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Actinic Keratoses

J. M. Spencer, MD, MS
Private Practice, St. Petersburg, FL

Actinic Keratosis

The actinic keratosis (AK) is a common lesion induced by ultraviolet light that represents the earliest manifestation of squamous cell carcinoma (SCC) of the skin.

The name means sun-induced (actinic) scaly, thickened growth of the skin (keratosis).

  • It is seen almost exclusively in Caucasians due to their fair skin and sun sensitivity.
  • The incidence increases closer to the equator and correlates with outdoor occupation.
  • It is typically seen on chronically sun-exposed parts of the body, i.e., the face, the scalp of bald men, the back of the hands, and the forearms.
  • It can arise in other parts of the body, if those areas receive significant sun exposure.
  • It has been described as a “precancer” but molecular and histologic features suggest it exists in a continuum with invasive SCC.
  • It has recently been proposed that AK be renamed to KIN, or keratinocytic intraepithelial neoplasia.

There is a roughly linear relationship with sun exposure and the development of AKs throughout life, as opposed to the development of melanoma, which correlates with recreational sun exposure prior to the age of 20. A small percentage of AKs can and do progress to become invasive SCC, although the fate of any one lesion is impossible to predict.

Histology

  • AKs are characterized by partial thickness dysplasia of the epidermis.
  • Cellular atypia is present, and mitotic figures may be seen upwards from the basal layer.
  • Lesions are the same as those seen in SCC, differing only in the degree to which they are present:
    -  AK: changes occupy only part of the epidermis and do not extend down hair follicles.
    -  SCC: in situ is characterized by full-thickness involvement of the epidermis and extension down hair follicles. Invasive SCC penetrates the basement membrane and invades the dermis.

Clinical Presentation

  • The AK begins as a small rough spot on sun-exposed skin; better felt than seen.
  • Over time, the lesions become larger and more visible, most often as scaly pink macules.
  • Most lesions are a few millimeters in diameter, but some can reach >2cm in diameter.
  • Variants include pigmented (brown) lesions, and lesions where the hyperkeratosis is so pronounced that a hornlike projection arises from the skin.
  • Multiple AKs may develop within a given anatomic area or cosmetic unit (e.g., cheek, forehead).
  • As the lesions enlarge, they may collide and become confluent.

An AK may follow one of three paths:

  • It may remain unchanged.
  • It may spontaneously resolve.
  • It may progress to an invasive SCC.

The estimated frequency of conversion is estimated to range from as low as 0.1% to as high as 10%–16%. While the exact progression rate is uncertain, it is clear that the rate is not zero. Eradication of lesions to prevent invasive SCC seems justified.

Treatment

Treatment may be broadly divided into destructive and medical:

  • Destructive therapies use a physical modality to kill the AK cells, hopefully limiting damage to the surrounding normal skin. Also referred to as “lesion-directed” therapy.
  • Medical therapies use a pharmacologic approach to destroy the AK cells and identify and treat subclinical lesions in the surrounding skin. Also referred to as a “field-directed” therapy.

Destructive Therapies

For >90% of treated AKs, destructive therapy is used, which is most often cryosurgery with liquid nitrogen.

  • Liquid nitrogen is -195.8oC and may be directly applied to the skin.
  • Once the skin temperature is lowered to around -40oC the keratinocytes of the epidermis (and the AK) will die.
  • The dermis, including collagen, blood vessels, and nerves, is relatively resistant to cold.
  • Melanocytes are sensitive to cold, so cryosurgery tends to often leave permanent white spots.

Other destructive methods include curettage and shave scalpel excision. As these methods may cause scarring they are generally used only when specimens are needed for histological examination to rule out SCC.

Medical Therapies

  • Include topical creams and lotions that can treat large areas.
  • Indicated for patients with many lesions.
  • Can also treat subclinical lesions, i.e., early lesions too small to clinically detect.
  • Weeks to months of treatment are usually required.
  • Can produce significant, though temporary, inflammation and discomfort.

There are currently four topical medications used for the treatment of AKs:

  • 5-fluorouracil (Efudex®, Fluoroplex® and Carac®)
    - Used for almost 4 decades with great success.
    - Associated with inflammation and discomfort that resolves once treatment is finished.
    - Available formulations include a 5% cream or solution, a 2% solution, a 1% cream or solution, and a micronized 0.5% cream.
    - The various concentrations seem to be equally effective.

  • Imiquimod cream (AldaraTM)
    - Is an immunomodulator, nonantimetabolite, chemotherapeutic agent.
    - Enhances a local immune response by upregulating a variety of cytokines.
    - Induces a non-specific immune response via the interferons and natural killer cells, and a specific immune response via T cells.

  • Diclofenac gel (SolarazeTM)
    - Is a nonsteroidal anti-inflammatory drug (NSAID) that eliminates AKs in an unknown way.
    - Produces less inflammation than other agents listed.
    - Requires a rather lengthy 3-month course of therapy.

  • Delta amino levulinic acid solution (Levulan® Kerastick®) followed by activation with visible light (photodynamic therapy)
    - May be performed with a solution of delta amino levulinic acid (ALA).
    • An intermediary in the heme biosynthetic pathway
    • Accumulates in the dysplastic cells of the AK following topical application
    • Inside keratinocytes converts to protoporphyrin IX, a potent photosensitizer.
    - After topical application, this conversion is allowed to take place over one to many hours, then the protoporphyrin IX is activated by exposure to visible light.
    - Generates reactive oxygen species and, ultimately, selective dysplastic cell death.
    - One or two such treatments are highly effective.
    - Produces a sunburn-like reaction lasting from a few days to > 2 weeks.

Conclusion

Actinic keratoses are a common, and easily treated, precursor to an invasive SCC. Destructive therapies are appropriate for a few lesions, while a medical approach is reserved for patients with many lesions.

Editor’s Comment

AKs are actually quite controversial in the dermatological world. Some authorities feel that AKs are best considered “premalignant” and clearly distinguishable from frank SCC.1 Other authors suggest that there is a reproducibly gradable clinicopathologic continuum between AKs and SCCs.2 Yet other influential dermatologists firmly believe that AKs are already true SCCs.3 The point of this ongoing debate is whether aggressive field-directed intervention is justified, conservative lesion-directed therapy is optimal, or treatment for AKs is even necessary at all. Although AK eradication is certainly an accepted standard of care, some have questioned, on pharmacoeconomic grounds, whether destroying the millions upon millions of incident AKs per year really prevents substantial morbidity and/or mortality.4

As Spencer points out in this synopsis, the practitioner can never predict which, if any, AK lesions will eventuate into an SCC with metastatic potential. Thus, clinical management dictates lesion ablation to avoid the worstcase scenario. However, the expectations of patients in the “baby-boom” generation are much different from those or prior generations, in that they expect such ablation to be carried out with rapid wound healing and minimal cosmetic alteration.5 Hypopigmentation and/or scarring, which may accompany lesion-directed therapy (especially cryosurgery), is best avoided by utilizing one of the field-directed modalities. Unfortunately, field-directed therapies take longer to accomplish, require several to multiple office visits for monitoring purposes, carry a larger economic burden, and may be associated with relatively severe inflammation. Thus, all AK treatment options possess both advantages and limitations.

The best approach is a pragmatic one. The patient with few AK lesions is most conveniently and cost effectively treated with a destructive technique (cryosurgery or curettage with light desiccation). Those with many AKs are candidates for medical therapy (such as 5-fluorouracil, imiquimod or diclofenac).6

Emerging therapies beyond the scope of this synopsis, but worth watching for, include total laser resurfacing and chemoprevention with systemically administered NSAIDs.7,8

References

  1. Davis DA, Donahue JP, Bost JE, Horn TD. The diagnostic concordance of actinic keratosis and squamous cell carcinoma. J Cut Pathol 2005;32:546-51
  2. Cockerell CJ, Wharton JR. New histopathological classification of actinic kerasis (incipient intraepidermal squamous cell carcinoma) J Drugs Dermatol 2005;4:462-67
  3. Ackerman AB, Mones JM. Solar (actinic) keratosis is squamous cell carcinoma. Br J Dermatol 2006;155:9-22
  4. Higashi MK, Veenstra DL, Langley PC. Health economic evaluation of non-melanoma skin cancer and actinic keratosis. Pharmacoeconomics 2004;22:83-94
  5. Spencer JM, Hazan C, Hsiung SH, Robins P. Therapeutic decision making in the therapy of actinic keratoses. J Drugs Dermatol 2005;4:296-301
  6. Wheeland RG. The pitfalls of treating all actinic keratoses as squamous cell carcinomas. Semin Cutan Med Surg 2005;24:152-54
  7. Ostertag JU, Quaedvlieg PJ, Neumann MH, Krekels GA. Recurrence rates and long-term follow-up after laser resurfacing as a treatment for widespread actinic keratoses on the face and scalp. Dermatol Surg 2006;32:261-67
  8. Butler GJ, Neale R, Green AC, Pandeva N, Whiteman DC. Nonsteroidal anti-inflammatory drugs and the risk of actinic keratoses and squamous cell cancers of the skin. J Am Acad Dermatol 2005;53:966-72

  1. Welcome to Skin Therapy Letter® US Family Practice Edition
  2. Topical Acne Treatment
  3. A Summary of Approved Topical Treatments for Rosacea
  4. Actinic Keratoses