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Advanced Diagnostics and Cytology,Joel L. Schwartz, D.M.D., D.M.Sc.Director of Oral Maxillofacial PathologyUniversity of Illinois at ChicagoCollege of Dentistry,New Directions,The future of oral and pharyngeal cancers is prevention New screening techniques are progressing that allow researchers to evaluate the risk prior to developing lesionsOral cytology testing using cells from the tongue is both cost-effective and accurateResearchers from UCLA report early success using saliva to detect oral cancer,A Mechanism for Oral Cancer Development,Damage to DNA,HPVEnvironmental CarcinogensTobacco CarcinogensAlcohol Abuse,DNA Repair,Cell Growth Regulation,DNA Content,Apoptosis,Nuclear Instability,Oral Cancer,Long Term Goal: To establish a set of markers to screen at risk individuals for oral cancer before a lesion is observed Approach: Test hypothesis for initial markers following exposure to carcinogen in human oral keratinocytesFurther evaluate markers during low dose oral carcinogenesis and inhibitionInvestigate expression of markers in at risk populations for oral cancer (e.g., smokers),Markers are required to:reduce the mortality rate among oral cancer patients (50% 5 year survival)screen individuals before lesions appearhelp monitor therapy,Why Do We Want Markers?,Tools for Studying Oral Cancer Prevention, Detection and Treatment,Cells- Growth of well differentiated oral keratinocytes (normal, premalignant, malignant)-Transformation with HPV Transformation with PAH, tobacco carcinogen, Betal NutAnimal modelsTobacco carcinogen induction of oral cancer,High Risk Types:16,18Lower Risk:6,11,31,Estimated: 35-55% of oral cancers positive for HPV70 subtypes documented,Human Papillomavirus,HPV+,No Cancer,HPV 16 Role in Oral Cancer,HPV+Tobacco or Environmental Carcinogen + Infection #2,Oral Cancer,Squamous Papilloma:Most common in 30 - 50 yr oldsEqually in males and femalesHPV-6,11 in 50% of the lesionsTongue and soft palate common sites,Papilloma Lesions of the Oral Cavity,Finger-like projections with fibrovascular core,Verruca Vulgaris(Common Wart),Common Wart:Found in children and middle ageFound frequently on vermillion border,labial mucosa, or anterior tongueHPV-2,4,40,Finger like projections with chronic inflammatory cellsCup-like appearanceKoilocytesEosinophilic intranuclear viral inclusions,STD associated lesion.Mouth and genitalia. HPV-6,11,16, 18,Koilocytes with keratohyalin granules,Condyloma Acuminatum (Venereal Wart),Oral Keratinocyte Laboratory Response to HPV Infection and/or PAH Exposure,Schwartz JL & Shklar. 1997. Eur J of Cancer 33: 431-438. (Hamster oral keratinocytes)Park NH, Gujuvula CN, Baek, JH. 1995. Intl J of Oncology 10: 2145-2153.(Human oral keratinocytes),HPV,HPV,HPV,No oral cancer formation,PAH,PAH,PAH,PAH,PAH,PAH,ORAL CANCER FORMATION,Conclusions,The combination of HPV 16,18 infection and treatment with low doses of environmental and/or tobacco carcinogens is capable of changing a non-cancer cell into a cancer cell,Common Interaction Sites of HPV and Tobacco Carcinogens,A regulation of tumor suppression and cell growth pathways (p53 pathway, retinoblastoma,p300 complex proteins)Influence upon cell protein chemistry (Ahr-Ahnt complex formation)Association with endocrine (hormonal effects : estrogen, androgen and glucocorticoids ),Pre-Clinical Oral Cancer Modeland Inhibition of Oral Carcinogenesis,Tobacco Carcinogens,Early Events Later EventsInitiationPromotion Cancer Formation,Mechanism For Induction and Prevention of Oral Carcinogenesis,DNA Damage,DNA Repair,Cell Growth,DNA Content,Apoptosis,Nuclear Instability,VEas Administration Inhibits Oral Carcinogenesis,Reduced DNA Damage Increased/Decreased Repair Decreased Cell GrowthReduced DNA Content Increased Apoptosis Reduced Nuclear Instability,Clinical Translational Early Screening Studies,We need to:,Screen before a lesion is observed Change behaviorProvide prevention treatment,Variations of Oral Squamous Carcinoma Presentations,Factors Influencing Mortality and Survival Time of diagnosis Access to treatment Success of treatment State of health at initial detectionNo improvement since 1973 in mortality or morbidity for tongue and floor of mouth Sq. CA.,Early Screening and Detection of Oral Mucosa Changes Before A Lesion Appears,Screening and Detection of Oral Cancer,Oral Biopsies-Pouch Biopsy-Incisional Biospy Oral Cytology of Lesions,State of the Art: Oral Cytology,Oral cytology = Exfoliative cytology, “Pap Smear”“Journal of the American Dental Association”“Oral cytology should be a part of every oral examination in which the dentist detects even the least suspicious lesion”-recommendations published 30 years ago.,Evaluation of current lesion for malignancy-analysis dependent on nuclear staining, pap stain, toluidine blue, feulgen stain-morphology-nuclear cytoplasmic ratio, bizarre mitoses, micronucleiLack of specific genetic and molecular markers,Determination of Malignancy,Present Indications for Oral Cytology,A mucosal lesion is present but it appears clinically innocuous and otherwise would not be biopsiedEvaluation of an extensive mucosal lesion when not possible to obtain adequate sampling.,Additional Uses for Oral Cytology,Patient too fragile for surgical biospy of lesion or patient refuses surgery. Follow-up for patients with a prior diagnosis of premalignant or malignant lesionFollow-up with patients, analyze single sites of suspicion,NEED TO:,Combine current genetic and molecular markers with the advantages of oral cytology.Screen for the risk for cancer before the presence of a lesion.,Oral Cells From Brush,Phosphate Buffered Saline pH 7.4,Flow Cytometric AnalysisDNA Content-”Ploidy”2. Cell Cycle,Apoptosis, etc.,Novel Extension of Current Method,Characteristics of Oral Cytology Samples,Viable cell number,(,Trypan,blue dye exclusion (0.25%):,Smokers,-,2.6 X10,6,cells/ml. Among nucleated cells,16,-,25% non,-,viable,80% viable.,Non,-,smokers,-,9.2X10,6,cell/ml. 5,-,8% non,-,viable,90% viable.,Toluidine,blue,-,Papanicolaou,staining,Smokers,-,40,-,60% (red hue,upper layer),40,-,60% (blue hue,lower layer, Nucleated cells about 90,-,98%),Non,-,smokers,-,80,-,90%(red hue, upper layer),10,-,20% (blue hue,lower layer,Nucleated cells about 60,-,85%),Histomorphometric,analysis: Kappa statistics analysis using,blinded determination for criteria:,nuclear,cytoplasmic,reversal,Hyperchromatism,pleomorphism,anaplasia, bizarre mitoses,And,keratotic,cells. 0,1 to 5 indicating relative scale % of cells,SIGNIFICANCE TO EXTENDED ORAL CYTOLOGY METHODS,Non-invasiveLow costSensitiveReliableConsistentHIGH CORRELATION TO RISK (requires more study)Relevant to risk for other tobacco cancers (e.g., Lung, bladder, etc.),Additional Validation Procedures,Clinical assessment among smokers of:premalignant malignant lesion-laser microdissection, single cell suspensions, DNA content staining, analysis using flow and laser scanning cytometryExposure of keratinocytes in laboratory to tobacco parent (BaP) and diol epoxide. Cells analyzed using identical flow and laser scanning procedures.,Non-smoker (60-70%Nucleated),Smoker (90-95%Nucleated),(3)Smoker (3) Non-smoker Mean % 44.26 3.14,8-OHdG Detection,ConclusionOral cytology which is relatively non-invasive, and low cost can provide a genetic and molecular survey approach of various markers linked to increased risk for oral cancerA base line of genetic and molecular status can be obtained before a lesion is observed. This information can be associated with disease risk.Prevention methods such as tobacco control and “chemoprevention” can be tested,Future Studies,Oral cytology validation requires further study with a larger population of smokers, former smokers, and non-smokers.Development of novel approaches to regulate tobacco carcinogen metabolism by controlling oral bacteriaSynthesize novel chemoprevention a