Quartz 4

9. OPMDs

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Oral Potentially Malignant Disorders

Oral Cancer Statistics

  • 2/3 of oral cancers are detected at advanced stage
  • 5-year survival rate is 50%
  • Early detection can lead to high survival rate

Pathogenesis Pathway

Normal → Hyperplasia → Dysplasia → Carcinoma in situ → Invasive carcinoma

  • For oral cancer to occur you need to have at least 6-8 genetic mutations
    • Some of these can be related to chromosomal (i.e.e P16, P53, CyclinD1, P10)

Nomenclature and Classification

Definition

  • OPMDs refer to a group of lesions and conditions characterised by a variably increased risk of developing cancers of the lip (C00) and the oral cavity (C02-C06)
  • ‘pre-cancer’, ‘precursor lesions’, ‘pre-malignant’, ‘intra epithelial neoplasia’ and ‘potentially malignant’ have been used in the international literature to broadly describe clinical presentations that may potentially become cancer.
  • Lesion vs condition:
    • Lesions are localized whereas conditions are found in multiple parts of the body

History of terminology

  • 1805: Precancer term proposed by European physicians (Baillie & Simms)
  • 1978: Oral Precancerous lesions and conditions (WHO Collaborating Center)
  • 2003: Oral Precursor Lesions (Oral epithelial dysplasia workshop, Oxford 2003)
  • 2005: Potentially Malignant Disorders (WHO Collaborating Center)
  • 2020: Oral Potentially Malignant Disorders (WHO Collaborating Center)

Supporting Literature: Nomenclature and Classification (2007)

Summary: Nomenclature and Classification of Oral Potentially Malignant Disorders (Warnakulasuriya et al., 2007) 1. Terminology Shift

  • The term “potentially malignant disorders” (PMDs) was recommended over “precancer” to reflect that not all such lesions inevitably progress to cancer.
  • This terminology better aligns with the concept of multi-step carcinogenesis in the oral mucosa and encourages more precise clinical communication. 2. Definition of Oral Leukoplakia
  • The Working Group proposed a refined definition: leukoplakia refers to “white plaques of questionable risk, having excluded other known diseases or disorders that carry no increased risk for cancer.”
  • This definition is exclusion-based, aiming to prevent misclassification of benign white lesions. 3. Diagnostic Guidelines
  • A diagnostic outline was proposed to help clinicians distinguish leukoplakia from other white oral lesions such as lichen planus or frictional keratosis.
  • The emphasis is on improving diagnostic accuracy and reducing overdiagnosis. 4. Classification Challenges
  • The article highlights inconsistencies and deficiencies in existing classification systems for PMDs.
  • It calls for standardization to improve research comparability and clinical decision-making. 5. WHO Workshop Consensus
  • The recommendations stem from a WHO-coordinated expert workshop, lending international credibility.
  • The consensus reflects decades of evolving understanding of oral carcinogenesis and aims to unify terminology and classification practices.

WHO classification 2005

Classification of precancerous lesions and conditions
Precancerous lesionsPrecancerous conditions
LeukoplakiaSubmucous fibrosis
ErythroplakiaActinic keratosis
Palatal lesions in reverse smokersLichen planus
Discoid lupus erythematosus
Hereditary disorders with increased risk: dyskeratosis congenita and epidermolysis bullosa

Classification of oral potentially malignant disorders

  • Leukoplakia
  • Proliferative verrucous leukoplakia
  • Erythroplakia
  • Oral submucous fibrosis
  • Oral lichen planus
  • Actinic Keratosis (Actinic Cheilitis)
  • Palatal changes in reverse smoking
  • Oral Lupus Erythematosus
  • Dyskeratosis Congenita

Newly included in 2021 classification

  • Oral Lichenoid Lesion
  • Oral Graft versus Host Disease

Remove from the 2021 classification due to limited evidence

  • Oral Epidermolysis Bullosa
  • Chronic hyperplastic candidosis
  • Exophytic verrucous hyperplasia/verrucous hyperplasia

OPMD Epidemiology

  • A recent systematic review included 22 epidemiological surveys that estimated a global prevalence of OPMDs at 4.47%
  • It was noted that prevalence may vary between populations and was generally higher in Asians and males.

Risk factors

  • nicotine products Smokers are also at 10 times higher risk for oral cancer compared to non-smokers.

Alcohol

Moderate drinkers have 1.8-fold higher risks of oral cavity and pharynx cancers and 1.4-fold higher risks of larynx cancers than non-drinkers, and heavy drinkers have 5-fold higher risks of oral cavity and pharynx cancers and 2.6-fold higher risks of larynx cancers.

Smoking and Drinking Combined

  • The combination of smoking and drinking is the most important aetiological factor for oral cancer and OPMDs
  • Many patients smoke and drink heavily (>5 standard drinks/day)
  • Both of these account for up to 75% of all OPMD cases

Betel quid/Areca nut

  • Areca nut
    • Abundant copper and flavonoids
      • Stabilize and enhance cross-linking of collagen
        • Fibrosis
    • Alkaloids (arecoline)
      • Stimulate collagen synthesis and reduce collagen degradation
      • Can be converted to carcinogenic nitrosamines
  • Gutka
    • Powdered tobacco, slaked lime, and spices wrapped in Piper betle leaf, also referred to as “betel leaf”
    • more rapid development of oral lesions

HPV

HPV is thought to cause 70% of oropharyngeal cancers in the United States.

Clinical types

Leukoplakia

Persistent white patch that cannot be rubbed off. Generally asymptomatic.

  • 1-4% in Western countries
  • Higher prevalence in SE Asia
  • Global prevalence: 2-3%
  • Homogeneous leukoplakia: Uniformly white, flat and thin, have a smooth surface and may exhibit shallow cracks.
  • Nodular leukoplakia: Small polypoid or rounded outgrowths, red or white excrescences.
  • Verrucous leukoplakia: The surface is raised, exophytic, wrinkled or corrugated.

Leukoplakia: Clinical and Histopathologic Features

Leukoplakia Diagnostic Pathway

  • White patch → Provisional clinical diagnosis of leukoplakia
  • Excluded other known conditions/disorders/diseases based on history and examination
    • White sponge naevus,
    • Frictional keratosis,
    • Alveolar ridge keratosis,
    • Chemical injury,
    • Acute pseudomembranous candidosis,
    • Leukoedema,
    • Fordyce’s spots/ condition,
    • Skin graft,
    • Hairy leukoplakia,
    • Leukokeratosis nicotina palate (Smoker’s palate)
  • BIOPSY
    • If other known disorder confirmed: Revise diagnosis to other disease/disorder
    • If other known disorder excluded:
      • Revise diagnosis to Leukoplakia with dysplasia
      • Revise diagnosis to Leukoplakia without dysplasia

Erythroplakia

  • Defined as “A predominantly fiery red patch that cannot be characterised clinically or pathologically as any other definable disease”
  • Discomfort, tingling and sensitivity to touch, hot beverages or spicy foods
  • Velvety
  • Granular
  • Red plaque
  • Usually painless
  • Flat or indurated

Erythroplakia: Conditions to Exclude

Clinical conditions to exclude in the diagnosis:

  • Erythematous candidiasis,
  • Denture-associated stomatitis on palate,
  • Erythema migrans.
  • Erosive and inflammatory / infective disorders, Desquamative gingivitis,
  • Discoid lupus,
  • Erosive lichen planus,
  • Pemphigoid

Proliferative verrucous leukoplakia

  • Multiple, thick, white patches in more than two different oral sites, frequently found on the gingiva, alveolar processes, and palate.
  • Majority present with a verrucous pattern.
  • Lesions spread and coalesce during development.
  • Recurrence in a previously treated area
    • Lesion starts on a small spot and keeps growing
    • Can only make a PVL diagnosis retrospectively , based on the clinical course

Oral submucous fibrosis

  • Diffuse, pale, marble-like, and keratotic areas
  • Makes it difficult to open the mouth
  • Sites
    • Buccal mucosa
    • Soft palate
    • Tongue
  • Symptoms
    • Burning
    • Increasing trismus
  • Clinical presentation
    • Blanching of oral mucosa
    • Marked loss of tongue papillae
    • Leathery mucosa
    • Fibrous bands
    • Limited mobility of tongue (rigidity)
    • Shrunken or deformed uvula
    • Limitation of mouth opening
      • Can go down all the way to 10mm
    • Sunken cheeks

Actinic cheilitis

  • UV light exposure
  • Aetiopathogenesis similar to that of actinic keratosis of the skin
  • Early
    • Atrophy (smooth, blotchy, pale areas)
    • Dryness
    • Fissuring
    • Blurring of the vermilion border
  • Late
    • Rough, scaly areas
    • May develop leukoplakia

Lichen Planus

  • Immune mediated
    • T lymphocytes mainly
  • Idiopathic vs drug induced
  • Prevalence
    • 0.22-5% worldwide
    • 30-80 year
    • Approximately 15% have cutaneous disease as well
  • Females > Males

Lichen Planus Diagnostic Criteria

Criteria TypeDetails
Clinical criteria- Presence of bilateral, more or less symmetrical white lesions affecting buccal mucosa, and/or tongue, and/or lip, and/or gingiva
- Presence of a white papular lesions and lace-like network of slightly raised white lines (reticular, annular, or linear pattern) with or without erosions and ulcerations
- Sometimes presents as desquamative gingivitis
Histopathological criteria- Presence of a well-defined band-like predominantly lymphocytic infiltrate that is confined to the superficial part of the connective tissue
- Signs of vacuolar degeneration of the basal and/or supra basal cell layers with keratinocyte apoptosis
- In the atrophic type, there is epithelial thinning and sometimes ulceration caused by failure of epithelial regeneration as a result of basal cell destruction. A mixed inflammatory infiltrate may be found

Disorders with insufficient epidemiological evidence

  • Chronic hyperplastic candidosis
  • Exophytic verrucous hyperplasia/Oral verrucous hyperplasia

Oral Epithelial Dysplasia

Summary: Oral Epithelial Dysplasia — Recognition, Grading and Clinical Significance (Odell et al., 2021) 1. Role in OPMDs

  • Histopathological grading of oral epithelial dysplasia remains the main laboratory method to assess malignant transformation risk in OPMDs.
  • The grading provides essential prognostic information and guides clinical management. 2. Pathogenesis and Histology
  • Reviews current understanding of molecular pathogenesis in dysplastic change.
  • Details how histological interpretation links cellular and architectural abnormalities to cancer risk. 3. WHO Diagnostic Criteria
  • Proposes revisions to the 2017 WHO criteria, placing greater emphasis on architectural features over purely cytological ones in diagnosing epithelial dysplasia. 4. Grading Systems
  • Summarises the predictive values of three‑grade systems (mild, moderate, severe) and binary systems (low‑risk vs high‑risk).
  • Discusses their relative strengths, limitations, and implications for reproducibility between pathologists. 5. Categories of Dysplasia Reviewed
  • Lichenoid and verrucous lesions
  • Keratosis of unknown significance
  • HPV‑associated dysplasia
  • Differentiated epithelial dysplasia
  • Basaloid epithelial dysplasia 6. Clinical Management Implications
  • The detection of epithelial dysplasia in a biopsy requires careful consideration of follow‑up, surveillance intervals, and possible intervention.
  • The article reflects the pathologist’s perspective on integrating histopathological findings into treatment planning.

WHO Classification 2022: Diagnostic Criteria

Architectural FeaturesCytological Features
Irregular stratificationAbnormal variation in nuclear size
Loss of polarity or disorganisation of basal cellsAbnormal variation in nuclear shape
Drop shaped rete processesAbnormal variation in cell size
Basal cell clustering/nestingAbnormal variation in cell shape
Expanded proliferative compartmentIncreased mitotic activity
Mitoses high in epitheliumIncreased nuclear size
Mitoses in maturing cellsIncreased nucleus:cytoplasm ratio
Generalized premature keratinizationAtypical mitotic figures
Keratin pearls in rete processesIncreased number and size of nucleoli
Reduced keratinocyte cohesionSingle cell keratinisation
Altered keratin pattern for oral sub-siteNuclear hyperchromasia
Verrucous or papillary architectureApoptotic mitoses
Extension of changes along minor gland ducts
Sharply defined margin to changes
Multiple different patterns of dysplasia
Multifocal or skip lesions
Hyperkeratosis and epithelial hyperplasia with no dysplasia (x100).

OPMD Malignant transformation

  • [A systematic review of 92 studies indicated the overall malignant transformation rate across all OPMD groups was **7.9% **]{.underline}
  • [Proliferative verrucous leukoplakia **49.5% **]{.underline}
  • [Erythroplakia 33.1%]{.underline}
  • [Leukoplakia **9.5 **]{.underline}
  • Oral Submucous Fibrosis 5.2%
  • Oral Lichenoid Lesions 3.8%
  • Lichen planus 1.4%

Supporting Literature: Risk of Progression

Oral potentially malignant disorders (OPMDs) have a statistically increased risk of progressing to cancer, but the risk varies according to a range of patient- or lesion-related factors. It is difficult to predict the risk of progression in any individual patient, and the clinician must make a judgment based on assessment of each case. The most commonly encountered OPMD is leukoplakia , but others, including lichen planus, oral submucous fibrosis and erythroplakia may also be seen. Factors

Features Associated with Increased Risk of Malignant Transformation

Need to know!

FeatureParameterAssociation
Clinical featuresSize of lesion>200mm²Strong
TextureNonhomogeneousStrong
ColourRed (Speckled)Strong
SiteTongue or floor of mouthStrong
SexFemaleMedium
Age>50 yearsMedium
HabitsNonsmokerweak
Histological and molecular featuresDysplasiaSevereStrong
High-gradeStrong
HPVHPV +16Medium
DNA contentAneuploidyMedium
LOHMany genes involvedMedium

Predictors of Malignant Transformation and Recurrence A recent systematic review revealed:

  • a higher rate of MT for non-homogeneous OL, affecting the tongue or the FOM, measuring >200mm², in patients without smoking habits.
  • non-homogeneous OL have a higher chance of recurrence after treatment compared with homogeneous ones.
  • PVL, we found a significantly higher risk of MT associated with the female sex.

Clinical tips

Differential diagnosis of mucosal lesions in the mouth

  • History of current illness
    • Onset, location, intensity, frequency, duration
    • Aggravating and/or relieving variables
    • Better, unchanged or worse over time
  • Medical, tobacco and alcohol history
    • Medical conditions
    • Medications and allergies
    • Tobacco and alcohol (type, frequency, duration)
  • Clinical examination
    • Extraoral
    • Intraoral
    • Lesion inspection (adjunct tools)
  • Differential diagnosis
  • Diagnostic tests
    • biopsy
  • Definitive diagnosis
  • Suggested management

Considerations in Differential Diagnosis

  • Number of possibilities
  • High frequency of insignificant lesions
  • Occasional very significant lesions

Lesion Categories for Differential Diagnosis

  • Not really an OPMD
  • Normal
  • Developmental
  • Traumatic
  • Infectious
  • Idiopathic

How to differentiate lesions

  • Carcinoma?
  • Is it normal?
  • Evidence for a developmental condition?
  • Habits and causes of friction?
  • Does site help - CHC, OHL, SN
  • Any striae?
  • Risk features for dysplasia or malignancy?
  • Smear it
  • Biopsy it

Clinical Pathway for the Evaluation of Potentially Malignant Disorders in the Oral Cavity

Clinicians^ should obtain or update a patient history and perform an intraoral and extraoral conventional visual and tactile examination in all adult patients.

A. No clinically evident lesion or symptomsB. A clinically evident, seemingly Innocuous lesion (not suspected to be malignant)C. A clinically evident, suspicious lesion (suspected to be either a PMD or malignant disorder)
Periodically follow up with patient to determine the need for further evaluation.Lesion resolves (either spontaneously or after treatment). → No further action is necessary at this time.Perform a biopsy of lesion or provide Immediate referral to a specialist.
Lesion persists or progresses or clinical diagnosis of PMD cannot be ruled out. → Use cytologic adjunct to triage patient and provide additional lesion assessment.Should a patient decline a biopsy or referral
Cytologic Adjunct Result:Definitive diagnosis of PMD or malignancy
- Positive or atypical test result: → Perform a biopsy of lesion or provide Immediate referral to a specialist.
- Negative test result: → Periodically follow up with patient to determine the need for further evaluation.

Summary

  • Oral cancer is a preventable disease
  • Early detection can improve survival rates and quality of life
  • Dentists and other dental team members play a significant role in detecting OPMDs
  • For patients with a clinically evident oral mucosal lesion considered to be suspicious of an OPMD, clinicians should perform a biopsy of the lesion or provide immediate referral to a specialist.
  • Cancer may arise during the natural history of an OPMD, patient follow-up at appropriate intervals is strongly recommended. The follow-up interval should be decided based on the individual’s risk assessment and patient compliance

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