FEATURE ARTICLE
2.0
Actinic Keratosis
A Review of Therapeutic Options
Joshua M. Berlin
ABSTRACT: Actinic keratoses are some of the most widely
encountered lesions in dermatology practices. They rep-
resent the second most common reason for patients to
visit a dermatologist. There are many different approaches
available to treat actinic keratoses, and the dermatology
nurse plays a pivotal part in educating patients about their
choices. The purpose of this article is to review how these
different treatments work and to address potential ad-
vantages and disadvantages of each.
Key words: Actinic Keratosis, Squamous Cell Carcinoma,
5-Fluorouracil, Ingenol Mebutate, Cryotherapy, Photo-
dynamic Therapy
I n most dermatology practices, patients present with
precancerous actinic keratosis on a daily basis. The
dermatology nurse plays an important role in help-
ing to explain to patients the various treatment op-
tions available. This article will review the mechanism
of action as well as some of the comparative advantages and
disadvantages associated with these treatments.
DESTRUCTIVE MEASURES
Cryotherapy with the use of liquid nitrogen is one of the
most common methods of treatment for actinic kerato-
ses. Liquid nitrogen can be applied either via a cryospray,
cryoprobe, or cotton tip. When liquid nitrogen makes con-
tact with the skin, the temperature of the treated area is
lowered to j50-C. The mechanism of action involves
direct cellular freezing as well as vascular stasis occurring
after thawing. The duration of freezing time for actinic
keratosis is dependent on the morphology of the partic-
Joshua M. Berlin, MD, Dermatology Associates PA of the Palm
Beaches, Boynton Beach, FL.
The author declares no conflicts of interest.
Correspondence concerning this article should be addressed to
Joshua M. Berlin, MD, Dermatology Associates PA of the Palm Beaches,
10301 Hagen Ranch Rd., Ste. D-930, Boynton Beach, FL, 33437.
E-mail: joshberlin@hotmail.com
DOI: 10.1097/JDN.0000000000000015
VOLUME 6 | NUMBER 1 | JANUARY/FEBRUARY 2014
Copyright © 2014 Dermatology Nurses' Association. Unauthorized reproduction of this article is prohibited.
Contact
Hours
ular lesion with thicker hyperkeratotic lesions requiring
up to 30 seconds of treatment and thinner lesions being
eradicated after a 5- to 7-second freeze time. Cryotherapy
is extremely effective with cure rates of up to 98% being
achieved (Lubritz & Smolewski, 1982). It is important to
advise patients that they will likely feel mild pain while
the procedure is performed and will be left with erythema,
crust formation, and even blister formation in some in-
stances. A potential long-term sequelae is hypopigmenta-
tion of the skin, which can be especially prevalent in darker
complected individuals. An important limitation of cryo-
surgery to convey to patients is that it only treats discrete
lesion and not subclinical actinic keratosis, which can be
found in wide photodamaged areas. Less common destruc-
tive measures to treat actinic keratoses include curettage,
medium-depth chemical peels with 35% trichloroacetic acid
and Jessner’s solution, and ablative lasers such as the car-
bon dioxide and erbium:yttrium-aluminum-garnet laser.
CHEMOTHERAPEUTIC MEASURES
In contrast to cryotherapy, topical therapies have the ad-
vantage of not only treating individual lesions but also
treating the subclinical areas of sun-damaged skin that are
not yet apparent. A hallmark of topical treatment for actinic
keratoses for the past 50 years has been 5-fluorouracil
(5-FU). The mechanism of action involves its ability to
interfere with the synthesis of nucleic acids through its
metabolite, 5-fluorodeoxyuridylic acid, which inhibits
thymidylate synthase (Menter, Vamvakias, & Jorizzo,
2008). This inhibition is significant as thymidylate syn-
thase catalyzes conversion of deoxyuridine 5-monophosphate
to the deoxyribonucleic acid (DNA) compound thy-
midine 5-monophosphate (Eaglestein, Weinstein, &
Frost, 1970). By interfering with DNA synthesis, 5-FU
clears actinic keratoses as these lesions have neoplastic
keratinocytes that have a higher rate of DNA synthesis
than normal skin. Another proposed mechanism of ac-
tion involves the incorporation of fluorouracil into ribo-
nucleic acid, which interferes with ribonucleic acid synthesis
(Eaglestein et al., 1970).
11
 There are a variety of regimens employed by derma-
tologists to use 5-FU in the management of actinic ker-
atoses. One of the most commonly used methods is
continuous once- or twice-daily application over a period
of 2Y3 weeks. The efficacy associated with 5-FU has been
reported up to 75% (Kurwa, Yong-Gee, Seed, Markey, &
Barlow, 1999). Major limitations associated with this treat-
ment are complaints of erythema, pruritus, and pain. These
troublesome adverse events often result in premature dis-
continuation of the product or noncompliance, which affects
efficacy of clearance. In addition, crusting and scabbing of
the skin can occur in the immediate posttreatment period
adversely affecting the patient’s cosmetic appearance. The
resulting noncompliance stresses the importance of der-
matological nursing education at the time of prescribing
the product, either through verbal explanation, photo-
graphs of patients during treatment and posttreatment, or
written handouts for patients to review and decide if the
treatment is appropriate for their lifestyle.
IMIQUIMOD
Imiquimod 5% cream was initially approved by the U.S.
Food and Drug Administration in 1997 for the treatment
of external genital and perianal human papillomavirus
infection (Berlin, 2010). It subsequently gained approval
for the treatment of nonhyperkeratotic, nonhypertrophic
actinic keratoses in 2004. The finding of human papillo-
mavirus DNA in 60.4% of actinic keratoses versus 4.7%
in controls in a study by Iftner et al. helps explain its ef-
fectiveness in both of these disease states (Iftner et al.,
2003). In addition, imiquimod activates innate immune
cells through the toll-like receptor 7 pathway, which in-
creases cytokine production (Gaspari, 2007). When applied,
imiquimod functions as an immunomodulator. Specifically,
lesional levels of interferon alpha, beta, and gamma are
increased along with lesional levels of tumor necrosis fac-
tor alpha. These and other cytokines activate natural killer
and cytotoxic T-cells resulting in a localized immune re-
sponse against the target cells (Weinberg, 2006). Although
imiquimod 5% cream has shown a median reduction in
precancerous lesions as high as 86% compared with base-
line, it is accompanied with adverse events such as scab-
bing, erythema, and flaking in as many as 73% of patients
(Korman et al., 2005). Given these high rates of side ef-
fects, a study was performed to examine the efficacy at a
lower strength of 3.75% in an attempt to mitigate ad-
verse events in patients (Swanson et al., 2010). In this
study, patients were treated with a once-daily application
cyclically for 2 weeks followed by a 2-week period of
rest and concluded with an additional 2-week treatment
period. The results found comparable efficacy with an
81.8% median reduction in lesion count with a lower de-
gree of adverse events. This cyclical regimen is presently
how it is most commonly prescribed under the brand
name of Zyclara cream (Valeant Pharmaceuticals). In choos-
ing this type of therapy, it is important to ensure the 6-week
12
Copyright © 2014 Dermatology Nurses' Association. Unauthorized reproduction of this article is prohibited.
cycle is compatible with a patient’s lifestyle. As mentioned
above, erythema, edema, crusting, and scabbing are com-
mon side effects of topical apy. As with most topical
medications, it is important that the patient be instructed
in proper application techniques to ensure proper use and
decrease the likelihood of adverse events. The dermatology
nurse should be proficient in relaying the expected and
adverse effect of using this modality. In addition to the
local cutaneous side effects, the nurse should also inform
the patient that topical imiquimod therapy has also been
associated with generalized flu-like symptoms including
malaise, fever, and headache.
DICLOFENAC SODIUM
Diclofenac sodium available commercially as Solaraze Gel
is a nonsteroidal anti-inflammatory agent whose mecha-
nism of action involves its ability to inhibit cyclooxygenase
(COX)-2 (Merk, 2007). The COX-2 enzyme is oversyn-
thesized in actinic keratoses and catalyzes the synthesis of
prostaglandins. The resulting inhibition of COX-2 decreases
the byproducts of arachidonic acid and thereby hinders
tumor angiogenesis (Weinberg, 2006). An initial study by
Rivers and McLean assessed the efficacy of diclofenac
sodium in hyaluronic acid in a study of 27 patients (Rivers
& McLean, 1997). This study showed compelling results
with a complete response found in 81% of patients at 1
month. Because of these findings, a larger randomized,
double-blind placebo-controlled study was undertaken
by Wolf et al. In this study, 96 patients with at least five
discrete actinic keratoses located on the face, scalp, arms,
or hands were treated with either the inactive gel vehicle,
hyaluronic acid, or diclofenac sodium in hyaluronic acid
twice daily for 90 days (Wolf, Taylor, Tschen, & Kang,
2001). The authors found that 79% of patients reported
complete or partial clearance of actinic keratoses in patients
receiving diclofenac sodium in hylaruronic acid. The med-
ication is reasonably well tolerated with less erythema and
crusting noted than with other topical medications. A sub-
sequent study investigated the use of diclofenac sodium in
hyaluronic acid to treat actinic keratoses after cryosurgery
(Berlin & Rigel, 2008). The purpose of this study was to
see if sequential therapy led to a higher overall cure rate
than that seen with each individual therapy. The authors
concluded that a synergistic effect occurred with the com-
bination of cryotherapy followed by diclofenac sodium in
hyaluronic acid as the mean number of target lesions re-
duced from 8.9 to 1.1. A postulated reason for the synergy
between these two treatment regimens is that both clin-
ically apparent actinic keratoses as well as subclinical lesions
can be treated. An important drawback about this therapy
to discuss with patients is the twice-a-day dosing regimen
over 2 months.
Compared with many of the other topical treatments
for actinic keratoses, topical diclofenac sodium has a
rather mild initial cutaneous response. For this reason,
it is important for the dermatology nurse to be able to
Journal of the Dermatology Nurses’ Association
educate the patient on the expected treatment course.
This is especially important in patients who may have
used 5-FU in the past and are expecting a similar reac-
tion. These patients are more likely to discontinue ther-
apy prematurely because they do not think that the medicine
is working. It is often just as important for the nurse to tell
the patient what not to expect as it is to tell the patient
what to expect.
INGENOL MEBUTATE
One of the most recent treatments available to treat actinic
keratoses is ingenol mebutate available commercially as
Picato gel. This new treatment is purified and extracted
from the sap of the plant Euphorbia peplus, and its mech-
anism of action involves its ability to cause cellular ne-
crosis through disruption of the plasma membrane and
mitochondria (Ogbourne et al., 2004). In addition, ingenol
mebutate stimulates neutrophil-mediated and antibody-
dependent cellular cytotoxicity to eradicate any residual
diseased cells (Challacombe et al., 2006).
A recent study examined the 12-month recurrence rates
associated with patients treated with ingenol mebutate gel
0.015% daily for 3 consecutive days for actinic keratoses
on the face or scalp and ingenol mebutate gel 0.05% daily
for 2 consecutive days for actinic keratoses on the trunk or
extremities (Lebwohl et al., 2013). The authors found that
sustained lesion reduction rates compared with baseline
were 87.2% for the face or scalp and 86.8% for the trunk
or extremities.
The convenient once-daily dosing for 2 days for the
trunk and extremities and 3 days for the face and scalp
makes this therapeutic agent a favorite of many patients.
With ingenol mebutate, patient education and instruc-
tion is especially important. Currently, ingenol mebutate
is approved to treat an area of 5.0 cm  5.0 cm. The me-
dication is dispensed in two or three single-use tubes, de-
pending on the area to be treated as described above. The
dermatology nurse must be able to educate the patient on
the importance of using the entire contents of the tube, but
only in the assigned treatment field. The patient who at-
tempts to treat an entire scalp or arm will likely end up
with an inadequate therapeutic effect. Ingenol mebutate,
like most of the other topical treatments for actinic ker-
atoses, is associated with significant erythema, edema,
crusting, and scabbing. Again, patient education is the key
to maximizing the patient’s therapeutic response while
minimizing any adverse events.
PHOTODYNAMIC THERAPY (PDT)
The use of topical 5-aminolevulinic acid (5-ALA) in com-
bination with either blue light (400Y450 nm) or red light
(640 nm) has become an increasingly popular choice for
patients and physicians alike in the treatment of actinic
keratoses. It was initially approved by the U.S. Food and
Drug Administration for the treatment of nonhyperkeratotic
actinic keratoses in 2000 (Gold, 2008; Zheng, 2005). After
VOLUME 6 | NUMBER 1 | JANUARY/FEBRUARY 2014
Copyright © 2014 Dermatology Nurses' Association. Unauthorized reproduction of this article is prohibited.
application, 5-ALA penetrates the stratum corneum and is
absorbed by actinic keratoses, pilosebaceous units, and
nonmelanoma skin cancer cells (Gold, 2008). Once the
prodrug 5-ALA is absorbed, it is converted into its active
drug, protoporphyrin IX, which can be detected in the
epidermis 4 hours after application (Peng et al., 1997).
The active drug can then peakly absorb with exposure to
either blue light, known as the Soret band, or red light
(Tschen, et al., 2006). Once activated, reactive oxygen inter-
mediates such as singlet oxygen are created that result in
apoptosis and vascular endothelial damage (Kennedy, Pottier,
& Pross, 1990). Studies have shown lesion cure rates ranging
from 70% to 90% (Jeffes et al., 1997). In general, the face
and scalp respond better than the trunk and extremities with
thinner actinic keratoses showing improved clinical outcomes
compared with thicker, hyperkeratotic lesions (Jeffes et al.,
2001). Three majors factors affecting the efficacy of PDT
are light fluence, tissue oxygen tension, and thickness of
the stratum corneum (Silapunt, Goldberg, & Alam, 2008).
A study by Robertson and Rees in 2010 showed signif-
icant variations in the thickness of the stratum corneum
layers of the face and forearm, 6.3 and 10.9 micrometers,
respectively. The thicker stratum corneum of areas on the
arms and trunk may inhibit the penetration of ALA further
into the epidermis and attenuate its therapeutic efficacy.
Before starting a patient on PDT, it is important to ex-
clude patients with a history of hepatic diseases, photo-
sensitivity disorders, or porphyria as well as elucidating
any prior history of herpes simplex virus. In patients with
a history of herpes simplex virus flaring with ultraviolet
light exposure, prophylactic antiviral therapy should be
initiated before therapy.
Before initiating PDT, it is important to document the
lesions being treated, and preoperative photography can
be useful to assess the final result. Although the technique
was initially approved with application of the photosen-
sitizer 14Y18 hours before exposure to the light source,
most practitioners apply the 5-ALA 1Y3 hours before
irradiation to reduce the associated pain experienced by
patients. In addition, most patients note feelings of warmth
or a burning sensation when exposed to the light source
that can be mitigated with fans and use of ice packs. At the
conclusion of treatment, the irradiated area will appear
edematous and erythematous. Although the pain level is
dramatically decreased when the light source is turned off,
some patients may require postoperative pain control with
the use of nonsteroidal anti-inflammatory agents or
acetaminophen. The phototoxic effects of PDT, including
pain, burning, itching, crusting, erythema, and blisters, are
considered normal and desired effects of the therapy. These
effects may take several weeks to fully resolve, but pain
medication is only typically needed for 7Y10 days after
procedure. Postprocedure sun and/or light exposure can make
these effects considerably worse. Therefore, it is imperative that
the dermatological nurse stress the importance of avoiding
sun exposure and exposure to strong artificial light sources
13
for at least 48 hours after treatment. As total sun or light
avoidance may be impractical for many patients, it is
important to instruct the patient on the proper use of
sunscreens (i.e., sun protection factor 30 or higher with
ultraviolet A and B protection, reapply every 2 hours) and
of photo protective clothing options. The patient should
also be told that it may take several weeks for the treated
lesions to heal entirely.
CONCLUSION
Actinic keratoses are a common problem encountered in
dermatology practice across the world every day. Al-
though the physician has the ultimate responsibility of
determining the treatment modality most appropriate for
an individual patient, the success of the treatment often
depends as much on patient instruction and education as
on product selection. The dermatology nurse’s ability to
convey the proper application instructions and techniques
and the planned course of treatment and explain and dif-
ferentiate between expected and unexpected side effects is
invaluable to a successful outcome. h toses. International Journal of Dermatology, 46, 12Y18.
REFERENCES
Berlin, J. M. (2010). Current and emerging treatment strategies for the
treatment of actinic keratoses. Clinical, Cosmetic and Investigational
Dermatology, 3, 119Y126.
Berlin, J. M., & Rigel, D. S. (2008). Diclofenac sodium 3% gel in the treatment
of actinic keratoses post cryosurgery. Journal of Drugs in Dermatology, 7,
669Y673.
Challacombe, J. M., Suhbier, A., Parsons, P. G., Jones, B., Hampson, P.,
Kavanagh, D., I Ogbourne, S. M. (2006). Neutrophils are a key
component of the antitumor efficacy of topical chemotherapy with
ingenol-3-angelate. Journal of Immunology, 177, 8123Y8132.
Eaglestein, W. H., Weinstein, G. D., & Frost P. (1970). Fluorouracil:
Mechanism of action in human skin and actinic keratoses. Effect on
DNA synthesis in vivo. Archives of Dermatology, 101, 132Y139.
Ericson, M. B., Sandberg, C., Stenquist, B., Gudmundson, F., Karlsson, M.,
Ros, A. M., I Rosdahl, I. (2004). Photodynamic therapy of actinic
keratosis at varying fluence rates: Assessment of photobleaching, pain
and primary clinical outcome. British Journal of Dermatology, 151,
1204Y1212.
Gaspari, A. A. (2007). Mechanism of action and other potential roles of an
immune response modifier. Cutis, 79, S36YS45.
Gold, M. H. (2008). Photodynamic therapy: Indications and treatment.
Aesthetic Surgery Journal, 28(5), 545Y552.
Iftner, A., Klug, S. J., Garbe, C., Blum, A., Stancu, A., Wilczynski, S. P.,
& Iftner, T. (2003). The prevalence of human papillomavirus
genotypes in nonmelanoma skin cancers of nonimmunosuppressed
individuals identifies high-risk genital types as possible risk factors.
Cancer Research, 63(21), 7515Y7519.
Jeffes, E. W., McCullough, J. L., Weinstein, G. D., Fergin, P. E., Nelson, J. S.,
Shull, T. F., I Fong, N. L. (1997). Photodynamic therapy of actinic
For more than 22 additional continuing education articles related to dermatology, go to NursingCenter.com\CE.
14
Copyright © 2014 Dermatology Nurses' Association. Unauthorized reproduction of this article is prohibited.
keratosis with topical 5-aminolevulinic acid. A pilot dose-ranging study.
Archives of Dermatology, 133, 727Y732.
Jeffes, E. W., McCullough, J. L., & Weinstein, G. D. (2001). Exploring a new
option in topical AK therapy. Skin Aging, 2, 4Y7.
Kennedy, J. C., Pottier, R. H., & Pross, D. C. (1990). Photodynamic therapy
with endogenous protoporphyrin IX: Basic principles and present
clinical experience. Journal of Photochemistry and Photobiology, 6,
143Y148.
Korman, N., Moy, R., Ling, M., Matheson, R., Smith, S., McKane, S., &
Lee, J. H. (2005). Dosing with 5% imiquimod cream 3 times per week
for the treatment of actinic keratosis: Results of two phase 3,
randomized, double-blind, parallel-group, vehicle-controlled trials.
Archives of Dermatology, 141, 467Y473.
Kurwa, H. A., Yong-Gee, S. A., Seed, P. T., Markey, A. C., & Barlow, R. J.
(1999). A randomized paired comparison of photodynamic therapy and
topical 5-fluorouracil in the treatment of actinic keratoses. Journal of the
American Academy of Dermatology, 41, 414Y418.
Lebwohl, M., Shumack, S., Stein Gold, L., Meigaard, A., Larsson, T., &
Tyring, S. K. (2013). Long-term follow-up study of ingenol mebutate gel
for the treatment of actinic keratoses. Journal of the American Medical
Association Dermatology, 149(6), 666Y670.
Lubritz, R. R., & Smolewski, S. A. (1982). Cryosurgery cure rate of actinic
keratoses. Journal of the American Academy of Dermatology, 7(5),
631Y632.
Menter, A., Vamvakias, G., & Jorizzo, J. (2008). One-week treatment with
once-daily fluorouracil cream 0.5% cream in participants with actinic
keratoses. Cutis, 81, 509Y516.
Merk, H. F. (2007). Topical diclofenac in the treatment of actinic kera-
Ogbourne, S. M., Suhbier, A., Jones, B., Cozzi, S. J., Boyle, G. M., Morris, M.,
I Parsons, P. G. (2004). Antitumor activity of 3-ingenyl angelate: Plasma
membrane and mitochondrial disruption and necrotic cell death. Cancer
Research, 64, 2833Y2839.
Peng, Q., Warloe, T., Berg, K., Moan, J., Kongshaug, M., Giercksky, K. E.,
& Nesland, J. M. (1997). 5-Aminolevulinic acid-based photodynamic
therapy-clinical research and future challenges. Cancer, 79,
2282Y2308.
Rivers, J. K., & McLean, D. I. (1997). An open study to assess the efficacy and
safety of topical 3% diclofenac in a 2.5% hyaluronic acid gel for the
treatment of actinic keratoses. Archives of Dermatology, 133, 1239Y1242.
Silapunt, S., Goldberg, L. H., & Alam, M. (2003). Topical and light-based
treatments for actinic keratoses. Seminars in Cutaneous Medicine and
Surgery, 22, 162Y170.
Swanson, N., Abramovits, W., Berman, B., Kulp, J., Rigel, D. S., & Levy, S.
(2010). Imiquimod 2.5% and 3.75% for the treatment of actinic
keratoses: Results of two placebo-controlled studies of daily application
to the face and balding scalp for two 2-week cycles. Journal of the
American Academy of Dermatology, 62(4), 582Y590.
Tschen, E. H., Wong, D. S., Pariser, D. M., Dunlap, F. E., Houlihan, A.,
& Ferdon, M. B.; Phase IV ALA-PDT Actinic Keratosis Study Group.
(2006). Photodynamic therapy using aminotaevulinic acid for patients
with nonhyperkeratotic actinic keratoses of the face and scalp: Phase
IV multicentre clinical trial with 12-month follow up. British Journal
of Dermatology, 155, 1262Y1269.
Weinberg, J. M. (2006). Topical therapy for actinic keratoses: Current and
evolving therapies. Revenue Recognition on Clinical Trials, 1, 53Y60.
Wolf, J. E., Jr. Taylor, J. R., Tschen, E., & Kang, S. (2001). Topical
3.0% diclofenac in 2.5% hyaluronan gel in the treatment of actinic
keratoses. International Journal of Dermatology, 40, 709Y713.
Zheng, H. (2005). A review of progress in clinical photodynamic therapy.
Technology in Cancer Research and Treatment, 4(3), 283Y293.
Journal of the Dermatology Nurses’ Association