Porth's Essentials of Pathophysiology, 4e

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Disorders of White Blood Cells and Lymphoid Tissues

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with MGUS will go on to develop a plasma cell dyscrasia (multiple myeloma or lymphoplasmacytic lymphoma). The strong link between MGUS and multiple myeloma suggests that a first oncogenic event produces MGUS and a second event results in multiple myeloma. 4 Multiple Myeloma Multiple myeloma is a B-cell malignancy of terminally differentiated plasma cells. 48–52 It accounts for 1% of all cancers in Western countries. Its incidence is higher in men and people of African-American descent. 4 It occurs most frequently in the elderly, with incidence peaking at the age of 63 to 70 years. Pathogenesis. Multiple myeloma is characterized by proliferation of malignant plasma cells in the bone mar- row and osteolytic bone lesions throughout the skeletal system. As with other hematopoietic malignancies, it is now recognized that multiple myeloma is associated with chromosomal abnormalities, including deletions of 13q and translocations involving the IgG locus on chro- mosome 14. 7 Changes also occur in the bone marrow microenvironment, including the induction of angio- genesis, the suppression of cell-mediated immunity, and the development of paracrine signaling loops involving cytokines such as IL-6 and vascular endothelial growth factor (VEGF). Other growth factors that are impli- cated in multiple myeloma include granulocyte-CSF, interferon- α , and IL-10. One of the characteristic features resulting from the proliferating neoplastic plasma cells in multiple myeloma is the unregulated production of an abnormal monoclonal paraprotein referred to as the M protein because it is detected as an M spike on protein electro- phoresis. In most cases the M protein is either IgG or IgA. In some cases, the plasma cells produce only the light chains of the immunoglobulin molecule. Because of their low molecular weight, the light chains are readily excreted in the urine, where they are termed Bence Jones proteins. More commonly, however, malignant plasma cells produce both complete immunoglobulins and free light chains; therefore, both M proteins and Bence Jones proteins are present. The excess light chains are directly toxic to renal tubular structures and are an important aspect of the pathophysiology of multiple myeloma. Manifestations. The main sites involved in multiple myeloma are the bones and bone marrow (Fig. 11-10). In addition to the abnormal proliferation of mar- row plasma cells, there is proliferation and activation of osteoclasts, which leads to bone resorption and destruction. This increased bone resorption predisposes the individual to pathologic fractures and hypercalce- mia. Very high concentrations of paraproteins may cause a hyperviscosity of body fluids. The light-chain component may break down into amyloid, a protein- aceous substance deposited between cells, causing heart failure and nephropathy. Renal involvement, gener- ally called myeloma nephrosis , is a distinctive feature

Failure of antibody production • Recurrent infections Plasma cell secretion of paraproteins • Hyperviscosity of body fluids • Amyloid deposits in heart and kidney

Osteolytic bone lesions • Bone pain • Hypercalcemia • Pathologic fractures Bone marrow infiltration • Thrombocytopenia (purpura)

Renal failure

Proteinuria • Bence Jones protein

Bone marrow infiltration

M protein spike (serum)

• Anemia (fatigue, pallor) • Neutropenia (decreased resistance to infection)

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Ab a 1

b g

FIGURE 11-10. Clinical features of multiple myeloma.

of multiple myeloma. Although multiple myeloma is characterized by excessive production of monoclonal immunoglobulin, levels of normal immunoglobulins are usually depressed. This contributes to a general suscep- tibility to recurrent bacterial infections. The malignant plasma cells also can form plasmacy- tomas (plasma cell tumors) in bone and soft tissue sites. The most common site of soft tissue plasmacytomas is the gastrointestinal tract. The development of plasmacy- tomas in bone tissue is associated with bone destruction and localized pain. Osteolytic lesions and compression fractures may be seen in the axial skeleton and proximal long bones. Occasionally, the lesions may affect the spi- nal column, causing vertebral collapse and spinal cord compression. Bone pain is one of the first symptoms to occur in approximately three fourths of all individuals diagnosed with multiple myeloma. Bone destruction also impairs the production of erythrocytes, leukocytes, and throm- bocytes. This predisposes the patient to anemia, recur- rent infections, and thrombocytopenic purpura. Many patients experience weight loss and weakness. Renal insufficiency occurs in 50% of patients. Neurologic manifestations caused by neuropathy or spinal cord compression also may be present.