Opinion Article
Actinic Keratosis: New Concepts and Therapeutic Approaches for an Ancestral Condition
Queratosis actínica: un proceso ancestral, nuevos conceptos y enfoques terapéuticos
A. Alomar
Departamento de Dermatología, Institut Universitari Quiron Dexeus, Universitat Autonoma de Barcelona, Barcelona, Spain
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Ruiz, E. Manubens, L. Puig" "autores" => array:3 [ 0 => array:2 [ "nombre" => "V." "apellidos" => "Ruiz" ] 1 => array:2 [ "nombre" => "E." "apellidos" => "Manubens" ] 2 => array:2 [ "nombre" => "L." "apellidos" => "Puig" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0001731013003530" "doi" => "10.1016/j.ad.2013.06.005" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0001731013003530?idApp=UINPBA000044" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1578219014002443?idApp=UINPBA000044" "url" => "/15782190/0000010500000009/v1_201410280115/S1578219014002443/v1_201410280115/en/main.assets" ] "en" => array:14 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Opinion Article</span>" "titulo" => "Actinic Keratosis: New Concepts and Therapeutic Approaches for an Ancestral Condition" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "809" "paginaFinal" => "812" ] ] "autores" => array:1 [ 0 => array:3 [ "autoresLista" => "A. Alomar" "autores" => array:1 [ 0 => array:3 [ "nombre" => "A." "apellidos" => "Alomar" "email" => array:1 [ 0 => "agustin.alomar@quiron.es" ] ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Departamento de Dermatología, Institut Universitari Quiron Dexeus, Universitat Autonoma de Barcelona, Barcelona, Spain" "identificador" => "aff1" ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Queratosis actínica: un proceso ancestral, nuevos conceptos y enfoques terapéuticos" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0190" class="elsevierStylePara elsevierViewall">As I write this contribution to Spain's most prestigious dermatology journal, it is clear I need not provide a description of actinic keratosis (AK), but I do feel that experience will allow me to reflect instructively and readably on the subject of how therapy has evolved over the years.</p><p id="par0010" class="elsevierStylePara elsevierViewall">Ours is a Mediterranean country with a high incidence of AK. We enjoy many more days of bright sunlight, and 70% of our marvelous coastline offers attractive access to the sea. Because our peninsula was invaded by Celtic tribes from northern Europe over 5000<span class="elsevierStyleHsp" style=""></span>years ago, our population now includes many individuals with the light skin and eyes that tend to photoaging.</p><p id="par0195" class="elsevierStylePara elsevierViewall">AK is among the classic clinical signs of that process, and after the age of 50<span class="elsevierStyleHsp" style=""></span>years nearly all Spaniards have—to one degree or another—lesions consistent with a diagnosis of solar keratosis. Today such lesions cannot be considered a mere cosmetic problem.</p><p id="par0020" class="elsevierStylePara elsevierViewall">For many years AK was classified as a premalignant lesion. Cockerel<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> insisted in 2003, however, that we define the process in terms of histopathologic evidence. A grading system known by the acronym KIN—for keratinocytic intraepidermal neoplasia—was introduced. In this system, AK grades I through III are defined according to the degree of epidermal dysplasia and the risk of malignant transformation to invasive squamous cell carcinoma.</p><p id="par0200" class="elsevierStylePara elsevierViewall">Since then, specialists have agreed to consider AKs to be true intraepidermal neoplasms, or neoplasms in situ.<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2,3</span></a> It is estimated that from 5% to 20% of preexisting lesions, including subclinical ones, may progress and grow to become invasive squamous cell carcinoma.</p><p id="par0205" class="elsevierStylePara elsevierViewall">Evidence led the drafters of the 2006 European Dermatology Forum guidelines to conclude that even though it is impossible to predict which AKs will undergo malignant transformation, these lesions have the potential to do so. For that reason, they concluded, AKs should be treated.”<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p><p id="par0210" class="elsevierStylePara elsevierViewall">A Spanish adaptation of those guidelines was recently published in <span class="elsevierStyleItalic">Actas Dermo-sifiliográficas.</span><a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">A more recent concept, field cancerization, involves subclinical lesions and mutated cells in sun-exposed areas. This concept addresses the risk of developing squamous cell carcinoma not merely on visible AKs but also throughout an entire field in which ongoing solar UV irradiation continues to act on subclinical lesions and mutated cells, generating further mutation and exercising an immunosuppressive effect. These processes have been well described and are fully understood today.<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6,7</span></a></p><p id="par0215" class="elsevierStylePara elsevierViewall">I recall that the treatment for AK that prevailed for decades consisted of destroying a lesion by scraping and electrocoagulating it, potentially causing scars. Alternatively, a dermatologist might have applied dry ice, providing a primitive type of cryotherapy that in the light of recent advances seems of debatable value, at least for the purpose of treating all lesions.</p><p id="par0050" class="elsevierStylePara elsevierViewall">The development of liquid nitrogen spray has provided a convenient way to reach the freezing point needed for cryotherapy. As the spray is easy to apply and gives more or less acceptable results, it has quickly become the most widely used procedure for treating individual AKs. This approach, though not new, is likely to continue to be the first choice for outpatient care of AK in Spain.</p><p id="par0220" class="elsevierStylePara elsevierViewall">I also recall the introduction of 5-fluorouracil (5-FU) cream to treat field cancerization with very good results. A drawback was that this formulation caused a painful inflammatory and ulcerative reaction that could compromise patient adherence.</p><p id="par0225" class="elsevierStylePara elsevierViewall">5-FU diminishes the proliferation of cells (especially those undergoing increased mitosis) through the action of its active ingredient, 5-fluorodeoxyuridine monophosphate. This antimetabolite is a pyrimidine analog that inhibits thymidylate synthetase, and also affects DNA synthesis and, to a lesser degree, RNA synthesis.</p><p id="par0230" class="elsevierStylePara elsevierViewall">The combination of 5-FU cream and retinoic acid was an advance that provided better results more quickly.</p><p id="par0235" class="elsevierStylePara elsevierViewall">5-FU continues to be an excellent treatment that can be used over extensive areas, and a recent meta-analysis ranked this cream as the most effective option.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> Only intolerance limits its use.</p><p id="par0075" class="elsevierStylePara elsevierViewall">A very interesting article published by a group at the Hospital Charité in Berlin compared clinical, histopathologic, and even immunohistochemical markers of the efficacy of 5-FU, imiquimod, and cryotherapy after 4<span class="elsevierStyleHsp" style=""></span>weeks of treatment.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> 5-FU and imiquimod were equivalent from the clinical standpoint and both were superior to cryotherapy. The histologic findings were slightly better with imiquimod than with 5-FU, and again both were superior to cryotherapy.</p><p id="par0080" class="elsevierStylePara elsevierViewall">Similarly, p-53 results were also better with imiquimod than with 5-FU in this study, and both these treatments were superior to cryotherapy; cosmetic outcomes were better with imiquimod than with either 5-FU or cryotherapy.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a></p><p id="par0240" class="elsevierStylePara elsevierViewall">A disadvantage for us in Spain is that 5-FU cream must be compounded by the pharmacist because a commercial form is unavailable here, but that situation that may soon change.</p><p id="par0090" class="elsevierStylePara elsevierViewall">A recent multicenter observational study lasting a year and a half (the unpublished AKces study of 2009–2010 on burden of disease, personal communication) recorded the treatment prescribed and applied in the first 5 patients who sought care for multiple AKs in 67 hospital dermatology clinics throughout peninsular Spain. The following treatments were used: only imiquimod, 47.1%; cryotherapy, 33.5%; photodynamic therapy, 6.5%; and other treatments or combinations, 12.6%.</p><p id="par0095" class="elsevierStylePara elsevierViewall">Returning to the useful concept of field cancerization, I recall that articles we would consider old today mentioned that the regression of incipient AKs can be achieved with the use of sunscreens. Trials are currently under way to determine whether sunscreens containing photolyase—an enzyme that can repair damaged DNA in keratinocytes—might be more effective, safer, and better tolerated in the treatment of field cancerization in patients with a predisposition to AK and nonmelanoma skin cancer.</p><p id="par0100" class="elsevierStylePara elsevierViewall">Photodynamic therapy with application of aminolevulinic acid (ALA) before exposure to a light source was introduced in the United States; later, European dermatologists began to apply photodynamic therapy with methyl aminolevulinate. Both approaches have progressed, achieving good results, in spite of certain difficulties, such as the need for several time-consuming sessions and specific equipment. In some cases anesthesia (a regional block of the area to be treated) is needed to alleviate the intense pain some patients feel during irradiation.</p><p id="par0245" class="elsevierStylePara elsevierViewall">The efficacy of photodynamic therapy, however, seems to be well demonstrated according to European practice guidelines.<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10,11</span></a></p><p id="par0250" class="elsevierStylePara elsevierViewall">A 5-ALA formulation with nanoparticles recently entered the Spanish market. This agent seems to offer enhanced bioavailability and a more intense phototoxic effect on tumor cells.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a></p><p id="par0255" class="elsevierStylePara elsevierViewall">In 2007 I had the pleasure of serving as principal investigator for the multicenter European trial required to register the use of imiquimod 5% cream for treating AK.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a></p><p id="par0260" class="elsevierStylePara elsevierViewall">Imiquimod's mechanism of action is well understood: it induces innate and acquired immune responses that destroy abnormal cells throughout the area where it is applied.</p><p id="par0265" class="elsevierStylePara elsevierViewall">The results of our trial showed complete clinical and histologic resolution in 55% of the treated area.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> Clinical clearing of lesions in 83% of patients has been observed in another trial, however.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a></p><p id="par0270" class="elsevierStylePara elsevierViewall">The protocol initially proposed (2<span class="elsevierStyleHsp" style=""></span>cycles in 4<span class="elsevierStyleHsp" style=""></span>weeks) is difficult to follow if there is a strong inflammatory reaction, as the patient is reluctant to undergo the second cycle.</p><p id="par0135" class="elsevierStylePara elsevierViewall">Another aspect of the initial proposal—limiting the size of the area treated to 25<span class="elsevierStyleHsp" style=""></span>cm<span class="elsevierStyleSup">2</span>—is not followed strictly in clinical practice. Larger areas than the limit specified in the prescribing information are commonly treated because the contents of a single-use packet will cover a slightly larger surface. It is important to remember that using more packets of imiquimod cream, however, can lead to flu-like symptoms in some patients due to the release of interferon and by other mechanisms.</p><p id="par0140" class="elsevierStylePara elsevierViewall">Another product recently introduced for treating field cancerization combines diclofenac 3% and hyaluronic acid 2.5%. The patient applies the gel twice a day for 16 weeks, using approximately 4<span class="elsevierStyleHsp" style=""></span>g (maximum, 8<span class="elsevierStyleHsp" style=""></span>g).</p><p id="par0145" class="elsevierStylePara elsevierViewall">The duration of this therapy makes it somewhat tedious, but it is usually well tolerated. In some patients, however, it can cause a certain degree of inflammation and even photosensitivity, a known side effect of various nonsteroidal anti-inflammatory drugs. The mechanism of action for this drug took time to unravel, although we can now say that inhibition of the cyclooxygenase-2 pathway and induction of apoptosis now seem to have been demonstrated.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">New drugs for treating this very common disease in Spain continue to appear. An example is 0.015%–0.05% ingenol mebutate gel. Evidence for this product's mechanism of action is lacking, although effects on the cell membrane of dysplastic keratinocytes and also on cell mitochondria have been described. Ingenol mebutate also induces an infiltrate, consisting of neutrophils and proinflammatory cytokines, with secondary cytotoxicity.</p><p id="par0275" class="elsevierStylePara elsevierViewall">These actions have possible side effects, such as irritation and inflammation in the treated zone, but a great advantage of the ingenol mebutate gel is that it is applied for only 2<span class="elsevierStyleHsp" style=""></span> or 3<span class="elsevierStyleHsp" style=""></span>days.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> However, the irritation can persist for several weeks and it is currently recommended to limit application to 25<span class="elsevierStyleHsp" style=""></span>cm<span class="elsevierStyleSup">2</span>. The duration of treatment efficacy has not been demonstrated by long-term follow-up studies.</p><p id="par0280" class="elsevierStylePara elsevierViewall">A preparation combining 0.5%<span class="elsevierStyleHsp" style=""></span>5-FU and 10%<span class="elsevierStyleHsp" style=""></span>salicylic acid, which is marketed in some European countries for treating individual lesions, seems to be very useful even for hyperkeratotic lesions.<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">17,18</span></a> This product may become available in Spain very soon.</p><p id="par0165" class="elsevierStylePara elsevierViewall">A formulation we can look forward to seeing in Spain is the imiquimod<span class="elsevierStyleHsp" style=""></span>3.75% cream. Indicated for field cancerization, it is already being marketed in the United States and some countries in Europe. The treatment protocol calls for 2<span class="elsevierStyleHsp" style=""></span>short cycles of 2<span class="elsevierStyleHsp" style=""></span>weeks each, with a resting period of 2<span class="elsevierStyleHsp" style=""></span>weeks between them. This treatment clears lesions completely in 35% of patients and partially in 60%.<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">19,20</span></a> Studies of field-directed treatment with this product showed that the highest count of lesions that were initially clinically invisible, but that became detectable with application (the Lmax concept), did so at the beginning the 2-week cycle; additionally, the greatest effect was achieved by treating the entire affected zone.<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a></p><p id="par0285" class="elsevierStylePara elsevierViewall">We have seen that AK—so commonplace in the population over the age of 50<span class="elsevierStyleHsp" style=""></span>years that it was considered of little importance a few years ago—is now being taken more seriously because our concept of the condition has changed. We now have a better understanding of photobiology and the cancerization process—both its induction and progression to nonmelanoma skin cancer—as well as a wide range of therapies that can cure these lesions to the degree a cure is possible.<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">22–29</span></a></p><p id="par0290" class="elsevierStylePara elsevierViewall">The dermatologist who is aware of the variety of treatments currently on hand can apply the knowledge in the interest of prevention—through relevant explanations about the use of sunscreens—or can treat lesions with a new arsenal of single or combined therapies. New approaches are available to target both individual hyperkeratotic AKs and field cancerization. Each option must be explained to the patient so that the greatest possible degree of adherence and the best curative outcome can be achieved.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Conflicts of Interest</span><p id="par0295" class="elsevierStylePara elsevierViewall">The author declares that he has provided advisory or consultancy services for the following laboratories: MEDA, Leopharma, and Almirall.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Conflicts of Interest" ] 1 => array:2 [ "identificador" => "xack99281" "titulo" => "Acknowledgments" ] 2 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Alomar A. Queratosis actínica: un proceso ancestral, nuevos conceptos y enfoques terapéuticos. Actas Dermosifiliogr. 2014;105:809–812.</p>" ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:29 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pathology and pathobiology of the actinic (solar) keratosis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "C.J. 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| 2023 Agosto | 73 | 20 | 93 |
| 2023 Julio | 67 | 36 | 103 |
| 2023 Junio | 59 | 41 | 100 |
| 2023 Mayo | 74 | 49 | 123 |
| 2023 Abril | 53 | 25 | 78 |
| 2023 Marzo | 69 | 32 | 101 |
| 2023 Febrero | 75 | 16 | 91 |
| 2023 Enero | 34 | 49 | 83 |
| 2022 Diciembre | 59 | 53 | 112 |
| 2022 Noviembre | 41 | 24 | 65 |
| 2022 Octubre | 24 | 25 | 49 |
| 2022 Septiembre | 22 | 36 | 58 |
| 2022 Agosto | 26 | 26 | 52 |
| 2022 Julio | 19 | 36 | 55 |
| 2022 Junio | 19 | 22 | 41 |
| 2022 Mayo | 49 | 25 | 74 |
| 2022 Abril | 71 | 32 | 103 |
| 2022 Marzo | 63 | 30 | 93 |
| 2022 Febrero | 54 | 28 | 82 |
| 2022 Enero | 66 | 37 | 103 |
| 2021 Diciembre | 48 | 28 | 76 |
| 2021 Noviembre | 53 | 37 | 90 |
| 2021 Octubre | 42 | 48 | 90 |
| 2021 Septiembre | 21 | 36 | 57 |
| 2021 Agosto | 27 | 34 | 61 |
| 2021 Julio | 25 | 23 | 48 |
| 2021 Junio | 29 | 32 | 61 |
| 2021 Mayo | 29 | 21 | 50 |
| 2021 Abril | 59 | 30 | 89 |
| 2021 Marzo | 42 | 8 | 50 |
| 2021 Febrero | 50 | 22 | 72 |
| 2021 Enero | 36 | 20 | 56 |
| 2020 Diciembre | 39 | 14 | 53 |
| 2020 Noviembre | 30 | 23 | 53 |
| 2020 Octubre | 23 | 11 | 34 |
| 2020 Septiembre | 29 | 8 | 37 |
| 2020 Agosto | 22 | 11 | 33 |
| 2020 Julio | 28 | 13 | 41 |
| 2020 Junio | 40 | 27 | 67 |
| 2020 Mayo | 30 | 16 | 46 |
| 2020 Abril | 51 | 10 | 61 |
| 2020 Marzo | 31 | 15 | 46 |
| 2020 Febrero | 7 | 0 | 7 |
| 2020 Enero | 4 | 0 | 4 |
| 2019 Diciembre | 8 | 2 | 10 |
| 2019 Noviembre | 4 | 2 | 6 |
| 2019 Octubre | 0 | 1 | 1 |
| 2019 Septiembre | 4 | 0 | 4 |
| 2019 Agosto | 4 | 0 | 4 |
| 2019 Julio | 4 | 3 | 7 |
| 2019 Junio | 6 | 9 | 15 |
| 2019 Mayo | 4 | 12 | 16 |
| 2019 Abril | 3 | 16 | 19 |
| 2019 Marzo | 4 | 5 | 9 |
| 2019 Febrero | 2 | 3 | 5 |
| 2019 Enero | 3 | 0 | 3 |
| 2018 Diciembre | 2 | 0 | 2 |
| 2018 Noviembre | 1 | 0 | 1 |
| 2018 Octubre | 4 | 0 | 4 |
| 2018 Septiembre | 4 | 0 | 4 |
| 2018 Abril | 0 | 1 | 1 |
| 2018 Marzo | 0 | 1 | 1 |
| 2018 Febrero | 37 | 10 | 47 |
| 2018 Enero | 30 | 6 | 36 |
| 2017 Diciembre | 26 | 14 | 40 |
| 2017 Noviembre | 31 | 10 | 41 |
| 2017 Octubre | 25 | 12 | 37 |
| 2017 Septiembre | 30 | 16 | 46 |
| 2017 Agosto | 45 | 12 | 57 |
| 2017 Julio | 30 | 8 | 38 |
| 2017 Junio | 30 | 19 | 49 |
| 2017 Mayo | 29 | 18 | 47 |
| 2017 Abril | 35 | 12 | 47 |
| 2017 Marzo | 17 | 14 | 31 |
| 2017 Febrero | 13 | 13 | 26 |
| 2017 Enero | 20 | 9 | 29 |
| 2016 Diciembre | 29 | 11 | 40 |
| 2016 Noviembre | 41 | 26 | 67 |
| 2016 Octubre | 29 | 23 | 52 |
| 2016 Septiembre | 0 | 5 | 5 |
| 2016 Agosto | 0 | 3 | 3 |
| 2016 Julio | 9 | 1 | 10 |
| 2016 Junio | 14 | 19 | 33 |
| 2016 Mayo | 15 | 5 | 20 |
| 2016 Abril | 13 | 2 | 15 |
| 2016 Marzo | 7 | 1 | 8 |
| 2016 Febrero | 18 | 19 | 37 |
| 2016 Enero | 12 | 23 | 35 |
| 2015 Diciembre | 11 | 16 | 27 |
| 2015 Noviembre | 6 | 23 | 29 |
| 2015 Octubre | 17 | 18 | 35 |
| 2015 Septiembre | 7 | 12 | 19 |
| 2015 Agosto | 12 | 4 | 16 |
| 2015 Julio | 24 | 2 | 26 |
| 2015 Junio | 28 | 8 | 36 |
| 2015 Mayo | 26 | 6 | 32 |
| 2015 Abril | 13 | 5 | 18 |
| 2015 Marzo | 18 | 6 | 24 |
| 2015 Febrero | 20 | 7 | 27 |
| 2015 Enero | 11 | 7 | 18 |
| 2014 Diciembre | 6 | 5 | 11 |
| 2014 Noviembre | 8 | 4 | 12 |
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