Bone marrow neoplastic
Bone marrow - plasma cell and lymphoid neoplasms
Plasma cell neoplasms
MGUS-non IgM
Editorial Board Member: Genevieve M. Crane, M.D., Ph.D.
Editor-in-Chief: Debra Zynger, M.D.
Topic Completed: 1 July 2018
Minor changes: 19 June 2020
Copyright: 2001-2020, PathologyOutlines.com, Inc.
PubMed Search: Monoclonal gammopathy of undetermined significance[TI] MGUS[TI]
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 answer #1 | Board review style question #2 | Board review answer #2Cite this page: Kaseb H. MGUS-non IgM. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/lymphomaMGUS.html. Accessed August 6th, 2020.
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
Microscopic (histologic) images
Contributed by Hatem Kaseb, M.D., Ph.D., M.P.H.
Bone biopsy
Cytology images
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 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 answer #1
B. 1% per year
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 answer #2
