Science of Skin

Actinic Keratosis (AK)

Snapshot
Other common terms: AK, Solar Keratosis, SK, senile keratosis
ICD-10 classification: L57.0
Prevalence: Very common; approximately 50% of the global population. Higher in fair skinned populations.
Causes: Chronic exposure to sunlight. Can be accelerated by immune suppression.
Symptoms: Dry, rough or scaly lesions on skin generally 2-6mm in diameter. Can take on ‘horned’ look. Can progress into squamous cell carcinoma skin cancer.
Treatments/cures: Tumour removal (surgery or cryotherapy), topical therapies, photodynamic therapy.
Differential diagnosis: Invasive squamous cell carcinoma skin cancer

Actinic Keratoses (AKs) are collections of abnormal skin cells (keratinocytes) found in the upper layers of skin (epidermis) that develop after prolonged exposure to sun light and ultraviolet light. Actinic Keratoses are in-situ squamous cell carcinoma (SCC) lesions (malignant cells still in their anatomically correct location). If left untreated, actinic keratoses may develop into invasive SCC skin cancer, a malignant skin tumor. AKs are very good indicators of significant past sun exposure, and are the strongest predictor that an individual may subsequently develop non-melanoma skin cancer (SCC or Basal Cell Carcinoma, BCC).

Actinic keratosis (AK) is also known as solar keratosis (SK).

Incidence

Actinic Keratosis
A cross section of skin showing keratinocytes

Actinic Keratoses are very common. It is reported that approximately 50% of the world's population suffers from skin problems resulting from AK. The prevalence of AK varies according to skin type and geography (latitude) with the incidence amongst Australians 40 years of age or older reported to be 40-60% compared with approximately 10-20% of the population in Europe and the US.

As age is another important risk factor in actinic keratosis, with AKs occurring in up to 80% of white adults aged 60-69 but in less than 10% of white adults 20-29 years. Males have a higher tendency towards developing actinic keratosis than females however this is likely the result of higher cumulative lifetime sun exposure in males than females.

Organ transplant recipients (OTR) patients are much more vulnerable to developing actinic keratosis and SCC, in part due to the immunosuppressive drugs they must take to prevent transplant rejection. OTRs are up to 250 times more likely to develop skin cancer than those who have not had an organ transplant.

Certain genetic conditions such as albinism or xeroderma pigmentosum place individuals at much greater risk of AKs.

Causes

There are several factors which contribute to the risk of AK developing;

  • Cumulative lifetime exposure to UV light and sun (see below);
  • fair skin characterized by freckles, the tendency to burn easily and lack of the ability to tan (Skin types I and II);
  • blue or light coloured eyes, and blond or red hair;
  • increasing age;
  • immunosuppression (e.g. after organ transplantation);
  • genetic conditions (albinism, xeroderma pigmentosum).

Cumulative sunlight and UV exposure and actinic keratosis

Cumulative lifetime sun-exposure is the most important contributing factor to the development of actinic keratosis and eventually Squamous Cell Carcinoma skin cancers. UV radiation may cause mutations in cellular DNA that, when un-repaired, may lead to uncontrolled cell growth and proliferation and eventually tumour formation. UV radiation also causes immunosuppression which impairs the cells’ capacity to repair the damaged DNA. This allows for the DNA mutations to persist and subsequently tumour rejection may not occur.

DNA is the main chromophore for UVB radiation. When photons of UVB light are absorbed by the DNA, damage is caused to the DNA helix, often resulting in C-T single mutations or CC-TT tandem mutations (cyclobutane pyrimidine dimers - CPD). These are commonly called ‘signature mutations’ and are indicative of photodamage due to UVB light. The photo damage caused by UVA light is less understood, but is likely to play a role in the transformation from normal to abnormal cells.

These ‘signature’ mutations are nearly always found in the p53 tumour suppressor gene (p53 is responsible for ensuring all DNA is repaired before allowing the cell to recommence cell division) which is found in the early developmental stages of actinic keratosis and SCC.

Multiple UV radiation induced-insults to the skin result in a pathway that begins with photo damaged skin, progresses to actinic keratosis and eventually, if left unchecked, may lead to an invasive SCC. Actinic keratoses are expanded clones of genetically abnormal cells that have escaped the normal DNA repair mechanisms and apoptosis (programmed cell death) to proliferate into what can be seen as an in-situ cancer of the skin.

Symptoms

Actinic keratoses appear as discrete, dry, rough or scaly lesions. They can be pink, red, tan, dark, light, or the same color as one’s skin. They are usually 2-6mm in diameter but may be many centimeters.

AKs are commonly found on a background of photodamaged (sun damaged) skin with dyspigmentation (loss of pigmentation), ephelides (freckles), telangiectases (dilated superficial blood vessels), and solar elastosis (decreased skin elasticity as a result of photodamage). 80% of AKs occur on sun-exposed sites and are particularly common on the back of hands, arms and scalp.

Itching, burning, stinging, bleeding and crusting are frequently associated with actinic keratosis. Increasing thickness, pain and ulceration are the main signs that an actinic keratosis may be transforming to a SCC and in this case a biopsy should be taken at the earliest time possible.

Subtypes of actinic keratosis

Hypertrophic keratoses are a subtype of actinic keratoses and manifest as thicker, scaly, rough plaques. A cutaneous ‘horn’ of skin is a conical protuberance and is often a further extension of the hypertrophic keratosis, however it can also represent an outgrowth of many other lesions including SCC. A biopsy of the skin can confirm the nature of an underlying lesion.

Actinic keratosis can also occur on the lips, in a condition called actinic cheilitis. This condition is characterized by red, scaly fissured lips and the lip border may become indistinct. If there are non-healing ulcerations on the lip, once again a biopsy should be taken to exclude SCC.

There are a few unusual variants of actinic keratosis including pigmented, spreading pigmented, proliferative and conjunctival.

Treatments

Actinic Keratoses are in-situ cancerous lesions and should be treated for their tendency to turn into invasive tumors. The type of treatment will depend on the size, location and number of lesions present as well as individual patient characteristics.

Physical removal of actinic keratosis

If there are only a small number of lesions to be treated, treatment is focused on physically removing individual lesions. These treatments may include:

  • Cryotherapy. Liquid nitrogen is applied with a cotton tip applicator or spray. Cryotherapy is easy to administer, does not rely on patient compliance and is performed without anaesthetic. Some of the disadvantages of this method include moderate pain and discomfort after the treatment and the potential for scarring.
  • Curettage. A curette is used to scrape away the abnormal skin layers. Electrocautery (high frequency electrical current) can be used to further destroy atypical cells and to provide hemostasis (cessation of bleeding). Local anaesthetic is required for this procedure.
  • Shave excision. A surgical blade is used to shave off the lesion. Local anaesthetic must be used for this procedure. The defect will take at least 1 week to heal. Infection, scarring and abnormal pigmentation are potential complications of this procedure.

Topical treatments for actinic keratosis

For more wide spread actinic keratoses, topical therapies are available. Often a combination of therapies sequentially with only a cluster of lesions treated at a time will be followed. Patients are advised to regularly check up with their health care professional to assess the treated lesions and address the next phase of treatment.

Topical treatments include:

  • 5-FU (Effudix) is topical chemotherapy and has been used for over 40 years. It selectively destroys actinically damaged (cancerous) cells but not normal skin. This triggers the body’s own immune system to mount an inflammatory reaction against the damaged cells which further contributes to its overall efficacy. There are many different treatment regimes so its use should be as directed by your doctor. 5-FU is estimated to have a 75% success rate (non recurrence) when lesions are treated appropriately. It is common for lesions to recur within a few years. Discomfort, burning, itch, redness, crusting and ulceration where the cream is applied are expected outcomes and usually begin to develop one week into treatment. Such a reaction is associated with successful resolution and a good prognosis.
  • 5% Imiquimod a relatively new therapy of AKs on the face and scalp which selectively destroys cancer cells. Imiquimod is generally only used in immunocompetant (normal immune function) adults. Treatments vary and patients should follow instruction by their physician.
    After one to two weeks of treatment a red papular reaction develops in the treated areas; erythematous papules and plaques which may crust and form erosions. The reaction is sometimes too uncomfortable to tolerate and then a week’s break from treatment should be taken before restarting therapy.
    Side effects of imiquimod include weeping, flaking and vesicle formation. Similarly to 5-FU, a more severe reaction is associated with better clearance of the actinic keratosis. Rarely, side effects such as flu-like symptoms, headaches and myalgias have been reported.
  • Diclofenac 3% gel, a non-steroidal anti-inflammatory drug (nsaid), can also be used for the treatment of widespread actinic keratosis. Its mechanism of action is not well understood but it’s thought to involve inhibition of cyclooxygenase which is a rate limiting step in the production of prostaglandins. Prostaglandins are inflammatory mediators thought to contribute to UV radiation induced DNA photodamage. Adverse events reported include mild local skin reactions with redness, itching and skin flaking. The severity of the reaction caused by diclofenac is much less than with 5-FU or with 5% Imiquimod. Resolution may occur in up to 50% of lesions.
  • Photodynamic Therapy (PDT) employs a topical agent in combination with UV light therapy. 5-aminolevulinic acid (ALA) is applied to the affected areas of skin and preferentially accumulates in the more rapidly dividing atypical skin cells. Here it is converted into protoporphyrin IX, a haem precursor and a photosensitiser. The ALA-treated skin is then exposed to a light source, which induces radical oxygen species and destroys the abnormal cells.
    PDT can cause considerable discomfort including redness, swelling and burning or deep pain during and after exposure to the light source. Some people with severe sun damage may experience intolerable pain with PDT in which case treatment should be discontinued. Allergic reactions have been associated with the application of ALA on occasion.
    After treatment it is very important to follow the protocol and limit sun exposure for the prescribed period after ALA application. If ALA is applied systemically, the skin is ‘sensitised’ by the photosensitiser ALA; severe phototoxic reactions will result if this is not obeyed. If ALA is applied on the skin only, it will be exhausted by the light treatment and will not lead to further phototoxic reactions.

Prevention

Avoiding UV sun exposure is the most effective way to decrease the risk of skin damage. Studies have shown that the critical time, the time of most sensitivity, is in childhood; education of young people is particularly important.

Complete avoidance of the sun is obviously not practical, but the next best thing - so far - is to avoid the strong midday sun between 10am and 4pm. Consistent application and reapplication of a broad-spectrum sunscreen, wearing UV protective clothing hats and sunglasses should always be employed.

Oral retinoids such as acitretin may be effective in preventing AKs but it must be taken consistently to observe a noticeable response. Topical retinoids such as retinoic acid cream have also been shown to prevent further lesions developing and so are sometimes used in combination with the oral therapy especially in high risk patients such as organ transplant recipients.

Prognosis

There are three most common outcomes for actinic keratoses. They may persist, regress or transform into Squamous Cell Carcinomas. There is no way of predicting the outcome of any given lesion. Limiting sun exposure and wearing sunscreen has been shown to increase AK regression.

References

  • Skincancerguide.ca (2008). Actinic Keratosis [Online]. [Accessed: 12/03/2008].
  • Euvrard, S, Kanitakis, J, Decullier, et al. (2006) 'Subsequent Skin Cancers in Kidney and Heart Translplant Recipients after the First Squamous Cell Carcinoma' Transplantation. Vol 81(8), pp1093-1100.
  • Anwar, J, Wrone, D A, Kimyai-Asadi, A & Alam, M. (2004) 'The Development of Actinic Keratosis into Invasive Squamous Cell Carcinoma: Evidence and Evoloving Classication Schemes', Clinics in Dermatology. Vol 22, pp189-196.
  • Oppel, T & Korting, H C. (2004) 'Actinic Keratosis: The Key Event in the Evolution from Photoaged Skin to Squamous Cell Carcinoma', Skin Pharmacology and Physiology. Vol 17(2), pp67-76.
  • Dwyer et al. (2002). “Cutaneous Melanin Density of Caucasians measured by spectrophotometry and risk of malignant melanoma, basal cell carcinoma and squamous cell carcinoma of the skin”, American Journal of Epidemiology. Vol 155, pp614-21.
  • Hoffman et al (2002). “Malignant melanoma in Cape Town, South Africa”, British Journal of Dermatology. Vol 138, pp998-1002.
  • Kromberg et al (1989). “Albinism and skin cancer in Southern Africa”, Clinical Genetics. Vol 36, pp43-52.
  • Tsai, T, Vu, C and Henson, D E (2005)."Cutaneous, ocular and visceral melanoma in African Americans and Caucasians", Melanoma Research. Vol 15, pp213-217.
  • Whiting, D A (1978). “Skin tumours in White South Africans. Part I. Patients, methods and incidence”, South African Medical Journal. Vol 53, pp98-102.

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