THE IMMUNOPROLIFERATIVE DISORDERS
The immunoproliferative disorders include a group of neoplasms that arise from a clone of im-munoglobulin-secreting cells and produce a monoclonal immunoglobulin (or part of an immunoglobulin). If the monoclonal immunoglobulin (Ig) is of the IgM class, the disease is Waldenstrom’s macroglobulinemia and the malignant cells are plasmacytoid lymphocytes. If the monoclonal immunoglobulin is of the IgG, IgA, IgD, or rarely the IgE class, the disease is multiple myeloma and the malignant cells are plasma cells. Normal plasma cells represent the most specialized cells in the B cell lineage. Figure 54-4 illustrates one scheme of maturation proceeding from a pluripotent stem cell to an early B cell to a well-differentiated plasma cell. The figure also indicates the malignant diseases that can arise from neoplastic proliferation at each stage of B cell maturation.
Plasma cells normally secrete immunoglobulins and are responsible for maintaining humoral immunity. The basic structure of all immunoglobulins is the same and includes two heavy (”H”) polypeptide chains and two light (”L”) polypeptide chains, bound together by disulfide bonds (Fig. 54-9). Both H chains and L chains have “constant” regions of amino acid sequence and “variable” regions that allow for antibody specificity. The five subclasses of immunoglobulin, immunoglobulin gamma (IgG), mu (IgM), alpha (IgA), delta (IgD), and epsilon (IgE) are determined by the constant region of their H chains. Light chains are of two types: kappa and lambda. Each antibody molecule has two identical H chains and two identical L chains; hybrid molecules are not synthesized. Table 54-18 outlines special properties of the five immunoglobulin classes. Protein electrophoresis provides the first step in detecting a monoclonal immunoglobulin in serum (Fig. 54-10). Analysis of the protein “spike” by agar gel immunoelectrophoresis using specific antibodies (e.g., anti-human IgG, anti-kappa chains, etc.) further defines the exact type of monoclonal immunoglobulin.
Monoclonal immunoglobulin elevations can be found in conditions other than multiple myeloma or Waldenstrom’s macroglobulinemia. Approximately 10 per cent of patients with chronic lymphocytic leukemia have monoclonal IgG or IgM spikes in their serum. In addition, a monoclonal spike on serum electrophoresis may be found in patients with no detectable associated disease. The “spike” is usually not large (i.e., is less than 2 gm/dl) and is accompanied by no other clinical or laboratory evidence of multiple myeloma or Waldenstrom’s macroglobulinemia. This finding, called “benign monoclonal gammopathy,” is found in .elderly patients (i.e., over 60); approximately 10 per cent of these patients later develop a true immunoproliferative disorder.
Multiple myeloma is a malignant disease of plasma cells that is characterized by the presence of monoclonal immunoglobulin or light chains in the serum and urine and bone destruction. The typical patient is over 50 and presents with back pain, mild anemia, and an elevated sedimentation rate. Initial bone x-rays may demonstrate only osteoporosis, although widespread lytic lesions are typical. Less frequently the patient will have hypercalcemia and renal disease (”light chain nephropathy”) at the time of diagnosis. Serum immunoelectrophoresis generally demonstrates a monoclonal elevation of one immunoglobulin (e.g., IgGk), with reciprocal depression of the other.
immunoglobulins (e.g., IgA and IgM). Free kappa or lambda light chains (Bence-Jones protein) are usually detected by a 24-hour urine immunoelec-trophoresis. About 20 per cent of patients with multiple myeloma will not have a monoclonal serum spike but will have free light chains detectable in urine and serum (”light chain disease”); about 1 per cent of patients with multiple myeloma will have neither monoclonal nor free light chains detectable. These patients with “nonsecretory” myeloma can be shown to have a malignant clonal proliferation of plasma cells byimmunofluorescent staining of the bone marrow. The plasma cells will be shown to stain with either the anti-kappa or anti-lambda antiserum, but not with both reagents.
Bone marrow aspiration is essential for the diagnosis of myeloma. Plasma cells usually make up less than 5 per cent of bone marrow cells; greater than 20 per cent plasma cells are required to make a bone marrow diagnosis of multiple myeloma. Some of the plasma cells may have bizarre morphology with binucleated and multinucleated plasma cells. The clinical manifestations of multiple myeloma center on the systemic effects of the monoclonal protein (the paraprotein) and the concomitant humoral immunodeficiency state, as well as the effects of the bone and bone marrow invasion by malignant cells. Table 54-19 outlines the common clinical syndromes associated with multiple myeloma. Despite high levels of paraprotein, syndromes of hyperviscosity are rare in myeloma.
The prognosis of multiple myeloma is a reflection of the tumor cell burden. A poor prognosis is associated with a high tumor cell burden, as reflected by anemia, decreased renal function, hypercalcemia, extensive bony involvement, and large monoclonal protein peaks. A patient without any of these poor prognostic criteria may have a median survival of five years; a patient in the poor prognosis category is likely to have a median survival of less than two years.
The treatment of a patient with multiple myeloma requires meticulous attention to supportive care as well as expertise in the administration of chemotherapy. Cautious exercise and ambulation are important to retard bone resorption. Bone lesions may require local radiotherapy to prevent a pathologic fracture. Adequate hydration and avoidance of intravenous dye injection (e.g., for intravenous pyelography) helps to prevent renal failure. Administration of pneumococcal vaccine and early detection and treatment of infections are important in these susceptible patients.
The current chemotherapy of multiple myeloma centers on the use of alkylating agents (single or multiple) and corticosteroids. Improvement in symptoms ensues in the majority of patients. Clinical remission is associated with a decrease of less than one log of tumor cells (e.g., 10″ to 10″). Eradication of all tumor cells aand cure of multiple myeloma is not attainable with available therapy.
Waldenstrom’s macroglobulinemia is a clonal disease of IgM-secreting plasmacytoid lymphocytes. It is a chronic disorder that usually affects older people. The patient commonly presents
with anemia and symptoms due to the physical properties of the elevated monoclonal IgM. IgM is a large molecule and remains primarily in the intravascular space. If the IgM level is elevated, plasma viscosity may be high. Nosebleeds, retinal hemorrhages, mental confusion, and congestive heart failure are clinical presentations of the hyperviscosity syndrome. Some IgM molecules precipitate in the cold. The patient with this type of IgM may manifest the clinical picture of cryoglobulinemia. Blue (cyanotic) fingers, toes, nose, and earlobes on exposure to cold are a typical presentation. Foot and leg ulcers may develop, and vascular occlusion with gangrene may ensue. Leu-kocytoclastic vasculitis is seen on biopsy of these skin lesions. Some IgM molecules may have activity directed against red cells, particularly the “I” antigen (see Hemolytic Anemias). This type of IgM, a cold agglutinin, agglutinates red cells at temperatures below 37°C (e.g., in the extremities). These patients present with Raynaud’s phenomenon and a hemolytic anemia. Keeping patients with cryoglobulinemia or the cold agglutinin syndrome warm is a primary part of their treatment. Peripheral neuropathy is a rare presentation of Waldenstrom’s macroglobulinemia. A few patients have been described in whom the IgM monoclonal protein had antimyelin activity. Splenomegaly and lymphadenopathy may develop during the course of Waldenstrom’s macroglobulinemia but are rarely a major cause of disability. Bone pain and hypercalcemia rarely occur.
The treatment of Waldenstrom’s macroglobulinemia is directed to relief of symptoms. If the symptoms are primarily due to the elevated IgM (e.g., hyperviscosity syndrome), plasmapheresis is a useful tool and may be combined with chemotherapy. If the IgM is a cold agglutinin or a cryoglobulin, the plasmapheresis must be done in a warm environment. Chemotherapy (e.g., alkylating agents) may be useful to decrease the lymphadenopathy and splenomegaly but does not alter the natural history of the disease. The median survival is about three years, although some patients may live ten or more years with indolent disease.
Rarely, a patient may present with heavy chain disease, a disorder that has some characteristics of myeloma or Waldenstrom’s macroglobulinemia but behaves clinically more like lymphoma. Analysis of the serum reveals only the heavy chain of IgG, IgA, or IgM. Gamma chain disease is associated with lymphadenopathy and edema of the soft palate. Alpha chain disease (”Mediterranean lymphoma”) is characterized by intestinal infill tration by lymphoma; mu chain disease is associated with chronic lymphocytic leukemia.