Actinic keratoses

Actinic keratoses are defined as proliferation of cytologically atypical keratinocytes in the zone of epidermal-dermal junction in photodamaged skin. In the northern hemisphere the prevalence of actinic keratoses ranges depending on different epidemiological studies from 11% to 25% for people aged 40 or older. The main cause of actinic keratoses is exposure to UVB radiation in sunlight UVB radiation induces mutations in the telomerase gene and in the tumor suppressor gene P53, which can also be detected in invasive squamous cell carcinoma. The only histological parameter to distinguish between actinic keratoses and SCC is the level of invasiveness. The risk for actinic keratoses to develop into SCC is about 16% over lo years. For this reason and because of the high prevalence of actinic keratoses, it has been suggested to replace the term,, actinic keratosis K with intraepidermal squamous cell carcinoma' to better characterize the lesion. In the following review recent aspects of pathogenesis and therapy of actinic keratoses are discussed.     

Aktinische Keratosen

Actinic keratoses primarily affect fair-skinned individuals over 50 years of age. Due to demographic changes, the prevalence of actinic keratoses has increased over the last years. An established risk factor is chronic UV-exposure (outdoor workers) inducing mutations of the tumor suppressor gene TP53 and the oncogene H-ras. This leads to an intraepidermal proliferation of atypical keratinocytes. The term “field cancerization” characterizes the presentation of multiple actinic keratoses in UV-exposed areas. Actinic keratoses are also termed squamous cell carcinoma (SCC) in situ. The risk for actinic keratoses to turn into a SCC is 6–10?%. Treatment should be provided early in the disease course to avoid the possibility of invasive growth. In recent years, multiple therapeutic options have been established. Depending on the clinical extent, lesion- or field-directed therapies with excellent clinical response and cosmetic results are available.     

皮肤鳞状细胞癌和光线性角化病的免疫组化研究

目的探讨光线性角化病[AK]的性质以及其与鳞状细胞癌(SCC)的关系。方法用免疫组化的方法研究了桥粒芯糖蛋白1(D sg1)和E-钙黏着蛋白(Ecad)在鳞状细胞癌和光线性角化病中的表达。结果与正常人皮肤相比桥粒芯糖蛋白1和E-钙黏着蛋白在光线性角化病中的表达减弱,在鳞状细胞癌中的表达显著减弱或完全消失,但两者在角化不良细胞处的表达非常相似。结论光线性角化病应及早治疗以阻止其发展。     

Actinic keratoses: review of clinical,dermoscopic, and therapeutic aspects

Actinic keratoses are dysplastic proliferations of keratinocytes with potential for malignant transformation. Clinically, actinic keratoses present as macules, papules, or hyperkeratotic plaques with an erythematous background that occur on photoexposed areas. At initial stages, they may be better identified by palpation rather than by visual inspection. They may also be pigmented and show variable degrees of infiltration; when multiple they then constitute the so-called field cancerization. Their prevalence ranges from 11% to 60% in Caucasian individuals above 40 years. Ultraviolet radiation is the main factor involved in pathogenesis, but individual factors also play a role in the predisposing to lesions appearance. Diagnosis of lesions is based on clinical and dermoscopic examination, but in some situations histopathological analysis may be necessary. The risk of transformation into squamous cell carcinoma is the major concern regarding actinic keratoses. Therapeutic modalities for actinic keratoses include topical medications, and ablative and surgical methods; the best treatment option should always be individualized according to the patient.     

Actinic Keratosis

Actinic keratoses are hyperkeratotic skin lesions that represent focal abnormal proliferation of epidermal keratinocytes. Some actinic keratoses evolve into squamous cell carcinoma of the skin, while others resolve spontaneously. The conversion rate of actinic keratosis to squamous cell carcinoma is not accurately known, but appears to be in the range of 0.25 to 1% per year. Although there is a low rate of conversion of actinic keratoses to squamous cell carcinoma, 60% of squamous cell carcinomas of the skin probably arise from actinic keratoses. The main cause of actinic keratoses in otherwise healthy Caucasians appears to be the sun. Therapy for actinic keratoses begins with prevention which starts with sun avoidance and physical protection. Sunprotection with sunscreens actually slows the return of actinic keratoses in patients already getting actinic keratoses. Interestingly, a few studies are available that demonstrate that a high fat diet is associated with the production of more actinic keratoses than is a low fat diet. One of the mainstays of therapy has been local destruction of the actinic keratoses with cryotherapy, and curettage and electrodesiccation. A new addition to this group of therapies to treat individual actinic keratoses is photodynamic therapy with topical aminolevulinic acid and light. In patients who have numerous actinic keratoses in an area of severely sun damaged skin, therapies which are applied to the whole actinic keratosis area are used. The goal of treating such an area of skin is to treat all of the early as well as the numerous clinically evident actinic keratoses at the same time. The classical approaches for treating areas of photodamaged skin without treating actinic keratoses individually include: the use of topically applied fluorouracil cream, dermabrasion, and cutaneous peels with various agents like trichloroacetic acid. Both topically as well as orally administered retinoids have been used to treat actinic keratoses but retinoids alone are probably not an optimal monotherapy. Photodynamic therapy with topical aminolevulinic acid and light is a new therapy for actinic keratoses. Aminolevulinic acid is a precursor of protoporphyrin IX (PpIX) which is synthesized in the actinic keratosis when it is treated with aminolevulinic acid, and the PpIX photosensitizes the actinic keratosis so that light exposure can lead to its destruction. Photodynamic therapy with topical aminolevulinic acid is approved in the US to treat multiple individual actinic keratoses on the face and scalp and has similar cure rates to those reported for cryotherapy and fluorouracil therapy.     

The presence of antibodies against virus-like particles of epidermodysplasia verruciformis-associated humanpapillomavirus type 8 in patients with actinic keratoses

Epidermodysplasia verruciformis-associated human papillomaviruses (EV-HPVs) are possibly involved in the development of actinic keratoses and may play a part in the pathogenesis of squamous cell carcinoma (SCC) of the skin, as the DNA of these viruses is frequently detected in biopsies of such lesions. Properly designed epidemiological studies, using serological tests to investigate the role of infection with EV-HPVs in cutaneous oncogenesis, are still rare. An IgG-specific enzyme-linked immunosorbent assay using virus-like particles composed of the major capsid protein L1 of the EV-specific HPV 8 (HPV 8 VLPs) was developed and used to test the seroprevalence of HPV 8 in 114 inhabitants of a tropical island, of whom 13 had developed SCC, and 19 had developed basal cell carcinoma. Gender, age, eye and hair colour, sun exposure and number of actinic keratoses were recorded for all individuals. The presence of antibodies against HPV 8 VLPs was associated with the development of large numbers of actinic keratoses. After adjusting for gender, age, eye and hair colour, and sun exposure, the odds ratio to develop 37 (the median in this dataset) or more actinic keratoses in the presence of antibodies against HPV 8 VLPs was 2.3 (95% confidence interval: 1.0; 5.3). Similarly, after adjustment for the same factors, the presence of these antibodies was associated with SCC with an odds ratio of 3.1 (0.74; 13.3), but the small number of individuals with SCC does not permit any definite conclusions. The presence of these antibodies did not appear to be associated with basal cell carcinoma as, after adjustment for the same factors, the odds ratio was 0.73 (0.23; 2.4). This study provides serological evidence that infection with EV-HPVs may play a part in the pathogenesis of actinic keratoses. The role of EV-HPVs in the development of SCC, however, remains to be elucidated.     

The Epidemiology of Non-Melanoma Skin Cancer: Who,Why and What Can We Do about It

Non-melanoma skin cancer (NMSC) comprised of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are the most common cancers in humans in many countries. Sunlight plays a major part in the development of these tumours which appear predominantly on areas of the most frequently exposed skin. The site distribution for BCC and SCC is not the same, with SCC being most common on the sites of very heavy exposure and BCC becoming more common on areas of only moderate exposure, e.g. upper trunk in men and women and lower leg in women. Incidence rates of NMSC, where they are being recorded, show rises over time. Mortality rates, on the other hand, have been dropping most of this century until they have been levelling out recently. The case fatality rate due to SCC appears to be between 1–2%. The malignant transformation rate of actinic keratoses to SCC appears to be very low. Studies on similar populations at different latitudes allow estimates to be made of increases which might occur with increasing exposure to ultraviolet radiation (UVR) over a life time. These have been used to estimate the possible increases in NMSC due to stratospheric ozone depletion. Finally, recent studies on the reduction of existing actinic keratoses and prevention of new ones with regular use of sunscreen augurs well for prevention of NMSC in the future.     

Actinic keratosis: Facts and controversies

Actinic keratoses are common lesions that are generally clinically diagnosed. Although currently most actinic keratoses are treated, whether this is truly necessary is debated. Treatment of all actinic keratoses is advocated because preliminary evidence indicates that actinic keratoses may progress to squamous cell carcinomas. Some also consider actinic keratoses equivalent to squamous cell carcinoma.     

Actinic keratosis among seafarers

The aim of this study was to assess the prevalence of UV-induced actinic keratosis and further skin lesions. A newly developed questionnaire about lifetime UV radiation exposure was completed by 514 seafarers. An experienced dermatologist inspected the whole-body skin status of all participants. The questionnaire revealed a pre-employment UV radiation exposure in 104 seafarers, sunbed use in 26 subjects and a median work-related UV radiation exposure at sea of 20 years. The diagnosis of actinic keratoses was made in 94 seafarers and the clinical diagnosis of skin cancers in 48 seafarers (28 basal cell carcinoma, 11 squamous cell carcinoma, 9 malignant melanoma). After age standardisation according to a European reference population, the male European seafarers in this study had a 1.80-fold increased risk of actinic keratosis. Actinic keratoses [OR 1.03 (1.01–1.05)] and squamous cell carcinoma [OR 1.07 (1.01–1.13)] were related to the duration of seafaring time in years. A significant association was also found between actinic keratosis/squamous cell carcinoma and sunlight exposure during home leave [OR 1.67 (1.03–2.81) and OR 6.19 (1.18–32.40)]. Furthermore, the engine room personnel—especially the technical officers—were at higher risk of developing actinic keratosis. Due to the high prevalence of actinic keratosis especially among older seafarers with fair skin, with longer duration of seafaring employment at sea and with higher UV exposure during home leave, more intensive advice should be given on sun protection both at sea and ashore.     

Imiquimod 5% cream for the treatment of actinic keratoses

Actinic keratoses (AKs) are premalignant inflammatory skin lesions with the potential to transform into squamous cell carcinoma (SCC). There are several treatment options available for patients presenting with multiple AKs. Imiquimod is believed to stimulate and enhance host immune responses locally against skin tumors and viral infections. Five clinical studies to date have demonstrated its safety and efficacy in the treatment of actinic keratoses. Long-term follow-up studies examining recurrence rates are limited.     

The influence of painful sunburns and lifetime sun exposure on the risk of actinic keratoses,seborrheic warts,melanocytic nevi,atypical nevi,and skin cancer

Painful sunburns are implicated in the pathogenesis of squamous cell carcinoma, basal cell carcinoma, and malignant melanoma. Chronic exposure to ultraviolet radiation is known as the most important risk factor for the development of actinic keratoses and squamous cell carcinoma. The purpose of the study was to assess the effect of painful sunburns and lifetime sun exposure on the development of actinic keratoses and seborrheic warts in relation to the development of squamous cell carcinoma and basal cell carcinoma, and on the development of melanocytic nevi and atypical nevi in relation to the development of malignant melanoma. We made use of a cohort of 966 individuals who participated in a case-control study to investigate environmental and genetic risk factors for skin cancer. Exposure measurements for sunlight were collected and actinic keratoses, seborrheic warts, melanocytic nevi, and atypical nevi were counted. Relative risks were estimated using exposure odds ratios from cross-tabulation. Multivariate logistic regression was used to adjust for potential confounders. The recall of painful sunburns before the age of 20 y was associated with an increased risk of squamous cell carcinoma, nodular basal cell carcinoma, and multifocal superficial basal cell carcinoma as well as actinic keratoses. Odds ratios with 95% confidence intervals adjusted for age, sex, and skin type were 1.5 (0.97; 2.3); 1.6 (1.1; 2.2); 2.6 (1.7; 3.8); and 1.9 (1.4; 2.6) for the three types of nonmelanoma skin cancer and actinic keratoses, respectively. Painful sunburns before the age of 20 y were also associated with an increased risk of malignant melanoma and the development of its precursors, melanocytic nevi and atypical nevi. Odds ratios with 95% confidence intervals adjusted for age, sex, and skin type were 1.4 (0.86; 2.1); 1.5 (1.1; 2.0); and 1.4 (0.88; 2.3) for malignant melanoma and the two types of precursors, respectively. Lifetime sun exposure was predominantly associated with an increased risk of squamous cell carcinoma (p-value for trend=0.03) and actinic keratoses (p-value for trend <0.0001) and to a lesser degree with the two types of basal cell carcinoma. By contrast, lifetime sun exposure appeared to be associated with a lower risk of malignant melanoma, despite the fact that lifetime sun exposure did not diminish the number of melanocytic nevi or atypical nevi. Neither painful sunburns nor lifetime sun exposure were associated with an increased risk of seborrheic warts.     

Ultraviolet B radiation regulates cysteine‐rich protein 1 in human keratinocytes

Background: Cysteine‐rich protein 1 (CRP1) is a growth‐inhibitory cytoskeletal protein that is induced by ultraviolet (UV) C radiation radiation in fibroblasts. Our aim was to investigate the effects of UV radiation on CRP1 in keratinocytes, the main cell type subjected to UV radiation in the human body. Methods: The effects of physiologically relevant doses of UVB radiation on CRP1 protein levels were studied in cultured primary keratinocytes and transformed cell lines (HaCaT, A‐431) by immunoblotting. UVB‐induced keratinocyte apoptosis was assessed by flow cytometry and monitoring caspase activity. Expression of CRP1 in human skin in vivo was studied by immunohistochemistry in samples of normal skin, actinic keratosis (AK) representing UV‐damaged skin and squamous cell carcinoma (SCC), a UV‐induced skin cancer. Results: CRP1 expression increased by UVB radiation in primary but not in immortalized keratinocytes. Upon high, apoptosis‐inducing doses of UV radiation, CRP1 was cleaved in a caspase‐dependent manner. In normal skin, CRP1 was expressed in smooth muscle cells, vasculature, sweat glands, sebaceous glands and hair root sheath, but very little CRP1 was present in keratinocytes. CRP1 expression was elevated in basal cells in AK but not in SCC. Conclusion: CRP1 expression is regulated by UVB in human keratinocytes, suggesting a role for CRP1 in the phototoxic responses of human skin.     

HLA and β2-microglobulin Expression in Basal and Squamous Cell Carcinomas of the Skin

Histologic sections of seven squamous cell carcinomas (SCC), 13 basal cell carcinomas (BCC), and a Bowenoid actinic keratoses were examined for expression of HLA class 1 antigens (HLA-ABC) using a monoclonal antibody and an immunoperoxidase technique. Expression of beta 2-microglobulin was examined with a polyclonal antibody method. Neither cell marker was detected within the Bowenoid actinic keratoses. Squamous cell carcinomas and basal cell carcinomas exhibited decreased expression of both HLA-ABC and beta 2-microglobulin and often did not express these antigens at all. HLA-ABC was present in only two of 13 basal cell carcinomas and four of seven squamous cell carcinomas. beta 2-microglobulin was present in one of 13 basal cell carcinomas and two of seven squamous cell carcinomas. When present, these antigens often were present in a few areas of the tumor, but absent in others. In both SCC and BCC, both antigens were usually lost simultaneously. In all tumors with beta 2-microglobulin, HLA-ABC also was retained. There was no apparent relationship of anatomic site or type of tumor with retention of surface antigens. Since some tumors or portions of tumors retained HLA-ABC and beta 2-microglobulin on their surfaces, the absence of these antigens is not an absolute marker for malignancy.     

HLA and β2-microglobulin Expression in Basal and Squamous Cell Carcinomas of the Skin

Abstract: Histologic sections of seven squamous cell carcinomas (SCC), 13 basal cell carcinomas (BCC), and a Bowenoid actinic keratoses were examined for expression of HLA class 1 antigens (HLA-ABC) using a monoclonal antibody and an immunoperoxidase technique. Expression of β₂-microglobulin was examined with a polyclonal antibody method. Neither cell marker was detected within the Bowenoid actinic keratoses. Squamous cell carcinomas and basal cell carcinomas exhibited decreased expression of both HLA-ABC and β₂-microglobulin and often did not express these antigens at all. HLA-ABC was present in only two of 13 basal cell carcinomas and four of seven squamous cell carcinomas. β₂-microglobulin was present in one of 13 basal cell carcinomas and two of seven squamous cell carcinomas. When present, these antigens often were present in a few areas of the tumor, but absent in others. In both SCC and BCC. both antigens were usually lost simultaneously. In all tumors with β₂-microglobulin, HLA-ABC a/so was retained. There was no apparent relationship of anatomic site or type of tumor with retention of surface antigens. Since some tumors or portions of tumors retained HLA-ABC and β₂-microglobulin on their surfaces, the absence of these antigens is not an absolute marker for malignancy.     

Hypertrophic lupus erythematosus: the diagnostic utility of CD123 staining

CD123-positive plasmacytoid dendrocytes are prominent in the infiltrate of discoid lupus erythematosus (LE). We hypothesized that these cells would also be present in hypertrophic LE and would aid in the histopathologic distinction from squamous cell carcinoma (SCC) and hypertrophic actinic keratosis (AK). Five cases of hypertrophic LE and 10 cases each of SCC and hypertrophic AK were stained with CD123. A heavy band of CD123-positive cells was present at the epidermal-dermal junction in all cases of hypertrophic LE, and only single or rare scattered clusters of CD123-positive cells were seen in SCC and actinic keratoses. The pattern of CD123 staining can be a useful feature to distinguish hypertrophic LE from SCC and hypertrophic AK.     

The development of actinic keratosis into invasive squamous cell carcinoma: evidence and evolving classification schemes

Actinic keratosis is an incipient form of cutaneous squamous cell carcinoma. Consequently, actinic keratoses must be treated expeditiously to forestall their downward growth. Several classification schemes have been proposed to better categorize actinic keratoses, and to guide their diagnosis and treatment. Among these approaches is the "keratinocyte intraepithelial neoplasia" (KIN) system developed by Cockerell; Goldberg's concept of the "proliferative actinic keratosis" (PAK), and Berhane's emphasis on the "inflamed actinic keratosis" (IAK). In the future, disparate classification schemes may be unified into a single pragmatic approach which accurately reflects the biological process whereby actinic keratoses devolve into invasive squamous cell carcinoma.     

C/EBPα expression is downregulated in human nonmelanoma skin cancers and inactivation of C/EBPα confers susceptibility to UVB-induced skin squamous cell carcinomas

Human epidermis is routinely subjected to DNA damage induced by UVB solar radiation. Cell culture studies have revealed an unexpected role for C/EBPα (CCAAT/enhancer-binding protein-α) in the DNA damage response network, where C/EBPα is induced following UVB DNA damage, regulates the G(1) checkpoint, and diminished or ablated expression of C/EBPα results in G(1) checkpoint failure. In the current study we observed that C/EBPα is induced in normal human epidermal keratinocytes and in the epidermis of human subjects exposed to UVB radiation. The analysis of human skin precancerous and cancerous lesions (47 cases) for C/EBPα expression was conducted. Actinic keratoses, a precancerous benign skin growth and precursor to squamous cell carcinoma (SCC), expressed levels of C/EBPα similar to normal epidermis. Strikingly, all invasive SCCs no longer expressed detectable levels of C/EBPα. To determine the significance of C/EBPα in UVB-induced skin cancer, SKH-1 mice lacking epidermal C/EBPα (CKOα) were exposed to UVB. CKOα mice were highly susceptible to UVB-induced SCCs and exhibited accelerated tumor progression. CKOα mice displayed keratinocyte cell cycle checkpoint failure in vivo in response to UVB that was characterized by abnormal entry of keratinocytes into S phase. Our results demonstrate that C/EBPα is silenced in human SCC and loss of C/EBPα confers susceptibility to UVB-induced skin SCCs involving defective cell cycle arrest in response to UVB.     

Case-based experience in the use of 5-fluorouracil cream 0.5% as monotherapy and in conjunction with glycolic acid peels for the treatment of actinic keratosis

Abstract

Actinic keratosis, commonly indicative of photodamage, requires treatment secondary to the risk of progression to squamous cell carcinoma. A number of effective treatments for actinic keratosis are available, including topical and lesion-directed therapies. While lesion-directed therapies such as cryotherapy are appropriate for isolated lesions, topical 5-fluorouracil is an effective modality for the treatment of multiple facial actinic keratoses. 5-Fluorouracil, available in a number of formulations, offers patients the benefit of treating subclinical lesions and may help to improve the overall appearance of the skin. In many cases, combination therapy is a better treatment option than monotherapy. The cases presented here demonstrate the use of topical 5-fluorouracil cream 0.5% as monotherapy and in conjunction with glycolic acid peels to treat facial actinic keratoses in two patients with extensive histories of prior actinic keratosis and skin cancer.     

Photocarcinogenesis: UVA vs. UVB radiation

Recent research is revealing combinations of disturbed oncogenic and tumor-suppressive signaling pathways by altered or missing genes in skin cancers: mutated PTCH (in the mitogenic Sonic Hedgehog pathway) and mutated p53 tumor suppressor gene in basal cell carcinomas (BCC), possibly an activated mitogenic RAS pathway and mutated p53 in squamous cell carcinomas (SCC), and possibly an activated MET/RAS pathway and inactive p16(INK4a) tumor suppressor in cutaneous melanomas. UV radiation damages DNA and can give rise to genomic alterations, varying from point mutations to crude chromosomal dislocations. UVB radiation (wavelength band 280-315 nm) is more carcinogenic than UVA radiation (315-400 nm) in experimental induction of SCC. The impact of UVB radiation can be clearly inferred from the characteristic point mutations in p53 found in human SCC and BCC. In contrast to UVB radiation, much of the mutagenic and carcinogenic action of UVA radiation appears to be mediated through reactive oxygen species (ROS). Experiments have shown that UVA1 (340-400 nm) exposure induces SCC largely without the characteristic point mutations in p53. Both UVB and UVA radiation can give rise to ROS-related point mutations (e.g. G to T) and crude genomic alterations (e.g. deletions) which may not be recognized as caused by UV radiation.     

Sorafenib-induced premalignant and malignant skin lesions

Purpose To review characteristics of patients who develop premalignant and malignant skin lesions while on sorafenib therapy and discuss implications for subsequent treatment of their primary malignancies. Background Sorafenib is a newly developed multitargeted protein kinase inhibitor reported to induce a variety of adverse cutaneous effects, rarely including actinic keratoses, keratocanthomas, and squamous cell carcinomas (SCCs). Methods Published reports of individuals who have developed cutaneous lesions demonstrating atypia of the epidermis are reviewed. In addition, a 77‐year‐old man who developed not only an SCC but also verrucas within one month of taking sorafenib monotherapy for metastatic adenocarcinoma of the lung is described. Results Cutaneous lesions develop most commonly in Caucasian men older than 40 years without previous histories of skin cancer, within two weeks to three years of starting sorafenib therapy. Currently there is no definitive explanation for the relationship between sorafenib and cutaneous neoplasms. Management typically involves treatment of skin lesions with cryotherapy or excision with at least a brief discontinuation of sorafenib. In patients whose primary malignancies were responding well, sorafenib therapy was continued with close follow‐up. Conclusions The possibility of rapidly developing actinic keratoses, keratocanthomas, verrucas, and SCC during treatment with sorafenib, warrants close dermatologic follow‐up and a lower threshold for biopsy and treatment of suspicious cutaneous lesions. Development of a sorafenib‐induced SCC is not an absolute contraindication for continued use of sorafenib therapy; however, the drug should be briefly discontinued until lesions are treated.