title: Aberrant expression of p53, p16INK4a and Ki-67 as basic biomarker for malignant progression of oral leukoplakias.
abstract: BACKGROUND
  The risk of malignant progression of oral leukoplakia with and without dysplasia is unpredictable.
  
  
  METHODS
  Leukoplakias without dysplasia of 35 patients, leukoplakias with dysplasia of 4 patients, and similar lesions obtained from tumor patients were retrospectively examined by immunohistochemistry for the expression of the proteins pRb, p53, p16(INK4a), Cyclin D1 and Ki-67. The predictive power of combined aberrant expression patterns for the progression of leukoplakias without dysplasia was examined.
  
  
  RESULTS
  Increased expression of p53, Ki-67 and Cyclin D1, and loss of p16(INK4a) occurred in 45.9%, 38.9%, 29.4% and 32.4% of the leukoplakias without dysplasia, respectively. All alterations increased with progression but had poor positive predictive value. However, the combined p53/p16(INK4a)/Ki-67 aberration occurred in only three (9%) cases, of which two patients (66.7%) experienced progression to dysplasia and carcinoma in situ. The combined p53/p16(INK4a)/Ki-67 alteration had a negative predictive value (NPV) and sensitivity of 100%, specificity of 97% and positive predictive value (PPV) of 67%. By contrast, the combined p53/p16(INK4a)/Cyclin D1 alteration had 97% NPV and sensitivity of 50%, specificity of 90% and only 25% PPV. Loss of pRb and concomitant overexpression of p16(INK4a) were not observed arguing against an involvement of HPV in oral leukoplakia.
  
  
  CONCLUSIONS
  We propose the combined p53/p16(INK4a)/Ki-67 alteration as a basic marker to define high risk leukoplakia patients. Lesions not showing this alteration appear to be harmless. Future studies should validate these findings and search for proteins which can further improve the PPV of the proposed basic marker.
authors: Department of Oral and Maxillofacial Surgery, University Hospital Heidelberg, Heidelberg, Germany.
authors: Wasim
authors: W
authors: Nasser
authors: Christa
authors: C
authors: Flechtenmacher
authors: Dana
authors: D
authors: Holzinger
authors: Christof
authors: C
authors: Hofele
authors: Franz X
authors: FX
authors: Bosch
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism*; D007972:Leukoplakia, Oral / Q000378:metabolism* / Q000473:pathology; D009062:Mouth Neoplasms / Q000378:metabolism* / Q000473:pathology; D009363:Neoplasm Proteins / Q000378:metabolism; D011237:Predictive Value of Tests; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16; D019394:Ki-67 Antigen; D009363:Neoplasm Proteins; D016159:Tumor Suppressor Protein p53