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Year : 2014  |  Volume : 4  |  Issue : 2  |  Page : 39-44

Leukoplakia of larynx: A review update

1 Department of Otolaryngology and Head and Neck Surgery, Maulana Azad Medical College, New Delhi, India
2 Department of Otolaryngology and Head and Neck Surgery, PGIMS, Rohtak, Haryana, India

Date of Web Publication21-May-2015

Correspondence Address:
Dr. Ishwar Singh
Department of Otolaryngology and Head and Neck Surgery, BL Taneja Block, Maulana Azad Medical College, New Delhi
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2230-9748.157464

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Leukoplakia of larynx has remained a debatable topic in laryngeal pathology for decades as per classification, histology and treatment is concerned. Smoking and alcohol are the major causes and there is sufficient evidence implicating gastroesophageal reflux and human papilloma virus in its pathogenesis. A wide range of therapeutic strategies are available for different grades of dysplasia. Despite this, a significant proportion of patients progress to carcinoma for which the patients with dysplasia need to be kept in regular follow-up.

Keywords: Cancer, leukoplakia, larynx, precancerous, tobacco

How to cite this article:
Singh I, Gupta D, Yadav S. Leukoplakia of larynx: A review update. J Laryngol Voice 2014;4:39-44

How to cite this URL:
Singh I, Gupta D, Yadav S. Leukoplakia of larynx: A review update. J Laryngol Voice [serial online] 2014 [cited 2022 Jul 6];4:39-44. Available from: https://www.laryngologyandvoice.org/text.asp?2014/4/2/39/157464

   Introduction Top

Leukoplakia is a Greek term that means white plaque. It presents as a white patch on the epithelium indicating keratin that cannot be scraped easily. It is a nonspecific clinical term and represents a wide variety of lesions without taking into account any etiological and histopathological features. It is usually a result of chronic inflammation or exposure to irritants and may histologically represent varying degrees of epithelial dysplasia ranging from keratotic hyperplasia to microinvasive cancer. [1]

Comprehensive meta-analysis of laryngeal leukoplakia by Isenberg et al. [1] revealed no dysplasia in 1173 out of 2188 biopsies (53.6%), mild to moderate dysplasia in 717 out of 2140 biopsies (33.5%) and severe dysplasia to carcinoma in situ in 375 out of 2471 biopsies (15.2%). In total, 8.2% cases underwent malignant transformation on a follow-up that ranged from 1 to 233 months in various studies. Overall 3.7% nondysplastic, 10.1% mild to moderate dysplastic and 18.1% severely dysplastic cases underwent malignant change. This data reveals that even in the absence of dysplasia on histopathology in leukoplakia, there is 3.7% chance of developing invasive laryngeal carcinoma. Hence, all these so-called benign nondysplastic lesions actually may not be called benign.

The average age of diagnosis of vocal fold keratosis is 50 years, a decade lower than the age of diagnosis of carcinoma larynx. Leukoplakia or keratosis affects more men than women. The annual incidence in United States is 10.2 in males and 2.1 in females/100,000 of the population. [2] Despite a major advancement in the treatment modalities of laryngeal carcinoma, the survival rate of patients has hardly become better. [3] Since the survival significantly depends on the stage of detection of disease, it is important to focus early in the pathogenesis of laryngeal carcinoma at the precancerous or leukoplakic stage to institute suitable therapy.

   Etiological Factors Top

Cigarette smoking and alcohol

The role of smoking is confirmed both clinically and experimentally. Bouquot and Gnepp [2] found 84% smokers and 35% alcohol abusers in a case series of 108 patients of laryngeal keratosis. Bosatra et al. [4] investigated 47 cases of laryngeal dysplasia and found a direct correlation between the degree of dysplasia and malignant transformation with the amount of cigarette smoking and alcohol consumption. Vaezi et al. [5] presented the data establishing diminishing likelihood of cancer development with smoking cessation, especially in the first 15 years although the risk did not vanish completely. It was also observed that the risk of developing laryngeal carcinoma, had a close correlation with the duration of smoking, with an increment of 23% for every 5 years of smoking. It was also linked to the intensity of smoking with the risk increasing approximately 4 times for every additional pack of smoking. The effect of alcohol is less apparent as compared to smoking. An additional drink of alcohol per day increases the risk of laryngeal malignancy by 17%. [5]

Gastroesophageal reflux

Olson was the first to suggest an association of gastroesophageal reflux disease (GERD) with laryngeal carcinoma as he identified five cases with posterior laryngeal carcinoma in a series of patients with GERD. [6] Vaezi et al. [5] found a significant association of GERD with laryngeal cancer and also a higher proportion of symptomatic GERD in cancer patients as compared with non-cancer ones (13.5% versus 5.7%). The potential role of GERD as an etiological factor for laryngeal dysplasia has recently gained attention but needs further validation with larger sample sizes and matched controls.

Human papilloma virus infection

Human papilloma virus (HPV) has been incriminated as one of the promoters of the laryngeal carcinogenesis, though not as an independent causative factor. HPV DNA is detected in approximately 9.6% of the normal larynges. [7] However, its presence has been confirmed in up to 23.6% cases of laryngeal carcinoma, most frequently identified viral type being HPV 16. [8] Hobbs et al. [9] determined weak relation (odds ratio of 2) of HPV with laryngeal cancer in their meta-analysis. The evidence linking HPV to laryngeal precancerous and cancerous lesions is still incomplete, and it is yet to be seen whether the virus can be linked as positively as in the case of oropharyngeal carcinomas.

Other risk factors

Chronic laryngitis, industrial exposure to wood and metal dust, vocal abuse and nutritional deficiency of vitamins are also incriminated in the pathogenesis of laryngeal carcinoma. Serum folate levels have also been found low in cases of laryngeal leukoplakia. Hypofolatemia probably does not act as an initiator independently. It acts synergically with other carcinogens making cells more vulnerable, thereby expediting the rate of tumor progression. [10]

   Histopathological Aspects Top

It is indispensable to subject leukoplakia to histopathological examination due to its nonspecific clinical polymorphism that may represent a wide range of epithelial changes in the laryngeal mucosa. It is, therefore, essential to subject these lesions to histological analysis to determine their biological nature. Numerous studies and classifications have been devised in attempts to correlate phenotypical changes with the biological behavior of the lesions. Furthermore, histopathological diagnosis is prone to errors of biopsy sampling and interpretations. Hence, any classification scheme employed should be utilitarian. This includes minimal interexaminer and intraexaminer pathologist conflict as well as valuable prognostication of lesional grades about their potential for malignant transformation. [11]

McGavran et al. [12] in 1960 suggested one of the first classification systems of laryngeal keratosis with four subgroups: Hyperkeratosis without atypia, hyperkeratosis with atypia, parakeratosis without atypia and parakeratosis with atypia. Kleinsasser classified into three groups according to internal epithelial structure: Simple hyperplasia of squamous epithelium, hyperplasia of the squamous epithelium with atypical cells in places and precancerous epithelium or carcinoma in situ. [13] Since then, many other classifications have been devised. In the larynx, the most frequently employed systems for vocal cord lesions are the Ljubljana grading system [14] and the World Health Organization (WHO) dysplasia classification. [15]

The Ljubljana classification was devised by Kambic and Lenart in 1971 which divides hyperplastic laryngeal epithelium into four grades:

  • Simple hyperplasia: A benign hyperplastic process with increased prickle cell layer thickness. The basal and parabasal cellular components of the epithelium (one to three layers) remain unchanged
  • Abnormal hyperplasia: A benign augmentation of basal and parabasal layers, extending up to one half of the total epithelial thickness retaining the stratification. The nuclei in the cells may be moderately enlarged but maintain uniform nuclear chromatin distribution
  • Atypical hyperplasia or risky epithelium: A recognizable alteration of epithelial cells towards malignancy though the stratification is still preserved. The nuclear/cytoplasmic ratio is increased, mitotic figures are augmented but not numerous and they are found within two-thirds of the epithelium above basement membrane
  • Carcinoma in situ: It shows the features of carcinoma without invasion. Three distinct changes usually coexist which are loss of stratification, marked cellular alterations and many mitotic figures.

The WHO classification divides the premalignant lesions of the larynx in following categories:

  • Squamous cell hyperplasia: Increase in the number of cells with regular stratification and no cellular atypia
  • Mild dysplasia: Architectural disturbance limited to the lower third of the epithelium accompanied by slight cytological atypia
  • Moderate dysplasia: Architectural disturbance is extending to the middle third of the epithelium with nuclear abnormalities more marked than mild dysplasia. There is no abnormal mitosis
  • Severe dysplasia: Architectural disturbance is extending to more than two thirds of the epithelium with associated cytological atypia. The epithelium shows marked nuclear abnormalities. Nuclear pleomorphism is high. Mitosis is present high up in the epithelium. The lesion is frequently associated with keratosis
  • Carcinoma in situ: Full thickness architectural abnormalities in the viable cellular layers accompanied by pronounced cytological atypia.

As may be seen from the above classification systems, despite the same basis of histological assessment (irregular epithelial stratification, loss of polarity, increased mitosis, cellular and nuclear atypia, hyperchromatism), there is no direct relationship between the two classifications. [16] As a result, there is no common grading criteria, and there is a discrepancy in available leukoplakic histology data.

Eversole [11] suggested a binary grading system including only two diagnostic categories (mild dysplasia versus severe dysplasia) and found an improvement in inter-rater agreement to the extent of 70%. His analysis showed poor level of agreement between the pathologists while using WHO criteria. Several authors also reported the involvement of premature keratinizing cells in the deeper layers (dyskeratosis) of the laryngeal epithelium in malignant change. Uno et al. [17] found dyskeratosis to be an important finding in the prediction of subsequent carcinoma. Velasco et al. [18] reported development of carcinoma in 6 out of 12 cases with dyskeratosis. Kambic and Gale. [19] in their retrospective study of 325 tissue samples of hyperplastic aberrations of laryngeal mucosa demonstrated the importance of dyskeratotic cells, basalification of epithelium and supepithelial stromal cellular infiltration in grouping of precancerosis or risky epithelium.

   Molecular Biology Top

Most of the laryngeal neoplastic lesions develop in the setting of continuous noxious exposure causing damage and incorporation of adducts into the DNA of damaged cells. Later, as the repair, DNA replication and subsequent proliferation happens, the probability of development of detrimental somatic mutations increases. This has been termed as "long term continuing damage, inflammation and repair." [20]

A variety of proliferation markers, cyclin kinases, oncoproteins, tumor suppressor mutations and DNA ploidy have been investigated in laryngeal dysplasias, which have provided insight into the molecular mechanism of carcinogenesis.

The abnormal protein of the mutated p53 gene was found 4 times greater in amount than the preinvasive states confirming its role in malignant transformation. [21] However, Ioachim et al. [22] did not find any correlation of the p53 protein expression in the benign, premalignant and malignant epithelial lesions of the larynx. Clinical studies with p53 overexpression have yielded rather inconsistent results about prognosis, survival and response to therapy.

Statistically significant difference was found in the expression of proliferative cell nuclear antigen as the laryngeal lesion became more aggressive. Metallollothionein, a low molecular weight protein has often been associated with rapidly proliferating tissues and its overexpression has been demonstrated in various carcinoma cell lines resistant to anticancer drugs. Its mean value of expression was 35.73 in laryngeal carcinoma and 11.86 in dysplastic epithelium. [22]

As compared to oral and oropharyngeal carcinomas, laryngeal carcinoma appears less amenable to diagnosis using cytokeratin 8 (K8) as it is also expressed in normal laryngeal mucosa. [23] Similarly, bcl-2 protooncogene, involved in the regulation of cell death by inhibiting apoptosis, has not been shown to have any significant relationship to a degree of dysplasia. [24]

It should be noted that immunohistochemical markers that mirror the changes observed microscopically are of no prognostic significance. Only those markers that can be demonstrated in premalignant lesions and whose presence may depict disease progression are of some important medical benefit. Bartlett et al. [25] revealed an 8.53-fold increase in expression of insulin-like growth factor 1 in dysplastic lesions as compared to nondysplastic lesions, marking it as a credible early marker for vocal fold cancerous proliferation. Other genes like matrix metalloproteinase-2, S100 calcium binding protein A4 and ependymin related protein 1 were also found to be significantly upregulated in patients with dysplastic lesions. [25]

   Diagnostic Techniques Top

Microlaryngoscopy introduced by Kleinsasser [26] in 1962 stays to be the standard method of diagnosing and endoscopically treating the precancerous lesions and early carcinoma of the larynx. In 1956, Whitaker and Siegler [27] studied exfoliative cytology of larynx and found it 100% effective in diagnosing leukoplakic lesions. The procedure described then as a preliminary report does not carry any importance in today's scenario. Subsequently, staining with toluidine blue to recognize dysplastic lesions came in vogue. [28] With the advent of stroboscopy, it became an indispensable part of patient work up. Vocal fold pathology produces changes in the appearance and vibratory pattern on stroboscopic examination. Djukic et al. [29] studied the different stroboscopic parameters in diagnosing premalignant laryngeal lesions and found it to be unreliable for classifying laryngeal dysplasia. Severe dysplasia was found to be related to both nonvibrating and vibrating segments of vocal cords.

Autofluorescence has been used to detect neoplastic laryngeal lesions since neoplastic cells do not exhibit much fluorescence because of significantly lower concentration of flavin mononucleotide that in its oxidized state emits green fluorescence when exposed to blue light. Malzahn et al. [30] in a case series of 127 patients reported a sensitivity of 97.3% and specificity of 83.8% of this technique in differentiating varying dysplastic laryngeal epithelium. Crosetti et al. [31] furthered it by introducing multistep endoscopy in which high definition white light endoscopy (HDTV Camera), stroboscopy and indirect autofluorescence were done sequentially. This method was found to have greater sensitivity and biological predictive value for neoplastic precursors of larynx.

Combining contact endoscopy with autofluorescence is the latest modification and is known as Compact endoscopy. Arens et al. [32] in a study of 83 patients reported 88% corresponding result of laryngeal dysplasia on compact endoscopy with histopathology. Martin et al. [33] performed in vivo hyperspectral imaging of three cases of leukoplakia and found clearly highlighted altered mucosa as single spectral clusters in all the cases. The success of the procedure shows that the collection of spectral signatures from histologically varied laryngeal lesions may in the future allow noninvasive optical biopsies.

All these methods described above are improvisation upon microlaryngoscopy though none of them can replace it. The real efficacy of these tests needs to be substantiated by doing comparative studies keeping microlaryngoscopy as the gold standard.

   Treatment Top

The management of laryngeal leukoplakia depends on its histopathology, which, in turn decides the biological nature of the lesion as determined by the presence and degree of dysplasia in tissue samples. It presents a unique clinical challenge. A watchful waiting approach by the otolaryngologist may lead to lost to follow-up of at-risk patients or may insidiously give rise to an aggressive disease. On the other hand, any surgical or radiation treatment may cause unnecessary damage to the larynx in a patient who may not have otherwise ever developed carcinoma.

Mainstay of treatment includes excision of the lesion, radiotherapy or vocal cord stripping. Sadri et al. [34] did meta-analysis of 16 studies including 605 patients and found 93.52% local control rate with radiotherapy, 81% with CO 2 laser excision and 77% with vocal cord stripping. The wider therapeutic field in radiotherapy explains these results. Hirano et al. [35] compared vocal function of patients of early glottis carcinoma treated with laser therapy and radiotherapy and found slightly more degree of hoarseness and incomplete glottis closure and decrease in vocal cord movement on operated side on stroboscopy after laser treatment when compared to radiotherapy. However, there was hardly any change in fundamental frequency, intensity and maximal phonation time, hence concluding insignificant difference in vocal quality between laser treated and postradiotherapy patients. Cutting lasers like CO 2 offer accurate treatment of leukoplakia while minimising surrounding tissue damage. Continuous laser is preferred for flat lesions like the leukoplakia due to its coagulative and hemostatic properties. Pulsed laser is more used for incisions since it incurs less surrounding tissue damage due to lesser heat building. [36]

Other strategies like radiofrequency coblation have been described by Zhang et al. [37] who treated 95 patients of vocal fold leukoplakia using coblation and found good preservation of voice quality. Coblation achieves low temperature molecular disintegration with minimal surrounding tissue necrosis. Mirza and Perloff [38] have recommended the hydrodissection technique for leukoplakia whereas Schweinfurth et al. [39] described microflap excision technique where mucosa along with lesion is elevated and removed without disturbing vocalis muscle. Photodynamic therapy as a treatment of leukoplakia has also been described with success. [40] It relies on the tissue specific absorption of the photosensitiser to selectively demolish atypical tissue. The disadvantages are the need of multiple procedures to address the regrowth and potential photosensitivity.

Several chemopreventive agents have been proposed to combat leukoplakia. Almadori et al. [41] treated 43 patients of glottis laryngeal leukoplakia with 5 mg folic acid thrice a day for 6 months. Folic acid is a virtually nontoxic compound with good oral bioavailability that can be safely administered for a long time. 28% patients had no response, 44% had a partial response, and 28% had a complete response. Such results offer a fascinating approach of addressing leukoplakia by folate supplementation, alone or in combination with other chemopreventive drugs. Papadimitrakopoulou et al. [42] performed a trial on 36 patients with advanced premalignant lesions of upper aerodigestive tract with administration of oral isotretinoin, oral alpha tocopherol and subcutaneous interferon alpha for 12 months. The overall favorable histological response rate was 48% and clinical response was 57% at 12 months. Authors concluded biochemoprevention to be a promising biological approach for laryngeal dysplasia.

One of the main issues in the management of laryngeal leukoplakia along with the mode of its resection is its tendency to recur, often to higher histological grades or transformation for which chemoprevention appears promising.

   Follow-Up Top

The latency between initial diagnosis of keratosis and invasive laryngeal carcinoma is <10 years. [43] It is important to follow these cases not only because of the anticipation of keratosis transforming into malignancy, but also because the incidence of laryngeal keratosis plus a primary tumor at a nonlaryngeal site is higher than the keratosis itself progressing to carcinoma. [44] Sllamniku et al. [43] recommend a follow-up period of at least 5 years and not more than 15-20 years from initial diagnosis. Contrary to the usual belief, the leukoplakia and carcinoma in situ in nonsmokers change into malignancy hence should be treated aggressively and followed-up diligently.

   References Top

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