Bone marrow neoplastic

• Accepted nomenclature for Amyloid is AX, where A stands for Amyloid and X represents the protein in the fibril
• Historically light chain amyloidosis (AL) referred to as primary amyloidosis
• Overall, > 30 different proteins can cause amyloidosis (Blood 2009;114:4957, Clin J Am Soc Nephrol 2010;5:2180)
• Those involving kidney recently grouped into the category of monoclonal gammopathies of renal significance (MGUS) to separate them from MGUS based on need for treatment (Blood 2012;120:4292)

• ICD-O: 9769/1 - immunoglobulin deposition disease
• ICD-10:
  • E85.9 - amyloidosis, unspecified (general, primary)
  • E85.81 - light chain (AL) amyloidosis

• Protean clinical presentation due to widespread organ involvement, involving all except possibly the brain (Expert Rev Hematol 2018;11:117)
• Survival mostly determined by extent of cardiac involvement (Blood 2016;128:159)

• Abnormal folding of a protein that is normally soluble as a result of a proteolytic event or mutation that renders it unstable / prone to self aggregation (Clin J Am Soc Nephrol 2006;1:1331)
• Aggregates form protofilaments that associate into amyloid fibrils
• Interactions with the extracellular environment may result in proteolytic cleavage and matrix components such as glycosaminoglycans and collagen may serve as scaffolds to facilitate aggregation and fibril buildup (Sci Rep 2016;6:29096)
• Only a subset of Ig light chains are amyloidogenic (12 - 15% of myeloma) (N Engl J Med 2003;349:583)
• Repertoire of variable region germline genes involved in systemic amyloidosis is restricted and certain gene usage may affect organ targeting; e.g. use of IGVL1-44 had 5 fold odds of dominant cardiac involvement (Blood 2012;119:144)
• Amyloid precursor proteins directly impair cardiac function independent of fibril formation, invoking oxidative stress, cellular dysfunction, apoptosis (Proc Natl Acad Sci U S A 2010;107:4188)

• ~30% present with advanced, irreversible organ damage (Blood 2016;128:159)
• General: dyspnea, fatigue, weight loss
• GI: macroglossia (highly suggestive of AL but only present in 10 - 15%), hepatomegaly (25 - 30%), malabsorption (5%)
• Renal: nephrotic syndrome (28%)
• Heart: restrictive cardiomyopathy, congestive heart failure (17%), amyloid precursor proteins with direct cardiotoxic effect (Proc Natl Acad Sci U S A 2010;107:4188)
• Neural: peripheral sensory neuropathy (17%), carpal tunnel syndrome (21%), autonomic dysfunction
• Bone pain (5%), periorbital or facial purpura
• Hemorrhage: can result from factor X binding to amyloid (Blood 2001;97:1885)
• Patients with underlying IgM-secreting lymphoplasmacytic lymphoma are typically older, higher prevalence of neuropathy and lymph node involvement and lower level of cardiac involvement than non IgM AL amyloidosis (Expert Rev Hematol 2018;11:117)

• Tissue diagnosis is the gold standard
• Laser microdissection with analysis by mass spectrometry is the most reliable method of characterizing amyloid type (Blood 2009;114:4957)
• Abdominal fat pad aspirate: most common and easily accessible tissue (positive in more than 80% of patients with primary amyloidosis)
• Rectal biopsies diagnostic in 80% of cases
• Biopsy of kidney, heart, liver
• Bone marrow: 60% of cases show amyloid; detection improved if adequate sized vessels present

• Serum and urine protein electrophoresis and immunoelectrophoresis identifies M spike (99% of cases); IgG most frequent (followed by light chain only, IgA, IgM and IgD); 80% lambda (Expert Rev Hematol 2018;11:117)
• Critical to test for free light chain as some patients lack circulating intact immunoglobulin
• Nephrotic range proteinuria and hypoalbuminemia with renal involvement
• Elevated erythrocyte sedimentation rate (ESR)
• Elevated brain natriuretic peptide (BNP), proBNP and troponin in cardiac involvement
• Cholestasis with elevated alkaline phosphatase with liver involvement
• AL / primary amyloidosis may also present with hypothyroidism / hypoadrenalism or hypopituitarism
• Scintigraphy with radiolabeled serum amyloid P(SAP) can be used to test for amyloid where SAP binds to the amyloid and reveals its presence (Annu Rev Med 2006;57:223)

• 18 year old man with primary AL (kappa light chain) amyloidosis manifesting as peripheral neuropathy (Clin Neuropathol 2005;24:118)
• 27 year old woman with primary systemic amyloidosis (Cent Eur J Immunol 2014;39:61)
• 70 year old woman with undiagnosed primary amyloidosis unmasked during surgical treatment (J Endocr Soc 2018;2:112)

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• Amyloidosis may or may not be apparent on macroscopic examination
• Classic gross appearance porcelain-like or waxy
• Involved organ may appear enlarged, gray, firm and waxy when amyloid accumulates in larger amounts

• Pale pink, extracellular, glassy, hyaline material on H&E staining, mostly deposited in vascular or perivascular location
• Characteristic cracking artifact
• Macrophages and foreign body giant cells may be found around deposits

Contributed by Meenakshi Bansal, M.D.

• Congo red: ordinary light imparts a pink to red color to amyloid deposits; the beta pleated sheet structure of amyloid produces an apple green birefringence under polarized microscopy when stained by Congo red or sirius red stain
• PAS: moderately positive
• Iodine: stains deep brown but turns blue after treatment with concentrated sulfuric acid ("iodine sulphuric reaction" historical review Histochemistry 1976;49:131)
• Crystal violet and toluidine blue: metachromatic staining
• Thioflavin T and thioflavin S: exhibits fluorescence
• Clonal plasma cells can also be identified

Contributed by Karen Vanderbilt and Bruce Goldman, M.D.

• Annu Rev Pathol 2017;12:277, Orphanet J Rare Dis 2012;7:54, Swerdlow: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues (IARC WHO Classification of Tumours),4th Edition, 2017

Which parameter is most closely linked to a poorer prognosis for primary amyloidosis?

1. Extent of cardiac involvement
2. Liver involvement
3. Macroglossia
4. Nephrotic range proteinuria
5. Presence of myeloma

A. The best answer is extent of cardiac involvement, which also results in 40% of deaths due to primary amyloidosis. Increased bone marrow plasma cells (> 10%) and involvement of multiple organs are also associated with a worse prognosis.

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Reference: Primary amyloidosis

Which genetic alteration is most overrepresented in primary amyloidosis compared to plasma cell myeloma?

1. del 17p
2. Hyperdiploidy
3. Monosomy 13q14
4. t(11;14)
5. TP53 mutation

D. t(11;14)

While all of these alterations have been described in plasma cell myeloma and may be seen in primary amyloidosis, the t(11;14) translocation is particularly overrepresented in primary amyloidosis (> 40% of cases).13q14 deletion is also common but del 17p is rarely seen.

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Reference: Primary amyloidosis