Risk Assessment for Malignant Transformation in Patients with Oral Proliferative Leukoplakia: A 10-Year Retrospective Cohort Study

<b>Objectives</b>: This study aimed to evaluate the malignant transformation (MT) risk profile in patients with oral proliferative leukoplakia (OPL) referred to the Oral Medicine and Oral Surgery units of Umberto I Hospital, Sapienza University of Rome. <b>Methods</b>: The departmental database and medical records of OPL patients were reviewed from January 2014 to June 2024. Demographic, clinical, and histopathological features and treatment strategies were collected in a de-identified dataset. <b>Results</b>: A total of 51 OPL patients (33 females and 18 males; mean age 62.86 ± 13.55 years) were included. MT occurred in 17.6% (<i>n</i> = 9) after a mean follow-up of 4.78 ± 2.59 years. A higher percentage of the presence of a previous history of solid or hematological tumor was observed in patients with MT, with an OR of 2.940 (95% CI 0.064-1.350), without statistical significance. The homogeneous clinical form was more common in patients without MT (78.57%), and the speckled clinical form was more common in patients with MT (44.44%). The percentage of patients with lesions located on the floor of the mouth, ventral surface of the tongue, and dorsal surface of the tongue was higher in patients with MT. The tongue was the most common site of MT, followed by the gingiva, buccal mucosa, and palate. At the histological level, a verrucous, nodular, or bulky architecture was more commonly observed in patients with MT, and the presence of band-like lymphocytic infiltrate was observed in all patients with MT. Higher dysplasia grades were significantly associated with MT (<i>p</i> = 0.009). No significant association was found between the treatment modality and MT risk, although laser ablation was associated with a trend toward lower risk. <b>Conclusions</b>: This study further suggests that the clinical morphology, lesion site, and histological grading may be important predicting factors for MT in OPL. The presence of a non-homogeneous lesion form, a higher grade of dysplasia, and a history of previous solid or hematological tumor led to a more aggressive disease course. Individualized risk assessment and long-term surveillance may be advisable.