In this review article, the clinical and histopathological characteristics of oral premalignant lesions, and primarily oral leukoplakia, are noted and the risk factors for malignant transformation of oral leukoplakia are discussed. Malignant transformation rates of oral leukoplakia range from 0.13 to 17.5%. The risk factors of malignant transformation in the buccal mucosa and labial commissure are male gender with chewing tobacco or smoking in some countries such as India, or older age and/or being a non-smoking female in other countries. Some authors have reported that leukoplakia on the tongue or the floor of the mouth showed a high risk of malignant transformation, although others have found no oral subsites at high risk. In concurrence with some authors, the authors of this review view epithelial dysplasia as an important risk factor in malignant transformation; however, there are conflicting reports in the literature. Many authors believe that nonhomogeneous leukoplakia is a high risk factor without exception, although different terms have been used to describe those conditions. The large size of lesions and widespread leukoplakia are also reported risk factors. According to some studies, surgical treatment decreased the rate of malignant transformation; however, many review articles state that no definitive treatment including surgery can decrease the malignant transformation rate of oral leukoplakia because of the lack of randomized control trials of treatment. Tobacco chewing and smoking may be causative agents for cancerization of oral leukoplakia in some groups, and evidence for a role of human papilloma virus in the malignant transformation of oral leukoplakia is inconsistent. Further research to clarify its role in malignant transformation is warranted.

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Recently, the epithelial-to-mesenchymal transition (EMT) has been demonstrated to contribute to normal and disease processes including cancer progression. To explore EMT-suppressive microRNAs (miRNAs), we established a cell-based reporter system using a stable clone derived from a pancreatic cancer cell line, Panc1, transfected with a reporter construct containing a promoter sequence of CDH1/E-cadherin in the 5′ upstream region of the ZsGreen1 reporter gene. Then, we performed function-based screening with 470 synthetic double-stranded RNAs (dsRNAs) mimicking human mature miRNAs using the system and identified miR-655 as a novel EMT-suppressive miRNA. Overexpression of miR-655 not only induced the upregulation of E-cadherin and downregulation of typical EMT-inducers but also suppressed migration and invasion of mesenchymal-like cancer cells accompanied by a morphological shift toward the epithelial phenotype. In addition, we found a significant correlation between miR-655 expression and a better prognosis in esophageal squamous cell carcinoma (ESCC). Moreover, ZEB1 and TGFBR2, which are essential components of the TGF-b signaling pathway, were identified as direct targets of miR-655, suggesting that the activation of the TGF-b-ZEB1-E-cadherin axis by aberrant downregulation of miR-655 may accelerate cancer progression.

BACKGROUND The management of occult cervical lymph node metastases originating from oral squamous cell carcinomas (OSCCs) remains controversial. The purpose of this study was to evaluate the value of cyclin D1 gene (CCND1) numerical aberrations in predicting the risk of late lymph node metastases. METHODS Fluorescence in situ hybridization (FISH), using a BAC clone specific for CCND1, was performed on OSCC specimens obtained by fine‐needle aspiration (FNA) biopsy from 45 patients with previously untreated TNM Stage I and II (T1‐2N0M0) disease who had not undergone elective cervical lymph node dissection. RESULTS CCND1 numerical aberrations were observed in 15 (33.3%) of the 45 patients and were significantly associated with the mode of invasion of the primary tumor (P = 0.01) and the presence of occult lymph node metastases (P < 0.001). Twelve of these 15 patients (80%) developed late cervical lymph node metastases within 2 years of surgery for primary OSCCs. All patients with cluster‐type amplification of CCND1 developed late lymph node metastases. Multivariate analysis showed that only CCND1 numerical aberrations (risk ratio, 8.685%, 95% confidence interval = 2.232–33.802, P = 0.002) independently predicted late cervical lymph node metastasis. CONCLUSIONS Aberrations in CCND1 numbers appear to be valuable in identifying patients at high risk of late lymph node metastasis in Stage I and II OSCCs. Analysis of CCND1 numerical aberrations using FISH on FNA biopsy specimens may be useful in selecting patients for elective cervical lymph node dissection. Cancer 2005. © 2005 American Cancer Society.

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