Lymphoma and plasma cell neoplasms
Plasma cell neoplasms
Plasma cell myeloma (multiple myeloma)

Author: Nikhil Sangle, M.D. (see Authors page)

Revised: 3 April 2017, last major update March 2011

Copyright: (c) 2001-2017, PathologyOutlines.com, Inc.

PubMed Search: plasma cell myeloma lymphoma

Cite this page: Plasma cell myeloma (multiple myeloma). PathologyOutlines.com website. http://pathologyoutlines.com/topic/lymphomamyeloma.html. Accessed April 25th, 2017.
Definition / General
  • Neoplastic proliferation of plasma cells with multifocal skeletal involvement
Etiology
  • Cell of origin is less differentiated than plasma cell; expresses antigens associated with myelomonocytes (CD33), megakaryocytes (Gp IIb / IIIa), erythroid cells (glycophorin)
Clinical Features
  • Constitutes 10 - 15% of hematopoietic neoplasms
  • Causes 1% of cancer deaths in Western countries, males > females, African Americans > Whites
  • Usually middle age to elderly patients with widespread skeletal lytic lesions, bone marrow plasmacytosis and monoclonal gammopathy
  • Also pathologic fractures and back pain; weakness, anemia, pallor, hepatosplenomegaly, hypercalcemia, primary amyloidosis (AL type) and renal insufficiency due to toxicity of light chains (Bence Jones proteins) to renal epithelium
  • Impaired humoral immunity leads to frequent infections with Streptococcus pneumoniae, Staphylococcus aureus, E. coli; cellular immunity is normal
  • Most commonly affects the bones with most active hematopoiesis - vertebrae (thoracic most common), ribs, skull, pelvis, femur; begins in medulla, then erodes cortical bone
  • Can spread to skin (0.5%), lymph nodes
  • Hyperviscosity syndrome present in 7%, usually due to IgA or IgG3
  • Radiologic lesions appear as punched out defects, associated with generalized osteoporosis
Clinical Variants
  • Asymptomatic (smoldering) myeloma: patients with no related organ or tissue impairment; 10% per year progress to symptomatic myeloma for the first 5 years, only 3% per year for the next 5 years and 1% per year for the subsequent 10 years (N Engl J Med 2007;356:2582)
  • Nonsecretory myeloma: 3% of plasma cell myelomas show absence of M protein by electrophoresis or immunofixation; clinical features similar to secretory myeloma except for low incidence of renal insufficiency and hypercalcemia
  • Plasma cell leukemia: clonal plasma cells > 20% of the leucocyte differential count; aggressive disease
Laboratory
  • In general, monoclonal secretion of immunoglobulins (called paraproteins) > 3 g/dl of IgG or > 2.5 g/dl of IgA in serum; or 6 mg/dl or > 1 g/24 hr of Bence Jones proteins in urine
  • M component: monoclonal immunoglobulin (M myeloma), up to 160 kd, restricted to plasma and extracellular fluid
  • 97% patients show M protein in serum or urine (IgG 50%, IgA 20%, light chain 20%, IgD, IgE, IgM and biclonal < 10%), appears as monoclonal spike in serum or urine electrophoresis
  • In 20% of cases, only monoclonal light chains (kappa or lambda) are present, usually in urine
  • Rouleaux formation occurs in peripheral blood (erythrocytes resemble stacked coins) due to protein present, parallels erythrocyte sedimentation rate
  • Usually elevated serum IL6
  • Patients frequently are infected with HHV8
  • Paraprotein may cause falsely elevated hemoglobin (Arch Pathol Lab Med 2000;124:616)
  • Occasionally light chains deposit in renal proximal tubules, thyroid follicular or gallbladder surface epithelial cells (Hum Pathol 2003;34:270)
Laboratory Images

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Various images

Serum protein immunofixation shows IgD lambda myeloma

Radiology Description
  • Multiple masses of neoplastic plasma cells throughout the skeletal system; generalized osteoporosis
Radiology Images

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Prominent skull defect

Prognostic Factors
  • Poor; < 1 year if multiple lesions and no treatment; many years if indolent
  • Median survival is 3 years with chemotherapy
  • 10% survive 10 years
  • Death due to uncontrolled disease or marrow failure
  • Poor prognostic factors: cyclin D1+ (associated with advanced stage, grade, Am J Clin Pathol 2001;116:535), IgD form, high IL6 levels, plasmablastic morphology, CD10+
  • Staging is done using the Durie and Salmon or the international staging systems
Case Reports
Treatment
  • Alkylating agent chemotherapy, bone marrow transplantation, anti-topoisomerase II alpha agents
  • Note: highly proliferative tumors usually are topo II alpha positive and sensitive to anti-topo II alpha agents
Gross Description

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Vertebrae with myeloma lesions

Skull lesions

Micro Description
  • Sheets or aggregates of plasma cells or plasmablasts
  • Mature plasma cells have abundant basophilic cytoplasm, low N/C ratio, eccentrically placed nucleus with clumped "spoke wheel" or "clock face" chromatin
  • The less mature cells show loose reticular chromatin, prominent nucleoli, high N/C ratio; also perinuclear hof (due to prominent Golgi apparatus), Mott Cells (blue grape-like cytoplasmic inclusions), Russell bodies (cytoplasmic cherry red refractive round bodies), Dutcher bodies (intranuclear crystalline rods)
  • Also "flaming" plasma cells, whose fiery fringes are formed by pseudopodic cytoplasmic projections that are carmine red after Wright-Giemsa staining; peripheral cytoplasm has numerous dilated endoplasmic reticulum cisterns distended with immunoglobulin that may fragment and appear around the cell; associated with IgA myeloma (Arch Pathol Lab Med 2001;125:1394)
  • Bone marrow biopsies often show plasma cells as > 10% of the nucleated cells, but no minimal percentage is designated by WHO since up to 5% of symptomatic myeloma patients have < 10% marrow plasma cells
Micro Images

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Hypercellular marrow with plasmacytoid cells

Bone marrow biopsy has blast-like cells


Lambda staining

Myeloma and sarcoidosis

Cytology Images

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Bone marrow aspirate has plasmacytoid cells

Peripheral blood shows plasma cells (right: with blastic features)

Positive Stains
Negative Stains
Flow Cytometry Images

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Prominent monotypic pattern
(lambda, with minimal kappa)

Molecular / Cytogenetics Description
  • 13q-, 14q rearrangements are common
  • t(4;14)(p16;q32) in 25 - 30% of cases, causing increased expression of FGFR3 (fibroblast growth factor receptor 3) and IgH
  • t(11;14)(q13;q32), involving cyclin D1 and IgH, is usually part of complex karyotype; may be missed by routine cytogenetics, particularly if the proliferative rate is low (Am J Clin Pathol 2000;113:831)
  • Also t(14;16)(q32;q23), involving IgH and c-Maf; t(16;22)(q23;q11), involving c-Maf and Ig lambda and t(6;14)(p25;q32), involving MUM1 / IRF4 and IgH
Differential Diagnosis