______________________________________________________ REVIEW

ARTICLE

Oral Leukoplakia: A Therapeutic Challenge-An Update

Blaggana A.1, Blaggana V.2, Vohra P.3

Abstract:
Owing to the stressful life patterns leading to harmful oral habits, dentistry is witnessing an
upsurge in various lesions, particularly leukoplakia. Though it is the most common precancerous lesion, yet it poses a major diagnostic and therapeutic challenge. An attempt has
been made to comprehensively lay down the clinical relevance, presentations, and the
therapeutic modalities available, employing a molecular approach for optimal clinical
management of the disease.
Key words: Leukoplakia, white patch, tobacco chewing, precancerous.

Introduction:

Based on work by the Pindborg

school[1], WHO defined leukoplakia as a
whitish patch or plaque that cannot be
characterized, clinically or pathologically, as
any other disease and which is not
associated with any other physical or
chemical causative agent except the use of
tobacco. The literature, however, strongly
indicates the role of alcohol, viruses and
systemic conditions, thus needing further
investigations[2,3]. Oral cancer accounts for
approximately 650,000 new cases each
year[4] with no reported improvement in the
survival rate in the last 30 years[5]. The 5year survival rate has reached 80% in cases
detected at the initial stage, 40% in cases of
regional involvement, and less than 20% in
cases with distant metastasis[4]. The delay in
diagnosis is yet another manipulative factor
occurring due to the fact that patients often

do not seek oral care for an unusual oral

situation which is coupled lack of
knowledge about these lesions among health
professionals [6]. Nowadays, certain authors
recommend that an initial clinical diagnosis
of leukoplakia should be considered
provisional and confirmed histologically if
the lesion persists after 2-4 weeks and when
all other possible etiologic risk factors have
been ruled out[7].
World Health Organization in
collaboration with the Center for Oral
Cancer and Precancer in the United
Kingdom in May 2005 replaced the term
pre-cancerous lesions to potentially
malignant disorders which included oral
leukoplakia among other diseases[8]. Dentists
therefore play an important role in early
detection of malignant and premalignant
conditions and providing timely therapeutic
intervention
to
institute
prevention.

Correspondence: Dr. Anshu Blaggana, Reader, Deptt. of Periodontics, PDM Dental College & Research Institute,
Bahadurgarh-124507, Haryana, India. E-mail: dranshublaggana@yahoo.co.in, Tel. no. +91-9953110980.
1

Reader, 2Reader, Deptt. of Periodontics, PDM Dental College & Research Institute, Bahadurgarh-124507, Haryana,
Lecturer, Deptt. of Oral Medicine and Radiology PDM Dental College & Research Institute, Bahadurgarh-124507,
Haryana, India.
3

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Clinical features:
Most commonly, older age group males in the
age group of 35-45 years are affected.
Prevalence in India is 0.2-4.9 percent, with most
common sites as buccal mucosa and
commissures, followed by lips, tongue, palate,
alveolar ridge, floor of mouth, soft palate and
gingiva[9,10].
Clinical Types: Homogenous: It is also called
as leukoplakia simplex. It accounts for 84
percent of cases. Morphologically it appears as a
localized lesion with extensive white patch, with
a relatively consistent pattern throughout.
Leukoplakias which are seen amongst clay pipe
smokers and betel quid chewers are generally of
homogenous type.
Ulcerated leukoplakia: It occurs in 13 percent
of cases. Appearance is characterized by red
area, which at times exhibit yellowish areas of
fibrin, giving the appearance of ulceration.
Nodular leukoplakia: It is also called as
leukoplakia erosiva or speckled leukoplakia. A
mixed red and white lesion is seen, in which
small keratotic nodules are scattered over an
atrophic patch of oral mucosa.
Verrucous leukoplakia: It is also called as
leukoplakia verrucosa. It is a white lesion with a
broken down surface due to multiple papillary
projections, which may be heavily keratinized.
In due course of time erythematous component
may develop in the lesion.
Malignant potential:
It is higher in women (6%) than men (3.9%),
due to involvement of endogenous factors.
Leukoplakia associated with habit of chewing
tobacco shows higher rate of transformation as
compared to others. In buccal mucosa and
commissure region 1.8 percent malignant
transformation occurs. In lip and tongue region
16 to 38.8 percent malignant transformation
occurs. The annual malignant transformation
rate has been determined to be 0.1% to
17%[11,12]. Less than half (33% to 42%) of
leukoplakias which undergo malignant change,

REPORT

does so within 2 years of diagnosis [13] and the

incidence of malignant transformation has been
discovered to increase with the duration of
follow up[14].
Nodular dysplasia has higher risk of malignant
transformation than other clinical types.
Idiopathic leukoplakia and candida-associated
leukoplakia have also been identified as high
risk cases.
Management:
Lodi et al[15] proposed a comprehensive
treatment plan for patients demonstrating a
variety of high to low risk potential of
conversion into malignant lesion as:
Active
Surgical removal of the lesion, including
surgical excision, laser surgery, cryotherapy.
Topical medical treatment, including antiinflammatory agents, antimycotic agents,
carotenoids and retinoids, cytotoxic agents, etc.
Systemic medical treatment.
Removal of predisposing habits (e.g. tobacco,
alcohol, etc.).
Other treatment (e.g. photodynamic therapy).
Combined treatment.
Control
Placebo.
No treatment.
The degree of epithelial dysplasia plays a pivotal
role while deciding onto the nature of treatment
to be dispensed for the patient. MartorellCalatayud[16] defined two risk groups and the
subsequent treatment options as:
1. Group with low risk of malignisation,
comprising:
a) Those leukoplakias lacking dysplasia, and b)
those that show mild dysplasia located in lowrisk areas or those with a thickness of less than
200 mm or that present clinically as
homogenous leukoplakia. A range of therapeutic
approaches can be taken in this group:
Regular patient follow-up. The interval
between follow-up visits should not exceed 12
months in order to detect any change, suggestive
of malignant transformation.
Treatment of lesions with topical or oral
retinoids. Experience in the use of this
therapeutic option is rather unsatisfactory as

Journal of Innovative Dentistry, Vol 1, Issue2, May-August 2011

____________________________________________________________CASE

lesions are not eradicated in the vast majority of

patients.
Treatments using nonsurgical ablative
techniques, such as cryotherapy and carbon
dioxide laser ablation.
Of these options, the use of laser light has shown
better results in terms of controlling the lesions,
and so it is considered the treatment of choice in
this low risk group.
2. Group of high-risk of malignant
transformation, which comprises:
a) Those leukoplakias with mild dysplasia
located in high-risk areas measuring more than
200 mm, or those associated with a
nonhomogenous clinical form;
b) Leukoplakias with moderate or severe
dysplasia; and
c) Verrucous leukoplakias.
In this group, there is justification for
aggressive surgical treatment, consisting of
excision of the entire thickness of the mucosa at
the site of the leukoplakia.
Among the many therapeutic options available,
however, eliminating risk factors (smoking,
alcohol) and identified etiological factors (sharp
broken down teeth, faulty metal restorations and
metal bridges etc.) is a preventive measure
applicable to all patients with these lesions[17].
Emphasizing upon the efficacy of a conservative
approach various authors[18,19,20] have advocated
it for the restitution of oral health and prevent
the possible recurrence.

Carotenoids have a protective effect on

the epithelium owing to their antioxidant properties. Beta () Carotene is
a known Vitamin A precursor, thereby
promoting epithelial turn over in the
face of injury. It has also been shown
that -carotene has a better therapeutic
clinical response in the prevention of
oral leukoplakia lesions in smoker
patients than in the nonsmokers[21]. A
therapeutic dose of 75,000 to 300,000
IU for 3 months is advocated. Vitamin
A may be used topically after painting
the lesion with podophyllin solution (it
inhibits mitosis). Vitamin A with
vitamin E therapy is given to inhibit
metabolic degradation. 13-Cis-Retinoic
Acid a synthetic analogue of vitamin A,

Journal of Innovative Dentistry, Vol 1, Issue2, May-August 2011

REPORT

usually given in high doses of 1.5 to 2

mg/kg body weight for 3 months.
Oral lycopene (a carotenoid without
provitamin A action) has the uncommon
feature of becoming bound to chemical
species that react to oxygen, thus being
the
most
efficient
biological
antioxidizing agent[22]. In addition to its
antioxidizing property, lycopene also
has the capacity to modify intercellular
exchange junctions, and this is
considered to be an anticancer
mechanism[22]. Singh et al[23] in his 3
months follow-up study found lycopene
to be a promising agent in the treatment
and management of oral leukoplakia.
Low-dose fenretinide, a synthetic
retinoid, has recently been found to be
clinically active in a 3 month trial in
patients with resistance or relapse with
natural retinoids by triggering a small
increase in apoptosis. Data on
antioxidant therapy shows that carotene supplementation can be
beneficial for treatment of oral
leukoplakia.
Nystatin therapy is given in candidal
leukoplakia. 500,000 IU twice daily plus
20 percent borax glycerol or 1 percent
gentian violet or mouth rinses with
chlorogen solution has revealed a
favorable response.
Vitamin B-complex is given as a
supplement in cases of commissural and
lingual lesions.
Antimycotic preparations like canesten
and pimafucin have also been found to
be effective.
Panthenol lingual tablet and oral spray
may be used against glossitis and
glossodynia, in case of tongue lesion.
Topical chemotherapy by topical
application
of
anticancer
chemotherapeutic agents such as
bleomycin and human fibroblast
interferon has been used with success in
limited cases of dysplastic leukoplakia.
Photodynamic therapy (PDT) is a
noninvasive method for the treatment of
premalignant lesions and head and neck

____________________________________________________________CASE

cancers[24,25]. The principle of PDT is a

nonthermal photochemical reaction,
which requires the simultaneous
presence of a photosensitising drug
(photosensitiser), oxygen, and visible
light. After a period to allow the
photosensitiser to collect in the target
tissue, the photosensitiser is activated by
exposure to low power visible light of a
drug-specific wavelength. Illumination
of the tumor by light at the activating
wavelength results in the destruction of
cells by a non-free radical oxidative
process. PDT damage heals mainly by
regeneration rather than scarring. Due to
the organ preserving principle of PDT,
important structures are maintained with
good
functional
and
cosmetic
outcome[26].
Supportive administration of estrogen
can be helpful in some cases.

Conclusion:
Some dysplastic lesions may have a worse
prognosis than isolated carcinomas without
leukoplakia owing to their unpredictable
behavior. However, employment of apposite
knowledge can allow for spontaneous remission
with negligible recurrence.
References:
1. Pindborg J.J., Reichart P., Smith C.J.
and Van der Waal I. World Health
Organization: histological typing of
cancer and precancer of the oral mucosa.
Berlin: Springer-Verlag; 1997.
2. Campisi G., Giovannelli L., Arico P.,
Lama A., Di Liberto C. and Ammatuna
P. et al. HPV DNA in clinically
different variants of oral leukoplakia and
lichen planus. Oral Surgery, Oral
Medicine, Oral Pathology, Oral
Radiology, and Endodontics 2004;
98(6):70511.
3. Dietrich T., Reichart P.A. and Scheifele
C. Clinical risk factors of oral
leukoplakia in a representative sample
of the US population. Oral Oncology
2004; 40(2):15863.
Journal of Innovative Dentistry, Vol 1, Issue2, May-August 2011

REPORT

4. Fedele S. Diagnostic aids in the

screening of oral cancer. Head Neck
Oncol 2009; 30:1-5.
5. Acha A., Ruesga M.T., Rodrguez M.J.,
Martnez-Pancorbo M.A. and Aguirre,
J.M. Applications of the oral scraped
(exfoliative) cytology in oral cancer and
precancer. Med Oral Patol Oral Cir
Bucal. 2005; 10: 95-102.
6. Diniz-Freitas M., Garca-Garca A.,
Crespo-Abelleira A., Martins- Carneiro
J.L. and Gndara-Rey J.M. Applications
of exfoliative cytology in the diagnosis
of oral cancer. Med Oral. 2004; 9: 35561.
7. Van der Waal I. and Axll T. Oral
leukoplakia: a proposal for uniform
reporting. Oral Oncol. 2002; 38:521-26.
8. Warnakulasuriya S., Johnson N.W. and
Van der Waal I. Nomenclature and
classification of potentially malignant
disorders of the oral mucosa. J. Oral
Pathol Med. 2007; 36:575-80.
9. Sccuba J.J. Oral leukoplakia. Critical
Rev Oral Biol Med 1995;(2):147-160
10. Schepman K.P. and Vander Waal I.
Proposal for Classification and Staging
System for Oral Leukoplakia: A
Preliminary
Study.
Oral
Oncology1995(3): 396-98
11. Reibel J. Prognosis of oral premalignant lesions: significance of
clinical,
histopathological,
and
molecular biological characteristics.
Critical Reviews in Oral Biology and
Medicine 2003; 14(1):4762.
12. Lodi G. and Porter S. Management of
potentially
malignant
disorders:
evidence and critique. Journal of Oral
Pathology and Medicine 2008; 37(2),
6369.
13. Lind P.O. Malignant transformation in
oral leukoplakia. Scandinavian Journal
of Dental Research 1987; 95(6):44955.
14. Shiu M.N., Chen T.H., Chang S.H. and
Hahn L.J. Risk factors for leukoplakia
and malignant transformation to oral
carcinoma: a leukoplakia cohort in
Taiwan. British Journal of Cancer 2000;
82 (11):187174.

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15. Lodi G., Sardella A., Bez C., Demarosi

F. and Carrassi A. Interventions for
treating oral leukoplakia (Review). The
Cochrane Library 2008; 4:1-29.
16. Martorell-Calatayud,a
R.
BotellaEstrada,a J.V. Bagn-Sebastin,b O.
Sanmartn-Jimnez,a
and
GuillnBaronaa C. Oral Leukoplakia: Clinical,
Histopathologic, and Molecular Features
and Therapeutic Approach. Acta
Dermosifiliogr. 2009;100:669-84
17. Sciubba J.J. Oral leukoplakia. Crit Rev
Oral Biol Med.1995; 6:147-60.
18. Garewal H.S., Katz R.V. and Meyskens
F. et al. Beta-carotene produces
sustained remissions in patients with
oral leukoplakia: results of a multicenter
prospective trial. Arch Otolaryngol
Head
Neck
Surg.
1999
Dec;
125(12):1305-10.
19. Zakrzewska J.M. Oral lycopene--an
efficacious
treatment
for
oral
leukoplakia. Evid Based Dent. 2005;
6(1):17-18.
20. Lippman S.M., Lee J.J. and Martin J.W.
et al. Fenretinide activity in retinoidresistant oral leukoplakia. Clin Cancer
Res. 2006 May 15; 12(10):3109-14.
21. Malaker K., Anderson B. J., Beecroft
W. A. and Hodson D. I. Management of
oral mucosal dysplasia with -carotene
retinoic acid: a pilot cross-over study.
Cancer Detection and Prevention 1991;
15(5):33540.
22. Rao A. V. and Agarwal S. Role of
antioxidant lycopene in cancer and heart
disease. Journal of the American
College of Nutrition 2000; 19(5):563
69.
23. Singh M., Krishanappa R., Bagewadi,
A. and Keluskar V. Efficacy of oral
lycopene in the treatment of oral
leukoplakia. Oral Oncology 2004; 40(6),
59196.
24. Sieron A., Namyslowski G., Misiolek
M., Adamek M., and Kawczyk-Krupka
A.
Photodynamic
therapy
of
premalignant
lesions
and
local
recurrence
of
laryngeal
and
hypopharyngeal cancers. European

Journal of Innovative Dentistry, Vol 1, Issue2, May-August 2011

REPORT

Archives of Oto-Rhino-Laryngology
2001; 258(7): 34952.
25. Kubler A. C. Photodynamic therapy.
Medical Laser Application 2005; 20(1),
3745.
26. Konopka K. and Goslinski T.
Photodynamic therapy in dentistry.
Journal of Dental Research 2007;
86(8):694707.