Application of 5-aminolevulinic acid-mediated Waterlase-assisted photodynamic therapy in the treatment of oral leukoplakia

www.nature.com/scientificreports OPEN Application of 5‑aminolevulinic acid‑mediated Waterlase‑assisted photodynamic therapy in the treatment of oral leukoplakia Jiali Ou1,2, Yijun Gao1,2, Huan Li1, Tianyou Ling1 & Xiaoyan Xie1* Photodynamic therapy (PDT) is an alternative microinvasive approach with satisfying results in the treatment of oral leukoplakia (OL). PDT combined with laser irradiation shows promise, safety and efficacy in treating OL. The efficacy of waterlase (YSGG) combined with PDT was studied by brush and tissue biopsy. Seventy-one patients with histologically diagnosed OL were enrolled, including patients with mild to moderate dysplasia, severe dysplasia and various dysplastic tissues. Patients were evaluated at baseline (t0), the end of treatment (t1) and 1 year later (t2). At t1, PDT showed a significant therapeutic effect on OL with mild to moderate dysplasia. Clinical and histological examinations revealed 60 cases (84.51%) of complete remission and 11 cases (15.49%) of partial remission. On brush biopsy, all PDT-treated patients showed reduced aneuploidy and normal histological findings. Unfortunately, at t2, 9 patients relapsed with OL, which may be related to continued smoking and betel nut chewing. At t2, 5 patients developed new severe epithelial dysplasia and even carcinoma in situ in other areas, mostly the tongue. ALA-mediated PDT combined with YSGG is effective in treating OL, particularly that with mild to moderate dysplasia. However, severe dysplasia may present undesirable effects, and the mechanism remains to be further investigated. ALA-mediated PDT combined with YSGG provides a new method for OL treatment. Oral leukoplakia (OL), according to the World Health Organization (WHO), is defined as a mainly white patch, plaque, or lesion on the oral mucosa that cannot be certainly classified clinically or histologically as any other ascertainable disorder1–4. OL is a well-known oral potentially malignant disorder (OPMD) with a potential risk of malignancy. It has been reported that 15.8–48.0% of patients with oral squamous cell carcinoma (OSCC) have a history of OL when diagnosed5. According to a systematic review of 24 retrospective studies, the prevalence rate of OL is 0.13–34%6. The main goal of the treatment of OL is to prevent malignant transformation and even reduce or eliminate lesions7. There are probably two traditional methods to treat OL, namely, conservative treatment and surgical resection. Medical interventions, such as vitamin A, retinoids, beta-carotene or bleomycin cannot reduce the possibility of oral cancer d evelopment8 and have low efficiency with a long treatment time1,9. Therefore, surgical methods, including conventional excision, cryosurgery therapy, electrocauterization and various forms of laser ablation, are the preferred choice in OL management for many c linicians8. However, when the diseased area extends to multiple locations or is located in potentially important functional areas, surgical methods may be impractical, as they can cause large tissue defects, therefore influencing function and aesthetics7. Additionally, data have shown that OL has a 13–42% recurrence rate after surgical removal1,9,10. Photodynamic therapy (PDT) is a less invasive method that can successfully be applied in the treatment of premalignant and malignant disorders of the skin, digestive tract, lungs, and genitourinary mucosa with vastly reduced morbidity and disfigurement. Since PDT is a cold photochemical process, there is no tissue heating and a much lower risk of damaging the integrity of the underlying functional structures compared to thermal laser techniques and other invasive approaches. PDT is preferred by patients due to its good effect, less postoperative pain, slight edema, and few areas of s carring11–13 and the fact that it can be repeated indefinitely at the same site without cumulative toxicity. 1 Department of Stomatology, The Second Xiangya Hospital, Central South University, 139 Renmin Middle Road, Changsha 410011, People’s Republic of China. 2These authors contributed equally: Jiali Ou and Yijun Gao. *email: Scientific Reports | (2022) 12:9391 | https://doi.org/10.1038/s41598-022-13497-3 1 Vol.:(0123456789) www.nature.com/scientificreports/ The technique of PDT is simple and consists of three fundamental elements, including oxygen, a photosensitizer and visible light at a specific wavelength. Aminolevulinic acid (ALA) serves as an endogenous precursor of the photosensitizer protoporphyrin IX (PpIX), shows superb tissue selectivity and targets proliferative epithelial cells and is thus used for the treatment of oral premalignant and malignant lesions7. Owing to the poor penetration of ALA, the pretreatment of lesions, for example, scaling with a scalpel and vaporization with a C O2 laser which creates microscopic vertical holes serving as channels with connections between treatment zones and upper tissues14, is usually performed before delivering topical PDT1,15. Waterlase (YSGG) has the feature of “point clearance” and generates vertical channels to provide direct delivery and better distribution and hence can also be used to pretreat OPMDs to enhance ALA penetration15. YSGG pretreatment has some advantages, such as decreasing bleeding; reducing pain, edema and risk of infection; and accelerating healing16. In our study, 71 patients with OL were treated with YSGG-PDT, with evaluation of the effects at baseline (t0), the end of treatment (t1) and 1 year later (t2). Our investigation will provide a reference for the application of YSGG-PDT in the treatment of OL. Materials and methods Sample collection. This study was approved by the Institutional Ethics Committee of the Second Xiangya Hospital of Central South University of China (20200606). All participants understood the nature of this study and provided written informed consent. Photographs of each participant’s lesions were carefully obtained, and each participant underwent clinical examination, brush biopsy and tissue biopsy of the lesion site. Seventy-one patients underwent treatment at the Department of Stomatology Center of the Second Xiangya Hospital, Central South University of China. All patients with clinically and histologically diagnosed OL were enrolled in this study. Eligible OL patients were recruited from the Department of Stomatology of the Second Xiangya Hospital, Central South University of China between July 2019 and June 2021. The age of the patients was between 18 and 75 years. All patients had untreated lesions identified on biopsy as mild, moderate or severe epithelial dysplasia as well as histologically verified OL. Exclusion criteria. The exclusion criteria were as follows: age under 18 years or beyond 75 years; allergy to photosensitizers; breast feeding or pregnancy; other oral mucosal diseases; oral cancer, ranging from microinvasive cancer to invasive cancer to metastatic cancer, etc.; coagulopathy; any psychosis; uncon (...truncated)