literature&#46;</p><p id="par0245" class="elsevierStylePara elsevierViewall">Jos&#233; Antonio Sanches&#58; Design and planning of the study&#44; drafting and editing of the manuscript&#59; critical review of the literature&#46;</p></span><span id="sec0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Conflicts of interest</span><p id="par0250" class="elsevierStylePara elsevierViewall">None declared&#46;</p></span></span>"
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              "identificador" => "sec0075"
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            5 => array:2 [
              "identificador" => "sec0080"
              "titulo" => "Head and neck"
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          "identificador" => "sec0110"
          "titulo" => "Conflicts of interest"
        ]
        12 => array:1 [
          "titulo" => "References"
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      ]
    ]
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    "fechaRecibido" => "2022-08-29"
    "fechaAceptado" => "2022-10-25"
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          "clase" => "keyword"
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          "identificador" => "xpalclavsec1672048"
          "palabras" => array:3 [
            0 => "Immunohistochemistry"
            1 => "Medical oncology"
            2 => "Neoplastic metastasis"
          ]
        ]
      ]
    ]
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    "resumen" => array:1 [
      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Cutaneous metastases from solid tumors are uncommon events in clinical practice&#46; Most of the time&#44; the patient already has the diagnosis of a malignant neoplasm when the cutaneous metastasis is detected&#46; However&#44; in up to one-third of cases&#44; cutaneous metastasis is identified before the primary tumor&#46; Therefore&#44; its identification may be essential for starting treatment&#44; although it is usually indicative of poor prognosis&#46; The diagnosis will depend on clinical&#44; histopathological&#44; and immunohistochemical analysis&#46; Sometimes the identification of the primary site is difficult&#59; however&#44; a thorough analysis using imaging tests and constant surveillance is important&#46;</p></span>"
      ]
    ]
    "NotaPie" => array:1 [
      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Study conducted at the Hospital das Cl&#237;nicas&#44; Universidade de S&#227;o Paulo&#44; S&#227;o Paulo&#44; SP&#44; Brazil&#46;</p>"
      ]
    ]
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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Patient with cutaneous metastases of melanoma with an ulcerated tumor lesion and several papules and satellite nodules on the foot</p>"
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          "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Erythematous infiltrated plaque on the chest of a patient with cutaneous metastasis of breast cancer</p>"
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      2 => array:8 [
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          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Tumor lesion with papules and satellite erythema on the anterior thorax in a patient with cutaneous metastasis of thyroid cancer&#46; Note the previous thyroidectomy scar</p>"
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      4 => array:8 [
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        "mostrarFloat" => true
        "mostrarDisplay" => false
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          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">&#40;A&#41; Atypical cell nodules inside dermal capillaries in a case of breast adenocarcinoma metastasis &#40;Hematoxylin &#38; eosin&#44; &#215;100&#41;&#46; &#40;B&#41; Positive GATA3&#44; &#40;C&#41; CK7 and &#40;D&#41; mammaglobin corroborate the diagnosis</p>"
        ]
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        "identificador" => "fig0030"
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        "mostrarFloat" => true
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        "figura" => array:1 [
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            "Ancho" => 3341
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          "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">&#40;A&#41; Atypical nodular proliferation in the deep dermis in a patient with cutaneous metastasis of colon adenocarcinoma &#40;Hematoxylin &#38; eosin&#44; &#215;100&#41;&#46; &#40;B&#41; Positive CK7&#44; &#40;C&#41; CDX2 and &#40;D&#41; EMA corroborate the diagnosis</p>"
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              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Cutaneous site&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Primary tumor&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Scalp&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Breast&#44; lung&#44; kidney&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Face and neck&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Squamous cell carcinoma of the head and neck&#44; kidney&#44; lung&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Anterior thorax&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Breast&#44; lung&#44; melanoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Abdomen&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Colon&#44; stomach&#44; lung&#44; ovary&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Umbilical region&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Stomach&#44; pancreas&#44; colon&#44; ovaries&#44; kidney&#44; breast&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pelvis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Colon&#44; bladder&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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        "descripcion" => array:1 [
          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Main locations of cutaneous metastases according to the primary tumor<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a></p>"
        ]
      ]
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        "identificador" => "tbl0010"
        "etiqueta" => "Table 2"
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Presence of neoplastic cells within lymphatic or blood vessels&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Nodules located in the reticular dermis and&#47;or hypodermis without contact with the epidermis &#40;grenz zone&#41;&#46;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Presence of neoplastic cells lined up between collagen fibers &#40;&#8220;single filing&#8221;&#41;&nbsp;\t\t\t\t\t\t\n
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              ]
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        "descripcion" => array:1 [
          "en" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Histopathological clues for suspected cutaneous metastases<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">58</span></a></p>"
        ]
      ]
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        "tabla" => array:1 [
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            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"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Primary tumor&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Positive immunohistochemical markers&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Negative immunohistochemical markers&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Breast adenocarcinoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CK7&#44; Estrogen and Progesterone Receptor&#44; Ber-EP4&#44; GATA3&#44; Mammaglobin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CK20&#44; CK5&#47;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Colon adenocarcinoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CK20&#44; CDX2&#44; CEA&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CK7 &#40;some cases may be positive&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Stomach adenocarcinoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CK20&#44; CK7&#44; CEA&#44; CDX2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CK7 &#40;some cases may be positive&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Lung adenocarcinoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">FTT-1&#44; CK7&#44; CEA&#44; EMA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CK5&#47;6&#44; CK20&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Small-cell lung cancer&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">FTT-1&#44; neuron-specific enolase &#40;NSE&#41;&#44; chromogranin&#44; synaptophysin&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">CK7&#44; CK20&#44; CD99&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Clear cell renal carcinoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">CAM5&#46;2&#44; EMA&#44; CD10&#44; RCC-Ma&#44; vimentin&#44; S100&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Melanoma&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Vimentin&#44; S100&#44; tyrosinase&#44; Melan-A&#44; HMB45&#44; MITF&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Bladder&#47;urothelial&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">P63&#44; CK5&#47;6&#44; CK7&#44; CK20&#44; uroplakin III&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Prostate&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">PSA&#44; prostatic acid phosphatase&#44;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">CK7&#44; CK20&#44; thrombomodulin&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Ovary&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">CA&#46;125&#44; CK7&#44; PAX8&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">CK20 &#40;except some mucinous variants&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Head and neck squamous cell carcinoma&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">CK5&#47;6&#44; p63&#44; CK903&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Thyroid&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">FTT-1&#44; thyroglobulin&#44; PAX8&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
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          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Summary of immunophenotypes of the main tumors that metastasize to the skin&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">58</span></a></p>"
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                          "etal" => true
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