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Table of Contents
REVIEW ARTICLE
Year : 2021  |  Volume : 4  |  Issue : 2  |  Page : 321-327

Vocal fold leukoplakia – An underestimated premalignant lesion of the larynx: A narrative review


1 Department of Otorhinolaryngology, IMS and SUM Hospital, Siksha “O” Anusandhan University, Bhubaneswar, Odisha, India
2 Medical Research Laboratory, IMS and SUM Hospital, Siksha “O” Anusandhan University, Bhubaneswar, Odisha, India

Date of Submission24-Jan-2021
Date of Decision06-Mar-2021
Date of Acceptance10-May-2021
Date of Web Publication30-Jun-2021

Correspondence Address:
Santosh Kumar Swain
Department of Otorhinolaryngology, IMS and SUM Hospital, “O” Anusandhan University, K8, Kalinga Nagar, Bhubaneswar - 751 003, Odisha
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/crst.crst_16_21

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  Abstract 


Vocal fold leukoplakia is the clinical term for a whitish patch on the vocal fold mucosa. It is caused by prolonged tobacco smoking, consumption of alcohol, and excessive drying or vocal abuse. Histopathologically, it displays varying degrees of dysplasia and hyperkeratosis. The presence of dysplastic cells in the vocal fold leukoplakia denotes a premalignant lesion. The common clinical presentations of vocal fold leukoplakia include hoarseness of voice, foreign-body sensation, and irritation in the throat. The prognosis of this lesion is uncertain, and it can vary from a non-dysplastic leukoplakia to a squamous cell carcinoma. Early diagnosis and treatment of vocal fold leukoplakia are often challenging, and its management includes excision of the lesion, close follow-up, and avoiding exposure to risk factors such as tobacco smoking and alcohol consumption. For this review, we identified 134 articles from the Scopus, PubMed, Cochrane, and Medline databases and Google Scholar using the search terms, “vocal fold leukoplakia,” “premalignant diseases of the larynx,” “laryngeal keratosis,” “vocal cord leukoplakia,” “glottis,” and “precancerous lesions of glottis.” A total of 52 articles were included in the review. We aimed to assess the epidemiology, etiopathology, clinical presentation, diagnosis, and the current treatment options of vocal fold leukoplakia.

Keywords: Dysplasia, larynx, laser, leukoplakia, smoking, vocal fold


How to cite this article:
Swain SK, Kar D. Vocal fold leukoplakia – An underestimated premalignant lesion of the larynx: A narrative review. Cancer Res Stat Treat 2021;4:321-7

How to cite this URL:
Swain SK, Kar D. Vocal fold leukoplakia – An underestimated premalignant lesion of the larynx: A narrative review. Cancer Res Stat Treat [serial online] 2021 [cited 2021 Jul 24];4:321-7. Available from: https://www.crstonline.com/text.asp?2021/4/2/321/320158




  Introduction Top


Vocal fold leukoplakia is defined as the presence of whitish lesions on the vocal fold that cannot be characterized as any other clinical entity.[1] Pathologically, this entity can be classified as keratosis with non-dysplasia or keratosis with dysplasia.[1] It has a tendency for malignant transformation, and hence, its early diagnosis is challenging. Its origin and development are associated with the long-standing effects of certain risk factors such as tobacco smoking, alcohol consumption, and laryngopharyngeal reflux. Malignancies such as squamous cell carcinoma of the vocal fold or glottis often arise from a precancerous pathology of the larynx such as vocal fold leukoplakia.[2] Vocal fold leukoplakia is often observed during the routine assessment of dysphonia.[2] The absence of dysplasia in leukoplakia does not convey its precancerous/premalignant potential; however, the presence of dysplasia is indicative of its precancerous potential.[3] The benign or malignant nature of the vocal fold leukoplakia cannot be determined on the basis of the clinical findings alone without a biopsy; therefore, the treatment options range from observation to wide/complete excision of the lesion.[4] It has been documented that early detection of vocal fold leukoplakia is an important determinant of prognosis of laryngeal cancers.[5] Therefore, the early identification and prompt treatment of vocal fold leukoplakia are vital issues in routine clinical practice. Wide excision of the leukoplakia from the vocal fold is usually recommended because of its tendency for malignant transformation and the opportunity for a histopathological diagnosis.[6] However, the possibility of malignant transformation or recurrence of this premalignant entity after surgical excision are important to recognize for clinicians. The variability in clinical features, underlying pathological changes, and treatment options for vocal fold leukoplakia continue to intrigue the clinicians and encourage research and debate in this area. In this review, we have elaborated on the epidemiology, etiopathology, clinical presentation, diagnosis, and current treatment for vocal fold leukoplakia.


  Methods Top


We searched the Scopus, PubMed, Cochrane, and Medline databases and Google Scholar for articles on vocal fold leukoplakia using the search terms, “vocal fold leukoplakia,” “premalignant diseases of the larynx,” “laryngeal keratosis,” “vocal cord leukoplakia,” “glottis,” and “precancerous lesions of glottis.” We developed a search strategy using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. We manually identified a total of 134 articles from the search results, and evaluated all the randomized controlled studies, observational studies, comparative studies, case series, and case reports for eligibility. As this review is focused on vocal fold leukoplakia, we excluded articles reporting on other laryngeal lesions. In addition, we excluded review articles with no primary research data and articles not published in the English language. After excluding a total of 82 articles, we included 52 articles in the review [Figure 1].
Figure 1: Flow diagram of the method of selection of the reference studies that were included in this review article on vocal fold leucoplakia

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  History Top


Schwimmer, in 1877, first used the word leukoplakia for describing a whitish patch on the tongue.[7] Leukoplakia of the larynx was first documented by Durant in 1880.[8] He described this lesion as white cicatrices adjacent to a glottic carcinoma. However, it was not until over 40 years later that Jackson proposed that this lesion may precede a laryngeal malignancy. Thereafter, this clinical entity was studied further in 1920 by Pierce and Jackson[8] and deemed a precancerous lesion for carcinoma of the larynx.[9] The histopathological assessment of the biological specimen obtained from the vocal fold leukoplakia can show hyperplasia with or without keratosis, mild dysplastic lesion, moderate dysplastic lesion, severe dysplastic lesion, carcinoma in situ (CIS), or invasive cancer.


  Epidemiology Top


The annual incidence of vocal fold leukoplakia is 4.2/100,000 people. It has a predilection for men, and the reported incidence is 10.2/100,000 men and 2.1/100,000 women in the United States of America In another study, 70%–76% of the affected persons were men.[10],[11] The median age at presentation for leukoplakia is 61.7–63 years; this suggests a possible association between leukoplakia and malignancy of the larynx, for which the median age at presentation is greater by 10–15 years.[12] Vocal fold leukoplakia is predominantly found along the medial border and superior edges of the true vocal cord and at the anterior commissure. In 78%–84% of the cases, leukoplakia occurs on the vocal folds only on one side of the larynx.[13] The posterior commissure of the glottis and false vocal cord is usually not affected by leukoplakia.[13] In one study on 208 biopsies from vocal fold leukoplakia, 33.5% of the biopsies showed mild-to-moderate dysplastic changes and 15.2% showed severe dysplastic changes.[14] In a recent study on 63 patients with vocal fold leukoplakia, hyperplasia with/without leukoplakia was observed in 42.9%, mild dysplastic changes in 22.2%, moderate dysplastic changes in 7.9%, severe dysplastic changes in 14.3%, and invasive cancer was observed in 12.7% of the patients.[15] Vocal fold leukoplakia can transform from a benign to malignant lesion.

One study has shown that tobacco smoking can impact the risk for malignant transformation.[16] In this study, out of 52 patients, 10 (19.2%) male patients developed squamous cell carcinoma and 4 (7.7%) with severe dysplasia developed squamous cell carcinoma within 19 months of the first direct laryngoscopy. In 6 (11.5%) other patients, squamous cell carcinoma developed within an average of 3.7 years. Male sex, heavy smoking and severe dysplasia in the initial biopsy were found to be significant risk factors for the development of squamous cell carcinoma. Another study revealed that the clinical diagnosis of vocal fold leukoplakia is associated with a 6%–7% chance of malignant transformation.[14] History of smoking and the number of years of smoking habit are considered significant risk factors for malignant transformation.[14] Epidemiological studies have shown that alcohol consumption is an independent risk factor for the transformation of vocal fold leukoplakia to laryngeal cancer.[17] The risk of malignant transformation increases with the amount of alcohol consumed. In a meta-analysis of 20 studies conducted in North America, Europe, Japan, and Korea, the multivariate relative risk was about 2 for 50 g (<4 drinks)/day and 4 for 100 g/day of alcohol compared to non-drinkers in the absence of evidence of a threshold.[17] In the absence of smoking, the relative and absolute risks for transformation are small in case of moderate alcohol consumption, but 2–10 times higher in case of increased alcohol consumption.[17]


  Etiopathology Top


The major risk factors for vocal fold leukoplakia are tobacco smoking and alcohol consumption.[6] Laryngopharyngeal reflux is also a trigger for vocal fold leukoplakia.[18] A high prevalence of laryngopharyngeal reflux has been observed in patients with squamous intraepithelial lesions and malignancies of the larynx, and this reflux is considered to be a common etiological factor for vocal fold leukoplakia and malignancy.[19] As the epithelium lining the vocal fold is non-keratinized, the leukoplakic changes represent an alteration of the epithelium itself. Long-standing cumulative stimuli from external factors such as tobacco smoking, alcohol consumption, vocal abuse, laryngopharyngeal reflux, infections, and air pollution can result in molecular alterations in the cells, leading to the activation and abnormal expression of oncogenes and other genes associated with tumor metastasis.[20] The etiological factors that cause vocal fold leukoplakia are also important predisposing agents for postoperative recurrence.[21] Smoking reduces the tone of the muscles in the lower part of the esophagus, which delays the emptying of the gastric contents and increases the secretions of gastric acid, thus increasing the chances of laryngopharyngeal reflux.[22] The gastric content of the laryngopharyngeal reflux disease plays a vital role in the recurrence of vocal fold leukoplakia after surgery.


  Classification of Vocal Fold Leukoplakia Top


Morphologically, vocal fold leukoplakia can be superficial, exophytic, or ulcerative.[15] Fang et al. have provided a classification of vocal fold leukoplakia on the basis of its morphological characteristics such as thickness, texture, color, hyperemia, size, and symmetry.[23] The morphological classification of vocal fold leukoplakia is presented in [Table 1]. Newer endoscopic techniques, particularly narrow-band imaging, have been utilized for the classification of vocal fold leukoplakia on the basis of microvascular changes. Recently, the macroscopic pictures of vocal fold leukoplakia have been associated with morphological alterations, which are considered the mainstay of correct diagnosis, prognosis, and treatment.[6] Based on the histopathological changes and the presence or absence of dysplasia, vocal fold leukoplakia can be classified as non-dysplasia, mild dysplasia, severe dysplasia, or carcinoma.[6] This grading is most commonly used in the pathological assessment of vocal fold leukoplakia. The World Health Organization Blue Book in 2017 suggested a two-tier classification based on which vocal fold leukoplakia can be categorized as no/mild dysplasia and moderate/severe dysplasia.[24]
Table 1: Morphological classification of vocal fold leukoplakia

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  Clinical Presentation and Diagnosis Top


Vocal fold is an important part of the larynx which helps to produce the voice. Any pathological lesions in the vocal fold result in hoarseness of voice.[25] Laryngeal leukoplakia is often found on the vocal fold, and hence called vocal fold leukoplakia. It results in speech defects. The diagnosis of vocal fold leukoplakia is made on the basis of direct observation of the vocal fold or larynx, and laryngoscopic examination is essential for the identification of a leukoplakic lesion.[26] Common clinical presentations of vocal fold leukoplakia include hoarseness of voice, throat discomfort, and irritating cough.[27] Leukoplakia is a clinical descriptor denoting any whitish plaque observed during clinical examination of the mucosal lining of the vocal fold by indirect laryngoscopy. Direct and indirect laryngoscopic examinations help in the diagnosis of vocal fold leukoplakia [Figure 2]. These are usually performed by indirect laryngoscopy, flexible nasopharyngolaryngoscopy, or 70° rigid laryngeal endoscopic examination followed by microlaryngeal surgery. The strongest prognostic indicator for vocal fold leukoplakia is early diagnosis. Stroboscopic examination of the vocal fold is helpful to determine the progress of the lesion and the stages of the dysplastic changes in the mucosal lining.[28] Stroboscopic findings such as decreased amplitude of the vocal fold vibration or mucosal wave are not always considered reliable features for predicting dysplasia or malignancy. Leukoplakia along the medial edge of the vocal fold can be better visualized using stroboscopy than flexible laryngoscopy. Additional benefits of laryngeal stroboscopy include greater illumination, ability to compare the findings over time, and features that allow for play back with slow motion or frame-by-frame evaluation, thus permitting the detailed evaluation of the medial edge of the vocal fold. In routine clinical practice, early detection and prompt treatment of vocal fold leukoplakia are the two most important issues. Narrow-band imaging endoscopy is a modern tool that allows for a better analysis of laryngeal lesions and is helpful in distinguishing between benign and malignant vocal fold leukoplakia.[29]
Figure 2 : Direct laryngoscopic picture of the vocal fold leukoplakia

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Vocal fold leukoplakia is considered benign if it has Type I, II, or IV vessels (according to the Ni classification) in the surrounding epithelium. Contrarily, it is considered malignant if intraepithelial papillary capillary loops of Type V are present.

However, the biological features of the vocal fold leukoplakia are not highlighted by narrow-band imaging. Instead, it highlights the vascularization.[30] Moreover, the visual obstruction by a thick layer of keratin covering the vocal fold also limits the use of narrow-band imaging.[31] However, normal laryngoscopic examination under white light is commonly used for observing vocal fold leukoplakia as it displays the lesion more clearly and directly. The degree of dysplasia or depth of the lesions of the vocal fold cannot be established on the basis of a laryngoscopic examination alone; therefore, a biopsy is needed to diagnose keratosis with dysplasia or malignancy or to confirm the benign nature of a keratosis.[32] The widely accepted method for confirming the diagnosis of vocal fold leukoplakia is an excisional biopsy, which is performed by direct laryngoscopy under general anesthesia followed by a histopathological examination. Based on the histopathological examination, vocal fold leukoplakia can be categorized as squamous cell hyperplasia, mild dysplasia, moderate dysplasia, severe dysplasia, or carcinoma.[33] Non-dysplastic changes are observed in around 50% of the cases of vocal fold leukoplakia, whereas low-or moderate-grade dysplasia is observed in approximately 33% of the cases.[34] High-grade dysplasia and CIS are usually observed in approximately 15% of the cases.[34] Severe dysplasia increases the chances of a malignant transformation of a vocal fold leukoplakia.


  Treatment Top


Vocal fold leukoplakia is managed based on whether it is benign or malignant. Complete surgical excision of the leukoplakia is recommended to circumvent the possibility of a malignant transformation and also because it allows for a histological diagnosis.[6] A safe and effective treatment for vocal fold leukoplakia is transoral laser microlaryngeal surgery with sub-epithelial cordectomy. An effective treatment for vocal fold leukoplakia with dysplasia of any grade is laser-assisted microlaryngeal surgery with sub-epithelial cordectomy. Carbon dioxide lasers produce better hemostatic effect than cold steel microlaryngeal surgery. During a laser surgery, it is easy to differentiate the vocal ligament from the superficial layer of the lamina propria and make a bloodless surgical field. Moreover, it is easy to perform a sub-epithelial cordectomy while preserving the vocal ligament by using an operating microscope to obtain a bloodless surgical field. Cases of vocal fold leukoplakia with a low risk for malignant transformation need conservative treatment or an observation-alone strategy.[35] Once an incisional biopsy confirms the presence of epithelial dysplasia, the lesion should be excised completely in view of the potential for malignant transformation. Around 50% of the cases of vocal fold leukoplakia do not show any features of dysplasia.[14] Therefore, a surgical treatment in such cases is unnecessary.[36] Beta-carotene and retinoids have been used in the past as antioxidant supplements for the conservative treatment of vocal fold leukoplakia. However, currently based on the evidence from Nagao et al.'s study, their use for chemoprevention is no longer recommended.[37] As laryngopharyngeal reflux is associated with vocal fold leukoplakia, treatment with proton pump inhibitors is also beneficial.[38] This non-surgical approach may be effective for reducing the size or eliminating the vocal fold leukoplakia lesions. Similarly, administration of oral alpha tocopherol and subcutaneous interferon alpha has been shown to reduce the size of the lesions.[39] In Papadimitrakopoulou et al.'s study, out of 36 patients, 10 (27.8%) showed complete response and 7 (19.4%) showed partial response at 12 months. Another study has shown that the administration of folic acid at a dose of 5 mg 3 times a day for 6 months may lead to partial to complete response[40] In this study, 28% of the patients showed no response. 44% showed partial response, and 28% showed complete response. It is important to emphasize that the non-surgical methods of management are not standard and that there are limited data on efficacy.

The patients with heterogeneous vocal fold leukoplakia need aggressive therapy. However, over-treatment may result in scars on the vocal fold and cause voice deterioration. Coblation is a minimally invasive low heat producing technique, which delivers a plasma layer causing dissolution of the target tissues. The laryngeal wand of the Coblator has a temperature of 40°C–70°C and causes minimum charring or burning.[41] Speech rehabilitation or therapy is an important measure after the excision of leukoplakia. Speech therapy includes ensuring vocal hygiene and educating the patients about voice conservation. The patients are advised to avoid vocal abuse, repetitive throat clearing, and other vocal fold irritants as well as products that may cause dehydration of the mucosa of the vocal folds including tobacco, alcohol, and antihistamines. Adequate fluid intake is recommended to counter dehydration. As tobacco and alcohol abuse are considered etiological factors for vocal fold leukoplakia or malignancy, it is imperative for clinicians to counsel their patients for cessation of smoking and alcohol.[15],[42] It might also be prudent to proactively seek treatment for laryngopharyngeal reflux and consider performing a pH probe evaluation to guide the treatment. A relatively new addition to the treatment options for vocal fold leukoplakia is andrographolide therapy, which has an antiproliferative effect.[43]


  Prevention Top


The preventive measures for vocal fold leukoplakia include cessation of tobacco smoking, alcohol consumption, and vocal abuse; treatment of laryngopharyngeal reflux; and avoidance of exposure to industrial pollutants.[44] It has been reported that cessation of tobacco smoking is an important factor that enhances the clearing of leukoplakia.[45],[46] The factors such as the type of vocal fold leukoplakia, gender and age of the patient, smoking and alcohol habits, vocal abuse, evidence of laryngopharyngeal reflux, and site of the lesion are often taken into consideration when deciding the course of treatment for vocal fold leukoplakia. The type of leukoplakia is an important factor associated with the clinical response to nonsurgical treatment or preventive measures.[47] Conservative or non-surgical treatment is more effective for smooth vocal fold leukoplakia than for heterogeneous vocal fold type leukoplakia. The preventive measures for vocal fold leukoplakia include cessation of smoking, alcohol abuse, and phonotrauma. Laryngopharyngeal reflux should be treated adequately along with the avoidance of industrial pollution for preventing the origin of the vocal fold leukoplakia.[48]


  Conclusion Top


Vocal fold leukoplakia is a whitish patch on the glottis which corresponds to several types of pathological lesions that are either benign or malignant. However, in majority of the patients with vocal fold leukoplakia, the risk of malignant transformation is low. Therefore, it is important to assess the characteristics of the lesion and the risk of malignant transformation. Vocal fold leukoplakia is usually diagnosed with an endoscopic examination of the larynx and a histopathological examination helps to confirm the presence of a malignancy. Complete excision of the lesion can be safely performed with laser-assisted surgery or coblation. Preventive measures for vocal fold leukoplakia include cessation of tobacco smoking, alcohol consumption, and vocal abuse, and adequate treatment of laryngopharyngeal reflux. Recently, andrographolide therapy in vocal fold leukoplakia is gaining attention; however, it is still investigational. Thus, the prevention of risk factors is an important part of the management of vocal fold leukoplakia and helps in lowering the risk of development of vocal fold leukoplakia.

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Conflicts of interest

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