Table of Contents
Definition / general | Essential features | Epidemiology | Pathophysiology | Etiology | Clinical features | Laboratory | Radiology description | Prognostic factors | Case reports | Treatment / management | Microscopic (histologic) description | Microscopic (histologic) images | Cytology images | Positive stains | Negative stains | Flow cytometry description | Molecular / cytogenetics description | Differential diagnosis | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Cite this page: Kaseb H. MGUS-non IgM. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/lymphomaMGUS.html. Accessed February 8th, 2023.
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 proliferation
- A subset are light chain MGUS: only monoclonal light chains with complete loss of heavy chain expression
- 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%, absence of plasma cell myeloma related end organ damage and amyloidosis
- Rarely plasma cell MGUS produces an IgM M protein (1% of cases, Swerdlow: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th Edition, 2017)
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 or amyloidosis
- Non-IgM MGUS may progress to a malignant plasma cell neoplasm (rate of 1% per year)
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
- No specific cause has been identified; however, a gene-environment interaction is possible (Hematol Oncol Clin North Am 2014;28:775)
- Associated with:
- Connective tissue disorders, peripheral neuropathies, dermatological diseases such as acquired C1 esterase inhibitor deficiency (angioedema), endocrine diseases and liver infections such as hepatitis C and HIV liver disease
- Radiation (Blood 2009;113:1639), pesticides (Blood 2009;113:6386) and obesity (Blood 2010;116:1056)
- First degree relatives have higher incidence (Blood 2012;119:4608)
- Risk increased by polymorphisms at 2p23.3, 3p22.1, 3q26.2, 6p21.33, 7p15.3, 17p11.2 and 22q13.1 (Blood 2014;123:2513)
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, 1% IgD, 1% IgE; monoclonal light chain in urine in 1/3 of cases (N Engl J Med 2006;354:1362); 20% with only light chain (Swerdlow: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th Edition, 2017)
- No myeloma related organ or tissue impairment such as hypercalcemia (> 1 mg/dL higher than the upper limit of normal or > 11 mg/dL), renal insufficiency (Cr clearance < 40 ml/min or serum Cr > 2 mg/dL), anemia (Hb > 20 g/L below lower limit of normal or < 100 g/L) or bone lesions (≥ 1 by skeletal radiography, CT or PET / CT) (=CRAB features of myeloma)
- 3 diagnostic criteria (Swerdlow: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th Edition, 2017):
- Serum monoclonal protein < 30 g/l
- < 10% clonal plasma cells in the bone marrow
- Absence end organ damage attributable to the plasma cell disorder (CRAB) and absence of amyloidosis
- Light chain only MGUS diagnostic criteria: abnormal light chain ratio (< 0.26 or > 1.65), urinary light chain must be < 0.5 g/24 h, < 10% plasma cells, end organ damage or amyloidosis
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
- Light chain MGUS: no immunoglobulin heavy chain on immunofixation electrophoresis
Radiology description
- Bone survey of skull, spine and pelvis (Xray, CT, MRI and PET with differing sensitivities)
- 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
- Considered a preneoplastic condition with an annual risk of progression of approximately 1%
- May progress to multiple myeloma, amyloidosis, Waldenström macroglobulinemia, solitary plasmacytoma or other lymphoproliferative disorder (Lancet Oncol 2014;15:e538)
- Risk of progression of non-IgM MGUS is lower than IgM MGUS (N Engl J Med 2018;378:241)
- Risk of progression is increased with M protein ≥ 15 g/l and abnormal free light chain ratio (N Engl J Med 2002;346:564)
- Light chain MGUS: lower rate of progression (0.3% per year)
Case reports
- 49 year old man with polycythemia and renal failure (Nephrol Dial Transplant 2012;27:448)
- 61 year old man with dystrophic plasma cells (Eur J Haematol 2012;88:461)
- 70 year old woman with Good syndrome (BMJ Case Rep 2012 Nov 27;2012)
- 74 year old woman with leukocyte cytoplasmic inclusions associated with cryoglobulinemia (Eur J Haematol 2011;86:550)
- 81 year old woman with crystalline keratopathy (Br J Haematol 2012;159:258)
- 82 year old man with von Willebrand disease and IgG MGUS (Blood Coagul Fibrinolysis 2014;25:631)
- 86 year old woman with blue finger syndrome (BMJ Case Rep 2013 Jan 3;2013)
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:
- Low risk MGUS: every 2 - 3 years without laboratory testing (CMAJ 2013;185:1345)
- Intermediate and high risk MGUS: clinical and laboratory follow-up every 6 months (Hematol Oncol Clin North Am 2014;28:775)
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
Cytology images
Positive stains
Negative stains
- CD19 (in contrast to normal plasma cells)
Flow cytometry description
- Monoclonal plasma cells that are CD38+ (bright) cells which may express aberrant CD56 or CD117
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% (but < 60%) 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 style question #1
What is the rate of progression of non-IgM monoclonal gammopathy of uncertain significance (MGUS) to more advanced disease?
- 0.5% per year
- 1% per year
- 1.5% per year
- 2% per year
Board review style answer #1
Board review style question #2
Which of the following factors is associated with increased risk of progression in non-IgM monoclonal gammopathy of uncertain significance (MGUS)?
- Generalized lymphadenopathy
- Lambda restriction of plasma cells in bone marrow aspirate
- M protein of 5 g/l
- M protein of 15 g/l
Board review style answer #2