Journal of Medicine, Radiology, Pathology & Surgery (2016), 2, 1822

REVIEW ARTICLE

Oral leukoplakia: A review and its update

E. B. Kayalvizhi1, V. L. Lakshman1, G. Sitra1, S. Yoga1, R. Kanmani2, N Megalai3
Department of Oral Medicine and Radiology, Indira Gandhi Institute of Dental Sciences, Pondicherry, India, 2Department of Oral Medicine and Radiology, SRM
Dental College & Hospital, Chennai, Tamil Nadu, India, 3Department of Paediatrics and Preventive Dentistry, Sri Venkateswara Dental College, Pondicherry, India
1

Keywords:
Candida, leukoplakia, oral mucosa, smoking
Correspondence:
E. B. Kayalvizhi, Department of Oral Medicine
and Radiology, Indira Gandhi Institute
of Dental Sciences, Pondicherry, India.
Phone:+91-9843717410.
Email: ebkdentalcare@gmail.com

Abstract
Oral leukoplakia (OL) is the most common potentially malignant disorder of the oral
mucosa. The etiological role of Candida in leukoplakia has been a subject of debate
in recent years. Candida invasion has been suggested to be a significant risk factor for
malignant transformation of OL and also it may be associated with certain clinical
characteristics such as lesion type, size, and site, dysplasia, and tobacco use. Several
studies showed that the greater risk of malignant change in women than men. Finally,
the management of this common condition remains a variable and includes local, topical,
and systemic therapies such as anti-oxidants, carotenoids, and antifungal therapies.

Received: 02 November 2015;

Accepted: 10 February 2016
doi: 10.15713/ins.jmrps.52

Introduction
Oral leukoplakia (OL) is one among important potentially
malignant disorder (PMD) of the oral mucosa. It has been
defined as a predominantly white lesion of the oral mucosa
that cannot be characterized as any other definable lesion.[1]
Leukoplakia is being recognized by two forms: Homogeneous
and the non-homogeneous type. Homogeneous leukoplakia
has predominantly white lesion of uniform flat, thin appearance,
smooth, wrinkled or corrugated surface throughout the lesion,
whereas non-homogeneous leukoplakia has been a mixture of
white-and-red lesion that may be either irregularly flat, nodular,
or verrucous.[2] Leukoplakia shows characteristic histologic
findings such as epithelial hyperplasia, and/or hyperkeratosis,
with or without epithelial dysplasia or carcinoma.[3] The pooled
estimate of the annual rate of OL malignant transformation is
1.36% (0.69-2.03%).[4] Increased malignant potential may be
associated with certain clinical characteristics such as lesion type,
size, and site, dysplasia, and tobacco use.
Terminology and Definitions of OL
International attempts to definerefine WHO definition of OL
are as follows: Kramer (1978) had recognized the malignant
potential of leukokeratosis and smokers patch and its relationship
to pipe smoking.[5] Paget (1860) recognized an association
18

between a white keratotic oral lesion and lingual carcinoma.[5]

Kramer (1978) suggested the term leukoplakia describe white
raised lesion involving oral mucosa. It was also called as leukoma,
smokers patch, leukokeratosis, and ichthyosis.[5]
Butlin (1885) related these lesions to smoking and considered
smokers patch to be an early stage of a more advanced white
raised lesion that he called as leukoma. Axll (1996) states
leukoplakia as a white patch measuring 5mm or more which
cannot be scrapped off and cannot be attributed to any other
diagnostic disease.[6]
The First International Conference on OL (1984) Malmo,
Sweden: Described leukoplakia as A white patch or plaque
that cannot be characterized clinically or pathologically as any
other disease and is not associated with any physical or chemical
causative agent except the use of tobacco.[1]
In a conference of Uppsala (1994), it was established that it
would be the predominantly white lesion of the oral mucosa
which could not be clinically or pathologically characterized as
another specific entity.[6] As per the International Symposium,
Uppsala, Sweden (1996): It is a predominantly white lesion
of the oral mucosa that cannot be characterized as any other
definable disease.[6]
The WHO (1997) described leukoplakia as a predominantly
white lesion of the oral mucosa that cannot be characterized as
any other definable lesion.[7] According to Warnakulasuriya
et al. (2007), leukoplakia should be used to recognize
Journal of Medicine, Radiology, Pathology & Surgery Vol. 2:2 Mar-Apr 2016

Kayalvizhi, et al.

Leukoplakia and its review

white plaques of questionable risk having excluded (other)

known diseases or disorders that carry no increased risk for
cancer.[1] Warnakulasuriya et al. (2007) defined this lesion as
a white plaque with an increasing questionable oral cancer risk
after excluding other known diseases and disorders that do not
increase the risk.[1]
Incidence and prevalence

In the year 1992, Gupta et al. found a wide range of leukoplakia

prevalence in various populations. In India, leukoplakia was
found in 0.2% and 4.9% of the population present over 15years
of age.[8] Bnczy (1983) found that the adult population
prevalence varied between 0.6% and 3.6%.[9] Downer and
Petti found an annual oral cancer incidence rate attributable to
leukoplakia between 6.2 and 29.1cases per 100,000 people.[10]
Martorell-Calatayud et al. found the prevalence of OL ranges
from 0.4% to 0.7% of the population.[11] Feller and Lemmer
estimated the prevalence of OL ranged from 0.5% to 3.46%, and
also found the malignant transformation of OL from 0.7% to
2.9%.[7]
Brouns et al. found the prevalence of OL is approximately 2%
with an annual mal ignant transformation of approximately 1%.[12]
Age and gender

Bnczy (1977) estimated that the incidence of malignant

transformation as 5.8% in women and 2.1% in men, and the
incidence was higher in patients who were habitual smokers
or drinker.[13] Bnczy (1977) found that the increased risk of
malignant change in women than men.[13] Bnczy revealed the
prevalence of leukoplakia in the age-group of 51-60years and sex
distribution showed a male:female ratio of 3.2:1.[13]
Espinoza (2003) reported the higher prevalence present
in men after 50years of age.[14] Espinoza et al. reported
leukoplakia in all age groups with increased prevalence in the old
population, ranging from 0.35% to 18.6%.[14] Downer and Petti
found leukoplakia to be significantly more prevalent in males
(prevalence ratio 3.22).[10]
Liu et al. conducted study on 218patients and he found
that peak incidence was the fifth decade of life (33.0%), and the
gender ratio was equal.[4] Brzak et al. in his study between 1998
and 2007, including 12,508patients found that women were
found as predominantly affected.[15] Brouns et al. found the mean
age of 57years among 275patients consisted of 112 men and
163 women.[12]
Site specificity

Axll et al. (1996) found that leukoplakia was commonly present

in buccal mucosa (76%), alveolar sulcus (19%), and tongue
(5%).[6] On the contrary, Schepmans (1998) conducted a
follow-up study in 166patients on hospital-based population
and found that the most frequent location of leukoplakia to be
the vestibular mucosa.
Martorell-Calatayud et al. found that leukoplakia usually
located on the floor of the mouth and in the ventrolateral region

of the tongue with a greater risk of malignant transformation

with an average rate of transformation of 43%. This is attributed
to the fact that these areas are more exposed to carcinogens in
salivary secretions and that the epithelium is more permeable in
this area.[11]
Liu et al. conducted a study on 218patients and found that
tongue was affected in 51.4% patients with OL and 32.6% in
buccal mucosa. Afew lesions on the floor of mouth (FOM) and
lip were probably due to the different ethnic population studied,
nature of habit, and placement of the quid.[4]
Brouns et al. found the location of the OL specified according
to eight subsites: Tongue, FOM, lower lip, hard palate, buccal
mucosa, upper alveolus and gingiva, lower alveolus, and gingiva
and finally in multiples sites.[12]
Clinical diagnosis

Leukoplakia usually present as a single or multiple lesion,

localized change of the oral mucosa. The site distribution
shows world-wide differences that are partly related to gender
and tobacco habits. In fact, any oral site may be affected. Two
clinical variants of leukoplakia such as homogeneous and the
non-homogeneous type.[2] Daftary et al. (1972) conducted a
study among leukoplakia patients and observed that 32% had
nodular leukoplakia, 16% had ulcerated leukoplakia, and 52%
had homogeneous leukoplakia.
Brouns et al. (2013) found that 52.7% had homogeneous
leukoplakia and 47.27% cases had non-homogeneous
leukoplakia. The reasons for the higher incidence of homogenous
leukoplakia in the present study are difficult to explain as they
are multifactorial. It could be due to variation in the availability
of tobacco products, consumption of tobacco with or without
slaked lime, duration and frequency of tobacco products
combined with alcohol usage in the Indian population.[13]
Etiopathogenesis

Roed-Petersen et al. (1972) and Daftary et al. (1972) found

that according to the recent reports etiological role of Candida
infection to be more important. Although Candida infection was
present only in 13.5%, of the total leukoplakia group. The role
of Candida in correlation with the clinical types and histological
dysplasias has been evaluated positively in the literature.[16]
Bnczy said that Candida albicans infection and the
simultaneous existence seemed to play a role in malignant
transformation among the etiological factors, and leukoplakia
found the highest risk of developing into cancer (25.9%).[13] Krogh
et al. have found that higher nitrosation potentials of candidal
organisms can be isolated from non-homogeneous leukoplakias
than homogeneous forms.[17]
Bnczy (1977) observed statistically significant decrease in
serum levels of Vitamin A, B12, C, beta carotene, and folic acid in
patients with OL compared to controls.[13] Soames and Southam
reported that the changes of developing leukoplakia were more
in the areas of epithelial atrophy and the conditions associated
with mucosal atrophy included iron deficiency, some vitamin

Journal of Medicine, Radiology, Pathology & Surgery Vol. 2:2 Mar-Apr 201619

Kayalvizhi, et al. 

deficiencies, and oral submucous fibrosis. Soames and Southam

reported mutations of p53 in the cells from dysplastic areas of
some leukoplakias who smoke and drink heavily.[18]
Schepman et al. found that smokers have 6times higher risk
of developing leukoplakia than non-smokers, despite lesions
of non-smokers having a greater probability to evolve into
cancer.[19]
Morse et al. observed that alcohol consumption was more
strongly associated with oral carcinoma than with epithelial
dysplasia, particularly where drinks such as beer and spirits and
high consumption levels were concerned.[20]
Caldeira et al. (2011) found a high-risk factor of leukoplakia
for malignant transformation is the infection with human
papilloma viruses as the expression of oncogenic proteins such
as human papillomavirus-16L1 can promote carcinogenesis.
Brzak et al. conducted study including 12,508patients between
1998 and 2007 and found the highest frequency of leukoplakia
in smokers.[15]
Various Forms of Leukoplakia
1. Proliferative verrucous leukoplakia (PVL): Hansen et al.
(1985) first described PVL is a distinct clinical form of OL.
PVL has a high rate of malignant transformation which was
described by the WHO. It is multifocal progressive lesions,
found in women. Most frequently affected area was the lower
gingival, tongue, buccal mucosa, and alveolar ridge[1]
2. Oral erythroleukoplakia (OEL) is a non-homogenous
lesion of mixed white and red components. It is defined
as a fiery red patch that cannot be characterized clinically
or pathologically as any other definable disease. OEL
shows a higher malignant transformation potential than
homogeneous leukoplakia[1]
3. Sublingual keratosis: It is a soft white plaque in the sublingual
region with a wrinkled surface, an irregular but well-defined
outline and sometimes a butterfly shape[21]
4. Candidal leukoplakia (CL) is a chronic, discrete elevated
lesions that are palpable, translucent, whitish areas to large,
dense, opaque plaques, hard and rough to the touch[22]
5. Oral hairy leukoplakia (OHL) otherwise known as
Greenspan lesion. In 1984, Greenspan et al. first described
OHL characterized by whitish patches with a corrugated
or hairy surface and most commonly present on the lateral
borders of the tongue. It is caused by the reactivation of a
previous Epstein-Barr virus infection.[23]
Overall Risk Factors for Malignant Transformation in
Leukoplakia
Warnakulasuriya et al. were listed as a risk for malignant
transformation in PMD.[1]
1. Female gender
2. Long duration of leukoplakia
3. Leukoplakia in non-smokers (idiopathic leukoplakia)
4. Location on the tongue and/or floor of the mouth
20

Leukoplakia and its review

5.
6.
7.
8.

Size >200 mm2

Non-homogeneous type
Presence of C. albicans
Presence of epithelial dysplasia.

Treatment

Cawson (1996) reported that leukoplakia showed improvement

and disappearance of a significant number of their cases with
polyene-nystatin (tablets) dissolved slowly in the mouth.[24]
Ramanathan et al. suggested that the candida-associated
leukoplakia (speckled leukoplakia) may respond to topical
antifungal agents including imidazoles.[25]
Lamey et al. (1994) reported an OL with epithelial dysplasia
that resolved within 11days of systemic treatment with
fluconazole antifungal agent.[26]
Garber found that the anti-candidal treatment strategy was
helpful in ruling out a possible fungal etiology for lesions. In
immuno-compromised persons, candidal lesions may require
the use of more toxic drugs such as amphotericin B.[27]
van der Waal and Axll stated if the patient had a white
lesion in oral mucosa, the clinician would first try to rule out
any of the definable white lesions before accepting a distinct
clinical diagnosis of leukoplakia. For instance, in the case of a
non-homogeneous white and red lesion, the result of antifungal
treatment may be awaited for a period of 2-4week. A2-4weeks
interval to observe the possible regression or disappearance of
a white lesion after elimination of possible causative factors,
including smoking habits, seems a fully acceptable period of
time for the general practitioner before taking a biopsy or before
referring the patient to a specialist for further advice.[2]
Lodi and Porter showed in a review of various treatments for
leukoplakias that carbon dioxide (CO2) LASER vaporization
showed maximal while CO2 LASER evaporation showed
minimal recurrence of leukoplakia. However, cryosurgery
and conventional blade surgery showed up to 22% and 13%
recurrence rates, respectively.[28]
Blaggana et al. suggested that beta-carotene, a therapeutic
dose of 75,000 to 300,000IU for a period of 3-month is advised,
and also suggested that 13-cis-retinoic acid a synthetic analog
of Vitamin A, given in doses of 1.5-2 mg/kg body weight for
3months.[29]
Blaggana (2011) found in his 3months follow-up study
lycopene appeared to be a promising agent in the management
of OL.[29]
Nystatin therapy is given in CL. 500,000IU twice daily with
20% borax glycerol or 1% gentian violet or mouth rinses with
chlorogen solution showed a favorable response. Along with
Vitamin B-complex is given as a supplement in cases of lesion
seen in commissural and lingual areas.[29]
Wu et al. concluded that patients with OL of the tongue with
epithelial dysplasia had much higher risk of candidal infection.
Antifungal therapy was further recommended to be the routine
treatment.[3]
Journal of Medicine, Radiology, Pathology & Surgery Vol. 2:2 Mar-Apr 2016

Leukoplakia and its review

Treatment Guidelines for OL-Longshore and

Camisa[30]
1. Eliminate all contributing factors
2. Absence of dysplasia or presence of mild dysplasia-surgical
excision/laser surgery of the lesions on the ventral/lateral
tongue, floor of the mouth, soft palate, and oropharynx. Close
observation and follow-up for all other anatomic locations
3. Presence of moderate or severe dysplasia-surgical excision
or laser therapy is preferred treatments
4. Red lesions (erythroplakia or leukoerythroplakia)-Surgical
removal is best
5. Proliferative verrucous leukoplakia-Complete surgical
excision/laser surgery if possible
6. Follow-up for all lesions.
Conclusion
A thorough knowledge on various aspects of these pre-cancerous
entities shall render a clinician to make appropriate diagnosis or
plan treatment. In an Indian scenario, mostly leukoplakia are habit
associated, tobacco usage over several years remains an important
etiologic factor, in particular, smoking tobacco including
chewing and other forms of tobacco are proven etiologic causes
of mucosal alterations as well. So, health education, counseling
the individual, and behavioral therapies are most essential
methods of prevention at a primary level. Understanding the
determinants of malignant transformation will help us better
to estimate the cumulative risk at which a specific individual is
with a leukoplakia. Thus, a complete knowledge from etiology of
the disorder to diagnosis and provision of appropriate treatment
is all in the benefit of preventing a leukoplakia from becoming
malignant.
References
1. Warnakulasuriya S, Johnson NW, van der Waal I. Nomenclature
and classification of potentially malignant disorders of the oral
mucosa. JOral Pathol Med 2007;36:575-80.
2. van der Waal I, Axll T. Oral leukoplakia: A proposal for uniform
reporting. Oral Oncol 2002;38:521-6.
3. Wu L, Feng J, Shi L, Shen X, Liu W, Zhou Z. Candidal infection
in oral leukoplakia: A clinicopathologic study of 396 patients
from eastern China. Ann Diagn Pathol 2013;17:37-40.
4. Liu W, Wang YF, Zhou HW, Shi P, Zhou ZT, Tang GY. Malignant
transformation of oral leukoplakia: A retrospective cohort study
of 218 Chinese patients. BMC Cancer 2010;10:685.
5. Kramer IR, Lucas RB, Pindborg JJ, Sobin LH. Definition of
leukoplakia and related lesions: An aid to studies on oral
precancer. Oral Surg Oral Med Oral Pathol 1978;46:518-39.
6. Axll T, Pindborg JJ, Smith CJ, van der Waal I. Oral white lesions
with special reference to precancerous and tobacco - Related
lesions: Conclusions of an International Symposium held in
Uppsala, Sweden, May 18-211994. International Collaborative
Group on Oral White Lesions. JOral Pathol Med 1996;25:49-54.
7. Feller L, Lemmer J. Oral leukoplakia as it relates to HPV
infection: Areview. Int J Dent 2012;2012:540561.

Kayalvizhi, et al.

8. Gupta PC, Mehta FS, Pindborg JJ, Bhonsle RB, Murti PR,
DaftaryDK, et al. Primary prevention trial of oral cancer in India:
A 10-year follow-up study. JOral Pathol Med 1992;21:433-9.
9. Bnczy J. Oral leukoplakia and other white lesions of the oral
mucosa related to dermatological disorders. J Cutan Pathol
1983;10:238-56.
10. Downer MC, Petti S. Leukoplakia prevalence estimate lower
than expected. Evid Based Dent 2005;6:12.
11. Martorell-Calatayud A, Botella-Estrada R, Bagn-Sebastin JV,
Sanmartn-Jimnez O, Guilln-Baronaa C. Oral leukoplakia:
Clinical, histopathologic, and molecular features and therapeutic
approach. Actas Dermosifiliogr 2009;100:669-84.
12. Brouns ER, Baart JA, Bloemena E, Karagozoglu H, van der
Waal I. The relevance of uniform reporting in oral leukoplakia:
Definition, certainty factor and staging based on experience with
275patients. Med Oral Patol Oral Cir Bucal 2013;18:e1926.
13. Bnczy J. Follow-up studies in oral leukoplakia. J Maxillofac
Surg 1977;5:69-75.
14. Espinoza I, Rojas R, Aranda W, Gamonal J. Prevalence of oral
mucosal lesions in elderly people in Santiago, Chile. J Oral
Pathol Med 2003;32:571-5.
15.
Brzak BL, Mravak-Stipetic M, Canjuga I, Baricevic M,
Balicevic D, Sikora M, et al. The frequency and malignant
transformation rate of oral lichen planus and leukoplakia A
retrospective study. Coll Antropol 2012;36:773-7.
16. Roed-Petersen B, Gupta PC, Pindborg JJ, Singh B. Association
between oral leukoplakia and sex, age, and tobacco habits. Bull
World Health Organ 1972;47:13-9.
17.
Krogh P, Hald B, Holmstrup P. Possible mycological
etiology of oral mucosal cancer: Catalytic potential of
infecting Candida albicans and other yeasts in production of
N-nitrosobenzylmethylamine. Carcinogenesis 1987;8:1543-8.
18. Soames JV, Southam JC. Oral Pathology. Oxford: Oxford
University of Press; 1999. p.139-40.
19. Schepman KP, Bezemer PD, van der Meij EH, Smeele LE,
van der Waal I. Tobacco usage in relation to the anatomical site
of oral leukoplakia. Oral Dis 2001;7:25-7.
20.
Morse DE, Psoter WJ, Cleveland D, Cohen D, MohitTabatabaiM, Kosis DL, et al. Smoking and drinking in relation
to oral cancer and oral epithelial dysplasia. Cancer Causes
Control 2007;18:919-29.
21. Scully C, Porter S. Orofacial disease: Update for the dental
clinical team: 3. White lesions. Dent Update 1999;26:123-9.
22. Scully C, el-Kabir M, Samaranayake LP. Candida and oral
candidosis: A review. Crit Rev Oral Biol Med 1994;5:125-57.
23. van der Waal I, Schepman KP, van der Meij EH, Smeele LE.
Oral leukoplakia: A clinicopathological review. Oral Oncol
1997;33:291-301.
24. Cawson RA. Chronic oral candidiasis and leukoplakia. Oral
Surg Oral Med Oral Pathol 1966;22:582-91.
25. Ramanathan K, Han NK, Chelvanayagam PI. Oral candidiasis
Its pleomorphic clinical manifestations, diagnosis and treatment.
Dent J Malays 1985;8:39-45.
26. Lamey PJ, Douglas PS, Napier SS. Secretor status and oral
cancer. Br J Oral Maxillofac Surg 1994;32:214-7.
27. Garber GE. Treatment of oral Candida mucositis infections.
Drugs 1994;47:734-40.
28. Lodi G, Porter S. Management of potentially malignant disorders:
Evidence and critique. JOral Pathol Med 2008;37:639.
29. Blaggana A, Blaggana V, Vohra P. Oral leukoplakia: Atherapeutic

Journal of Medicine, Radiology, Pathology & Surgery Vol. 2:2 Mar-Apr 201621

Kayalvizhi, et al. 

challenge-An update. JInnov Dent 2011;1:1-5.

30. Longshore SJ, Camisa C. Detection and management of
premalignant oral leukoplakia. Dermatol Ther 2002;15:
229-35.

22

Leukoplakia and its review

How to cite this article: Kayalvizhi EB, Lakshman VL,

Sitra G, Yoga S, Kanmani R, Manimegalai. Oral leukoplakia:
Areview and its update. JMed Radiol Pathol Surg 2016;2:18-22.

Journal of Medicine, Radiology, Pathology & Surgery Vol. 2:2 Mar-Apr 2016