Plasma Cell Neoplasms and Related Disorders

• These B-cell proliferations contain neoplastic plasma cells that virtually always secrete a monoclonal Ig or Ig fragment, which serve as tumor markers and often have pathologic consequences.

• The most common and deadly of these neoplasms is multiple myeloma.

• A monoclonal Ig identified in the blood is referred to as an M component, in reference to myeloma.

• Because complete M components have molecular weights of 160,000 or higher, they are restricted to the plasma and extracellular fluid and excluded from the urine in the absence of glomerular damage.

• neoplastic plasma cells often synthesize excess light chains along with complete Igs.

• Occasionally only light chains are produced, and rare tumors secrete only heavy chains.

• In patients with plasma cell tumors, the level of free light chains is usually elevated and is markedly skewed toward one light chain (e.g., kappa) at the expense of the second (e.g., lambda).

• Because free light chains are small in size, they are also excreted in the urine, where they are referred to as Bence-Jones proteins.

• Terms used to describe the abnormal Igs associated with plasma cell neoplasms include monoclonal gammopathy, dysproteinemia, and paraproteinemia.

• These abnormal proteins are associated with the following clinicopathologic entities:

- Multiple myeloma (plasma cell myeloma)- Plasmacytoma- Smoldering myeloma (lack of symptoms)- Waldenström macroglobulinemia (high levels of IgM ,

hyperviscosity of the blood)- Heavy-chain disease- Primary or immunocyte-associated amyloidosis- Monoclonal gammopathy of undetermined significance (MGUS)

Multiple Myeloma

• Multiple myeloma is a plasma cell neoplasm commonly associated with:

- lytic bone lesions,

- hypercalcemia,

- renal failure,

- and acquired immune abnormalities.

It is chiefly a disease of older adults, with a peak age of incidence of 65 to 70 years.

• Pathogenesis:- Multiple myeloma is associated with frequent rearrangements involving the IgH locus and various proto-oncogenes.- The proliferation and survival of myeloma cells are dependent on several cytokines, most notably IL-6. It is produced by the tumor cells themselves and by resident marrow stromal cells.- Myeloma cell growth and survival are also augmentedby direct physical interactions with bone marrow stromalcells.- Factors produced by neoplastic plasma cells mediate bone destruction, the major pathologic feature of multiple myeloma

• MORPHOLOGY:- Multiple myeloma usually presents as destructive plasmacell tumors (plasmacytomas) involving the axial skeleton.- The bones most commonly affected (in descending order offrequency) are the vertebral column, ribs, skull, pelvis, femur,clavicle, and scapula. - Lesions begin in the medullary cavity, erode cancellous bone, and

progressively destroy the bony cortex, often leading to pathologic fractures; these are most common in the vertebral column, but may occur in any affected bone.

- Less commonly, widespread myelomatous bone disease produces diffuse demineralization (osteopenia) rather than focal defects.

• the marrow contains an increased number of plasma cells, which usually constitute more than 30% of the cellularity.

• Relatively normal-appearing plasma cells, plasmablasts with vesicular nuclear chromatin and a prominent single nucleolus, or bizarre, multinucleated cells may predominate.

• flame cells

• Mott cells

• Russell bodies

• Dutcher bodies

Flame cell

Mott cells

Russell bodies

Dutcher bodies

• the high level of M proteins causes red cells in peripheral blood smears to stick to one another in linear arrays, a finding referred to as rouleaux formation.

• Rouleaux formation is characteristic but not specific, as it may be seen in other conditions in which Ig levels are elevated, such as lupus erythematosus and early HIV infection.

• Bence Jones proteins are excreted in the kidney and contribute to a form of renal disease called myeloma kidney.

• Clinical Features:

The clinical features of multiple myeloma stem from:

(1) the effects of plasma cell growth in tissues, particularly the bones;

(2) the production of excessive Igs, which often have abnormal physicochemical properties;

(3) the suppression of normal humoralimmunity.

• Bone resorption often leads to pathologic fractures and chronic pain.

• hypercalcemia can give rise to neurologic manifestations (confusion, weakness, lethargy, constipation, and polyuria), and contributes to renal dysfunction.

• Decreased production of normal Igs sets the stage for recurrent bacterial infections. Cellular immunity is relatively unaffected.

• renal insufficiency, occurs in up to 50% of patients, the single most important factor seems to be Bence-Jones proteinuria, as the excreted light chains are toxic to renal tubular epithelial cells.

• amyloidosis

• Marrow involvement often gives rise to a normocytic normochromic anemia, sometimes accompanied by moderate leukopenia and thrombocytopenia

• In 99% of patients, laboratory analyses reveal increased levels of Igs in the blood and/or light chains (Bence-Jones proteins) in the urine.

• The monoclonal Igs are usually first detected as abnormal protein “spikes” in serum or urine electrophoresis and then further characterized by immunofixation.

• more than 3 gm/dL of serum Ig

• and/or more than 6 mg/ dL of urine Bence-Jones protein.

• The most common monoclonal Ig (“M protein”) is IgG (approximately 55% of patients), followed by IgA (approximately 25% of cases). Myelomas expressing IgM, IgD, or IgE occur but are rare.

• Both free light chains and a serum M protein are observed together in 60% to 70% of patients.

• However, in about 20% of patients only free light chains are present. Around 1% of myelomas are nonsecretory; hence, the absence of detectable M proteins does not completely exclude the diagnosis.

definitive diagnosis requires a bone marrow examination.

• The median survival is 4 to 7 years, and cures have yet to be achieved

• Patients with multiple bony lesions, if untreated, rarely survive for more than 6 to 12 months, whereas patients with “smoldering myeloma” may be asymptomatic for many years.

• Treatment:

- Proteasome inhibitors (misfolded proteins activate apoptotic pathways)

- Thalidomide and related compounds (protein degradation)

- Biphosphonates

Solitary Myeloma (Plasmacytoma)

• Solitary osseous plasmacytoma almost inevitably progresses to multiple myeloma, but this can take 10 to 20 years or longer.

• extraosseous plasmacytomas, particularly those involving the upper respiratory tract, are frequently cured by local resection.

Smoldering Myeloma

• Plasma cells make up 10% to 30% of the marrow cellularity

• the serum M protein level is greater than 3 gm/dL

• patients are asymptomatic.

• About 75% of patients progress to multiple myeloma over a 15-year period.

Monoclonal Gammopathy of Uncertain Significance.

• patients are asymptomatic

• the serum M protein level is less than 3 gm/dL.

• Approximately 1% of patients with MGUS develop a symptomatic plasma cell neoplasm, usually multiple myeloma, per year,

• MGUS is an early stage of myeloma development.