Pathology > Basic Hematology > White Cell Disorders > Immunosecretory Disorders: Myeloma

Immunosecretory Disorders: Myeloma

The most common of the malignant plasma cell disorders is myeloma. Myeloma is a proliferation of plasma cells, mainly in the bone marrow, causing lytic bone lesions.

Myeloma is a generalized disorder, leading to bone destruction, marrow and renal failure, extraosseous involvement, neurologic complications, and in <10% hyperviscosity or amyloidosis.

Disorders Associated with Monoclonal Gammopathies

Myeloma

14 %

Primary amyloidosis

9 %

Macroglobulinemia-Waldenstrom's

7 %

Chronic lymphocytic leukemia

2 %

Plasmacytoma

1 %

*Monoclonal gammopathy of unknown significance

67 %

*Nearly 70% of monoclonal gammopathies have no underlying cause. These are the monoclonal gammopathies of unknown significance (MGUS). MGUS is seen in 5% of people >70yrs of age. About 10% of MGUS patients develop myeloma within 5 years.

 

In 1990 there were an estimated 11,800 new cases of myeloma in the US or approximately 3 cases/100,000 persons.

Myeloma is rare before the age of 40 (<2% under 40), but thereafter increases steadily with age. Myeloma is much more common in blacks than whites (14:1).

The clinical disease is, for the most part, a result of the increasing plasma cell mass and excess immunogobulin.

Common signs and (symptoms) of PCDs include anemia; lytic bone lesions (bone pain & pathologic fractures); hypercalcemia (mental status D, renal calculi, bone pain & abdominal cramping); increased serum Ig (hyperviscosity syndrome, Raynaud's phenomenon (severe intermittent pallor of digits), bleeding, confusion) and renal failure.

Decreased production of normal Igs produces a high risk of bacterial infection (especially pneumococcal infection).

The clinical disease is, for the most part, a result of the increasing plasma cell mass and excess immunogobulin. Common signs and (symptoms) of PCDs include anemia; lytic bone lesions (bone pain & pathologic fractures); hypercalcemia (mental status D, renal calculi, bone pain & abdominal cramping); increased serum Ig (hyperviscosity syndrome, Raynaud's phenomenon (severe intermittent pallor of digits), bleeding, confusion) and renal failure. Decreased production of normal Igs produces a high risk of bacterial infection (especially pneumococcal infection).

The standard "workup" for a monoclonal gammopathy begins with serum protein electrophoresis (SPEP) and a 24 hour urine for total protein and protein electrophoresis to confirm the presence of a monoclonal protein.

Urine protein eletrophoresis is important because monoclonal spikes in urine are virtually diagnostic of an immunoproliferative malignancy.

Immunoelectrophoresis (IEP) of the serum and/or urine identifies the heavy and light chain characteristics of the monoclonal protein ie., a monoclonal IgA kappa protein.

Radiographic bone surveys may identify lytic lesions - often multiple and pathologic fractures.

Bone marrow aspirate/biopsy and peripheral blood CBC evaluate marrow function.

Chemistry studies evaluate renal function (BUN,creatinine, creatinine clearance) and total protein,albumin, calcium, and uric acid.

Other studies such as serum viscosity, b-2 microglobulin, ESR, and biopsy may be useful in your patient evaluation.

The malignant proliferation of plasma cells we call myeloma is characterized by multiple* lytic bone lesions resulting from the physical expansion of masses of plasma cells (click button below for elaboration) and, more importantly, the plasma cell secretion of an osteoclast activating factor (OAF) causing bone resorption leading to lytic lesions. Bone pain, pathologic fractures (fractures caused by ordinary activities), and hypercalcemia may result.

Painful vertebral compression fractures are common (gross photo & X-ray). Epidural masses are common and cause spinal cord compression, for which prompt diagnosis and decompression is crucial.

Roetgenograms show "punched out" lucent lesions secondary to the bone destruction.

Plasma cell masses often infiltrate the kidney, liver and spleen.

*The term "mutiple myeloma" derives from the presence of multiple plasma cell lesions.

Bone marrow aspiration and biopsy reveals increased numbers of plasma cells (classically >30%, but may be only 10-30%), often forming clusters or sheets of cells replacing normal marrow elements. This results in anemia, leukopenia, and thrombocytopenia.

The growth factor IL-6 is produced in excess in MM and correlates with the proliferation of myeloma cells.

The plasma cells seen in the marrow can be mature - with classic PC features or immature - with prominent nucleoli.

Binucleate and multinucleate PCs can be seen. Masses of immunoglobulin may form intracytoplasmic globules or Russell bodies.

 

Myeloma cells may also contain crystalline inclusions of immunoglobulin (below left).

Cells containing multiple immunoglobulin globules are known as Mott cells (below right).

The excessive production of an abnormal immunoglobulin is the second major characteristic of myeloma. The abnormal Ig is most often IgG (50%) and sometimes IgA (25%), but rarely (<1%) IgM,IgD, or IgE. Production of excess light chain is frequent and is excreted in the urine as Bence Jones proteins. About 20-25% of cases produce only light chains which are often detectable only in the urine. Fewer than 5% of myelomas are nonsecretory.

I mmunoglobulin filled cytoplasm may invaginate into the nucleus creating the appearance of an intranuclearinclusion (a Dutcher body).

 

Excess Ig in the peripheral blood may result in Rouleaux formation in which immunoglobulin coated RBCs cling together (resembling overlapping pennies). The ESR may be increased secondary to hyperviscosity.

Hyperviscosity is most common with IgM, but can be seen with polymerization of IgA and IgG3.

M-proteins can interfere with clotting factors and fibrin polymerization, and can block aggregation by coating platelets.

 

In approximately 75% of patients excess immunoglobulin light chain precipitates in renal tubules forming dense tubular casts and leads to tubular cell atrophy and destruction in a condition known as "myeloma kidney".

Although we think of Ig as being in plasma, remember that the majority of Ig is extravascular.

 

In about10% of myeloma patients a waxy substance known as amyloid is deposited in vessel walls and extravascular tissues secondary to excess light chain (usually l) production. Amyloid stains lightly eosinophilic with H&E, red-orange with Congo Red, and is birefringent when polarized.

Amyloid stained with Congo red.

Polarized birefringent amyloid.

The EM appearance of amyloid is that of a mass of nonbranching linear fibrils of indeterminant length, 7-10 nm dia.

Accumulation of amyloid primarily in glomeruli, but also in vessels and interstium is a major cause of renal failure and death.

Heart failure is 2' to amyloid deposition in the conduction system.

GI tract infiltration can cause macroglossia, hemorrhage, malabsorption, diarrhea, and obstruction. Vascular damage results in amyloid purpura of the face (eyelids & periorbital tissue), neck and chest. Soft tissue accumulation may lead to the carpal tunnel syndrome.

 

The major diagnostic criteria for myeloma (any two are needed for the diagnosis) include:

- bone marrow plasmacytosis of > 30% of all marrow cells or masses of infiltrating plasma cells
- extraosseous plasmacytoma
- monoclonal gammopathy ( IgG > 35 g/L and IgA > 20 g/L )
- urinary light chain excretion of > 1g / 24 hours

Minor criteria (one or more of which together with one major criteria are needed for the diagnosis) include

- marrow plasmacytosis of < 30%
- lytic bone lesions
- evidence of a monoclonal protein but lessor amounts than above
- hypoglobulinemia of normal proteins

The prognosis for myeloma is highly variable, but left untreated, most patients survive only 6-18 months. Survival correlates with the extent of disease at diagnosis.

Myeloma Staging

Stage I

Stage II

Stage III

all criteria must be meet

-Hgb >100g/L
-normal serum Ca
-normal bone X-ray or
single bone plasmacytoma
-sm amounts of monoclonal Ig
-IgG < 50g/L
-IgA < 30g/L
-urine light chain<4g/24hr
low myeloma cell mass

neither Stage I or II

intermediate myeloma cell mass

one or more criteria needed
-Hgb < 85g/L
-serum Ca > 12mg/dL
-multiple lytic bone lesions
-large amounts of monoclonal Ig
-IgG > 70g/L
-IgA > 50g/L
-urine light chain>12g/24hr
high myeloma cell mass

Median survival is approximately 6.5 years for stage I myeloma; 5 years for stage II myeloma, and 2 years for stage III myeloma.

 

b2 macroglobulin is another prognostic factor that is predictive of prognosis: levels greater than 6mg corresponding to stage II or III disease. The presence of amyloid, an IgA M-protein, or CD10 + myeloma cells are poor prognositic factors.

During the early stages of myeloma, especially in asymptomatic patients, the doubling time is long and growth slow, thus initially one may forego treatment.

Classic myeloma requires treatment for pain, hypercalcemia, renal failure or anemia. Although no curative therapy exists, a number of theraputic modalities are available. While surgery and radiotherapy play a role in treatment of spinal cord compression and pathologic fractures, chemotherapy is the primary basis of therapy. Standard chemotherapy is remains prednisone and L-phenylalanine mustard (Alkeran) or melphalan. Supportive therapy for dealing with hypercalcemia, infection, and hyperviscosity is essential to good patient care.

Death is most often secondary to infection or renal failure.

 

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