Lung nontumor
Other nonneoplastic disease
Amyloidosis


Topic Completed: 24 June 2020

Minor changes: 24 June 2020

Copyright: 2003-2020, PathologyOutlines.com, Inc.

PubMed Search: Pulmonary amyloidosis[title] “loattrfree full text”[sb]

Related Topics: nodular amyloid (amyloidoma)

Brian D. Stewart, M.D.
Andras Khoor, M,D., Ph.D.
Page views in 2019: 602
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Cite this page: Stewart BD, Khoor A. Amyloidosis. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/lungnontumoramyloid.html. Accessed August 13th, 2020.
Definition / general
  • Amyloidosis in the lung can present in three distinct manners: diffuse alveolar septal amyloidosis, nodular pulmonary amyloidosis and tracheobronchial amyloidosis
  • Different types are distinguished by the pattern of deposition within the lung tissue; however, they are all characterized by deposition of an eosinophilic amorphous material that stains bright red with Congo red and shows an apple green birefringence upon polarization
  • Ultrastructurally, it is composed of haphazardly arranged nonbranching fibrils that measure 8 to 10 nm in diameter
Essential features
  • Heterogenous group of entities caused by deposition of amyloid, an abnormal protein with a beta pleated structure composed of haphazardly arranged nonbranching fibrils measuring 8 to 10 nm in diameter
  • Light microscopy shows amorphous eosinophilic deposits that show apple green birefringence under polarized light
  • Main pulmonary forms are diffuse alveolar septal, nodular and tracheobronchial
  • Most commonly caused by AL amyloidosis: the deposition of light chains due to a monoclonal hematologic process
    • AL is associated with hematologic malignancies, commonly multiple myeloma
  • Subtyping should be performed with mass spectrometry
Terminology
  • Amyloidosis in general (not organ / lung specific)
    • Primary amyloidosis (now systemic AL amyloidosis)
    • Secondary amyloidosis (now systemic AA amyloidosis)
    • Age related or senile systemic amyloidosis (now systemic wild type ATTR amyloidosis)
    • Familial amyloid polyneuropathy (now systemic hereditary ATTR amyloidosis) (Amyloid 2014;21:221)
  • Pulmonary amyloidosis subtypes
    • Diffuse alveolar septal amyloidosis
      • Diffuse parenchymal amyloidosis
    • Nodular pulmonary amyloidosis
      • Nodular parenchymal amyloidosis, nodular amyloidoma
    • Tracheobronchial amyloidosis
ICD coding
  • ICD-10:
    • E85.9 - Amyloidosis, unspecified
    • E85.2 - Heredofamilial amyloidosis, unspecified
    • E85.8 - Other amyloidosis
    • E85.3 - Secondary systemic amyloidosis
    • E85.4 - Organ limited amyloidosis
    • E85.82 - Wild type transthyretin related (ATTR) amyloidosis
  • ICD-11:
    • 5D00 - Amyloidosis
    • 5D00.1 - AA amyloidosis
    • 5D00.2 - Hereditary amyloidosis
    • 5D00.20 - Hereditary ATTR amyloidosis
    • 5D00.21 - Nonneuropathic heredofamilial amyloidosis
    • 5D00.2Y - Other specified hereditary amyloidosis
    • 5D00.2Z - Hereditary amyloidosis, unspecified
    • 5D00.3 - Dialysis associated amyloidosis
    • 2A83.5 - Monoclonal immunoglobulin deposition disease
    • 2A83.50 - Heavy chain deposition disease
    • 2A83.51 - Light and heavy chain deposition disease
    • 2A83.52 - Light chain deposition disease
    • 5D00.Y - Other specified amyloidosis
    • 5D00.Z - Amyloidosis, unspecified
Epidemiology
Sites
Pathophysiology
  • ~ 95% composed of fibril proteins
    • 31 human fibril proteins have met the criteria from the International Society of Amyloidosis (ISA) Nomenclature Committee (Amyloid 2014;21:221)
    • Insoluble fibril proteins from improper folding of soluble precursors
      • When produced in excessive amounts:
        • Immunoglobulin light chains
        • Serum amyloid A
        • Wild type transthyretin
      • Abnormal amino acid sequence (i.e., transthyretin variants)
  • ~ 5% serum amyloid P component and other glycoproteins
  • Systemic AL amyloidosis
    • Monoclonal plasma cell proliferative disorder
    • Monoclonal immunoglobulin light chains deposit in tissues
    • Can follow monoclonal gammopathy of undetermined significance (MGUS), multiple myeloma and Waldenström macroglobulinemia (N Engl J Med 2002;346:564)
  • Systemic AA amyloidosis
    • Deposition of serum amyloid A (Apo), an acute phase reactant produced in the liver
    • Usually secondary to a chronic inflammatory condition
  • Systemic wild type ATTR amyloidosis
    • Deposition of unmutated transthyretin (prealbumin) in tissues that accumulates with age
  • Systemic hereditary ATTR amyloidosis
    • Mutations in the transthyretin gene
Etiology
Clinical features
Diagnosis
  • Diffuse alveolar septal amyloidosis
    • Usually incidental
    • Symptoms due to amyloid deposition in other organs
    • Pulmonary involvement usually made at autopsy
  • Nodular pulmonary amyloidosis
    • Chest imaging
  • Tracheobronchial amyloidosis
  • DNA sequencing may be needed to distinguish between wild type and hereditary ATTR amyloidosis when a family history is not apparent (J Am Coll Cardiol 2015;66:2451)
Laboratory
  • Diffuse alveolar septal amyloidosis
  • Tracheobronchial amyloidosis
    • Decreased airflow with proximal airway involvement on pulmonary function tests
    • Normal airflow if just distal involvement
Radiology description
  • Nodular pulmonary amyloidosis
    • One or more solid lung nodules:
      • May have spiculated borders and be confused with malignancy
      • May have calcifications
    • Cystic features have been described (Eur Respir J 2007;30:589)
  • Tracheobronchial amyloidosis
    • Extensive thickening of the trachea or bronchi with or without calcification
    • May show postobstructive changes (atelectasis, pneumonia or long term bronchiectasis) (J Thorac Imaging 2005;20:41)
Radiology images

Contributed by Tan-Lucien H. Mohammed, M.D.

Tracheobronchial amyloidosis

Airway thickening

Ground glass consolidation


Pulmonary nodular amyloidosis

Basilar gradient

Scattered nodules

Multiple nodules and cysts



Prognostic factors
  • Systemic AL amyloidosis
    • Depends on the organs affected
  • Systemic AA amyloidosis
    • High mortality due to end stage renal disease, infection, heart failure, bowel perforation or GI bleeding if left untreated
  • Systemic wild type ATTR amyloidosis
    • Survival is better than AL amyloidosis
Case reports
Treatment
  • Typing of the amyloid is essential because treatment depends on the form
    • Systemic AL amyloidosis
    • Systemic AA amyloidosis
    • Systemic wild type ATTR amyloidosis
      • Chemotherapy and stem cell transplant contraindicated
    • Systemic hereditary ATTR amyloidosis
  • Diffuse alveolar septal amyloidosis
    • Prognosis worse with primary amyloidosis compared to other types
      • Death usually due to cardiac involvement or less often pulmonary hypertension
  • Nodular pulmonary amyloidosis
    • Conservative excision usually curative
    • Long term prognosis excellent
  • Tracheobronchial amyloidosis
Clinical images

Images hosted on other servers:

Primary endobronchial amyloidosis

Gross description
Microscopic (histologic) description
  • General: amyloid appears as glassy amorphous eosinophilic material
  • Diffuse alveolar septal amyloidosis
    • Low magnification: well preserved pulmonary architecture
    • Higher magnification
      • Alveolar septae thickened amyloid
      • Vessel walls involved and may form small nodules
      • Amyloid may be seen in visceral pleura
      • May see scant plasma cells
  • Nodular pulmonary amyloidosis
    • Well circumscribed nodules
    • Homogenous, densely eosinophilic material with associated small aggregates of lymphocytes and plasma cells
    • May see foreign body type giant cells, calcification, ossification and cartilage (Arch Pathol Lab Med 2017;141:247)
  • Tracheobronchial amyloidosis
    • Deposits of homogeneous eosinophilic material around seromucinous glands and cartilage
    • Involvement of submucosal vessels
    • Plasma cells, foreign body type giant cells, calcification, ossification (Arch Pathol Lab Med 1986;110:212)
Microscopic (histologic) images

Contributed by Brian D. Stewart, M.D.

Nodular deposits

Vascular deposition

Congo red

Congo red, polarized



Contributed by Andras Khoor, M.D., Ph.D.

Ossification


Diffuse septal deposition

Periarteriolar accentuation

Tracheobronchial deposition

Subepithelial deposits

Cytology description
  • Limited value in routine smears
  • Cell block of pleural fluid may show amorphous waxy material with a rim of reactive mesothelial cells (Diagn Cytopathol 2018;46:522)
Immunofluorescence description
  • Thioflavin T is a fluorescent dye and is viewed under a fluorescent microscope
Positive stains
Negative stains
Electron microscopy description
Electron microscopy images

Images hosted on other servers:

Beta pleated sheet

Amyloid fibrils

Molecular / cytogenetics description
  • Mass spectrometry based proteomic analysis
    • Performed on formalin fixed, paraffin embedded tissue after microdissection
    • Considered the preferred method for amyloid subtyping (Blood 2009;114:4957)
Videos

Definition, historical aspects and properties

Pathogenesis and classification

Pathology, clinical features and prognosis

Sample pathology report
  • Lung, right lower lobe, transbronchial biopsy:
    • Nodular pulmonary amyloidosis (see comment)
    • Comment: Sections show bronchial wall and alveolated lung parenchyma with nodular deposits of eosinophilic amorphous material deposited mostly within the vascular walls. Congo red special stain shows apple green birefringence upon polarization, supporting the diagnosis. The specimen will be sent for mass spectrometry for amyloid typing and these results will be issued as an addendum.
Differential diagnosis
Board review style question #1

The process demonstrated in the two photomicrographs of a transbronchial biopsy is most commonly caused by which of the following?

  1. Uric acid crystal deposition
  2. Deposition of improperly folded fibril proteins
  3. Calcium pyrophosphate crystal deposition
  4. Increased collagen production
  5. Microscopic thromboemboli
Board review answer #1
B. Deposition of improperly folded fibril proteins. This is amyloidosis.

Reference: Amyloidosis

Comment Here
Board review style question #2
In the diffuse alveolar septal manifestation of amyloidosis, which of the following may be seen?

  1. Destruction of the pulmonary architecture
  2. Emphysematous changes
  3. Diffuse alveolar damage
  4. Thickened vascular walls
  5. Acute inflammatory reaction
Board review answer #2
D. Thickened vascular walls

Reference: Amyloidosis

Comment Here
Board review style question #3

Which of the following is the preferred method for subtyping amyloid, shown in the images above?

  1. Polymerase chain reaction
  2. Electron microscopy
  3. Mass spectrometry
  4. Xray crystallography
  5. Gas chromatography
Board review answer #3
C. Mass spectrometry

Reference: Amyloidosis

Comment Here
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