Plasma Cell Myeloma

Definition

• Multifocal clonal proliferation of plasma cells based in the bone marrow
  • May be designated as either asymptomatic/smoldering or symptomatic, see below

Alternate/Historical Names

• Multiple myeloma
• Myelomatosis
• Medullary plasmacytoma
• Kahler’s disease

Diagnostic Criteria

• Asymptomatic / smoldering vs. symptomatic myeloma are separated based on the presence of complications
  • Asymptomatic / smoldering myeloma requires defined levels of evidence of clonality but lacks complications
    • Elevated M protein (>3g/dL) AND/OR
    • >10% clonal plasma cells in marrow
    • Must not have characteristic clinical complications or end organ/tissue damage
  • Symptomatic myeloma requires any level of evidence of clonality plus characteristic complications
    • Any level of clonal bone marrow plasma cells (usually >10%) OR
    • Any level of M protein in serum or urine
      • Usually >3 g/dL IgG or >2.5 g/dL IgA or
      • >1 g/24 hr urine light chain
    • Must have characteristic clinical complications including:
      • Skeletal destruction with osteolytic lesions, pathological fractures, bone pain
      • Hypercalcemia, anemia, hyperviscosity
      • Renal insufficiency
      • Amyloidosis
  • (MGUS comprises those cases exhibiting both lower levels of M protein and marrow involvement and lacking complications)
• Variants:
  • Non-secretory myeloma (<5% of cases)
    • Same as above but absence of M protein by immunofixation electrophoresis; detectable by serum free light chain analysis in 2/3 cases
  • Plasma cell leukemia
    • Symptomatic plasma cell myeloma WITH
    • ≥2K/uL or ≥20% circulating clonal plasma cells (frequently lymphocytoid)
    • Frequent extramedullary involvement
• Morphologic characteristics
  • Distribution: interstitial (clusters not associated with blood vessels), or sheets
  • Plasma cell characteristics:
    • Eccentric nuclei
    • Moderate to abundant basophilic cytoplasm
    • Pale perinuclear “hof” representing the golgi zone.  
  • Variable morphology may be seen:
    • Large cells with prominent nucleoli to small cells with “lymphocytoid” appearance
    • Monotonous to pleomorphic
  • Cytologic atypia:
    • While suggestive, is not diagnostic of plasma cell dyscrasia
    • Nuclear pleomorphism, blastic chromatin most specific
    • Plasmablastic morphology is associated with poorer prognosis
      • Large central nucleolus, dispersed chromatin
      • High N:C ratio, large nucleus
      • Loss of nuclear eccentricity and perinuclear hof

Dita Gratzinger MD PhD

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

Initial posting and updates:: 9/1/07, 2/23/08, 4/14/10

Supplemental studies

Immunohistology and Flow

• Plasma cell quantitation is performed by differential count on the bone marrow aspirate or by immunohistochemistry for CD138 on the bone marrow biopsy
  • Flow cytometry may significantly underestimate plasma cell percentage
    • It does establish clonality and can differentiate residual clonal plasma cells from admixed polytypic plasma cells

• CD45 absent or dim in >99%

• CD138 >99%
• CD38 >99%
• CD79a, most
• CD20 variable, often absent
• CD19 variable, often absent
• CD56 up to 80% -- aberrant antigen
• Cytoplasmic kappa or lambda light chain by flow cytometry, in situ hybridization, or immunohistochemistry

• Cyclin D1 (Bcl1) positive plasma cell myelomas often lymphoplasmacytic, CD20+, have better prognosis

Cytogenetics

• Loss of 13q14
  • Most common abnormality
  • Associated with poor prognosis
• t(11:14)(q13:q32)
  • Associated with:
    • Cyclin D1 overexpression
    • Lymphoplasmacytic or small lymphocytic morphology
  • Better prognosis

Useful Laboratory Tests

• Serum or urine protein electrophoresis, immunofixation, light chain quantification
• Quantitation and typing of monoclonal immunoglobulin / light chain
• 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

Plasma cell leukemia

• Frequently CD20+, CD56-,  t(11;14)+
• Frequently unusual M component (non-secretory, IgD, IgE, light chain only)

Differential Diagnosis

• Reactive plasmacytosis
• Plasmacytoma
• Monoclonal gammopathy of uncertain significance
• Lymphoplasmacytic lymphoma
• Plasmablastic lymphoma

Plasmacytoma / Myeloma	Reactive Plasmacytosis
Light chain restriction by flow cytometry, immunohistochemistry or in situ hybridization	No light chain restriction

Plasmacytoma	Myeloma
Single osseous or extraosseus lesion	Lytic bony lesions
No increase away from lesion	Usually increased plasma cells on random bone marrow biopsy
No end-organ damage	May have end-organ damage

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

Plasmacytoma / Myeloma	Lymphoplasmacytic Lymphoma and Nodal, Extranodal and Splenic Marginal Zone Lymphomas
Plasma cells may be pleomorphic or plasmablastic	Plasma cell component usually not markedly atypical
Uniform plasma cell morphology	Plasma cells mixed with small lymphocytes
IgG or IgA M component most common	IgM or IgG M component most common
CD20 often negative	CD20 80%
Uniformly CD138 positive	Scattered CD138 positive cells
Often CD56+, CD19-, CD45-	CD56-, CD19+, CD45+

Plasmablastic Lymphoma	Anaplastic (Plasmablastic) Plasmacytoma/Myeloma
Plasmablastic morphology	Subset plasmablastic
Often HIV+ or otherwise immunosuppressed	Usually not immunosuppressed
Often in oral cavity or mucosal areas of head	Extraosseous sites overlap
~60% EBV+	usually EBV negative

Plasmacytoma and plasmablastic lymphoma have the same immunophenotype, other than EBV and are generally separated based on clinical grounds

Clinical

• 15% of all hematologic malignancies
• Median age 69 years
• Median survival 3 years
  • May present with / cause bone pain, pathologic fractures, renal failure, hypercalcemia, recurrent infections due to hypogammaglobulinemia
• Non-secretory variant (1%)
  • No M protein
  • Less renal damage
• Asymptomatic/smoldering myeloma
  • Minority of patients
  • Initially 10 % annual progression to myeloma
• Plasma cell leukemia
  • >20% circulating plasma cells
  • Poor survival

Grading / Staging / Report

• Grading is not applicable

Durie-Salmon Staging System

• Stage I
  • Hemoglobin >10 g/dL
  • Serum IgG <5 g/dL
  • Serum IgA <3 g/dL
  • Normal serum calcium
  • Urine monoclonal protein excretion <4 g/day
  • No generalized lytic bone lesions
• Stage II
  • Intermediate between stages I and III
• Stage III One or more of the following:
  • Hemoglobin <8.5 g/dL
  • Serum IgG >7 g/dL
  • Serum IgA >5 g/dL
  • Serum calcium >12 g/dL
  • Urine monoclonal protein excretion >12 g/day
  • Advanced lytic bone lesions

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

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