Received: 7 May 2018 | Revised: 7 July 2018
DOI: 10.1111/phpp.12415
Daylight photodynamic therapy for the treatment of
actinic cheilitis
Assi Levi1,2 | Emmilia Hodak1,2 | Claes D. Enk3 | Igor Snast1,2
Slodownik4,5 | Moshe Lapidoth1,2
1
Photodermatosis Clinic and Laser
Unit, Department of Dermatology, Rabin
Medical Center, Petah Tikva, Israel
2
Sackler Faculty of Medicine, Tel Aviv
University, Tel Aviv, Israel
3
Department of Dermatology, Hadassah-
Hebrew University Medical Center,
Jerusalem, Israel
4Department of Dermatology, Tel Aviv
Sourasky Medical Center, Tel Aviv, Israel
5 natural daylight serves as the light source, showed promising results in the treatment
Sackler Faculty of Medicine, School of
Public Health, Department of Environmental
and Occupational Health, Tel Aviv University,
Tel Aviv, Israel
Correspondence: Assi Levi, MD, Department of
Dermatology, Rabin Medical Center— Beilinson
Hospital, 39 Jabotinsky St., Petah Tikva
4941492, Israel (docalevi@gmail.com).
Photodermatol Photoimmunol Photomed. 2019;35:11–16.
| Accepted: 16 July 2018
| Dan
Summary
Background: Actinic cheilitis (AC) is a common, chronic premalignant condition re-
sulting from protracted sun exposure affecting the vermilion border of the lower lip.
Treatment of AC aims at terminating the progression to squamous cell carcinoma by
obliterating the primary lesion, and includes ablative methods; nonablative modali-ties
such as cryotherapy, electrodessication, chemical peeling, topical imiquimod and 5-
-fluorouracil; and photodynamic therapy (PDT). Daylight--activated PDT, in which
of actinic keratoses with substantially less pain than conventional PDT.
Purpose: To determine the safety and efficacy of daylight PDT in a series of patients
with AC.
Methods: Eleven patients with AC were treated with daylight PDT. All patients un-
derwent repeated treatment sessions until clinical and histological remission were
achieved.
Results: Cure rate was 91% (10 of 11 patients, three females/eight males; mean age
59.2 ± 14.4 years). Mean number of treatments to attain cure was 2.7. Patients expe-
rienced mild erythema and minimal to no pain during treatment.
Conclusions: Daylight PDT is a promising modality for the treatment of AC, with im-
pressive cosmetic results and few side effects.
Actinic cheilitis is a common premalignant condition of the lower lip that requires
treatment to prevent its progression to squamous cell carcinoma. We describe our
therapeutic experience using a daylight photodynamic therapy. Treatment sessions
continued until achieving clinical and histological remission. Symptoms were resolved
in 10 of 11 patients (91%) after a median of two (range 1--6) treatments, with only few
adverse effects. Daylight photodynamic therapy is a promising modality for the
treatment of actinic cheilitis.
KEYWORDS
actinic cheilitis, daylight, photodynamic therapy
wileyonlinelibrary.com/journal/phpp © 2018 John Wiley & Sons A/S. | 11
Published by John Wiley & Sons Ltd
12 | LEVI et al.
1 | INTRODUCTION
Actinic cheilitis (AC) is the mucosal equivalent of the much more prevalent
cutaneous actinic keratosis.1 The term “cheilitis” implies inflammation and
therefore is a misnomer, as inflammation is com-mon but not mandatory
for the diagnosis, and a more accurate term would therefore be “solar
2
cheiliosis.” Nevertheless, AC is still the most widely used term. The vast
majority of cases (90%--100%) occur on the lower lip, specifically at the
vermilion border, the transition zone between the buccal mucosa and the
skin.3 A white, scaly plaque with a sandpapery feel on palpation is the most
common presenta-tion of AC, though other manifestations (such as
vermilion border atrophy, erosions, and ulcerations) might also occur. 4
The exact prevalence of this condition is unknown. Available data
refers to the prevalence of squamous cell carcinoma (SCC) on the
lower lip. In the United States, it is estimated there are 3500 new case
of lip cancer every year, 90% of whom are SCC.5 The liter-ature
reports a highly heterogeneous risk of developing cutaneous SCC
from AK, ranging from less than 1% to more than 10%.6 The likelihood
that AC would progress to SCC is believed to be greater than SCC
7 feel on palpation and/or erosions and ulcerations. Biopsies obtained
developing from cutaneous AK, yet exact statistics are unavailable.
The etiology is mainly related to chronic ultraviolet (UV) expo-sure
and to factors enhancing the risk for those exposures, such as lower
Fitzpatrick skin photo--types, age, and occupation, leisure activities
involving prolonged sun exposure, geographic latitude of residence,
male gender, not using lip protective agents, genetic pre-disposition,
and immunosuppression.8
Fortunately, a few decades of solar exposure are usually required
9 affected lip, and then left uncovered.
for AC to progress to lip SCC, and therefore, early diagnosis and
treatment of AC offer a high probability of preventing progression to
10
lip SCC.
Treatment of AC is therefore aimed at terminating progression to SCC
by obliterating the primary lesion through both ablative and nonablative
modalities, such as: surgical vermilionectomy,11 laser evaporation (mainly
CO2 laser),12 electrodessication,12 dermabra-sion, cryotherapy; and a
variety of topical applications, such as ret-inoids, 5 FU,13 imiquimod,14
diclofenac,15 and ingenol mebutate.16 Of note, although the latter was
reported to be of some benefit in treating AC, the FDA posted a warning
concerning the use of ingenol mebutate around the mouth, lips, and eyes
area.17 PDT is another available treatment modality.18 In conventional
PDT, a photosen-sitizer (usually aminolevulinic acid [ALA] or methyl--ALA
[MAL]) is locally applied using an occlusive and opaque dressing. It takes
ap-proximately 2 hours for this prodrug to absorb into the malignant and
premalignant cells and transform into its active component, pro-
toporphyrin IX (PpIX). Illumination in the appropriate action spec-trum in
the presence of oxygen causes free radicals formation and subsequently
photochemical destruction of the diseased tissue.
Photodynamic therapy was found to be effective for treating AC in
several publications.19-22 However, there are limitations to
performing PDT for this purpose: (a) technical complexity, mak-ing it
time consuming for both patients and physicians, (b) high
financial costs: expensive illumination equipment and photosensi-
tizer; and (c) side effects, such as initial erythema, edema, burning
sensation, and pain. Pain is a major adverse effect of PDT, caused
by the sudden release of accumulated PpIX by light illumination
following occlusion of the ALA--treated lesion. When treating AC, this
disadvantage becomes especially critical as the lip is a very sensitive
area.
Recent studies have shown that continuous PpIX activation in
cutaneous actinic keratosis lesions without previous occlusion and
accumulation of PpIX is associated with significantly less pain and is
as effective as conventional PDT in eliminating the lesions.23
The aim of this study was to present our clinical experience in the
treatment of AC with daylight PDT.
2 | METHODS
This is a retrospective study. All patients portrayed clinical findings
compatible with AC, that is white, scaly plaques, with a sandpapery
prior to treatment displayed findings characteristic of AC: hyper-
keratosis, solar elastosis, mild to moderate epithelial dysplasia and
perivascular inflammation.
Treatment consisted of applying SPF--20 sunscreen with organic
filter to the face to protect against UV exposure. Scales were re-
moved from the affected lip by gentle curettage, and a thick layer of
MALcream (Photonamic GmbH, Wedel, Germany) was applied to the
We exposed the patients to sunlight in the hospital garden be-tween 8
and 11 pm for 2.5 hours, and then instructed them to remain indoors, the
rest of the day, in order to prevent further light exposure.
In cases when additional treatments were required, patients were
able to choose whether to self--treat at home, or have the treat-ments
performed in a hospital.
The study was approved by the ethics committee of Rabin Medical
Center (RMC--0029--18).
2.1 | Statistical analysis
Data were analyzed using descriptive statistics. Categorical varia-bles are
presented as number and percent, and continuous variables as mean and
standard deviation (SD) or median and range.
3 | RESULTS
3.1 | Patients
Table 1 lists the patient’s main characteristics. The study included 11
patients (eight males, three females) of mean age 59.2 (±14.4) years. One
of the female patients (patient no. 4) suffered from AC of the upper lip,
unlike the other patients who had AC of the lower lip. This unusual location
is likely due to decades of UVC unprotected expo-sure during her work in
a research lab. Aside from patient no. 6, all
LEVI et al. | 13

TA B LE 1 Patients’ main characteristics

Patient no. Age (y) Gender Previous treatments Location

1 26 M Cryotherapy, CO2 Lower lip

vermilionectomy
2 57 M Cryotherapy Lower lip
3 50 M Topical retinoids, cryotherapy Lower lip
4 63 F Cryotherapy Upper lip
5 71 M Cryotherapy, surgical Lower lip
vermilionectomy
6 40 M Topical lubricants Lower lip
7 70 M Cryotherapy Lower lip
8 73 F Topical lubricants, cryotherapy Lower lip
9 73 F Topical lubricants Lower lip
10 67 M Topical lubricants Lower lip
11 61 M Topical lubricants Lower lip
Sum 59.2 ± 14.4 8 M; 3 F

(A) (B)

(C) (D)

FI G U R E 1 A, Patient no. 5. Lower lip prior to daylight PDT (black arrows point to erosions). B, Patient no. 5. Resolution of lesions
following daylight PDT. C, Patient no. 10. Lower lip prior to daylight PDT (black arrows point to erosions). D, Patient no. 10. Resolution of
lesions following daylight PDT [Colour figure can be viewed at wileyonlinelibrary.com]

patients had tried other therapeutic options with no success, such as

3.2 | PDT treatment
topical lubricants and retinoids, cryotherapy, CO2 laser vermilionec-
tomy, and surgery. Patient no. 1 experienced recurrence 3 months All patients underwent repeated treatment sessions every 2--4 weeks until

after undergoing CO2 vermilionectomy, whereas it took patient no. 5 clinical remission was achieved (Figure 1) or considered im-probable (in

more than 20 years after a surgical vermilionectomy for the condi-tion patient number 7) using only PDT. The median follow--up period was 30
to reoccur. months (range 6--60 months). Cure rate was 91%
14 | LEVI et al.

(10 of 11 patients). Only patient number 7 failed to achieve remis-sion with
a single 0.2 cm diameter area on his left lower lip remaining unchanged
after four repeated treatment sessions. This patient re-quired an additional
treatment with CO2 laser targeting that location. The median number of
treatment sessions to obtain cure was two (range 1--6). Five patients
(45%) also underwent repeated histologi-cal evaluation at the end of
treatment, which also proved remission. In five patients, clinical outcome
was flawless with no suspicious looking area from which to acquire a
histologic specimen. It should be noted that patient no. 1 (six treatment
sessions in a 60 months follow--up period) achieved a clinical and
histological cure after three treatment sessions. Remission was sustained
for 36 months, until complaints of lip exfoliation recurred. Although
repeated histologi-cal evaluation did not demonstrate recurrence, an
additional three treatment sessions were performed until symptoms were
amelio-rated. This patient is currently in complete remission for 23 months.
After demonstrating the procedure during the first treatment
session, patients were offered the choice to perform the procedure in
the comfort of their own home using a photosensitizer provided to
them. Patients who opted for this choice self--administered sub-
sequent treatment sessions. Only two patients (18%) performed all
treatment sessions in the hospital garden: patient no. 6 required only
a single session to attain cure and therefore subsequent sessions
were irrelevant; patient no. 7 underwent four treatment sessions and
is the only patient who did not experience complete remission. Table
2 summarizes the PDT sessions and follow--up period for the different
patients.
Side effects were mild and included mild erythema (all patients),
mild pain during the procedure (four patients) and slight edema last-
ing less than 48 hours after the procedure (four patients).
4 | DISCUSSION
Actinic cheilitis is a premalignant condition, with the potential to
develop into invasive SCC.2 Surgical vermilionectomy is the gold
standard of treatment,11 yet it requires high surgical skills, is related
to substantial patients’ morbidity and the esthetic outcome might be
disappointing.24 Other treatment modalities exist yet none is per-fect,
as they either lack sufficient clinical efficacy or cause substan-tial side
effects.
Photodynamic therapy is a relatively novel intervention for AC, first
reported by Alexiades--Armenakas and Geronemus.25 Since then,
several publications have demonstrated the efficacy of this modal-ity for
the treatment of AC.19-22 A recent publication demonstrated limited
efficacy in 16 patients treated with conventional PDT, how-ever, the
patients only underwent two PDT sessions.26 Based on our data, we
suggest that many patients require more than two sessions to achieve
remission, thus there is a need to simplify the procedure and reduce costs.
The procedure could be significantly simplified by performing daylight
PDT, in which the sun serves as the light source instead of an artificial and
expensive lamp. This novel approach was shown to be effective in treating
cutaneous lesions.23 The utilization of daylight PDT not only saves time
and money, it also substantially reduces pain during the procedure, by
altering the release of accu-mulated PPIX instead of suddenly releasing
high amounts of PpIX, a continuous consumption of PPIX takes place.23
The minimal light dose required for effective treatment of AKs ranges
between 3.5 and 8 J/cm2.27-29 Our study was conducted in Israel, a
Mediterranean country where the climate is temperate with sunny days
throughout most of the year. A previous study has shown that the mean
total daily sunlight dose in Israel ranged between 55

TA B LE 2 Treatment characteristics

Number of PDT Follow--up

Patient no. Disease duration (mo) sessions Hospital sessions Home sessions time (mo)

1 37a 6 5 1 60
2 15 4 1 3 54
3 11 2 1 1 46
4 5 3 1 2 33

5 8b 3 1 2 30
6 18 1 1 0 30

7 9 4c 4 0 28
8 14 2 1 1 22
9 12 2 1 1 18
10 4 2 1 1 14
11 17 2 1 1 6
Sum 13.6 ± 8.6 2.7 ± 1.3 1.6 ± 1.4 1.2 ± 0.8 31 ± 15.9
PDT, photodynamic therapy.
aPatient no. 1 underwent several therapeutic trials (cryotherapy, CO laser vermilionectomy), yet none brought prolonged remission.
2
bTime of untreated recurrence prior to the first PDT session. Prior to recurrence patient no. 5 experienced remission which lasted about 20 y following a
surgical vermilionectomy.
cPatient no. 7 did not achieve clearance following PDT.
LEVI et al.
and 211 J/cm2 from July through December.30 Thus, we were able to
perform daylight PDT on nearly all days throughout the year.
Only two reports are available in the literature describing treat-ing
AC with daylight PDT. The first is the preliminary experience of part
of our group in two cases with histological clearance after 3--4
treatment sessions.31 A second publication by Fai et al reports a ret-
rospective chart review of ten patients treated by daylight PDT for AC:
3 months after the procedure 7 of 10 patients (70%) obtained a
complete response, which was maintained in five patients over an
observational period of 6--12 months.32 Our current study demon-
strates clinical (and for some patients also histologic) remission in 10
of 11 patients (91%) with minimal side effects. Furthermore, pa-tients
were enabled to perform treatment in the comfort of their own homes
(after demonstrating competence at least once), without hampering
the procedure efficacy, thus demonstrating the proce-dure’s
simplicity.
Our study’s main limitations include a relatively small sample size
and a retrospective design.
5 | CONCLUSION
Daylight PDT is effective for the treatment of AC. Although ad-ditional
studies are indicated with higher numbers of patients and longer
follow--up periods, this study provides encouraging support toward
providing home treatment for AC.
AC K N OW L E D G M E N T S
We would like to acknowledge the help of Dr. Debby Mir in writing the
manuscript.
ORCID
Igor Snast http://orcid.org/0000-0002-7126-2193
REFERENCES
1. Shah AY, Doherty SD, Rosen T. Actinic cheilitis: a treatment review.
Int J Dermatol. 2010;49:1225‐1234.
2. Jadotte YT, Schwartz RA. Solar cheilosis: an ominous precursor: part
I. Diagnostic insights. J Am Acad Dermatol. 2012;66:173‐184; quiz
185–6.
3. de Oliveira Ribeiro A, da Silva LCF, Martins-Filho PRS. Prevalence
of and risk factors for actinic cheilitis in Brazilian fishermen and
women. Int J Dermatol. 2014;53:1370‐1376.
4. Lopes ML, Silva Júnior FL, Lima KC, Oliveira PT, Silveira ÉJ.
Clinicopathological profile and management of 161 cases of actinic
cheilitis. An Bras Dermatol. 2015;90:505‐512.
5. Boring CC, Squires TS, Tong T. Cancer statistics, 1993. CA Cancer
J Clin. 1993;43:7‐26.
6. Fernandez Figueras MT. From actinic keratosis to squamous cell
carcinoma: pathophysiology revisited. J Eur Acad Dermatol
Venereol. 2017;31(Suppl 2):5‐7.
7. Baker SR. Risk factors in multiple carcinomas of the lip. Otolaryngol
Head Neck Surg. 1980;88:248‐251.
| 15
8. Singh G, Chatterjee M, Grewal R, Verma R. Incidence and care of
environmental dermatoses in the high--altitude region of ladakh,
India. Indian J Dermatol. 2013;58:107‐112.
9. Main JH, Pavone M. Actinic cheilitis and carcinoma of the lip. J Can
Dent Assoc. 1994;60:113‐116.
10. Vieira RA, Minicucci EM, Marques MEA, Marques SA. Actinic cheili-
tis and squamous cell carcinoma of the lip: clinical, histopathological
and immunogenetic aspects. An Bras Dermatol. 2012;87:105‐114.
11. Satorres Nieto M, Gargallo Albiol J, Gay Escoda C. Surgical
manage-ment of actinic cheilitis. Med Oral. 2001;6:205‐217.
12. Laws RA, Wilde JL, Grabski WJ. Comparison of electrodessication
with CO2 laser for the treatment of actinic cheilitis. Dermatol Surg.
2000;26:349‐353.
13. Epstein E. Treatment of lip keratoses (actinic cheilitis) with topical
fluorouracil. Arch Dermatol. 1977;113:906‐908.
14. McDonald C, Laverick S, Fleming CJ, White SJ. Treatment of actinic
cheilitis with imiquimod 5% and a retractor on the lower lip: clinical
and histological outcomes in 5 patients. Br J Oral Maxillofac Surg.
2010;48:473‐476.
15. Lima Gda S, Silva GF, Gomes AP, de Araújo LM, Salum FG.
Diclofenac in hyaluronic acid gel: an alternative treatment for actinic
cheilitis. J Appl Oral Sci. 2010;18:533‐537.
16. Tzika E, Masouyé I, Mühlstädt M, Laffitte E. Ingenol mebutate for
recalcitrant chronic actinic cheilitis. Dermatology. 2016;232(Suppl
1):1‐3.
17. Research C for DE and. Drug Safety and Availability—FDA Drug
Safety Communication: FDA warns of severe adverse events with
application of Picato (ingenol mebutate) gel for skin condition; re-
quires label changes [WWW Document]. https://www.fda.gov/
Drugs/DrugSafety/ucm459142.htm. Accessed July 4, 2018.
18. Yazdani Abyaneh M-A, Falto-Aizpurua L, Griffith RD, Nouri K.
Photodynamic therapy for actinic cheilitis: a systematic review.
Dermatol Surg. 2015;41:189‐198.
19. Sotiriou E, Apalla Z, Chovarda E, Panagiotidou D, Ioannides D.
Photodynamic therapy with 5--aminolevulinic acid in actinic chei-litis:
an 18--month clinical and histological follow--up. J Eur Acad
Dermatol Venereol. 2010;24:916‐920.
20. Rossi R, Assad GB, Buggiani G, Lotti T. Photodynamic therapy: treat-
ment of choice for actinic cheilitis? Dermatol Ther. 2008;21:412‐415.
21. Kodama M, Watanabe D, Akita Y, Tamada Y, Matsumoto Y.
Photodynamic therapy for the treatment of actinic cheilitis.
Photodermatol Photoimmunol Photomed. 2007;23:209‐210.
22. Berking C, Herzinger T, Flaig MJ, Brenner M, Borelli C, Degitz K. The
efficacy of photodynamic therapy in actinic cheilitis of the lower lip: a
prospective study of 15 patients. Dermatol Surg. 2007;33:825‐830.
23. Wiegell SR, Wulf HC, Szeimies R-M, et al. Daylight photody-namic
therapy for actinic keratosis: an international consensus:
International Society for Photodynamic Therapy in Dermatology. J
Eur Acad Dermatol Venereol. 2012;26:673‐679.
24. Barry RBM, McKenzie J, Berg D, Langtry A. Direct primary closure
without undermining in the repair of vermilionectomy defects of the
lower lip. Br J Dermatol. 2012;167:1092‐1097.
25. Alexiades-Armenakas MR, Geronemus RG. Laser--mediated
photodynamic therapy of actinic cheilitis. J Drugs Dermatol.
2004;3:548‐551.
26. Chaves YN, Torezan LA, Lourenço SV, Neto CF. Evaluation of the
efficacy of photodynamic therapy for the treatment of actinic chei-litis.
Photodermatol Photoimmunol Photomed. 2017;33:14‐21.
27. Wiegell SR, Haedersdal M, Eriksen P, Wulf HC. Photodynamic ther-
apy of actinic keratoses with 8% and 16% methyl aminolaevulinate
and home--based daylight exposure: a double--blinded randomized
clinical trial. Br J Dermatol. 2009;160:1308‐1314.
28. Wiegell SR, Fabricius S, Gniadecka M, et al. Daylight--mediated
photodynamic therapy of moderate to thick actinic keratoses of
16 | LEVI et al.

the face and scalp: a randomized multicentre study. Br J Dermatol. 32. Fai D, Romanello E, Brumana MB, et al. Daylight photodynamic
2012;166:1327‐1332. therapy with methyl--aminolevulinate for the treatment of actinic
29. Wiegell SR, Heydenreich J, Fabricius S, Wulf HC. Continuous ultra-- cheilitis. Dermatol Ther. 2015;28:355‐368.
low--intensity artificial daylight is not as effective as red LED light in
photodynamic therapy of multiple actinic keratoses. Photodermatol
Photoimmunol Photomed. 2011;27:280‐285.
How to cite this article: Levi A, Hodak E, Enk CD, Snast I,
30. Wiegell SR, Fabricius S, Heydenreich J, et al. Weather conditions and
daylight--mediated photodynamic therapy: protoporphyrin IX-- Slodownik D, Lapidoth M. Daylight photodynamic therapy for
weighted daylight doses measured in six geographical locations. Br J the treatment of actinic cheilitis. Photodermatol Photoimmunol
Dermatol. 2013;168:186‐191. Photomed. 2019;35:11–16. https://doi.org/10.1111/
31. Levi A, Wulf HC, Enk CD. Two cases of actinic cheilitis responsive to
phpp.12415
daylight--activated photodynamic therapy (DA--PDT). Photodermatol
Photoimmunol Photomed. 2013;29:268‐271.