Primary or immunocyte-associated amyloidosis results from a monoclonal proliferation of plasma cells secreting light chains that are deposited as amyloid. Some http://ebooksmedicine.net patients have overt multiple myeloma, but others have only a minor clonal population of plasma cells in the marrow.
• Waldenström macroglobulinemia is a syndrome in which high levels of IgM lead to symptoms related to hyper-viscosity of the blood. It occurs in older adults, most commonly in association with lymphoplasmacytic lymphoma (described later).
With this background, we now turn to some of the specific clinicopathologic entities. Primary amyloidosis was discussed along with other disorders of the immune system in Chapter 5.
Multiple myeloma is one of the most common lymphoid malignancies; approximately 20,000 new cases are diagnosed in the United States each year. The median age at diagnosis is 70 years, and it is more common in males and in people of African origin. It principally involves the bone marrow and usually is associated with lytic lesions throughout the skeletal system.
The most frequent M protein produced by myeloma cells is IgG (60%), followed by IgA (20%–25%); only rarely are IgM, IgD, or IgE M proteins observed. In the remaining cases, the plasma cells produce only κ or λ light chains. Because free light chains are small in size, they are also excreted in the urine, where they are referred to as Bence Jones proteins. In many cases, the malignant plasma cells secrete both complete immunoglobulins and free light chains and thus produce both M proteins and Bence Jones proteins. As described later, the excess light chains have important pathogenic effects.
As with most other B cell malignancies, myeloma often has chromosomal translocations that fuse the IgH locus on chromosome 14 to oncogenes such as the cyclin D1 and cyclin D3 genes. As might be surmised from this, dysregulation of D cyclins is common in multiple myeloma and is believed to contribute to increases in cell proliferation. Proliferation of myeloma cells also is supported by the cytokine interleukin 6 (IL-6), which is produced by fibroblasts and macrophages in the bone marrow stroma. Late in the course, translocations involving MYC are sometimes observed, particularly in patients with aggressive disease.
Multiple myeloma has a number of untoward effects on the skeleton, the immune system, and the kidney, all of which contribute to morbidity and mortality:
Factors produced by neoplastic plasma cells mediate bone destruction, the major pathologic feature of multiple myeloma. Of particular importance, myelomaderived factors upregulate the expression of the receptor activator of NF-κB ligand (RANKL) by bone marrow stromal cells, which in turn activate osteoclasts. Other factors released from tumor cells are potent inhibitors of osteoblast function. The net effect is increased bone resorption, leading to hypercalcemia and pathologic fractures.
Myeloma causes defects in humoral immunity. Through still-uncertain mechanisms, myeloma cells compromise the function of normal B cells. Ironically, although the plasma has elevated levels of immunoglobulin owing to the presence of an M protein, the production of functional antibodies often is profoundly depressed. As a result, patients are at high risk for bacterial infections.