Actinic keratosis L57.0

Author: Prof. Dr. med. Peter Altmeyer

Co-Autors: Julian Baur, Dr. med. Nikolas Bounas-Pyrros

All authors of this article

Last updated on: 21.07.2021

Dieser Artikel auf Deutsch

Synonym(s)

Actinic keratoses; Actinic keratosis; AK; crasse de Vieillard; early in situ SCC type AKI; Early in situ SCC Type AKII; In situ SCC Type AKIII; Irritated actinic keratoses; keratoma senile; Keratosis actinic; keratosis senilis; keratosis solaris; KIN; SCC type actinic keratosis; solar keratosis

History
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Dubreuilh, 1896; Freudenthal, 1926

Definition
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Solar damage to the skin of fair-skinned, light-sensitive people caused by chronic, cumulative exposure to light (duration of exposure > 10 to 60 years) with the formation of single or multiple, circumscribed or diffuse, reddish or reddish-brownish spots, papules, plaques or nodules. Actinic keratoses (AK) are today defined as non-invasive, early (in situ) squamous cell carcinomas. This view is clarified by new names such as SCC (squamous cell carcinoma in situ) of the actinic keratosis type or KIN (keratinocytic intraepidermal neoplasia).

Classification
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A therapy-relevant clinical classification essentially refers to the extent and number of actinic keratoses (AK):

  • Patients with few (<5) individual AK lesions
  • patients with multiple (6 and >6) AK lesions
  • Patients with field cancer
  • Patients with simultaneous immunosuppression

The individual lesion can be classified clinically as follows:

This classification is a rough orienting clinical classification. The variants shown can usually be clearly defined and assigned. However, mixed types are often formed (e.g. formation of an erythematous type with a defined keratotic component).

Clinical and histological classification of actinic keratoses
Clinic Histology
Erythematous type Bowenoid type/Atrophic type
Keratotic type/ Cornu-cutaneum type Hypertrophic type
Acantholytic type
Pigmented type Pigmented type
Lichenoid type (Lichen planus type) Lichenoid type

Occurrence/Epidemiology
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Light-skinned, redheaded or blond individuals(skin type I/II according to Fitzpatrick) with high chronic sun exposure have a varying risk of developing actinic keratoses, depending on the intensity of the UV rays and age. The number of new cases is estimated at 240,000 per year. It is assumed that currently about 1.7 million people in Germany are under dermatological treatment for actinic keratosis (Schaefer 2014).

  • Prevalence (Central Europe; in patients > 40 years): 6-15%.
  • Prevalence (USA; in patients > 40 years): 11-26%.
  • Prevalence (Australia; for patients > 40 years): 45-60%.
  • Prevalence (Central Europe; in patients > 70 years): 52%.

Etiopathogenesis
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Multiplicative factors (e.g. hair colour, positive family history, degree of tanning, sun exposure, especially UV rays) play an essential role in the development of the disease:

I. Radiation

a) UV rays: UVB rays induce so-called signature mutations (pyrimidine dimers) in the basal cell layer. In addition, there is an immunosuppressive effect by long-wave UVA rays. Carcinogenesis occurs long before visible lesions develop. In UV-exposed (non-lesional) skin, as the earliest molecular biological correlate of carcinogenesis, key mutations (so-called driver mutations) can be detected in about 25% of all cases. UV rays lead to point mutations in one of the numerous kinetochor genes coding for a kinetochor protein. Kinetochor (Greek kínesis 'motion' and chōros 'locus') is a special, plate- or hemispherical structure of proteins and DNA segments, which sits on the side of the centromere and serves as a point of attachment for the fibres of the spindle apparatus during nuclear division processes. The upregulation of different Kinetochor genes could be detected in various malignant tumors, including actinic keratoses and squamous cell carcinoma of the skin (KNSTRN gene).

In squamous cell carcinomas,UVA radiation leads to a reduced expression of the Notch signalling pathway. The Notch 1 protein regulates (via p21) numerous cellular processes in keratinocytes such as cell differentiation, proliferation and apoptosis. A deficiency of Notch, as demonstrated in studies of squamous cell carcinomas, promotes its occurrence.

UVB rays also lead to a transition from cytidine to thymidine in the tumour suppressor gene Tp53. This mutation can be detected > 50% of all AK. P53 plays an important role in the regulation of cell growth during normal function. A loss of function leads to an uncontrolled growth of keratinocytes. UVB rays further induce H-Ras mutations. These are detected in 21% of squamous cell carcinomas. The H-Ras gene product plays an important role in the Erk1/Erk2 signaling pathway. The mutation of H-Ras leads to an altered Ras protein and increased cell production.

b) X-rays/ionising radiation

(c) Infrared radiation

II Chemical carcinogens

Chemical carcinogens such as aromatic hydrocarbons (see MOAH below) or arsenic are recognized as full-fledged carcinogens in the induction of cutaneous PEKs.

III Biological carcinogens

HPV: The proven high proportion (> 80%) of oncogenic HPV (human papillomaviruses) in actinic keratoses suggests that HPV might be etiologically relevant in interaction with UV radiation. In actinic keratoses, a prevalence of HPV in organ transplants between 40 to 90% vs. 35 to 85% in immunocompetents was found. The HPV types are mostly epidermodysplasia verruciformis types.

IV. Predisposition factors

a) Immunosuppression: >30% of organ transplants have at least 5 actinic keratoses, whereby skin types I/II are also preferably affected. Furthermore, immunosuppressed patients show a more aggressive growth behaviour with a faster transition to squamous cell carcinoma.

b) Clinical syndromes predisposing to actinic keratoses:

  1. Albinism
  2. Rothmund-Thomson Syndrome
  3. Cockayne Syndrome
  4. xeroderma pigmentosum
  5. Bloom Syndrome

Elevated COX-2 (see below cyclooxygenases) and prostaglandin E2 levels were found in actinic keratoses (see below diclofenac).

Manifestation
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Especially occurring in light-skinned, sunburn prone and elderly people. Men are more frequently affected than women. Actinic keratoses are the first clinically manifest skin changes in a UV-damaged area of skin, in which potentially further lesions can develop. This is known as " field carcinogenesis".

Localization
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Chronically light-exposed skin areas of the scalp, especially forehead, bald head, nose, auricles, cheeks, back of the hand, red lips (Cheilitis actinica). Less frequently: décolleté, extensor side of the forearms, back of the hands, lower legs,

Clinical features
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Keratosis actinica erythematous type: Initially a few millimetres in size, round, oval or irregular, always sharply defined, inflammatory reddened papules or plaques, also interspersed with telangiectasias, with a rough, horny surface. Gradual increase in size (up to 1 cm or > 1 cm). Tendency to bleed after small injuries.

Keratosis actinica keratotic type/cornu cutaneum type: Papules and plaques with formation of whitish-grey, but also yellowish to brown or grey-black, differently thick, often adhering to the surface. In the keratotic type, the skin may develop irregular, firmly adhering horns (see also Cornu cutaneum).

Pigmented type: actinic keratoses tinged brownish due to increased pigment formation with a tendency to spread growth.

Lichenoid type (Lichen-planus type - related to the erythematous type): Clinically there are 0.2-2.0 cm large, but also larger, deep red spots, papules or plaques with shiny, smooth or rough surface. Histologically there are merkma le of lichen planus with acanthosis, hypergranulosis and orthohyperkeratosis as well as subepithelial lichenoidal lichenoidal round cell infiltrate.

Clinically the degree of Olsen's disease (grade I-III) is defined (see below clinical classification of keratosis actinica). A well-evaluated "scoring" index for the quantitative and qualitative assessment of actinic keratoses on the head is the AKASI (acronym for "actinic keratosis area and severity index") (Dirschka T et al. 2017).

Irritated actinic keratoses: This phenomenon can be observed about 1 week after the start of cytostatic therapy, e.g. with 5-fluoracil, and is accompanied by redness, swelling and scaling, obviously as a sign of a cytotoxic effect(cytostatic drugs).

Histology
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The histological picture is characterized by hyperkeratosis and parakeratosis on acanthotic widened or atrophic epithelium. Atypical pleomorphic keratinocytes are scattered over the epithelial band. Displaced nuclear-plasma relation, increased mitosis. Single cell dyskeratoses are always detectable, characterized by an amorphous, eosinophilic cytoplasm with a pynotic or missing nucleus. Rarely suprabasal acantholysis. Partially inflammatory infiltrate. Invasivity (i.e. invasion into the papillary body) is not present in actinic keratosis (by definition). An important differential diagnostic criterion for actinic keratosis (differentiation from Bowen's disease) is the absence of the acral adnexal structures (infundibulum, acrosyringium). The excretory ducts wind their way through the altered surface epithelium like a road.

Hypertrophic actinic keratosis: acanthosis, slight papillomatosis, strikingly emphasized hyper- and parakeratosis. Hyperkeratosis can lead to a grotesque disproportion between epithelial thickness and horny layer. This histological finding is consistent with the clinical findings of the cornu cutaneum.

Atrophic actinic keratosis: flat atrophic epithelial band with loss of the reteleal strips; slight hyperkeratosis; cell atypia mostly in the lower third of the epithelium. Here focal bulges towards the dermis. No invasiveness!

Bowenoid actinic keratosis: Hyperkeratosis and parakeratosis on acanthotic dilated epithelium. Atypical pleomorphic keratinocytes are scattered over the epithelial ligament in dense seeding. In addition, epithelial giant cells as well as numerous, bizarre mitoses and dyskeratoses show up. The differentiation from Bowen's disease is based on the detection of the uninvolved adnexal structures.

Acantholytic actinic keratosis: In addition to the typical picture of actinic keratosis a suprabasal acantholysis is observed.

Pigmented actinic keratosis: In addition to the epithelial changes of the AK, there is a simultaneous proliferation of melanocytes and an increased pigment accumulation in the basal keratinocytes.

Lichenoid actinic keratosis: Mostly picture of atrophic actinic keratosis with accompanying distinct lichenoid (band-shaped) infiltrate in the upper dermis. Often numerous dyskeratoses.

Regarding the histological classification according to the degree of dysplasia (KIN I-III) see below CHIN.

Differential diagnosis
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Clinical:

  • Verruca seborrhoica: rather dull surface structure, mostly even pigmentation. No rough keratoses of the surface
  • Arsenic keratoses: a special form of actinic keratosis which is rarely found today (mostly localized on palmoplantar tissue).
  • Lupus erythematodes chronicus discoides: red, scaly plaques at the edges. The history of the patient shows no signs of chronic UV damage.
  • M. Bowen: mostly solitary plaque; clinically difficult to distinguish.
  • Basal cell carcinoma: grey-shiny plaque, emphasizing the edges, more prominent when the huat is stretched.
  • Lentigo solaris/maligna: non-palpable, rounded spot, smooth surface structure, colour dark brown to black-brown.

Histological:

  • Verruca seborrhoica: errant forms of Verruca seborhhoica. Not always easily distinguishable due to the Borst-Jadassohn phenomenon. However, the broad cellular polymorphism of actinic keratosis is missing.
  • Lentigo maligna: Lentigo maligna lacks the distinct polymorphism of the keratinocytes. Irregular proliferation of atypical melanocytes which penetrate the epithelial band. This phenomenon is missing in actinic keratosis.
  • Superficial basal cell carcinoma: rather circumscribed basaloid epithelial proliferation separated from the normal epithelium. Broad cleavage to the surrounding connective tissue.
  • Porokeratosis actinic: typically columnar parakeratosis cones; outside the parakeratosis dyskeratotic cells which are otherwise rather absent.

External therapy
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Selected lesion- and field-directed therapy options for AK (var. according to EDF guidelines)
Curettage 1x, repetition up to 2x
Cryotherapy 1x, several repetitions possible
Carbon dioxide (CO2) laser 1x, several repetitions possible
Er:YAG laser 1x, several repetitions possible
5-FU (0.5%)+ SA(10%) 1x daily for 6-12 weeks
5-ALA-PDT i.A. 1.0h incubation time
MAL-PDT 1.A 2.5h incubation time
Diclofenac-(3%) in 2,5% hyaluronic acid 2x/day for 60-90 days
5-FU (5%) 1x or 2x/day for 2-4 weeks
Imiquimod (3.75%) 1x/day for 2 weeks, then 14 days break (1 or 2 cycles)

Alternatively: 5-fluorouracil in combination with salicylic acid and DMSO (Actikerall®).1 g of the solution contains 5 mg fluorouracil, 100 mg salicylic acid and 80 mg dimethylsulfoxide. This combination preparation is used for flat or moderately thickened actinic keratoses. The colourless varnish is applied 1x/day strictly lesionally until complete healing. Multiple actinic keratoses (up to 10 lesions) can be treated simultaneously. Experience is available for this. The total area of the skin to be treated with Actikerall should not exceed 25 qcm (5 cm x 5 cm). (S. a. No 757 GOÄ)

Alternative: 5-fluorouracil (as monotherapy): In case of multiple areal actinic keratoses, local treatment with an ointment containing 5% 5-fluorouracil (e.g. Efudix®) is possible. In the case of monotherapy, the 5-fluorouracil ointment is applied 1-2 times/day, the treatment lasts 3-6 weeks. The area to be treated must be < 500 qcm. In combination with curettage: Apply a thick layer of 5-fluorouracil ointment to the curetted lesion immediately after curettage; renew every 2nd day. For lesions < 1 cm 5-fluorouracil patch every 2-3 days.

Cave! When using 5-fluorouracil, inform the patient about the application method and NW! Eye protection!

Alternative combination: 5-fluorouracil + retinoids: In case of multiple surface expansion, good results have also been reported with a 5%fluorouracil ointment in combination with isotretinoin (e.g. Isotretinoin-ratiopharm; Isoderm). 5% 5-fluorouracil (e.g. Efudix ointment) applied twice a day, isotretinoin 10-20 mg/day p.o., therapy duration 3-5 weeks. Strong inflammatory reactions are to be expected, if necessary apply glucocorticoid-containing creams such as 0.25% prednicarbate (e.g. Dermatop cream) in the meantime, in case of superinfection systemic antibiosis.

Alternatively: Imiquimod (Aldara® 5%, Zyclara®3,5%) Topical immunomodulation with 5% Imiquimod 1-3 times/week for a total of 8-16 weeks (USA: 2 times/week for 16 weeks). Local inflammation of actinic keratosis occurs, not of healthy skin. If the irritation is too severe, the frequency of application is reduced to 2 times/week. The success of this therapy has been proven by numerous studies, the healing rate is 40-50%. The therapy is approved in Germany. For Aldara, the therapy is limited to a treatment area of 25qcm. For Zyclara no limitation.

Alternative: Photodynamic therapy. For single lesions the patch photodynamic therapy (Alacare® for up to 6 single lesions) is a good alternative.

Alternative: Photodynamic daylight therapy: Also for single lesions the photodynamic daylight therapy with Methyl-ALA is suitable. Methyl-ALA (Luxerm®) accumulates in the tumor cells and is converted into the photosensitizer protoporphyrin IX, which is effective under daylight (advantage for the patient!).

Externa for field carcinogenesis:

Diclofenac: Very good results were obtained with the local, well-tolerated application of a 3% diclofenac gel(Solaraze®, 2 times/day; Solacutan ®). No limitation of the treatment area! Inhibition of the arachidonic acid cycle induces apoptosis and suppresses angiogenesis. In the literature remission rates of 40% are reported for clinically visible lesions.

Alternatively, external retinoids such as 0.3% Adapal Gel and Tazarotene Gel have also been shown to be effective in various clinical studies (off-label use). Here, external skin irritations, especially during long-term therapy, must be considered.

Alternative: photodynamic therapy. In case of field carcinogenesis, local photosensitization with 20% delta-aminolevulinic acid (ALA) and subsequent irradiation with infrared light is suitable.

Alternatively: photosensitization with methyl-ALA and irradiation with Aktilite®.

Operative therapie
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In principle, it is recommended to arrange for a meaningful histological examination of the scraped material for the following lesion-directed therapy procedures.

  • Lesion-directed curettage: After prior local anaesthesia in the case of isolated actinic keratoses, curettage is performed with a flat, sharp curette. Actinic keratoses usually detach easily in toto. Histological examination of the scraped material is recommended.
  • Lesion-directed laser therapy with ablative laser (e.g. Erbium-YAG-Laser) have a very good response rate. An ablative laser treatment with an Er:YAG laser showed an almost 90% healing rate. It is recommended to take curettage material immediately before the laser treatment to histologically secure the findings.
  • Lesion-directed electrocaustics with ball: Pass the ball over the lesion with a low current and gently cure it with a curette.
  • Lesion-directed cryosurgery with cotton swabs: This treatment is a good alternative to curettage, especially in several smaller foci. Immerse the cotton swab in liquid nitrogen and press continuously on the lesion for 5-10 seconds.
  • Lesion-directed cryosurgery in open spray technique: For large-area actinic keratoses with or without local anaesthesia. Spray the lesion briefly so that the area is covered with a white layer of ice. If necessary, repeat the procedure after defrosting. Protect surrounding skin with moulage (e.g. perilesional application of a thick layer of vaseline).

Progression/forecast
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The guidelines (Stockfleth 2016) assume a low (0-7.2%) probability of complete spontaneous regression.

The data on the development of squamous cell carcinomas on the basis of actinic keratoses (AK) vary considerably. They are indicated with 0.1%- 20%. A higher risk can be expected if > 5 AKs are present. In this clientele, the total risk of developing an invasive squamous cell carcinoma within 10 years is assumed to be 6.1-10% (Hommel 2016).

How does the progression of AK into squamous cell carcinoma proceed? It was assumed that an increasing intraepidermal stratification disorder of AK leads to squamous cell carcinoma. First, pleomorphic keratinocytes develop in the lower third of the epidermis (CHIN I) before they also penetrate higher epidermal layers (CHIN II/III). Only then would infiltrating growth occur. This formalistic progression model, however, does not adequately map the transformation of AK into an invasive squamous cell carcinoma, as invasiveness can develop from any KIN stage (Fernandez-Figueras 2015).

Prophylaxis
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Avoid greater exposure to the sun through textile, chemical (e.g. Daylong actinica) and physical sun protection measures as well as regular check-ups.

More recent studies (Chen AC 2015) indicate that taking vitamin B3 (2x 500mg) has a UV-protective effect. The new formation of actinic keratoses is significantly reduced.

Good individual experiences exist with the topical application of photolyases gfls. in combination with a sun protection preparation (Eryfotona®) for mild actinic keratoses.

Practical tips
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GOÄ Tips:

Treatment includes no. 1 GOÄ (consultation), no. 7 GOÄ (examination of skin organ), 750 GOÄ (dermoscopy), if necessary video dermoscopy (no. 612 GOÄ analogue).

No. 612 GOÄ analogue and No. 750 GOÄ are to be applied next to each other if they refer to different skin changes. (750 for melanocytic nevus, 612 analogue for actinic keratosis).

No. 744 GOÄ (80 points) is used for a skin punch. The number is to be charged only once.

No. 303 GOÄ concerns a test biopsy with a needle, e.g. 2mm punch biopsy which is not sutured (80 points). It can be billed several times (e.g. for the evaluation of a marginal infiltration of a tumorous lesion - sclerodermiform basal cell carcinoma).

No. 2401 GOÄ (133 points) concerns a sample biopsy. The number defines an excision. If necessary, it can be billed several times.

No. 2403 GOÄ concerns the therapeutic excision of a small tumour (up to the size of a cherry stone). The number can be charged more than once

No. 2404 GOÄ concerns the therapeutic excision of a larger tumour (from the size of a cherry stone). Remark: On head and hands every finding is considered as large (Lit Haut 03/16). The figure can be applied more than once.

Further therapeutic services:

No. 745 GOÄ (wart removal with sharp spoon) can be applied analogously for a curettage.

No. 746 GOÄ (electrolysis) can be applied as electrodissection, also in addition to No. 745 GOÄ analogously.

No. 757 GOÄ chemosurgical treatment of a precancerous lesion, e.g. with fluorouracil, can be charged only once for one lesion, even in the case of several sessions. No. 757 can be charged several times for several lesions.

Laser treatments of an actinic keratosis: according to the recommendations of the German Medical Association (BÄK of 2002, supplement and specification for actinic keratoses in the DÄB of 27.12.2010) the following numbers are to be charged:

  • No. 2440 GOÄ analog (surgical removal of a nevus flammeus)
  • alternatively no. 2885 GOÄ analog (removal of a small blood vessel tumour)
  • alternatively no. 2886 GOÄ analog. (Removal of a large blood vessel tumour)
  • No. 444 GOÄ: (surcharge for outpatient performance of surgical services rated at 800-1199). The approach is justified (Lit Haut 03/16) is however often disputed.

The recommendations for laser ablation listed here correlate with the S1-guideline of the Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften (AWMF) for the treatment of actinic keratoses, which was lead-managed by the Deutsche Dermatologische Gesellschaft (German Dermatological Society). According to this guideline, ablative laser treatment of actinic keratoses is a highly effective therapy option, with described complete remissions of 90-91%. This high complete remission rate particularly justifies this therapeutic approach, which takes into account the clinically not always noticeable transition of actinic keratosis into an invasive growing squamous cell carcinoma.

Photodynamic therapy of actinic keratosis: to be applied according to the recommendations of the German Medical Association (DÄB of 18.1.2002) are the following numbers:

  • NR: 5442 GOÄ(static renal scintigraphy) analogous as photodynamic diagnostics
  • No. 566 GOÄ (phototherapy of a newborn) analogously as photodynamic light irradiation, up to 2 x in the treatment case.
  • No. 5800 GOÄ (preparation of a radiation plan) analogously as radiation plan for photodynamic therapy. The number is to be applied once per treatment case.
  • No. 5802 GOÄ (orthovoltage irradiation per fraction). This figure is used as a supplementary figure in addition to No. 566 GOÄ for 2 further irradiation fields.
  • No. 5803 GOÄ (supplement to No. 5802) analogous . This figure is applied as a supplementary figure in addition to no. 566 GOÄ for each additional irradiation field.
  • No. 209 GOÄ: Application of the photosensitizer
  • No. 200 GOÄ: Application of the occlusive tape
  • No. 530 GOÄ: Application of a cold pack.
  • No. 745 GOÄ. In case of pre-treatment of a lesion, the figure for curettage can be applied.

Literature
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  1. Ackerman AB et al (2006) Solar (actinic) keratosis is squamous cell carcinoma. Br J Dermatol 155: 9-22
  2. Braakhuis BJ et al (2003) A genetic explanation of Slaughter's concept of field cancerization: evidence and clinical implications. Cancer Res 63: 1727-1730
  3. Chen AC et al (2015) A phase 3 randomized trial of nicotinamide for skin cancer chemoprevention. N Engl J Med 373:1618-1626.
  4. Dirschka T et al. (2017) A proposed scoring system for assessing the severity of actinic keratosis on the head: actinic keratosis area and severity index. J Eur Acad Dermatol Venereol 31:1295-1302
  5. Dubreuilh WA (1896) Des hyperkeratoses circonscrites. Ann Dermatol Venereol 27: 1158-1164
  6. Fernández-Figueras MT et al.(2015)Actinic keratosis with atypical basal cells (AK I) is the most common lesion
  7. associated with invasive squamous cell carcinoma of the skin. J Eur Acad Dermatol Venereol 29:991-997.
  8. Freudenthal W (1926) Verruca senilis and keratoma senile. Arch Dermatol Syphilol (Berlin) 158: 539-544.
  9. Fritsch C, Ruzicka Th (2003) Fluorescence diagnosis and photodynamic therapy of skin diseases. Atlas and handbook. Springer, Heidelberg Berlin
  10. Hengge UR, Stark R (2001) Topical imiquimod to treat intraepidermal carcinoma. Arch Dermatol 137: 709-711
  11. Hommel T et al (2016) Actinic keratoses. Dermatol 67: 867-875
  12. Kang S et al (2003) Assessment of adapalene gel for the treatment of actinic keratosis and lentigines: A randomized trial. J Am Acad Dermatol 49: 83-90
  13. Nakaseko H et al (2003) Histological changes and involvement of apoptosis after photodynamic therapy for actinic keratoses. Br J Dermatol 148: 122-127
  14. Nicolas M et al (2003) Notch1 functions as a tumor suppressor in mouse skin. Nat Genet 33:416-421.
  15. Röwert-Huber J et al (2007) Actinic keratosis is an early in situ squamous cell carcinoma: a proposal for reclassification. Br J Dermatol 156 (Suppl 3) 8-12
  16. Schaefer I et al. (2014) Prevalence and risk factors of actinic keratoses in Germany--analysis of multisource data. J Eur Acad Dermatol Venereol 28:309-313.
  17. Stege H et al. (2017) New approaches to the prevention of actinic keratoses. Dermatologist 68: 354-358
  18. Stockfleth E et al. (2004) Low incidence of new actinic keratoses after topical 5% imiquimod cream treatment: a long-term follow-up study. Arch Dermatol 140: 1542
  19. Werner RN et al. (2015) Evidence- and consensus-based (S3) Guidelines for the Treatment of Actinic
  20. Keratosis - International League of Dermatological Societies in cooperation with the European Dermatology Forum - Short version. J Eur Acad Dermatol Venereol 29: 2069-2079.
  21. Wolf JE et al. (2001) Topical 3% diclofenac in 2.5% hyaluronan gel in the treatment of actinic keratoses. Int J Dermatol 40: 709-713
  22. Zeicher J et al. (2009) Placebo-controlled, double-blind, randomized pilot study of imiquimod 5% cream applied once per week for 6 months for the treatment of actinic keratoses. JAAD 60: 59-62

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Last updated on: 21.07.2021