Lymphoma and plasma cell neoplasms
Plasma cell neoplasms
Non-IgM monoclonal gammopathy of undetermined significance (MGUS)

Author: Hatem Kaseb, M.D., Ph.D., M.P.H. (see Authors page)
Senior Author: Stanley David Hudnall, M.D.
Editor-in-Chief Review: Debra Zynger, M.D.

Revised: 16 October 2018, last major update July 2018

Copyright: (c) 2001-2018, PathologyOutlines.com, Inc.

PubMed Search: Monoclonal gammopathy of undetermined significance[TI] MGUS[TI]

Cite this page: Kaseb, H. Non-IgM monoclonal gammopathy of undetermined significance (MGUS). PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/lymphomaMGUS.html. Accessed October 18th, 2018.
Definition / general
  • Term monoclonal gammopathy of undetermined significance (MGUS) was introduced in 1978 by Robert Kyle to describe the benign asymptomatic patients having an M protein that may progress to other malignancies
  • By definition, no evidence of multiple myeloma, other B cell lymphoproliferative disorder or other disease known to produce an M protein
  • 2 distinct types of MGUS: non-IgM MGUS (the focus of this topic) and IgM MGUS
    • Non-IgM MGUS and IgM MGUS (lymphoplasmacytic lymphoma / Waldenström macroglobulinemia) are considered separate entities by the WHO classification 2017 due to the differences in cell of origin, clinical picture and disease progression (Lancet Oncol 2014;15:e538)
    • Non-IgM MGUS (IgG, IgA, IgD or light chain MGUS) accounts for most MGUS cases and is characterized by a monoclonal plasma cell
  • Non-IgM MGUS is a benign premalignant plasma cell disorder that is characterized by the presence of serum M protein < 30 g/l, bone marrow clonal plasma cells < 10% and absence of plasma cell myeloma related end organ damage
Essential features
  • Non-IgM MGUS is a benign premalignant plasma cell disorder that is characterized by the presence of serum M protein < 30 g/l, bone marrow clonal plasma cells < 10% and absence of plasma cell myeloma related end organ damage
  • Non-IgM MGUS may progress to a malignant plasma cell neoplasm
Epidemiology
  • Most common plasma cell disorder (Blood 2009;113:5412)
  • Incidence increases with age and is found in approximately 2 - 3% of adults over age 50 and 5% of adults over age 70 (N Engl J Med 2018;378:241)
  • More common than multiple myeloma (1 million versus 13,000 cases/year in U.S.)
  • More prevalent in African Americans than Caucasians (2 - 3 fold) (Leukemia 2014;28:1537)
  • More common in men than women (1.5:1)
  • Non-IgM MGUS represents up to 85% of MGUS cases
Pathophysiology
  • Origin is clonal mature plasma cells residing in the bone marrow that harbor somatic hypermutation and class switched variable regions
  • The transformation of the plasma cell to full blown plasma cell myeloma is the result of a combination of primary and secondary genetic events (Clin Cancer Res 2013;19:985)
    • Primary genetic events include IgH translocation, hyperdiploidy and cyclin D dysregulation
    • Secondary genetic events include:
      • NRAS, KRAS and BRAF mutations
      • NFkB pathway mutations
      • TP53, PTEN and RB inactivation
  • Most non-IgM MGUS cases are IgG, followed by IgA, biclonal and IgD
Etiology
Clinical features
  • Most patients are asymptomatic; usually diagnosed as an incidental finding on protein electrophoresis performed to evaluate peripheral neuropathy, vasculitis, hemolytic anemia, skin rashes, hypercalcemia or elevated erythrocyte sedimentation rate
  • Diagnosis should be established only if the disease persists and is not transient (CMAJ 2013;185:1345)
  • Paraprotein incidence: 70% IgG, 15% IgM, 12% IgA, 3% biclonal; monoclonal light chain in urine in 1/3 of cases (N Engl J Med 2006;354:1362)
  • No myeloma related organ or tissue impairment such as hypercalcemia, renal insufficiency, anemia or bone lesions (=CRAB features of myeloma)
  • 3 diagnostic criteria (Swerdlow: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th Edition, 2017):
    1. Serum monoclonal protein < 30 g/l
    2. < 10% clonal plasma cells in the bone marrow
    3. Absence of symptoms suspicious for plasma cell myeloma
Laboratory
  • Need thorough investigation to exclude other plasma cell neoplasms
    • Complete blood count / peripheral smear: usually normal but some cases show rouleaux formation
    • Serum calcium and creatinine: important in differentiating non-lgM MGUS from plasma cell myeloma
    • Serum protein electrophoresis and immunofixation, serum free light chains, urine protein electrophoresis and immunofixation assay, quantitation of IgM
  • Quantification of M protein is useful to monitor disease course (Hematol Oncol Clin North Am 2014;28:775)
    • Serum protein electrophoresis can be performed on agarose gel or capillary zone electrophoresis
    • Serum free light chains: measures κ and λ light immunoglobulin chains that circulate unbound to heavy chains in the serum; the normal ratio for κ/λ is 0.26 - 1.65
Radiology description
  • Bone survey of skull, spine and pelvis (Xray, CT, MRI and PET)
    • Important in differentiating non-lgM MGUS from other plasma cell neoplasm entities and other B cell lymphoproliferative disorders
    • Osteolytic bone destruction (≥ 5 mm in size) on imaging is considered positive for bone involvement of plasma cell myeloma or plasmacytoma (Lancet Oncol 2014;15:e538)
Prognostic factors
Case reports
Treatment / management
  • Management requires an understanding of the risk of progression
  • Follow-up of MGUS patients depends on the risk assessment
  • Risk stratification (Blood 2005;106:812):
    • Serum monoclonal protein level ≥ 15 g/l
    • Non-IgG MGUS (i.e. IgA, IgM and IgD MGUS)
    • Abnormal serum free light chain ratio
  • Patients are categorized by number of risk factors present:
    • 3 risk factors: high risk MGUS
    • 2 risk factors: high intermediate risk MGUS
    • 1 risk factor: low intermediate risk MGUS
    • 0 risk factors: low risk MGUS
  • Despite close observation, can progress abruptly to plasma cell myeloma
  • Follow-up:
Microscopic (histologic) description
  • < 10% clonal plasma cells in bone marrow aspirate / biopsy
  • Plasma cells evenly scattered or in occasional small clusters
  • Plasma cells lack nucleoli
Microscopic (histologic) images

Images hosted on PathOut server:

Contributed by Hatem Kaseb, M.D., Ph.D., M.P.H.

Bone biopsy

Cytology images

Images hosted on PathOut server:

Contributed by Hatem Kaseb, M.D., Ph.D., M.P.H.

Bone marrow aspirate

Positive stains
Negative stains
  • CD19 (in contrast to normal plasma cells)
Flow cytometry description
  • Monoclonal plasma cells that are CD38+ (bright) cells with aberrant CD56 population (may also be negative)
Molecular / cytogenetics description
  • Usually shows a normal karyotype because of the relatively small number of plasma cells
  • Possible chromosomal alterations include t(11;14), t(4;14), t(14;16), deletions of 13q and hyperdiploidy; no clinical correlation for these genetic alterations have been found in non-IgM MGUS
Differential diagnosis
  • Smoldering plasma cell myeloma:
    • Serum M protein ≥ 3 g/dL, bone marrow plasma cells ≥ 10% and absence of CRAB symptoms
  • Waldenström macroglobulinemia (smoldering or symptomatic):
    • IgM on immunofixation
  • Light chain monoclonal gammopathy of undetermined significance (LC-MGUS):
    • Monoclonal protein that lacks the immunoglobulin heavy chain component
  • Monoclonal gammopathy of renal significance:
    • Meets diagnostic criteria for MGUS as well as renal insufficiency and monoclonal immunoglobulin deposits in the kidney by immunofluorescence (Blood 2012;120:4292)
  • Light chain smoldering multiple myeloma (idiopathic Bence Jones proteinuria):
    • Presence of monoclonal light chains in the urine (Bence Jones proteinuria) and no immunoglobulin heavy chain expression in the serum or urine
  • Primary (amyloid light chain) amyloidosis and light chain deposition disease:
    • Plasma cell neoplasm associated with the pathologic deposition of monoclonal light chains in tissue
    • Presence of amyloid in tissue and evidence of plasma cell neoplasm
  • Other B cell lymphoproliferative disorders:
    • Diagnosis of the specific entity is based on biopsy, IHC, cytogenetics and molecular studies
Board review question #1
What is the rate of progression of non-IgM monoclonal gammopathy of uncertain significance (MGUS) to more advanced disease?

  1. 0.5% per year
  2. 1% per year
  3. 1.5% per year
  4. 2% per year
Board review answer #1
B. 1% per year
Board review question #2
Which of the following factors is associated with increased risk of progression in non-IgM monoclonal gammopathy of uncertain significance (MGUS)?

  1. Generalized lymphadenopathy
  2. Lambda restriction of plasma cells in bone marrow aspirate
  3. M protein of 5 g/l
  4. M protein of 15 g/l
Board review answer #2
D. M protein of 15 g/l