Background/Objectives:Oral squamous cell carcinoma (OSCC) often presents at an advanced stage; therefore, the early detection of precursor lesions is crucial. However, the risk assessment of precursor lesions such as oral epithelial dysplasia (OED) remains challenging because of the subjectivity of histopathological grading. We aimed to identify molecular markers that enhance the diagnostic accuracy and prognostic stratification of OSCC and explore the differences in the molecular characterization of OED and OSCC using a few selected markers.Methods:A two-step diagnostic workflow was applied: (1) FISH evaluation ofEGFRamplification andCDKN2Adeletion to distinguish OED from OSCC and identifyEGFR-dependent tumors, and (2) HRAS immunohistochemistry performed exclusively inEGFR-negative OSCCs to stratifyEGFR-independent cases. Fluorescence in situ hybridization (FISH) was used to assess sevenEGFR/cell cycle-related genes (CCND1,CDKN2A,EGFR,PIK3CA,PTEN,TP53, and 1p36 locus) in 117 formalin-fixed paraffin-embedded samples (66 OED and 51 OSCC) and 10 normal mucosa samples. HRAS expression was evaluated using immunohistochemistry (IHC) in 36EGFRamplification-negative OSCCs samples.Results:EGFRamplification was frequent in OSCC, whereasCDKN2Adeletion was common in OED. TheEGFR-amplified/CDKN2A-intact profile showed high specificity for OSCC and improved diagnostic performance (area under the curve = 0.77) when combined with the Ki-67 labeling index. It also predicted poor disease-free survival (hazard ratio [HR] = 5.08,p= 0.016) and overall survival (HR = 6.10,p= 0.047). AmongEGFR-negative OSCCs, HRAS overexpression was associated with advanced-stage disease and a poor prognosis (HR = 6.15,p= 0.043).Conclusions:EGFRamplification was frequent in OSCC, andCDKN2Adeletion was prevalent in OED, supporting their use as molecular markers for differential diagnoses. FISH forEGFR/CDKN2Aand HRAS IHC can stratify OSCC by diagnosis and prognosis, enabling practical molecular subclassification, includingEGFR-negative cases.
背景/目的：口腔鳞状细胞癌（OSCC）常于晚期才被发现，因此早期检测其前驱病变至关重要。然而，由于组织病理学分级的局限性，口腔上皮异型增生（OED）等前驱病变的风险评估仍具挑战性。本研究旨在识别能提高OSCC诊断准确性和预后分层的分子标志物，并利用部分选定标志物探讨OED与OSCC在分子特征上的差异。 方法：采用两步诊断流程：（1）通过荧光原位杂交（FISH）评估EGFR扩增和CDKN2A缺失，以区分OED与OSCC，并识别EGFR依赖性肿瘤；（2）仅在EGFR阴性OSCC中进行HRAS免疫组化检测，以对EGFR非依赖性病例进行分层。研究对117例福尔马林固定石蜡包埋样本（66例OED和51例OSCC）及10例正常黏膜样本，使用FISH技术检测了7个EGFR/细胞周期相关基因（CCND1、CDKN2A、EGFR、PIK3CA、PTEN、TP53及1p36位点）。在36例EGFR扩增阴性的OSCC样本中，通过免疫组化（IHC）评估了HRAS表达。 结果：EGFR扩增在OSCC中常见，而CDKN2A缺失在OED中更为普遍。EGFR扩增/CDKN2A完整型特征对OSCC具有高度特异性，且与Ki-67标记指数结合时诊断性能更优（曲线下面积=0.77）。该特征还预示较差的无病生存期（风险比[HR]=5.08，p=0.016）和总生存期（HR=6.10，p=0.047）。在EGFR阴性OSCC中，HRAS过表达与疾病晚期和不良预后相关（HR=6.15，p=0.043）。 结论：EGFR扩增在OSCC中常见，CDKN2A缺失在OED中普遍存在，支持其作为鉴别诊断的分子标志物。EGFR/CDKN2A的FISH检测及HRAS免疫组化分析可根据诊断和预后对OSCC进行分层，实现包括EGFR阴性病例在内的实用分子亚分类。
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