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Lymphoma - B cell neoplasms

Plasma cell neoplasms

Plasma cell myeloma (multiple myeloma)


Reviewer: Nikhil Sangle, M.D., University of Utah and ARUP Laboratories (see Reviewers page)
Revised: 7 February 2012, last major update March 2011
Copyright: (c) 2001-2011, PathologyOutlines.com, Inc.

Definition
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● Neoplastic proliferation of plasma cells with multifocal skeletal involvement

Etiology
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● Cell of origin is less differentiated than plasma cell; expresses antigens associated with myelomonocytes (CD33), megakaryocytes (Gp IIb/IIIa), erythroid cells (glycophorin)

Clinical features
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● Constitutes 10-15% of hematopoietic neoplasms
● Causes 1% of cancer deaths in Western countries, males > females, African Americans > Whites
● Usually middle-aged 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
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Asymptomatic (smoldering) myeloma: patients with no related organ or tissue impairement; 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)
Non-secretory 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

Prognosis
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● 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 (see below), high IL-6 levels, plasmablastic morphology, CD10+
Staging is done using the Durie and Salmon or the international staging systems

Radiology
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● Multiple masses of neoplastic plasma cells throughout the skeletal system; generalized osteoporosis

Radiology images
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Prominent skull defect

Laboratory
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● In general, monoclonal secretion of immunoglobulins (called paraproteins) >3g/dl of IgG or >2.5 g/dl of IgA in serum; or 6 mg/dl or >1g/24hr of Bence Jones proteins in urine
● M component: monoclonal immunoglobulin (M-myeloma), up to 160kd, 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 IL-6
● 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

Treatment
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● 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

Case reports
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● 49 year old woman with coexisting sarcoidosis (Arch Pathol Lab Med 2002;126:365)
● 64 year old woman and 70 year old man who presented with subcutaneous nodules and mediastinal masses simulating hemangioma (Arch Pathol Lab Med 2000;124:628)
● 77 year old man with coexisting acute monocytic leukemia (Arch Pathol Lab Med 2003;127:1506)
● Plasmablastic transformation resembling acute leukemia (Hum Pathol 2003;34:710)

Gross images
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Vertebrae with myeloma lesions


Skull lesions

Micro description
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● 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 grapelike 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 and peripheral blood images
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Bone marrow aspirate has plasmacytoid cells

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

Positive stains
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● Kappa or lambda light chains (usually one markedly more than the other), CD38 (plasma cells), CD79a, CD138
● Also EMA (70%), vimentin (70%), CD33 (myelomonocytes), GP IIb/IIIa, glycophorin
● CD56 often positive on myeloma cells (67–79%) but negative in plasma cell leukemia
● Aberrant expression of CD117 > CD20 > CD52 > CD10; rarely expresses cyclin D1
Note: cutaneous plasmacytomas uniformly express CD117 (Arch Pathol Lab Med 2003;127:1596)

Negative stains
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● CD19, CD20

Flow cytometry images
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Prominent monotypic pattern (lambda, with minimal kappa)

Molecular
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● 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 mum/irf4 and IgH

Differential diagnosis
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Reactive synovitis: may have Dutcher bodies (Arch Pathol Lab Med 2002;126:199, images)

End of Lymphoma - B cell neoplasms > Plasma cell neoplasms > Plasma cell myeloma / multiple myeloma


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