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J. M. Spencer, MD, MS
Private Practice, St. Petersburg, FL
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.
- 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.
- 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
Treatment may be broadly divided into destructive and
- 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.
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.
- 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,
- 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
- May be performed with a solution of delta amino
levulinic acid (ALA).
- 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.
- 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.
- 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.
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.
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
Emerging therapies beyond the scope of this synopsis,
but worth watching for, include total laser resurfacing and
chemoprevention with systemically administered NSAIDs.7,8
- 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
- Cockerell CJ, Wharton JR. New histopathological classification of actinic kerasis (incipient intraepidermal squamous cell carcinoma) J Drugs Dermatol 2005;4:462-67
- Ackerman AB, Mones JM. Solar (actinic) keratosis is squamous cell carcinoma. Br J Dermatol 2006;155:9-22
- Higashi MK, Veenstra DL, Langley PC. Health economic evaluation of non-melanoma skin cancer and actinic keratosis. Pharmacoeconomics 2004;22:83-94
- Spencer JM, Hazan C, Hsiung SH, Robins P. Therapeutic decision making in the therapy of actinic keratoses. J Drugs Dermatol 2005;4:296-301
- Wheeland RG. The pitfalls of treating all actinic keratoses as squamous cell carcinomas. Semin Cutan Med Surg 2005;24:152-54
- 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
- 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