Amyloid

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Amyloid is one of those things clinicians can put in many differential diagnoses. The pathologist can diagnose it.

Amyloid
Diagnosis in short

Cardiac amyloidosis. H&E stain.

LM typically extracellular, amorphous (no specific shape), acellular and pink (on H&E stain) -- cotton candy like, classically has a "cracked" appearance
Subtypes multiple subclassifications: Robbins (AL amyloidosis, AA amyloidosis, non-AA and non-AL), set of six subtypes (primary (AL amyloidosis), secondary (AA amyloidosis, hemodialysis-related, localized), hereditary, senile systemic amyloidosis)
LM DDx fibrin, collagen, smooth muscle
Stains Congo red +ve, Masson trichrome blue-gray staining
EM non-branching fine fibrils - usually 8-12 nm in diameter (accepted range 8-15 nm)
Molecular beta sheet
Gross waxy appearance
Site pretty much anywhere, blood vessels

Associated Dx very many
Clinical history variable
Prevalence uncommon
Prognosis dependent on subtype

This article is a general overview of the topic. Links are provided to articles that deal with amyloidosis at specific sites, see site specific section below.

Overview

Definition

  • Disorder of protein folding - structure: beta sheet.[1]

Appearance

Light microscopy

Features:[2]

  • Pink (on H&E stain).
  • Extracellular location.
  • Amorphous - no specific shape.
  • May have a "cracked" appearance.[citation needed]

Classic DDx - ABCs of pink:

  • Amyloid.
  • Blood (fibrin).
  • Collagen.
  • Smooth muscle.

Other considerations:

  • Foreign material, e.g. lifting agent "O'rise".[3]

Images

Electron microscopy

Features:[4]

  • Fine fibrils, non-branching.
    • Usually 8-12 nm in diameter; accepted range 8-15 nm.[5]

Images:

DDx

  • CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy).
    • Typically has basophilic granularity in the blood vessels.[6]

Stains

Sign out

BONE LESION, RIGHT ILIAC, BIOPSY:
- AMYLOID ASSOCIATED WITH HISTOCYTES, GIANT CELLS AND A FEW LYMPHOCYTES
  AND PLASMA CELLS.

COMMENT:
The presence of amyloid is confirmed with congo red staining and polarization.

There are no histomorphologic findings suggestive of a plasma cell neoplasm
in this biopsy.

Clinical correlation with serum protein electrophoresis, urine protein electrophoresis
and bone marrow sampling is suggested.

Associations - DDx

Classification

Amyloidosis can be classified a number of different ways.

Six subtypes classification

Amyloid classified into six groups:[7]

  1. Primary (AL amyloidosis).
    • Monoclonal light chains in serum and/or urine, may be due to plasma cell dyscrasia.
  2. Secondary (AA amyloidosis).
  3. Hemodialysis-related.
    • Beta-2 microglobulin.[15]
  4. Localized.
  5. Hereditary.
  6. Senile systemic amyloidosis.

How to remember: Two As = secondary amyloidosis.

Three main types - Robbins classification

Amyloid classified into three groups:[1]

  1. AL amyloidosis - "AL" = Amyloid Light chain.[18]
    • Primary amyloidosis.[12]
    • Bence Jones protein (light chains -- kappa or lambda) +ve -- necessary for amyloidosis but not sufficient.[19]
  2. AA amyloidosis - "AA" = Amyloid Associated.[20]
    • Secondary amyloidosis.
  3. Abeta amyloid - found in Alzheimer's disease.[21]

Additional types:

  • ATTR = Amyloid Transthyretin (TTR)
    • Transthyretin - serum protein that transport thyroxine and retinol; transthyretin AKA prealbumin.

Treatment

The very short version:

  • AL - chemotherapy & stem cell transplant.[7]
  • AA - treat underlying cause.[7]

Classification of amyloid - differentiation

Biochemical techniques

  • Pre-treated with potassium permanganate, to obliterate congo red reactivity, was though be definitive for AA amyloidosis;[22] this is now generally considered to be unreliable.[23]

Immunohistochemistry

  • IHC may be useful for the subclassification of amyloidoses.[24]
    • The reliability of IHC for the subclassification of amyloidoses is thought to be low.[25][26]
      • Extreme caution is advised when interpreting IHC results.

Possibly useful immunostains:

  • Kappa.
  • Lambda.
  • Transthyretin.
    • The name transthyretin is from transports thyroxine and retinol (previous unknown as prealbumin).

Mass spectroscopy

Types

Secondary amyloidosis

  • AKA AA amyloidosis.
  • Pathophysiology: acute-phase reactant serum amyloid A (SAA) - degraded + deposits.[12][30]

Cerebral amyloid angiopathy

A common cause of lobar hemorrhage (cerebral cortex, cerebellar cortex) in the elderly.

Senile systemic amyloidosis

  • Abbreviated SSA.

General

  • Previously known as senile cardiac amyloidosis.[31]
  • May be referred to as ATTR = amyloidosis TTR; in SSA the TTR is not mutated, some call it: wt transthyretin amyloidosis (ATTR).
    • There is a hereditary form of amyloidosis with mutated TTR deposition known as ATTR type FAP = ATTR type Familial Amyloid Polyneuropathy.
      • Hereditary TTR: deposits in the heart, nerves and leptomeningeal amyloidosis.

Epidemiology:

  • Common in the elderly, as the word senile suggests.
  • Found in approx. 25% of elderly over 80 years old,[31] and in upto 65% of patients over 90 years old.[32]

Treatment:

  • Liver transplantation, RNAi therapy (patisiran) and antisense oligonucleotides (inotersen).[33]

Gross pathology

  • Grey/black "peppering" of left atrial endocardium - in fixed specimens.[34]
    • "Peppering" should be present if severe.

Microscopic

Features:

  • Heart most commonly involved, followed by lungs and then by kidney (renal papilla).
  • DDx of pink of H&E is important to remember: amyloid, muscle, collagen, clotted blood.
    • Amyloid vs. Fibrosis? Subendocardial fibrosis may have rim of (diffusion) preserved myocytes. (???)
  • Amyloid often present in the subepicardial tissue[32] - less commonly affected by ischemia.

Images

Site specific

Abdomen

Abdominal fat pad biopsy redirects here.

General

  • Abdominal fat pad biopsy - common screen for amyloidosis.
    • May be done with FNA.
      • Suffers for poor sensitivity.[8]

Microscopic

Features:

  • Small-to-intermediate sized arteries with a thickened amorphous eosinophilic media.
    • Thickening classically nodular.
    • Apple green-birefringence -- with polarization.

Note:

  • Evaluation of at least 15 small blood vessels is recommended.[8]

Sign out

SOFT TISSUE, ABDOMEN, BIOPSY:
- AMYLOIDOSIS.

Negative

SOFT TISSUE, ABDOMEN, BIOPSY:
- BENIGN FIBROADIPOSE TISSUE.
- NEGATIVE FOR AMYLOIDOSIS WITH CONGO RED STAINING AND POLARIZED LIGHT.

COMMENT:
Correlation with serum protein electrophoresis, urine protein electrophoresis
and bone marrow sampling should be considered within the clinical context.

Cardiac amyloidosis

General

Cardiac amyloidosis - subtypes:

  1. AL amyloidosis - associated with plasma cell dyscrasia - most common cardiac amyloidosis.[32]
  2. Senile systemic amyloidosis - TTR-related amyloidosis (unmutated TTR).
  3. Hereditary amyloidosis.
  4. AA amyloidosis is uncommon.

Clinical:

  • CHF, conduction abnormalities.
  • Kidney disease (proteinuria) - associated with AL amyloidosis.

Pulmonary amyloidosis

  • Very rare.

Renal amyloidosis

General

  • Both AL and AA amyloidosis can affect the kidney.[9]

Clinical:

Microscopic

Features:

  • Paucicellular mesangial expansion.
  • Fluffy hyaline material in medium-sized blood vessels.

DDx:

Images

www:

Urinary bladder amyloidosis

GI amyloidosis

  • GI amyloidosis can lead to obstruction and usually is greatest in the small bowel.[7]

Liver amyloidosis

Features:

  • Parenchymal deposition (common).
  • Portal triad deposition (less common).

Gastric amyloidosis

Bone

Amyloid is reported in association with:

See also

References

  1. 1.0 1.1 Lachmann HJ, Hawkins PN (2006). "Amyloidosis and the lung". Chron Respir Dis 3 (4): 203-14. PMID 17190124. http://crd.sagepub.com/cgi/pmidlookup?view=long&pmid=17190124.
  2. Cotran, Ramzi S.; Kumar, Vinay; Fausto, Nelson; Nelso Fausto; Robbins, Stanley L.; Abbas, Abul K. (2005). Robbins and Cotran pathologic basis of disease (7th ed.). St. Louis, Mo: Elsevier Saunders. pp. 259. ISBN 0-7216-0187-1.
  3. Pezhouh MK, Burgart LJ, Chiu K, Cohen DA, Hutchings DA, Sanderson SO, Shirazi M, Stanich PP, VandenBussche CJ, Voltaggio L, Willhoit ED, Xue Y, Arnold CA (June 2020). "Characterization of Novel Injectable Lifting Agents Used in Colonic Polyp Removal: An Emerging Amyloid Mimic". Am J Surg Pathol 44 (6): 793–798. doi:10.1097/PAS.0000000000001435. PMID 31934919.
  4. 4.0 4.1 URL: http://www.fondazionedamico.org/biopsiarenale_atlas/seco/amil/amil21.htm. Accessed on: 9 November 2010.
  5. Alpers, CE.; Kowalewska, J. (Jan 2008). "Fibrillary glomerulonephritis and immunotactoid glomerulopathy.". J Am Soc Nephrol 19 (1): 34-7. doi:10.1681/ASN.2007070757. PMID 18045849.
  6. Kleinschmidt-DeMasters BK, Prayson RA (November 2006). "An algorithmic approach to the brain biopsy--part I". Arch. Pathol. Lab. Med. 130 (11): 1630–8. PMID 17076524.
  7. 7.0 7.1 7.2 7.3 7.4 Ebert EC, Nagar M (March 2008). "Gastrointestinal manifestations of amyloidosis". Am. J. Gastroenterol. 103 (3): 776-87. doi:10.1111/j.1572-0241.2007.01669.x. PMID 18076735.
  8. 8.0 8.1 8.2 Devata, S.; Hari, P.; Markelova, N.; Li, R.; Komorowski, R.; Shidham, VB. (2011). "Detection of amyloid in abdominal fat pad aspirates in early amyloidosis: Role of electron microscopy and Congo red stained cell block sections.". Cytojournal 8: 11. doi:10.4103/1742-6413.82278. PMID 21760829.
  9. 9.0 9.1 Nishi S, Alchi B, Imai N, Gejyo F (April 2008). "New advances in renal amyloidosis". Clin. Exp. Nephrol. 12 (2): 93-101. doi:10.1007/s10157-007-0008-3. PMID 18175051.
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  11. Kunnath-Velayudhan S, Larsen BT, Coley SM, De Michele S, Santoriello D, Colby TV, Bhagat G, Saqi A (March 2021). "Masson Trichrome and Sulfated Alcian Blue Stains Distinguish Light Chain Deposition Disease From Amyloidosis in the Lung". Am J Surg Pathol 45 (3): 405–413. doi:10.1097/PAS.0000000000001593. PMID 33002919.
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  14. Cotran, Ramzi S.; Kumar, Vinay; Fausto, Nelson; Nelso Fausto; Robbins, Stanley L.; Abbas, Abul K. (2005). Robbins and Cotran pathologic basis of disease (7th ed.). St. Louis, Mo: Elsevier Saunders. pp. 261. ISBN 0-7216-0187-1.
  15. Cotran, Ramzi S.; Kumar, Vinay; Fausto, Nelson; Nelso Fausto; Robbins, Stanley L.; Abbas, Abul K. (2005). Robbins and Cotran pathologic basis of disease (7th ed.). St. Louis, Mo: Elsevier Saunders. pp. 260. ISBN 0-7216-0187-1.
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  20. Cotran, Ramzi S.; Kumar, Vinay; Fausto, Nelson; Nelso Fausto; Robbins, Stanley L.; Abbas, Abul K. (2005). Robbins and Cotran pathologic basis of disease (7th ed.). St. Louis, Mo: Elsevier Saunders. pp. 259. ISBN 0-7216-0187-1.
  21. Cotran, Ramzi S.; Kumar, Vinay; Fausto, Nelson; Nelso Fausto; Robbins, Stanley L.; Abbas, Abul K. (2005). Robbins and Cotran pathologic basis of disease (7th ed.). St. Louis, Mo: Elsevier Saunders. pp. 259. ISBN 0-7216-0187-1.
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