1258
The Effect of Retinoids on Premalignant Oral Lesions
Focus on Topical Therapy
Meir Gorsky, D.M.D.1
2,3
Joel B. Epstein, D.M.D., M.S.D.
1
The Maruice and Gabriela Goldschleger School of
Dental Medicine, Tel Aviv University, Tel Aviv, Is-
rael.
2
British Columbia Cancer Agency, Vancouver,
British Columbia, Canada.
3
Department of Oral Medicine, University of
Washington, Seattle Washington.
Address for reprints: Joel B. Epstein, D.M.D.,
M.S.D., British Columbia Cancer Agency, 600 W
10th Avenue, Vancouver, British Columbia, Canada
V5Z 4E6; Fax: 604-872-4596; E-mail: jepstein@
bccancer.bc.ca
Received October 19, 2001; revision received April
11, 2002; accepted April 22, 2002.
© 2002 American Cancer Society
BACKGROUND. Retinoids have been studied as chemopreventive treatment for
patients with oropharyngeal carcinoma. Vitamin A modulates growth and differ-
entiation of cells, and its deficiency enhances susceptibility to carcinogenesis. The
chemopreventive mechanism of action of vitamin A is discussed, and a review of
clinical results and side effects of the systemic use of vitamin A is included. The
objective of the current report was to review the possible role of topical vitamin A
and vitamin A derivatives in the management of patients with oral lesions with a
risk of transformation to carcinoma.
METHODS: A Medline search was conducted and references identified within the
identified papers were also reviewed.
RESULTS. Only four studies using topical vitamin A for patients with oral leuko-
plakia have been reported. A complete response was achieved in 10 –27% of
patients, and a partial response was achieved in 54 –90% of patients; however,
recurrence of leukoplakia was reported after withdrawing the medication in ap-
proximately 50% of patients. The side effects of the topical use were minimal.
CONCLUSIONS. Although the direct application of higher concentrations of retinoic
acid results in suppression of oral leukoplakias only, its use in the treatment of
patients with recurrent and persistent lesions may be justified for controlling
lesions that otherwise may progress. Further controlled clinical studies are needed.
Cancer 2002;95:1258 – 64. © 2002 American Cancer Society.
DOI 10.1002/cncr.10874
KEYWORDS: vitamin A, retinoic acid, retinoids, oral leukoplakia, oral dysplasia.
T he term leukoplakia is a clinical descriptive term for a white lesion
of the oral mucosa that does not represent any specific histologic
condition.1,2 Any lesion in which the etiology is known should be
described with the etiology as a modifier, for example, tobacco-
associated leukoplakia and frictional or traumatic leukoplakia. Leu-
koplakia may represent histologic findings of a wide variety of con-
ditions from epithelial hyperkeratosis, hyperplasia, and dysplasia to
carcinoma. If a specific histologic diagnosis is made, then these
findings should be included in the diagnosis, for example, dysplastic
leukoplakia and hyperplastic candidiasis. Although only up to 10% of
leukoplakias may represent dysplastic lesions, up to 17.5% of the
lesions may transform into carcinoma, depending on the severity of
dysplasia.3 Because a transformation risk as high as 43% was reported
for dysplastic leukoplakias,4 patients with such lesions must be man-
aged and followed closely, so that, if malignant degeneration of the
lesion occurs, early diagnosis and treatment of the malignancy is
possible.
Recent studies have documented molecular profiles of oral dys-
plasia and the risk of progression of dysplastic lesions to malignant
disease.5–19 These molecular markers include loss of heterozygosity
 Topical Vitamin A for Oral Leukoplakia/Gorsky and Epstein
often at 3p, 9p, 17p, 8q, 11q, and 13q and other mak-
ers, such as p53. These findings that predict the pro-
gression of oral lesions to dysplasia and carcinoma
may allow the identification of lesions for treatment,
may serve as intermediate markers of interventions,
and may lead to new treatment approaches.
Current treatment approaches for patients with
oral dysplastic lesions include excision that may be
indicated for localized and accessible lesions. How-
ever, surgical management may be limited for patients
with widespread lesions when they involve sensitive
anatomic structures, such as over the ducts of major
salivary glands, or when lesions recur after repeated
excision. Excision may cause postoperative morbidity.
In addition, recurrence after local excision is common
and has been reported in 10 –35% of patients.3,4,20 –23
Chemoprevention may provide an additional ap-
proach to the management of patients with leukopla-
kia who have premalignant oropharyngeal lesions and
cannot be managed surgically or in patients who de-
velop recurrent lesions after undergoing excision. It
has been reported that topical bleomycin provides an
additional approach to the management of patients
with oral dysplastic lesions.24 Initial studies of topical
retinoids also have been reported in case series.25–27
The objective of this article was to review the current
understanding of the role of vitamin A and its deriva-
tives in the management of patients with oral lesions
who have an increased risk of malignant transforma-
tion, with a focus on topical approaches.
MATERIALS AND METHODS
A Medline search was conducted using the following
keywords: Vitamin A, retinoic acid, retinoids, oral leu-
koplakia and dysplasia. References identified within
papers identified on Medline were also reviewed.
RESULTS AND DISCUSSION
Vitamin A
Vitamin A is required in the normal pathway of epi-
thelial cell differentiation. Growth and differentiation
of normal and malignant cells in vitro have been mod-
ulated by retinoids by their effects on gene expres-
sion.28 The retinoids induce apoptosis, leading to nor-
mal maturation of dividing cells, and suppress
carcinogenesis;29,30 therefore they have been assessed
in the control and suppression of carcinogenesis. A
decrease in growth rate after exposure of epithelial
cells to retinoids also has been documented.31
Free-radical reactions can cause changes in enzy-
matic functions and DNA mutations, increasing the
risk of developing malignant cell lines. Reducing free
radicals using antioxidants, such as vitamin A, may
prevent such cellular changes.32 An association be-
tween vitamin A deficiency and the enhanced suscep-
1259
tibility to carcinogenesis was reported with an in-
creased risk for developing different epithelial
carcinomas of the lung, colon, pharynx, larynx, and
esophagus.33
Systemic Vitamin A, Oral Carcinoma, and Oral
Leukoplakia
Epidemiological studies have demonstrated that nu-
tritional factors may represent a strategic approach to
decreasing the development of squamous cell carci-
noma,34 with the retinoids showing potential as prom-
ising molecules.35,36 Retinoids are derivative com-
pounds of natural vitamin A (retinol). More than 1500
such compounds have been synthesized, and several
of these suppress cell mitosis. Retinoids have the abil-
ity to maintain adequate balance between growth,
differentiation, and cell loss. This homeostatic balance
is disturbed in malignant disease and has to be re-
stored to obtain equilibrium between proliferation
and the death of cells. Although it is believed that
retinoids have the potential to control an imbalance,
the exact mechanism is not known precisely.
13-cis retinoic acid may prevent the development
of second primary squamous cell carcinoma.37 The
expression of retinoic acid receptor ␤ (RAR-␤) mRNA,
which is lost in premalignancy, can be restored by
treatment with 13-cis retinoic acid,38 suggesting an
encouraging response to the treatment.
It is well established that p53 alteration is associ-
ated with genetic instability and tumorigenesis. The
level of p53 protein is also is associated directly with
histologic grade and response to retinoids.39 Shin et
al.40 reported a lower response rate to isotretinoin in
patients with lesions that had high baseline p53 pro-
tein levels compared with lesions in patients with low
p53 protein levels. The investigators assumed that the
high level of p53 proteins in their patients may have
been associated with mutant p53 proteins that usually
do not undergo apoptosis and have long half-lives. It is
speculated that the success of chemoprevention is
associated with specific biomarkers, including the p53
alterations, nuclear antigens, and epidermal growth
factor receptor (EGFr).41
The mechanism of action of the retinoids proba-
bly is linked to different nuclear RARs.42 The availabil-
ity of RARs and retinoids is involved in the regulation
of cell growth.43 After binding to the receptors, tran-
scription factors (heterodimers or homodimers) are
formed that bind to specific DNA sequences, leading
to an up-regulation or down-regulation that ulti-
mately affects gene transcription. It is believed that
retinoids act by regulating gene expression through
RAR nuclear receptors.44 A recent study by Beenken et
al.45 showed that pretreatment expression levels of
transforming growth factor ␣ (TGF-␣) and EGFr were
1260 CANCER September 15, 2002 / Volume 95 / Number 6
increased significantly in dysplastic leukoplakias com-
pared with normal appearing mucosa. The expression
ratios of TGF-␣ in dysplastic leukoplakias deceased
significantly after patients received systemic treat-
ment using the 13-cis retinoic acid. EGFr serves as a
biomarker for the prognostic value of retinoid treat-
ment for leukoplakia. The EGFr expression ratio in
patients with dysplastic oral leukoplakia, even though
it was decreased, was not altered significantly by sys-
temic retinoid treatment in one study.45 However,
other studies showed a reduction of EGRr expression
after exposure of cell lines to retinoic acid.46 The
mechanisms underlying the effect of retinoids on
TGF-␣ and EGFr expression are not understood fully,
although, it has been suggested46 that it occurs pri-
marily through decreased gene transcription and by
normalizing the rates of TGF-␣ and EGFr mRNA in the
cells.
The homeostasis of normal tissue represents a
balance between cell proliferation and cell apoptosis.
It has been demonstrated that retinoids alter gene
expression and induce apoptosis, as mentioned
above. Scher et al.30 investigated the effect of (4-hy-
droxyphenyl)retinamide) (4-HPR) on the growth of
head and neck squamous cell carcinoma cell lines in
vitro and found a significant antiproliferative effect.
The effect of 4-HPR occurred in a dose and time de-
pendent fashion. DNA fragmentation into multiple
base pairs of oligonucleosomes, which is one of the
features of apoptosis, was detected in some of the cell
lines treated with 4-HPR.
Because 4-HPR is well tolerated and may be less
toxic than other retinoic acids,50 and because it had
greater growth inhibition and induction of apoptosis
compared with 13-cis-retinoic acid,47,48 it was specu-
lated30 that 4-HPR controls proliferation by an addi-
tional mechanism of action. Epithelial malignancies
were suppressed in vitro by the synthetic retinoid
fenretinide (4-HPR).47,48 Other studies reported that
this retinoid was an effective chemotherapeutic agent
for nonoral tumors49 and that it had a preventive and
a well-tolerated effect on oral leukoplakia.50 It has
been shown that 4-HPR/retinamide induces apoptosis
and enhances the generation of reactive oxygen spe-
cies.51–53
The expression of apoptotic bodies was examined
in patients with oral leukoplakia who were treated
topically with 13-cis-retinoic acid.54 A significant in-
crease in apoptotic bodies was observed after the top-
ical treatment, indicating that 13-cis retinoic acid has
potential in the topical management of patients with
oral mucosal leukoplakia. Further studies will be es-
sential for the identification of specific retinoid-sensi-
tive markers and nuclear receptors for a more success-
ful outcome of chemoprevention therapy with
retinoids in patients with premalignant oral condi-
tions.
A decrease in the size of oral leukoplakia was
reported in 67% of patients who were provided sys-
temic 13-cis retinoic acid (1–2 mg/kg per day) for 3
months.55 The leukoplakia was reversed in ⬎ 80% of
patients after 6 months without the medication. Side
effects, mainly skin and mucosal dryness as well as
hypertriglyceridemia, were reported in ⬎ 50% of pa-
tients, requiring isotretinoin dose reduction; however,
the side effects reversed after the patients discontin-
ued therapy. It was demonstrated that lower doses of
13-cis retinoic acid (0.5 mg/kg per day) administered
over an extended period were less toxic compared
with high doses56 but were associated with a lower
recurrence rate after cessation of treatment. Another
study57 reported clinical improvement of oral leuko-
plakia in 62% of patients. Reversal of dysplastic laryn-
geal lesions was reported using 13-cis-retinoic acid,
␣-tocopherol, and interferon-␣ in approximately 50%
of patients at 6 months, compared with patients who
had oral lesions, in whom the protocol lead to a re-
sponse rate of ⬍ 10% at 6 months, and there were no
responses at 1 year.58,59 Recently, Leuing et al.60 used
high doses of retinyl palmitate for the treatment of six
patients with oral dysplastic leukoplakia and reported
complete histologic resolution of the dysplastic le-
sions.
The effect of Spirulina fusiformis, which is a di-
etary source of vitamin A, was evaluated in India for
chemoprevention.61 Although a significant regression
of oral leukoplakias (45% of patients) was found in
tobacco chewers, compared with only 7% of individ-
uals in a placebo control group, approximately 50% of
lesions recurred after patients discontinued the sup-
plements. Another study performed in India62 re-
ported the complete regression of oral precancerous
lesions with systemic vitamin A in 52% of patients; in
that study, two-thirds of the lesions recurred after the
patients stopped supplementation. Stich et al.63 com-
pared the outcome of 200,000 IU of vitamin A daily for
6 months on oral leukoplakia of 65 Indian tobacco/
betel nut chewers versus placebo treatment. Fifty-
seven percent of the patients who received vitamin A
demonstrated a complete response and a complete
preventive effect for the possible development of new
lesions compared with a response rate of only 3% in
the control group. Over 21% of individuals in the pla-
cebo control group developed new lesions. Silverman
et al.64 reported partial or complete resolution of leu-
koplakia in 44% of their patients who were treated
using systemic vitamin A. Discontinuation of the sys-
temic therapy resulted in recurrence of the leukopla-
kia in 75% of the patients who experienced complete
resolution. Only 30% of 10 patients with oral leuko-
 Topical Vitamin A for Oral Leukoplakia/Gorsky and Epstein
TABLE 1
Toxicity Profile of Systemic Vitamin A and Retinoids
Dermatologic
Dry skin and dermatitis
Thinning of hair
Nail dystrophy
Facial erythema and skin rash
Peeling of palms and soles
Tinnitus
Musculoskeltal
Arthralgia
Chest pain and tachycardia
Skeltal hyperostosis
Mucosal and internal
Dry lips (chielitis)
Burning lips/tongue
Epistaxis
Dry eyes
Inflammatory bowel diseases
Xerostomia
Mucositis
Bleeding of gums
Conjunctivitis and photophobia
Abnormal menses
Systemic
Headache and malaise
Decreased night vision
Liver toxicity
Decrease in serum HDL level
Elevated sedimentation rate
Elevated fasting sugar
Weight loss
Teratogenisis
Depression or psychosis
Hypertrigliceridemia
Elevation of serum cholesterol
Anemia and leukopenia
Proteinuria and hematuria
HDL: high-density lipoprotein.
plakia who received 50 mg per day of isotretinoin
experienced some response;65 however, drug toxicity
forced a dose reduction in 60% of their patients.
In conclusion, a complete resolution was achieved
in 44 –57% of patients who were treated with systemic
retinoids. The recurrence rate of those patients ranged
between 66% and 80%. A decrease in the size of the
lesions was reported in 45– 67% of patients.
Considerable dose dependant toxicity has been
seen with use of systemic vitamin A and its derivatives
(Table 1). In prophylactic doses, the toxicities include
mainly skin rash, dryness and bleeding of the nasal
mucosa, conjunctivitis, oral mucositis, cheilitis, hy-
pertriglycerinemia, and teratogenic effects.55,66 It was
reported that the systemic use of vitamin A and its
derivatives in patients with leukoplakia,64,67 as well as
in patients with other oral conditions,68 was associ-
ated with a high prevalence of side effects. Natural
vitamin A at clinically tolerated doses has only limited
1261
activity against human neoplastic conditions.69 There-
fore, clinical work has focused on the systemic deriv-
atives with a higher therapeutic index.
In some patients, systemic treatment is much less
tolerable than the disease itself and the lesion is sup-
pressed, with recurrence if treatment is discontinued.
It was suggested44 that high-dose induction using reti-
noic acid followed by low-dose therapy as mainte-
nance may reduce toxicity, control the lesion, and
provide be a viable approach to management.
Topical Vitamin A
The topical use of vitamin A compounds for oral white
lesions is well known. Although vitamin A was used for
controlling oral lesions of lichen planus,70,71 to the
best of our knowledge, only preliminary studies using
topical vitamin A for oral leukoplakia have been re-
ported (Table 2). Topical therapy has the potential
advantages of high local dose with low systemic expo-
sure, limiting the risk of systemic side effects. How-
ever, topical application requires patient willingness
and ability to comply with repeated local application.
In addition, there may be sites where topical applica-
tion is difficult, and the medication may be diluted by
saliva. Local tissue irritation may occur in the form of
tissue sensitivity and burning with current topical ap-
plications due to the acidic nature of the topical prod-
ucts or the base in which the medication is placed.
A 6-month dose ranging trial of isotretinoin loz-
enges was performed that included 16 patents with
oral leukoplakia.72 When the effect of retinoids (in the
form of 1–5 mg 13-cis retinoic acid oral lozenges) on
oral leukoplakia was evaluated clinically,72 thinning of
the leukoplakia and a reduction in the white surface
was noted as the initial visible response. Three of 11
patients who completed the trial had a complete, vis-
ible clinical response (27%), and 6 of 11 patients (54%)
had a partial response, which was defined as a de-
crease ⱖ 50% in the size of the lesion. In 2 of 3 patients
(67%) who achieved a complete response, leukoplakia
returned within 5 weeks. In 1 patient (33%), leukopla-
kia has not recurred during 11 months of follow-up,
although his final histopathologic examination
showed hyperkeratosis. Toxicity, consisting of skin
and mucosal dryness, epistaxis, and mucositis, was
mild. Although the trial by Shah et al.72 is considered
a topical approach to the management of patients
with leukoplakia, this form of drug delivery represents
a combination of topical and systemic dosing. Indeed,
the systemic side effects may serve as a confirmation
of such a systemic effect.
Although 80% of the patients who were treated by
Shah et al., along with other patients with leukoplakia
who were treated systemically, had documented re-
mission that was credited directly to the use of retin-
1262 CANCER September 15, 2002 / Volume 95 / Number 6
TABLE 2
Impact of Topical Vitamin A on Oral Leukoplakia
Study Location Patients
Shah et al.72 USA 11
Epstein and Gorsky25 Canada 26
Piattelli et al.54 Italy 10
Tete et al.73 Italy 14
N/A: not available.
a
At least 50% reduction in clinical size.
oids, spontaneous remission does occur. Pindborg et
al.4 reported that 37.4% of patients with leukoplakia
will reverse spontaneously either totally or partially
without any medical clinical intervention.
Epstein and Gorsky25 used 0.05% tretinoin gel that
was applied topically 4 times per day for the manage-
ment of nonmalignant oral white lesions in 26 patients
(17 men and 9 women) with a mean age of 62 years.
The vitamin A acid gel was applied locally for a mean
of 3.5 years in patients who experienced clinical im-
provement. Although a complete clinical remission
was reported in 27% of patients, a partial response was
noted in 54% of patients, and clinical recurrence was
experienced in about 50% of patients after the topical
treatment was discontinued. Side effects of only a
localized soreness were reported by only 19% of pa-
tients.
In a study by Piattelli et al.,54 topical 0.1% 13-cis
retinoic acid (isotretinoin) gel was applied 3 times per
day in 10 patients (6 males and 4 females; mean age,
61 years) with oral leukoplakia. The medication was
used for 4 months, and a complete response was
noted in 1 patient (10%), although 90% of patients
experienced a reduction in size of at least 50%, repre-
senting a partial response. No side effects were re-
ported. Tete et al.73 evaluated the effect of 0.1%
isotretinoin gel applied topically 3 times per day on 14
patients with oral leukoplakia, and complete remis-
sion was noted in 3 patients (21.5%). A marked im-
provement (a reduction in size ⱖ 50%) was achieved
in 11 patients (78.5%) in 4 months of treatment.
The combined results of the two similar studies
from Italy54,73 indicate a complete response in 16.5%
of patients who were treated with topical 0.1% isotreti-
noin and complete resolution in ⬎ 25% of patients
who applied 0.05% tretinoin in the study reported by
Epstein and Gorsky.25 Further studies will be neces-
sary to confirm the complete and partial response
rates with topical retinoid applications.
It is possible that the local application of retinoic
acid results in a higher concentration of the substance
directly in the target tissue, while avoiding systemic
Mean age Complete response Partial response Clinical recurrence Follow-up
(yrs) (%) (%)a (%) (mos)
N/A 27 54 90 11
62 27 54 40 3.5 yrs
61 10 90 N/A 4
N/A 21.5 78.5 N/A 4
side effects. It is important to recognize that, even with
clinical effect, cellular (phenotypic) and molecular ef-
fects may or may not occur, and the use of molecular
markers may provide additional information for as-
sessing the intermediate effects of intervention. Stud-
ies of systemic and topical delivery of vitamin A and
retinoids show that, in patients who respond, lesions
frequently will recur when the application is discon-
tinued, suggesting that suppression of the condition
may be achieved but that cure is not certain, even with
clinical improvement or, indeed, clinical resolution.
However, in patients with recurring and persisting
lesions for whom other treatments have failed or are
not provided, prevention of disease progression with a
therapy of limited toxicity, such as topical retinoids,
may control some lesions that otherwise may
progress.
CONCLUSIONS
Although vitamin A and derivative retinoids have been
successful in temporarily decreasing the clinical pres-
ence of leukoplakia, the toxicity of the medications
with systemic administration remains a significant
problem and has an important impact on common
and long-term usage. The long-term effectiveness of
chemoprevention has not been established to date,
and the choice of agents requires further study. Ad-
vances in single or combined chemopreventive med-
ications for the topical or systemic control of leuko-
plakia may decrease the potential of malignant
transformation. Similar outcomes appear to have
been achieved with systemic and topical retinoids,
with resolution in 27–57%, of patients, a partial re-
sponse in 45–90% of patients, and recurrences in ap-
proximately 50% of patients if the retinoid is discon-
tinued. Prospective controlled studies are needed to
establish the value of chemoprevention in patients
with oral leukoplakia and to assess the potential role
of topically applied retinoids. The preliminary studies
to date provide support for further study, and double-
blind, randomized, controlled clinical trials with top-
ical retinoids are needed. Further studies should as-
 Topical Vitamin A for Oral Leukoplakia/Gorsky and Epstein
sess the mucosal lesions according to accepted
criteria,2,74,75 including the size and nature of lesions,
and they should include analysis of the histology and
possibly of molecular components.
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