Amyloid

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
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

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

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.

Appearance

Light microscopy

Features:

• 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 (lifting agent "O'rise").
• Fine fibrils, non-branching.
  • Usually 8-12 nm in diameter; accepted range 8-15 nm.

Images:

• Amyloid (fondazionedamico.org).
• Amyloid (fondazionedamico.org).

DDx

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

Stains

• Congo red +ve.
  • Positive:
    • Orange/light red (non-polarized light).
    • Apple green birefringence (polarized light).
  • Negative:
    • Blue birefringence (polarized light) = collagen fibers.
• Thioflavin T stain.
• Sodium sulphate-Alcian Blue stain +ve.

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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

• Infections:
  • Tuberculosis.
  • Leprosy.
  • Chronic osteomyelitis.
  • Bronchiectasis.
• Idiopathic conditions:
  • Rheumatoid arthritis - relatively common (compared to others below).
  • Anklyosing spondylitis - renal amyloidosis.
  • Crohn's disease.
  • Familial Mediterranean fever.
• Malignancy.
  • Plasmacytoma.
    • 5-15% of patients with multiple myeloma develop amyloidosis - some say 10-20%.
  • Medullary thyroid carcinoma.
  • Renal cell carcinoma.
• Many other conditions...

Classification

Amyloidosis can be classified a number of different ways.

Six subtypes classification

Amyloid classified into six groups:

1. Primary (AL amyloidosis).
   • Monoclonal light chains in serum and/or urine, may be due to plasma cell dyscrasia.
2. Secondary (AA amyloidosis).
   • Infections (osteomyelitis), neoplasia (Hodgkin's lymphoma).
3. Hemodialysis-related.
   • Beta-2 microglobulin.
4. Localized.
   • Abeta amyloid found in Alzheimer's disease.
   • Pancreatic amyloid deposition associated with diabetes mellitus type 2.
     • Image: Amyloid in DM (med.utah.edu).
5. Hereditary.
6. Senile systemic amyloidosis.

How to remember: Two As = secondary amyloidosis.

Three main types - Robbins classification

Amyloid classified into three groups:

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

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.
• AA - treat underlying cause.

Classification of amyloid - differentiation

Biochemical techniques

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

Immunohistochemistry

• IHC may be useful for the subclassification of amyloidoses.
  • The reliability of IHC for the subclassification of amyloidoses is thought to be low.
    • 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

• Can be typed using mass spectroscopy.
  • Considered to be the definitive test.
    • High specificity and sensitivity vis-à-vis clinicopathologic correlation.
  • May be done on formalin-fixed paraffin embedded (FFPE) material.

Types

Secondary amyloidosis

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

Cerebral amyloid angiopathy

Main article: 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.
• 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, and in upto 65% of patients over 90 years old.

Treatment:

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

Gross pathology

• Grey/black "peppering" of left atrial endocardium - in fixed specimens.
  • "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 - less commonly affected by ischemia.

Images

• 

  Senile systemic amyloidosis - H&E. (WC)

• 

  Senile systemic amyloidosis - congo red. (WC)

• 

  Senile systemic amyloidosis - Movat's. (WC)

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.

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.

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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

• Common cause of restrictive cardiomyopathy.

Cardiac amyloidosis - subtypes:

1. AL amyloidosis - associated with plasma cell dyscrasia - most common cardiac amyloidosis.
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

Main article: Pulmonary amyloidosis

• Very rare.

Renal amyloidosis

Main article: Medical kidney diseases

General

• Both AL and AA amyloidosis can affect the kidney.

Clinical:

• Usually Nephrotic range proteinuria.

Microscopic

Features:

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

DDx:

• Diabetic nephropathy.
• Idiopathic nodular glomerulosclerosis.
• Light chain deposition disease.
• Fibrillary glomerulopathy.
• Immunotactoid glomerulopathy.

Images

• 

  Renal amyloidosis - high mag. (WC)

• 

  Renal amyloidosis - high mag. (WC)

• 

  Renal amyloidosis - very high mag. (WC)

www:

• Renal amyloidosis - several images (upmc.edu).

Urinary bladder amyloidosis

Main article: Urinary bladder amyloidosis

GI amyloidosis

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

Liver amyloidosis

Main article: Liver amyloidosis

Features:

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

Gastric amyloidosis

Main article: Amyloidosis of the stomach

Bone

Amyloid is reported in association with:

• Multiple myeloma ~40% of patients in one series.
• Chronic osteomyelitis ~10% of patients in one series.
• Diabetes (one case).

See also

• Basics.
• Neuropathology.
• Fibrillary glomerulonephritis.

External links

• Amyloidosis - wikipedia.org.