Abstract
Oral leukoplakia (OL) is the most common premalignancy in the oral cavity and can progress to oral squamous cell carcinoma (OSCC). SMAD4 is a tumor suppressor implicated in multiple cancer types including OSCC. To assess the role of SMAD4 in oral leukoplakia malignant transformation, the authors investigated SMAD4 expression patterns in OL and OSCC using a highly specific antibody and correlated the patterns with the risk of malignant transformation oral leukoplakia. Immunohistochemistry and a quantitative imaging system were used to measure SMAD4 expression in OL from 88 OL patients, including 22 who later went through malignant transformation, and their OSCC counterpart. Forty-three (48.9%) of the 88 OL patients had strong SMAD4 expression. SMAD4 expression had no significant correlation with patients' clinicopathological parameters. Interestingly, 17 (39.5%) of the 43 OL lesions with strong SMAD4 expression went through malignant transformation whereas only 5 (11.1%) of the 45 OL lesions with weak SMAD4 expression did so (p = 0.002). The SMAD4 expression in OL was much higher than that in their OSCC counterpart. Kaplan-Meier analysis revealed that the combination of SMAD4 expression and histological grade of dysplasia (p = 0.007) is a better predictor for the malignant transformation of oral leukoplakia. In the multivariate analysis, both SMAD4 expression and grade of dysplasia were identified as independent factors for OL malignant transformation risk (p = 0.013 and 0.021, respectively). It was concluded that high SMAD4 expression may be indicative of an early carcinogenic process in OL and serve as an independent biomarker in assessing malignant transformation risk in patients with OL, and the combination of SMAD4 expression and histological grade of dysplasia is a better predictor for the malignant transformation of oral leukoplakia.
Highlights
Oral squamous cell carcinoma (OSCC), which comprises approximately half of head and neck cancer, is the most common subtype of head and neck carcinoma[1,2]
We found that the combination of strong SMAD4 expression and high grade of dysplasia predicted the malignant transformation of oral leukoplakia better than either single factor did. (Fig.2C, p = 0.007)
Our original hypothesis was that loss of SMAD4 expression might play a role in the malignant transformation in patients with Oral leukoplakia (OL) and evaluation of SMAD4 expression might be useful in predicting the clinical outcome of OL lesions
Summary
Oral squamous cell carcinoma (OSCC), which comprises approximately half of head and neck cancer, is the most common subtype of head and neck carcinoma[1,2]. OL represents the most common oral precancerous condition with 17% to 35% of the lesion going through malignant transformation[6,7]. Histopathological assessment for the grade of epithelial dysplasia is the most important method to determine malignant potential of patients with OL[8]. Grading epithelial dysplasia is subjective, and the predictive value of dysplasia for OL malignant transformation is poor. Due to the high morbidity and mortality of advanced stage OSCC, there is an urgent need to develop biomarkers independent of histopathological assessment for the prediction
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