Elsevier

Journal of Voice

Volume 24, Issue 2, March 2010, Pages 235-239
Journal of Voice

Laryngeal Amyloidosis Causing Hoarseness and Airway Obstruction

https://doi.org/10.1016/j.jvoice.2008.07.006Get rights and content

Summary

Amyloidosis constitutes a fraction of 1% of benign localized laryngeal tumors and may occasionally be associated with systemic disease. A chronic, insidious, progressive, recurrent disease characterized by hoarseness, dyspnea, and stridor, it is caused by extracellular deposition of insoluble, abnormal tissue injurious fibrils. Submucosal lesions occur frequently in the vestibular folds and ventricles, less commonly in the subglottis and aryepiglottic folds and least on the vocal folds. Apple green birefrigence under polarized light after Congo red staining, electron microscopic fibrillar structure, and a β-pleated sheet structure observed by x-ray diffraction are confirmatory. Two presented cases add to the small literature review of similar patients. Case 1 was a 70-year-old man with severe hoarseness, incomplete glottic closure, ovoid concentric stenosis of the inferior glottis and subglottis, who initially was not diagnosed by several laryngologists and speech therapists. He required multiple microlaryngoscopic excisions and dilations. Because low dose radiation induces plasma cell apoptosis in other diseases, external beam radiation therapy (EBRT) was hypothesized to eliminate amyloidogenic plasma cells. Case 2 was a 46-year-old welder with progressive dyspnea for 2–3 years and hoarseness, voice loss, and stridor over 6–7 months. Masses caused airway obstruction of the anterior commissure, vestibular, and vocal folds, with extension to the subglottis. Two phonomicrosurgical CO2 laser-assisted resections relieved upper airway obstruction and restored voice. Conservative surgical intervention and long-term followup are essential. Further studies are needed to determine if a radiation dose response relationship exists to control laryngeal amyloidosis.

Introduction

Amyloidosis is a clinical disorder caused by extracellular deposition of insoluble abnormal fibrils that injure tissue. The fibrils are formed by the aggregation of acellular misfolded, normally soluble proteins. In humans, more than 20 different, unrelated proteins are known to form amyloid fibrils. A major fibrillar protein defines the type of amyloid in approximately 90%, with various minor components. All fibrils share certain physical and pathological properties. These include amorphous eosinophilic appearance on light microscopy after hematoxylin and eosin staining, bright green fluorescence observed under polarized light after Congo red staining, regular fibrillar structure as observed by electron microscopy, a β-pleated sheet structure as observed by x-ray diffraction and solubility in water and buffers of low ionic strength. The latter presumably contributes to the great stability of the protein aggregates. This characteristic then allows amyloid to accumulate as a nonreactive proteinaceous deposit that causes structural damage by pressure effects on adjacent tissues.1, 2

Until 40 years ago, various descriptive classifications were proposed, based on organ distribution of amyloid findings and clinical presentation. Primary or idiopathic amyloidosis had no associated clinical condition identified. Secondary amyloidosis was associated with chronic inflammatory conditions. Other classification systems included myeloma-associated, familial and localized amyloidosis. Beginning in the late 1960s and early 1970s, the development of methods to solubilize amyloid fibrils permitted chemical amyloid studies and redefined amyloidosis classification.

Amyloid is now classified chemically. Proteins that form amyloid fibrils differ in size, function, amino acid sequence, and native structure. They become insoluble aggregates that are similar in properties and structure. Protein misfolding results in formation of fibrils that show a common β-sheet pattern based on x-ray diffraction. The amyloidoses are referred to with a capital “A” for amyloid followed by an abbreviation for the fibril protein. In most cases, formerly called primary amyloidosis and myeloma-associated amyloidosis, the fibril protein is an immunoglobulin light chain, or light chain fragment abbreviated L. These patients, designated AL, are termed to have light chain amyloidosis. The most common precursor proteins are L chains of the lambda class, twice as prevalent as kappa L chains. Most cases previously termed to be senile systemic amyloidosis (SSA-cardiomyopathy in males older than 70 years) or familial amyloid polyneuropathy, are now termed ATTR, because the fibrils consist of the transport protein transthyretin (TTR), with more than 80 variations of exact gene mutation. In amyloid A (AA-secondary amyloidosis), harmful deposits of amyloid are produced due to various inflammatory diseases.3, 4, 5 The present project confines itself to amyloidosis localized in the larynx.

Laryngeal involvement in amyloidosis is rare and accounts for less than 1% of all benign laryngeal tumors. It usually occurs in the 40–60 years age range, with a male to female predominance of about 2:1.4 A chronic and a slowly progressive disease of insidious onset, it is characterized by hoarseness, dyspnea, cough, stridor, and rarely, hemoptysis.2 The lesion is usually a firm, nonulcerated yellow, orange, or gray submucosal nodule, mass, or pedunculated polypoid lesion. The location of amyloid deposits is highest in the ventricles and vestibular folds, less common in the subglottis and the aryepiglottic folds and least common in the vocal folds.3 It is rare for vocal fold fixation or cicatricial stenosis to occur unless other predisposing factors are also present.6 A cystic lesion7 or infiltrating tumor of the vocal folds and subglottis, multinodular subglottic, tracheal, mainstem bronchial and pulmonary deposits may occur.4, 8

Four histologic patterns of amyloidosis have been described. These include amorphorous random masses, deposits around blood vessels, deposits in continuity with the basilar membrane of seromucinous glands, and deposits within adipose tissue.4 In one series, more than 60% of laryngeal deposits displayed a lambda light chain staining pattern, and 25% a kappa pattern. 3

In isolated laryngeal amyloidosis, treatment is primarily endoscopic surgical removal of masses that interfere with laryngeal or airway function. The likelihood of recurrent or residual disease is significant.7 Because of the propensity of amyloid to infiltrate blood vessels, cold resection of amyloid lesions may be complicated by bleeding. Although CO2 laser excision may be advantageous, if used in very extensive lesions, there may be scarring.7, 8 Usually, coring out subglottic lesions has a lasting and effective result.9 In very large lesions, external approaches, employing laryngofissure for treatment of diffuse subglottic and tracheal amyloidosis have been used. Repeated excision and curettage may be necessary to achieve stabilization of lesions and subsequent decannulation of those patients who are tracheotomy dependent.4 Local or systemic steroids are ineffective in controlling or reversing lesions of amyloidosis.2, 4

Bronchoscopy is important to identify significant subglottic amyloid deposits and more distal tracheal or bronchial lesions. Tracheotomy is usually reserved for extensive subglottic lesions that must be resected and controlled. 4 While the prognosis for laryngeal amyloidosis is usually good, death has rarely been reported. This usually occurs from diffuse tracheobronchial disease with pulmonary failure.3

Section snippets

Case reports

Two cases add to the small literature of similar patients treated with phonomicrosurgical cold and CO2 laser-assisted resection. Case 1 raises the issue of adjuvant external beam radiation therapy (EBRT).

Discussion

Based on a review of 11 cases of laryngeal amyloidosis over 37 years, in 2000, Thompson et al12 concluded that all parts of the larynx were affected, with deposition usually localized, but multifocal or systemic disease in the upper aerodigestive tract or tumor proliferation was seen. A sparse lymphoplasmacytic infiltrate was present in the three cases that demonstrated light chain restriction by immunohistochemistry (kappa-2, lambda-1). Serum and urine electrophoreses were negative in all

Summary

Vigilance in establishing an accurate tissue diagnosis in patients who present with hoarseness and glottic or supraglottic tumefactions or obstructing airway lesions is mandatory.

The mechanism by which EBRT exerts its effects on amyloid deposits in tracheobronchial amyloidosis was found to be unclear by Neben-Wittich et al in 2007 at the Mayo Clinic.18 They reported a series of seven patients treated with EBRT with the same techniques subsequently adapted by Truong for Case 1.11 All responded

Acknowledgments

The authors are grateful for the assistance at Mercy Medical Center, Springfield, MA, of Gerald Nash, M.D., pathologist and Krystyna Sikorska, M.D., Medical Director, Life Labs; Ramon Franco, M.D. at Massachusetts Eye & Ear Infirmary; John L Berk, M.D., Gregory Grillone, M.D., and Minh Tam Truong, M.D. at The Amyloid Clinic, Boston Medical Center.

References (18)

There are more references available in the full text version of this article.

Cited by (36)

  • Localized laryngeal amyloidosis: A systematic review

    2022, American Journal of Otolaryngology - Head and Neck Medicine and Surgery
    Citation Excerpt :

    Our preliminary database search produced a total of 2085 articles (Fig. 1). After applying exclusion criteria, 129 articles published between 1891 and 2021 met criteria for inclusion (Supplemental Table 2) [11–139]. This systematic review is comprised of data from 282 patients with LA extracted from 79 case reports and 50 case series.

  • Airway Amyloidosis: A Retrospective Analysis of 43 Patients

    2022, Journal of Bronchology and Interventional Pulmonology
View all citing articles on Scopus
View full text