Oral squamous cell carcinoma (OSCC) is the most frequently encountered form of oral cancer, and in 29 % of cases, it arises from preexisting lesions called Oral Potentially Malignant Disorders. Oral leukoplakia (OLK) is the most researched OPMD in the scientific literature. This review article was compiled by synthesizing evidence from studies published between 2020 and 2025 on biomarkers in OSCC and OLK to identify diagnostic and prognostic biomarkers for the development and progression of OSCC and for the risk of malignant transformation (MT) in OLK. Lactate dehydrogenase, chemerin, matrix metalloproteinase-9, and phytosphingosine have the highest sensitivity as biomarkers for the diagnosis and prognosis of OSCC. Compared with healthy controls, oral cancer patients had higher salivary levels of IL-8, IL-6, TNF-α, IL-1β, and IL-10. TNF-α exhibited the highest diagnostic accuracy for oral cancer. For OLK, podoplanin and loss of heterozygosity are the most promising, although p53 and PDPN are the most frequently reported proteins. DNA ploidy can also be a potential indicator of MT risk, either alone or in combination with histopathological grading of oral epithelial dysplasia. Novel markers, such as cancer stem cell markers, DAPK-1, maspin, cytokeratins 13, 17, and 19, provide new insights into OLK progression to OSCC. While some biomarkers have demonstrated statistical significance across various studies and settings, there is still no consensus on the most specific biomarker or the most valuable panel for diagnostic and clinical purposes in OSCC and OLK.

Background/Objectives: Oral leukoplakia (OLK) is an oral mucosal lesion classified in the oral potentially malignant disorder group and is associated with an increased risk of malignant transformation (MT). The aim of this study was to compare the clinical and histopathological features of two OLK groups, a group of smokers and a group of non-smokers. Methods: In this retrospective study, a cohort of 154 patients with OLK was divided into two groups based on the presence of smoking as a major risk factor. OLK diagnoses were established via clinical and histopathological examination. Results: Females were more abundant in the non-smoking group than in the smoking group, where males were more abundant (p < 0.001). The average age of the smokers was lower than that of the non-smokers (p = 0.003). In the smokers, the buccal mucosa was most frequently affected, while in the non-smokers, the gums and the tongue were primarily involved (p = 0.016). In female smokers, involvement of the buccal area and multiple-site involvement were statistically significantly more frequently observed compared to that in female non-smokers (p = 0.006). Non-dysplastic lesions were predominant in both groups, with severe dysplasia observed more frequently in the non-smokers than in the smokers. MT was higher in the non-smoker group compared to that in the smoker group. Conclusions: OLK in smokers is different from OLK in non-smokers concerning female gender involvement, site location, the number of lesions, and the MT rate.