Amyloidosis Pathology Case Example

Return to: Laryngeal Amyloidosis

Clinical Presentation

Common presenting symptoms per Pai et al. in a systematic review (Pai 2022):

1. Dysphonia - 95%
2. Difficulty breathing - 27%

Pathology

1. Pathogenesis
   1. Amyloidosis is an umbrella term for any buildup of mis-folded (beta pleated sheets) proteins in the extracellular space (Galluzzi 2023).
   2. Types of amyloid:
      1. Systemic
         1. Primary Amyloidosis (AL) - Most common systemic amyloidosis in western world. Excess monoclonal immunoglobulin light chain secondary to acquired plasma cell disorder including multiple myeloma, lymphoma, and Waldenstrom's macroglobulinemia.  Can see amyloid deposition in kidneys, heart, liver, nerves, tongue, skin/soft tissue.  
         2. Secondary (AA) - Most common systemic amyloidosis in developing world. Excess acute phase reactant serum amyloid A (SAA) secondary to chronic infection or inflammatory disorder including rheumatoid arthritis, inflammatory bowel disease, ankylosing spondylitis, chronic infections, familial periodic fever syndromes, or idiopathic.  Most commonly affects kidney, also heart, liver, GI tract.
         3. Familial - Most common is due to mutation in transthyretin gene, resulting in excess transthyretin protein (ATTR). May also be seen with unmutated (non-familial) TTR manifesting as cardiomyopathy in older men (previously called "senile systemic amyloid") (Aimo 2022).
         4. Dialysis associated - Excess beta2 microglobulin accumulates because it can not pass through the dialysis filter.  Patients commonly present >5 years after starting dialysis with joint complaints.
      2. Localized
         1. Local amyloidosis rarely develops into systemic amyloidosis but local findings may be due to systemic disease.
         2. Larynx
            1. Most often Ig light chain (>90% of reported cases) deposition in submucosal soft tissue theorized to be due to local plasma cell light chain overproduction or increased vascular permeability secondary to local inflammation.
         3. Other organs affected by local amyloidosis include respiratory tract/lung, skin, GI tract, eye, GU tract, lymph nodes.  These deposits are almost always AL type amyloid.
         4. Special cases of localized amyloid include:
            1. Medullary thyroid carcinoma: associated with cutaenous lichen amyloidosis (Mathiesen 2022)
            2. Cerebral amyloid angiopathy and Alzheimer's: deposition of Abeta amyloid (derived from amyloid precursor protein (APP)) around vessels or in brain parenchyma respectively
2. Gross findings
   1. Gross findings depend on organ involved but may include:
      1. Heart - often no gross abnormality; disfunction due to disruption of cardiomyocytes and conduction disturbance
      2. Kidney - may have enlarged kidney and/or visible pale deposits in cortex
      3. Liver - hepatomegaly, may be firm with waxy pale discoloration
      4. Tongue/muscle - macroglossia/muscle enlargement
      5. Skin - waxy skin/ecchymosis
      6. Larynx - smooth surfaced nodule with pale homogenous cut surfaces
3. Histopathology 
   1. Amorphous homogenous eosinophilic material deposited extracellularly
   2. Stains with Congo Red with apple green birefringence under polarized light
   3. Metachromatic pink-violet staining with methyl violet or crystal violet

References:

1. Biewend ML, Menke DM, Calamia KT. The spectrum of localized amyloidosis: a case series of 20 patients and review of the literature. Amyloid. 2006;13(3):135-42.
2. Ghiso J and Frangione B. Cerebral amyloidosis, amyloid angiopathy, and their relationship to stroke and dementia. J Alzheimers Dis. 2001:3(1):65-73.
3. Khurana R, Agarwal A, Bajpai VK, Verma N, Sharma AK, Gupta RP et al. Unraveling the amyloid associated with human medullary thyroid carcinoma. Endocrinology. 2004;145(12):5465-70.
4. Merlini G, Comenzo RL, Seldin DC, et al. Immunoglobulin light chain amyloidosis. Expert Rev Hematol 2014; 7:143.
5. Pinney JH, Lachmann HJ. Systemic AA amyloidosis. Subcell Biochem 2012; 65:541.
6. 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. 2012;138(5):509-511.
7. Thompson LD, Derringer GA, Wenig BM. Amyloidosis of the larynx: a clinicopathologic study of 11 cases.  Mod Pathol. 2000;13(5):528-535.
8. Westermark P, Bergström J, Solomon A, et al. Transthyretin-derived senile systemic amyloidosis: clinicopathologic and structural considerations. Amyloid 2003; 10 Suppl 1:48.
9. Yamamoto S, Kazama JJ, Narita I, Naiki H, Gejyo F. Recent progress in understanding dialysis-related amyloidosis. Bone. 2009;45 Suppl 1:S39-42.
10. 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.
11. Galluzzi F, Garavello W. Surgical treatment of laryngeal amyloidosis: a systematic review. Eur Arch Otorhinolaryngol. 2023 Jul;280(7):3065-3074. doi: 10.1007/s00405-023-07881-6. Epub 2023 Feb 15. PMID: 36790723.
12. Aimo A, Castiglione V, Rapezzi C, Franzini M, Panichella G, Vergaro G, Gillmore J, Fontana M, Passino C, Emdin M. RNA-targeting and gene editing therapies for transthyretin amyloidosis. Nat Rev Cardiol. 2022 Oct;19(10):655-667. doi: 10.1038/s41569-022-00683-z. Epub 2022 Mar 23. PMID: 35322226.
13. Mathiesen JS, Effraimidis G, Rossing M, Rasmussen ÅK, Hoejberg L, Bastholt L, Godballe C, Oturai P, Feldt-Rasmussen U. Multiple endocrine neoplasia type 2: A review. Semin Cancer Biol. 2022 Feb;79:163-179. doi: 10.1016/j.semcancer.2021.03.035. Epub 2021 Apr 1. PMID: 33812987.