Introduction
Vocal fold leukoplakia is characterised by a white plaque covering the vocal fold surface that cannot be classified as any other condition. Its clinical presentation varies along a pathological spectrum, ranging from benign keratosis to atypical hyperplasia, carcinoma in situ and squamous cell carcinoma (SCC).Reference Ali, Smith and Hogikyan1 In clinical practice, the risk of cancer progression within 5 to 10 years after a vocal fold leukoplakia diagnosis is approximately 20 per cent, with a notably higher risk among men aged 65 years and over.Reference Garrel, Uro Coste, Costes-Martineau, Woisard, Atallah and Remacle2 The likelihood of malignant transformation increases with the severity of dysplasia: 30.4 per cent of cases of severe dysplasia and carcinoma in situ progress to malignancy compared with only 10.6 per cent of cases of mild to moderate dysplasia.Reference Weller, Nankivell, McConkey, Paleri and Mehanna3 Given the significant risk of malignancy, timely identification and intervention in vocal fold leukoplakia are of paramount importance.
More importantly, some studies suggest that certain cases of vocal fold leukoplakia can be effectively managed with conservative treatment.Reference Li, Zhang, Wang, Cheng, Wu and Chen4 Additionally, research indicates that more than one-third of patients with vocal fold leukoplakia have either non-dysplasia or mild dysplasia following surgical intervention, raising concerns about potential overtreatment.Reference Chen, Chen, Cheng and Wu5 Therefore, careful consideration of the timing of vocal fold leukoplakia surgery and efforts to avoid unnecessary interventions are crucial.
Contemporary approaches to the clinical management of vocal fold leukoplakia are divided into conservative and surgical modalities. Conservative strategies include pharmacotherapy, observation and watchful waiting, although these approaches carry the risk of disease progression and potential malignancy.Reference Ma, Wang, Xiao, Ye, Xu and Yang6 Conversely, surgical intervention, typically involving carbon dioxide (CO2) laser submucosal resection of the vocal fold, may pose risks such as post-operative impacts on sound quality and the financial burden of the procedure.Reference Lim, Park, Kang, Lee, Baek and Na7
Currently, limited research directly compares conservative and surgical treatments for vocal fold leukoplakia. This study aimed to investigate the treatment and prognosis of vocal fold leukoplakia, evaluating the effectiveness of both approaches across different pathological types.
Materials and methods
Patients
The retrospective study protocol received approval from the Institutional Review Committee of the First Affiliated Hospital of Sun Yat-sen University (ID Number (2024) No. 701). Between 2018 and 2023, the study enrolled patients diagnosed with vocal fold leukoplakia at our hospital. Initial examination using electronic white-light laryngoscopy identified 473 individuals provisionally diagnosed with vocal fold leukoplakia. After follow up, 351 patients met the inclusion criteria, which required visible white plaque lesions under laryngoscopy and a pathological classification of benign keratosis, hyperplasia with mild atypical hyperplasia, moderate atypical hyperplasia, severe atypical hyperplasia or carcinoma in situ. The exclusion criteria were laryngeal tuberculosis or laryngeal fungal infections, the absence of pretreatment laryngoscopy data and poor image quality preventing adequate morphological evaluation. Additionally, patients who had undergone open throat surgery or radiation therapy were excluded.Reference Li, Yu, Zhu, Wang, Li and Yang8
Clinical data
Clinical data relevant to the study parameters were collected, including demographic attributes such as age and sex, lifestyle factors such as smoking and alcohol consumption, and the presence of pharyngeal reflux. Additionally, pre-operative laryngoscopy images and pathological grading information were documented. Excessive vocal use was assessed based on professional voice status, including occupations such as teachers, anchors, telemarketers, salespeople, instructors, singers and actors. Lesion size was categorised as either less than 50 per cent (the sum of all vocal fold leukoplakia is less than half the length of one true vocal fold) or equal to or greater than 50 per cent (the sum of all leukoplakia is half or more than half the length of one true vocal fold) according to previous studies.Reference Fang, Lin, Lee, Young, Lee and Chang9, Reference Young, Lin, Lee, Lee, Hsin and Liao10 Treatment outcomes, recurrence rates and the incidence of cancer progression were recorded during subsequent follow up.
Morphological types and pathological grades
The laryngoscopy images of vocal fold leukoplakia were independently classified by two laryngologists who were blind to the pathological diagnosis and other clinically related information. Their consensus was the final evaluation result. When the results were inconsistent, a third experienced laryngologist made the judgment and selected the result that aligned with the conclusions of the first two doctors. Based on the assessment of laryngoscopic white-light images, vocal fold leukoplakia is classified into three distinct morphological types.Reference Zhang, Cheng, Chen, Chen, Yang and Xie11
The flat and smooth type presents a smooth surface with no protrusions along its periphery, allowing it to blend seamlessly with the surrounding mucosa. The texture is uniform and regular, with consistent coloration throughout the lesion.
The raised and smooth type is similar to the flat type, but this variant retains a smooth surface. However, the lesion’s border appears elevated, creating a distinct separation from the adjacent mucosa. Despite this elevation, the texture remains uniform and regular, with even coloration across the lesion.
The rough type is characterised by a wrinkled or undulating surface. The lesion’s perimeter has raised margins that are sharply demarcated from the surrounding mucosa. The texture is uneven and irregular, often showing colour variations and accompanied by erosions or ulcerations (Figure 1).
(A) Flat and smooth type. (B) Raised and smooth type. (C) Rough type.
Patients receiving conservative treatment obtained pathological results through biopsy, while patients undergoing surgical treatment received results based on post-operative pathology. Histological assessment was conducted according to the World Health Organization (WHO) (2005) guidelines in which vocal fold leukoplakia is divided into the following categories: squamous hyperplasia, mild dysplasia, moderate dysplasia, severe dysplasia and carcinoma in situ.Reference Thompson12 Vocal fold leukoplakia was then classified into two categories: low-grade dysplasia (including squamous hyperplasia and mild dysplasia) and high-grade dysplasia (including moderate dysplasia, severe dysplasia and carcinoma in situ) according to the WHO (2017) guidelines.Reference Gale, Poljak and Zidar13
Treatment
Patients undergoing conservative treatment were instructed to follow a regimen that included rest, avoiding excessive voice use, and ceasing smoking and alcohol consumption.Reference Johnson14 Additionally, patients with laryngeal reflux were treated with acid-suppressing drugs. Treatment efficacy was assessed based on laryngoscopy images and the resolution of symptoms. Complete remission was defined as the total disappearance of vocal fold leukoplakia on laryngoscopy and the resolution of the patient’s symptoms at follow up. Cases in which leukoplakia persisted on examination were classified as incomplete remission.
Patients who opted for surgical intervention underwent CO2 laser resection surgery.Reference Remacle, Friedrich, Dikkers and de Jong15 Following surgical treatment, data on post-operative recurrence and cases of cancer progression were collected during follow up. The follow-up period ranged from 12 to 72 months, with a median follow up of 42 months.
Statistical analysis
All statistical analyses were performed using SPSS 27.0 software, New York, United States. First, one-way analysis of variance and Fisher’s test were used to compare differences among the laryngoscopic classification groups. Second, a logistic regression model was constructed to identify factors influencing complete remission in the conservative treatment group. Third, another logistic regression model was used to analyse factors affecting recurrence in the surgical treatment group. Finally, Fisher’s test was employed to compare the effectiveness of conservative and surgical treatments, as well as differences between the carcinogenesis and non-carcinogenesis groups of vocal fold leukoplakia. A two-sided p value less than 0.05 was considered statistically significant.
Results
Clinical data of patients with vocal fold leukoplakia
Out of 473 patients, our study enrolled 351 individuals who were followed up, including 229 who underwent surgical treatment and 122 who received conservative treatment. Among the follow-up patients, 323 were male and 28 were female, with a median age of 54.29 ± 11.82 years. A total of 207 patients were smokers, while 122 consumed alcohol. Bilateral vocal fold lesions were observed in 172 patients and 216 patients were diagnosed with pharyngeal reflux. Lesions exceeding 50 per cent of the total vocal fold length were found in 90 individuals. Additionally, 69 patients were identified as having excessive voice use. Over the course of follow up, 53 patients experienced recurrent vocal fold leukoplakia and 8 progressed to SCC (Table 1).
General information of 351 patients with vocal fold leukoplakia
SD = standard deviation
Correlation between laryngoscopic white-light classification and pathological grading
The patients were classified into three types based on laryngoscopic white-light imaging: 113 cases (32.2 per cent) of the flat and smooth type, 101 cases (28.8 per cent) of the raised and smooth type, and 137 cases (39.0 per cent) of the rough type. The average age of patients with rough leukoplakia was 58.47 years, which was significantly higher than that of patients with the raised and smooth type (53.43 years) and the flat and smooth type (49.99 years), with a statistically significant difference (p < 0.001). Significant differences (p < 0.001) were also observed among the different subtypes regarding lesion size, treatment methods and the presence of laryngopharyngeal reflux. Pathological classification revealed that 11 patients (9.7 per cent) with the flat and smooth type had high-grade dysplasia, compared with 26 patients (25.7 per cent) with the raised and smooth type, and 88 patients (64.2 per cent) with the rough type. A statistically significant correlation (p < 0.001) was found between laryngoscopic white-light classification and pathological grading (Table 1).
Efficacy of conservative treatment in patients with vocal fold leukoplakia
Among the 122 patients who were followed up, 90 (73.8 per cent) achieved complete remission while 32 (26.2 per cent) did not. Three patients experienced relapse after initially achieving remission with conservative treatment and subsequently underwent surgery. The complete remission rate varied among different morphological types: 77.2 per cent for the flat and smooth type, 75.7 per cent for the raised and smooth type, and 64.3 per cent for the rough type. Multivariate logistic regression analysis indicated that smoking significantly hindered the effectiveness of conservative treatment and the likelihood of curing vocal fold leukoplakia, with statistical significance (odds ratio = 0.085 (0.024–0.301), p < 0.001). Additionally, lesion size was identified as a significant factor influencing complete remission (odds ratio = 4.424 (1.106–17.691), p = 0.035). Other factors did not show statistical significance (Table 2).
Logistic regression model for complete remission of vocal fold leukoplakia treated conservatively
Factors influencing recurrence in surgical patients with vocal fold leukoplakia
Among the 229 surgical patients who were followed up, 50 (21.8 per cent) experienced recurrence while 179 (78.2 per cent) did not. Patients were categorised into a recurrence group and a non-recurrence group. The recurrence rate varied by morphological type, with 12.5 per cent of patients in the flat and smooth type experiencing recurrence compared with 25.0 per cent in the raised and smooth type and 24.8 per cent in the rough type. Multivariate logistic regression analysis identified lesion size as an independent prognostic factor for vocal fold leukoplakia recurrence (odds ratio = 2.341 (1.160–4.724), p = 0.018). Other factors did not show statistical significance (Table 3).
Logistic regression model for recurrence of vocal fold leukoplakia treated surgically
Conservative versus surgical treatment in patients with vocal fold leukoplakia
Among the 351 patients, 122 (34.8 per cent) received conservative treatment while 229 (65.2 per cent) opted for surgical treatment. Treatment was considered effective if patients remained free of recurrence or cancer progression within one year following surgical treatment or if they achieved complete remission with conservative treatment within the same period without recurrence or cancer progression. The effectiveness of both treatment approaches is summarised in Table 4. As the pathological grade increased, treatment effectiveness decreased. In cases of squamous hyperplasia, the effectiveness of conservative and surgical treatments was 73.5 and 83.1 per cent, respectively (p = 0.223). For mild dysplasia, the effectiveness rates were 67.6 and 72.7 per cent, respectively (p = 0.634). In moderate dysplasia, conservative and surgical treatments had effectiveness rates of 60.0 and 66.7 per cent, respectively (p = 0.758). None of these differences reached statistical significance, therefore, in clinical practice, conservative treatment should be prioritised for patients with moderate dysplasia or milder conditions. If conservative treatment fails to provide adequate relief, surgical intervention becomes necessary.
Effectiveness of conservative and surgical treatment
Carcinogenesis cases
Among all patients, eight progressed to laryngeal SCC, all of whom were classified as the rough type based on laryngoscopic evaluation. These eight patients underwent surgery and were diagnosed with laryngeal SCC within six months to three years post-operatively. Of the eight patients, two had mild dysplasia, three had moderate dysplasia, two had severe dysplasia and one had carcinoma in situ (Table 5). According to the WHO (2017) guidelines, 6 of the 8 patients (75 per cent) had high-grade dysplasia, while 2 patients (25 per cent) had low-grade dysplasia. The findings indicate that laryngoscopic white-light classification was significantly associated with cancer progression in vocal fold leukoplakia (p = 0.01). However, there was no statistically significant difference in pathological grade (p = 0.153) (Table 6).
Summary of eight cases with laryngeal carcinoma
Factors influencing cancer of vocal fold leukoplakia
Discussion
To date, there is no consensus on the optimal treatment approach for vocal fold leukoplakia. Clinicians tend to follow a more standardised approach for the management of benign keratosis, severe atypical hyperplasia and carcinoma in situ. Benign keratosis is typically managed with conservative treatment, whereas severe atypical hyperplasia and carcinoma in situ are generally treated with surgical intervention.Reference Mehanna, Paleri, Robson, Wight and Helliwell16 However, optimal treatment strategies for intermediate pathological grades remain uncertainReference Hu and Liu17, Reference McLaren, Burnett, Goodlad, Howatson, Lang and Lee18 and few studies have directly compared conservative versus surgical treatment. Additionally, the factors influencing the prognosis of vocal fold leukoplakia remain inconsistent across different studies.
This study first investigated the correlation between the morphology and clinical characteristics of vocal fold leukoplakia patients using white-light laryngoscopy. The results demonstrated that morphological types of vocal fold leukoplakia were significantly associated with pathological grades, patient age, lesion size and laryngopharyngeal reflux. Similarly, Chen et al. also found a strong correlation between morphological types and pathological grades.Reference Chen, Li, Yang, Cheng and Wu19 Therefore, in clinical practice, patients with rough-type vocal fold leukoplakia should undergo more aggressive biopsies, a recommendation that aligns with previous research findings.
Our study also examined the treatment outcomes of patients undergoing conservative interventions, identifying smoking and lesion size as key factors influencing treatment success. The complete remission rate in our study was 73.8 per cent. In previous research, Chen et al. found that morphology was a significant variable affecting clinical response, reporting a 68 per cent complete remission rate for the conservative treatment of vocal fold leukoplakia.Reference Chen, Cheng, Li, Chen, Shu and Wu20 These findings suggest that smoking and lesion extent play a crucial role in conservative treatment outcomes, offering valuable insights for clinical decision-making.
Moreover, our study confirmed that lesion size significantly influenced post-operative recurrence in surgically treated patients. Yang et al. identified pharyngeal reflux as a potential contributor to vocal fold leukoplakia recurrence,Reference Yang, Chao, Lee, Chang, Hsieh and Chen21 whereas Yin’s findings emphasised the pathological subtypes and lesion size as key factors affecting recurrence risk.Reference Yin, Huang, Sun and Zhang22 These discrepancies may be due to differences in sample size and the inherent limitations of retrospective studies. Given these findings, patients with risk factors for recurrence should receive closer clinical monitoring during follow up to ensure timely intervention.
Most importantly, we compared the effectiveness of conservative and surgical treatments for vocal fold leukoplakia across different pathological grades. Our findings confirmed that there was no statistically significant difference in response rates between the two treatment approaches for patients with hyperplasia, mild dysplasia and moderate dysplasia. Based on these results, conservative treatment may be recommended as the primary approach for patients with these conditions in clinical practice, reserving surgical intervention for cases where conservative management fails to achieve remission.
Regarding cases of carcinogenesis, our study confirmed that rough-type vocal fold leukoplakia is associated with an increased risk of cancer. However, because of the relatively small number of cases with malignant transformation, this conclusion requires further validation. Lee’s study, which analysed 13 cases of malignant vocal fold leukoplakia, concluded that lesion size and pathological grade were key factors influencing malignant transformation.Reference Lee, Yoon, Lee and Lim23 Additionally, multiple studies have reported that the risk of vocal fold leukoplakia progressing to carcinoma is directly related to the severity of histopathological abnormalities.Reference Isenberg, Crozier and Dailey24 However, these studies also had limited sample sizes, making definitive conclusions challenging.
In our study, the median follow-up duration was 42 months, while the mean follow-up time for patients who progressed to cancer was 19.8 months. Comparatively, Bartlett et al. reported 10 cases of vocal fold leukoplakia-associated cancer, with a mean follow up of 73 months.Reference Jabarin, Pitaro, Marom and Muallem-Kalmovich25 These findings suggest that vocal fold leukoplakia may undergo malignant transformation over an extended period, highlighting the need for long-term clinical follow up. However, whether the duration of transformation from vocal fold leukoplakia to SCC is directly associated with pathological grade remains an area of limited research and warrants further investigation.
In this study, we explored the relationship between laryngoscopic classification of vocal fold leukoplakia and its clinical features, assessed the prognosis of different treatment modalities and compared the effectiveness of conservative and surgical treatments. However, retrospective studies have inherent limitations. A small sample size and a high rate of loss to follow up may have influenced the outcomes and retrospective designs are more susceptible to bias. In addition, variations in the surgeon’s technique and patient adherence to conservative treatment may have affected the results of the study. Future prospective studies with more rigorous experimental designs are therefore warranted to provide more robust evidence and further clarify the optimal management strategies for vocal fold leukoplakia.
• To date, there is no consensus on the optimal treatment approach for vocal fold leukoplakia and the results of research on the prognostic factors of vocal fold leukoplakia are not uniform
• This study explored the influencing factors of conservative versus surgical treatment of vocal fold leukoplakia, comparing the effectiveness of conservative and surgical treatments for vocal fold leukoplakia across different pathological grades
• The results suggest that the key factors influencing conservative treatment outcomes are smoking and lesion size, while lesion size is the primary factor affecting recurrence after surgical treatment
• Based on these findings, conservative treatment may be considered as the preferred approach for patients with hyperplasia, mild dysplasia and moderate dysplasia, reserving surgery for cases where conservative management is ineffective
• Prospective studies with more rigorous experimental designs are needed to clarify further the optimal management strategies for vocal fold leukoplakia
Conclusion
Our study suggests that white-light laryngoscopic classification is associated with the pathological type, with rough-type leukoplakia warranting active biopsy in clinical practice. The key factors influencing conservative treatment outcomes are smoking and lesion size, while lesion size is the primary factor affecting recurrence after surgical treatment. Based on our findings, conservative treatment may be considered as the preferred approach for patients with hyperplasia, mild dysplasia and moderate dysplasia, reserving surgery for cases where conservative management is ineffective.
Acknowledgments
The author thanks Angela Morben, DVM, ELS, from Liwen Bianji (http://www.liwenbianji.cn/), for editing the English text of a draft of this manuscript. The author also thanks all physicians who provided cases for this study. This work was supported by the National Natural Science Foundation of China (W.S., grant numbers 81972527).
Competing interests
None declared
