Keratoza aktyniczna (solar keratoza)
Patofizjologia i mechanizm
Rogowacenie słoneczne (actinic keratosis) to przedrakowe zmiany skórne powstające w wyniku kumulacyjnej ekspozycji na promieniowanie UVB (290-320 nm) i UVA (320-400 nm), prowadzące do proliferacji atypowych keratynocytów i potencjalnej transformacji w raka kolczystokomórkowego (SCC). Patogeneza obejmuje uszkodzenia DNA (mutacje C-T i G-T), stres oksydacyjny, immunosupresję oraz mutacje w genach supresorowych nowotworów, zwłaszcza TP53 (obecne w 30-50% przypadków), a także NOTCH1/2, p16, PTEN/AKT i aktywację szlaku MAPK. Przewlekły stan zapalny i infekcja HPV (obecność DNA HPV w 40% zmian) dodatkowo nasilają proces kancerogenezy. Immunosupresja indukowana przez UV i zaburzenia apoptozy (m.in. supresja CD95, regulacja p53) umożliwiają przetrwanie uszkodzonych komórek. Ryzyko transformacji pojedynczej zmiany rogowacenia słonecznego w SCC wynosi 0,025-16% rocznie, a u pacjentów z wieloma zmianami ryzyko rozwoju SCC sięga 10-15%.
- Patogeneza rogowacenia słonecznego
- Rola promieniowania UV w patogenezie
- Zmiany genetyczne i molekularne
- Mechanizmy prozapalne i stres oksydacyjny
- Immunosupresja i zaburzenia apoptozy
- Rola wirusa brodawczaka ludzkiego (HPV)
- Zaburzenia cyklu komórkowego i remodelowanie tkanek
- Transformacja w raka kolczystokomórkowego
- Regresja i samoistne ustępowanie zmian
- Znaczenie kliniczne i implikacje terapeutyczne
Patogeneza rogowacenia słonecznego
Rogowacenie słoneczne (łac. actinic keratosis, solar keratosis) to przedrakowe zmiany skórne powstające w wyniku kumulacyjnej ekspozycji na promieniowanie ultrafioletowe (UV). Zmiany te charakteryzują się proliferacją atypowych keratynocytów naskórkowych i mogą potencjalnie przekształcić się w raka kolczystokomórkowego (squamous cell carcinoma, SCC).12
Rola promieniowania UV w patogenezie
Głównym czynnikiem etiologicznym w rozwoju rogowacenia słonecznego jest przewlekła ekspozycja na promieniowanie UV, zarówno UVB (290-320 nm) jak i UVA (320-400 nm).1 Promieniowanie to działa jako inicjator i promotor kancerogenezy poprzez wywoływanie patologicznych zmian w keratynocytach naskórka, zakłócając szlaki regulacyjne związane ze wzrostem i różnicowaniem komórek.12
Mechanizmy działania promieniowania UV w rozwoju rogowacenia słonecznego obejmują:
- Promieniowanie UVB bezpośrednio uszkadza DNA komórkowe, powodując powstawanie dimerów tymidynowych oraz innych fotoproduktów, co prowadzi do charakterystycznych mutacji DNA polegających na zastąpieniu cytozyny tyminą (C-T)1
- Promieniowanie UVA wnika głębiej w skórę i stymuluje produkcję reaktywnych form tlenu (ROS), które uszkadzają błony komórkowe, jądra komórkowe i białka; UVA promuje również mutacje polegające na zastąpieniu guaniny (G) tyminą (T) w DNA2
- Uszkodzenia wywołane przez UV prowadzą do aktywacji szlaków sygnałowych, które skutkują zmianami poziomów cytokin regulacyjnych, efektami immunosupresyjnymi oraz zaburzeniami różnicowania komórkowego i apoptozy3
Zmiany genetyczne i molekularne
Kluczową rolę w rozwoju rogowacenia słonecznego odgrywają mutacje w genach supresorowych nowotworów, szczególnie w genie TP53. Mutacje te wykryto w 30-50% próbek skóry pacjentów z rogowaceniem słonecznym.12 Gen TP53 jest zaangażowany w regulację cyklu komórkowego, apoptozę i naprawę DNA. Jego mutacja może prowadzić do zaburzenia normalnych odpowiedzi apoptotycznych na uszkodzenia wywołane przez UV, pozwalając na dalszą proliferację i rozwój nowych nieprawidłowości genetycznych.2
Inne ważne zmiany genetyczne i molekularne w patogenezie rogowacenia słonecznego to:
- Mutacje w genach NOTCH1 i NOTCH21
- Inaktywacja białka supresorowego p16, które jest zaangażowane w zatrzymanie cyklu komórkowego – jego inaktywacja prowadzi do ciągłego cyklu komórkowego i rozwoju rogowacenia słonecznego w kierunku nowotworu skóry2
- Zmiany w szlaku PTEN/AKT1
- Aktywacja szlaku MAPK, który odgrywa wiodącą rolę w procesie inwazji2
- Nadekspresja metaloproteinazy macierzy-1 (MMP-1), która jest związana z wczesnym rozwojem rogowacenia słonecznego2
Mechanizmy prozapalne i stres oksydacyjny
Przewlekły stan zapalny jest silnie związany z rozwojem raka kolczystokomórkowego oraz progresją zmian typu rogowacenia słonecznego.1 Proces zapalny w patogenezie rogowacenia słonecznego jest mediowany przez:
- Szlak kwasu arachidonowego1
- Produkcję cytokin prozapalnych2
- Aktywację komórek tucznych i czynnika hamującego migrację makrofagów3
Aktywacja tych mediatorów prowadzi do peroksydacji lipidów, zwiększenia poziomu limfocytów T i komórek Langerhansa w zmianach, zwiększenia ekspresji p53 i Bcl-2 oraz zmniejszenia ekspresji Fas (CD95) i liganda Fas, które są ważnymi początkowymi czynnikami w procesie apoptozy komórek zmutowanych przez UV.4
Stres oksydacyjny również odgrywa istotną rolę w procesie fotokancerogenezy. Nadmierna ekspozycja na promieniowanie UV prowadzi do produkcji reaktywnych form tlenu, co skutkuje peroksydacją lipidów i zniszczeniem komórek, z uszkodzeniem DNA genomowego i mitochondrialnego.1 Transformacja złośliwa rogowacenia słonecznego jest silnie skorelowana ze zwiększonym poziomem stresu oksydacyjnego i znaczną ilością reaktywnych form tlenu.2
Immunosupresja i zaburzenia apoptozy
Rozwój rogowacenia słonecznego wiąże się ze zwiększeniem liczby regulatorowych limfocytów T (Tregs), a uwolnienie czynnika aktywującego płytki (PAF) i konwersja tUCA do cUCA są dwoma początkowymi zdarzeniami w immunosupresji wywołanej przez UV.1 Immunosupresja indukowana przez UV jest jednym z głównych mechanizmów umożliwiających przetrwanie komórek z uszkodzonym DNA i rozwój zmian przedrakowych.2
Zaburzenia apoptozy w rogowaceniu słonecznym występują poprzez:
- Supresję, eliminację lub aktywację mediatorów apoptotycznych, takich jak CD95 i czynnik martwicy nowotworów związany z apoptozą1
- Wpływ na proapoptotyczne geny supresorowe nowotworów2
- Regulację aktywności apoptotycznej p533
Rola wirusa brodawczaka ludzkiego (HPV)
W ostatnich latach pojawiło się coraz więcej dowodów na to, że wirus brodawczaka ludzkiego (HPV) odgrywa znaczącą rolę w rozwoju rogowacenia słonecznego i raka kolczystokomórkowego skóry, wraz z przewlekłym naświetlaniem UV, immunosupresją i predyspozycjami genetycznymi.1 Wirus HPV został wykryty w zmianach typu rogowacenia słonecznego, a mierzalne ładunki wirusowego DNA HPV zmierzono w 40% tych zmian.2
Mechanizm działania HPV w rozwoju rogowacenia słonecznego nie jest w pełni wyjaśniony, ale wiadomo, że:
- Białko HPV-E6 może zmniejszać ekspresję białka Bak, które jest jednym z kluczowych regulatorów procesu apoptozy1
- HPV inaktywuje TP53 i może hamować śmierć komórkową wywołaną przez UV, co może prowadzić do nieprawidłowej naprawy DNA, powodując gromadzenie się mutacji wywołanych przez UV i transformację nowotworową2
- Podwyższony poziom HPV w zmianach typu rogowacenia słonecznego odzwierciedla wzmożoną replikację wirusowego DNA, co wiąże się z nieprawidłową proliferacją i różnicowaniem keratynocytów, co sprzyja replikacji HPV3
Zaburzenia cyklu komórkowego i remodelowanie tkanek
Rogowacenie słoneczne powstaje, gdy proliferują dysplastyczne wewnątrznaskórkowe keratynocyty, a ta proliferacja jest wzmacniana przez czynniki takie jak uszkodzenie DNA, stan zapalny, immunosupresja i mutageneza.1 Procesy te prowadzą do zaburzeń cyklu komórkowego i nieprawidłowej proliferacji komórek.
W rozwoju rogowacenia słonecznego obserwuje się również remodelowanie tkanek, które obejmuje zmiany w strukturze i organizacji naskórka i skóry właściwej. Nadekspresja metaloproteinaz macierzy może odgrywać rolę w tym procesie, przyczyniając się do degradacji macierzy zewnątrzkomórkowej i ułatwiając inwazję komórek nowotworowych.2
Transformacja w raka kolczystokomórkowego
Rogowacenie słoneczne jest powszechnie uznawane za zmianę przedrakową, która może przekształcić się w raka kolczystokomórkowego (SCC).1 Proces kancerogenezy w rogowaceniu słonecznym następuje według modelu wieloetapowej kancerogenezy: początkowa mutacja w genie supresorowym nowotworu prowadzi do powstania zmiany prekursorowej, a późniejsze mutacje w onkogenach nadają cechy inwazyjne.1
Częstość transformacji rogowacenia słonecznego w SCC jest różnie podawana w literaturze:
- Według niektórych badań, ryzyko transformacji pojedynczej zmiany rogowacenia słonecznego w SCC wynosi od 0,025% do 16% rocznie1
- Chociaż ryzyko przejścia pojedynczej zmiany w raka jest niskie (5-10%), to u pacjenta z wieloma zmianami rogowacenia słonecznego ryzyko wystąpienia SCC na którymś etapie jest szacowane na około 10-15%23
- Według niektórych autorów, 60-80% przypadków SCC rozwija się w obszarach wcześniejszego rogowacenia słonecznego1
Choć nie wszystkie zmiany typu rogowacenia słonecznego rozwiną się w raka, są one wczesnymi zmianami na kontinuum chorobowym, które może postępować w kierunku nowotworu.1 Istotne jest, że nie ma jeszcze wiarygodnych kryteriów histologicznych, które pozwalałyby przewidzieć, które zmiany rogowacenia słonecznego przekształcą się w raka kolczystokomórkowego in situ lub inwazyjnego.2
Czynniki ryzyka progresji do raka
Ryzyko progresji rogowacenia słonecznego do SCC zależy od różnych czynników:1
- Czas trwania zmian – dłużej istniejące zmiany mają wyższe ryzyko transformacji2
- Liczba zmian – obecność dziesięciu zmian rogowacenia słonecznego wiąże się z 14% ryzykiem rozwoju SCC w ciągu pięciu lat3
- Immunosupresja – osoby z upośledzoną funkcją układu immunologicznego mają wyższe ryzyko rozwoju SCC4
- Lokalizacja zmian – zmiany na wargach, nosie, uszach lub powiekach wiążą się ze zwiększonym ryzykiem rozwoju SCC5
- Rozmiar zmiany – większe zmiany mają wyższe ryzyko transformacji6
Kliniczne cechy sugerujące zwiększone ryzyko progresji do SCC można rozpoznać jako „IDRBEU”: I (induracja/stan zapalny), D (średnica > 1 cm), R (szybkie powiększanie się), B (krwawienie), E (rumień) i U (owrzodzenie).7
Regresja i samoistne ustępowanie zmian
Rogowacenie słoneczne może wykazywać nieregularny przebieg w czasie. Niektóre zmiany mogą samoistnie ustępować, choć mechanizmy leżące u podstaw tej regresji nie są w pełni zrozumiałe i są przedmiotem trwających badań.12
Niektóre czynniki mogące przyczyniać się do samoistnej regresji rogowacenia słonecznego to:
- Aktywacja układu immunologicznego skutkująca eliminacją atypowych komórek1
- Ograniczenie ekspozycji na promieniowanie UV i ochrona skóry przed słońcem23
- Stosowanie nikotynamidu (witaminy B3) w dawce 500 mg dwa razy dziennie może zmniejszyć liczbę i nasilenie zmian rogowacenia słonecznego4
Badania wykazały, że suplementacja nikotynamidem może prowadzić do znacznego wzrostu poziomu NAD+ w surowicy, co wiąże się z ochronnymi efektami w zakresie zmian rogowacenia słonecznego. Obserwowane zmniejszenie poziomu NADH wraz ze wzrostem poziomu NAD+ sugeruje zmianę stanu redoks, potencjalnie kluczową w regulacji metabolizmu komórkowego i utrzymaniu homeostazy w tkankach o wysokim wskaźniku odnowy, takich jak skóra.5
Co ciekawe, podczas gdy poziomy SIRT1 w surowicy nie zmieniały się istotnie po podaniu nikotynamidu, aktywność jądrowa SIRT1 w komórkach jednojądrzastych krwi obwodowej wyraźnie wzrosła. To odkrycie sugeruje, że wpływ nikotynamidu na SIRT1 jest głównie jądrowy, podkreślając potencjalny mechanizm, poprzez który nikotynamid chroni przed uszkodzeniami DNA i niestabilnością genomową.6
Znaczenie kliniczne i implikacje terapeutyczne
Zrozumienie złożonej patogenezy rogowacenia słonecznego ma istotne implikacje kliniczne i terapeutyczne. Ponieważ zmiany te reprezentują wczesne stadium procesu kancerogenezy skóry, ich prawidłowe leczenie może zapobiec rozwojowi inwazyjnego raka kolczystokomórkowego.1
Obecność rogowacenia słonecznego jest ważnym biomarkerem nadmiernej ekspozycji na promieniowanie UV i zwiększonego ryzyka raka skóry.1 Osoby z rogowaceniem słonecznym są również narażone na ryzyko rozwoju rogowacenia słonecznego warg (actinic cheilitis), raka podstawnokomórkowego (BCC), czerniaka i rzadkich form raka skóry, takich jak rak z komórek Merkla.2
Różne mechanizmy patogenetyczne rogowacenia słonecznego stanowią potencjalne cele terapeutyczne:
- Imikwimod działa poprzez indukowanie odpowiedzi immunologicznej wrodzonej i nabytej, która niszczy nieprawidłowe komórki w całym obszarze, gdzie jest stosowany1
- Diklofenak działa poprzez hamowanie cyklooksygenazy, wpływając na proces zapalny2
- 5-fluorouracyl (5-FU) działa na szybko dzielące się komórki3
- Ingenol mebutate (Picato) indukuje śmierć komórek w leczeniu zmian rogowacenia słonecznego, choć dokładny mechanizm działania nie jest znany4
- Tirbanibulin działa poprzez zabijanie szybko rosnących nieprawidłowych komórek5
Pole kanceryzacji (field cancerization) to nowsze pojęcie, które odnosi się do obszarów skóry z wieloma zmianami rogowacenia słonecznego związanymi z tłem rumienia, teleangiektazji i innych zmian obserwowanych w skórze uszkodzonej przez słońce. Te obszary są prawdopodobnie bardziej narażone na rozwój SCC, zwłaszcza jeśli pozostaną nieleczone, dlatego zaleca się, aby były leczone bardziej intensywnie.6 Leczenie powinno być stosowane na całym obszarze pola kanceryzacji, a nie tylko na pojedynczych zmianach.7
Głównym celem leczenia jest zmniejszenie całkowitej liczby zmian, które pacjent ma w danym momencie – im mniej zmian, tym mniejsze ryzyko rozwoju SCC.8 Najskuteczniejszą metodą profilaktyki jest ścisła ochrona przed słońcem, która pomaga zmniejszyć liczbę nowych zmian rogowacenia słonecznego i obniżyć ryzyko rozwoju raka skóry indukowanego przez słońce.910
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Materiały źródłowe
- #1 Actinic Keratosis – StatPearls – NCBI Bookshelfhttps://www.ncbi.nlm.nih.gov/books/NBK557401/
Actinic keratoses are premalignant cutaneous lesions that may progress to squamous cell carcinoma. These lesions commonly appear on sun-exposed areas of the skin in individuals with a history of cumulative sun exposure. […] Actinic keratoses primarily arise due to the cumulative effects of ultraviolet (UV) radiation on the skin, which occurs over an individual’s lifetime of sun exposure. […] The pathophysiology of actinic keratosis development is complex. Excessive and cumulative UV radiation exposure from the sun can trigger pathological changes in the epidermal keratinocytes by disrupting regulatory pathways involved in cell growth and differentiation. This disruption leads to inflammation and immunosuppression, contributing to the intraepidermal proliferation of dysplastic keratinocytes, the precursors of actinic keratosis.
- #1 Actinic Keratosis Pathology: Overview, Etiology, Clinical Featureshttps://emedicine.medscape.com/article/1976538-overview
Actinic keratosis is an erythematous scaly papule or plaque that develops on sun-damaged skin as a result of chronic exposure to ultraviolet radiation, typically in elderly patients with lighter skin types. This condition is related to squamous cell carcinoma of the skin and is often described as a precursor or early form of squamous cell carcinoma in situ, although most actinic keratoses will not progress to invasive squamous cell carcinoma. […] Chronic exposure to ultraviolet light (UV) or sunlight is one of the most important factors in the development of actinic keratoses. Both UVB (290-320 nm) and UVA (320-400 nm) likely play a role in the development of these conditions. UV radiation acts as an initiator and promoter of carcinogenesis in actinic keratosis and squamous cell carcinoma.
- #1 SciELO Brazil – Actinic keratoses: review of clinical, dermoscopic, and therapeutic aspects, Actinic keratoses: review of clinical, dermoscopic, and therapeutic aspects,https://www.scielo.br/j/abd/a/KNfmyRfzPpytwPWZnTrK8Br/
UVB radiation is absorbed by cellular DNA, promoting errors in the repair of cyclobutane pyrimidine dimers and production of 6-4 photoproducts, as well as characteristic cytosine-thymine (C-T) DNA substitutions. […] Thus, mechanisms involved in the onset of actinic keratoses include inflammation, oxidative stress, immunosuppression, impaired apoptosis, cell cycle deregulation and cell proliferation, and tissue remodeling. […] The inflammatory process is mediated by the arachidonic acid pathway, by the production of proinflammatory cytokines, and by the activation of mast cells and inhibitory factor of macrophage migration; the results of the activation of these mediators include lipid peroxidation, increase in intralesional levels of T lymphocytes and Langerhans cells, increase of p53 and Bcl-2, and reduction in Fas (cd95) and Fas-ligand, which are important initial factors in the apoptosis process of UV-mutated cells.
- #1 Actinic Keratosis Pathology: Overview, Etiology, Clinical Featureshttps://emedicine.medscape.com/article/1976538-overview
UV-induced mutations of the tumor suppressor gene TP53 are of major importance in the development of actinic keratosis. Basal keratinocytes with mutated TP53 may not respond normally to UV-induced apoptosis, allowing further proliferation and development of new genetic abnormalities. […] Ultraviolet (UV) radiation induces abnormalities that initiate and promote the development of actinic keratosis. Many of the same genetic alterations are found in cutaneous squamous cell carcinoma as well as other malignancies. The interplay of alterations in cell cycle regulators, signal transduction pathways, and other genetic alterations in the development and progression of actinic keratoses to squamous cell carcinoma is a subject of great interest and active research. […] Mutations in TP53 appear to play a crucial role in the development of actinic keratosis. When exposed to UVB light, mice with severe combined immune deficiency (SCID) with transplanted human skin will develop actinic keratoses associated with specific TP53 mutations.
- #1 Pathology Outlines – Actinic keratosishttps://www.pathologyoutlines.com/topic/skintumornonmelanocyticactinickeratosis.html
Intraepidermal keratinocytic lesion secondary to solar damage […] Most common precursor of cutaneous squamous cell carcinoma (SCC) […] Cumulative solar damage causes a high mutation burden in the germinative (basal) layer of keratinocytes […] Chronic sun damage (ultraviolet UVB radiation and UVA to a lesser extent) […] Main driver mutations present in cutaneous invasive squamous cell carcinoma such as TP53, NOTCH1 and NOTCH2 are already present in actinic keratosis […] MAPK pathway seems to play a leading role in invasion.
- #1 Actinic Keratosis Pathology: Overview, Etiology, Clinical Featureshttps://emedicine.medscape.com/article/1976538-overview
The immunosuppressive cyclosporin may also affect the PTEN/AKT pathway in the development of actinic keratosis. Overexpression of matrix metalloproteinase-1 (MMP-1) is also associated with early development of actinic keratosis and metalloproteinases may also play a role in mediating the epidermal growth factor receptor (EGFR)/ERK/AKT/cyclin D1 pathways and cell cycle progression induced by UVB radiation. […] Although the majority of cutaneous squamous cell carcinomas arise from or in association with actinic keratosis, the risk of progression of actinic keratosis to squamous cell carcinoma is low. No reliable histologic criteria have been established that predict which actinic keratoses will progress to squamous cell carcinoma in situ or invasive squamous cell carcinoma.
- #1 Advancements in elucidating the pathogenesis of actinic keratosis: present state and future prospectshttps://pmc.ncbi.nlm.nih.gov/articles/PMC10985158/
AK is formed when dysplastic intra-epidermal keratinocytes proliferate, and this proliferation is enhanced by factors such as DNA damage, inflammation, immunosuppression, and mutagenesis. […] The development of squamous cell carcinoma is strongly associated with chronic inflammation. […] The probability of developing skin tumors is higher due to chronic inflammation, which can occur through two pathways. […] Emerging evidence indicates that the Tumor Suppressor Gene (TSG) plays a vital role in various cellular processes, such as DNA damage repair, cell division inhibition, apoptosis induction, and metastasis suppression. […] The malignant transformation of AK is highly correlated with an increased level of oxidative status and a significant quantity of ROS. […] In recent years, there has been growing evidence that HPV plays a significant role in the development of AK and cSCC, along with chronic UV irradiation, immunosuppression, and genetic predispositions.
- #1 SciELO Brazil – Actinic keratoses: review of clinical, dermoscopic, and therapeutic aspects, Actinic keratoses: review of clinical, dermoscopic, and therapeutic aspects,https://www.scielo.br/j/abd/a/KNfmyRfzPpytwPWZnTrK8Br/
Oxidative stress is also involved in the photocarcinogenesis process, as a result of the excessive exposure to ultraviolet radiation, which leads to the production of reactive oxygen species and culminates with lipid peroxidation and cell destruction, with damage to genomic and mitochondrial DNA. […] Apoptosis disorders occur by suppression, elimination, or activation of apoptotic mediators, such as CD95 and tumor necrosis factor-associated apoptosis, and of pro-apoptotic tumor suppressor genes, as well as by regulation of p53 apoptotic activity. […] The five most important independent risk factors for actinic keratoses development are age, sex, phototypes I and II, previous history of cutaneous neoplasms, and sun exposure due to occupational reasons. […] The development of actinic keratoses in immunosuppressed patients involves the factors previously described and aspects related to immunosuppressive medications that may even act as carcinogens.
- #1 Advancements in elucidating the pathogenesis of actinic keratosis: present state and future prospectshttps://pmc.ncbi.nlm.nih.gov/articles/PMC10985158/
The development of cSCC from AK is highly associated with the rise in Tregs, whereas the release of PAF and the conversion of tUCA to cUCA are two initial occurrences in UV-induced immunosuppression. […] The development of AK involves various intricate mechanisms, which offer potential avenues for treatment.
- #1 Actinic keratosis â diagnostic and therapeutic recommendations of the Polish Dermatological Societyhttps://www.termedia.pl/Actinic-keratosis-diagnostic-and-therapeutic-recommendations-of-the-Polish-Dermatological-Society,56,54724,1,1.html
UVB rays directly impact nucleic acids and lipid membranes, while UVA rays cause indirect damage through the generation of reactive oxygen species. These compounds interfere with normal cell proliferation and intracellular signaling. […] UVR induces immunosuppression, enhances the expression of prostaglandins and cyclooxygenase-2, increases the secretion of pro-inflammatory cytokines and anti-inflammatory interleukin (IL)-10, and promotes the formation of regulatory T lymphocytes. Inflammation, oxidative stress, impaired apoptosis, local immunosuppression, and dysregulated cell cycle collectively create an environment that promotes tumor development. Another significant factor implicated in the development of AK is infection with human papillomavirus (HPV). The underlying mechanism of this phenomenon is not fully understood. However, it is known that HPV-E6 protein can reduce the expression of Bak protein, which is one of the key regulators in the apoptosis process.
- #1 Actinic Keratosis – StatPearls – NCBI Bookshelfhttps://www.ncbi.nlm.nih.gov/books/NBK557401/
The primary histopathologic feature of actinic keratosis is the presence of atypical keratinocytes within sun-damaged skin that is limited to the lower third of the epidermis. […] Actinic keratosis can exhibit erratic behavior over time. Some actinic keratoses may spontaneously regress, though the mechanisms behind this regression are not fully understood and are an area of ongoing research. […] However, it is essential to note that actinic keratoses have the potential to progress and evolve into invasive squamous cell carcinoma (SCC), a type of skin cancer. Most squamous cell carcinomas develop from preexisting actinic keratoses or with areas that contain actinic keratoses.
- #1 Actinic Keratosis (AK): Causes, Symptoms, and Treatmenthttps://patient.info/doctor/actinic-keratosis-pro
Actinic keratoses are ultraviolet (UV) light-induced lesions of the skin, which are by far the most common lesions with malignant potential to arise on the skin. In some cases, they progress to invasive squamous cell carcinoma (SCC). […] The condition is caused by UV-induced DNA damage within the skin. […] Human papillomaviruses (HPVs) have been implicated as co-carcinogens in the pathogenesis. […] Actinic keratosis is considered by some to be the earliest manifestation of SCC. […] The most important complication is the progression to malignant change if left untreated. […] Progression to SCC occurs slowly. Although known to be pre-malignant, the probability of a lesion undergoing transformation to SCC is not known; however, evidence suggests this ranges from 0.025% to 16% per year.
- #1 SciELO Brazil – Actinic keratoses: review of clinical, dermoscopic, and therapeutic aspects, Actinic keratoses: review of clinical, dermoscopic, and therapeutic aspects,https://www.scielo.br/j/abd/a/KNfmyRfzPpytwPWZnTrK8Br/
The carcinogenic process in actinic keratoses follows the multi-stage carcinogenesis model: an initial mutation in a tumor suppressor gene leads to a precursor lesion, and later mutations in oncogenes lead to invasive properties. […] Data about the risk of malignant transformation of a single actinic keratosis ranges from 0.1% to 16%. […] According to some authors, 60-80% of SCCs develop in areas of actinic keratoses.
- #1 Actinic Keratosis | Treatments and Pictures| Cancer Imageshttps://www.skymd.com/conditions/actinic-keratosis
Actinic keratoses (AKs) or solar keratoses are superficial tumors consisting of proliferations of abnormal skin cells that develop in response to prolonged exposure to ultraviolet (UV) radiation. […] AKs have historically been considered precancerous or premalignant lesions with a potential for developing into skin cancer. However, in recent years there has been an effort to redefine AKs as malignant neoplasms, because these lesions are essentially the initial stage of cancer in evolution. […] Although not all AKs become cancers, AKs are the initial lesion in a disease continuum that may progress to cancer. […] The prognosis of AK includes persistence, regression, or malignant transformation into invasive SCC. […] The relative risk of progression to SCC depends on factors related to the AK itself, such as the length of time an AK has been present and the number of baseline AKs that are on the skin.
- #1 Actinic Keratosis | Treatments and Pictures| Cancer Imageshttps://www.skymd.com/conditions/actinic-keratosis
It was observed that before an AK progresses to skin cancer, it may become clinically tender and inflamed. […] The presence of AK is therefore an important biomarker of excessive UV exposure and increased skin cancer risk. […] Tumor protein 53 (TP53) is a tumor suppressor gene, which helps to repair cells when DNA is damaged by UVR and causes cell death when the damage cannot be repaired. Mutations of TP53 are frequently seen in AK. […] p16 is also a tumor suppressor protein. It is involved in the arrest of the cell cycle and its mutations can also be caused by UVR. Inactivation of p16 leads to continuous cell cycling and it is thought that inactivated p16 advances AK to skin cancer. […] The great majority of AKs occur on light-exposed sites in fair-skinned people who have had excessive exposure to UVR.
- #1 Actinic keratoses – BAD Patient Hubhttps://www.skinhealthinfo.org.uk/condition/actinic-keratoses/
Actinic keratoses can be treated but tend to recur over time. Their presence indicates there is sun damage to the skin and so, whilst an individual actinic keratosis can be cured, the affected individual is at risk of developing more in the future. […] Some actinic keratoses may go away without treatment, especially if they are small and if the skin is protected from the sun. […] Treatments that your doctor can provide for actinic keratoses: Creams (topical treatments): Several types of cream or gel can be prescribed for use at home. These include 5-fluorouracil or imiquimod which are effective treatments. […] Freezing with liquid nitrogen (cryotherapy): This is an effective treatment which does not normally leave a scar but may make the treated area lose its natural pigment permanently.
- #1 Actinic Keratosis: New Concepts and Therapeutic Approaches for an Ancestral Condition | Actas Dermo-Sifiliográficashttps://www.actasdermo.org/es-actinic-keratosis-new-concepts-therapeutic-articulo-S1578219014002339
Since then, specialists have agreed to consider AKs to be true intraepidermal neoplasms, or neoplasms in situ. It is estimated that from 5% to 20% of preexisting lesions, including subclinical ones, may progress and grow to become invasive squamous cell carcinoma. […] 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 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.
- #1 Actinic Keratosis: New Concepts and Therapeutic Approaches for an Ancestral Condition | Actas Dermo-Sifiliográficashttps://www.actasdermo.org/es-actinic-keratosis-new-concepts-therapeutic-articulo-S1578219014002339
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. […] We have seen that AKs so commonplace in the population over the age of 50 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.
- #2 Actinic Keratosis: Practice Essentials, Background, Pathophysiologyhttps://emedicine.medscape.com/article/1099775-overview
Actinic keratosis (AK) is an ultraviolet (UV) lightinduced skin lesion that may progress to invasive squamous cell carcinoma (SCC). It is by far the most common lesion with malignant potential to arise on the skin. Actinic keratosis is seen in fair-skinned persons on skin areas that have had long-term sun exposure. […] Actinic keratosis frequency correlates with cumulative UV exposure. […] DNA analysis of the cells within actinic keratoses shows characteristic UV-induced mutations in key genes, including TP53 and deletion of the gene coding for p16 tumor suppressor protein. […] In both histologic and molecular parameters, actinic keratoses share features with squamous cell carcinoma, and over time, a small percentage of actinic keratoses may transform into invasive squamous cell carcinoma.
- #2 Advancements in elucidating the pathogenesis of actinic keratosis: present state and future prospectshttps://pmc.ncbi.nlm.nih.gov/articles/PMC10985158/
Solar keratosis, also known as actinic keratosis (AK), is becoming increasingly prevalent. It is a benign tumor that develops in the epidermis. Individuals with AK typically exhibit irregular, red, scaly bumps or patches as a result of prolonged exposure to UV rays. […] However, the underlying causes of AK remain poorly understood. Previous research has indicated that the onset of AK involves various mechanisms including UV ray-induced inflammation, oxidative stress, complex mutagenesis, resulting immunosuppression, inhibited apoptosis, dysregulated cell cycle, altered cell proliferation, tissue remodeling, and human papillomavirus (HPV) infection. […] Multiple risk factors and diverse signaling pathways collectively contribute to its complex pathogenesis. […] The primary cause of AK is the accumulation of excessive ultraviolet radiation from the sun. This excessive UV radiation can disrupt complex regulatory pathways involved in cell growth and differentiation, leading to various pathological alterations in epidermal keratinocytes.
- #2 SciELO Brazil – Actinic keratoses: review of clinical, dermoscopic, and therapeutic aspects, Actinic keratoses: review of clinical, dermoscopic, and therapeutic aspects,https://www.scielo.br/j/abd/a/KNfmyRfzPpytwPWZnTrK8Br/
Actinic keratoses are dysplastic proliferations of keratinocytes with potential for malignant transformation. […] Ultraviolet radiation is the main factor involved in pathogenesis, but individual factors also play a role in the predisposing to lesions appearance. […] The risk of transformation into squamous cell carcinoma is the major concern regarding actinic keratoses. […] Excessive exposure to UV radiation is the major factor, acting as a complete carcinogen, both inducing and promoting tumor expansion. […] UV radiation activates molecular signaling cascades that result in modifications of regulatory cytokines levels, immunosuppressive effects, and defective cell differentiation and apoptosis. […] UVA radiation penetrates the skin more deeply and stimulates reactive oxygen species production, which damage cell membranes, their nuclei, and proteins; in addition, UVA promotes guanine (G) to thymine (T) replacement mutations in DNA.
- #2 Actinic keratosis: Epidemiology, clinical features, and diagnosis – UpToDatehttps://www.uptodate.com/contents/actinic-keratosis-epidemiology-clinical-features-and-diagnosis
Actinic keratosis (AK; also known as solar keratosis) is a cutaneous lesion that results from the proliferation of atypical epidermal keratinocytes. AK represent early lesions on a continuum with squamous cell carcinoma (SCC) and occasionally progress to SCC. […] Ultraviolet radiation is known to contribute to the development of AK through the induction of mutations in epidermal keratinocytes that lead to increased survival and proliferation of atypical cells. […] Mutations in the p53 tumor suppressor gene, a gene involved in cell cycle regulation, apoptosis, and deoxyribonucleic acid (DNA) repair, have been detected in 30 to 50 percent of lesional skin samples from patients with AK. […] In addition, many genetic and epigenetic alterations have been identified that impact divergent oncogenic pathways leading to AK and squamous cell carcinoma (SCC).
- #2 Actinic Keratosis Pathology: Overview, Etiology, Clinical Featureshttps://emedicine.medscape.com/article/1976538-overview
UV-induced mutations of the tumor suppressor gene TP53 are of major importance in the development of actinic keratosis. Basal keratinocytes with mutated TP53 may not respond normally to UV-induced apoptosis, allowing further proliferation and development of new genetic abnormalities. […] Ultraviolet (UV) radiation induces abnormalities that initiate and promote the development of actinic keratosis. Many of the same genetic alterations are found in cutaneous squamous cell carcinoma as well as other malignancies. The interplay of alterations in cell cycle regulators, signal transduction pathways, and other genetic alterations in the development and progression of actinic keratoses to squamous cell carcinoma is a subject of great interest and active research. […] Mutations in TP53 appear to play a crucial role in the development of actinic keratosis. When exposed to UVB light, mice with severe combined immune deficiency (SCID) with transplanted human skin will develop actinic keratoses associated with specific TP53 mutations.
- #2 Actinic Keratosis | Treatments and Pictures| Cancer Imageshttps://www.skymd.com/conditions/actinic-keratosis
It was observed that before an AK progresses to skin cancer, it may become clinically tender and inflamed. […] The presence of AK is therefore an important biomarker of excessive UV exposure and increased skin cancer risk. […] Tumor protein 53 (TP53) is a tumor suppressor gene, which helps to repair cells when DNA is damaged by UVR and causes cell death when the damage cannot be repaired. Mutations of TP53 are frequently seen in AK. […] p16 is also a tumor suppressor protein. It is involved in the arrest of the cell cycle and its mutations can also be caused by UVR. Inactivation of p16 leads to continuous cell cycling and it is thought that inactivated p16 advances AK to skin cancer. […] The great majority of AKs occur on light-exposed sites in fair-skinned people who have had excessive exposure to UVR.
- #2 Pathology Outlines – Actinic keratosishttps://www.pathologyoutlines.com/topic/skintumornonmelanocyticactinickeratosis.html
Intraepidermal keratinocytic lesion secondary to solar damage […] Most common precursor of cutaneous squamous cell carcinoma (SCC) […] Cumulative solar damage causes a high mutation burden in the germinative (basal) layer of keratinocytes […] Chronic sun damage (ultraviolet UVB radiation and UVA to a lesser extent) […] Main driver mutations present in cutaneous invasive squamous cell carcinoma such as TP53, NOTCH1 and NOTCH2 are already present in actinic keratosis […] MAPK pathway seems to play a leading role in invasion.
- #2 Actinic Keratosis Pathology: Overview, Etiology, Clinical Featureshttps://emedicine.medscape.com/article/1976538-overview
The immunosuppressive cyclosporin may also affect the PTEN/AKT pathway in the development of actinic keratosis. Overexpression of matrix metalloproteinase-1 (MMP-1) is also associated with early development of actinic keratosis and metalloproteinases may also play a role in mediating the epidermal growth factor receptor (EGFR)/ERK/AKT/cyclin D1 pathways and cell cycle progression induced by UVB radiation. […] Although the majority of cutaneous squamous cell carcinomas arise from or in association with actinic keratosis, the risk of progression of actinic keratosis to squamous cell carcinoma is low. No reliable histologic criteria have been established that predict which actinic keratoses will progress to squamous cell carcinoma in situ or invasive squamous cell carcinoma.
- #2 SciELO Brazil – Actinic keratoses: review of clinical, dermoscopic, and therapeutic aspects, Actinic keratoses: review of clinical, dermoscopic, and therapeutic aspects,https://www.scielo.br/j/abd/a/KNfmyRfzPpytwPWZnTrK8Br/
UVB radiation is absorbed by cellular DNA, promoting errors in the repair of cyclobutane pyrimidine dimers and production of 6-4 photoproducts, as well as characteristic cytosine-thymine (C-T) DNA substitutions. […] Thus, mechanisms involved in the onset of actinic keratoses include inflammation, oxidative stress, immunosuppression, impaired apoptosis, cell cycle deregulation and cell proliferation, and tissue remodeling. […] The inflammatory process is mediated by the arachidonic acid pathway, by the production of proinflammatory cytokines, and by the activation of mast cells and inhibitory factor of macrophage migration; the results of the activation of these mediators include lipid peroxidation, increase in intralesional levels of T lymphocytes and Langerhans cells, increase of p53 and Bcl-2, and reduction in Fas (cd95) and Fas-ligand, which are important initial factors in the apoptosis process of UV-mutated cells.
- #2 Advancements in elucidating the pathogenesis of actinic keratosis: present state and future prospectshttps://pmc.ncbi.nlm.nih.gov/articles/PMC10985158/
AK is formed when dysplastic intra-epidermal keratinocytes proliferate, and this proliferation is enhanced by factors such as DNA damage, inflammation, immunosuppression, and mutagenesis. […] The development of squamous cell carcinoma is strongly associated with chronic inflammation. […] The probability of developing skin tumors is higher due to chronic inflammation, which can occur through two pathways. […] Emerging evidence indicates that the Tumor Suppressor Gene (TSG) plays a vital role in various cellular processes, such as DNA damage repair, cell division inhibition, apoptosis induction, and metastasis suppression. […] The malignant transformation of AK is highly correlated with an increased level of oxidative status and a significant quantity of ROS. […] In recent years, there has been growing evidence that HPV plays a significant role in the development of AK and cSCC, along with chronic UV irradiation, immunosuppression, and genetic predispositions.
- #2 Actinic keratosis â diagnostic and therapeutic recommendations of the Polish Dermatological Societyhttps://www.termedia.pl/Actinic-keratosis-diagnostic-and-therapeutic-recommendations-of-the-Polish-Dermatological-Society,56,54724,1,1.html
UVB rays directly impact nucleic acids and lipid membranes, while UVA rays cause indirect damage through the generation of reactive oxygen species. These compounds interfere with normal cell proliferation and intracellular signaling. […] UVR induces immunosuppression, enhances the expression of prostaglandins and cyclooxygenase-2, increases the secretion of pro-inflammatory cytokines and anti-inflammatory interleukin (IL)-10, and promotes the formation of regulatory T lymphocytes. Inflammation, oxidative stress, impaired apoptosis, local immunosuppression, and dysregulated cell cycle collectively create an environment that promotes tumor development. Another significant factor implicated in the development of AK is infection with human papillomavirus (HPV). The underlying mechanism of this phenomenon is not fully understood. However, it is known that HPV-E6 protein can reduce the expression of Bak protein, which is one of the key regulators in the apoptosis process.
- #2 SciELO Brazil – Actinic keratoses: review of clinical, dermoscopic, and therapeutic aspects, Actinic keratoses: review of clinical, dermoscopic, and therapeutic aspects,https://www.scielo.br/j/abd/a/KNfmyRfzPpytwPWZnTrK8Br/
Oxidative stress is also involved in the photocarcinogenesis process, as a result of the excessive exposure to ultraviolet radiation, which leads to the production of reactive oxygen species and culminates with lipid peroxidation and cell destruction, with damage to genomic and mitochondrial DNA. […] Apoptosis disorders occur by suppression, elimination, or activation of apoptotic mediators, such as CD95 and tumor necrosis factor-associated apoptosis, and of pro-apoptotic tumor suppressor genes, as well as by regulation of p53 apoptotic activity. […] The five most important independent risk factors for actinic keratoses development are age, sex, phototypes I and II, previous history of cutaneous neoplasms, and sun exposure due to occupational reasons. […] The development of actinic keratoses in immunosuppressed patients involves the factors previously described and aspects related to immunosuppressive medications that may even act as carcinogens.
- #2 Actinic keratosis – Wikipediahttps://en.wikipedia.org/wiki/Actinic_keratosis
Evidence also suggests that the human papillomavirus (HPV) plays a role in the development of AKs. The HPV virus has been detected in AKs, with measurable HPV viral loads measured in 40% of AKs. Similar to UV radiation, higher levels of HPV found in AKs reflect enhanced viral DNA replication. This is suspected to be related to the abnormal keratinocyte proliferation and differentiation in AKs, which facilitate an environment for HPV replication. This in turn may further stimulate the abnormal proliferation that contributes to the development of AKs and carcinogenesis. […] It is thought that ultraviolet (UV) radiation induces mutations in the keratinocytes of the epidermis, promoting the survival and proliferation of these atypical cells. Both UV-A and UV-B radiation have been implicated as causes of AKs. UV-A radiation reaches more deeply into the skin and can lead to the generation of reactive oxygen species, which in turn can damage cell membranes, signaling proteins, and nucleic acids. UV-B radiation causes thymidine dimer formation in DNA and RNA, leading to significant cellular mutations. In particular, mutations in the p53 tumor suppressor gene have been found in 30-50% of AK lesion skin samples.
- #2 Actinic Keratosis | Treatments and Pictures| Cancer Imageshttps://www.skymd.com/conditions/actinic-keratosis
AKs are commoner in people who have worked outdoors, which carries a fourfold increase in risk as compared to outdoor hobbies which carries a 1.3 times higher risk. […] Human papillomavirus (HPV) is present in significant numbers in AK, although the precise mechanism by which HPV infection contributes to AK development is not fully understood. […] HPV inactivates TP53 and can also inhibit UV-induced cell death. This may in turn lead to abnormal DNA repair, resulting in an accumulation of UV-induced mutations and cancerous transformation. […] There is a direct relationship between AK and chronic sun exposure. […] AKs are also more common following phototherapy, ionizing radiation and sunbed usage.
- #2 Actinic keratoses (Solar keratosis): Diagnosis and Treatment â DermNethttps://dermnetnz.org/topics/actinic-keratosis
Actinic keratoses are the result of abnormal skin cell development due to DNA damage by short wavelength UVB. […] They are more likely to appear if the immune function is poor, due to ageing, recent sun exposure, predisposing disease, or certain drugs. […] The main concern is that actinic keratoses indicate an increased risk of developing cutaneous squamous cell carcinoma. […] It is rare for a solitary actinic keratosis to evolve to squamous cell carcinoma (SCC), but the risk of SCC occurring at some stage in a patient with more than 10 actinic keratoses is thought to be about 10 to 15%. […] Because they are sun damaged, people with actinic keratoses are also at risk of developing actinic cheilitis, basal cell carcinoma (BCC, which is more common than SCC), melanoma, and rare forms of skin cancer such as Merkel cell carcinoma. […] Actinic keratoses are prevented by strict sun protection. […] The number and severity of actinic keratoses can also be reduced by taking nicotinamide (vitamin B3) 500 mg twice daily. […] Patients who have been treated for actinic keratoses are at risk of developing new keratoses.
- #2 Actinic Keratosis | Treatment & Management | Point of Carehttps://www.statpearls.com/point-of-care/17121
Actinic keratoses primarily arise due to the cumulative effects of ultraviolet (UV) radiation on the skin, which occurs over an individual’s lifetime of sun exposure. […] The pathophysiology of actinic keratosis development is complex. Excessive and cumulative UV radiation exposure from the sun can trigger pathological changes in the epidermal keratinocytes by disrupting regulatory pathways involved in cell growth and differentiation. This disruption leads to inflammation and immunosuppression, contributing to the intraepidermal proliferation of dysplastic keratinocytes, the precursors of actinic keratosis. […] The primary histopathologic feature of actinic keratosis is the presence of atypical keratinocytes within sun-damaged skin that is limited to the lower third of the epidermis. […] Actinic keratosis can exhibit erratic behavior over time. Some actinic keratoses may spontaneously regress, though the mechanisms behind this regression are not fully understood and are an area of ongoing research. […] However, it is essential to note that actinic keratoses have the potential to progress and evolve into invasive squamous cell carcinoma (SCC), a type of skin cancer. Most squamous cell carcinomas develop from preexisting actinic keratoses or with areas that contain actinic keratoses.
- #2 Actinic keratoses – BAD Patient Hubhttps://www.skinhealthinfo.org.uk/condition/actinic-keratoses/
Actinic keratoses can be treated but tend to recur over time. Their presence indicates there is sun damage to the skin and so, whilst an individual actinic keratosis can be cured, the affected individual is at risk of developing more in the future. […] Some actinic keratoses may go away without treatment, especially if they are small and if the skin is protected from the sun. […] Treatments that your doctor can provide for actinic keratoses: Creams (topical treatments): Several types of cream or gel can be prescribed for use at home. These include 5-fluorouracil or imiquimod which are effective treatments. […] Freezing with liquid nitrogen (cryotherapy): This is an effective treatment which does not normally leave a scar but may make the treated area lose its natural pigment permanently.
- #2 Actinic Keratoses Treatments – Medical Clinical Policy Bulletins | Aetnahttps://www.aetna.com/cpb/medical/data/500_599/0567.html
Imiquimod is a Toll7 like receptor agonist that activates immune cells. Its specific mechanism of action for treating actinic keratosis (AK), however, is unknown. […] Ingenol mebutate (Picato) is a dermatologic agent indicated for the topical treatment of actinic keratosis. The mechanism of action by which Picato (ingenol mebutate) induces cell death in treating actinic keratosis lesions is unknown. […] The authors concluded that field-directed therapy with BF-200 ALA and BF-RhodoLED lamp is highly effective and well tolerated for multiple mild-to-moderate AK lesions, providing greatly improved skin quality.
- #3 SciELO Brazil – Actinic keratoses: review of clinical, dermoscopic, and therapeutic aspects, Actinic keratoses: review of clinical, dermoscopic, and therapeutic aspects,https://www.scielo.br/j/abd/a/KNfmyRfzPpytwPWZnTrK8Br/
Actinic keratoses are dysplastic proliferations of keratinocytes with potential for malignant transformation. […] Ultraviolet radiation is the main factor involved in pathogenesis, but individual factors also play a role in the predisposing to lesions appearance. […] The risk of transformation into squamous cell carcinoma is the major concern regarding actinic keratoses. […] Excessive exposure to UV radiation is the major factor, acting as a complete carcinogen, both inducing and promoting tumor expansion. […] UV radiation activates molecular signaling cascades that result in modifications of regulatory cytokines levels, immunosuppressive effects, and defective cell differentiation and apoptosis. […] UVA radiation penetrates the skin more deeply and stimulates reactive oxygen species production, which damage cell membranes, their nuclei, and proteins; in addition, UVA promotes guanine (G) to thymine (T) replacement mutations in DNA.
- #3 SciELO Brazil – Actinic keratoses: review of clinical, dermoscopic, and therapeutic aspects, Actinic keratoses: review of clinical, dermoscopic, and therapeutic aspects,https://www.scielo.br/j/abd/a/KNfmyRfzPpytwPWZnTrK8Br/
UVB radiation is absorbed by cellular DNA, promoting errors in the repair of cyclobutane pyrimidine dimers and production of 6-4 photoproducts, as well as characteristic cytosine-thymine (C-T) DNA substitutions. […] Thus, mechanisms involved in the onset of actinic keratoses include inflammation, oxidative stress, immunosuppression, impaired apoptosis, cell cycle deregulation and cell proliferation, and tissue remodeling. […] The inflammatory process is mediated by the arachidonic acid pathway, by the production of proinflammatory cytokines, and by the activation of mast cells and inhibitory factor of macrophage migration; the results of the activation of these mediators include lipid peroxidation, increase in intralesional levels of T lymphocytes and Langerhans cells, increase of p53 and Bcl-2, and reduction in Fas (cd95) and Fas-ligand, which are important initial factors in the apoptosis process of UV-mutated cells.
- #3 SciELO Brazil – Actinic keratoses: review of clinical, dermoscopic, and therapeutic aspects, Actinic keratoses: review of clinical, dermoscopic, and therapeutic aspects,https://www.scielo.br/j/abd/a/KNfmyRfzPpytwPWZnTrK8Br/
Oxidative stress is also involved in the photocarcinogenesis process, as a result of the excessive exposure to ultraviolet radiation, which leads to the production of reactive oxygen species and culminates with lipid peroxidation and cell destruction, with damage to genomic and mitochondrial DNA. […] Apoptosis disorders occur by suppression, elimination, or activation of apoptotic mediators, such as CD95 and tumor necrosis factor-associated apoptosis, and of pro-apoptotic tumor suppressor genes, as well as by regulation of p53 apoptotic activity. […] The five most important independent risk factors for actinic keratoses development are age, sex, phototypes I and II, previous history of cutaneous neoplasms, and sun exposure due to occupational reasons. […] The development of actinic keratoses in immunosuppressed patients involves the factors previously described and aspects related to immunosuppressive medications that may even act as carcinogens.
- #3 Actinic keratosis – Wikipediahttps://en.wikipedia.org/wiki/Actinic_keratosis
Evidence also suggests that the human papillomavirus (HPV) plays a role in the development of AKs. The HPV virus has been detected in AKs, with measurable HPV viral loads measured in 40% of AKs. Similar to UV radiation, higher levels of HPV found in AKs reflect enhanced viral DNA replication. This is suspected to be related to the abnormal keratinocyte proliferation and differentiation in AKs, which facilitate an environment for HPV replication. This in turn may further stimulate the abnormal proliferation that contributes to the development of AKs and carcinogenesis. […] It is thought that ultraviolet (UV) radiation induces mutations in the keratinocytes of the epidermis, promoting the survival and proliferation of these atypical cells. Both UV-A and UV-B radiation have been implicated as causes of AKs. UV-A radiation reaches more deeply into the skin and can lead to the generation of reactive oxygen species, which in turn can damage cell membranes, signaling proteins, and nucleic acids. UV-B radiation causes thymidine dimer formation in DNA and RNA, leading to significant cellular mutations. In particular, mutations in the p53 tumor suppressor gene have been found in 30-50% of AK lesion skin samples.
- #3 Actinic Keratoseshttps://signaturederm.com/services/actinic-keratoses/
Actinic keratosis (ak-TIN-ik ker-uh-TOE-sis) is a rough, scaly patch on the skin that develops from years of sun exposure. It’s often found on the face, lips, ears, forearms, scalp, neck, or back of the hands. […] Also known as a solar keratosis, an actinic keratosis grows slowly and usually first appears in people over 40. […] Left untreated, the risk of actinic keratoses turning into a type of skin cancer called squamous cell carcinoma is about 5% to 10%. […] Actinic keratoses vary in appearance. Signs and symptoms include: Rough, dry or scaly patch of skin, usually less than 1 inch (2.5 centimeters) in diameter; Flat to slightly raised patch or bump on the top layer of skin; In some cases, a hard, wartlike surface; Color variations, including pink, red or brown; Itching, burning, bleeding or crusting; New patches or bumps on sun-exposed areas of the head, neck, hands, and forearms.
- #3 Actinic keratosis, solar keratosishttps://www.pcds.org.uk/clinical-guidance/actinic-keratosis-syn-solar-keratosis
An actinic keratosis (AK) is a common sun-induced scaly or hyperkeratotic lesion, which has the potential to become malignant. NICE estimates that over 23% of the UK population aged 60 and above have AK. Although the risk of an AK transforming into a squamous cell carcinoma (SCC) is very low, this risk increases over time and with larger numbers of lesions. The presence of ten AK is associated with a 14% risk of developing an SCC within five years. […] AK are a consequence of cumulative long-term sun-exposure. […] Genetic factors play a role and individuals with fair skin, blue eyes and blonde hair are at higher risk, whereas lesions are exceedingly rare in patients of skin types IV-VI. […] Artificial UV radiation such as UVB and PUVA, used to treat psoriasis and a number of other skin conditions, as well as the use of sun beds, increase the risk.
- #3 Precancers (actinic keratoses) — ARCHER DERMATOLOGYhttps://www.archerdermatology.com/precancers-actinic-keratoses
Some actinic keratoses will resolve without treatment, especially if they are smaller and milder. […] Several types of cream or gel can be prescribed for use at home. […] Freezing with liquid nitrogen (cryotherapy): This is an effective treatment which does not normally leave a scar but may make the area lose its natural pigment. […] Surgical removal leaves a scar, but provides a skin sample that can be analysed in the laboratory to confirm the diagnosis. […] Protecting your skin from the sun will help reduce the number of new actinic keratoses you get and will reduce the risk of developing a sun-induced skin cancer.
- #3 Actinic keratoses – BAD Patient Hubhttps://www.skinhealthinfo.org.uk/condition/actinic-keratoses/
Actinic keratoses can be treated but tend to recur over time. Their presence indicates there is sun damage to the skin and so, whilst an individual actinic keratosis can be cured, the affected individual is at risk of developing more in the future. […] Some actinic keratoses may go away without treatment, especially if they are small and if the skin is protected from the sun. […] Treatments that your doctor can provide for actinic keratoses: Creams (topical treatments): Several types of cream or gel can be prescribed for use at home. These include 5-fluorouracil or imiquimod which are effective treatments. […] Freezing with liquid nitrogen (cryotherapy): This is an effective treatment which does not normally leave a scar but may make the treated area lose its natural pigment permanently.
- #4 SciELO Brazil – Actinic keratoses: review of clinical, dermoscopic, and therapeutic aspects, Actinic keratoses: review of clinical, dermoscopic, and therapeutic aspects,https://www.scielo.br/j/abd/a/KNfmyRfzPpytwPWZnTrK8Br/
UVB radiation is absorbed by cellular DNA, promoting errors in the repair of cyclobutane pyrimidine dimers and production of 6-4 photoproducts, as well as characteristic cytosine-thymine (C-T) DNA substitutions. […] Thus, mechanisms involved in the onset of actinic keratoses include inflammation, oxidative stress, immunosuppression, impaired apoptosis, cell cycle deregulation and cell proliferation, and tissue remodeling. […] The inflammatory process is mediated by the arachidonic acid pathway, by the production of proinflammatory cytokines, and by the activation of mast cells and inhibitory factor of macrophage migration; the results of the activation of these mediators include lipid peroxidation, increase in intralesional levels of T lymphocytes and Langerhans cells, increase of p53 and Bcl-2, and reduction in Fas (cd95) and Fas-ligand, which are important initial factors in the apoptosis process of UV-mutated cells.
- #4https://myhealth.alberta.ca/Health/pages/conditions.aspx?hwid=tr5806spec
Actinic keratosis is a skin growth caused by sun damage. It can turn into skin cancer, but this isn’t common. Actinic keratoses, also called solar keratoses, are small red, brown, or skin-coloured scaly patches. […] Actinic keratosis may turn into skin cancer, but this isn’t common. There is no way to find out whether actinic keratosis will progress to squamous cell carcinoma or how fast this might occur. […] People who have a weak immune system have a higher risk of developing squamous cell carcinoma.
- #4 Actinic keratoses (Solar keratosis): Diagnosis and Treatment â DermNethttps://dermnetnz.org/topics/actinic-keratosis
Actinic keratoses are the result of abnormal skin cell development due to DNA damage by short wavelength UVB. […] They are more likely to appear if the immune function is poor, due to ageing, recent sun exposure, predisposing disease, or certain drugs. […] The main concern is that actinic keratoses indicate an increased risk of developing cutaneous squamous cell carcinoma. […] It is rare for a solitary actinic keratosis to evolve to squamous cell carcinoma (SCC), but the risk of SCC occurring at some stage in a patient with more than 10 actinic keratoses is thought to be about 10 to 15%. […] Because they are sun damaged, people with actinic keratoses are also at risk of developing actinic cheilitis, basal cell carcinoma (BCC, which is more common than SCC), melanoma, and rare forms of skin cancer such as Merkel cell carcinoma. […] Actinic keratoses are prevented by strict sun protection. […] The number and severity of actinic keratoses can also be reduced by taking nicotinamide (vitamin B3) 500 mg twice daily. […] Patients who have been treated for actinic keratoses are at risk of developing new keratoses.
- #4 Actinic Keratoses Treatments – Medical Clinical Policy Bulletins | Aetnahttps://www.aetna.com/cpb/medical/data/500_599/0567.html
Imiquimod is a Toll7 like receptor agonist that activates immune cells. Its specific mechanism of action for treating actinic keratosis (AK), however, is unknown. […] Ingenol mebutate (Picato) is a dermatologic agent indicated for the topical treatment of actinic keratosis. The mechanism of action by which Picato (ingenol mebutate) induces cell death in treating actinic keratosis lesions is unknown. […] The authors concluded that field-directed therapy with BF-200 ALA and BF-RhodoLED lamp is highly effective and well tolerated for multiple mild-to-moderate AK lesions, providing greatly improved skin quality.
- #5 Actinic Keratoses Treatments – Medical Clinical Policy Bulletins | Aetnahttps://www.aetna.com/cpb/medical/data/500_599/0567.html
Actinic keratoses (AKs), also known as solar keratoses, are common, sun-induced pre-cancerous skin lesions that are confined to the epidermis. The lesions typically appear as circumscribed, rough, scaly patches on sun exposed skin, ranging from flesh-colored to reddish-brown. […] Actinic keratoses may also progress to squamous cell carcinoma (SCC), a form of skin cancer. […] Several studies have demonstrated an association between the presence of AKs and the development of SCCs, and 2 studies suggest a progression rate of 1 to 2 SCCs per 1,000 AKs. […] There is consensus that immunosuppressed individuals, people with a prior history of skin cancer, and people with AKs of the lips, nose, ear or eyelid are at increased risk of developing SCC. […] The mechanism of action of topical diclofenac sodium in the treatment of actinic keratoses (AK) is unknown.
- #5 Role of Nicotinamide in the Pathogenesis of Actinic Keratosis: Implications for NAD+/SIRT1 Pathwayhttps://www.mdpi.com/2218-273X/14/12/1512
Our findings confirm NAMâs protective effects on AK lesions and indicate that NAM treatment leads to a notable increase in serum NAD+ levels without significantly altering total NAD levels. […] The observed reduction in NADH levels alongside the increase in NAD+ levels suggests a shift in the redox state, potentially crucial in regulating cellular metabolism and maintaining homeostasis in high-turnover tissues such as the skin. […] Interestingly, while serum levels of SIRT1 did not change significantly following NAM administration, nuclear SIRT1 activity in PBMCs increased markedly. This finding suggests that NAMâs influence on SIRT1 is mainly nuclear, highlighting a potential mechanism by which NAM protects against DNA damage and genomic instability. […] Our evidence supports NAMâs potential chemoprotective effects via nuclear SIRT1 activity modulation, suggesting NAM not only serves as a preventive agent but also modulates key molecular pathways involved in cellular protection and repair.
- #5 Actinic Keratoses – Skin Disorders – Merck Manual Consumer Versionhttps://www.merckmanuals.com/home/skin-disorders/sunlight-and-skin-damage/actinic-keratoses
Actinic keratoses (solar keratoses) are precancerous growths caused by long-term sun exposure. […] Many years of sun exposure can cause actinic keratoses to develop on the skin. […] Actinic keratoses can progress to squamous cell carcinoma, a type of skin cancer. […] In addition to many years of sun exposure, other risk factors for actinic keratoses include older age, an impaired immune system, blond or red hair, blue eyes, and skin type I or II. […] Doctors diagnose actinic keratoses by looking at and touching them. […] Because of their rough texture, actinic keratoses are often easier to feel than see. […] Imiquimod is useful in treating actinic keratoses because it helps the immune system to recognize and destroy precancerous skin growths and early skin cancer. […] Tirbanibulin is a newer medication that works by killing fast-growing abnormal cells. […] If a person is not helped by any of these treatments, doctors may do a biopsy to rule out squamous cell carcinoma.
- #6 Actinic keratosis – Wikipediahttps://en.wikipedia.org/wiki/Actinic_keratosis
The presence of ulceration, nodularity, or bleeding should raise concern for malignancy. Specifically, clinical findings suggesting an increased risk of progression to squamous cell carcinoma can be recognized as „IDRBEU”: I (induration/inflammation), D (diameter 1 cm), R (rapid enlargement), B (bleeding), E (erythema), and U (ulceration). AKs are usually diagnosed clinically, but because they are difficult to clinically differentiate from squamous cell carcinoma, any concerning features warrant biopsy for diagnostic confirmation.
- #6 Role of Nicotinamide in the Pathogenesis of Actinic Keratosis: Implications for NAD+/SIRT1 Pathwayhttps://www.mdpi.com/2218-273X/14/12/1512
Our findings confirm NAMâs protective effects on AK lesions and indicate that NAM treatment leads to a notable increase in serum NAD+ levels without significantly altering total NAD levels. […] The observed reduction in NADH levels alongside the increase in NAD+ levels suggests a shift in the redox state, potentially crucial in regulating cellular metabolism and maintaining homeostasis in high-turnover tissues such as the skin. […] Interestingly, while serum levels of SIRT1 did not change significantly following NAM administration, nuclear SIRT1 activity in PBMCs increased markedly. This finding suggests that NAMâs influence on SIRT1 is mainly nuclear, highlighting a potential mechanism by which NAM protects against DNA damage and genomic instability. […] Our evidence supports NAMâs potential chemoprotective effects via nuclear SIRT1 activity modulation, suggesting NAM not only serves as a preventive agent but also modulates key molecular pathways involved in cellular protection and repair.
- #6 Actinic keratosis, solar keratosishttps://www.pcds.org.uk/clinical-guidance/actinic-keratosis-syn-solar-keratosis
If squamous cell carcinoma is a differential the patient must be referred urgently to Secondary Care without a biopsy. […] Field change refers to areas of skin that have multiple AK associated with a background of erythema, telangiectasia and other changes seen in sun-damaged skin. These areas are probably more at risk of developing SCC, especially if left untreated and, as such, it is recommended that they should be treated more vigorously. As such, the treatments should be applied to the whole area of field change and not just the individual lesions. […] The primary aim of treatment is to reduce the total number of lesions that the patient has at any one time, the fewer lesions a patient has the less risk they have for developing an SCC.
- #7 Actinic keratosis – Wikipediahttps://en.wikipedia.org/wiki/Actinic_keratosis
The presence of ulceration, nodularity, or bleeding should raise concern for malignancy. Specifically, clinical findings suggesting an increased risk of progression to squamous cell carcinoma can be recognized as „IDRBEU”: I (induration/inflammation), D (diameter 1 cm), R (rapid enlargement), B (bleeding), E (erythema), and U (ulceration). AKs are usually diagnosed clinically, but because they are difficult to clinically differentiate from squamous cell carcinoma, any concerning features warrant biopsy for diagnostic confirmation.
- #7 Actinic keratosis, solar keratosishttps://www.pcds.org.uk/clinical-guidance/actinic-keratosis-syn-solar-keratosis
If squamous cell carcinoma is a differential the patient must be referred urgently to Secondary Care without a biopsy. […] Field change refers to areas of skin that have multiple AK associated with a background of erythema, telangiectasia and other changes seen in sun-damaged skin. These areas are probably more at risk of developing SCC, especially if left untreated and, as such, it is recommended that they should be treated more vigorously. As such, the treatments should be applied to the whole area of field change and not just the individual lesions. […] The primary aim of treatment is to reduce the total number of lesions that the patient has at any one time, the fewer lesions a patient has the less risk they have for developing an SCC.
- #8 Actinic keratosis, solar keratosishttps://www.pcds.org.uk/clinical-guidance/actinic-keratosis-syn-solar-keratosis
If squamous cell carcinoma is a differential the patient must be referred urgently to Secondary Care without a biopsy. […] Field change refers to areas of skin that have multiple AK associated with a background of erythema, telangiectasia and other changes seen in sun-damaged skin. These areas are probably more at risk of developing SCC, especially if left untreated and, as such, it is recommended that they should be treated more vigorously. As such, the treatments should be applied to the whole area of field change and not just the individual lesions. […] The primary aim of treatment is to reduce the total number of lesions that the patient has at any one time, the fewer lesions a patient has the less risk they have for developing an SCC.
- #9 Actinic keratoses (Solar keratosis): Diagnosis and Treatment â DermNethttps://dermnetnz.org/topics/actinic-keratosis
Actinic keratoses are the result of abnormal skin cell development due to DNA damage by short wavelength UVB. […] They are more likely to appear if the immune function is poor, due to ageing, recent sun exposure, predisposing disease, or certain drugs. […] The main concern is that actinic keratoses indicate an increased risk of developing cutaneous squamous cell carcinoma. […] It is rare for a solitary actinic keratosis to evolve to squamous cell carcinoma (SCC), but the risk of SCC occurring at some stage in a patient with more than 10 actinic keratoses is thought to be about 10 to 15%. […] Because they are sun damaged, people with actinic keratoses are also at risk of developing actinic cheilitis, basal cell carcinoma (BCC, which is more common than SCC), melanoma, and rare forms of skin cancer such as Merkel cell carcinoma. […] Actinic keratoses are prevented by strict sun protection. […] The number and severity of actinic keratoses can also be reduced by taking nicotinamide (vitamin B3) 500 mg twice daily. […] Patients who have been treated for actinic keratoses are at risk of developing new keratoses.
- #10 Actinic keratoses – BAD Patient Hubhttps://www.skinhealthinfo.org.uk/condition/actinic-keratoses/
Surgical removal: This involves an anaesthetic (numbing) injection into the affected skin, after which the actinic keratosis can be scraped off with a sharp spoon-like instrument (a curette), or it can be cut out and the wound closed with stitches. […] Photodynamic Therapy (PDT): A special wavelength of light is shone onto the affected areas after a medicated cream has been applied. […] Laser treatment: An ablative laser device can be used to destroy the top layer of skin patch allowing new skin to appear. […] Protecting your skin from the sun will help reduce the number of new actinic keratoses and will reduce the risk of developing skin cancer.
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promieniowanie UVB metaloproteinaza macierzy-1 stres oksydacyjny stan zapalny 5-fluorouracyl diklofenak imikwimod wirus brodawczaka ludzkiego rogowacenie słoneczne warg promieniowanie ultrafioletowe rak podstawnokomórkowy nikotynamid gen TP53 limfocyt T rak kolczystokomórkowy ingenol mebutate czerniak białko Bak rak z komórek Merkla rogowacenie słoneczne pole kanceryzacji regulatorowy limfocyt T peroksydacja lipidów tirbanibulin komórka Langerhansa promieniowanie UVA immunosupresja reaktywne formy tlenu