Bone marrow neoplastic

Bone marrow - plasma cell and lymphoid neoplasms

Plasma cell neoplasms

MGUS-non IgM

Authors: Hatem Kaseb, M.D., Ph.D., M.P.H., Stanley David Hudnall, M.D.

Editorial Board Member: Genevieve M. Crane, M.D., Ph.D.

Editor-in-Chief: Debra L. Zynger, M.D.

Topic Completed: 1 July 2018

Minor changes: 11 May 2021

Copyright: 2001-2021, PathologyOutlines.com, Inc.

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

Page views in 2020: 2,486

Page views in 2021 to date: 2,643

Table of Contents

Cite this page: Kaseb H. MGUS-non IgM. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/lymphomaMGUS.html. Accessed October 15th, 2021.

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):
1. Serum monoclonal protein < 30 g/l
2. < 10% clonal plasma cells in the bone marrow
3. 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

CD138, CD79a, strong CD38, MUM1, EMA (similar to normal plasma cells)
Monoclonal light chain restriction: kappa or lambda

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

B. 1% per year

Comment Here

Reference: MGUS-non IgM

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

D. M protein of 15 g/l

Comment Here

Reference: MGUS-non IgM