5/21/2015
What we will cover Oral Epithelial Dysplasia, Grading, Management and Significance • Leukoplakia, erythroplakia • Causes of oral epithelial dysplasia • Terminology & grading Richard C. Jordan DDS PhD FRCPath • Risk of transformation to cancer Professor of Oral Pathology, Pathology & • Treatment Radiation Oncology • Verrucous hyperplasia & carcinoma • Proliferative verrucous leukoplakia (PVL)
Potentially malignant disorders International Workshop on Oral Potentially Malignant Disorders London, May 2005
Leukoplakia Leukoplakia ‘The term leukoplakia should be used to recognise white plaques of questionable risk having excluded (other) known Erythroplakia diseases or disorders that carry no increased risk for cancer’
1 5/21/2015
Erythroplakia Tobacco smoking
“a red patch on the oral mucosa which cannot • definite relationship with be characterised clinically or histologically as oral cancer due to any other condition” • risk is greatest in heavy users (>20/day) • risk is greater if accompanied by alcohol use • risk may be greater in ‘reverse ’ smoking and with pipes and cigars
2 5/21/2015
Nicotine stomatitis
Epidemiology of leukoplakia
‘Reverse smoking’ 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
3 5/21/2015
Leukoplakia Leukoplakia - Histology
Homogeneous Up to 80% show no dysplasia flat and plaque-like, uniformly white
Non-homogeneous nodular, verruciform, exophytic, speckled
Homogeneous Non-homogeneous Leukoplakia Leukoplakia
Only about 20% About 50% are are dysplastic dysplastic
4 5/21/2015
Dysplasia grading schemes Dysplasia gradingOral epithelial schemes dysplasia
Oral epithelial Squamous intra- Classic larynx Oral epithelial Squamous intra- Classic larynx Llubljana scheme Llubljana scheme dysplasia epithelial neoplasia scheme dysplasia epithelial neoplasiaHyperplasia scheme
Hyperplasia N/A Simple hyperplasia Laryngeal keratosis Hyperplasia N/A Simple hyperplasia Laryngeal keratosis Mild Basal/parabasal Basal/parabasal Mild SIN 1 Hyperplasia Mild SIN 1 Hyperplasia hyperplasia hyperplasia Moderate Moderate SIN 2 Moderate SIN 2
Keratosis with Severe Keratosis with Severe Atypical hyperplasia dysplasia Severe Atypical hyperplasia dysplasia
SIN 3 SIN 3 Ca-in-situ Ca-in-situ Ca-in-situ Ca-in-situ Ca-in-situ Ca-in-situ Ca-in-situ
(Based on Barnes et al, ‘WHO Blue Book’ 2005, Bouquot et al, 2006) (Based on Barnes et al, ‘WHO Blue Book’ 2005, Bouquot et al, 2006)
Increasing severity (Hyperchromatism & crowding) Architectural (Tissue) changes: • Loss of polarity • Disordered maturation from basal to squamous cells
Normal • Includes top-to-bottom change of carcinoma in keratinocytes situ • Increased cellular density • Basal cell hyperplasia Atypical keratinocytes • Dyskeratosis (premature keratinization and keratin pearls deep in epithelium) Mild Moderate Severe • Bulbous drop shaped rete pegs dysplasia dysplasia dysplasia • Secondary extensions (nodules) on rete tips Progression of dysplasia Barnes L et al: 2005 WHO Classification
5 5/21/2015
Cellular changes: 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 Pleomorphism of cells and nuclei Barnes L et al: 2005 WHO Classification Courtesy P. Speight U. Sheffield
Cellular changes Architectural changes
Bulbous rete pegs
Hyperchromatism & increased nuclear size and nuc/cyt ratio Basal cell hyperplasia Loss of basal polarity & cell crowding
Courtesy P. Speight U. Sheffield Courtesy P. Speight U. Sheffield
6 5/21/2015
Mild epithelial dysplasia Moderate epithelial dysplasia
Changes extend in Changes are limited to the middle 1/3 of to the lower 1/3 of the epithelium the epithelium
Courtesy P. Speight U. Sheffield Courtesy P. Speight U. Sheffield
Severe epithelial dysplasia Carcinoma-in-situ
Changes extend in Changes extend to the upper 1/3 of through the full the epithelium thickness of the epithelium
Courtesy P. Speight U. Sheffield Courtesy P. Speight U. Sheffield
7 5/21/2015
Doppelgängers Doppelgängers
Famous actor Tom Hanks Not so famous pathologist Richard Jordan
Doppelgängers Reactive atypia in inflammatory lesions
Famous model Fabio His twin with great hair
8 5/21/2015
Reactive epithelial atypia vs epithelial dysplasia
• Reactive atypia • Epithelial dysplasia Is epithelial dysplasia a useful – Enlarged, vesicular – Basaloid appearing marker of potential progression of nuclei & prominent – Hyperchromatic nuclei oral precursor lesions? nucleoli – No or minimal – Associated inflammation inflammation, either – Abnormal mitoses at acute or chronic, odd levels – Increase in normal mitotic activity – Degenerate cells
What becomes of dysplastic lesions? What lesions progress to cancer?
Malignant 20% Mild < 5% Regress 20% No change 40% Moderate 5% – 15% Increase in size 20% Severe 10% - 50%
9 5/21/2015
Epithelial dysplasia is not a good Grading of oral epithelial dysplasia predictor of malignant transformation:
Grading is subjective based on a • Dysplastic lesions: 36% progressed combination of cellular and architectural features • Non-dysplastic lesions 16% progressed Grading is regarded as unreliable
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
Inter-examiner variability in diagnosis Leukoplakia and malignancy
Dysplasia % agreement κs None Mild Moderate Severe Brothwell et al, 2003 0.51 (0.42 - 0.58) 77 (75 – 85) Number of lesions 45 47 Karabulut et al, 1995 0.35 (0.27 - 0.45) 55 (49 – 69) Number progressed 3 11 Abbey et al, 1995 0.46 (0.29 - 0.57) 82 (66 – 86)
% progressed 6 23 K values calculated for presence/absence of dysplasia
Values show fair to moderate agreement only 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.
10 5/21/2015
Binary classification system
Low Risk High Risk
No dysplasia Moderate Borderline Severe Mild Ca-in-situ
Managing dysplasia Verrucous carcinoma
• Rare variant of SCC 1-3/million • Remove any residual lesion • Tobacco, not HPV • Don’t chase microscopic margins • Slow growing exophytic verrucous patch • Re-biopsy if lesion changes (they often • Locally destructive, rarely metastasizes recur) • Buccal mucosa>gingiva>tongue>palate>other • Retinoids don’t help • Well differentiated carcinoma; little or no dysplasia • Excision, prognosis excellent
11 5/21/2015
12 5/21/2015
PVL - history
• Described by Hansen 1985 in 30 patients • Prior to 1985 “oral florid papillomatosis” • Slowly growing, persistent hyperkeratosis, multifocal • Resistant to treatment Verrucous hyperplasia Verrucous carcinoma • to 2014 – 69 papers on PVL
PVL clinical
• 80 % women • Mean age 71 years • Gingiva > BM > palate • Starts as a flat white lesion progressing to verruciform lesion • Multifocal
13 5/21/2015
Hyperkeratosis Hyperkeratosis
Verruciform Verruciform Papillary SCC Papillary SCC hyperkeratosis hyperkeratosis
Verrucous carcinoma Verrucous carcinoma
Verrucous hyperplasia Verrucous hyperplasia
PVL & HPV PVL transform to carcinoma
Author Year # pts Mean age Tobacco % CA % Author Year Method HPV +
Palefsky 1995 PCR 8/9 (HPV16: 7/9) Hansen 1985 30 66 62 90 Zakrzewska 1996 10 64 50 90 Gopalakrishnan 1997 PCR 2/10 (HPV16/18) Silverman 1997 54 62 31 85
Fettig 2000 PCR 0/10 Fettig 2000 10 65 38 100
Campisi 2004 PCR 14/58 (24%) Bagan 2003 30 71 23 87 Campisi 2004 58 66 29 - Bagan 2007 PCR 0/10 Gandolfo 2009 47 66 37 -
Govea 2010 12 70 25 33
14 5/21/2015
What we will cover Oral Epithelial Dysplasia, Grading, Management and Significance • Leukoplakia, erythroplakia • Causes of oral epithelial dysplasia • Terminology & grading Richard C. Jordan DDS PhD FRCPath • Risk of transformation to cancer Professor of Oral Pathology, Pathology & • Treatment Radiation Oncology • Verrucous hyperplasia & carcinoma • Proliferative verrucous leukoplakia (PVL)
Potentially malignant disorders International Workshop on Oral Potentially Malignant Disorders London, May 2005
Leukoplakia Leukoplakia ‘The term leukoplakia should be used to recognise white plaques of questionable risk having excluded (other) known Erythroplakia diseases or disorders that carry no increased risk for cancer’
1 5/21/2015
Erythroplakia Tobacco smoking
“a red patch on the oral mucosa which cannot • definite relationship with be characterised clinically or histologically as oral cancer due to any other condition” • risk is greatest in heavy users (>20/day) • risk is greater if accompanied by alcohol use • risk may be greater in ‘reverse ’ smoking and with pipes and cigars
2 5/21/2015
Nicotine stomatitis
Epidemiology of leukoplakia
‘Reverse smoking’ 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
3 5/21/2015
Leukoplakia Leukoplakia - Histology
Homogeneous Up to 80% show no dysplasia flat and plaque-like, uniformly white
Non-homogeneous nodular, verruciform, exophytic, speckled
Homogeneous Non-homogeneous Leukoplakia Leukoplakia
Only about 20% About 50% are are dysplastic dysplastic
4 5/21/2015
Dysplasia grading schemes Dysplasia gradingOral epithelial schemes dysplasia
Oral epithelial Squamous intra- Classic larynx Oral epithelial Squamous intra- Classic larynx Llubljana scheme Llubljana scheme dysplasia epithelial neoplasia scheme dysplasia epithelial neoplasiaHyperplasia scheme
Hyperplasia N/A Simple hyperplasia Laryngeal keratosis Hyperplasia N/A Simple hyperplasia Laryngeal keratosis Mild Basal/parabasal Basal/parabasal Mild SIN 1 Hyperplasia Mild SIN 1 Hyperplasia hyperplasia hyperplasia Moderate Moderate SIN 2 Moderate SIN 2
Keratosis with Severe Keratosis with Severe Atypical hyperplasia dysplasia Severe Atypical hyperplasia dysplasia
SIN 3 SIN 3 Ca-in-situ Ca-in-situ Ca-in-situ Ca-in-situ Ca-in-situ Ca-in-situ Ca-in-situ
(Based on Barnes et al, ‘WHO Blue Book’ 2005, Bouquot et al, 2006) (Based on Barnes et al, ‘WHO Blue Book’ 2005, Bouquot et al, 2006)
Increasing severity (Hyperchromatism & crowding) Architectural (Tissue) changes: • Loss of polarity • Disordered maturation from basal to squamous cells
Normal • Includes top-to-bottom change of carcinoma in keratinocytes situ • Increased cellular density • Basal cell hyperplasia Atypical keratinocytes • Dyskeratosis (premature keratinization and keratin pearls deep in epithelium) Mild Moderate Severe • Bulbous drop shaped rete pegs dysplasia dysplasia dysplasia • Secondary extensions (nodules) on rete tips Progression of dysplasia Barnes L et al: 2005 WHO Classification
5 5/21/2015
Cellular changes: 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 Pleomorphism of cells and nuclei Barnes L et al: 2005 WHO Classification Courtesy P. Speight U. Sheffield
Cellular changes Architectural changes
Bulbous rete pegs
Hyperchromatism & increased nuclear size and nuc/cyt ratio Basal cell hyperplasia Loss of basal polarity & cell crowding
Courtesy P. Speight U. Sheffield Courtesy P. Speight U. Sheffield
6 5/21/2015
Mild epithelial dysplasia Moderate epithelial dysplasia
Changes extend in Changes are limited to the middle 1/3 of to the lower 1/3 of the epithelium the epithelium
Courtesy P. Speight U. Sheffield Courtesy P. Speight U. Sheffield
Severe epithelial dysplasia Carcinoma-in-situ
Changes extend in Changes extend to the upper 1/3 of through the full the epithelium thickness of the epithelium
Courtesy P. Speight U. Sheffield Courtesy P. Speight U. Sheffield
7 5/21/2015
Doppelgängers Doppelgängers
Famous actor Tom Hanks Not so famous pathologist Richard Jordan
Doppelgängers Reactive atypia in inflammatory lesions
Famous model Fabio His twin with great hair
8 5/21/2015
Reactive epithelial atypia vs epithelial dysplasia
• Reactive atypia • Epithelial dysplasia Is epithelial dysplasia a useful – Enlarged, vesicular – Basaloid appearing marker of potential progression of nuclei & prominent – Hyperchromatic nuclei oral precursor lesions? nucleoli – No or minimal – Associated inflammation inflammation, either – Abnormal mitoses at acute or chronic, odd levels – Increase in normal mitotic activity – Degenerate cells
What becomes of dysplastic lesions? What lesions progress to cancer?
Malignant 20% Mild < 5% Regress 20% No change 40% Moderate 5% – 15% Increase in size 20% Severe 10% - 50%
9 5/21/2015
Epithelial dysplasia is not a good Grading of oral epithelial dysplasia predictor of malignant transformation:
Grading is subjective based on a • Dysplastic lesions: 36% progressed combination of cellular and architectural features • Non-dysplastic lesions 16% progressed Grading is regarded as unreliable
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
Inter-examiner variability in diagnosis Leukoplakia and malignancy
Dysplasia % agreement κs None Mild Moderate Severe Brothwell et al, 2003 0.51 (0.42 - 0.58) 77 (75 – 85) Number of lesions 45 47 Karabulut et al, 1995 0.35 (0.27 - 0.45) 55 (49 – 69) Number progressed 3 11 Abbey et al, 1995 0.46 (0.29 - 0.57) 82 (66 – 86)
% progressed 6 23 K values calculated for presence/absence of dysplasia
Values show fair to moderate agreement only 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.
10 5/21/2015
Binary classification system
Low Risk High Risk
No dysplasia Moderate Borderline Severe Mild Ca-in-situ
Managing dysplasia Verrucous carcinoma
• Rare variant of SCC 1-3/million • Remove any residual lesion • Tobacco, not HPV • Don’t chase microscopic margins • Slow growing exophytic verrucous patch • Re-biopsy if lesion changes (they often • Locally destructive, rarely metastasizes recur) • Buccal mucosa>gingiva>tongue>palate>other • Retinoids don’t help • Well differentiated carcinoma; little or no dysplasia • Excision, prognosis excellent
11 5/21/2015
12 5/21/2015
PVL - history
• Described by Hansen 1985 in 30 patients • Prior to 1985 “oral florid papillomatosis” • Slowly growing, persistent hyperkeratosis, multifocal • Resistant to treatment Verrucous hyperplasia Verrucous carcinoma • to 2014 – 69 papers on PVL
PVL clinical
• 80 % women • Mean age 71 years • Gingiva > BM > palate • Starts as a flat white lesion progressing to verruciform lesion • Multifocal
13 5/21/2015
Hyperkeratosis Hyperkeratosis
Verruciform Verruciform Papillary SCC Papillary SCC hyperkeratosis hyperkeratosis
Verrucous carcinoma Verrucous carcinoma
Verrucous hyperplasia Verrucous hyperplasia
PVL & HPV PVL transform to carcinoma
Author Year # pts Mean age Tobacco % CA % Author Year Method HPV +
Palefsky 1995 PCR 8/9 (HPV16: 7/9) Hansen 1985 30 66 62 90 Zakrzewska 1996 10 64 50 90 Gopalakrishnan 1997 PCR 2/10 (HPV16/18) Silverman 1997 54 62 31 85
Fettig 2000 PCR 0/10 Fettig 2000 10 65 38 100
Campisi 2004 PCR 14/58 (24%) Bagan 2003 30 71 23 87 Campisi 2004 58 66 29 - Bagan 2007 PCR 0/10 Gandolfo 2009 47 66 37 -
Govea 2010 12 70 25 33
14