laryngeal leukoplakia

laryngeal leukoplakia

1. Nassr Saif ALBarhi

2. Outline Introduction. Aim of study. Methods. Discussion Epidemiology. Risk factors. Pathology. Diagnosis. Treatment. New direction.

3. Introduction Its descriptive term “white plaque’’ on the vocal fold that can correspond to a variety of pathologies: Benign keratosis. Dysplasia. Carcinoma in situ. Squamous carcinoma. A proper diagnosis is the first step toward determining prognosis and a treatment plan.

4. Managing this problem is especially challenging due to: The variety of pathology. Degree of dysplasia. Predicting prognosis. Balancing voice preservation with surgical excision of the disease. Management relates to the lesions’ frequent position along the vibratory edges of the vocal folds, where scarring may have functionally important consequences to voice quality.

5. The aim of this study to Describe the epidemiology, diagnosis, and management of vocal fold leukoplakia, with focus on recent advances . In the interest of focusing on the distinct clinical entity of leukoplakia, they excluded squamous papilloma and verrucous hyperplasia. Dilemmas and controversies will be discussed, and the techniques and philosophies reviewed are applicable to the general otolaryngologist as well as the laryngology specialist.

6. Methods A detailed literature search was performed in the PubMed/ MEDLINE database for publications related to : Vocal cord and laryngeal leukoplakia, dysplasia , hyperkeratosis, leukoplakia endoscopy, and leukoplakia management . Search based on certain criteria : Literature was chosen based on current practices and techniques for management of leukoplakia, with specific regard to voice preservation and functional outcomes. A literature search was performed to include studies that focused on epidemiology, oncologic follow-up, and long-term outcomes.

7. Discussion

8. Epidemiology In the United States, the annual incidence of vocal fold leukoplakia and keratosis is: 4.2 per 100,000, with a male predilection of 10.2 incidences per 100,000 compared to 2.1 in females in 1 study and an estimated 70% to 76% of male predominance in others . About median age of leukoplakia incidence from 61.7 to 63 years old suggests a temporal relationship between leukoplakia and laryngeal carcinoma whose median age is 10 to 15 years older. Most lesions tend to occur on the medial and superior edges of the mid-true vocal fold and anterior commissure; lesions are unilateral in 78% to 84% of cases . Posterior glottis nor the false vocal folds are typically not involved

9. Risk factors Cigarette smoking is the major risk factor for development of laryngeal squamous intraepithelial lesions and laryngeal malignancy. The incidence of cigarette smoking in patients with leukoplakia and keratosis is 67%, and increased duration of smoking has been associated with higher rates of malignant transformation . A recent large retrospective review of 1184 patients in Germany with leukoplakia revealed increased risk for malignancy with advanced age and male sex, with odds ratio: 4.90 for patient more than 65 years of ages. 2.55 for patients ages 50 to 65. OR of 4.09 for men .

10. The increased association of human papillomavirus (HPV)–positive oropharyngeal cancers may explain a similar increase in glottic cancer patients who are presenting younger and without smoking histories . It is not clear at this time if there will be an impact of the HPV vaccine on the development of laryngeal leukoplakia, but classic leukoplakia very rarely presents with laryngeal papillomatosis.

11. GERD is also hypothesized to be a risk factor for development of laryngeal leukoplakia and malignancy . Well-performed meta-analyses controlling for smoking and drinking do suggest reflux is related to laryngeal cancer, although this has not been extended to leukoplakia. However , a limitation of these meta-analyses is how sources assess exposure to reflux. Most epidemiological studies use patient survey or history of esophagitis as proxy measures for laryngopharyngeal reflux exposure . Some reports also suggest that treatment of reflux may lead to some improvement in laryngeal leukoplakia for some patients

12. Pathology, Grading, and Risk of Malignant Transformation It is important to note that both benign and dysplastic vocal fold leukoplakia lesions carry some risk of malignant transformation.

13. In a comprehensive review and meta-analysis of laryngeal leukoplakia, 33.5% of leukoplakia patients were noted to have mild to moderate dysplasia, and 15.2% had severe dysplasia or carcinoma in situ . Following these patients over time, squamous cell carcinoma developed in: 3.7 % of those with no dysplasia on initial biopsy . 10.1 % of those with mild to moderate dysplasia. 18.1 % of patients whose initial biopsies demonstrated severe dysplasia.

14. Analysis of patients with recurrent leukoplakia demonstrates that even patients with initial pathologic diagnosis of benign hyperkeratosis or no histopathologic dysplasia still carry risk for recurrence and progression to malignancy, with a 14% malignant transformation rate on biopsy with direct laryngoscopy. A pooled meta-analysis shows that overall risk of progression to malignancy among patients with vocal cord dysplasia is 14.1%

15. Ability to rely on degree of dysplasia as a prognostic factor may be further limited by difficult pathologic assessment of those features that lead to categorization as mild, moderate, or severe dysplasia. Despite difficulties in pathologic staging, general trends suggest that while all severities of dysplasia may ultimately progress to malignancy, mild dysplasia does so at lower rate than moderate dysplasia and severe dysplasia.

16. Difficulties with consistency among these 3 tiers led the World Health Organization (WHO) to collapse assessment of vocal cord dysplasia severity into a 2-tiered system in 2017, and now pathologists are encouraged to grade things simply as low grade or high grade. Consistent rating of severity of dysplasia within these laryngeal lesions remains difficult even in this 2-tier system , and data correlating this 2-tiered approach to pathologic staging with clinical behavior are not yet available.

17. Diagnosis Leukoplakia is a clinical diagnosis made by physical inspection of the larynx, and laryngoscopy remains the workhorse for otolaryngology recognition of a leukoplakic lesion. Indirect mirror laryngoscopy . Trans-nasal flexible laryngoscopy. 70-degree rigid laryngoscopy traditionally followed by direct microlaryngoscopy (DML) in the operating room. Early detection is the strongest prognostic factor in determining the survival of patients with vocal cord leukoplakia, presumably a premalignant disease.

18. Laryngeal stroboscopy has been demonstrated to be helpful in: Determining progressive thickness of laryngeal epithelium as the dysplasia stage progresses, increasing mass effect, as well as infiltrating disease that affects the mucosal wave . (this is not always true). Good for Leukoplakic lesions at the medial border of the vocal folds compare to FOL scope. The ability to archive and compare exams over time, and the ability to play back with slow motion or frame-by-frame analysis, which permits detailed analysis of the medial edge of the vocal fold.

19. Narrow-band imaging (NBI) and other versions of blue light wavelength filtering visually highlight blood vessels of the vocal folds, allowing identification of neoplastic lesions. Multiple studies demonstrate improved identification of lesions and their associated effects on the vocal fold microcapillary network within the superficial lamina propria .

20. Office biopsy, if performed correctly using a channeled flexible laryngoscope, can be cost-effective, potentially providing earlier diagnosis. Surgeons consider office biopsy for tissue sampling for pathologic diagnosis in an awake patient at the time of presentation without general anesthesia. However, it is important to note that office biopsy often under-stages the severity of the lesion.

21. A study by Cohen et al of 102 in-office biopsies demonstrated a high false-negative rate of 33.0%, essentially not recognizing the severity of disease. After obtaining repeat biopsy/excision under micro-laryngoscopy , 30 of 91 patient samples had underestimated the presence of dysplasia or malignancy . This discrepancy was again noted by Richards et al in a study of 76 in-office biopsies followed by biopsy/excision in the operating room, demonstrating sensitivity of 60% and specificity of 87%.

22. Major limitations are related to: Small tissue sample in large islands of leukoplakia that have heterogeneous pathology. Poor depth of biopsy that excludes the basement membrane. Inability to visualize or biopsy lesions in difficult areas to access in an awake patient.

23. Laryngeal contact endoscopy uses a rigid endoscope to illuminate and magnify tissue in areas suspected of malignancy, noting the ability to visualize patterns of cells and nuclear to cytoplasm ratios in more suspicious areas. Has the greatest potential to target areas of biopsy or excision in a patient under general anesthesia undergoing direct microlaryngoscopy . Has limitations in an awake patient due to access of the scope to the larynx, movement of the patient, and the ability to tolerate laryngeal manipulation.

24. Treatment The mainstay of treating laryngeal leukoplakia is : Determining the severity of pathology and risk of progression to malignancy. Eradicating disease that demonstrates at least severe dysplasia in an oncologic procedure. Respecting or improving the voice.

25. DML under general anesthesia in the operating room offers advantages of phonomicrosurgical technique that appreciates the multilayered vocal fold histology and has as its goal the preservation of vibratory function. Microflap techniques with removal of the epithelial disease and preservation of underlying superficial lamina propria (SLP) are preferred. This approach can be done with or without injection of saline or adrenaline to expand the SLP prior to epithelial resection, and it can be done with or without laser use in the operating room .

26. Schweinfurth et al established the efficacy of microflap excision in 20 patients with laryngeal dysplasia, with only 1 patient progressing to invasive disease and an overall reduction in severity of dysplasia with each additional procedure. Benefits of the microflap approach include preservation of epithelium not involved with leukoplakia, thereby preserving or improving voice function.

27. The carbon dioxide (CO2) laser has a role in managing vocal fold leukoplakia . Its use as a ‘‘coagulating scalpel’’ allows for hemostatic cutting of the epithelium through the basement membrane at the time of microflap excision. This laser is also the mainstay for the varying degrees of cordectomy that are performed for the progression of micro-invasive squamous carcinoma to more invasive disease .

28. A prospective randomized controlled trial by Benninger : Demonstrated this point, following 37 patients who underwent CO2 microsurgery vs traditional phonosurgical resection of benign vocal fold lesions, revealing no significant difference in recovery or voice outcomes . Angiolytic therapy, previously 585-nm pulsed dye lasers (PDLs) and more recently 532-nm potassium titanyl phosphate (KTP) lasers, target oxyhemoglobin as their chromophore and therefore are designed for superficial treatment of epithelial disease.

29. These lasers are fiber based, allowing the surgeon to vary distance between the tip of the fiber and target tissue, to achieve a variety of treatment effects, ranging from gentle blanching of superficial lesions to more thorough ablation as needed . In the case of leukoplakia, the laser can be used to photocoagulate hyper-vasculature associated with tumor-related angiogenesis and do so without associated thermal damage to vibratory tissue

30. Radiotherapy is rarely used for leukoplakia in the absence of an established invasive cancer diagnosis. However , it may play a role under certain conditions for patients with severe dysplasia/carcinoma in situ. Recurring and pathologically advancing disease despite multiple excisions. The potential for insufficient demonstration of microinvasion due to a near-margin dissection or tissue destruction from a laser margin.

31. Observation may be reasonably performed without treatment of the lesion only if the lesion has been histopathologically proven nonmalignant, which should be performed with DML if feasible. While the authors do not recommend biopsy that does not also excise the lesion, as this leaves ‘‘untreated disease’’ behind that might then progress to malignancy, this may be a reasonable option if a surgeon doubts their ability to preserve voice quality by offering an appropriate microflap resection rather than ‘‘stripping.

32. New Directions Biomarkers of nuclear mutations and their cellular phenotypic destiny would be an ideal way of determining prognosis in patients with leukoplakia. The cumulative effect of genetic mutations is thought to be associated with progression of dysplasia in the head and neck to invasive carcinoma. Identification of biomarkers and genetic mutations may also support the theory of field cancerization; while macroscopic disease and microscopic disease may not be present in certain tissue, genetic alterations and mutations of apparently normal tissue may lead to disease progression and recurrence

33. Identification of these abnormalities in adjacent tissues to the index lesion and other normal mucosa may provide guidance for mapping the treatment area.

34. Conclusion There has been a paradigm shift away from performing ‘‘vocal cord stripping’’ procedures that can cause irreversible hoarseness toward voice preservation surgery while achieving comparable oncologic control. Surgical technical and instrumental developments have been designed to maximally treat superficial disease while preserving underling vibratory mucosa.

35. Recent improvements in histopathological grading systems and advances in biomarker classification may allow for improved oncologic risk stratification. Furthermore , improvements in endoscopic imaging capabilities and contact endoscopy are currently being studied for their potential diagnostic significance.

36. Implications for Practice To optimally manage vocal fold leukoplakia, the otolaryngologist should become familiar with the oncologic implications of the disease and the importance of obtaining pathologic diagnosis to rule out malignancy. In addition, the surgeon should maintain surgical techniques and knowledge of available instruments and lasers that can assist in surgical management while prioritizing the preservation of vibratory tissue and voice quality . Finally, the surgeon and the patient should understand the clinical importance of routine endoscopic surveillance.

37. In conclusion: This representative nationwide study of otorhinolaryngology practices in Germany revealed that approximately 1 in 5 patients with vocal cord leukoplakia exhibited either carcinoma at diagnosis or malignant transformation within 5 years. A high index of suspicion by physicians is required in older patients, particularly in men . A close follow-up of high-risk patients is recommended, even if the results of the initial biopsy were negative.

38. Thank you