BDIAP London, November 2010 School of Clinical Dentistry University of Sheffield Diagnostic difficulties with lesions of the oral mucosa Paul M Speight Dept Oral & Maxillofacial Pathology University of Sheffield
Aim To provide an overview of some key problems in oral mucosal pathology Outline To review oral potentially malignant lesions To review grading schemes for epithelial dysplasia To describe the clinico-pathological features of lesions which may be confused with cancer or precancer
Potentially malignant lesions Leukoplakia Erythroplakia
Epidemiology of leukoplakia Prevalence: Ranges from 0.9% to 26.9% Depends on site and size of study Recent systematic review shows worldwide prevalence of: 2.6% Petti (2003). Oral Oncology, 39, 770-780
PML and malignancy Leukoplakia Homogeneous 1-5% Non-homogeneous 20% Erythroplakia 80%
Leukoplakia and malignancy Overal only about 5% become malignant 95% do not progress How do we identify this 5%?
Epithelial dysplasia Is epithelial dysplasia a useful marker of progression in oral potentially malignant lesions?
Leukoplakia - Histology Up to 80% show no dysplasia 20% - 50% show dysplasia 5% show carcinoma-in-situ 5% are squamous cell carcinoma
Dysplasia grading schemes Oral epithelial dysplasia Squamous intraepithelial neoplasia Llubljana scheme Classic larynx scheme Hyperplasia N/A Simple hyperplasia Laryngeal keratosis Mild SIN 1 Basal/parabasal hyperplasia Hyperplasia Moderate SIN 2 Severe Atypical hyperplasia Keratosis with dysplasia Ca-in-situ SIN 3 Ca-in-situ Ca-in-situ (Based on Barnes et al, WHO Blue Book 2005, Bouquot et al, 2006)
Grading of oral epithelial dysplasia Mild Moderate Severe Carcinoma-in-situ Grading is subjective based on a combination of cellular and architectural features
Cellular changes: Abnormal variation in nuclear size and shape (anisonucleosis and pleomorphism) Abnormal variation in cell size and shape (anisocytosis and pleomorphism) Increased nuclear/cytoplasmic ratio Enlarged nuclei and cells Hyperchromatic nuclei Increased mitotic figures Abnormal mitotic figures (abnormal in shape or location) Increased number and size of nucleoli Barnes L et al: 2005 WHO Classification
Architectural (Tissue) changes: Loss of polarity Disordered maturation from basal to squamous cells Includes top-to-bottom change of carcinoma in situ Increased cellular density Basal cell hyperplasia Dyskeratosis (premature keratinization and keratin pearls deep in epithelium) Bulbous drop shaped rete pegs Secondary extensions (nodules) on rete tips Barnes L et al: 2005 WHO Classification
Cellular changes Pleomorphism of cells and nuclei
Hyperchromatism & increased nuclear size and nuc/cyt ratio Cellular changes
Architectural changes Bulbous rete pegs Basal cell hyperplasia Loss of basal polarity & cell crowding
Changes are limited to the lower 1/3 of the epithelium Mild epithelial dysplasia
Changes extend in to the middle 1/3 of the epithelium Moderate epithelial dysplasia
Changes extend in to the upper 1/3 of the epithelium Severe epithelial dysplasia
Changes extend through the full thickness of the epithelium Carcinoma-in-situ
Progression of dysplastic lesions Mild < 5% Moderate 5% 15% Severe 10% - 50%
Leukoplakia and malignancy Malignant change None Mild Moderate Severe Number of lesions 45 47 Number progressed 3 11 % progressed 6 23 Schepman KP et al 1998 Malignant transformation of oral leukoplakia: a follow-up study of a hospital-based population of 166 patients with oral leukoplakia from The Netherlands. Oral Oncol; 34: 270 5.
Epithelial dysplasia is not a good predictor of malignant transformation: Dysplastic lesions: 36% progressed Non-dysplastic lesions 16% progressed Lesions without dysplasia may also progress Silverman et al. 1984. Oral leukoplakia and malignant transformation. A follow up study of 257 patients. Cancer; 53: 563-568
Grading of oral epithelial dysplasia Grading is subjective based on a combination of cellular and architectural features Grading is regarded as unreliable
Inter-examiner variability in diagnosis κs % agreement Brothwell et al, 2003 0.51 (0.42-0.58) 77 (75 85) Karabulut et al, 1995 0.35 (0.27-0.45) 55 (49 69) Abbey et al, 1995 0.46 (0.29-0.57) 82 (66 86) K values calculated for presence/absence of dysplasia Values show fair to moderate agreement only
68 cases 4 observers Calculated κs and for the 5 point scale and for the binary scale
Kujan et al: 5 point scale Binary scale κw 0.63 (0.45 0.77) 0.5 (0.35 0.67) Agreement 93% (88 97) 74% (65 84) Moderate to good agreement
Binary classification system Low Risk High Risk No dysplasia Borderline Mild Moderate Severe Ca-in-situ
Binary classification system Low Risk High Risk No dysplasia Borderline Mild Moderate Severe Ca-in-situ
Conclusions Epithelial dysplasia is still probably the best indicator of malignant progression in oral potentially malignant lesions BUT there are still major issues to be resolved:
Conclusions There is a consensus that better tools are needed for the prediction of malignant progression in oral potentially malignant lesions Biomarkers DNA ploidy analysis Cytology
Bernard Ackerman: The term dysplasia has never been defined in a lucid, comprehensible, repeatable way and.. has no place in the parlance of pathology
Bernard Ackerman: The term dysplasia has never been defined in a lucid, comprehensible, repeatable way and.. has no place in the parlance of pathology
Reviewed 60 cases 10% progressed to SCC within 5 years
Proliferative verrucous leukoplakia A potentially malignant lesion Characterised by Multiple and recurrent white patches Lesions persist and progress Lesions are non-homogeneous: Papillary or verruciform surface pattern Cytologically bland
Later lesions become endophytic with a pushing invasive front
Proliferative verrucous leukoplakia Histology Start as flat hyperkeratotic lesions Develop into hyperplasia with papillary/verrucous surface Verruciform hyperplasia Usually exophytic Cytological atypia is minimal
Proliferative verrucous leukoplakia A potentially malignant lesion 70% - 100% become malignant Progress to conventional squamous carcinoma Diagnosis is retrospective and can only be made on the basis of a history of recurrent and persistent lesions Zakrzewska JM et al. 1996 Proliferative verrucous leukoplakia: a report of ten cases Oral Surg;82:396-40
Epithelial dysplasia??
Problems in oral mucosal pathology Lesions which may be confused with cancer or precancer
Viral atypia (koilocytic dysplasia) Fornatora et al. OOOE 1996; 82; 47
Viral Atypia Bizarre atypia HIV positive patients 80% HPV positive (IHC) Present as papillomas or condylomas Often multiple Not potentially malignant?
Pseudoepitheliomatoushyperplasia
Median Rhomboid Glossitis
Median Rhomboid Glossitis Midline dorsum of tongue Aetiolgy unclear Associated with candida infection Pseudoepitheliomatous hyperplasia common Often mistaken clinically and histologically for carcinoma Presents at a site which is v rare for malignancy
Chronic hyperplastic candidosis
Granular cell tumour
Granular cell tumour
Granular cell tumour Benign and rarely recurs May be multifocal Of neural origin S-100 positive granular cells Often in tongue May be multiple lesions Associated with pseudoepitheliomatous hyperplasia
Necrotising sialometaplasia
Necrotising sialometaplasia Benign inflammatory disease of glands of the palate and less commonly lips or other intraoral sites Clinically and microscopically resembles malignancy
Necrotising sialometaplasia Usually arises on the palate Mean age 50 years M:F 3:1 Appears as a malignant ulcer Aetiology unclear traumatic? Completely benign Heals spontaneously 4-10 weeks Presents at a site which is rare for malignancy
Pictures courtesy of Prof John Eveson
May see reactive atypia in ulcerated epithelium and in lichenoid reactions
Reactive atypia in infammatory lesions
Summary Epithelial dysplasia is the best guide to potential progression of precursor lesions Grading is subjective No molecular markers currently available Overall only 5% of lesions progress Care is needed in the interpretation of atypia