Actinic Keratosis | Treatments, Causes and Pictures

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. These lesions are also called senile keratoses. Actinic keratosis literally means a condition (-osis) of excessive horny (kerat-) tissue induced by a ray of light (aktis), presumably UV light. 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. This concept of a progression along a spectrum is analogous to that of cervical carcinoma, for which cervical intraepithelial neoplasia (CIN) is the initial, “precancerous” lesion.

AKs are clinically important lesions, not only because of their potential to develop into skin cancer, but because they are one of the strongest predictors that an individual may subsequently develop melanoma or nonmelanoma skin cancer. With the increasing incidence and prevalence of melanomas and nonmelanomas, persons with AKs are the perfect candidates for careful longitudinal observation for prevention of cutaneous malignancy and early intervention.

Patients are usually middle-aged or elderly and develop rough scaly areas on sun-exposed sites, which are generally asymptomatic. Many patients give a history of relapsing and/or remitting lesions, which often disappear either spontaneously or after sun avoidance and use of sunscreens.

Actinic keratoses are commonly present on light-exposed areas such as the face, scalp and back sides of the hands. The sides of the neck are involved in both sexes, but the ears predominate in men. The lower lip may also be involved, with a much higher incidence in men than women. The variants of AK include:

1. Erythematous AK: The typical AK lesion is called the erythematous AK. Lesions are usually multiple and comprise of patches with a rough scaly surface resulting from disorganized skin growth and a variable degree of inflammation. Lesions vary in size from less than 1 mm to over 2 cm and are usually asymptomatic. In many individuals, the number of lesions can be better appreciated by skin palpation, which is a sensitive way of detecting the characteristic roughness associated with smaller lesions. Many of these small lesions may pass unnoticed by most patients, and the diagnostic changes often only appear later as a dry rough adherent and often yellow- or brown-colored scale. The adherent scale can only be picked off with difficulty, revealing a base with punctate bleeding points. In some cases, scaling may be prominent and in time may become thick and horny. The edge of the AK is usually sharply demarcated and the reddening is usually closely confined to the area immediately below the area of abnormal scaling. There is often associated ‘field change’, with areas of photodamage; skin atrophy, vessel dilatation and pigmentary change which surrounds and extends beyond clinical AKs.
2. Hypertrophic AK: The hypertrophic AK (HAK) presents as a thicker, scaly, rough plaque that is skin-colored, gray-white, or erythematous. It can be found on any habitually sun-exposed site on the body but has a propensity for the back sides of hands, arms, and scalp. A typical erythematous AK can progress into an HAK. It can be difficult to distinguish an HAK from a skin cancer, clinically necessitating a biopsy. Biopsies must be taken to a level deep enough to ensure that the extent of proliferation can be evaluated in order to obtain an unequivocal histopathologic diagnosis. Induration or thickness, pain, and ulceration are the main clues to the transition of AK to cancer.
3. Cornu Cutaneuum: Cutaneous horn, also known as cornu cutaneum, refers to a reaction pattern and not a particular lesion. In reference to AKs, a cutaneous horn is a type of HAK that presents with a conical protuberance emanating from a skin-colored to erythematous base. Classical definitions of a cutaneous horn maintain that the height is at least one half of the largest diameter. Thirty-eight percent to 40% of all cutaneous horns represent AKs. The pathology underlying a cutaneous horn can be a number of different lesions, such as AK, skin cancer, seborrheic keratosis, filiform verruca vulgaris, keratoacanthoma. The most common underlying lesion in elderly, fair-skinned persons is an HAK.
4. Actinic Cheilitis: Actinic cheilitis represents confluent AKs on the lips, most often the lower lip. Persons with this condition have red, scaly, chapped lips, and at times erosions or fissures may be present. The border of the lip is often indistinct, and thickening and white patches may also be seen. Individuals with this condition often complain of persistent dryness and cracking of the lips, and the diagnosis of actinic cheilitis should always be suspected in photodamaged patients with such complaints. Persistent ulcerations or indurated areas on the lip require biopsy to ensure that cancer is not present.

A number of classifications have been proposed but none have shown accurate clinicopathological correlation. The term Keratotic Interepithelial Neoplasia (KIN) has been described with KIN1 having minimal cancerous changes at the basal layer to KIN3 showing severe cell changes. However, there is poor clinical correlation with this pathological staging.

Some dermatologists describe the clinical thickness of disease by using the term ‘mild’ with thin slightly palpable disease to ‘moderate’ where AKs are easily seen and felt, to ‘thick’, but this does not take into account any pathological changes.

Actinic keratoses are usually asymptomatic but patients may complain of local itching and discomfort. Most patients find them a cosmetic nuisance. Patients with AK are at a higher risk of concurrent skin cancer and melanoma. Quality of life (QoL) may be affected and can be determined using the AKQoL questionnaire.

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. In addition, the risk for skin cancer increases with increased UV radiation exposure and with certain individual patient characteristics, such as suppressed immune status. It was observed that before an AK progresses to skin cancer, it may become clinically tender and inflamed.

Studies in patients with AK have established, first, that there is a high probability of developing new lesions; and, second, that many lesions undergo spontaneous resolution. Rates of regression of single lesions have been reported to range from 15% to 63% after 1 year. Data available on recurrence rates of single lesions 1 year after regression indicate a recurrence rate of 15-53%. Although the rate of progression of an individual AK to invasive SCC has been estimated to be low (less than 1 in 1000/year), an individual with an average of 7.7 AKs has a probability of around 10% of one AK transforming to a skin cancer over a 10-year period. The presence of AK is therefore an important biomarker of excessive UV exposure and increased skin cancer risk.

The estimated rates of metastases arising from actinically derived SCC have ranged from 1% to 2% to over 20% depending primarily on depth of invasion, location (with the lip, ear, and scalp representing the sites of highest risk), differentiation, and the presence of invasion around neurons.

Diagnosis of AK is made on clinical grounds but a skin biopsy may be necessary to differentiate from a skin cancer or Bowen disease. More recently, non-invasive techniques such as reflectance confocal microscopy and high-definition optical coherence tomography have been used to determine the optical features of AK and differentiate these from cancer.

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Epidemiology

• The prevalence of AK is high in many countries and is influenced by the amount of ambient UV radiation (UVR), the proportion of susceptible individuals in the population, the age structure of the population and the time spent in outdoor occupations and recreations. Epidemiological studies in the UK and Ireland have shown a prevalence of 19-24% of at least one AK in individuals over the age of 60 years. The rate of new AK has been estimated to be 149/1000 person-years. AKs are found in younger age groups with 3.6% of men aged 40-49 years developing AK. Studies in Japan show a substantially lower prevalence rate at 0.4%, illustrating significant global variation, likely due to environmental as well as genetic factors. Not surprisingly, there are high prevalence rates in Australia, at up to 60% in some studies.
• Age: Actinic keratoses are more common in the elderly. In a UK study, the overall prevalence of AK was 15.4% in men and 5.9% in women over the age of 40 years and 34% and 18% in men and women, respectively, aged 70 years and over. There was a linear increase in prevalence from 60 to 80 years in men but not in women.
• Sex: Actinic keratoses are common in both sexes but there is a preponderance in men.
• Ethnicity: This condition is much more common in the white population, particularly those who have lived or live in areas of high sunlight exposure. In these areas such as Australia, there is a prevalence rate of 43% with 18% having more than 10 AKs.
• Associated diseases: Patients may present with other UVR-induced skin cancers and full examination of the skin should be undertaken. A large European study showed that patients presenting with AK have coexisting squamous cell carcinoma in 58%, basal cell carcinoma in 30%, in situ melanoma in 12% and invasive melanoma in 6% of cases.

Pathophysiology

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.

• Predisposing factors: The great majority of AKs occur on light-exposed sites in fair-skinned people who have had excessive exposure to UVR. They 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. AKs are commoner in people with red hair and those with blue eyes. People with brown eyes and/or black hair carry the lowest risk for AK development. There is a higher prevalence in organ transplant recipients (OTR) on chronic immunosuppression. In a large European study, there was a suggestion that some photosensitizing drugs, such as thiazides, amiodarone and diltiazem increased the risk, even when corrected for age. Lesions with similar clinical and histological features may be induced by ionizing radiation or radiant heat and in workers exposed to pitch and other products of coal distillation.
• Causative organisms: 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. AKs can occur without HPV infection and HPV is now considered to be a co-carcinogen.
• Environmental factors: There is a direct relationship between AK and chronic sun exposure. AKs are also more common following phototherapy, ionizing radiation and sunbed usage. Historically, arsenic and chemicals from coal distillation increased the risk of AK development.

Management of patients with AK needs to begin with a thorough explanation of the nature, natural history and risks associated with the presence of these lesions. As AKs are a highly sensitive marker of levels of UV exposure capable of producing malignant change, patients are educated in the signs and symptoms of skin malignancy and given information in written and pictorial format to assist them in recognizing skin cancers. Asymptomatic patients with ‘low-risk’ disease and few thin AKs may decide that no treatment is a reasonable option. Other patients may wish to simply use emollients but all should be advised to use sun blocks. Regular sunscreen use has shown to reduce the rate of development of new AK indicating that continuing UVR exposure plays an important role in promoting the development of clinical lesions.

When a decision to treat has been made, particularly in those in the ‘high-risk’ group, there are a number of therapeutic options available, with the aim to control and reduce the number of AK and to reduce the rate of progression of AK to cancer.

First line Treatments

There are a number of creams/gels, destructive treatments which are selective such as PDT and non-selective such as cryotherapy, and surgical techniques such as curettage and cautery, available to treat AKs. Treatment depends on local expertise, availability of the particular therapy, patient choice and area of AKs to be treated.

• Cryotherapy: Liquid nitrogen cryosurgery is the most common destructive procedure and is typically administered with a spray device or a cotton-tipped applicator. The overall complete clearance rate when the patients are checked 3 months after treatment is 67.2%. A subgroup analysis of these data based on actual freeze times indicates that a complete response occurs in 39% of cases with freeze times of 5 seconds or less, in 69% with freeze times between 6 seconds and 20 seconds, and in 83% with freeze times longer than 20 seconds. Hypopigmentation is seen in 29% of sites from which AK was eradicated most probably those with longer freeze times as the melanin cells are particularly susceptible to cold injury. The benefits of cryosurgery are its ease of administration in trained hands, the lack of need for anesthetic, and the lack of reliance on patient compliance other than in posttreatment care of treated lesions. Potential disadvantages of cryosurgery include pain and discomfort, the presence of unsightly blisters and crusted wounds for a week or longer, hypopigmentation, scarring, and possible alopecia in treated areas. In rare cases, serious injury to underlying tendons and nerves may occur with deep or prolonged liquid nitrogen application to the hands. Most important, cryosurgery is best used to treat a limited number of clinically perceptible or symptomatic lesions.
• Curettage: Curettage, with or without electrosurgery, is another destructive lesion-targeted treatment for AKs. This procedure and cryosurgery together constitute approximately 80% of all treatments for AKs in the United States. A curette is used to mechanically scrape away the atypical cells comprising the AK. Electrosurgery may or may not be used to further destroy atypical cells and to provide hemostasis. If electrosurgery is employed, minimal use is advised to enhance the final cosmetic result. A local anesthetic is needed for this procedure, and hemostatic agents such as aluminum chloride can be used to stop the bleeding if electrosurgery is not utilized. Patients can expect some discomfort with injection of the local anesthetic, and the treated area will take a few weeks to heal completely. This technique is most appropriate for patients with relatively few AKs. It is also beneficial for treatment of lesions after biopsy and for the treatment of HAKs. Potential side effects include infection, scarring, and dyspigmentation. If a biopsy is to be performed, procurement of a shaved specimen before curettage provides a much more acceptable histopathologic portrait and avoids over or under-interpretation. Obtaining biopsy samples through curettage produces crushed and fragmented specimens that are difficult to interpret, which can lead to erroneous diagnoses.
• Shave Excision: The third lesion-targeted destructive therapy for AKs is shave excision. This technique involves injection of a local anesthetic followed by tangential excision of the lesion with a surgical blade. Hemostatic agents must also be used to stop the bleeding. Healing time may be 1-2 weeks, and potential complications include infection, scarring, and dyspigmentation. Use of this technique is most often indicated when a clinically apparent AK is suspicious for skin cancer and histopathologic examination is needed. Shave excision offers the patient an attempt at curative therapy simultaneous with a diagnostic procedure. Signs and symptoms that should arouse suspicion of skin cancer include marked erythema, pain, ulceration, bleeding, induration, or failure to respond to prior destructive therapies. Care is taken to shave deeply enough to avoid transecting the AK at the deep margin, because this precludes unequivocal interpretation due to the proclivity for invasive skin cancer to develop at the deepest extensions of the atypical cells in AKs.
• 3% diclofenac in 2.5% hyaluron gel: This non-steroidal anti-inflammatory drug's mechanism of action in AK is not known but may be related to the inhibition of the cyclo-oxygenase pathway leading to reduced prostaglandin E2 (PGE2) synthesis. In studies, complete clearance rates of 47% compared with 19% for placebo were observed at 30 days follow-up after 90 days of treatment.
• 5% 5-fluorouracil cream and 0.5% 5-fluorouracil combined with 10% salicylic acid: The mechanism of action is not clear but it is believed to act through inhibition of DNA synthesis, leading to cell death. The addition of salicylic acid in the 0.5% formulation leads to a breakdown effect and reduces the thick skin associated with AK. 5% 5-fluorouracil cream has the advantage that it can be applied to large areas and often causes an inflammatory response with crusting. In a study comparing 0.5% 5-fluorouracil combined with 10% salicylic acid with 3% diclofenac in 2.5% hyaluron gel and placebo, complete clearance rates were 55.4%, 32% and 15.1%, respectively, at 8 weeks follow-up after 12 weeks of treatment.
• 3.75% and 5% imiquimod cream: Imiquimod upregulates the expression of pro-inflammatory genes. It also upregulates the pro-apoptotic CD95 receptor that is known to be downregulated in AKs and skin cancers. In studies, 3.75% imiquimod cream was compared to placebo in large treatment areas with clearance rates of 35.6% and 6.3%, respectively, at 8 weeks follow-up after two cycles of 2-week treatment with a 2-week rest period between each cycle. 5% imiquimod cream has been compared with placebo in a study, which showed complete clearance rates of 55% and 2.3%, respectively, at 8-week follow-up after one or two cycles of three times per week over 4 weeks of treatment. Both treatments can cause marked inflammatory reactions which settle within a few weeks.
• Ingenol mebutate gel: The mode of action is not clear but appears to have a dual mechanism of action; rapid cell death and specific antibody-dependent cellular cytotoxicity. In studies, complete clearance rates for the face and scalp with 0.015% ingenol mebutate were 42.2% and 3.7% for placebo and with 0.05% ingenol mebutate for the trunk and extremities, 34.1% and 4.7% for placebo at day 57 after a 3-day treatment period for the face and scalp and a 2-day treatment period for the trunk and extremities.
• Photodynamic therapy: This is a treatment modality involving the administration of photosensitizing compound, which selectively accumulates in the dividing target cells followed by local irradiation with visible light, causing selective damage to target tissue by cell death. 5-aminolaevulinic acid (ALA)-PDT and its methyl ester, MAL-PDT, have been licensed and approved for the treatment of AK. In a study comparing ALA-PDT to placebo-PDT, complete clearance rates were 64% and 11%, respectively. When ALA-PDT was compared to MAL-PDT and placebo-PDT in a study, complete response rates were 78.2%, 64.2% and 17.1%, respectively. MAL-PDT is superior in efficacy, cosmetic outcome and overall patient satisfaction. Whilst MAL-PDT was more expensive it is also more cost-effective than 3% diclofenac in 2.5% hyaluron gel.

Second Line Treatments

Topical retinoids have been used to treat AKs with limited benefit. Oral retinoids (acitretin) have shown some benefit in reducing the number of AK but evidence remains poor. Sequential therapy has been reported to decrease AK when single agents have failed but further work is required to determine which treatments and their order of delivery are best at achieving reduction or clearance.

Third Line Treatments

Dermabrasion and chemical peels with trichloroacetic acid have been widely used in some countries for the treatment of AK and severe photodamage. There is some evidence that this approach may provide more long-term effective prophylaxis against AK. Non-ablative fractional resurfacing has also been reported to reduce AKs and improve skin quality in small studies. A study comparing ablative carbon dioxide laser to cryotherapy in lesion-directed treatment, showed that at 3 months 78.2% and 72.4% of lesions remained clear, respectively. However, at 12 months follow-up of the lesions clear at 3 months, there was a significant difference with 37% of lesions remaining clear in the carbon dioxide arm and 66.8% in the cryotherapy arm. It was concluded that cryotherapy was more effective for thick AK.

Given the potential of AKs to progress to malignant lesions, it is important to focus on the prevention of these precancerous lesions. Educational and preventive efforts should be directed toward children, targeted high-risk populations, and all patients. Avoidance of UV radiation is the single most effective means of decreasing the risk of AKs. A strategy designed to limit the amount and intensity of sun exposure, starting in childhood and continuing throughout the person’s life, will likely decrease the number of AKs an individual will develop. Because complete avoidance of the sun is impractical, the next best preventive measures are to avoid exposure to intense midday sun; consistently apply and reapply broad-spectrum sunscreens; wear UV-protective clothing, hats, and sunglasses; install UV-protective windows where indicated; and make sure to take an oral vitamin D supplement if necessary to avoid vitamin D insufficiency or deficiency.

Numerous studies have shown that the use of sunscreen can decrease the incidence and prevalence of AKs, reduce the number of AK lesions, and increase their rate of regression. There is also evidence that sunscreen use can prevent certain types of skin cancer. There is limited evidence that adhering to a diet low in fat may decrease the incidence of AKs.

Unlike the controversy with topical retinoids, there is strong evidence for the use of systemic retinoids in preventing AKs, especially in high risk populations, such as organ transplant recipients, patients with xeroderma pigmentosum, and other chronically immunosuppressed patients. Unfortunately, the systemic retinoids are only effective while the patient is taking them and their use is also limited by the frequent occurrence of systemic toxicities, including hypercholesterolemia, hypertriglyceridemia, mucocutaneous xerosis, musculoskeletal abnormalities, and alteration in liver function. Thus, when considering the use of systemic retinoids in such high-risk patients, one must weigh these risks and benefits.

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