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This review will focus on the most relevant aspects of epidemiology&#44; pathogenesis and immune system&#44; clinical characteristics&#44; surgical management&#44; and systemic treatment of cutaneous melanoma in elderly patients&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Materials and Methods</span><p id="par0010" class="elsevierStylePara elsevierViewall">A literature review was undertaken in Pubmed&#44; EMBASE&#44; and Scholar Google&#46; The search terms used were &#40;&#8220;elderly&#8221; OR &#8220;older age&#8221; OR &#8220;aged&#8221; OR &#8220;aged 80 and over&#8221;&#41; AND &#8220;cutaneous melanoma&#44;&#8221; adding different terms according to the subsection under study &#40;<a class="elsevierStyleCrossRef" href="#sect0095">Table 1</a> of the supplementary material&#41;&#46; The reference lists of the selected articles were also reviewed to identify additional relevant articles&#46;</p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Epidemiology</span><span id="sec7020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0740">Advanced Age and Frequency of Melanoma</span><p id="par0020" class="elsevierStylePara elsevierViewall">The largest epidemiological registry in existence&#44; the National Cancer Institute&#39;s Surveillance&#44; Epidemiology and End Results &#40;SEER&#41;&#44; reported in 2015 an incidence of melanoma of 14&#46;4 cases&#47;100&#160;000 inhabitants for patients under 65 years of age&#44; 101&#46;7&#47;100&#160;000 inhabitants for those over 65 years&#44; and 114&#46;7 cases&#47;100&#160;000 inhabitants for those over 75 years &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">3</span></a> with a larger yearly percentage increase in men over 65 years&#46;<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">4</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0025" class="elsevierStylePara elsevierViewall">In Spain&#44; a recent meta-analysis by Tejera-Vaquerizo et al&#46;<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">5</span></a> reported a raw overall incidence of 8&#46;82 &#40;95&#37; confidence interval &#91;CI&#93;&#44; 7&#46;59-10&#46;04&#41;&#47;100&#160;000 person-years&#44; with differences between studies conducted several decades ago &#40;3-4&#47;100&#160;000 person-years&#41; and those conducted from the 1990s onwards&#44; with rates greater than 7&#47;100&#160;000 person-years&#44; reflecting the possible increase in melanoma incidence&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Advanced Age and Melanoma Prognosis</span><p id="par0030" class="elsevierStylePara elsevierViewall">Elderly patients are more likely to die from melanoma than young ones&#44;<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">6</span></a> with an annual increase in incidence rate of 1&#46;7&#37; &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">4</span></a> Although melanomas in elderly individuals account for 40&#37; of such tumors diagnosed&#44; they are cause of 60&#46;2&#37; of melanoma-related deaths&#46;<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">7</span></a></p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0035" class="elsevierStylePara elsevierViewall">In Spain&#44; the ARIADNA Interactive Epidemiology Information System&#44; managed by the Instituto de Salud Carlos III&#44;<a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">8</span></a> shows an increase in mortality for men and women&#44; both in terms of raw rates and those adjusted to the world population &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">9</span></a></p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0040" class="elsevierStylePara elsevierViewall">The SEER data suggest that the raw incidence of melanoma is significantly greater in patients aged over 60 years and that mortality is higher than in other age groups&#46; The age group with highest percentage of deaths due to melanoma corresponds to patients between 75 and 84 years&#46;<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">10</span></a> A study that analyzed 3 different cohorts&#44; including the SEER cohort&#44; with more than 300&#160;000 patients&#44; found that age is a predictor of worse melanoma-specific survival &#40;MSS&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0520"><span class="elsevierStyleSup">11</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">In a multicenter study&#44; which analyzed more than 7000 patients with cutaneous melanoma&#44; age was identified as an independent prognostic factor in patients with stage <span class="elsevierStyleSmallCaps">i</span>-<span class="elsevierStyleSmallCaps">iii</span> disease&#46;<a class="elsevierStyleCrossRef" href="#bib0525"><span class="elsevierStyleSup">12</span></a> In elderly patients&#44; melanoma was more frequently located on the head and neck&#44; and had a greater thickness&#44; mitotic rate&#44; and ulceration&#46; In patients with regional lymph node involvement &#40;stage <span class="elsevierStyleSmallCaps">iii</span>&#41;&#44; age was still an important prognostic factor when variables such as number of positive sentinel lymph nodes&#44; tumor burden&#44; and ulceration of the primary tumor were included&#46; Moreover&#44; a progressive decrease in overall survival at 5 years was observed&#44; such that survival in patients aged 60-70 years was 20&#37; greater than those aged 80-90 years&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">In a retrospective study of 4785 patients&#44; increased age and male sex was associated with greater tumor thickness and ulceration&#46; MSS at 10 years was 10&#37; lower in patients over 65 years&#46;<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">13</span></a> The fact that advanced age was maintained as an independent factor of poor prognosis after adjusting for histological characteristics of the tumor&#44; socioeconomic level&#44; and comorbidity suggest that the differences observed in overall survival do not depend solely on delayed diagnosis &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">14</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0725" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0945">Lymphatic System in Elderly Patients With Cutaneous Melanoma</span><p id="par0060" class="elsevierStylePara elsevierViewall">Baltch et al&#46;<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">16</span></a> observed that sentinel lymph node involvement occurred less frequently in elderly patients&#44; even in cases with more aggressive phenotypes&#46; This observation has also been made in other studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0585"><span class="elsevierStyleSup">24&#8211;28</span></a> It is believed that atrophy of cutaneous lymphatic vessels may contribute to a decrease in immune response and explain the low rate of positive sentinel lymph node dissection&#46;<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">14</span></a> Conway et al&#46;<a class="elsevierStyleCrossRef" href="#bib0610"><span class="elsevierStyleSup">29</span></a> demonstrated that lymphatic function&#44; as measured by radiocolloid transit to and uptake within the sentinel lymph node&#44; decreased with age&#46; Some authors concluded that this lymphatic dysfunction might have an impact on metastatic spread&#44; with predominance of hematogenous dissemination&#46;<a class="elsevierStyleCrossRef" href="#bib0615"><span class="elsevierStyleSup">30</span></a></p></span></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Role of the Immune System in Elderly Patients With Cutaneous Melanoma</span><p id="par0065" class="elsevierStylePara elsevierViewall">With age&#44; immune system function changes&#44; resulting in a different response to infections and tumors&#44; with decreased defense against infections and tumors&#46;<a class="elsevierStyleCrossRefs" href="#bib0620"><span class="elsevierStyleSup">31&#44;32</span></a> Tumor infiltrating lymphocytes &#40;TIL&#41;&#44; a marker of host immune response&#44; are considered an indicator of good prognosis&#46; Weiss et al&#46;<a class="elsevierStyleCrossRef" href="#bib0520"><span class="elsevierStyleSup">11</span></a> observed that the intensity of TIL in the primary tumor was positively correlated with MSS and that this effect appeared to be greater in patients aged more than 45 years&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">In elderly patients&#44; imbalances between the effector and regulatory components of immune response are present&#59; this state is known as immunosenescence<a class="elsevierStyleCrossRef" href="#bib0625"><span class="elsevierStyleSup">32</span></a> and arises because of chronic antigen stimulation and oxidative stress during the lifetime of the individual&#46;<a class="elsevierStyleCrossRef" href="#bib0630"><span class="elsevierStyleSup">33</span></a> The increase in proinflammatory lymphokines due to chronic antigen stimulation leads to an increase in Th1 response and tumor cell death&#46; This effect is amplified when tumor antigens are generated by cell death caused by chemotherapy &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>&#41;&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Clinical Aspects of Melanoma in Elderly Individuals</span><p id="par0075" class="elsevierStylePara elsevierViewall">Although the same clinical presentation of cutaneous melanoma occurs in elderly patients and their younger counterparts&#44; melanomas in elderly patients are diagnosed in more advanced stages&#46; This can be explained by multiple factors&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">Superficial-spreading melanoma is the most common histological subtype&#44; but in elderly patients&#44; thicker and more ulcerated tumors tend to be diagnosed compared with younger patients&#44; due to the higher proportion of nodular clinicopathologic subtypes&#46;<a class="elsevierStyleCrossRefs" href="#bib0635"><span class="elsevierStyleSup">34&#44;35</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">Furthermore&#44; in elderly patients&#44; there is a higher proportion of fast-growing melanomas&#44;<a class="elsevierStyleCrossRefs" href="#bib0645"><span class="elsevierStyleSup">36&#44;37</span></a> many of which are nodular and amelanotic&#46;<a class="elsevierStyleCrossRef" href="#bib0655"><span class="elsevierStyleSup">38</span></a> This hinders early diagnosis&#44; as the lesions do not follow the classic clinical description of asymmetry&#44; borders&#44; color&#44; and diameter &#40;ABCD rule&#41;&#46; Thus&#44; there are suggestions to add the term <span class="elsevierStyleItalic">E</span> to this classic diagnostic mnemonic&#44; which refers not only to the elevation of the lesion but also to <span class="elsevierStyleItalic">evolving</span> lesions during follow-up&#46;<a class="elsevierStyleCrossRef" href="#bib0660"><span class="elsevierStyleSup">39</span></a> Other authors propose adding the acronym EFG<a class="elsevierStyleCrossRef" href="#bib0635"><span class="elsevierStyleSup">34</span></a> &#40;elevated&#44; firm&#44; and growing&#41; to help identify these lesions &#40;<a class="elsevierStyleCrossRefs" href="#fig0025">Figs&#46; 5 and 6</a>&#41;&#46;</p><elsevierMultimedia ident="fig0025"></elsevierMultimedia><elsevierMultimedia ident="fig0030"></elsevierMultimedia><p id="par0090" class="elsevierStylePara elsevierViewall">Clinically&#44; these nodular lesions have been described in dermoscopy as typical multiple and irregular peripheral dots and globules&#44; with blue-white veil&#44; homogeneous blue pigmentation&#44; more than 5 colors&#44; and black color&#46;<a class="elsevierStyleCrossRef" href="#bib0665"><span class="elsevierStyleSup">40</span></a> Often&#44; these melanomas are completely amelanotic on clinical examination&#46; To assist with diagnosis&#44; dermoscopy has been reported to feature the presence of milky-red areas and an atypical vascular pattern&#44; but these are criteria that at times are insufficient for diagnosis of nodular amelanotic melanoma &#40;<a class="elsevierStyleCrossRef" href="#fig0035">Fig&#46; 7</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0670"><span class="elsevierStyleSup">41</span></a> The fast-growing variant appears to be more likely to present with the above findings simultaneously&#46;<a class="elsevierStyleCrossRef" href="#bib0675"><span class="elsevierStyleSup">42</span></a></p><elsevierMultimedia ident="fig0035"></elsevierMultimedia><p id="par0095" class="elsevierStylePara elsevierViewall">In elderly patients&#44; the lentigo maligna melanoma histological subtype is more common&#44; with a predilection for the head and neck&#46;<a class="elsevierStyleCrossRef" href="#bib0680"><span class="elsevierStyleSup">43</span></a> The dermoscopic criteria described for diagnosis include presence of grey dots&#44; isobar sign &#40;circle-within-a-circle structure&#41;&#44; pigmented rhomboidal structures&#44; target-like patterns&#44; follicular occlusion&#44; and grey-white scar-like areas&#46;<a class="elsevierStyleCrossRef" href="#bib0685"><span class="elsevierStyleSup">44</span></a> Lentigo maligna lesions on the cheeks occur more frequently in women whereas lesions on the nose and scalp are more frequent in men&#46; But the most notable difference with respect to age is that in the eldest patients&#44; lentigo maligna lesions are located on areas with lesions of chronic sun damage&#44; unlike the case in younger individuals&#44; who do not show such an extent of skin damage&#46;<a class="elsevierStyleCrossRef" href="#bib0685"><span class="elsevierStyleSup">44</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">Another characteristic described recently is the low frequency of association of melanoma with nevus&#44; whether common or atypical&#46;<a class="elsevierStyleCrossRef" href="#bib0690"><span class="elsevierStyleSup">45</span></a></p><span id="sec0635" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect6055">Possible Causes of Delayed Diagnosis in Elderly Patients</span><p id="par0110" class="elsevierStylePara elsevierViewall">In addition to the characteristic phenotypic features of melanoma in elderly patients described above&#44; there are other possible causes for the delay in melanoma diagnosis &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41; and these may contribute to the increased thickness of melanomas observed in this population&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0115" class="elsevierStylePara elsevierViewall">In the case of site&#44; there are some relevant characteristics&#46; One of these is that melanoma may present in anatomical sites with low visibility&#46; Thus&#44; a Dutch epidemiological study reported a greater propensity&#44; almost double&#44; for melanoma to present on the trunk in men compared with women&#44; and this may contribute to a greater thickness&#46;<a class="elsevierStyleCrossRef" href="#bib0580"><span class="elsevierStyleSup">23</span></a> The scalp is also a more frequent site in this risk group of elderly men&#44; with the same characteristics as the more aggressive phenotype&#46;<a class="elsevierStyleCrossRef" href="#bib0730"><span class="elsevierStyleSup">53</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">There are a series of demographic factors related to a longer delay in diagnosis&#46; The fact that elderly patients have lower income has been independently associated with diagnosis of thicker melanoma&#46;<a class="elsevierStyleCrossRefs" href="#bib0570"><span class="elsevierStyleSup">21&#44;46&#44;47&#44;54</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">Marital status has also been associated with thickness of melanomas&#46; Thus&#44; patients who are single&#44; separated&#44; or widowed&#44; with predominance for males&#44; have thicker melanomas compared with married ones&#46; It seems that the partner contributes to recognition of suspected lesions that would otherwise not be noticed&#46;<a class="elsevierStyleCrossRef" href="#bib0700"><span class="elsevierStyleSup">47</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">Among the patient-dependent causes&#44; elderly patients are less likely to participate in prevention campaigns&#44;<a class="elsevierStyleCrossRef" href="#bib0715"><span class="elsevierStyleSup">50</span></a> or conduct whole-body skin self-examinations&#46;<a class="elsevierStyleCrossRef" href="#bib0710"><span class="elsevierStyleSup">49</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">Finally&#44; possible causes related to quality of health care have also been described as a possible reason for delay in diagnosis&#46; Data are contradictory in terms of frequency of whole-body skin examinations by the primary care physician&#46; Some studies have reported that fewer whole-body skin examinations are performed in older patients than younger ones&#44;<a class="elsevierStyleCrossRefs" href="#bib0720"><span class="elsevierStyleSup">51&#44;54</span></a> whereas another study of the population in Queensland&#44; Australia&#44; did not observe this difference&#46;<a class="elsevierStyleCrossRef" href="#bib0740"><span class="elsevierStyleSup">55</span></a> Moreover&#44; up to a third of the population over 50 years of age had had a partial skin examination in the past year&#46;</p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Surgical Locoregional Management of Melanoma in Elderly Patients</span><span id="sec9040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect6955">Treatment of the Primary Lesion</span><p id="par0145" class="elsevierStylePara elsevierViewall">Primary excision of melanoma is considered a minor surgical procedure that can generally be performed under local anesthetic&#46;<a class="elsevierStyleCrossRef" href="#bib0745"><span class="elsevierStyleSup">56</span></a> However&#44; elderly patients are often not considered candidates for surgical treatment&#44; resulting in lower rate of excision of suspected pigmented lesions and failure to comply with recommendations for tumor management&#46;<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">6</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">Thus&#44; Marks et al&#46;<a class="elsevierStyleCrossRef" href="#bib0750"><span class="elsevierStyleSup">57</span></a> showed that the ratio between nevus and melanoma in excised pigmented lesions was 27&#58;2 in patients between 21 and 40 years of age&#44; and 1&#58;4 in those aged over 60 years&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">There is also a greater tendency to perform incisional biopsy in large pigmented lesions that are often found on elderly patients&#44; but this technique complicates histopathological study and should be avoided&#44; unless&#44; as for other age groups&#44; diagnosis is uncertain and excisional biopsy requires complex reconstruction&#46;<a class="elsevierStyleCrossRef" href="#bib0755"><span class="elsevierStyleSup">58</span></a></p><p id="par0160" class="elsevierStylePara elsevierViewall">Finally&#44; elderly patients have a higher proportion of head and neck melanoma&#44;<a class="elsevierStyleCrossRefs" href="#bib0760"><span class="elsevierStyleSup">59&#44;60</span></a> with a functional and esthetic impact on complex areas&#44; such as the nose and eyelids&#46; The tendency to reduce the surgical margin&#44; along with the difficulty in establishing margins for lentiginous lesions&#44; which are more frequent in elderly individuals&#44; is responsible for a higher proportion of peritumoral resections or resections with inadequate margins&#46;<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">14</span></a> Although this does not have an impact on overall survial&#44;<a class="elsevierStyleCrossRef" href="#bib0770"><span class="elsevierStyleSup">61</span></a> it could be significant for determining the risk of local recurrence&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">On analyzing more than 18&#160;000 patients with melanoma in the SEER&#44;<a class="elsevierStyleCrossRef" href="#bib0775"><span class="elsevierStyleSup">62</span></a> it was found that in patients aged 65 years or more&#44; excision with inadequate margins was more frequent than in those under 65 years &#40;risk ratio&#44; 1&#46;37&#41;&#44; and this difference was even greater for those aged 75 years or more &#40;risk ratio&#44; 2&#46;38&#41;&#46; In a retrospective study conducted in France&#44; in which variations in treatment of patients with stage <span class="elsevierStyleSmallCaps">i</span>-<span class="elsevierStyleSmallCaps">iii</span> melanoma were assessed&#44; it was found that the factors associated with excision with inadequate margins as defined by the recommendations of the clinical guidelines were age greater than 60 years&#44; greater tumor thickness&#44; and site on the head and neck&#46;<a class="elsevierStyleCrossRef" href="#bib0780"><span class="elsevierStyleSup">63</span></a> These latter 2 factors are&#44; furthermore&#44; more frequent in elderly patients&#46;</p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Selective Sentinel Lymph Node Biopsy</span><p id="par0170" class="elsevierStylePara elsevierViewall">With regards SLNB&#44; although a previous study suggested that age did not influence whether one was performed&#44;<a class="elsevierStyleCrossRef" href="#bib0780"><span class="elsevierStyleSup">63</span></a> other studies have found that the procedure is indicated less frequently in patients aged 75 years or more&#44;<a class="elsevierStyleCrossRefs" href="#bib0760"><span class="elsevierStyleSup">59&#44;64&#44;65</span></a> regardless of their comorbidities&#46;</p><p id="par0175" class="elsevierStylePara elsevierViewall">Moreno-Ram&#237;rez et al&#46;<a class="elsevierStyleCrossRef" href="#bib0795"><span class="elsevierStyleSup">66</span></a> showed that the main deciding factor for performing SLNB was Breslow thickness&#44; such that 71&#46;6&#37; of patients with tumors with a thickness of 1&#46;01-4&#46;00<span class="elsevierStyleHsp" style=""></span>mm underwent SLNB&#46; In this group&#44; the Karnofsky performance status and age were the most significant deciding factors in patients with tumors thicker than 4<span class="elsevierStyleHsp" style=""></span>mm&#44; while age was the most relevant determinant for lack of indication of SLNB&#44; performed in 64&#46;1&#37; of patients under 70 years of age and only in 8&#46;7&#37; of those over 70 years&#46;</p><p id="par0180" class="elsevierStylePara elsevierViewall">Unlike for excision of the primary tumor&#44; SLNB may require spinal or general anesthesia&#44; and so&#44; in these cases&#44; the procedure is associated with anesthetic risk&#46; This risk can be calculated with general comorbidity scales or more specific scales&#44; such as the American Society of Anesthesiologists Physical Status System classification system&#46;<a class="elsevierStyleCrossRef" href="#bib0800"><span class="elsevierStyleSup">67</span></a> These patients require a preoperative study &#40;that includes analysis with coagulation&#44; plain chest X-ray&#44; and electrocardiogram&#41;&#59; detailed knowledge of the patient&#769;s general clinical condition&#44; cardiorespiratory function&#44; and usual medications&#59; meticulous surgical planning&#59; intraoperative monitoring&#59; and appropriate postoperative follow-up&#46;<a class="elsevierStyleCrossRefs" href="#bib0745"><span class="elsevierStyleSup">56&#44;67</span></a> The most important clinical trial of SLNB in melanoma&#44; the Multicenter Selective Lymphadenectomy Trial-I &#40;MSLT-I&#41;&#44; excluded patients over 75 years of age<a class="elsevierStyleCrossRef" href="#bib0805"><span class="elsevierStyleSup">68</span></a>&#59; however&#44; other studies have shown the undoubted prognostic value of this test in elderly individuals and its feasibility in patients with a reasonable life expectancy&#46;<a class="elsevierStyleCrossRef" href="#bib0810"><span class="elsevierStyleSup">69</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Lymphadenectomy</span><p id="par0185" class="elsevierStylePara elsevierViewall">Lymphadenectomy after positive SLNB &#40;immediate complete lymphadenectomy &#91;ICL&#93;&#41; is also indicated less frequently in elderly patients&#46;<a class="elsevierStyleCrossRefs" href="#bib0815"><span class="elsevierStyleSup">70&#44;71</span></a> Moreover&#44; age greater than 75 years has been identified as a predictive factor for not complying with the recommendations in terms of performing ICL&#44; with a lower mean number of lymph nodes dissected during the procedure in older patients&#46;<a class="elsevierStyleCrossRef" href="#bib0820"><span class="elsevierStyleSup">71</span></a></p><p id="par0190" class="elsevierStylePara elsevierViewall">Some authors consider that this lower level of intervention in elderly patients is a possible explanation for the greater mortality observed in this age group&#46;<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">1</span></a> However&#44; the lower frequency of metastasis in SLNB and the results of the Multicenter Selective Lymphadenectomy Trial-II &#40;MSLT-II&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0825"><span class="elsevierStyleSup">72</span></a> which show a lack of survival benefit in patients with positive SLNB and ICL &#40;compared with observation and therapeutic lymph node dissection once the patient develops identifiable lymph node metastasis&#41;&#44; would not support a possible association between undertreatment and mortality&#46; In any case&#44; of note is that the age range established as an inclusion criterion in the MSLT-II was 18 to 75 years&#46; Although the consistency of the results of the trial suggest that they could be extrapolated to elderly patients&#44; we still lack high quality evidence to support ICL in these patients&#46; Confirmation of the regional control observed in patients treated with ICL in the MSLT-II would&#44; moreover&#44; have been of great interest to guide decisions in elderly patients&#46;<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">1</span></a></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Treatment of Advanced Locoregional and Metastatic Disease</span><span id="sec0650" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0670">Advanced Locoregional Disease</span><p id="par0200" class="elsevierStylePara elsevierViewall">Several studies have shown that the efficacy of intraarterial chemotherapy with melphalan &#40;with or without tumor necrosis factor alfa or actinomycin&#41; administered by hyperthermic isolated limb perfusion in the treatment of locally advanced malignant melanoma &#40;unresectable lesions&#44; with in-transit metastasis&#41; was similar in patients aged 75 years or more than in younger patients&#46;<a class="elsevierStyleCrossRefs" href="#bib0830"><span class="elsevierStyleSup">73&#8211;76</span></a> Moreover&#44; perioperative mortality does not increase with increasing age and most events were of locoregional toxicity&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Systemic Treatment</span><p id="par0205" class="elsevierStylePara elsevierViewall">The elderly population has certain characteristics &#40;greater presence of other diseases&#44; several concomitant pharmacological treatments with the potential for drug-drug interactions&#44; possibility of cognitive decline&#44; and general state of the patient&#41; that make it particularly important to assess the benefit-risk of each treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0850"><span class="elsevierStyleSup">77</span></a> There is evidence that geriatric assessment prior to an oncological therapeutic plan could help achieve more satisfactory outcomes in terms of survival&#44; quality of life&#44; functional status&#44; and risk of hospitalization in elderly patients with cancer&#46;<a class="elsevierStyleCrossRef" href="#bib0855"><span class="elsevierStyleSup">78</span></a></p><p id="par0210" class="elsevierStylePara elsevierViewall">Before 2010&#44; treatment of metastatic melanoma was limited to classic chemotherapy with dacarbazine or the use of high-dose interleukin 2&#46; Both treatments had low efficacy and a high toxicity that limited their use in elderly patients&#46;<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">14</span></a> In 2010&#44; the results of the first clinical trials with vemurafenib and ipilimumab were published&#44; and treatment of advanced melanoma entered a new era&#46; Information on the usefulness of these new therapies in elderly patients is derived mainly from subgroup analyses of this population who participated in the clinical trials&#44; with the associated limitations of such an approach&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Therapeutic Target</span><p id="par0215" class="elsevierStylePara elsevierViewall">The clinical utility of treatment with BRAF inhibitors &#40;vemurafenib and dabrafenib&#41; alone or&#44; as currently employed&#44; in combination with MEK inhibitors &#40;cobimetinib or trametinib&#41; is limited to melanomas carrying the BRAF kinase mutation&#46; Several studies suggest that the frequency of appearance of BRAF mutations is inversely correlated with age&#46;<a class="elsevierStyleCrossRefs" href="#bib0860"><span class="elsevierStyleSup">79&#44;80</span></a> In an Australian cohort of more than 300 patients with metastatic melanoma&#44; all patients under 30 years of age had the BRAF mutation&#44; whereas only 25&#37; of those over 70 years did&#46;<a class="elsevierStyleCrossRef" href="#bib0865"><span class="elsevierStyleSup">80</span></a> Interestingly&#44; in elderly patients&#44; the proportion of individuals with the most frequent BRAF mutation&#44; V600E&#44; decreases whereas other less common BRAF mutations&#44; such as the V600K BRAF mutation&#44; increase in frequency&#46;</p><p id="par0220" class="elsevierStylePara elsevierViewall">Although the low number of elderly patients recruited to clinical trials is a global problem in oncology&#44;<a class="elsevierStyleCrossRef" href="#bib0870"><span class="elsevierStyleSup">81</span></a> in trials involving this therapeutic target&#44; the decrease in BRAF mutation frequency with age has surely also contributed to their underrepresentation&#46;</p><p id="par0225" class="elsevierStylePara elsevierViewall">Currently&#44; the regimen most widely used for this therapeutic target is a combination of a BRAF inhibitor with a MEK inhibitor&#44; as this not only offers greater efficacy but also limits adverse cutaneous effects&#46; In the analysis by age subgroups&#44; no differences in efficacy were observed&#46;<a class="elsevierStyleCrossRefs" href="#bib0875"><span class="elsevierStyleSup">82&#44;83</span></a></p><p id="par0230" class="elsevierStylePara elsevierViewall">With regards the safety of these treatments in the elderly population&#44; it seems that the overall frequency of adverse effects is similar to the younger population&#46; However&#44; the most severe adverse effects &#40;grade <span class="elsevierStyleSmallCaps">iii</span>-<span class="elsevierStyleSmallCaps">iv</span>&#41;&#44; as well as the risk of withdrawing treatment&#44; are greater in the elderly population&#46;<a class="elsevierStyleCrossRef" href="#bib0885"><span class="elsevierStyleSup">84</span></a></p></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Immunotherapy</span><p id="par0235" class="elsevierStylePara elsevierViewall">Ipilimumab&#44; a CTLA-4 inhibitor&#44; was the first immunotherapy agent to be approved for metastatic melanoma&#46; A response rate of 10&#37; to 15&#37; was achieved with its use&#46;<a class="elsevierStyleCrossRef" href="#bib0890"><span class="elsevierStyleSup">85</span></a> Subsequently&#44; in 2015&#44; anti-PD-1 agents &#40;nivolumab and pembrolizumab&#41; became available&#44; with better efficacy and safety profiles than ipilimumab&#46; Anti-PD-1 agents in monotherapy can achieve response rates of between 33&#37; and 40&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0895"><span class="elsevierStyleSup">86</span></a> The combination of ipilimumab with an anti-PD-1 agent is the most effective immunotherapy regimen&#44; with a response rate of 61&#37;&#44; although this combination is the one that generated greatest toxicity&#46;<a class="elsevierStyleCrossRef" href="#bib0900"><span class="elsevierStyleSup">87</span></a></p><p id="par0240" class="elsevierStylePara elsevierViewall">There is currently some debate as to whether the elderly population is particularly sensitive to immunotherapy&#46; While some studies have found differences between the efficacy of immunotherapy in different age groups&#44;<a class="elsevierStyleCrossRef" href="#bib0905"><span class="elsevierStyleSup">88</span></a> others have even pointed to a better response&#44; particularly for anti-PD1 agents in elderly patients&#46; In a recent retrospective cohort study&#44; in which all patients treated with new immunotherapy agents in the Hospital of Lyon&#44; France&#44; were reviewed&#44; the authors reported longer disease-free survival in patients aged over 65 years compared with those under 65 years&#46;<a class="elsevierStyleCrossRef" href="#bib0910"><span class="elsevierStyleSup">89</span></a> Another recent multicenter study found that the risk of progression under treatment with pembrolizumab decreased by 13&#37; for every decade of life of the patient on starting treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0915"><span class="elsevierStyleSup">90</span></a> The mechanisms that might explain this possible benefit are not yet understood&#44; but they focus on the potential of immunotherapy for reverting changes in the immune system that arise during old age&#46;<a class="elsevierStyleCrossRef" href="#bib0920"><span class="elsevierStyleSup">91</span></a></p><p id="par0245" class="elsevierStylePara elsevierViewall">Given the particular mechanism of action of immunotherapy&#44; deterioration in the function of several organs &#8212;characteristic of aging &#8212;is of greater relevance&#46; For example&#44; there is no contraindication for use of immunotherapy in patients with renal or heart failure&#46; Nevertheless&#44; it is of vital importance that patients and their caregivers are aware of potential unwanted effects of immunotherapy&#44; particularly those such as asthenia and arthralgia&#44; which could be attributed to aging&#46; The best option for minimizing immunotherapy toxicity is one centered on diagnosis and early management of adverse effects&#46; Toxicity associated with immunotherapy does not appear to increase with increasing age&#46;<a class="elsevierStyleCrossRefs" href="#bib0890"><span class="elsevierStyleSup">85&#44;89&#44;90</span></a></p><p id="par0250" class="elsevierStylePara elsevierViewall">In Spain&#44; the only approved adjuvant for high-risk melanoma is high-dose interferon alfa-2b&#46; Given the substantial toxicity and limited benefit&#44; this treatment is not usually used in elderly patients&#46;<a class="elsevierStyleCrossRef" href="#bib0925"><span class="elsevierStyleSup">92</span></a></p><p id="par0255" class="elsevierStylePara elsevierViewall">Currently&#44; treatment of metastatic disease with targeted therapy and immunotherapy is thought to have a comparable effect on overall survival in elderly patients&#44; without a substantial increase in toxicity in elderly patients&#46;<a class="elsevierStyleCrossRef" href="#bib0930"><span class="elsevierStyleSup">93</span></a> Nevertheless&#44; it is necessary to perform studies in every-day clinical practice in elderly patients treated with these new drugs&#44; given that these patients&#44; who are increasingly numerous&#44; are excluded from clinical trials&#46;</p><p id="par0260" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a> shows the level of evidence for each therapeutic procedure in patients with melanoma&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></span></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Conflicts of Interest</span><p id="par0265" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest&#46;</p></span></span>"
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          "identificador" => "xres1216305"
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        1 => array:2 [
          "identificador" => "xpalclavsec1131857"
          "titulo" => "Keywords"
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          "titulo" => "Resumen"
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          "titulo" => "Palabras clave"
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        4 => array:2 [
          "identificador" => "sec0005"
          "titulo" => "Introduction"
        ]
        5 => array:3 [
          "identificador" => "sec0010"
          "titulo" => "Materials and Methods"
          "secciones" => array:8 [
            0 => array:3 [
              "identificador" => "sec0015"
              "titulo" => "Epidemiology"
              "secciones" => array:3 [
                0 => array:2 [
                  "identificador" => "sec7020"
                  "titulo" => "Advanced Age and Frequency of Melanoma"
                ]
                1 => array:2 [
                  "identificador" => "sec0020"
                  "titulo" => "Advanced Age and Melanoma Prognosis"
                ]
                2 => array:2 [
                  "identificador" => "sec0725"
                  "titulo" => "Lymphatic System in Elderly Patients With Cutaneous Melanoma"
                ]
              ]
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            1 => array:2 [
              "identificador" => "sec0025"
              "titulo" => "Role of the Immune System in Elderly Patients With Cutaneous Melanoma"
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            2 => array:3 [
              "identificador" => "sec0030"
              "titulo" => "Clinical Aspects of Melanoma in Elderly Individuals"
              "secciones" => array:1 [
                0 => array:2 [
                  "identificador" => "sec0635"
                  "titulo" => "Possible Causes of Delayed Diagnosis in Elderly Patients"
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            3 => array:3 [
              "identificador" => "sec0035"
              "titulo" => "Surgical Locoregional Management of Melanoma in Elderly Patients"
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                0 => array:2 [
                  "identificador" => "sec9040"
                  "titulo" => "Treatment of the Primary Lesion"
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              "identificador" => "sec0040"
              "titulo" => "Selective Sentinel Lymph Node Biopsy"
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            5 => array:2 [
              "identificador" => "sec0045"
              "titulo" => "Lymphadenectomy"
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            6 => array:3 [
              "identificador" => "sec0050"
              "titulo" => "Treatment of Advanced Locoregional and Metastatic Disease"
              "secciones" => array:3 [
                0 => array:2 [
                  "identificador" => "sec0650"
                  "titulo" => "Advanced Locoregional Disease"
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                  "titulo" => "Systemic Treatment"
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                2 => array:2 [
                  "identificador" => "sec0060"
                  "titulo" => "Therapeutic Target"
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              "titulo" => "Immunotherapy"
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          "titulo" => "Conflicts of Interest"
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          "titulo" => "References"
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    "fechaRecibido" => "2018-09-19"
    "fechaAceptado" => "2018-11-04"
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        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec1131857"
          "palabras" => array:7 [
            0 => "Melanoma"
            1 => "Elderly"
            2 => "Prognosis"
            3 => "Surgery"
            4 => "Sentinel lymph node"
            5 => "Review"
            6 => "Health services for the aged"
          ]
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      ]
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        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec1131856"
          "palabras" => array:7 [
            0 => "Melanoma"
            1 => "Anciano"
            2 => "Pron&#243;stico"
            3 => "Cirug&#237;a"
            4 => "Ganglio centinela"
            5 => "Revisi&#243;n"
            6 => "Servicio de salud para el anciano"
          ]
        ]
      ]
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Cutaneous melanoma &#40;CM&#41; causes more deaths than any other skin tumor&#44; and incidence and mortality rates have risen in recent years&#44; especially in patients of advanced age&#46; There are differences in the biological behavior of CM tumors in the elderly as well as differential management of the disease&#44; evidently influenced by such factors as limited life expectancy&#44; the high incidence of concomitant conditions in older patients&#44; and issues of quality of life unrelated to CM itself&#46; We review relevant current literature on the epidemiology&#44; etiology&#44; pathogenesis&#44; and immunology of CM as well as research on the clinical features&#44; prevention&#44; and management of these tumors in the elderly&#46;</p></span>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">El melanoma cut&#225;neo &#40;MC&#41; es el tumor cut&#225;neo que m&#225;s muertes provoca&#44; con un aumento importante de la incidencia y la mortalidad en las &#250;ltimas d&#233;cadas&#44; especialmente en el paciente anciano&#46; Existen evidencias del diferente comportamiento biol&#243;gico&#44; as&#237; como de las diferencias en el manejo del MC en este subgrupo de pacientes con respecto al resto de otras franjas de edad&#44; evidentemente condicionadas por unas limitadas expectativas de supervivencia y calidad de vida ajenas al melanoma y una elevada incidencia de comorbilidades&#46; El presente art&#237;culo revisa los datos actuales m&#225;s relevantes de la epidemiolog&#237;a&#44; etiopatogenia e inmunolog&#237;a&#44; cl&#237;nica&#44; prevenci&#243;n y manejo del MC en el anciano&#46;</p></span>"
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    "NotaPie" => array:1 [
      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Iglesias-Pena N&#44; Paradela S&#44; Tejera-Vaquerizo A&#44; Boada A&#44; Fonseca E&#46; Melanoma cut&#225;neo en el anciano&#58; revisi&#243;n de un problema creciente&#46; Actas Dermosifiliogr&#46; 2019&#59;110&#58;434&#8211;447&#46;</p>"
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            "apendice" => "<p id="par0275" class="elsevierStylePara elsevierViewall"><elsevierMultimedia ident="upi0005"></elsevierMultimedia></p>"
            "etiqueta" => "Appendix A"
            "titulo" => "Supplementary data"
            "identificador" => "sec0080"
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      ]
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      0 => array:7 [
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Age-adjusted melanoma incidence in the Surveillance&#44; Epidemiology and End Results &#40;SEER&#41; Program&#44; National Cancer Institute&#46;</p>"
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      1 => array:7 [
        "identificador" => "fig0010"
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          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Registry of age-adjusted melanoma mortality in the Surveillance&#44; Epidemiology and End Results &#40;SEER&#41; Program&#44; National Cancer Institute&#46;</p>"
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          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Mortality due to melanoma in Spain by sex &#40;data from the ARIADNA Interactive Epidemiological Information System&#44; dependent on the <span class="elsevierStyleItalic">Instituto de Salud Carlos III</span>&#41;&#46;</p>"
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          "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Proposed interaction between the innate and adaptive immune system in elderly patients&#59; the age-related increase in antigen load leads to overstimulation of the innate immune system thereby increasing proinflammatory cytokines&#46; This has an impact on the acquired immune system&#44; giving rise to poor coordination between CD4&#44; CD8&#44; and B lymphocytes&#44; and an imbalance between Th1 and Th2 cytokine production&#46; The activity of cytotoxic T lymphocytes under Th1 conditions favors autoimmunity and chronic inflammatory diseases&#59; under Th2 conditions&#44; immune tolerance is favored&#46;</p> <p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Adapted from Hegde et al&#46;<a class="elsevierStyleCrossRef" href="#bib0630"><span class="elsevierStyleSup">33</span></a></p>"
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        "identificador" => "fig0025"
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          "en" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Ulcerated&#44; fast-growing nodular amelanotic melanoma of 4 months standing on the left temple of an 87-year-old man&#44; with a Breslow thickness of 7<span class="elsevierStyleHsp" style=""></span>mm and 8 mitoses per mm&#46;<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">2</span></a></p>"
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          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">A&#44; Fast-growing nodular melanoma of 3 months standing in the right scapular region on a prior flat lesion of several years standing&#46; The Breslow thickness was 4<span class="elsevierStyleHsp" style=""></span>mm&#44; the lesion was not ulcerated&#44; and there were 5 mitoses per mm&#46;<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">2</span></a> Presence of perilesional in situ melanoma in the histopathological study&#46; B&#44; Detail of the lesion base where pigmentation is observed&#44; corresponding to the in situ component of the prior lesion&#46;</p>"
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        "etiqueta" => "Figure 7"
        "tipo" => "MULTIMEDIAFIGURA"
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          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Ulcerated&#44; fast-growing nodular melanoma on the left temple with a Breslow thickness of 4<span class="elsevierStyleHsp" style=""></span>mm and 10 mitoses por mm&#46;<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">2</span></a> B&#44; Dermoscopy of the lesion in which several colors and small milky areas are observed with atypical vascularization&#46;</p>"
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          "leyenda" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Abbreviations&#58; A&#44; anatomic site&#59; C&#44; Clark level&#59; Cox&#44; Cox proportional risks survival analysis&#59; DFS&#44; disease-free survival&#59; G&#44; sex&#59; H&#44; histologic subtype&#59; HR&#44; hazard ratio &#40;95&#37; confidence interval&#41;&#59; f&#44; female&#59; m&#44; male&#59; M&#44; presence of distant metastasis&#59; N&#44; presence of lymph node metastasis&#59; n&#46;a&#46; not available&#59; RER&#44; relative excess risk &#40;95&#37; CI&#41;&#59; RR&#44; relative risk&#59; S&#44; stage&#59; SLNB&#44; sentinel lymph node biopsy&#59; T&#44; Breslow tumor thickness&#59; U&#44; ulceration&#46;</p><p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Adapted from Lasithiotakis et al&#46;<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">14</span></a></p>"
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                  <table border="0" frame="\n
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                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
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                  \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">Reference&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Stage&#47;N&#47;Type of Sample&#47;Country&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">Measurement of Age as Prognostic Factor&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Method of Outcome Assessment&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">Other Independent Prognostic Factors&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Kemeny et al&#46;<a class="elsevierStyleCrossRef" href="#bib0540"><span class="elsevierStyleSup">15</span></a></td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">All stages&#47;N<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>23&#160;341&#47;population&#47;US</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">m &#8804; 45 vs f &#8804; 45&#44; HR&#58; 1&#46;9 &#40;1&#46;6-2&#46;3&#41;&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;0001&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  " rowspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cox&#47;DFS</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">S&#44; H&#44; A</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">f &#8805; 55 vs m &#8804; 45&#44; HR&#58; 2&#46;8 &#40;2&#46;3-3&#46;3&#41;&#44; <span class="elsevierStyleItalic">P</span> &#60;<span class="elsevierStyleHsp" style=""></span>&#46;0001&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">m &#8805; 55 vs f &#8804; 45&#44; HR&#58; 3&#46;6 &#40;3&#46;0-4&#46;2&#41;&#44; <span class="elsevierStyleItalic">P</span> &#60;<span class="elsevierStyleHsp" style=""></span>&#46;0001&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">Balch et al&#46;<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">16</span></a>&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">I&#44; II &#47;N<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>13&#160;581&#47;hospital&#47;international&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">Decades of increasing age&#44; RR&#58; 1&#46;1 &#40;1&#46;07-1&#46;13&#41;&#44; <span class="elsevierStyleItalic">P</span> &#60;<span class="elsevierStyleHsp" style=""></span>&#46;00001&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">Cox&#47;DFS&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">T&#44; U&#44; A&#44; G&#44; C&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">Azzola et al&#46;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">17</span></a>&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">I&#44; II&#47;N<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3661&#47;hospital&#47;Australia&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">Decades of increasing age&#44; RR&#58; 1&#46;15 &#40;1&#46;07-1&#46;2&#41;&#44; <span class="elsevierStyleItalic">P</span> &#60;<span class="elsevierStyleHsp" style=""></span>&#46;0001&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">Cox&#47;DFS&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">T&#44; U&#44; A&#44; G&#44; IM&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">Leiter et al&#46;<a class="elsevierStyleCrossRef" href="#bib0555"><span class="elsevierStyleSup">18</span></a>&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">Breslow &#8804; 1 mm&#47;N<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>11&#160;927&#47;hospital&#47;Germany&#44; Austria&#44; Switzerland&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#62; 50 vs &#8804; 60&#44; HR&#58; 1&#46;6 &#40;1&#46;1-1&#46;2&#41;&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;0075&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">Cox&#47;DFS&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">T&#44; H&#44; A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Lindholm et al&#46;<a class="elsevierStyleCrossRef" href="#bib0560"><span class="elsevierStyleSup">19</span></a>&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">I&#44; II&#47;N<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>6191&#47;population&#47;Sweden&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">&#8805; 70 vs &#60;<span class="elsevierStyleHsp" style=""></span>50&#44;HR&#58; 1&#46;59 &#40;1&#46;23-2&#46;06&#41;&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;0005&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">Cox&#47;DFS&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">T&#44; U&#44; A&#44; G&#44; C&#44; H&#44; DM&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">Carac&#242; et al&#46;<a class="elsevierStyleCrossRef" href="#bib0565"><span class="elsevierStyleSup">20</span></a>&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">I&#44; II referred for SLNB&#47;N<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>399&#47;hospital&#47;Italy&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"><span class="elsevierStyleHsp" style=""></span>&#62; 50 vs &#60;<span class="elsevierStyleHsp" style=""></span>50&#44; OR&#58; 1&#46;95 &#40;1&#46;13-3&#46;39&#41;&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;01&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">Cox&#47;DFS&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">T&#44; U&#44; G&#44; SLNB&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Reyes-Ortizet al&#46;<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">21</span></a></td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">All&#47;N<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>23&#160;068&#47;population&#47;US</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">70-74 vs 65-69&#44; HR&#58; 1&#46;15 &#40;1&#46;01-1&#46;3&#41;&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;04&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">Cox&#47;DFS&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">T&#44; A&#44; G&#44; S&#44; H&#44; income&#44; civil status&#44; race&#44; year of diagnosis&#44; comorbidities&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">75-79 vs 65-69&#44; HR&#58; 1&#46;24 &#40;1&#46;08-1&#46;3&#41;&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8805; 80 vs 65-69&#44; HR&#58; 1&#46;48 &#40;1&#46;3-1&#46;68&#41;&#44; <span class="elsevierStyleItalic">P</span> &#60;<span class="elsevierStyleHsp" style=""></span>&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Downing et al&#46;<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">22</span></a>&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">All&#47;N<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3127&#47;population&#47;United Kingdom&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">Increasing age in years&#44; HR&#58; 1&#46;04 &#40;1&#46;04-1&#46;05&#41;&#44; <span class="elsevierStyleItalic">P</span>&#58; n&#46;a&#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">Cox&#47;DFS&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">T&#44; A&#44; G&#44; H&#44; socioeconomic status&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">Lasithiotakis et al&#46;<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">13</span></a>&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">I&#44; II&#44; IIIA&#47;N<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>4785&#47;population&#47;Germany&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">Increasing age in years&#44; HR&#58; 1&#46;01 &#40;1&#46;003-1&#46;013&#41;&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;005&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">Cox&#47;DFS&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">T&#44; U&#44; A&#44; G&#44; H&#44; C&#44; SLNB&#44; year of diagnosis&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">De Vries et al&#46;<a class="elsevierStyleCrossRef" href="#bib0580"><span class="elsevierStyleSup">23</span></a>&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">All&#47;N<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>10&#160;538&#47;population&#47;Netherlands&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">65-74 vs &#60;<span class="elsevierStyleHsp" style=""></span>45&#44; RER&#58; 1&#46;37 &#40;1&#46;15-1&#46;64&#41;&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>n&#46;a&#46;75-84 vs &#60;<span class="elsevierStyleHsp" style=""></span>45&#44; RER&#58; 2&#46;2 &#40;1&#46;8-2&#46;7&#41;&#8805; 85 vs &#60;<span class="elsevierStyleHsp" style=""></span>45&#44; RER&#58; 2&#46;18 &#40;1&#46;39-3&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Multivariate model&#47;DFS&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">T&#44; A&#44; G&#44; H&#44; N&#44; geographic region&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="spar0055" class="elsevierStyleSimplePara elsevierViewall">Studies With Multivariate Analyses That Included Age as a Prognostic Factor in Cutaneous Melanoma&#46;</p>"
        ]
      ]
      8 => array:8 [
        "identificador" => "tbl0010"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at2"
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        "tabla" => array:2 [
          "leyenda" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Adapted from Lasithiotakis et al&#46;<span class="elsevierStyleSup">&#46;</span><a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">14</span></a></p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><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">Cause of Delay&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">Remarks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Aspects pertaining to melanoma</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Increased frequency of fast-growing 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">Increase in nodular subtypes<a class="elsevierStyleCrossRef" href="#bib0635"><span class="elsevierStyleSup">34</span></a> which do not follow the classic ABCD rule and which are hypomelanotic or amelanotic<a class="elsevierStyleCrossRef" href="#bib0655"><span class="elsevierStyleSup">38</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Increased frequency of lentigo maligna 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">Very slow-growing lesions on photoaged skin<a class="elsevierStyleCrossRef" href="#bib0685"><span class="elsevierStyleSup">44</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Site&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">More frequent location of melanomas in elderly patients in areas difficult to observe&#44; particularly in men<a class="elsevierStyleCrossRef" href="#bib0580"><span class="elsevierStyleSup">23</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Aspects pertaining to the patient</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Low socioeconomic status&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">Low income has been associated with thicker melanomas<a class="elsevierStyleCrossRefs" href="#bib0570"><span class="elsevierStyleSup">21&#44;46&#44;47</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Marital status&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">Single&#44; separated&#44; or widowed patients have thicker melanomas than married patients<a class="elsevierStyleCrossRef" href="#bib0700"><span class="elsevierStyleSup">47</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Level of education&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">The stage on diagnosis bears an inverse relationship with level of education of the patient<a class="elsevierStyleCrossRefs" href="#bib0695"><span class="elsevierStyleSup">46&#44;48</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Whole-body skin self-examination and participation in screening campaigns&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">Less frequent in elderly patients<a class="elsevierStyleCrossRefs" href="#bib0710"><span class="elsevierStyleSup">49&#44;50</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Aspects pertaining to the physician</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Whole-body skin examination&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">Elderly patients undergo fewer routine whole-body skin examinations<a class="elsevierStyleCrossRef" href="#bib0720"><span class="elsevierStyleSup">51</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Level of training of the physician&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">Longer delay when the lesion is seen by a primary care physician than by a dermatologist<a class="elsevierStyleCrossRef" href="#bib0725"><span class="elsevierStyleSup">52</span></a>&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="spar0070" class="elsevierStyleSimplePara elsevierViewall">Causes of Delay in Diagnosis of Melanoma in Elderly Patients&#46;</p>"
        ]
      ]
      9 => array:8 [
        "identificador" => "tbl0015"
        "etiqueta" => "Table 3"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at3"
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        "tabla" => array:2 [
          "leyenda" => "<p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">Levels of evidence &#40;USPSTF&#41;&#58; <span class="elsevierStyleSmallCaps">ii</span>&#44; at least one randomized&#44; controlled clinical trial with appropriate design&#59; <span class="elsevierStyleSmallCaps">ii</span>-1&#44; well-designed&#44; controlled clinical trials&#44; but not randomized&#59; <span class="elsevierStyleSmallCaps">ii</span>-2&#44; well designed cohort studies or case-control studies&#44; preferably multicenter&#59; <span class="elsevierStyleSmallCaps">ii</span>-3&#44; multiple series compared over time&#44; with or without intervention&#44; and surprising results in uncontrolled studies&#59; <span class="elsevierStyleSmallCaps">iii</span> opinions based on clinical experience&#44; descriptive studies&#44; clinical observations&#44; or expert committee reports&#46;</p><p id="spar0090" class="elsevierStyleSimplePara elsevierViewall">Strength of Recommendation&#58; A&#44; extremely recommended &#40;good evidence that the measure is effective and that the benefits easily outweigh the harms&#41;&#59; B&#44; recommended &#40;at least moderate evidence that the measure is effective and that the benefits outweigh the harms&#41;&#59; C&#44; not recommended or unadvised &#40;at least moderate evidence that the measure is effective but the benefits are similar to the harms and cannot justify a general recommendation&#41;&#59; D&#44; unadvised &#40;at least moderate evidence that the measure is ineffective or that the harms exceed the benefits&#41;&#59; I&#44; insufficient evidence&#44; of poor or contradictory quality&#44; and the balance between benefits and harms cannot be determined&#46;</p><p id="spar0095" class="elsevierStyleSimplePara elsevierViewall">Abbreviations&#58; LMM&#44; lentigo maligna melanoma&#59; SLNB&#44; selective sentinel lymph node biopsy&#59; USPSTF&#44; United States Preventive Services Task Force</p><p id="spar0100" class="elsevierStyleSimplePara elsevierViewall">Adpated from Lasithiotakis et al&#46;<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">14</span></a></p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><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">Intervention&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">Remarks&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">Level of Evidence and Strength of Recommendation &#40;USPSTF&#41;&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">Primary excision&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">Same recommendation as for other age groupsLMM requires adequate margins to be established around the lesion&#44; ideally through Mohs micrographic surgery&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">III A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">SLNB&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">Staging&#44; no therapeutic benefit&#46;Lower rate of positive findings &#40;lower sensitivity&#44; rate of micrometastasis&#44; or lymphatic spread&#63;&#41;Assess anesthetic risk&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">II-2 B&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">Lymphadenectomy&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">Morbidity &#40;lymphedema&#44; nerve damage&#44; surgical wound complications&#41;No impact on survival demonstrated&#46;Palliative treatment if clinically relevant lymph node metastasis&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">III C&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">Adjuvant treatment&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">Little information available on benefit-riskFavorable response to immunotherapy due to imbalance in immune system&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">III I&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">Intraarterial chemotherapy via hyperthermic isolated limb perfusion&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">Assess in locally advanced melanoma &#40;unresectable&#44; in transit metastasis&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">III-2 B&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">Treatment of metastatic melanoma &#40;immunotherapy&#44; targeted therapy&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Same therapeutic approach as in young patientsAssess prior geriatric assessment&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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