Bone marrow neoplastic

Bone marrow - plasma cell and lymphoid neoplasms

Plasma cell neoplasms

MGUS-IgM



Topic Completed: 29 November 2021

Minor changes: 29 November 2021

Copyright: 2020-2021, PathologyOutlines.com, Inc.

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

Shuchi Zinzuwadia, B.S.
Ameet R. Kini, M.D., Ph.D.
Page views in 2020: 313
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Cite this page: Zinzuwadia S, Zinzuwadia SS, Raouf MF, Gupta R, Kini AR. MGUS-IgM. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/lymphomaMGUSIgM.html. Accessed December 3rd, 2021.
Definition / general
  • IgM monoclonal gammopathy of undetermined significance (MGUS) is characterized by < 3 g/dL of monoclonal IgM protein, < 10% clonal lymphoplasmacytic or clonal plasma cells, with no anemia, constitutional symptoms, hyperviscosity, lymphadenopathy or hepatosplenomegaly
Essential features
  • Serum IgM monoclonal protein < 3 g/dL
  • Bone marrow clonal lymphoplasmacytic cells or clonal plasma cells < 10% of cellular elements
  • No anemia, constitutional symptoms, hyperviscosity, lymphadenopathy or hepatosplenomegaly caused by the underlying disorder
  • Can progress to lymphoplasmacytic lymphoma / Waldenström macroglobulinemia, IgM multiple myeloma or AL amyloidosis
ICD coding
  • ICD-O: 9761/1 - IgM monoclonal gammopathy of undetermined significance
  • ICD-10: D47.2 - monoclonal gammopathy
Epidemiology
Sites
  • Monoclonal IgM kappa and lambda proteins are found in the serum or urine
  • Clonal plasma cells or lymphocytes can be seen in the bone marrow
Pathophysiology
  • Initial step is an abnormal immune response to an antigenic stimulus (F1000Res 2017;6:2142)
  • MYD88 (42 - 54%) and CXCR4 (7%) mutations are seen in IgM MGUS
  • Additional steps (such as the 6q deletion) may be involved in progression to Waldenström macroglobulinemia (F1000Res 2017;6:2142)
  • Noncoding RNAs may drive development of Waldenström macroglobulinemia (Cancers (Basel) 2020;12:320)
  • IgM MGUS patients with t(11:14) may progress to IgM plasma cell myeloma
Etiology
  • Unknown
Clinical features
  • Patients with IgM MGUS do not have constitutional symptoms (Clin Lymphoma Myeloma 2009;9:17)
  • Progression among IgM MGUS patients is 2% per year in the first 10 years and 1% per year thereafter (N Engl J Med 2018;378:241)
  • Risk of progression is higher than non-IgM MGUS
  • Some patients have associated peripheral neuropathy
Diagnosis
  • Diagnosis of IgM MGUS is based on the presence of a serum IgM monoclonal protein < 3 g/dL, fewer than 10% clonal lymphoplasmacytic or plasma cells in the bone marrow and lack of evidence of progression to lymphoplasmacytic lymphoma / Waldenström macroglobulinemia, IgM multiple myeloma or AL amyloidosis (Blood 2018;131:163)
Laboratory
  • Serum electrophoresis shows a restricted band (< 3 g/dL)
  • Serum immunofixation shows an IgM kappa or IgM lambda monoclonal protein
Radiology description
  • Skeletal survey does not show lytic lesions
  • CT / PET scans are negative for lymphoma
Prognostic factors
  • Risk factors for progression are initial concentration of the monoclonal protein (≥ 1.5 g/dL) and abnormal serum free light chain ratio (N Engl J Med 2018;378:241)
  • Overall survival rate at 30 years is 4% for patients with IgM MGUS and 7% for non-IgM MGUS, compared with 12% in an age and sex matched control population (N Engl J Med 2018;378:241)
Case reports
  • 62 year old immunocompetent woman was admitted with cytomegalovirus (CMV) infection, pulmonary embolism, splenic vein thrombosis and monoclonal gammopathy of undetermined significance (MGUS) (BMJ Case Rep 2019;12:e226448)
  • 70 and 84 year old Caucasian men showed an M spike by protein electrophoresis (J Med Case Rep 2020;14:75)
  • 72 year old Japanese man with diabetes mellitus and hypertension presented with an acutely elevated serum creatinine level (CEN Case Rep 2020;9:109)
  • 72 year old Japanese woman was hospitalized because of massive proteinuria (Front Med (Lausanne) 2021;8:608741)
  • 75 year old woman presented with maculopapular purpura and erythematous (inflammatory) retiform purpura on her lower leg (JAAD Case Rep 2019;5:288)
Treatment
  • Treatment is not recommended for asymptomatic patients with IgM MGUS (F1000Res 2017;6:2142)
  • "Wait and watch" approach is usually followed
  • Patients with peripheral neuropathy are treated with IVIG, rituximab, steroids or plasma exchange
Microscopic (histologic) description
  • Bone marrow biopsy is usually normocellular with normal trilineage hematopoiesis
  • Plasma cells and CD20+ B cells may be slightly increased but do not form prominent aggregates
Microscopic (histologic) images

Contributed by Ameet R. Kini, M.D., Ph.D. and Maryam F. Raouf, M.D.
Increased CD20+ B cells

Increased CD20+ B cells

Cytology description
  • Bone marrow aspirate smears show normal trilineage hematopoiesis
  • Plasma cells and lymphocytes may be slightly increased but are < 10% of cells
Cytology images

Contributed by Ameet R. Kini, M.D., Ph.D. and Maryam F. Raouf, M.D.
Increased plasma cells

Increased plasma cells

Peripheral smear description
  • Peripheral blood smear shows no abnormal findings
Positive stains
Negative stains
Flow cytometry description
Flow cytometry images

Contributed by Ameet R. Kini, M.D., Ph.D. and Maryam F. Raouf, M.D.
Abnormal plasma cells

Abnormal plasma cells

Molecular / cytogenetics description
  • FISH analysis may detect presence of t(11;14), CCND1-IGH in plasma cells
  • MYD88 mutation may be detected (Blood 2013;121:2051)
Molecular / cytogenetics images

Contributed by Ameet R. Kini, M.D., Ph.D. and Maryam F. Raouf, M.D.
CCND1-IGH fusion

CCND1-IGH fusion

Videos

Introduction to MGUS

MGUS diagnosis

MGUS management


MGUS associated diseases

IgM MGUS pathophysiology

Sample pathology report
  • Bone marrow, right posterior iliac crest, core biopsy, clot section, aspirate smears and touch imprint:
    • Normocellular bone marrow (50%) with trilineage hematopoiesis and slightly increased plasma cells (4%) (see comment)
    • Comment: Review of laboratory data shows a monoclonal protein in the serum (IgM lambda, 1.2 g/dL). The CBC is within normal limits. Imaging studies reveal bone marrow lytic lesions and no lymphadenopathy or organomegaly.
    • The bone marrow core biopsy is normocellular for age (50%). Trilineage hematopoiesis is present. Megakaryocytes are adequate and appear normal in morphology.
    • The aspirate clot section is adequate and shows features similar to the core biopsy.
    • The bone marrow aspirate smear is adequate. The myeloid and erythroid precursors show progressive and orderly maturation. Megakaryocytes are adequate in number and show normal morphology. Blasts are not increased. Plasma cells are slightly increased (4% plasma cells based on a 500 cell differential count performed on the bone marrow aspirate smear).
    • The touch preparation findings are similar to the aspirate smear.
    • Flow cytometry shows a small abnormal plasma cell population (CD45 negative, bright CD38 positive) with expression of CD20, CD56 and CD117. These plasma cells show lambda light chain restriction. Gating on the lymphocytes shows no evidence of a monoclonal B cell population or T cell abnormality based on the markers assayed. There is no increase in blasts.
    • FISH analysis performed on an enriched plasma cell population reveals presence of t(11;14). Molecular analysis for the MYD88 mutation is negative.
    • The findings are consistent with IgM MGUS. IgM MGUS patients can progress to lymphoplasmacytic lymphoma / Waldenström macroglobulinemia, IgM multiple myeloma or AL amyloidosis.
Differential diagnosis
  • IgM myeloma:
    • IgM protein monoclonal ≥ 3 g/dL or ≥ 10% clonal plasma cells
    • Lytic bone lesions may be seen
  • Lymphoplasmacytic lymphoma:
    • IgM protein monoclonal ≥ 3 g/dL or ≥ 10% clonal lymphoplasmacytic cells
    • Hyperviscosity and lymphadenopathy may be seen
  • AL amyloidosis:
    • Presence of amyloid deposits that display apple green birefringence under polarized microscopy on Congo red stain
Additional references
Board review style question #1

A 58 year old woman with a past medical history significant for type 2 diabetes and hypertension presents to her PCP office for routine care. The patient's diabetes and hypertension are well controlled and she reports no significant constitutional symptoms. Physical exam shows no lymphadenopathy or organomegaly. Laboratory studies show her CBC within normal limits. Serum electrophoresis shows a restricted band at 1.5 g/dL. A serum immunofixation is shown above (ELP = serum electrophoresis, G = IgG, A = IgA, M = IgM, K = kappa, L = lambda). This patient's most likely diagnosis is

  1. IgG MGUS
  2. IgM MGUS
  3. Polyclonal gammopathy
  4. Smoldering myeloma
  5. Waldenström macroglobulinemia
Board review style answer #1
B. IgM MGUS

Comment Here

Reference: MGUS-IgM
Board review style question #2
A 69 year old man with a history of acute myeloid leukemia presents to his oncologist for follow up. The patient was diagnosed 5 years ago and after treatment, has been in complete remission. His CBC is within normal limits. A serum immunofixation shows a small IgM lambda monoclonal protein. A bone marrow biopsy was performed and shows slightly increased lymphocytes, some of which are plasmacytoid. Flow cytometry shows a small B cell population with expression of CD19, CD20 and lambda light chain restriction. Blasts are not increased and show normal immunophenotype. A mutation in which gene is mostly likely to be detected by molecular studies?

  1. CALR
  2. FLT3
  3. JAK2
  4. MYD88
  5. SF3B1
Board review style answer #2
D. MYD88

Comment Here

Reference: MGUS-IgM
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