Clinical Oral Investigations

https://doi.org/10.1007/s00784-019-02895-z

REVIEW

Treatment of actinic cheilitis: a systematic review

Arthur Pias Salgueiro 1 & Luciano Henrique de Jesus 1 & Isadora Follak de Souza 1 & Pantelis Varvaki Rados 1 &
Fernanda Visioli 1

Received: 27 August 2018 / Accepted: 3 April 2019

# Springer-Verlag GmbH Germany, part of Springer Nature 2019

Abstract
Objectives Actinic cheilitis is a potentially malignant disorder caused by excessive sun exposure. It affects the lower lip of
individuals, mostly those with light skin color. Different treatments have been proposed for AC; however, no consensus has been
reached on the best option available.
Materials and methods The present study describes the results of a computer-based systematic search conducted on electronic
databases to identify the best therapies.
Results A total of 29 journal articles were selected, and the results were divided according to the type of treatment employed:
laser therapy, chemotherapy agents, surgical treatment, and application of anti-inflammatory agents. Clinically, photodynamic
therapy showed positive results, with improvement in up to 100% of the patients; however, histopathological improvement varied
greatly, from 16 to 100%. Among the chemotherapeutic agents assessed, imiquimod showed the best results: clinical improve-
ment in 80 to 100% of the patients, and histopathological improvement in 73 to 100%. Regarding studies describing surgical
approaches, the main focus was the search for the best technique, rather than the cure of AC. Finally, studies employing anti-
inflammatory agents are sparse and have small samples, thus providing limited results.
Conclusion The scientific evidence available on the treatment of AC is scarce and heterogeneous, photodynamic therapy, and
imiquimod application are promising.
Clinical relevance The study of the treatments for AC in the form of a systematic review allows us to evaluate the results against
the different treatments. Being a potentially malignant lesion, it is important to seek evidence about the best results found.

Keywords Actinic cheilitis . Imiquimod . Vermilionectomy . Laser . Systematic review

Introduction

Actinic cheilitis (AC) is a potentially malignant disorder that

affects the lips of individuals who are excessively exposed to
sunlight. Ultraviolet radiation can cause DNA mutations and
* Fernanda Visioli thus induce the onset of lip cancer [1, 2]. In this sense, AC is
fernanda.visioli@ufrgs.br considered to be the labial counterpart of actinic keratosis
(AK), a lesion that affects the skin and serves as a prognostic
Arthur Pias Salgueiro
arthurpsalgueiro@gmail.com marker of increased risk for non-melanoma skin cancer [2].
AC is more frequently observed in male patients aged 40 to
Luciano Henrique de Jesus
drlhjesus@gmail.com
80 years, and almost exclusively affects the vermilion of the
lower lip of individuals who work outdoors or have the habit
Isadora Follak de Souza of spending long periods of time exposed to sunlight [3]. Most
isa.follak@gmail.com
patients have fair skin and sunburn easily [1, 2]. A higher
Pantelis Varvaki Rados prevalence of AC is also observed in people with low-
pantelis@ufrgs.br
schooling levels and poor life conditions [4].
1 Initially, AC presents as a dry, cracked lip, and with no
Oral Pathology Department, Universidade Federal do Rio Grande do
Sul, Ramiro Barcelos 2492, Room 503, Porto Alegre, RS 90035-003, associated pain. The lesion develops slowly, and therefore it
Brazil is often erroneously seen as a common characteristic of aging,

hindering diagnosis [1, 3]. As the condition evolves, the ver-
milion of the lower lip becomes severely dry, with areas show-
ing deep lines and an exfoliative aspect. The lip may become
whitish or present spots, keratotic plaques may form, the de-
marcation between the vermilion zone and the adjacent skin
may become blurred or disappear, and in some cases, ulcers
may develop [3, 5]. Histologically, AC epithelium is charac-
terized by the presence of hyperkeratosis or
hyperparakeratosis, and it may be atrophic or acanthotic,
showing different degrees of dysplasia. The connective tissue
underlying the epithelium shows an amorphous, basophilic
cell layer, called solar elastosis, characterized by collagen
and fiber alterations caused by ultraviolet light [1].
Some treatment modalities have been described for AC
[5–7]. Vermilionectomy is the surgical method most common-
ly employed. It consists of the total removal of the affected lip
and may vary with regard to the thickness of the tissue to be
removed. However, this technique is aggressive and may lead
to several complications [6, 7]. Topical use of chemotherapeu-
tic agents is another possibility, more commonly used in the
treatment of actinic keratosis of the skin. A more recent treat-
ment modality is photodynamic therapy (PDT), which con-
sists of the use of a light source and a photosensitizer that is
activated to produce oxygen-free radicals that destabilize cell
membranes and organelles, inducing cell death [8]. Finally,
some anti-inflammatory agents have been used topically as
another treatment approach.
Despite the different treatment modalities available, there is
no consensus in the literature on the best treatment option for
AC—surgical treatments have several adverse effects, and the
effectiveness of less invasive options is questionable.
Therefore, the objective of this study was to perform a sys-
tematic review of the literature to identify the most effective
treatment option for AC, as well as to evaluate, among the
therapies available, which performs best in terms of lesion
remission and preservation of the vermilion border, while in-
ducing minimal side effects.
Methods
Search strategy
A computer-based systematic search was conducted in the
following databases: Medline, EMBASE, Cochrane Library,
and Bireme. In all databases, the following keywords were
used: Bcheilitis^[MeSH Terms] OR (BActinic cheilitis^
[Supplementary Concept] OR BActinic cheilitis^[All Fields]
OR Bactinic cheilosis^ [All Fields])) OR (actinic [All Fields]
OR queilitis [All Fields] AND lip [All Fields]) (Btherapy^
[Subheading] OR Btherapy^ [All Fields] OR Btreatment^
[All Fields] OR Btherapeutics^ [MeSH Terms] OR
Btherapeutics^ [All Fields]). During the search, no
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constrains/limits were applied with regard to year of publica-
tion, publication status, or language of publication. This study
protocol was registered at PROSPERO (CRD42017058781).
Data collection and analysis
In the first stage of literature selection, titles and abstracts were
assessed to identify full-length articles reporting on clinical
and/or surgical therapies for AC in humans. In the second
stage, inclusion and exclusion criteria were applied to the
full-length articles, as described below.
Inclusion and exclusion criteria
The following inclusion criteria were taken into consideration
with regard to study type, observational studies, case series,
clinical trials, and cohort studies were included; with regard to
the type of participants assessed, clinical studies should in-
volve human participants of any gender and age. The outcome
measures used to determine clinical improvement of AC were
lesion disappearance (remission, removal) and preservation of
the vermilion border; in some studies, the degree of histolog-
ical alterations was also assessed. Articles published before
1980 and those with case series including fewer than 5 indi-
viduals were excluded.
Study selection and data extraction and management
After the application of inclusion and exclusion criteria, all the
selected studies were subjected to independent methodologi-
cal evaluation and data extraction by two reviewers.
For each study included, qualitative and quantitative data
were extracted, namely year of publication, number of patients
assessed, study and follow-up time, intervention and compar-
ison, result evaluation method, type of study, and any other
information deemed necessary to assess methodological qual-
ity. Any disagreement was discussed between the two re-
viewers until consensus was reached.
Risk of bias assessment in the studies included
The same reviewers performed risk of bias assessment, also
independently, using a table specifically designed for this sys-
tematic review as part of the data extraction process. Bias
analysis was performed using specific criteria, namely patient
selection (randomization), blinding for treatment (whether the
patient was blind to the treatment received), blinding for as-
sessment (whether the examiner was blind to the treatment
received by the patient), and statistical analysis. The risk of
bias of each study was analyzed and classified according to
the four pre-established domains. Studies were classified as
follows: low risk of bias, if three or more domains did not
show risk of bias; moderate risk of bias, if two domains did
Clin Oral Invest
not show risk of bias; and high risk of bias, if one or more
domains did not show risk of bias [9, 10].
Results
A total of 29 manuscripts were included in the final sample
after all stages of the data collection process (Fig. 1). To facil-
itate data analysis, the results were separated according to the
treatment employed; however, some studies are reported more
than once because evaluated different types of treatment.
Laser therapy
This category included articles that treated AC with both low-
and high-power laser (Table 1). A total of 19 articles were
found in this category, namely 17 uncontrolled experimental
studies and only two clinical trials, being one randomized
[11–29]. Follow-up time varied from 8 to 262 weeks in these
studies.
Seven studies assessed low-power laser in PDT, in which a
photosensitizer is applied topically to the lesion site before
laser irradiation, inducing cell death and generating oxygen
reactive species [30]. This modality has been studied for the
treatment of AC and is currently used in superficial skin can-
cers other than melanoma [31]. Clinical analysis of the pa-
tients revealed improvement of the clinical aspect of the lesion
in most studies, with an improvement rate ranging from 47 to
100% of the patients. Five studies assessed histological alter-
ations in addition to clinical aspects [13, 15, 23, 25, 26]. Only
Ribeiro et al. (2012), observed lower degrees of dysplasia after
Fig. 1 Flowchart of studies
selection
Pubmed = 585
treatment in 100% of the patients; in the other studies, histo-
logical improvement varied from 16 to 73%. PDT therapy
presented a high frequency of adverse effects. The most com-
mon effects reported were erythema (33.33–100%), edema
(26.6–80%), pain (33.3–100%), and crust formation (10.5–
100%).
Twelve studies assessed high-power lasers, including car-
bon dioxide (CO2), erbium:yttrium-aluminum-garnet (YAG),
ablative, and vaporizing lasers. These methods act as tissue
ablation devices [32]. Five studies assessed both clinical and
histological characteristics [11, 17, 20, 21, 27] and seven
assessed clinical aspects only [12, 14, 16, 18, 22, 24, 29]. In
all studies, clinical improvement was observed in 60 to 100%
of the patients treated. In four studies, the histological findings
obtained before and after the biopsy were compared: three of
them [12, 17, 27] reported improvement in all patients, with
decreases in atypia, dysplasia, and solar elastosis. In the article
by Laws et al. [21], of the six patients subjected to histological
analysis, only two showed improvement. Whitaker [27], at the
end of the treatment protocol, observed the absence of atypical
cells in the epithelium of the 16 patients assessed, as well as a
marked decrease of solar elastosis in most cases. Johnson et al.
[20] observed improvement in the degrees of dysplasia in all
14 patients treated. Finally, de Godoy Peres et al. [17] also
found reduced degrees of dysplasia in the 40 patients
investigated.
High-power lasers resulted in more severe side effects as
paresthesia (33%), granulation at the site (8.3–10.52%,
dysesthesia (7.69–10.4%) when compared with lower-power
lasers. It was also frequently reported: pain (15.38–85%),
burning sensation (18.2%–100%), and edema (6.97–58.3%).
“(actinic cheilitis) AND lip AND
treatment OR therapy”
Embase = 79 Bireme = 96
Total = 760
Titles and abstract analysis
Exclusion of papers
published before 1980
183 articles remained
Exclusion of duplicated
references = 109
74 articles selected
Exclusion after full-text
analysis = 45
25 literature reviews
29 articles analyzed
5 no lip analysis
11 series of cases < 5 participants
4 conference proceedings
Table 1 Laser therapy

Author/year Type of study Mean age No. of patients and Follow-up Aspects studied Main results Adverse effects
type of treatment

Zaiac & Clement, Uncontrolled, 45.5 N: 15 12 weeks Clinical At the end of treatment, 12 patients Scaling, crusting, erythema, edema,
2011 [28] experimental PDT showed good improvement and mild pain (during treatment
3 complete improvements 33.3%, after 20%)
Burning sensation (during treatment
93.33%, after 0%)
Ribeiro et al., 2012 Uncontrolled, 62 N: 19 (10 male, 9 8 to 9 weeks Clinical and histological Patients reported clinical Decreasing order of frequency:
[23] experimental female) improvement of 80% (± 40). immediate pain, crusts, labial
PDT Histopathologically, there was a herpes, edema, scaling,
decrease in the degree of erythema, itch, and paresthesia
dysplasia after treatment.
Fai et al., 2015 [19] Uncontrolled, 74.7 N: 10 (6 male, 4 female) 12 to 48 weeks Clinical Seven patients showed complete During treatment: mild discomfort
experimental PDT response, which was maintained (50%). After: erythema and mild
in five patients over a period of edema (60%)
6–12 months.
Chaves et al., 2017 Uncontrolled, 64.13 N: 16 (10 male, 6 12 weeks Clinical, histological, and Complete clinical response was Erythema, edema, crusts, and
[15] experimental female) immunohistochemical observed in 62.5%. One patient erosions. Labial herpes after the
PDT presented histopathological first session (6.25%)
improvement, 6 presented
aggravations of histological
alterations. No statistically
significant changes in Ki-67,
surviving and p53 values before
vs. after treatment.
Sotiriou et al., Uncontrolled, 64.8 N: 38 (38 male) 72 weeks Clinical and histological 26 of 38 (68.42%) patients showed Mild erythema (68.42%), moderate
2010 [26] experimental PDT complete clinical response. None erythema (31.57%), edemas
of the patients progressed to (63.5%), bubbles (26.3%), crusts
invasive SCC. The clinical (10.5%)
recurrence rate was 15.38%, During treatment: pain and burning
while the histological recurrence sensation (100%)
rate was 34.61%.
Sotiriou et al., Uncontrolled, 65.26 N: 34 (33 male, 1 48 weeks Clinical and histological The clinical response rate was 80% PDT, during treatment: pain and
2011 [25] experimental female) and the complete histological burning sensation (100%),
PDT and imiquimod 5% response rate was 73%. erythema (100%), edema (80%),
cream bubbles, and crusts (20%)
Imiquimod, during treatment:
itching (47%), burning sensation
(40%), erythema (100%), scaling
(83%), crusts (83%), edema
(70%), superficial erosions, and
ulcerations (47%).
Berking et al., Uncontrolled, 68 N: 15 (male, 6 female) 12 weeks Clinical and histological Complete clinical response was During treatment: pain.
2007 [13] experimental PDT observed in 47%. Histological After: light to moderate erythema
alterations remained in 62%. (33.33%), edema (26.66%),
crusts, superficial, and
hemorrhagic scaling (100%).
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Table 1 (continued)

Author/year Type of study Mean age No. of patients and Follow-up Aspects studied Main results Adverse effects
type of treatment
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Armenores et al., Uncontrolled, 52.8 N: 99 (68 male, 31 10 weeks Clinical 84 (84.8%) patients had clinical Pain (75.3%), bleeding (67.5%),
2010 [12] experimental female) improvement without swelling (55.8%), exudation
YAG laser recurrence. (54.8%), erythema (48.1%),
burning (18.2%), cracking
(18.2%), dryness (18.2%),
dysesthesias (10.4%), pruritus
(5.2%)
Alamillos-Granados Uncontrolled, 61 N: 19 (19 male) 24 weeks
et al., 1993 [11] experimental Carbon dioxide laser and
vermilionectomy
Clinical Clinical After treatment:
improvement pain (36.84%),
was observed in edema
all patients. (26.31%),
granulation
tissue on the
surgical site
(10.52%)
Zelickson & Uncontrolled, 70 N: 43 (38 male, 5 80 weeks Clinical Clinical improvement was observed After treatment: edema (6.97%)
Roenigk, 1990 experimental female) in 60.4% of the patients.
[29] Carbon dioxide laser
Whitaker, 1987 Uncontrolled, 66 N: 16 (16 male) 56 weeks Clinical and histological Clinically all patients remained free None reported
[27] experimental Carbon dioxide laser of actinic cheilitis or SCC at the
end of treatment. No atypical
cells were detected in the
epithelium.
Orenstein et al., Uncontrolled, 52.67 N: 12 32 to 156 weeks Clinical Clinical improvement was observed After treatment: pain (33%),
2007 [22] experimental Er:YAG laser in all patients without recurrence. bleeding (41.7%), paresthesia
(33%), edema (58.3%), pyogenic
granuloma (8.3%), infection
(8.3%), slight tingling sensation
(8.3%)
de Godoy Peres Uncontrolled, 42.47 N: 40 (36 male, 4 24 to 120 weeks Clinical and histological A reduction in the intensity of After treatment: scaling (2.5%),
et al., 2009 [17] experimental female) epithelial dysplasia was observed ulcer (2.5%), white patch (7.5%)
Carbon dioxide laser in patients undergoing both
using two different protocols. Clinical recurrence
protocols occurred in 12.5% of the patients
for each protocol. No difference
was found between the protocols
(p > 0.05).
Castiñeiras et al., Uncontrolled, 67.9 N: 43 (34 male, 9 117.6 weeks Clinical 3/43 patients had a local recurrence None reported
2010 [14] experimental female) of AC after 13 months. These
Carbon dioxide laser patients improved after a new
vaporization CO2 laser application with total
resolution of the lesions. Two
Table 1 (continued)

Author/year Type of study Mean age No. of patients and Follow-up Aspects studied Main results Adverse effects
type of treatment

patients developed SCC after

12 months.
Robinson, 1989 Clinical trial Fluoracil: 59 N: 10 fluoracil 50 weeks Clinical Fluoracil: 5 patients showed clinical Lip shave: hematoma (10%),
[24] Chemical peel: N: 10 chemical peel recurrence. paresthesia (10%).
59.5 N: 10 lip shave Chemical peel: 7 patients showed Fluoracil: pain and irritation
Lip shave: 67.5 N: 10 carbon dioxide clinical recurrence. (100%), difficulty eating, and
Carbon dioxide laser Lip shave: no recurrence. speaking (10%)
laser: 60.5 Carbon dioxide laser: no Carbon dioxide laser: difficulty
recurrence. ingesting and eating (no. of not
informed).
Chemical peel: none reported
Dufresne et al., Uncontrolled, 67 N: 13 (8 male, 5 female) 44 weeks Clinical Clinical improvement was observed Pain (15.38%) and dysesthesia
1988 [18] experimental Carbon dioxide laser in all patients without recurrence. (7.69%)
Laws et al., 2000 Uncontrolled, 68 N: 14 (13 male, 1 12 weeks Clinical There were no differences between After treatment: minimum pain
[21] experimental female) treatments in relation to pain and (100%), burning sensation
Electrodessication and clinical appearance, but only in (85.71%)
carbon dioxide laser relation to healing. CO2 laser
healed faster than
electrodessication. 100% of the
patients showed clinical
improvement. Only 2 patients
showed histological
improvement.
Johnson et al., Uncontrolled, 63.5 N: 14 (12 male, 2 52 weeks Clinical and histological Clinically and histologically, no Minimal pain (85%), moderate pain
1992 [20] experimental female) evidence of recurrence was (7.14%), severe pain (7.14%)
Carbon dioxide laser observed; improvement in
relation to levels of dysplasia
was detected for all patients.
Choi et al., 2015 Randomized Er:YAG AFL N: 33 (20 male, 13 24 weeks Clinical Er:YAG AFL MAL-PDT was sig- Er:YAG AFL MAL-PDT: erythema
[16] clinical trial MAL-PDT: female) nificantly more effective (92% (100%), burning (100%),
66.7 N: 14 Er:YAG AFL complete response rate) than swelling (39%), hemorrhagic
MAL-PDT: 69.4 MAL-PDT MAL-PDT (59%; p = 0.04) at crusting (23%), blistering (15%).
N: 19 MAL-PDT the 3-month follow-up and MAL-PDT: erythema (100%),
remained significant after burning (100%), swelling (35%),
12 months (85% in Er:YAG hemorrhagic crusting (12%),
AFL MAL-PDT and 29% in blistering (6%).
MAL-PDT). The recurrence rate
was significantly lower for
Er:YAG AFL MAL-PDT (8%)
than for MAL-PDT (50%) at
12 months (p = 0.029).

AFL, ablative fractional laser; ER, erbium; MAL, methyl aminolevulinate; PDT, photodynamic therapy; YAG, yttrium-aluminum-garnet; SCC, squamous cell carcinoma
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Table 2 Chemotherapeutic agents
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Author/year Type of study Mean age No. of patients and type of Follow-up Aspects Main results Adverse effects
treatment studied

McDonald et al., Uncontrolled Not informed N: 5 6 weeks Clinical and All patients presented clinical During treatment: pain and ulceration
2010 [34] experimental 5% imiquimod and retractor histological improvement. The degree of dysplasia (100%)
was decreased in all patients.
Sotiriou et al., Uncontrolled 65.26 N: 34 (33 male, 1 female) 48 weeks Clinical and The clinical response rate was 80% and the PDT during treatment: pain and burning
2011 [25] experimental Photodynamic therapy and histological complete histological response rate was sensation (100%), erythema (100%),
imiquimod 5% cream 73%. edema (80%), bubbles, and crusts
(20%)
Imiquimod during treatment: itching
(47%), burning sensation (40%),
erythema (100%), scaling (83%), crusts
(83%), edema (70%), superficial
erosions, and ulcerations (47%)
Smith et al., 2002 Uncontrolled 65.6 N: 15 (12 male, 3 female) 68 weeks Clinical All patients showed clinical improvement. During treatment: moderate inflammation,
[35] experimental Topical 5% imiquimod edema, erosion, or superficial
ulceration (33.33%).
After 4 weeks: residual inflammation and
edema (40%).
At the end of follow-up: inflammation,
edema, superficial ulcerations, and
erosions (60%).
Spyridonos et al., Uncontrolled Control: 64.7 N: 8 (6 male, 2 female) 5 weeks Clinical The proposed quantitative marker Local irritation, pain, and redness (12.5%)
2014 [36] experimental Treatment: 68.6 Imiquimod and cryosurgery (segmentation algorithm for lower lip
border based on spatial fuzzy c-means
clustering with adaptive selection of
fuzzy exponent m) was able to detect
clinical improvement in all patients.
Robinson, 1989 Clinical trial Fluoracil: 59 N: 10 fluoracil 50 weeks Clinical Fluoracil: 5 patients showed clinical Lip shave: hematoma (10%), paresthesia
[24] Chemical peel: N: 10 chemical peel recurrence. (10%), difficulty eating and eating (no.
59.5 N: 10 lip shave Chemical peel: 7 patients showed clinical not informed).
Lip shave: 67.5 N: 10 carbon dioxide laser recurrence. Fluoracil: pain and irritation (100%),
Carbon dioxide Lip shave: no recurrence. difficulty eating and speaking (10%).
laser: 60.5 Carbon dioxide laser: no recurrence. Carbon dioxide laser: difficulty ingesting
and eating (no. not informed).
Chemical peel: none reported.
Warnock et al., Uncontrolled Not informed N: 6 Not informed Clinical and In clinical improvement in all patients, Not informed
1981 [37] experimental Topical 5-fluoracil histological there was worsening of
histopathological alterations in 5 of 6
patients.
Flórez et al., 2017 Uncontrolled 72.8 N: 7 (4 male, 3 female) 1 to 2 weeks Clinical 3 patients achieved complete clinical Erythema, scales, erosions, crusts, and
[33] experimental Ingenol mebutate gel response. vesicles involving more than 50% of
4 showed clinical improvement but not the lip (100%)
complete.

Chemotherapeutic agents
This category included articles in which AC was treated with
topical chemotherapeutic drugs (Table 2). Seven articles were
found, including treatment with the drugs imiquimod, 5-
fluorouracil (5-FU), and ingenol mebutate. One study is a
clinical trial, while 6 are uncontrolled experimental studies
[24, 25, 33–37]. Follow-up time considering all treatments
varied from 1 to 68 weeks.
Imiquimod acts on a type 7 receptor that is part of the innate
immune system. Activation of this receptor provokes intracel-
lular signaling, leading to the release of interferon and pro-
inflammatory cytokines. Imiquimod is commonly used in the
treatment of penile warts, actinic keratosis, and basal cell car-
cinoma [34]. Four studies assessed the topical application of
imiquimod 5% cream in cases of AC, and all reported clinical
improvement in 80 to 100% of the patients [25, 34–36]; two
also reported histological improvement [25, 34]. McDonald
et al. [34] assessed the degrees of dysplasia, which decreased
after treatment in all patients. Sotiriou et al. [25] also assessed
the degrees of dysplasia and found complete histological re-
gression in 73% of the patients. Imiquimod caused pain (12.5–
100%), ulceration (33.33–100%), and edema (33.33–70%)
during treatment.
5-FU blocks the synthesis of DNA through the inhibi-
tion of thymidylate synthase. Commonly used in the treat-
ment of breast and gastric cancer [37], this drug was
assessed in two studies for the treatment of AC.
Robinson [24] conducted a clinical trial comparing 5-FU
with other treatment modalities, including chemical peel,
lip shave, and CO2 laser. Five patients in the group treated
with 5-FU presented clinical recurrence. Warnock et al.
[37] used 5-FU topically, evaluating both clinical and his-
tological aspects, and observed clinical improvement in all
patients; conversely, none of the patients showed histolog-
ical improvement. Only Robinson et al. [24] reported side
effects with 5-FU: difficulty eating and speaking (10%),
pain and irritation (100%).
One study assessed the application of ingenol mebutate gel,
which is derived from a substance extracted from an
Australian plant called Euphorbia peplus. Its mechanism of
action is the inhibition of the Hedgehog intracellular signaling
pathway (frequently, basal cell skin carcinomas show muta-
tions that lead to the activation of this pathway). This drug was
used topically, and only three of a total of seven patients
showed complete clinical improvement [33]. The side effects
reported were erythema, scales, erosions, crusts, and vesicles
(100%).
Surgical treatment
Articles in this category treated AC surgically (Table 3). Six
articles were found, employing mucosal advancement flap
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(MAF), vermilionectomy, chemical peel, cryosurgery, and
electrodessication [21, 24, 36, 38–40]. These therapies act
resecting affected tissue [40]. Three studies were clinical tri-
als, being one randomized and three uncontrolled experimen-
tal studies. Follow-up time for all therapies varied from 5 to
72 weeks.
The surgical treatment most commonly employed was
vermilionectomy [24, 38–40]. This technique consists of the
complete removal of the mucosa that lines the lip, and thus it is
considered a radical, aggressive procedure [41]. Menta
Simonsen Nico et al. [38] assessed the results obtained with
vermilionectomy in 20 patients and focused on histological
findings only, by conducting a biopsy and analyzing the tissue
before and after the procedure. Ten patients showed more
severe histological abnormalities at the end of the treatment
protocol. Two studies [39, 40] compared classic
vermilionectomy with modified versions of the procedure,
but these did not focus on its effectiveness in curing AC,
rather, these authors focused on functional and cosmetic out-
comes. Sand et al. [40] conducted a randomized clinical trial
involving 18 patients and compared the mucosal advancement
flap (MAF) versus primary closure (PC) after
vermilionectomy. All patients were subjected to reconstruc-
tion with successful results using either MAF or PC after
vermilionectomy, and a symmetrical result was achieved in
all cases. Rossoe et al. [39] compared classic vermilionectomy
in relation to the W-plasty technique: statistical differences
were observed only in relation to the scarring process, i.e.,
there was a greater chance of scar retraction in patients treated
with the classic technique.
Robinson [24] compared vermilionectomy with other treat-
ment methods, namely chemical peel with 50% trichloroacetic
acid, topical application of 5-FU, and CO2 laser ablation, in 40
patients. In the group treated with vermilionectomy, clinical
improvement was observed in 100% of the patients. This
treatment modality was superior to the pharmacological treat-
ments assessed.
Important side effects caused by vermilionectomy were
paresthesia (10–33.3%), infection (10%), and necrosis
(10%). Moreover, bruising (12.5–40%), swelling (50–
100%), and hematomas (10%) were also reported.
Laws et al. [21] compared electrodessication with a CO2
laser in 14 patients. Even though all patients showed clinical
improvement, only two out of the six patients who performed
post-treatment biopsy showed histological improvement. This
procedure resulted in pain (100%) and burning sensation
(85.71%).
Cryosurgery was investigated in only one study [36], used
concomitantly with the chemotherapeutic agent imiquimod.
The authors assessed clinical aspects in eight patients using
quantitative markers and observed clinical improvement in all
patients treated. Cryosurgery caused pain, local irritation, and
redness in 12.5% of patients.
Table 3 Surgical treatment

Author/year Type of study Mean age No. of patients and type of Follow-up Aspects Main results Adverse effects
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treatment studied

Sand et al., 2010 [40] Randomized MAF: 5.7 N: 10 MAF 52 weeks Clinical All patients underwent successful MAF: bruising (40%), swelling (100%),
clinical trial PC: 72.4 N: 8 PC (18 male) reconstruction after vermilionectomy infection (10%), partial flap necrosis
using MAF or PC, and a symmetrical (10%), small wound dehiscence (10%),
result was achieved in all cases. pain level 0–10 scale (1.3)
PC: bruising (12.5%), swelling (50%),
infection (0%), partial flap necrosis
(0%), small wound dehiscence (0%),
pain level 0–10 scale (0.8).
Rossoe et al., 2011 [39] Clinical trial 63 N: 17 classic 76 weeks Clinical There was greater scar retraction in Classic vermilionectomy: dry lip (11.8%),
vermilionectomy patients submitted to the classical paresthesia (23.5%), suture dehiscence
N: 15 W-plasty (13 male, 19 technique. No functional change was (11.8%).
female) detected in relation to smile and W-plasty: dry lip (13.4%), paresthesia
function in both groups. (33.3%)
Menta Simonsen Nico Experimental 57,6 N = 20 (11 male, 9 female) Not Histological Comparison between biopsies and most Not informed
et al., 2007 [38] uncontrolled Entire vermilion and previous informed severe changes on vermilionectomies
biopsy revealed coincidental changes in 10
cases (50%), more severe changes on
biopsy occurred in two cases (10%) and
in eight cases (40%), the changes on
vermilionectomy were more severe.
Robinson, 1989 [24] Clinical trial Fluoracil: 59 N: 10 fluoracil 50 weeks Clinical Fluoracil: 5 patients showed clinical Lip shave: hematoma (10%), paresthesia
Chemical peel: N: 10 chemical peel recurrence. (10%), difficulty eating (no. of not
59.5 N: 10 lip shave Chemical peel: 7 patients showed clinical informed).
Lip shave: 67.5 N: 10 carbon dioxide laser recurrence. Fluoracil: pain and irritation (100%),
Carbon dioxide Lip shave: no recurrence. difficulty eating and speaking (10%)
laser:60.5 Carbon dioxide laser: no recurrence Carbon dioxide laser: difficulty ingesting
and eating (no. of not informed)
Chemical peel: none reported
Spyridonos et al., 2014 Uncontrolled Control: 64.7 N: 8 (6 male, 2 female) 5 weeks Clinical The proposed quantitative marker Local irritation, pain, and redness (12.5%)
[36] experimental Treatment: 68.6 Imiquimod and cryosurgery (segmentation algorithm for lower lip
border based on spatial fuzzy c-means
clustering with adaptive selection of
fuzzy exponent m) was able to detect
clinical improvement in all patients.
Laws et al., 2000 [24] Uncontrolled 68 N: 14 (13 male, 1 female) 12 weeks Clinical There were no differences between After treatment: minimum pain (100%),
experimental Electrodessication and carbon treatments in relation to pain and burning sensation (85.71%)
dioxide laser clinical appearance, only in relation to
healing. CO2 laser healed faster than
electrodessication. 100% of the patients
showed clinical improvement. Only 2
of patients showed histological
improvement.

MAF, mucosal advancement flap; PC, primary closure after vermilionectomy


Anti-inflammatory agents
This category included studies in which AC was treated with
the use of topical anti-inflammatory drugs (Table 4). Two
articles were found, both using diclofenac gel as treatment
[42, 43]. Both articles were uncontrolled experimental studies,
and follow-up time varied from 6 to 52 weeks.
Lima et al. [42] assessed the clinical performance of
diclofenac 3% gel with hyaluronic acid 2.5% in 27 patients.
Of the patients who completed the study, 12 (44%) showed
complete remission of the whitish plaques and exfoliative
areas and 15 (56%) showed partial clinical remission of AC.
Ulrich et al. [43] assessed the use of diclofenac 3% gel in six
patients and observed clinical improvement in four.
Diclofenac gel as treatment caused edema (100%), erythe-
ma, and burning sensation (number of affected individuals not
reported).
Bias analysis
Bias analysis (Table 5) revealed that 27 of the 29 articles
included in the analysis showed a high risk of bias. Only
two studies performed patients randomization [16, 40]. None
of the studies reported blinding for treatment or assessment.
Only eight studies statistically analyzed the data.
Discussion
This literature review confirmed that several treatment modal-
ities are available for AC, including surgery, laser application,
and topical therapies with chemotherapeutic or anti-
inflammatory agents. The studies assessed were very hetero-
geneous, and most of them showed a high risk of bias. Most
studies were non-controlled experimental trials and non-
randomized clinical trials. Mean follow-up time was 40 weeks,
and sample sizes were small, ranging from 6 to 40 patients on
average, preventing adequate conclusions. Therefore, the sci-
entific evidence available on the treatment of AC is still very
Table 4 Anti-inflammatory agents
Author/year Type of study Mean No. of patients and
age type of treatment
Lima et al., Uncontrolled 58 N: 27 (24 male, 3
2010 [42] experimental female)
Diclofenac with
hyaluronic acid gel
Ulrich et al., Uncontrolled 69.6 N: 6 (3 male, 3
2007 [43] experimental female)
Diclofenac 3% gel
Clin Oral Invest
limited, and it is not possible to reach a consensus on the best
therapy available.
Among the chemotherapeutic agents assessed, imiquimod
showed the best results, with clinical improvement in 80 to
100% of the patients and histopathological improvement in 73
to 100%. Clinically, the low-power laser used with photody-
namic therapy also showed positive results, with improvement
in up to 100% of the patients. However, histological improve-
ment varied greatly, from 16 to 100%. With regard to the
studies employing surgical methods, the main focus was on
the search for the technique with the best functional and es-
thetic results, not on the cure of AC. Studies on the effects of
anti-inflammatory agents are scarce and have small sample
sizes, therefore presenting very limited results.
Side effects were reported for all treatment modalities. The
most common side effects were pain, burning sensation,
flakes, swelling, and erythema. It is important to highlight
the presence of more severe side effects in patients treated
with laser therapy and surgery, including paresthesia and
necrosis.
AC is a potentially malignant condition; however, its
malignancy potential has not so far been assessed as the
main outcome. According to Pilati et al. [44], clinical
knowledge does not suffice; it is also necessary that the
histological aspects of AC are known for a better under-
standing of the factors associated with the malignant trans-
formation of this lesion. Squamous cell carcinoma of the
lip is preceded by AC in more than 90% of the cases.
Therefore, histopathological assessment and patient moni-
toring are crucial. Very often, the lack of knowledge about
AC epithelial alterations leads to late diagnosis and a
smaller chance of survival [45]. From the studies that re-
ported histological findings, it is possible to highlight that
the treatments with topical imiquimod and high-power la-
sers resulted in best histological improvement. Still, most
studies did not assess the effects of treatment on the degree
of epithelial alteration, limiting their analyses to clinical
outcomes. Moreover, the follow-up times reported were
not long enough to evaluate this variable.
Follow-up Aspects Main results Adverse effects
studied
52 weeks Clinical 12 (44%) patients presented Edema, erythema, and
complete remission of the burning sensation
whitish plaques and (no. of not reported).
exfoliative areas, and 15
(56%) showed partial
clinical remission.
6 weeks Clinical Four of the six patients Edema (100%)
presented clinical
improvement.
Clin Oral Invest

Table 5 Analysis of bias

Author and year Selection Blinding Blinding Statistics Risk of

(randomization) (treatment) (assessment) bias

Laser therapy
Zaiac & Clement, 2011 [28] No No No No High
Ribeiro et al., 2012 [23] No No No Chi-square or Fisher’s exact test High
Fai et al., 2015 [19] No No No No High
Chaves et al., 2017 [15] No No No McNemar test High
Sotiriou et al., 2010 [26] No No No No High
Sotiriou et al., 2011 [25] No No No No High
Berking et al., 2007 [13] No No No No High
Armenores et al., 2010 [12] No No No Descriptive statistics High
Alamillos-Granados et al., 1993 No No No No High
[11]
Zelickson & Roenigk, 1990 [29] No No No No High
Whitaker, 1987 [27] No No No No High
Orenstein et al., 2007 [22] No No No No High
de Godoy Peres et al., 2009 [17] No No No McNemar test High
Castiñeiras et al., 2010 [14] No No No No High
Robinson, 1989 [24] No No No No High
Dufresne et al., 1988 [18] No No No No High
Laws et al., 2000 [21] No No No Paired t test High
Johnson et al., 1992 [20] No No No No High
Choi et al., 2015 [16] Yes No No Independent t test Moderate
Chemotherapeutic agents
McDonald et al., 2010 [34] No No No No High
Sotiriou et al., 2011 [25] No No No No High
Smith et al., 2002 [35] No No No No High
Spyridonos et al., 2014 [36] No No No Spatial c-means algorithm High
Robinson, 1989 [24] No No No No High
Warnock et al., 1981 [37] No No No No High
Flórez et al., 2017 [33] No No No No High
Surgical treatment
Sand et al., 2010 [40] Yes No No Kolmogorov Smirnov test and t Moderate
test
Rossoe et al., 2011 [39] No No No No High
Menta Simonsen Nico et al., 2007 No No No No High
[38]
Robinson, 1989 [24] No No No No High
Spyridonos et al., 2014 [36] No No No Spatial c-means algorithm High
Laws et al., 2000 [24] No No No Paired t test High
Anti-inflammatory agents
Lima et al., 2010 [42] No No No No High
Ulrich et al., 2007 [43] No No No No High

It is interesting to draw a parallel between AC and
actinic keratosis, as scientific evidence supporting the
treatment of the latter pathology is far more robust.
Actinic keratosis is a potentially malignant skin lesion
with similar characteristics and the same etiology (exces-
sive sun exposure) as AC. Major preventive initiatives
have been undertaken in preventing this lesion, with sev-
eral events and programs aimed to educate the population
on the risk of skin cancer, appropriate protection, and
early skin cancer detection—a markedly different situa-
tion when compared to AC and lip cancer. The best treat-
ment approach for actinic keratosis is determined based

on lesion severity, systemic and immunological character-
istics of the patient, and quality of life [46]. In 2015, the
International League of Dermatological Societies, along
with the European Dermatology Forum, issued guidelines
for the treatment of actinic keratosis, in which they rec-
ommend that single lesions should be treated preferably
with cryotherapy, whereas multiple lesions with field
cancerization should be treated with 0.5% 5-FU, followed
by imiquimod 3.75%, then 0.0015%, and 0.05% ingenol
mebutate, and finally methyl-aminolevulinate and
aminolevulinic acid PDT [47].
In conclusion, determining the best therapy to treat AC
lesions is still a subject of debate, and randomized clinical
trials are necessary to provide more robust evidence. Future
studies should focus more specifically on the relevance of
histopathological alterations when treating potentially malig-
nant disorders as actinic cheilitis.
Funding The work was supported by the CNPq (Conselho Nacional de
Desenvolvimento Científico e Tecnológico, Brazil).
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of
interest.
Ethical approval This article does not contain any studies with human
participants or animals performed by any of the authors.
Informed consent For this type of study, formal consent is not required.
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