Monoclonal gammopathy of undetermined significance (MGUS)

Epidemiology and Etiology:

• Not considered neoplastic because it does not always progress to overt malignancy
• IgM paraprotein (IgM MGUS) is associated with a clone of lymphoplasmacytic cells that may progress to a lymphoplasmacytic lymphoma and/or Waldenstrom macroglobulinemia (WM)
• Non-IgM MGUS (IgG, IgA) is associated with the presence of clonal plasma cells, and may progress to a malignant plasma cell neoplasm
• With sensitive techniques, MGUS is found in approximately 3% of people > 50 y. and > 5 % of people > 70 y.
• More than twice as frequent in African Americans as in Caucasians
• May be associated with:
• Connective tissue disorders
• Peripheral neuropathies
• Dermatological diseases
• Endocrine diseases
• Liver diseases

Common sites:

• BM (IgM and non-IgM MGUS)
• Spleen (IgM MGUS)
• Lymph nodes (IgM MGUS)

Gross features:

Histologic features:

• Bone marrow clonal plasma cells < 10 % (required)
• Fraction of BM plasma cells with an abnormal immunophenotype is prognostic
• No evidence of B-cell lymphoma or other disease known to produce an M-protein

Immunophenotype:

Marker:

Sensitivity:

Specificity:

Molecular features:

• Rarely abnormal karyotype
• FISH abnormal in most patients (same abnormalities as in MM for non-IgM MGUS)
• DNA aneuploidy detection is prognostic
• KRAS mutations (~5%)
• Much less frequent than in MM

Other features:

• M-protein in serum < 30 g/L (required)
• 70% IgG
• 15% IgM (greater risk of progression)
• 12% IgA (greater risk of progression)
• 3% biclonal
• Light chain only (up to 20%), detected only by serum free light chain assay
• Size of M-protein is prognostic
• 25 g/L is > 4 times risk of progression than < 5 g/L
• No end-organ damage (required)
• CRAB:
• Hypercalcemia
• Renal insufficiency
• Anemia
• Bone lesions
• Asymptomatic
• Usually M-protein discovered unexpectedly on serum protein electrophoresis
• Flow cytometry:
• Frequently shows two populations of plasma cells:
• Normal (CD38 bright+, CD19+, CD56-, polyclonal)
• Monoclonal:
• CD19-/CD56+ maybe
• CD19-/CD56- maybe
• CD38 weaker maybe
• Other aberrant antigen expression maybe
• Clinical course is stable in most cases
• Risk of progression is 1% per year and indefinite (persisting even after 30 years)
• 1.5 % per year for IgM or IgA
• Subnormal levels of polyclonal Ig is a risk factor

References:

• Swerdlow et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues (2008)