Oral Potentially Malignant Disorders

Oral Potentially Malignant Disorders (OPMD): WHO Definition

Heterogeneous group of clinically defined conditions with a variable risk of progression to oral squamous cell carcinoma. Most produce clinically visible lesions.

OPMD: 2 Major Precursor Lesion Types

LEUKOPLAKIA and ERYTHROPLAKIA

Leukoplakia

"white plaque"

more common

~85% of oral precancers

Erythroplakia

"red plaque"

higher risk of developing cancer

OPMD Other Precursor Lesions: Actinic Cheilosis

Premalignant lesion on lower lip vermilion

Chronic UV light exposure

Esp. older males

(Analogous to actinic keratosis of skin)

Actinic Cheilosis =

= lower lip vermillion

What are the indications for biopsy to rule out carcinoma in Actinic Cheilosis?

Crusting, ulceration, induration, thickening, leukoplakia

What does the treatment for Actinic Cheilosis depend on?

Microscopic diagnosis

What are the treatment options for high-grade dysplasia in Actinic Cheilosis?

Excision or vermilionectomy

What preventive measures should be taken for Actinic Cheilosis?

Use sunscreen and avoid sun exposure

What is the prognosis for patients with Actinic Cheilosis regarding lip squamous cell carcinoma?

~2-fold risk for lip squamous cell carcinoma (SCC)

What is a precursor lesion associated with betel quid use?

Oral Submucous Fibrosis

In which demographic is Oral Submucous Fibrosis most commonly seen?

Young adults

What is a common symptom of Oral Submucous Fibrosis?

Trismus (involves limited mouth opening)

What symptom of Oral Submucous Fibrosis?

Stomatopyrosis (burning sensation in the mouth)

What are two physical signs of Oral Submucous Fibrosis?

Mucosal pallor and stiffness

What are the treatment options for Oral Submucous Fibrosis?

Steroids and surgery

What is the prognosis for Oral Submucous Fibrosis after cessation of the habit?

Does not regress despite habit cessation

What percentage of patients with Oral Submucous Fibrosis may develop squamous cell carcinoma (SCC)?

~4-6%

OPMD Other Precursor Lesions: Palatal Lesions in Reverse Smoking

OPMD Other Precursor Lesions: Smokeless Tobacco

usually reversible w/ tobacco cessation

biopsy any lesion that remains despite cessation

Prognosis: low-risk (is this a true leukoplakia?)

Other sequel of smokeless tobacco use

Gingival recession

Dental caries

Extrinsic staining of teeth

SCC (conventional or verrucous) (may take several decades of exposure)

OPMD Other Precursor Lesions: "Candidal Leukoplakia"

Controversial

Hyperplastic candidiasis vs. true leukoplakia with superimposed candidiasis

Candidal Leukoplakia - hyperplastic

white

cannot be wiped away

Candidal Leukoplakia - true leukoplakia with superimposed candidasis

colonizing fungal infection underneath lesion

OPMD: Other Conditions/Disorders - Heritable conditions

Fanconi anemia, xeroderma pigmentosum, Bloom syndrome, dyskeratosis congenita, epidermolysis bullosa

OPMD: Other Conditions/Disorders - Immune dysregulation / suppression

oral lichen planus (low risk/MTR

OPMD: Other Conditions/Disorders - Nutritional disorders

Plummer-Vinson syndrome, malnutrition, vitamin deficiencies (e.g., A,B,C)

Leukoplakia: Definitions - 1 (old)

white plaque

that cannot be wiped away

that cannot be characterized clinically or pathologically as any other disease

Leukoplakia: Definitions - 2 (new)

white plaques of questionable risk having excluded (other) known diseases or disorders that carry no increased risk for cancer (WHO 2017)

Leukoplakia: Definitions - 3

***clinical (or clinicopathologic) diagnosis / microscopic correlation often required, but NOT A MICROSCOPIC DX

"Not Leukoplakia": MORSICATIO

biting of buccal/tongue -> thickening of cells appears white

"ragged white plaque on buccal mucosa or tongue"

"Not Leukoplakia": BENIGN ALVEOLAR RIDGE KERATOSIS

very common

keratosis = thickening of keratin layer

"Not Leukoplakia":WHITE SPONGE NEVUS

autosomal dominant mutations in genes for keratins 4 and 13

WHITE SPONGE NEVUS histology

"Not Leukoplakia": HEREDITARY BENIGN INTRAEPITHELIAL DYSKERATOSIS

Oral lesions similar to white sponge nevus

Ocular plaques also

"Not Leukoplakia": ORAL HAIRY LEUKOPLAKIA

Caused by EBV

Usually immunosuppressed patients

Treatment: address underlying immunosuppression

ORAL HAIRY LEUKOPLAKIA - differenetial diagnosis

hyperplastic candidiasis (burning sensation)

morsicato (biting abrasion)

"Not Leukoplakia": NICOTINE STOMATITIS

appears as inflamed cells

Why is it important to precisely define leukoplakia?

Better define those w/ risk for cancer

Impact on study results:

- Prevalence

- Malignant transformation rates

- Clinical trials

OPMD: Etiology

Tobacco

EtOH

Betel quid

Sanguinaria

UV light (lower lip)

Genetic factors

Immune factors

(Candida? Syphilis? High-risk HPV?)

Etiopathogenetic Model of nicotine

nicotine addiction -> carcinogens --(metabolic activation)-> DNA adducts -> mutations (TP53, RAS) -> CANCER

Multistep Carcinogenesis

increases genomic instability

NL -> hyperplasia -> dysplasia/CIS -> SCC

Pathogenesis: Field Cancerization

widespread carcinogen- & age-related mutations

migration of altered cells

"cancer-primed" cells without morphologic change

Epidemiology: Worldwide Prevalence Estimates

OPMD 4.5%

Oral leukoplakia 4.1%

Oral erythroplakia

Oral Leukoplakia & Erythroplakia: Key Clinical Features

M>F

Esp. middle-aged to elderly

Major risk factor = tobacco use

What are the favored sites for Oral Leukoplakia?

Lip vermilion, buccal mucosa, gingiva

Which sites are likely to harbor dysplasia or carcinoma in Oral Leukoplakia?

Ventrolateral tongue, floor of mouth, lip vermilion, buccal mucosa (betel quid users)

Is Oral Leukoplakia often symptomatic or asymptomatic?

Often asymptomatic

Oral Leukoplakia: Clinical Subtypes - HOMOGENEOUS

Thin (pictured)

Thick

Homogeneous Thick Leukoplakia

Oral Leukoplakia: Clinical Subtypes - NON-HOMOGENEOUS

Erythroleukoplakia

Verrucous

Nodular/granular

Ulcerated

****GREATEST RISK FOR CANCER****

Non-homogeneous Leukoplakia (verrucous)

Non-homogeneous Leukoplakia (erythropleukoplakia)

Non-homogeneous Leukoplakia (nodular)

What is Proliferative Verrucous Leukoplakia (PVL)?

A variant of leukoplakia.

What is the gender prevalence for Proliferative Verrucous Leukoplakia (PVL)?

More common in females (F>M).

Is there a strong association between tobacco use and Proliferative Verrucous Leukoplakia (PVL)?

There is minimal association with tobacco use.

What are the characteristics of Proliferative Verrucous Leukoplakia (PVL) lesions?

Multiple, spreading white plaques with rough surface projections.

Where are Proliferative Verrucous Leukoplakia (PVL) lesions especially found?

Especially on the gingiva.

What is the risk associated with Proliferative Verrucous Leukoplakia (PVL)?

High risk for transformation into squamous cell carcinoma (SCC).

What is erythroplakia?

A red plaque or patch that cannot be attributed to any other pathophysiologic process.

What are the most common intraoral sites for erythroplakia?

Floor of mouth, buccal mucosa, and soft palate.

What is the clinical significance of erythroplakia?

High risk for high-grade dysplasia or squamous cell carcinoma (SCC) at presentation.

Correlating Clinical & Microscopic Findings

Why white?

Hyperkeratosis

Acanthosis / hyperplasia

Correlating Clinical & Microscopic Findings

Why red?

Inflammation

Increased vascularity

Epithelial atrophy

What is a typical microscopic diagnosis in OPMD? (without dysplasia)

Hyperkeratosis without dysplasia (involves thickening of the outer layer of skin)

What is a typical microscopic diagnosis in OPMD? (with dysplasia)

Hyperkeratosis with dysplasia (involves thickening of the outer layer of skin with abnormal cell changes)

What is a typical microscopic diagnosis in OPMD characterized by the presence of abnormal cells that have not invaded surrounding tissues?

Carcinoma in situ

What is a typical microscopic diagnosis in OPMD that represents invasive cancer of the skin?

Squamous cell carcinoma

What are other possible microscopic findings in OPMD besides the typical diagnoses?

Epithelial hyperplasia, acanthosis, inflammation, ulceration

Is leukoplakia considered a microscopic diagnosis in OPMD?

No

Histopathology: Hyperkeratosis without dysplasia

Histopathology: Squamous Acanthosis

Histopathology: Hyperkeratosis & Epithelial Hyperplasia

Histopathology: Hyperkeratosis with Mild Dysplasia

Histopathology: Hyperkeratosis with Moderate to Severe Dysplasia

Histopathology: Carcinoma in situ

Histopathology: Squamous cell carcinoma

Oral Epithelial Dysplasia: Features

"disordered growth"

architectural & cytologic changes associated w/ increased risk for progression to SCC

~5% - 46% oral leukoplakia & nearly all oral erythroplakia

Oral Epithelial Dysplasia: Criteria - ARCHITECTURAL

Irregular epithelial stratification

Loss of basal cell polarity

Drop-shaped rete

Mitoses high in the epithelium

Premature keratinization

Keratin pearls

Loss of cohesion

Verrucous/papillary

Oral Epithelial Dysplasia: Criteria - CYTOLOGIC

Abnormal variation in cell size/shape & nuclear size/shape

Increased N/C ratio

Atypical mitotic figures

Increased # & size of nucleoli

Hyperchromasia

What is the malignant transformation rate for oral leukoplakia (OL) per year?

Approximately 1-3% per year

What is the malignant transformation rate for oral leukoplakia with mild/moderate epithelial dysplasia?

Approximately 10%

What is the malignant transformation rate for oral leukoplakia with severe dysplasia or carcinoma in situ (CIS)?

Approximately 24%

What is the risk of malignant transformation for oral leukoplakia without epithelial dysplasia?

Risk is low but not zero

What is the average time to malignant transformation for oral leukoplakia?

0.5 to 17 years

OPMD: Other Adverse Prognostic Factors

non-homogeneous

size >200mm2

subsite: ventrolateral tongue, floor of mouth

F>M

non-smoker / no known risk factors

multiple lesions

PVL (very high risk)

prior h/o head and neck squamous cell carcinoma

OPMD Evaluation: If not sure what it is?

BIOPSY or REFER FOR EVALUATION/BIOPSY

if you suspect a cause -> address cause and re-eval in 2 weeks _. persists? biopsy/refer out

OPMD Treatment - Major options:

If not cancer:

Careful observation

Surgical excision (esp. high-grade dysplasia, adverse clinical factors)

OPMD Treatment - Alternatives:

Laser ablation, cryotherapy, photodynamic therapy

OPMD Treatment

Habit cessation & long-term surveillance

What is the aim of chemoprevention?

Halt malignant transformation; may result in regression or eradication.

Name agents investigated for chemoprevention.

retinoids, beta-carotene, green tea extract, COX-2 inhibitors, EGFR inhibitors

What is an advantage of chemoprevention?

May address field cancerization; noninvasive.

What are disadvantages of chemoprevention?

Relapse and toxicity

Molecular Biomarkers

Risk asessment

Early diagnosis

Targeted therapy

Other Diagnostic Adjuncts

Autofluorescence

Chemiluminescence

In vivo microscopy

Vital staining

Brush cytology