Bradley Kyle T, Budnick Steven D, Logani Sanjay
Department of Pathology and Laboratory Medicine, Emory University Hospital, Atlanta, GA 303322, USA.
Mod Pathol. 2006 Oct;19(10):1310-6. doi: 10.1038/modpathol.3800649. Epub 2006 Jun 23.
Significant intra- and interobserver variability exists in diagnosing and grading oral epithelial dysplasia. Mutations in the tumor-suppressor gene p16 are common in oral cavity dysplastic lesions, but whether immunohistochemical detection of the gene product p16(INK4a) (p16) can be used as a reliable biomarker for dysplasia is unclear. In total, 119 biopsy specimens representing various oral cavity sites and degrees of dysplasia were retrieved from the pathology files of Emory University Hospital. Formalin-fixed, paraffin-embedded sections were stained with hematoxylin and eosin (H&E) and with a monoclonal antibody to p16 (LabVision Corporation, Clone JC2). A blinded review of the H&E slides and the pattern and degree of p16 expression was independently performed by two pathologists. A consensus was obtained when diagnoses differed. Morphologic diagnoses were then compared to p16 immunohistochemical expression. Overall, 61/119 (51%) cases showed no p16 immunoreactivity, including 12/33 (36%) cases of no dysplasia, 11/28 (39%) cases of mild dysplasia, and 38/58 (66%) cases of moderate/severe dysplasia. The remaining cases showed p16 expression limited to the basal and suprabasal nuclei and generally confined to the lower one-third of the epithelium. A logistic regression model showed a trend toward absent p16 expression with increasing severity of dysplasia (P=0.006). Decreased expression of p16 in dysplastic lesions, as found in this study, may reflect the biologic events involving loss of p16 gene function in the pathogenesis of oral cancer. Our findings suggest that p16 immunohistochemistry is not helpful in differentiating dysplastic from nondysplastic mucosa in oral cavity biopsies, and thus is not a reliable biomarker for use in routine clinical practice.
在口腔上皮发育异常的诊断和分级中，观察者之间以及观察者自身均存在显著差异。肿瘤抑制基因p16的突变在口腔发育异常病变中很常见，但免疫组织化学检测该基因产物p16(INK4a)（p16）是否可作为发育异常的可靠生物标志物尚不清楚。我们从埃默里大学医院的病理档案中总共检索到119份代表口腔不同部位和发育异常程度的活检标本。用苏木精和伊红（H&E）以及抗p16单克隆抗体（LabVision公司，克隆JC2）对福尔马林固定、石蜡包埋的切片进行染色。两名病理学家独立对H&E切片以及p16表达模式和程度进行盲法评估。当诊断结果不同时达成共识。然后将形态学诊断与p16免疫组织化学表达进行比较。总体而言，61/119（51%）例病例未显示p16免疫反应性，其中无发育异常的病例为12/33（36%），轻度发育异常的病例为11/28（39%），中度/重度发育异常的病例为38/58（66%）。其余病例显示p16表达仅限于基底核和基底上层核，且通常局限于上皮的下三分之一。逻辑回归模型显示，随着发育异常严重程度增加，p16表达缺失呈趋势（P = 0.006）。本研究发现，发育异常病变中p16表达降低可能反映了口腔癌发病机制中涉及p16基因功能丧失的生物学事件。我们的研究结果表明，p16免疫组织化学无助于在口腔活检中区分发育异常与非发育异常的黏膜，因此不是常规临床实践中可靠的生物标志物。
