return to: Management of Specific Voice Disorders

see also: Case Example Laryngeal Amyloidosis; Amyloidosis (Laryngeal) Pathology; Amyloidosis Pathology Case Example

GENERAL CONSIDERATIONS

1. Definitions
   1. Amyloidosis = group of diseases defined by extracellular deposition of amyloid fibrils with features
      1. 'twisted beta-pleated sheet' protein configuration
      2. presence of amyloid P component (SAP)
      3. affinity for Congo red dye
      4. resistance to proteolytic digestion 
   2. The peptide subunit of the protein fibrils varies - basis for classification
   3. Amylodosis initally described by Rokitansky in 1842 and first laryngeal case documented by Borow in 1873.
   4. Accounts for 0.2% of benign laryngeal tumors, however the larynx is the most common site of occurrence in the head and neck
2. Histopathologic Diagnosis
   1. 'Apple-green birefringence' produced after Congo red stain and viewed under crossed polarized light
   2. Pathology: see description of pathology
3. Broad classification into two types
   1. Systemic: widespread deposition in organs and tissues
      1. Systemic hereditary AApoAI amyloidosis
      2. Multiple variants: phenotypic spectrum is wides and not yet fully recognized in full (Hazenburg 2009)
   2. Localized: restricted to a single organ, tissue or site of the body
      1. Localized light chain-derived
      2. Most common presentation for laryngeal involvement
      3. Initial presentation as localized may rarely presage systemic involvement
4. Other classification (Ferri 2009)
   1. Immunoglobulin light chain related amyloidosis (AL; formerly known as primary amyloidosis), affecting the kidneys, heart, liver, intestines, skin, peripheral sensory nervous system, spleen, and lungs.
   2. Acquired amyloidosis (AA), associated with chronic inflammatory diseases such as rheumatoid arthritis. Deposition of amyloid fibrils derived from SSA (circulating acute-phase reactant serum amyloid A protein) causes systemic AA
5. Other classification (Ferri 2009)
   1. Acquired systemic amyloidosis (immunoglobulin light chain, multiple myeloma, hemodialysis amyloidosis)
   2. Heredofamilial systemic (polyneuropathy, familial Mediterranean fever)
   3. Organ limited (Alzheimer's disease)
   4. Localized endocrine (pancreatic islet, medullary thyroid carcinoma)
6. Evaluation
   1. Presenting symptoms of laryngeal amyloidosis
      1. Most common: progressive dysphonia
      2. Less commonly: dyspnea, cough, stridor, odynophagia, and rarely hemoptysis
   2. Clinical evaluation of laryngeal amyloidosis:
      1. Larygneal exam: "firm, noulcerating, orange-yellow to gray epithelial nodule" (Barnes 1977)
      2. CT imaging
   3. With laryngeal involvement, isolation to the subglottis/glottis/and supraglottis most common - extension elsewhere is possible such as for the presumed tracheal involvement in the video immediately below. Note the involvement of the posterior left false vocal cord sparing the true vocal cords and subglottis:

1. Systemic evaluation - suggest management by a medical oncologist with experience in management of amyloidosis. Broad suggestions below (see Bartels 2004)
   1. Physical examination: Look for tender bones, heart failure, edema, or enlargement of the liver, spleen, and lymph nodes
   2. Serum: alkaline phosphatase, creatinine, look for free kappa or lambda light chains
   3. Urine: creatinine clearance, proteinuria, kappa or lambda light chains
   4. Consider: abdominal SQ fat aspiration rectal biopsy, bone marrow biopsy
   5. Yearly followup to evaluate for development of systemic disease
2. Management
   1. Biopsy to establish diagnosis
   2. Manage symptoms if progressive laryngeal disease becomes clinically relevant: microsurgical removal of deposits that interfere with laryngeal or airway function
   3. Defer complex management of systemic disease to medical oncology
   4. Consider referral to center with experience in systemic amyloidosis
      1. Assessment for and management of systemic disease
         1. apoAI genotyping
         2. Eval for serum free light chanis
      2. Genetic counselling
   5. Experience with radiation is limited  but has received support from a recent publication of treatment of a single patient with favorable 11 months followup (Neuner 2010)
      1. Neuner's article offers a nice review of past experience with radiotherapy largely composed of case reports
      2. 'Justification' for use of radiotherapy: "localized laryngeal amyloidosis may represent a form of benign soft tissue EMP" (extramedullary plasmacytoma)
      3. Management with radiotherapy need be carefully considered in the context of the limited experience with it for amyloidosis, lack of long term followup for patients with amyloidosis and potential complications from its use -- see: Management Consideration Radiation Induced Malignancy in the Head and Neck

REFERENCES

Hazenberg AJC, Dikkers FG, Hawkins PN, Bijzet J, Rowczenio D, Gilbertson J, Posthumus MD, Leijsma MK an dhazenberg BPC: laryngeal presenation of systemic apolipoprotien A-I-derived amyloidosis. Laryngoscope vol 119, Issue 3, pp 608-615

Bartels H, Dikkers FG, Lokhorst HM, van der Wal JE, Hazenberg BP. Laryngeal amyloidosis: localized versus systemic disease and update on diagnosis and therapy.Ann Otol Rhinol Laryngol 2004;113: 741-748

Barnes E and Zafar T: Laryngeal amyloidosis: clinicopathologic study of seven cases. AnnOtol rhinol Laryngol 1977;86:856-63

Ferri FF: "Amyloidosis" in Ferri's Clinical Advisor 2010, 1st Edition Mosby 2009

Neuner GA, Badros AA, Meyer TK, Nanaji NM and Regine WF: Complete Resolution of Laryngeal Amyloidosis with Radiation Treatment. Head & Neck DOI 10.1002/hed   Case Report Section2010

Flint, PW et al. Cummings Otolaryngology - Head and Neck Surgery, 5th ed. Chap 64. Mosby-Elsevier 2010. Philadelphia, PA

Stevenson R, Witteles R, Damrose E, Arai S, Lafayette RA, Schrier S, Afghani A, and Liedtke M: MOre than a Frog in the Throat: A case Series and Review of Localized Laryngeal Amyloidosis" Arch Otolaryngol/vol 138 (no.5) May 2012 pp 509-511.

Burns H, Phillips N. Laryngeal amyloidosis. Curr Opin Otolaryngol Head Neck Surg. 2019 Dec;27(6):467-474. doi: 10.1097/MOO.0000000000000579. PMID: 31651423.

Pai KK, Omiunu AO, Llerena PA, Shave SM, Desai HA, Fang CH, Eloy JA, Young VN. Localized laryngeal amyloidosis: A systematic review. Am J Otolaryngol. 2022 Sep-Oct;43(5):103550. doi: 10.1016/j.amjoto.2022.103550. Epub 2022 Jul 28. PMID: 35917657.