Oral Premalignant Lesions and Early Detection

Nikolaos G. Nikitakis, MD, DDS, PhDDiplomate, American Board of Oral and Maxillofacial PathologyFellow AAOMP – Fellow AAOM Associate Professor, Dept. of Oral Pathology and Medicine, University of Athens, GreeceSecretary General, European Association of Oral MedicinePresident, Hellenic Society of Oral Medicine and Oral Pathology

Lecture Outline

Epidemiologic aspects of oral cancer

Classification Clinicopathologic features Diagnosis Malignant transformation Management

EPIDEMIOLOGIC ASPECTS OF ORAL CANCER

Head and Neck Squamous Cell Carcinoma Comprises tumors of oral cavity,

oropharynx, hypopharynx, larynx, nasopharynx and sinonasal tract

HNSCC Incidence

EtiologyExternal factors Internal factors

Tobacco (smoking – smokeless)42-87% of patents are smokers>80 cigarettes/day: 17-23-fold higher risk

Idiopathic – Genetic factors

Alcoholcombined with smoking: 6-15-fold higher risk

Immunosuppressed patients(transplantation, HIV)

Viral infections (HPV) Poor nutrition (Fe, vitamins Α, Β, C)

Microorganisms (?Microbiome)

Ultraviolet radiation

Chronic trauma

Sanguinaria

Antony et al, J Oral & Max illofacial Pathology 2011

Multistep Oral Carcinogenesis

CISHyperplasia

EGFR 9p21 delp16/p14Trisomy 7

Telomerase

3p del17p13

(p53 mut)Tetraploidy

Dysplasia

11q1313q21 8p del

Cyclin D1Aneuploidy

18q del10q23 3p26pTEN

Normal SCC

Califano, Sidransky et al.

Epidemiology of Oral Cancer

Patients with HNSCC frequently present with advanced stage disease

Prognosis for oral cancer: relatively unchanged despite treatment advances

Many cases of oral cancer are preceded by premalignant lesions (most notably leukoplakia and erythroplakia), allowing their early detection and eradication

Epidemiology of Oral Precancer

Oral leukoplakia

Global Prevalence 2.6%

23 studies: 17 countries, 1986-2002

Petti S. Pooled estimate of world leukoplakia prevalence: a systematic review. Oral Oncol 2003; 39: 770–80.

CLASSIFICATION AND NOMENCLATURE OF ORAL PMDs

WHO Workshop 2005

Potentially malignant disorder

Premalignant lesion

Premalignant condition

Warnakulasuriya et al. J Oral Pathol Med. 2007Van der Waal Oral Oncol. 2009

Definitions

Premalignant lesion

• A morphologically altered tissue in which oral cancer is more likely to occur than in its apparently normal counterpart

Premalignant condition

• A generalized state associated with a significantly increased risk of cancer

Potentially malignant disorder

• A lesion, disease, or condition associated with a greater than normal risk of developing malignancy

WHO Workshop 1978

WHO Workshop 1978

WHO Workshop 2005 – Neville et al. 2016

Frequent Less frequent RareLeukoplakia Lichen planus Discoid lupus

erythematosusErythroplakia Actinic cheilitis Inherited syndromes:

•Dyskeratosis congenita•Epidermolysis bullosa

Palatal lesions in reverse smokersSubmucous fibrosis

Warnakulasuriya et al, J Oral Pathol Med 2007

Classification of oral PMDs

A white plaque of questionable risk having excluded (other) known diseases or disorders that carry no increased risk for cancer

Diagnosis of exclusion Clinical term that does not indicate specific

histopathologic features Presence or absence of dysplasia

WHO 2005

Definition of Leukoplakia

CLINICOPATHOLOGIC FEATURES

HOMOGENEOUS NON-HOMOGENEOUS Flat Corrugated Wrinkled Pumice

Verrucous Nodular Erythroleukoplakia

or Speckled

Pindborg et al (1997) World Health Organization: Histological typing of cancer and precancer of the oral mucosa, 2nd edn. Springer, BerlinAxell T, Pindborg JJ, Smith CJ et al (1996) Oral white lesionswith special reference to precancerous and tobacco-relatedlesions. J Oral Pathol Med 25:49–54

Clinical Appearance

Homogeneous Leukoplakia

Non-Homogeneous Leukoplakia

Multifocal Leukoplakia

Βagan , Oral Dis 2010

Proliferative verrucousleukoplak ia

Histopathologic Features Epithelial hyperplasia (80-85%)

Hyperkeratosis (hyperorthokeratosis, hyperparakeratosis)

Acanthosis Epithelial dysplasia (15-20%)

Mild Moderate Severe

Carcinoma in situ Superficially infiltrating SCCa

WHO 2005

Low risk

High risk

Binary system

Erythroplakia Red patch or plaque that cannot be

characterized clinically as any other specific disease entity

Lack of keratinization and epithelial atrophy 90% of cases represent severe dysplasia, Ca in situ

or superficially invasive cancer Progression: 18-47%

Actinic Cheilitis

Premalignant lesion secondary to prolonged exposure to ultraviolet radiation

The lower lip is most often involved Slow to develop Pale blotchy appearance that gradually becomes

scaly Squamous carcinoma develops in 6-10% cases

DIAGNOSIS

‘Gold standard’

for diagnosis

History

Clinical Exam

Biopsy

DIAGNOSIS AND MANAGEMENT

ELIMINATION OF POSSIBLE CAUSES (reexamination in

2-4 weeks)NO POSSIBLE CAUSES

BIOPSYNO RESPONSEGOOD RESPONSE

KNOWN LESIONMANAGE ACCORDINGLY

HISTOPATHOLOGICALLY PROVEN DIAGNOSIS

DYSPLASTIC LEUKOPLAKIA

NON-DYSPLASTIC LEUKOPLAKIA

TREATMENT/FOLLOW UP(6-12 MONTHS; LIFELONG)

TREATMENT/FOLLOW UP(3-6 MONTHS; LIFELONG)

KNOWN LESIONMANAGE

ACCORDINGLY

Van der Waal 2010

Scalpel or punch biopsy

Currently, the only definitive diagnostic method

Sample should be taken from the most suspicious areas

Multiple (geographic) biopsies

Geographic Biopsy

Greer, J Calif Dent Assoc 1999

Lee et al. 2007 Underdiagnosis from a single biopsy versus multiple biopsies was 29.5% and 11.9%, respectively

Proliferative verrucousleukoplakia

SCC

Proliferative verrucousleukoplakia

SCC (Second primary)

SCC (in multifocal leukoplakia)

Diagnostic Aids

Autofluorescence– VELscope– Identafi 3000

• Chemiluminence• Vizilite Plus with

Tοluidine blue• MicroLux DL

Toluidine blue

Oral cytology– Oral CDx brush Test

Saliva markers– microRNAs– mRNAs– Proteins

Diagnostic adjuncts to scalpel biopsy Useful if used by properly trained clinicians

in the proper setting In the hands of an inexperienced clinician,

these techniques may prove confusing, unnecessary and/or dangerous

They should not be used as a substitute of scalpel biopsy because of lack of confidence, lack of appropriate training in minor oral surgery, or ease of performance and reimbursement

MALIGNANT TRANSFORMATION

Malignant Transformation

Overall, 4-11% (3.6-17.5%) of oral leukoplakiasbecome squamous cell carcinoma

Annual MT rate: 1-3%– Average: 1.36% (Petti, Oral

Oncol 2003) Progression to invasive

carcinoma can range from a few weeks to 10 or more years, average 3 years

Malignant Transformation

Lesions of the floor of mouth and ventral tongue have a progression rate of 16% to 39% and, if female, 47%

Moderate dysplasia: 4-11%

Severe dysplasia: 20-35%

Factors associated with increased risk of malignant transformation

1. Female gender2. Long duration3. Non-smokers4. Location on the tongue and/or floor of mouth5. Size >200mm2 (5.4-fold higher risk)6. Non-homogeneous type 7. Presence of C. albicans8. Presence of epithelial dysplasia

Van der Waal, Oral Oncol. 2010

The use of molecular markers Advanced

knowledge of the molecular basis of cancer has prompted the investigation of a number of molecules as possible biomarkers

Investigated molecular predictors in oral PMDs

Cytogenetics– Loss of heterozygocity (LOH)–Aneuploidy

Cell cycle, proliferation and apoptosis

Cell signaling

Only 4 biomarkers were associated with a significantly increased risk of progression to cancer:– LOH (3p and/or 9p)– Survivin– MMP-9– DNA content

MANAGEMENT

AIMS

Prevention of malignant transformation– Avoidance of progression – Elimination of lesion

Clinically Microscopically Molecularly

– Prevention of recurrence or new lesion development

Early detection of malignant transformation

Discontinuation/removal of etiologic factors Follow-up – Repeat biopsy Therapeutic intervention – Surgical removal

– Depends upon Histopathologic examination: presence and

degree of dysplasia Size and location of the lesions

Strategy

Systematic review and meta-analysis of 14 studies (992 patients)

Mean MT rate: 12.1% Mean time to MT: 4.3

years The risk of MT was

significantly higher in– High grade

dysplasia– Non removed

lesionsMehana et al.

Head Neck 2014

THERAPEUTIC APPROACHES Surgical

– Conventional (scalpel)– Laser– Cryosurgery– Electrosurgery

Conservative– Photodynamic therapy– Chemoprevention

Van der Hem et al 2005: 200 patients with 282 leukoplakias – follow up for 52 months:

251 (89%) no recurrence 28 (9.9%) recurrence 3 (1.1%) malignant transformation

2 months later

The various therapeutic approaches frequently have only transient results

Despite clinical or microscopic remission, molecular alterations remain

Limitations

Lodi, Cochrane Database Syst Rev 2004

Field cancerization

Presence of one or more mucosal areas harboring cancer-associated genetic or epigenetic alterations

Provides an explanation for the high frequency of recurrences and second primary tumors in a large mucosal area

Has been associated with– Diffuse exposure to carcinogens– Lateral expansion and migration of a monoclone

of genetically altered cells

Braakhuis et al. Nat Rev Cancer. 2011;11:9-22.

Malignant Transformation-Example 1

Malignant Transformation-Example 2

Chemoprevention

Carcinogenesis – multistep process Use of natural or synthetic substances

with the potential to prevent, stop, or reverse the process of carcinogenesis

Conclusion

At present, improvement in oral cancer survival lies in prevention– Primary: discontinuation of

predisposing factors– Secondary: regular and careful oral

examination of all dental patients for early detection of premalignant lesions