Stanford School of Medicine

Surgical Pathology Criteria

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Plasma Cell Myeloma


  • 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
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 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


  • 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

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


  • 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



Plasma cell neoplasms / Immunosecretory disorders (WHO 2008)


  • 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.
  • Chang ST, Liao YL, Lu CL, Chuang SS, Li CY. Plasmablastic cytomorphologic features in plasma cell neoplasms in immunocompetent patients are significantly associated with EBV. Am J Clin Pathol. 2007 Aug;128(2):339-44.
  • Greipp PR, Leong T, Bennett JM, Gaillard JP, Klein B, Stewart JA, Oken MM, Kay NE, Van Ness B, Kyle RA. Plasmablastic morphology--an independent prognostic factor with clinical and laboratory correlates: Eastern Cooperative Oncology Group (ECOG) myeloma trial E9486 report by the ECOG Myeloma Laboratory Group. Blood. 1998 Apr 1;91(7):2501-7
  • Heerema-McKenney A, Waldron J, Hughes S, Zhan F, Sawyer J, Barlogie B, Shaughnessy JD Jr. Clinical, immunophenotypic, and genetic characterization of small lymphocyte-like plasma cell myeloma: a potential mimic of mature B-cell lymphoma. Am J Clin Pathol. 2010 Feb;133(2):265-70.
  • Hoyer, JD, Hanson, CA, Fonseca, R, et al. The (11;14)(q13;q32) translocation in multiple myeloma. A morphologic and immunohistochemical study. Am J Clin Pathol 2000; 113:831.
  • Kyle, RA, Gertz, MA, Witzig, TE, et al. Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clin Proc 2003; 78:21.
  • 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]
  • Robillard, N, Avet-Loiseau, H, Garand, R, et al. CD20 is associated with a small mature plasma cell morphology and t(11;14) in multiple myeloma. Blood 2003; 102:1070.
  • Soverini, S, Cavo, M, Cellini, C, et al. Cyclin D1 overexpression is a favorable prognostic variable for newly diagnosed multiple myeloma patients treated with high-dose chemotherapy and single or double autologous transplantation. Blood 2003; 102:1588.
  • 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.
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