Oral cavity & oropharynx

Potentially malignant & dysplasia

Leukoplakia

Author: Ivan J. Stojanov, D.M.D., M.M.Sc.

Editorial Board Member: Kelly Magliocca, D.D.S., M.P.H.

Editor-in-Chief: Debra L. Zynger, M.D.

Topic Completed: 15 February 2021

Minor changes: 15 February 2021

Copyright: 2002-2022, PathologyOutlines.com, Inc.

PubMed Search: Oral leukoplakia[TI] review[PT]

Page views in 2021: 24,005

Page views in 2022 to date: 1,518

Table of Contents

Cite this page: Stojanov IJ. Leukoplakia. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/oralcavityleukoplakia.html. Accessed January 21st, 2022.

Definition / general

Hyperkeratotic (white) plaque / patch of mucosa exhibiting clonality and representing precursor lesion to squamous cell carcinoma
- Approximately 40% of leukoplakias exhibit keratinizing dysplasia (Oral Surg Oral Med Oral Pathol Oral Radiol 2014;118:713)
- Remaining exhibit hyperkeratosis / parakeratosis characterized genomically by KMT2C, TP53, TIAM1 or other mutations (Oral Dis 2019;25:1707)
Term leukoplakia / leukoplakic also used descriptively in clinical setting to denote any white lesion without a readily apparent diagnosis
- Such use may skew understanding of leukoplakia biology / behavior due to preponderance of frictional / reactive keratoses in oral cavity, which are not always recognizable clinically but have no malignant potential (Head Neck Pathol 2019;13:423)
Defined by WHO as a white plaque of questionable risk having excluded (other) known diseases or disorders that carry no increased risk for cancer (J Oral Pathol Med 2007;36:575)
Leukoplakia may occur throughout the upper aerodigestive tract

Essential features

Hyperkeratotic (white) plaque / patch of mucosa exhibiting clonality and representing precursor lesion to squamous cell carcinoma
Approximately 40% of leukoplakias exhibit keratinizing dysplasia; the remainder are characterized by hyperkeratosis alone
Annual malignant transformation rate is 3% and most strongly predicted by presence of dysplasia on biopsy; increasing duration, increasing size and nonhomogenous appearance also associated with malignant transformation
Leukoplakia exhibiting hyperkeratosis that is not frictional / reactive exhibits a malignant transformation rate of approximately 5%, similar to that of mild epithelial dysplasia
Histologic appearance of leukoplakia indistinguishable from proliferative (verrucous) leukoplakia and requires clinical correlation
Surgical excision reduces risk of malignant transformation approximately 3 times

Terminology

Leukoplasia, erythroleukoplakia, erythroplakia

ICD coding

ICD-10: K13.21 - Leukoplakia of oral mucosa, including tongue

Epidemiology

Worldwide prevalence approximately 0.5% (Oral Oncol 2003;39:770, Oral Oncol 2009;45:317)
Characteristically a disease of older males (M:F = 3:1)

Sites

May present on any mucosal surface
Associated with highest incidences of malignant transformation when occurring on ventrolateral tongue or floor of mouth (Oral Oncol 2009;45:317)

Pathophysiology

Leukoplakia exhibiting keratinizing dysplasia characterized by genomic alterations including TP53 mutations and loss of heterozygosity at 3p and 9p (Cancer Prev Res (Phila) 2012;5:1081)
Leukoplakia exhibiting hyperkeratosis alone characterized by genomic alterations including KMT2C, TP53 and TIAM1 mutations (Oral Dis 2019;25:1707)
Genetic progression model of head and neck cancer not well worked out, particularly with regards to early precursor lesions (Clin Cancer Res 2000;6:347)

Etiology

Associated with smoking / smokeless tobacco, alcohol and areca nut (betel quid) use
HPV associated with only a very small percentage of cases (Mod Pathol 2017;30:1646)

Clinical features

Hyperkeratosis on mucosal sites not amenable to frictional / factitial trauma, particularly when sharply demarcated, considered clinically concerning (J Oral Maxillofac Surg 2017;75:723)
Biopsy proven leukoplakia may clinically appear homogenous or nonhomogenous (Oral Oncol 2009;45:317)
- Homogenous leukoplakia: uniformly thin or thick hyperkeratosis, frequently sharply demarcated
- Nonhomogenous leukoplakia: irregular texture with fissuring, nodular / verrucous components or erythematous components (erythroleukoplakia)
Proliferative (verrucous) leukoplakia: uncommon and significantly more aggressive (60 - 100% malignant transformation rate) disease characterized by multifocal oral mucosal involvement and a predilection for middle aged / elderly females with no / minimal history of tobacco or alcohol exposure (Oral Dis 2018;24:749)
- Best considered a separate disease on the basis of differing demographic / clinical presentation, biologic behavior and patient management considerations

Diagnosis

Biopsy required for diagnosis and risk stratification
Leukoplakia with dysplasia readily diagnosed on basis of conventional histopathologic features of epithelial dysplasia (Head Neck Pathol 2019;13:423)
Leukoplakia without dysplasia requires clinicopathologic correlation and exclusion of frictional / factitial features as identified clinically or histopathologically

Prognostic factors

Annual malignant transformation rate 3% (Oral Oncol 1998;34:270)
Presence of epithelial dysplasia most significant risk factor for malignant transformation (Oral Oncol 2009;45:317, Mod Pathol 2017;30:S112)
- Severe epithelial dysplasia: 28.4% risk
- Moderate epithelial dysplasia: 22.5% risk
- Mild epithelial dysplasia: 5.7% risk
- Hyperkeratosis: 4.9% risk
Reported overall malignant transformation rates of 0.36 - 34% difficult to interpret due to historical inclusion of frictional / reactive keratoses in leukoplakia cohorts and variability in followup duration (J Oral Pathol Med 2016;45:155)
Length of duration, increasing size and nonhomogenous appearance associated with increased risk of malignant transformation

Case reports

21 year old man with amalgam associated leukoplakia (J Oral Sci 2016;58:445)
59 and 66 year old men with tongue leukoplakia and squamous cell carcinoma (Mol Med Rep 2017;16:6780)
75 year old man with tongue lesion (Cleve Clin J Med 2020;87:133)

Treatment

Surgical excision results in 3 times reduction in risk of malignant transformation (Head Neck 2009;31:1600)
Leukoplakia with high grade (moderate / severe) dysplasia should be excised whenever possible
Close clinical observation may be appropriate for extensive leukoplakia or patients with comorbidities but otherwise appears to have a limited role when conservative surgical management is possible (J Oral Maxillofac Surg 2017;75:723)

Clinical images

Contributed by Ivan J. Stojanov, D.M.D., M.M.Sc.

Left posterior maxillary leukoplakia

Right posterior maxillary leukoplakia

Left ventral tongue leukoplakia

Extensive leukoplakia of tongue

Microscopic (histologic) description

Leukoplakia with dysplasia exhibits characteristic architectural and cytological features of keratinizing dysplasia
- Features include hyperkeratosis / parakeratosis, epithelial atrophy or hyperplasia with bulbous rete ridges, basal cell hyperplasia with nuclear hyperchromasia or increased nuclear cytoplasmic ratio, variable suprabasal or atypical mitoses, dyskeratosis or glassy cytoplasm, dyscohesion
- Approximately 33% of dysplasias are characterized by an inflammatory infiltrate and should not be misdiagnosed as lichen planus (Oral Surg Oral Med Oral Pathol Oral Radiol 2014;117:511)
Leukoplakia without dysplasia exhibits hyperkeratosis with no histologic features of a frictional / reactive process but is otherwise less well characterized
- Histologic features include (Head Neck Pathol 2019;13:423):
  - Compact hyperkeratosis with hypergranulosis
  - Subtle verrucoid architecture
  - Epithelial atrophy or hyperplasia
- If the periphery of the leukoplakia is sampled, hyperkeratosis will appear sharply demarcated
Some leukoplakias without dysplasia may exhibit prominent verrucous architecture and be reported as verrucous hyperplasia

Microscopic (histologic) images

Contributed by Ivan J. Stojanov, D.M.D., M.M.Sc.

Undulating / verrucoid surface architecture

Absence of epithelial atypia

Sharply demarcated hyperkeratosis

Verrucous hyperplasia

Leukoplakia periphery

Moderate dysplasia

Leukoplakia with no dysplasia

Parakeratosis and epithelial hyperplasia

Hyperkeratosis and epithelial atrophy

Minimal cytologic dysplastic features

Cytology description

Currently limited role for cytology:
- Difficulty sampling adequate tissue in unanaesthetized patients
- Epithelial atypia, if present, difficult to classify as reactive or dysplastic in absence of architectural features
- Patterns of keratinization cannot be assessed
- Oral cavity sites readily amenable to incisional biopsy

Molecular / cytogenetics description

See Pathophysiology

Molecular / cytogenetics images

Images hosted on other servers:

CGH leukoplakia versus SCC

Genes implicated in malignant transformation

Sample pathology report

Mandible, gingiva, incisional biopsy:
- Hyperkeratosis, epithelial atrophy and mild chronic inflammation, not reactive (see comment)
- Comment: The hyperkeratosis exhibits no features of a frictional / reactive process and resembles the surface keratinization commonly seen in epithelial dysplasias. Cytologic atypia is minimal / absent in this specimen but leukoplakia without dysplasia (hyperkeratosis that is not reactive) has malignant transformation rates of approximately 5%, similar to that of leukoplakia with mild dysplasia. The findings are consistent with the clinically observed leukoplakia, which in approximately 60% of cases presents without dysplasia. If the clinical context is appropriate, proliferative (verrucous) leukoplakia may also be considered.

Differential diagnosis

Benign alveolar ridge keratosis:
- Histologic features similar to lichen simplex chronicus
- Epithelial hyperplasia with verrucous / undulating surface and wedge shaped hypergranulosis
- Compact hyperkeratosis that tapers towards the edges and is not sharply demarcated
- Elongated rete ridges, occasionally confluent at tips
- No epithelial atypia
- Fibrosis and sparse chronic inflammation
Chronic frictional / factitial keratosis:
- Shaggy / macerated parakeratosis with superficial bacterial colonization
- Epithelial hyperplasia with keratinocyte edema but no epithelial atypia
- Variable fibrosis, acute and chronic inflammation and leukocyte exocytosis
Lichen planus / lichenoid mucositis:
- Squamatization / degeneration of the basal cell layer with Civatte bodies (dyskeratotic keratinocytes)
- Band-like lymphoplasmahistiocytic infiltrate in the superficial lamina propria with leukocyte exocytosis and spongiosis
Proliferative (verrucous) leukoplakia:
- Characterized clinically by multifocal leukoplakia
  - Gingival involvement common
- Predilection for middle aged / elderly females and with no / minimal tobacco or alcohol exposure
  - Reason for this association is unclear
- Indistinguishable histologically from leukoplakia
- Verrucous epithelial architecture common but not necessarily present

Board review style question #1

A 57 year old male smoker presents with a leukoplakia on the left ventral tongue. What is the most important predictor of malignant transformation?

Duration
Homogenous appearance
Nonhomogenous appearance
Presence of epithelial dysplasia on biopsy
Size

Board review style answer #1

D. Presence of epithelial dysplasia on biopsy

Comment Here

Reference: Leukoplakia

Board review style question #2

Which of the following is true regarding leukoplakia without dysplasia?

It can be readily recognized by histologic features of a frictional / reactive process
It can undergo malignant transformation
It is usually associated with HPV infection
It is diagnostic of proliferative (verrucous) leukoplakia
It is rarely encountered in leukoplakia biopsies

Board review style answer #2

B. It can undergo malignant transformation

Comment Here

Reference: Leukoplakia