The natural history of actinic keratosis: a systematic review
TL;DR: No reliable estimates concerning the frequency of AK developing into invasive carcinoma can be given, and further studies are needed, as available data are limited.
Abstract: Summary
Knowledge about the development of untreated actinic keratosis (AK) and risk of progression into squamous cell carcinoma (SCC) is important. Therefore, we set out to synthesize primary data on the natural history of AK. We carried out a systematic literature search (Medline, Medline in Process, Embase, Cochrane) of studies on the natural course of AK, regarding (i) progression and regression rates per lesion-year, (ii) changes in total lesion counts over time, and (iii) spontaneous field regression and recurrence rates, taking into account studies on participants without immunosuppression and history of skin cancer, immunosuppressed patients and participants with a history of skin cancer and sunscreen use. Twenty-four eligible studies were identified providing data on at least one of the outcomes. Progression rates of AK to SCC ranged from 0% to 0·075% per lesion-year, with a risk of up to 0·53% per lesion in patients with prior history of nonmelanoma skin cancer. Rates of regression of single lesions ranged between 15% and 63% after 1 year. The data available on recurrence rates of single lesions 1 year after regression indicate a recurrence rate of 15–53%. Data on the relative change of total AK count over time are heterogeneous, and range from −53% to +99·1%. Spontaneous complete field regression rates range from 0% to 21%, with recurrences in 57%. In general, the available data are limited. Important methodological limitations apply. Currently, no reliable estimates concerning the frequency of AK developing into invasive carcinoma can be given, and further studies are needed.
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National and Kapodistrian University of Athens1, Paris Diderot University2, Université libre de Bruxelles3, Catholic University of the Sacred Heart4, German Cancer Research Center5, Medical University of Graz6, Versailles Saint-Quentin-en-Yvelines University7, National Institute for Health Research8, Odense University Hospital9, Aix-Marseille University10
TL;DR: The EDF-EADO-EORTC consensus group recommends a standardised minimal margin of 5 mm even for low-risk tumours and a lymph node ultrasound is highly recommended, particularly in tumours with high-risk characteristics.
370 citations
Cites background from "The natural history of actinic kera..."
...While most cSCCs will arise in the context of actinic keratosis, the rate of transformation of AKs into invasive cSCC is apparently low, at least in a few years period of follow-up (less than 1/1000 per year during a 5-year follow up) [32,33]....
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TL;DR: It is recommended the establishment of a global research consortium to further study the natural history of OPMDs based on the classification and nomenclature proposed here, and link them to evidence-based interventions, to facilitate the prevention and management of lip and oral cavity cancer.
Abstract: Oral potentially malignant disorders (OPMDs) are associated with an increased risk of occurrence of cancers of the lip or oral cavity. This paper presents an updated report on the nomenclature and the classification of OPMDs, based predominantly on their clinical features, following discussions by an expert group at a workshop held by the World Health Organization (WHO) Collaborating Centre for Oral Cancer in the UK. The first workshop held in London in 2005 considered a wide spectrum of disorders under the term "potentially malignant disorders of the oral mucosa" (PMD) (now referred to as oral potentially malignant disorders: OPMD) including leukoplakia, erythroplakia, proliferative verrucous leukoplakia, oral lichen planus, oral submucous fibrosis, palatal lesions in reverse smokers, lupus erythematosus, epidermolysis bullosa, and dyskeratosis congenita. Any new evidence published in the intervening period was considered to make essential changes to the 2007 classification. In the current update, most entities were retained with minor changes to their definition. There is sufficient evidence for an increased risk of oral cancer among patients diagnosed with "oral lichenoid lesions" and among those diagnosed with oral manifestations of 'chronic graft-versus-host disease'. These have now been added to the list of OPMDs. There is, to date, insufficient evidence concerning the malignant potential of chronic hyperplastic candidosis and of oral exophytic verrucous hyperplasia to consider these conditions as OPMDs. Furthermore, due to lack of clear evidence of an OPMD in epidermolysis bullosa this was moved to the category with limited evidence. We recommend the establishment of a global research consortium to further study the natural history of OPMDs based on the classification and nomenclature proposed here. This will require multi-center longitudinal studies with uniform diagnostic criteria to improve the identification and cancer risk stratification of patients with OPMDs, link them to evidence-based interventions, with a goal to facilitate the prevention and management of lip and oral cavity cancer.
306 citations
Charité1, Mayo Clinic2, University of Porto3, St. Vincent's Health System4, University of Melbourne5, University of Toronto6, Medical University of Graz7, Henry Ford Hospital8, Eastern Virginia Medical School9, Wake Forest Baptist Medical Center10, University of Sydney11, Oregon Health & Science University12, University of São Paulo13
TL;DR: Actinic keratosis is a frequent health condition attributable to chronic exposure to ultraviolet radiation and several treatment options are available and evidence based guidelines are missing.
Abstract: Background
Actinic keratosis (AK) is a frequent health condition attributable to chronic exposure to ultraviolet radiation. Several treatment options are available and evidence based guidelines are missing.
Objectives
The goal of these evidence- and consensus-based guidelines was the development of treatment recommendations appropriate for different subgroups of patients presenting with AK. A secondary aim of these guidelines was the implementation of knowledge relating to the clinical background of AK, including consensus-based recommendations for the histopathological definition, diagnosis and the assessment of patients.
Methods
The guidelines development followed a pre-defined and structured process. For the underlying systematic literature review of interventions for AK, the methodology suggested by the Cochrane Handbook for Systematic Reviews of Interventions, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was adapted. All recommendations were consented during a consensus conference using a formal consensus methodology. Strength of recommendations was expressed based on the GRADE approach. If expert opinion without external evidence was incorporated into the reasoning for making a certain recommendation, the rationale was provided. The Guidelines underwent open public review and approval by the commissioning societies.
Results
Various interventions for the treatment of AK have been assessed for their efficacy. The consenting procedure led to a treatment algorithm as shown in the guidelines document. Based on expert consensus, the present guidelines present recommendations on the classification of patients, diagnosis and histopathological definition of AK. Details on the methods and results of the systematic literature review and guideline development process have been published separately.
Conclusions
International guidelines are intended to be adapted to national or regional circumstances (regulatory approval, availability and reimbursement of treatments).
238 citations
Cites background from "The natural history of actinic kera..."
...8 concerning the determination of lesions at risk of progression, an adequate treatment of the AK lesions or the affected field is presumed to be necessary.(35)...
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TL;DR: Progression from actinic keratosis to invasive squamous cell carcinoma (iSCC) of the skin is thought to occur after the development of full thickness epidermal neoplasia, as in the classic pathway of cervical cancer, but cutaneous iSCC may also directly arise from a proliferation of atypical basaloid cells.
Abstract: Background
Progression from actinic keratosis (AK) to invasive squamous cell carcinoma (iSCC) of the skin is thought to occur after the development of full thickness epidermal neoplasia, as in the classic pathway of cervical cancer. Nevertheless, cutaneous iSCC may also directly arise from a proliferation of atypical basaloid cells limited mostly to the epidermal basal layer (AK I), akin to what happens in the ‘differentiated pathway’ of iSCC of the vulva, oral cavity and other locations.
Objective
To evaluate the prevalence of classic and differentiated pathways in the development of cutaneous iSCC.
Methods
The epidermis adjacent to and overlying iSCC, assumed to be representative of pre-existing lesions, was histologically studied in 196 skin biopsy specimens showing iSCC.
Results
AK I, AK II and AK III lesions overlying iSCC were present in 63.8%, 17.9% and 18.4% of cases respectively. The corresponding percentages in the epidermis adjacent to iSCC were 77.9%, 6.6% and 8.3% respectively (stage could not be assessed in 8.1% of cases). Focal epidermal ulceration overlying iSCC was seen in 32% of AK I, 28.6% of AK II and 33.3% of AK III instances. Adnexal involvement by atypical keratinocytes (proliferative AK) was present more frequently in cases with overlying AK I (39/125, 31.2%) than with AK II (8/35, 22.9%) and AKII I (5/36, 13.9%).
Conclusion
Direct invasion from proliferating basaloid atypical keratinocytes limited to the epidermal basal layer (AK I), known as the differentiated pathway, was the most common form of progression to cutaneous iSCC in our series. On the other hand, stepwise progression from AK I to AK II and AK III (classic pathway) was seen to be operative in a substantial proportion of iSCC cases. All AK lesions, irrespective of intraepidermal neoplasia thickness, are therefore potentially invasive and tumour advance along adnexal structures might facilitate iSCC development from AK I lesions.
180 citations
TL;DR: Main mechanisms of actions of these compounds in the chemoprevention of these cancers include suppression of cell proliferation, induction of apoptosis, stimulation of antimetastatic and antiangiogenic responses and increased antioxidant and anti-inflammatory activity.
Abstract: The risk of onset of cancer is influenced by poorly controlled chronic inflammatory processes. Inflammatory diseases related to cancer development include inflammatory bowel disease, which can lead to colon cancer, or actinic keratosis, associated with chronic exposure to ultraviolet light, which can progress to squamous cell carcinoma. Chronic inflammatory states expose these patients to a number of signals with tumorigenic effects, including nuclear factor kappa B (NF-κB) and mitogen-activated protein kinases (MAPK) activation, pro-inflammatory cytokines and prostaglandins release and ROS production. In addition, the participation of inflammasomes, autophagy and sirtuins has been demonstrated in pathological processes such as inflammation and cancer. Chemoprevention consists in the use of drugs, vitamins, or nutritional supplements to reduce the risk of developing or having a recurrence of cancer. Numerous in vitro and animal studies have established the potential colon and skin cancer chemopreventive properties of substances from marine environment, including microalgae species and their products (carotenoids, fatty acids, glycolipids, polysaccharides and proteins). This review summarizes the main mechanisms of actions of these compounds in the chemoprevention of these cancers. These actions include suppression of cell proliferation, induction of apoptosis, stimulation of antimetastatic and antiangiogenic responses and increased antioxidant and anti-inflammatory activity.
169 citations
Cites background from "The natural history of actinic kera..."
...On the other hand, AKs have also been shown to regress spontaneously [272]....
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References
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TL;DR: A structured summary is provided including, as applicable, background, objectives, data sources, study eligibility criteria, participants, interventions, study appraisal and synthesis methods, results, limitations, conclusions and implications of key findings.
31,379 citations
TL;DR: Cutaneous squamous- cell carcinoma, but not basal-cell carcinoma seems to be amenable to prevention through the routine use of sunscreen by adults for 4.5 years, and there was no beneficial or harmful effect on the rates of either type of skin cancer, as a result of betacarotene supplementation.
872 citations
TL;DR: At event rates below 1 per cent the Peto one‐step odds ratio method was the least biased and most powerful method, and provided the best confidence interval coverage, provided there was no substantial imbalance between treatment and control group sizes within trials, and treatment effects were not exceptionally large.
Abstract: For rare outcomes, meta-analysis of randomized trials may be the only way to obtain reliable evidence of the effects of healthcare interventions. However, many methods of meta-analysis are based on large sample approximations, and may be unsuitable when events are rare. Through simulation, we evaluated the performance of 12 methods for pooling rare events, considering estimability, bias, coverage and statistical power. Simulations were based on data sets from three case studies with between five and 19 trials, using baseline event rates between 0.1 and 10 per cent and risk ratios of 1, 0.75, 0.5 and 0.2. We found that most of the commonly used meta-analytical methods were biased when data were sparse. The bias was greatest in inverse variance and DerSimonian and Laird odds ratio and risk difference methods, and the Mantel-Haenszel (MH) odds ratio method using a 0.5 zero-cell correction. Risk difference meta-analytical methods tended to show conservative confidence interval coverage and low statistical power at low event rates. At event rates below 1 per cent the Peto one-step odds ratio method was the least biased and most powerful method, and provided the best confidence interval coverage, provided there was no substantial imbalance between treatment and control group sizes within trials, and treatment effects were not exceptionally large. In other circumstances the MH OR without zero-cell corrections, logistic regression and the exact method performed similarly to each other, and were less biased than the Peto method.
830 citations
784 citations
TL;DR: Regular use of sunscreens prevents the development of solar keratoses and, by implication, possibly reduces the risk of skin cancer in the long-term.
Abstract: Background The incidence of and mortality from skin cancer are increasing in many countries. In view of the added concern about ozone depletion, many organizations are promoting the regular use of sunscreens to prevent skin cancer, despite the absence of evidence that these products have this effect. Solar (actinic) keratosis is a precursor of squamous-cell carcinoma of the skin. Methods We conducted a randomized, controlled trial of the effect on solar keratoses of daily use of a broad-spectrum sunscreen cream with a sun-protection factor of 17 in 588 people 40 years of age or older in Australia during one summer (September 1991 to March 1992). The subjects applied either a sunscreen cream or the base cream minus the active ingredients of the sunscreen to the head, neck, forearms, and hands. Results The mean number of solar keratoses increased by 1.0 per subject in the base-cream group and decreased by 0.6 in the sunscreen group (difference, 1.53; 95 percent confidence interval, 0.81 to 2.25). The sunscr...
708 citations