Myeloma of bone

Bone
Hematologic neoplasms
Myeloma of bone

Author: Sheren Younes, M.D. (see Authors page)

Revised: 28 October 2016, last major update April 2014

Copyright: (c) 2003-2016, PathologyOutlines.com, Inc.

PubMed search: myeloma [title] bone

Related topics: Indolent myeloma, multilobated nuclei, nonsecretory myeloma, osteosclerotic myeloma, plasma cell leukemia (primary), smoldering myeloma

Table of Contents

Cite this page: Myeloma of bone. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/bonemyeloma.html. Accessed July 14th, 2017.

Definition / general

Multiple myeloma (MM) is a neoplastic proliferation of terminally differentiated plasma cells with multifocal skeletal involvement and organ dysfunction
Characterized by clonal plasma cells and production of a monoclonal immunoglobulin or its fragment
The neoplastic plasma cells can produce:
- Any of the five immunoglobulin subtypes
- Production and secretion of light chain only (κ or λ type)
- Nonsecretory MM

Epidemiology

Most common bone neoplasm (40% of total bone neoplasms, 50% of malignancies), usually diagnosed by marrow aspiration and biopsy
50 - 80 years
Males > females
African Americans > Whites

Sites

Multifocal involving vertebral column, ribs, skull, pelvis, sternum
Begins in medulla, then erodes cortical bone
Can spread to skin, lymph nodes

Pathophysiology

Myeloma cells interact with bone marrow stromal cells, leading to local cytokine production and signaling changes
Cytokines include IL6, insulin like growth factor 1 (IGF1), VEGF, tumor necrosis factor 1 (TNF1), transforming growth factor-B (TGF-B), IL17, IL21, CXC chemokine ligand 12 (CXCL12), and others (Nat Rev Cancer 2007;7:585)
Myeloma symptoms are caused by marrow infiltration, bone involvement, organ dysfunction, cytokine production, Ig deposition in tissue and therapy effect (chemotherapy and pain killers)

Clinical features

Usually older patients (rare before 40 years), 2 / 3 male, with widespread skeletal lytic lesions, pathologic fractures and back pain
Also weakness, normochromic normocytic anemia with rouleux formation, pallor, hepatosplenomegaly, hypercalcemia, primary amyloidosis (AL type) and renal insufficiency due to toxicity of light chains (Bence Jones proteins) to renal epithelium
Causes 1% of cancer deaths in Western countries
Infections common (due to impaired humoral immunity) with Streptococcus pneumoniae, Staphylococcus aureus, E coli
Cellular immunity is normal
Hyperviscosity syndrome present in 7%, usually due to IgA or IgG3
Most patients have elevated serum levels of IL6

Diagnosis

History and examination
Lab investigations
Peripheral blood smear
Bone marrow examination, aspirate and trephine, immunophenotyping, cytogenetics
Radiologic investigations
WHO Diagnostic criteria for MM
- M protein in serum or Urine
- Bone marrow (clonal) plasma cells or plasmacytoma
- Related organ or tissue impairment (end organ damage, including bone lesions)

Laboratory

CBC
Differential leukocytic count
Serum calcium
Serum protein electrophoresis to detect clonality, mostly associated with IgG, followed by IgA, light chains only and other Ig types
Kidney function tests
β2 microglobulin
Lactate dehydrogenase
C reactive protein
24 hour Bence-Jones proteins in urine

Serum protein electrophoresis images

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Monoclonal gammopathy

Serum protein immunofixation images

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IgD lambda myeloma in 68 year old woman

In 20% of cases, only monoclonal light chains (Kappa or Lambda) are present, usually in urine
Rouleux formation in peripheral smear (erythrocytes resemble stacked coins) is due to protein present, parallels erythrocyte sedimentation rate

Radiology description

Disseminated MM has two common radiological appearances,
- Numerous, well circumscribed lytic bone lesions (more common) - punched out lucencies without sclerosis (pepperpot skull or raindrop skull with endosteal scalloping)
- Generalized osteopenia (less common), often associated with vertebral compression fractures

Radiology images

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Skull xray - contributed by Dr. Mark R. Wick

Tibia xray - contributed by Dr. Mark R. Wick

Plasma cell myeloma

Solitary plasma cell myeloma

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Prominent skull defect

Prognostic factors

Overall poor prognosis; < 1 year if multiple lesions and no treatment; many years if indolent
- See Staging
- Median survival is 3 years with chemotherapy; 10% survive 10 years
- Poorer prognosis if plasmablastic morphology, CD10+ , IgA myeloma, β microglobulin, more than 3 lytic bone lesions, hypercalcemia, high IL6
- Unfavorable cytogenetics: t(4;14), t(14;16), t(14;20), del 17p13, hypoploidy, del 13 or aneuploidy
- Patient related factors include age, performance status, renal failure

Case reports

49 year old woman with associated sarcoidosis (Arch Pathol Lab Med 2002;126:365)
52 year old patient with maxillary solitary recurrent plasmacytoma (Chirurgia (Bucur) 2013;108:732)
65 year old woman with initial presentation as maxillary lesion (Med Oral Patol Oral Cir Bucal 2007;12:E344)
70 year old man with bilateral humerus involvement (Rev Med Chir Soc Med Nat Iasi 2013;117:160)
Plasmablastic transformation (Hum Pathol 2003;34:710)

Treatment

Alkylating agent chemotherapy, bone marrow transplantation, anti topoisomerase II alpha agents

Gross description

Multiple masses of soft, red, currant jelly-like material throughout skeletal system; may resemble lymphoma
Generalized osteoporosis

Gross images

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Plasma cell myeloma

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Vertebrae with myeloma lesions

Microscopic (histologic) description

Bone marrow trephine biopsy shows focal, interstitial or diffuse infiltrate, with variable percentage of involvement
Bone marrow biopsies should have > 10% plasma cells to diagnose myeloma
Variable degree of plasmacytic maturation, from plasmablastic to plasma cells
Cells have large nuclei, may be multinucleated
Often with prominent nucleoli, perinuclear hof (due to prominent Golgi apparatus), Mott Cells (blue grapelike inclusions), Russell bodies (cytoplasmic crystalline rods), Dutcher bodies (intranuclear crystalline rods), hyaline inclusions, vacuoles or granules
Reticulin deposition, graulomas, decreased hematopoiesis, increased marrow vascularity may be seen
10% have amyloid in vessel walls or as masses

Microscopic (histologic) images

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Bone marrow - high power

With amyloid production - contributed by Dr. Mark R. Wick

Contributed by Dr. Mark R. Wick

Kappa light chain, contributed by Dr. Mark R. Wick

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Bone marrow - low power

Bone marrow - high power

Bone marrow smear

Flame cell

Plasma cells forming rosettes

Prominent kappa staining

Prominent lambda staining

Sarcoidosis and myeloma

Cytology description

Variable percentage of involvement
Variable morphology of plasma cells: mature, immature, intermediate and plasmablastic
Mature plasma cells have eccentric nucleus, condensed chromatin and perinuclear hof
Dysplastic forms exist showing nucleocytoplasmic asynchrony with mature cytoplasm compared to nuclei showing diffuse chromatin and nucleli, pleomorphism, high N / C ratio, multilobated and convoluted nuclei, multinuclearity, and mitotic figures
Cytoplasm may show basophilia, eosinophilia and flaming crystalline inclusions, Russel body type inclusions, Dutcher body type inclusions
Mott cells may be seen

Peripheral blood images

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Plasma cell

Plasma cells with blastic features

Positive stains

Kappa or lambda light chains (usually one markedly more than the other), CD38 (plasma cells), CD79a, CD138
Variable EMA, variable CD10, may be positive for CD56, CD117, CD52

Negative stains

Keratin, CD45 / LCA, CD19, CD20

Flow cytometry Images

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Prominent monotypic pattern

Molecular / cytogenetics description

del 17p, del 13 or 13q
t(4;14)(p16.3;q32) in 25% of cases, causing increased expression of FGFR3 (fibroblast growth factor receptor 3) and IgH
t(11;14)(q13;q32) [cyclin D1]:
- 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)
Hyperdiploidy and hypoploidy

Differential diagnosis

Lymphoma
Metastatic carcinoma
Osteomyelitis with plasma cell predominance: other inflammatory cells, capillary proliferation, plasma cells not monoclonal
Reactive synovitis with Dutcher bodies (Arch Pathol Lab Med 2002;126:199)