Monoclonal Gammopathy of Undetermined Significance

Definition

• Serum monoclonal immunoglobulin (M-protein) in absence of plasma cell myeloma or B cell lymphoproliferative disorder

Alternate/Historical Names

• MGUS

Diagnostic Criteria

• Presence of serum M-protein <3 g/dL
• Bone marrow clonal plasma cells present but <10%
• No renal insufficiency, anemia, hypercalcemia, lytic bone lesions, or other organ/tissue damage
• If any of above criteria are exceeded, classify as plasma cell myeloma
• If low grade B cell lymphoma is present, classify with the lymphoma

Dita Gratzinger MD PhD

Department of Pathology
Stanford University School of Medicine
Stanford CA 94305-5342

Initial posting / updates: 9/1/07, 4/14/10

Supplemental studies

Immunohistology and Flow Cytometry

• Plasma cell quantitation is best performed by differential count on the bone marrow aspirate or by immunohistochemistry on the bone marrow biopsy.
• Flow cytometry may significantly underestimate plasma cell percentage, but does establish clonality.

Hematolymphoid markers

• CD45 absent or dim in >99%

B cell and plasma cell markers

• CD138 >99%
• CD38 >99%
• CD79a most
• CD20 variable, often absent
• CD19 variable, often absent
• CD56 10-60%, weak (aberrant, but may be seen in reactive conditions)
• Cytoplasmic kappa or lambda light chain by flow cytometry, in situ hybridization, or immunohistochemistry

Cytogenetics

• IgG/IgA MGUS: hyperdiploidy, translocations involving 14q32, deletion 13q
  • Not useful prognostically or in differential diagnosis from plasma cell myeloma
  • FISH (fluorescence in situ hybridization) much more sensitive than karyotyping

Useful Laboratory Tests

• Serum or urine protein electrophoresis, immunofixation, light chain quantification
• Quantitation and typing of monoclonal immunoglobulin / light chain
  • 70% IgG, 15%IgM, 12% IgA
• Serum free light chain analysis may be required to demonstrate clonal light chains
• These studies may be used to
  • Establish presence of a monoclonal plasma cell population
  • Quantitation helps subtype the plasma cell dyscrasia (i.e. >3g/dL serum monoclonal protein is a major criterion for myeloma)
  • Track disease burden over time

Differential Diagnosis

• Myeloma
• B cell lymphomas
  • M-protein may be associated with: lymphoplasmacytic lymphoma, chronic lymphocytic leukemia, other low grade B cell lymphomas
• Reactive plasmacytosis

Symptomatic Plasma Cell Myeloma	Asymptomatic / Smoldering Myeloma	MGUS
Usually but not always >10% clonal plasma cells in bone marrow or plasmacytoma	** ≥10% clonal plasma cells in bone marrow AND/OR	<10% clonal plasma cells in bone marrow
M protein in serum or urine or free light chain in urine	Serum M-protein >3g/dL	Serum M-protein <3g/dL
** Lytic bony lesions or  end-organ damage (hypercalcemia/ anemia/ renal insufficiency etc)	No lytic lesions or end-organ damage	No lytic lesions or end-organ damage

** Critical points: bone marrow plasma cells or M-protein above threshholds separates asymptomatic myeloma from MGUS and bone or other end organ damage separates symptomatic from asymptomatic myeloma

MGUS	Lymphoplasmacytic Lymphoma, Chronic Lymphocytic Leukemia or Other Low Grade B Cell Lymphoma with M-protein
Uniform plasma cell morphology	Lymphoid component present
CD20 often negative	CD20 usually uniformly positive
Uniformly CD138 positive	Scattered CD138 positive cells in plasmacytoid component

MGUS	Reactive Plasmacytosis
Light chain restriction by flow cytometry, immunohistochemistry or in situ hybridization	No light chain restriction
Aberrant immunophenotype (e.g. CD56+, CD19-)	CD19+, CD56-
Myeloma-associated cytogenetic abnormalities by FISH in >50%	Normal cytogenetics by FISH

Clinical

• Present in approximately 3% of general population over age 50
  • 10% of population over age 80
• 1-1.5% annual risk of progression to plasma cell or B cell neoplasm
  •  Risk increases with % plasma cells, size of M component, serum free light chain ratio
  • IgG and IgA MGUS may progress to plasma cell myeloma or primary amyloidosis
  • IgM MGUS may progress to non-Hodgkin B cell lymphoma, especially lymphoplasmacytic lymphoma or chronic lymphocytic leukemia/small lymphocytic lymphoma, or primary amyloidosis
• May also be associated with non-neoplastic conditions including
  • Infection
  • Autoimmune disease
  • Dermatologic disorders

Grading / Staging / Report

• Grading is not applicable

• Staging is not applicable

The pathology report should contain the following information:

• Diagnosis in the World Health Organization (WHO) classification
  • Equivalent diagnosis in other classifications used by relevant clinicians
• Results of supplementary studies if performed
• Relationship to other specimens from the same patient
• Information relevant to staging if available

Lists

Plasma cell neoplasms / Immunosecretory disorders (WHO 2008)

• Monoclonal gammopathy of undetermined significance (MGUS)
• Plasma cell myeloma
  • Variants:
    • Non-secretory
    • Smoldering
    • Plasma cell leukemia
• Plasmacytoma
  • Solitary plasmacytoma of bone
  • Extraosseus (extramedullary) plasmacytoma
• Monoclonal immunoglobulin deposition diseases
  • Primary amyloidosis
  • Systemic light chain and heavy chain deposition diseases
• Osteosclerotic myeloma (POEMS syndrome)
• Heavy chain diseases (variants of lymphoma rather than plasma cell neoplasms)
  • Gamma heavy chain disease (see lymphoplasmacytic lymphoma)
  • Mu heavy chain disease (see chronic lymphocytic leukemia)
  • Alpha heavy chain disease / immunoproliferative small intestinal disease (variant of extranodal marginal zone lymphoma)

Bibliography

• Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW . WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, International Agency for Research on Cancer, Lyon, 2008
• Warnke RA, Weiss LM, Chan JKC, Cleary ML, Dorfman RF . Tumors of the Lymph Nodes and Spleen, Atlas of Tumor Pathology, AFIP Third Series, Fascicle 14, 1995
• Blade J, M. Dimopoulos, L. Rosinol, S. V. Rajkumar, and R. A. Kyle. Smoldering (Asymptomatic) Multiple Myeloma: Current Diagnostic Criteria, New Predictors of Outcome, and Follow-Up Recommendations J. Clin. Oncol., February 1, 2010; 28(4): 690 - 697.
• Martin W, Abraham R, Shanafelt T, Clark RJ, Bone N, Geyer SM, Katzmann JA, Bradwell A, Kay NE, Witzig TE. Serum-free light chain-a new biomarker for patients with B-cell non-Hodgkin lymphoma and chronic lymphocytic leukemia. Transl Res. 2007 Apr;149(4):231-5.
• Perez-Persona E et al,  New criteria to identify risk of progression in monoclonal gammopathy of uncertain significance and smoldering mutliple myeloma based on multiparameter flow cytometry analysis of bone marrow plasma cells. Blood 2007 Oct 1;110(7):2586-92.
• Raja KR, Kovarova L, Hajek R.Review of phenotypic markers used in flow cytometric analysis of MGUS and MM, and applicability of flow cytometry in other plasma cell disorders. Br J Haematol. 2010 Mar 1. [Epub ahead of print]
• Van Camp B, Durie BG, Spier C, De Waele M, Van Riet I, Vela E, Frutiger Y, Richter L, Grogan TM. Plasma cells in multiple myeloma express a natural killer cell-associated antigen: CD56. Blood. 1990 Jul 15;76(2):377-82.