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INTRODUCTIONA. Definition. Plasma cell dyscrasias (= monoclonal gam mopathies = paraproteinemias) are malignancies of the B lymphocyte system. Common plasma cell dysplasias include multiple myeloma and Waldenstrom's macro globulinemia.
B. Clinical manifestations of plasma cell dyscrasias
I. The clinical manifestations of all plasma cell dyscra sias result from:
a. Proliferation of the neoplastic cells and invasion of various organs
b. Secretion of cell products (either immunoglobu lins or subunits)
c. The host's response to the tumor
2. Patients with plasma cell dyscrasias often have M (monoclonal) components in their serum.
a. The M component represents the immunoglobu lin (or light or heavy chain) that is being secreted and can be quantitated by performing serum pro tein electrophoresis. Qualitative assessment is made using immunoelectrophoresis.
b. M components are not specific to plasma cell dyscrasias. They are also seen in leukemia, lymphoma, sarcoidosis, rheumatoid arthritis. monoclonal gammopathy of uncertain signifi cance (MGUS), and other diseases.
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MULTIPLE MYELOMAA. Epidemiology. Myeloma accounts for 1 % of all malignant disease and more than 1 0% of hematologic malignancies in the United States.
1. It is a disease of older people; the median age at diagnosis is 61 years.
2. The incidence in African-Americans is twice that in Caucasians.
B. Clinical manifestations of multiple myeloma. The most common presenting symptoms are related to anemia, bone pain, and infection. The important clinical manifes tations of multiple myeloma can be remembered using the mnemonic, "PLASMA":
376 Chapter 66 Important Clinical Manifestations of Multiple Myeloma ("PLASMA")
Proteinuria/renal insufficiency Lytic bone lesions and hypercalcemia Anemia and Abnormal bleeding Sepsis and infections
Marrow involvement
Amyloidosis
1. Proteinuria/renal insufficiency is multifactorial in eti ology, with causes including light-chain proteinuria, hypercalcemia, hyperuricemia, amyloidosis, and py elonephritis.
2. Lytic bone lesions and hypercalcemia. Bone pain
occurs in 70% of patients, usually involving the back and ribs. Because the lesions are lytic, plain radio graphs are better than bone scans.
3. Anemia and abnormal bleeding. The majority of pa
tients will have anemia (usually normocytic) due to various causes. Paraproteinemias may cause platelet
dysfunction, leading to abnormal bleeding.
4. Sepsis and infections. Seventy-five percent of. pa tients will have a serious infection at some tIme, primarily either pneumonia (due to Streptococcus pneumoniae, Staphylococcus aureus. Haemophilus influenzae, or Klebsiella pneumoniae) or pyelone phritis (due to Escherichia coli or other gram-nega tive rods).
5. Marrow involvement. The bone marrow is infiltrated by plasma cells, which initially causes anemia and may lead to bone marrow failure. The extent of mar row plasmacytosis ranges from 5%-100%.
6. Amyloidosis develops in a minority of patients and may lead to carpal tunnel syndrome, congestive heart failure (CHF), or liver disease.
C. Laboratory findings
1. Proteinuria may be evident on urinalysis, bur the dipstick is often negative because it tests for albumin, not globulin.
2. Anemia is usually normocytic and normochromic, and rouleau formation may be noted on the periph eral smear.
3. Narrow anion gap. Because globulin is cationic, the
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Plasma Cell Dyscrasias 377
increased unmeasured cations decrease the anion gap.
4. Low serum bicarbonate. A type 2 renal tubular acido
sis may result from proximal tubular damage as a result of filtered light chains.
5. Pseudohyponatremia may result from increased
paraprotein, which can cause laboratory errors.
6. Hypercalcemia may occur from increased osteo
clast activity.
7. Elevated erythrocyte sedimentation rate (ESR). The ESR is frequently elevated, but this is a nonspe cific finding.
D. Approach to the patient
1. Protein electrophoresis on serum and urine is usually ordered based on suspicious symptoms, signs, or lab oratory test results.
a. Procedure. Albumin and a, {3, and l' globulin
are separated by differing mobilities in an elec tric field. In myeloma, increased paraprotein causes an abnormal spike (usually in the (3 or 1' region).
b. Results. When used together, serum and urine
protein electrophoresis will miss approximately 1 % of myeloma patients (those that are minimal or nonsecretors). However, of patients who have a variant of myeloma (solitary bone plasmacy toma or extramedullary plasmacytoma), fewer than 30% will have a positive protein electropho resis.
(1) Serum protein electrophoresis will confirm the diagnosis of myeloma in 80%-90% of pa tients. Approximately two-thirds of patients with positive serum protein electrophoresis results will also test positive on urine protein electrophoresis.
(2) Urine protein electrophoresis. In the re maining patients, only the light chain is se creted. The light chain can only be detected using urine protein electrophoresis.
378 Chapter 66
HOT
The diagnosis of myeloma is usually established by the following triad:
K E Y
• Marrow plasmacytosis > 1 0%
• Lytic bone lesions
• M component in serum (usually > 3 g/dl) or urine
IgG (50% of patients)
IgA (25% of patients)
Light chains only (20% of patients)
IgD ( l % of patients)
3. Immunoelectrophoresis is then perfonned to deter mine if the abnonnal spike is polyclonal or mono clonal.
HOT
K E Y
a. A polyclonal spike is seen in reactive conditions (e.g., infection, malignancy, collagen vascular disease).
b. A monoclonal (M component) spike often signi
fies myeloma, but may also be found in many other conditions (e.g., chronic lymphocytic leu kemia, lymphoma, sarcoidosis). Therefore, this test should not be used to screen asymptomatic patients because the clinical setting is critical to interpreting the test correctly.
An IgG spike > 3.5 g/dl or an IgA spike > 2 g/dl almost always represents myeloma (ond will therefore be monoclonal when tested by immunoelectropho. resis).
4. Differential diagnosis. The main disorder to distin guish from myeloma is MGUS. Characteristics of MGUS usually include:
a. M component usually < 2 g/dl b. Absence of Bence Jones proteinuria
c. Marrow plasmacytosis < 5%
d. Absence of anemia, renal disease, hypercalce mia, and bone lesions
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Plasma Cell Dyscrasias 379
HOT
In approximately 1 0%-25% of patients, MGUS prog resses to multiple myeloma (over many years or de cades).
K E Y
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E. Treatment. Unless the patient undergoes bone marrow transplant, the goal is primarily palliation.
L Chemotherapy. Various chemotherapeutic regimens are available for patients with symptomatic my eloma.
2. Radiation is also used for bone lesions.
F. Prognosis. Median survival without treatment is 6 months; with treatment, survival is extended to 3 years. Tumor burden is an important predictor of survival.
1. Patients with a low tumor burden (i.e., IgG spike < 5 gldl, no more than one lytic lesion, and absence of severe anemia, renal failure, or hypercalcemia) have a median survival of approximately 5 years. 2. Those with a high tumor burden (IgG spike > 7 g/dl,
serum calcium > 12 mg/dl, more than three lytic lesions, or a hematocrit < 25%) have a median sur vival of approximately 1 year.
WALDENSTROM'S MACROGLOBULINEMIA. In Walden
strom's macroglobulinemia, the abnonnal cells are a hybrid between lymphocytes and plasma cells.
A. Clinical manifestations of Waldenstrom's macroglobu linemia. The hybrid cells secrete IgM, which accounts for most of the clinical manifestations. The clinical mani festations are similar to those of myeloma; however, there are important differences.
1. Hyperviscosity is much more common in Walden strom's macroglobulinemia than in multiple my eloma. Symptoms may include altered mental status, visual disturbances, and mucosal bleeding.
2. Hepatomegaly, adenopathy, and splenomegaly are commonly seen in Waldenstrom's macroglobulin emia, but not in myeloma.