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

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

Revised: 16 June 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://www.pathologyoutlines.com/topic/lymphomamyeloma.html. Accessed June 23rd, 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

Microscopic (histologic) 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
Microscopic (histologic) 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, occurs in up to 20% of cases, and iis 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
Board review question #1
A 56 year old man was brought to emergency by his wife, who reported that he was playing catch with his son when he suddenly experienced acute pain in his right arm, accompanied almost immediately by swelling and loss of mobility. An Xray revealed a fracture of the right humerus with an associated lytic lesion. A needle biopsy of the lesion and a bone marrow biopsy were performed, with similar findings, shown below (bone marrow biopsy).



All of the following are true of this patient EXCEPT:

  1. An immunohistochemical stain for CD20 will most likely be negative.
  2. An immunohistochemical stain for CD38 will most likely be positive.
  3. An immunohistochemical stain for cyclin D1 will most likely be positive.
  4. Plasma cells typically make up at least 10% of the nucleated cells.
  5. t(4;14) is seen in 25% of cases.
Board review answer #1
C.. Immunostains for cyclin D1 are typically negative (except when t(11;14) is present, which occurs in up to 20% of cases)


Source: BoardVitals, 2/5/2014