CHAPTER 104 PLASMA CELL NEOPLASMS: GENERAL CONSIDERATIONS
CHAPTER 104 PLASMA CELL NEOPLASMS: GENERAL CONSIDERATIONS
STEPHEN M. BAIRD
Definition and History
Plasma Cell Neoplasms
Essential Monoclonal Gammopathy
Chronic Cold Agglutinin Syndrome
Transient M Proteins
Etiology and Pathogenesis
Immunoelectrophoresis and Immunofixation Electrophoresis
Immunoglobulin Gene Rearrangements
Quantitative Immunoglobulin Assays
Plasma cell neoplasms are monoclonal tumors of plasma cells and their precursors. It is important to distinguish these conditions from conditions that are considered benign and that do not require specific therapy. Although monoclonal immunoglobulin protein generally is detected in plasma cell myeloma, other conditions also may result in the production of a relative excess of monoclonal immunoglobulin. This chapter summarizes the laboratory studies that are used to evaluate for monoclonal proteinemia or monoclonal immunoglobulin gene rearrangements. This chapter also delineates laboratory features that can be used to distinguish plasma cell myeloma from related conditions that may give rise to a relative excess of monoclonal immunoglobulin. This chapter provides references to relevant chapters in the textbook that focus on a particular plasma cell or B-cell disorder.
Acronyms and abbreviations that appear in this chapter include: CSF, cerebrospinal fluid; EBV, Epstein-Barr virus; GM-CSF, granulocyte-monocyte colony stimulating factor; IFN-a, interferon alpha; IL-6, interleukin-6; KSHV, Kaposi’s-sarcoma-associated herpesvirus; MGUS, monoclonal gammopathy of undetermined significance; MHC, major histocompatibility complex; OAF, osteoclast activating factor.
DEFINITION AND HISTORY
PLASMA CELL NEOPLASMS
Plasma cell neoplasms are monoclonal tumors comprised of plasma cells and their precursors. All the differentiated cells within such a neoplasm produce the same whole immunoglobulin chain or chain fragment. In a given neoplasm the monoclonal proteins generally have the same heavy-chain class (g, a, µ, d, or e), same light-chain (k or l), and same idiotypes (or antigenic determinants of the immunoglobulin variable regions, see Chap. 83).1 The neoplastic plasma cells and their precursor small lymphocytes have the same immunoglobulin gene rearrangements and chromosomal anomalies, if any are present.2,3,4 and 5 Since Henry Bence Jones first discovered what turned out to be monoclonal light chains in the urine of multiple myeloma patients 150 years ago,6 the monoclonal immunoglobulin molecules (or their constituent chains) produced by plasma cell neoplasms have remained the best examples of tumor-specific antigens in the entire field of oncology. These proteins are usually called M proteins, which at various times in history has stood for malignant, myeloma, and now, monoclonal proteins. The diseases associated with M proteins are listed in Table 104-1. Some are benign and nonprogessive, while some are frankly malignant.
TABLE 104-1 DISEASES ASSOCIATED WITH M PROTEINS
ESSENTIAL MONOCLONAL GAMMOPATHY
The term benign must be used with caution when describing monoclonal gammopathies in patients who do not have overt malignant plasmacytoma or multiple myeloma. Clinical and laboratory features consistent with essential monoclonal gammopathy are an M protein level less than 2.5 g/dl, few or no monoclonal light chains in the urine, and no anemia or change in serum calcium (Table 104-2). There are no bony lesions on skeletal surveys, and the plasmacytosis in the marrow, if present, is less than 30 percent.12,13 The concept that this condition is benign is based on its generally indolent biologic behavior. However, a low but significant percentage of patients with monoclonal gammopathy develop frank B-cell malignancies each year.7,8,9,10 and 11 For this reason, the term benign monoclonal gammopathy largely has been replaced by the term essential monoclonal gammopathy (see Chap. 105).
TABLE 104-2 SOME BIOLOGICAL FEATURES OF MONOCLONAL GAMMOPATHY
CHRONIC COLD AGGLUTININ SYNDROME
Chronic cold agglutinin syndrome is a disease in which elderly patients produce a monoclonal IgM molecule that binds red blood cells and causes their agglutination at temperatures significantly below 37°C (98.6°F) (see Chap. 56). It may be seen in patients without other apparent evidence of malignant disease, in patients with lymphoma (see Chap. 103), or in patients with Waldenström macroglobulinemia (see Chap. 108). The apparently benign form of the disease also may progress to malignancy.19,20 This disorder bears no relationship to acute, postinfectious cold agglutinin syndrome, in which the offending immunoglobulins are polyclonal and disappear after the inciting infectious agent is eradicated.
Cryoglobulins are complexes of immunoglobulins that precipitate on exposure to cold (see Chap. 108).21 Three classes of cryoglobulins have been recognized for convenience of description. Type 1 cryoglobulins are monoclonal IgM, IgG, or IgA molecules. Type 2 cryoglobulins are monoclonal immunoglobulins, usually of the IgM class, with antibody activity against other immunoglobulins, usually IgG. An association of type 2 cryoglobulins with hepatitis B and C infection has been reported.21,22 and 23 Type 3 cryoglobulins are composed of polyclonal immunoglobulins with anti-immunoglobulin activity. Cryoglobulins may cause a variety of pathologic conditions, all related to the formation of immune complexes and the attendant inflammation and coagulation disorders. They are detected by allowing serum to stand and precipitate at 4°C (39.2°F) for 24 to 72 h.
TRANSIENT M PROTEINS
Transient M proteins occasionally may be associated with inflammation (see Chap. 105).24,25 and 26 Molecules also have been described in hyperimmunized laboratory animals. They do not progress to malignant disease and are not always high-affinity antibodies to the presumed cause of inflammation or experimental immunogen.
Patients with any of a variety of congenital immunodeficiencies in which the T-cell arm of immunity is more affected than the B-cell arm may develop transient, low-level monoclonal gammopathies, typically of the IgM class (see Chap. 105). These have become apparent as more-sensitive techniques for their detection have been developed. Immunodeficient patients receiving marrow transplants also frequently exhibit a transient monoclonal gammopathy early in their posttransplant course.27,28 If the patient or donor is infected with Epstein-Barr virus (EBV), the gammopathy may be oligoclonal and herald the development of an EBV-driven lymphoproliferative disorder that may be fatal.
The incidence of multiple myeloma in individuals over 25 years of age is about 30 per 100,000. The incidence of monoclonal gammopathy is about 100 times as high, and the transient monoclonal gammopathies associated with all the various forms of inflammation and immunodeficiency are about 400 times more frequent.15 All rise dramatically with age. The monoclonal gammopathies in immunodeficient hosts occur at a much younger age than multiple myeloma or monoclonal gammopathy.
ETIOLOGY AND PATHOGENESIS
In the mouse, the genetic background of the animal is an important risk factor for developing monoclonal gammopathy or plasmacytomas. About 60 percent of C57BL/Ka mice develop M proteins of the IgM class by 21 months of age. Also, about 40 percent of C3H and NZB mice develop M proteins of the IgM class. However, BALB/c and CBA/Kij strains have a very low incidence of spontaneous plasma cell neoplasm.14 Surprisingly, mice of the BALB/c strain are most susceptible to developing plasmacytomas following repeated intraperitoneal injections of mineral oil. NZB mice also are fairly susceptible to the induction of plasmacytomas by this method. However, C57BL/Ka mice are resistant.29
Human families with a high incidence of plasma cell neoplasms also have been reported.30,31 No consistent genetic aberrations have been described in these families. Multiple myeloma also occurs more frequently in relatives of patients with the disease than in the general population.32,33 In the United States, African Americans have a higher incidence of multiple myeloma than Caucasians.34 All these observations indicate that the genetic background of the host is an important risk factor for the development of plasma cell neoplasms in mammals.
There have been numerous attempts to induce plasmacytomas that secrete antibodies to specific antigens in BALB/c mice. Such animals were hyperimmunized with any one of a variety of antigens in mineral oil. Although plasmacytomas arose, they virtually never made antibodies reactive with the injected antigen.35 Thus, there is no apparent relationship between chronic antigenic stimulation and the development of plasma cell neoplasms in these animals. However, this is not the case with Aleutian minks infected with the Aleutian disease virus.36 Many of these animals develop M proteins consisting of antibodies that bind specifically to the infecting virus. In humans, there is no consistent relationship between prior inflammatory disease and subsequent development of a plasma cell neoplasm. However, monoclonal gammopathies have been described to occur at increased frequency in patients with inflammatory and autoimmune diseases.24,25,37,38 and 39
About 90 percent of mouse plasmacytomas induced by mineral oil in mice show consistent chromosomal anomalies.40 In these the c-myc gene on mouse chromosome 15 is fused with either the immunoglobulin heavy-chain locus on mouse chromosome 12 or the immunoglobulin k light-chain locus on mouse chromosome 6.40,41 The fusion of c-myc with an immunoglobulin heavy- or light-chain locus resembles the typical chromosomal anomalies seen in human Burkitt lymphoma.42 However, the biologic behaviors of murine plasmacytomas and human Burkitt lymphoma are radically different, and no virus (such as EBV) has been associated with murine or human plasmacytomas.
Certain chromosomal abnormalities in neoplastic cells may be seen repeatedly in patients with multiple myeloma or plasma cell leukemia (a late, preterminal stage of multiple myeloma) (see Chap. 106).43 Additions to the long arm of chromosome 14 (14q+) have been described in 30 to 50 percent of multiple myeloma patients. Often the donated material is from chromosome 11, generating a t(11;14) (q13;q32).44 Multiple myeloma and plasma cell leukemia cells also may have abnormalities of chromosome 1 in about 50 to 70 percent of the cases. These anomalies are highly variable, though, and no consistent deletions, additions, or translocations have been found. Finally, rare patients have deletions of chromosome 22 in the region of the immunoglobulin l light-chain locus. Interestingly, chromosomal anomalies associated with the immunoglobulin k light-chain region on chromosome 2 have not been described in humans, even though about two-thirds of M proteins express k light chains.
Patients with trisomies of chromosomes 6, 9, and 17 tend to have prolonged survival while patients with monosomy 13 (loss of Rb) have shortened survival66 (see Chap. 106). However, cytogenetic studies are not normally performed on multiple myeloma patients. Because neoplastic plasma cells or their precursors often divide relatively slowly, the inability to find an abnormal karyotype in some biopsy specimens merely may reflect the fact that only normal hematopoietic cells were induced into metaphase. Therefore, negative results may be false negatives.
Interleukin-6 (IL-6) is a potent stimulator of plasmacytoma growth.45,46,47,48 and 49 In cultures of freshly isolated marrow cells from patients with multiple myeloma, IL-6 is produced predominantly by monocytoid cells and fibroblasts. With time in culture, the myeloma cells themselves may produce IL-6, which in turn may stimulate plasma cell growth in vitro. IL-6 may play such a role in patients with multiple myeloma. In one study, injected monoclonal antibodies to IL-6 significantly inhibited tumor cell growth in vivo.48 In addition, other cytokines, such as granulocyte-monocyte colony stimulating factor (GM-CSF), IL-3, IL-1, or low-dose interferon alpha (IFN-a), may synergize with IL-6 to stimulate the growth of plasmacytomas. Kaposi’s sarcoma-associated herpesvirus (KSHV) has been found in bone marrow dendritic cells of patients with multiple myeloma and occasionally in patients with MGUS. KSHV-encoded IL-6 was shown to be transcribed in these bone marrow dendritic cells.67 Malignant precursors of myeloma cells appear to adhere to these dendritic cells.68 Finally, rearrangements of the IL-6 receptor gene in myeloma cells also have been described, in at least one case. As the tumor progresses, malignant cells may escape from their dependency on IL-6. None of these studies has related the effects of cytokines to the observed chromosomal anomalies prevalent in multiple myeloma. The gene for IL-1 is on chromosome 2q; IL-3 and GM-CSF are on 5q; IFN-a is on 9p; IFN-g is on 12q; and IL-6 is on 7p.44
The malignant cells of multiple myeloma also produce other cytokines that contribute to the noted pathophysiology of this disease. Multiple myeloma means multiple tumors in the marrow. This term was adopted because patients with this disease often develop numerous tumors in the bone that can be detected radiographically as osteolytic lesions. These osteolytic lesions result in the weakening of the bone matrix and may lead to pathologic fractures. These lesions are produced by osteoclasts that are activated by cytokines released by the malignant plasma cells themselves. Formerly called osteoclast activating factor (OAF), it is now thought that the factor involved actually may be a combination of different cytokines, including IL-1, tumor necrosis factor-alpha (TNF-a), IL-5, TNF-b, and/or IL-6.18,50,51
Cell marker studies have shown a great deal of lineage infidelity in multiple myeloma. Malignant B cells may express both early and late B-cell antigens along with antigens characteristic of granulocytes, monocytes, or megakaryocytes.52,53 and 54 This has led some investigators to suggest that the transformed cell of multiple myeloma is really the marrow stem cell. However, lineage infidelity commonly is seen in marker studies of a variety of neoplasms. Such lineage infidelity may be reflective of dysregulation in the expression of cellular differentiation antigens secondary to malignant transformation. Nonetheless, it is probable that multiple myeloma is not a disease in which the transforming event occurs in mature plasma cells.
Cells resembling small lymphocytes may have the same immunoglobulin gene rearrangements, immunoglobulin idiotypes, and surface antigens as all malignant plasma cells.52 As such, these neoplasms may be composed of transformed B cells that have retained their ability to mature into plasma cells. Thus myeloma contrasts with lymphocytic lymphomas which usually do not produce significant numbers of plasma cells. This may be analogous to the difference between chronic myelogenous leukemia, in which malignant cells may mature into segmented neutrophils, and acute myelogenous leukemia, in which very few do (see Chap. 93 and Chap. 94). Indeed, in the spectrum of M-protein-producing disorders, we find tumors of small lymphocytes, such as CLL and small lymphocytic lymphoma, and tumors of plasmacytoid lymphocytes, such as Waldenström macroglobulinemia. These types of tumor usually produce IgM, whereas plasmacytomas usually produce IgG or IgA.
In the case of multiple myeloma, cells from a single transformed clone can have the morphology of a small lymphocyte, a lymphoblast, or a plasma cell. Although it is conventional to assume that a fully mature plasma cell cannot reenter the cycle of cell division, this has not been demonstrated rigorously in plasma cell neoplasms. In fact, on histologic sections of marrow from multiple myeloma patients, many plasma cells have nuclei with an immature chromatin pattern, rather than the highly condensed pattern of normal plasma cells. There also is an increased frequency of bi- or multinucleate cells. The ability to divide or incorporate tritiated thymidine into DNA are criteria that are quite useful in distinguishing “malignant” plasma cell neoplasms from “benign.”12,51 These criteria are not routinely used in the clinical laboratory because other, less expensive tests yield similar information.
The most common screening test for an M protein is serum electrophoresis. In this test, a few microliters of serum are spotted onto a support medium, such as cellulose acetate, that has been equilibrated at a basic pH. When an electric current is applied across the support medium, the proteins in the serum migrate toward the anode with a velocity proportional to the ratio of their negative charge to molecular weight. After a period of migration of about half an hour, depending on the precise conditions, the cellulose acetate is taken up, dried, immersed in a stain that detects proteins, such as Ponceau SX or Coomassie Blue, and examined by eye or densitometry. The procedure and typical results are illustrated in Fig. 104-1.
FIGURE 104-1 Normal serum electrophoresis. (A) Apply serum to support medium; (B) electrophoretically separate proteins, stain, observe, scan.
The most abundant protein in normal serum is albumin. This protein migrates as a sharp peak because, except in rare cases, all albumin molecules have exactly the same amino acid sequence and hence the same electrophoretic mobility. In contrast, the gamma globulins comprise immunoglobulins that have millions of different amino acid sequences and varying carbohydrate side chains. Consequently these proteins migrate in a very broad band that typically contains IgA and IgM in the front (toward the b globulins) and IgG spread through the entire range of globulins. IgD and IgE are normally secreted at such low levels that they are not detectable by this method. When a plasma cell neoplasm produces an M protein, the electrophoretic pattern is altered, as shown in Fig. 104-2.
FIGURE 104-2 M protein electrophoresis. (A) Fast-moving M protein spike; (B) slow-moving M protein spike.
A monoclonal immunoglobulin protein may migrate anywhere in the globulin region. IgM and IgA M proteins tend to migrate faster than most IgG molecules. Accordingly, the M protein in example 1 of Fig. 104-2 probably is an IgA or IgM, while the spike in example 2 probably is an IgG molecule. To distinguish these immunoglobulin classes with certainty requires either immunoelectrophoresis or immunofixation electrophoresis, which will be described later. False monoclonal proteins are illustrated in Fig. 104-3.
FIGURE 104-3 False M proteins. Band 1 is typical of fibrinogen, which may be confused with M proteins of the IgA or IgM class. If fibrinogen is present, the serum was incompletely clotted or plasma was used. Band 2 is hemoglobin-haptoglobin complexes or high levels of transferrin, which may be seen in intravascular hemolysis or iron deficiency respectively. Band 3/4 may be seen with hyperalphaglobulinemia (one of the acute phase reactants, as is haptoglobin) and with some of the congenital hyperlipoproteinemias. Band 5 is an albumin variant resulting from a rare autosomal trait, bisalbuminemia, or from some drugs, such as penicillin, that bind to albumin and alter its electrophoretic mobility.
SPINAL FLUID AND URINE
Electrophoresis also can be performed on concentrated specimens of cerebrospinal fluid (CSF) or urine. Evaluation of the cerebrospinal fluid allows for detection of an M-protein-secreting plasmacytoma in the central nervous system. Evaluation of the urine is useful for detecting excessive and unbalanced synthesis of immunoglobulin molecules. Because the proteins larger than albumin (or 67 kDa) normally do not pass through the glomeruli, whole immunoglobulins ordinarily do not pass into the urine. However, free immunoglobulin light chains are only approximately 25 kDa and hence pass freely through the glomerulus. Patients with a circulating M protein who pass whole immunoglobulins in their urine generally have severe renal dysfunction, often due to renal amyloidosis secondary to deposition of immunoglobulin chains in the renal parenchyma.
When free light chains appear in the urine, they can be detected by sulfosalicylic acid precipitation, electrophoresis of concentrated urine, immunoelectrophoresis, or immunofixation electrophoresis. These last two techniques also are useful for evaluation of whether the immunoglobulin light chains are only k, l, or both. The common urine dipstick relies on bromphenol blue, a dye that binds rather specifically to albumin.55 Thus, dipsticks are not reliable screening tools for Bence Jones protein, and sulfosalicylic acid should be used.
Urine electrophoresis is one of the most important tools for the diagnosis and follow-up of patients with plasma cell neoplasms. The neoplastic B cells of many myeloma patients produce excess immunoglobulin light chain or light chain alone. When the amount of immunoglobulin light chain filtered through the glomeruli exceeds the resorption capacity of the proximal tubules, free light chains are excreted into the urine. The amount of light chain excreted in a fixed amount of time often is proportional to the amount of light chain produced, which in turn is proportional to the number of neoplastic plasma cells. Thus, serial measurements of the amount of immunoglobulin light chain excreted over time are a convenient way to follow tumor mass and the effects of therapy.
Measurements of immunoglobulin light chains in urine, however, do not always correlate with the rate of immunoglobulin light-chain production. Immunoglobulin light chains normally are reabsorbed and metabolized in the proximal tubules of the kidney. As renal damage progresses, the amount of light chains excreted in the urine increases, in part due to deteriorating renal function. For this reason, the best estimate of tumor cell mass in a patient with multiple myeloma is through the measurement of the M protein in the serum. However, mutations of tumor cells causing them to secrete less immunoglobulin, hydration of the patient, and renal disease also may influence the amount of serum M protein independent of tumor cell burden.
IMMUNOELECTROPHORESIS AND IMMUNOFIXATION ELECTROPHORESIS
The principles of immunoelectrophoresis and immunofixation electrophoresis are illustrated in Fig. 104-4 and Fig. 104-5 respectively. These techniques are useful for identifying the immunoglobulin heavy-chain class and light-chain type in putative M proteins.
FIGURE 104-4 Immunoelectrophoresis. (A) Sample application. A few microliters of serum are placed at the origin in a support medium such as cellulose acetate. (B) Electrophoresis. Proteins separate on the basis of charge-to-weight ratio at a given pH. (C) Application of antibody in trough. Antibody to serum protein diffuses from trough toward electrophoretically size-separated proteins. (D) Formation of precipitin arcs. Precipitate forms where antibody reacts with antigenic serum protein(s). (E) Typical patterns: a, Antibody to whole serum detects many different proteins. b, The typical arc formed by antibody to IgG is very broad. Normal IgG molecules vary in amino acid sequence and hence electrophoretic mobility. The antiserum detects them all, due mostly to its reactivity with immunoglobulin heavy chains. c, Anti-IgG detecting a monoclonal IgG within a polyclonal background. The monoclonal IgG distorts the smooth arc because of its increased amount relative to that of other IgG species and its unique electrophoretic mobility. d, A monoclonal immunoglobulin heavy or light chain with no polyclonal background. The arc is narrower than the polyclonal pattern because of the unique electrophoretic mobility of the monoclonal proteins.
FIGURE 104-5 Immunofixation electrophoresis. (a) Serum samples are placed in each of several lanes of an agarose gel support medium for protein electrophoresis. (b) Overlay each lane with antiserum to a specific immunoglobulin heavy or light chain, typically anti-a, -µ, -g, -k, or -l. Allow precipitation to occur. (c) Wash and stain. Only immunoprecipitates remain in the gel. Nonprecipitated proteins wash out. Results show an IgGk protein.
Table 104-3 lists several clinical conditions that generally are associated with a serum protein abnormality that could be detected by electrophoresis, immunoelectrophoresis, or immunofixation electrophoresis. Note that these techniques are useful for detecting a variety of serum protein abnormalities other than M proteins.
TABLE 104-3 CLINICAL INDICATIONS FOR ELECTROPHORESIS OF SERUM AND URINE PROTEINS
IMMUNOGLOBULIN GENE REARRANGEMENTS
The most specific means to determine whether a lymphoproliferative disorder is monoclonal is through analysis for immunoglobulin gene rearrangement. In the laboratory the most common technique is flow cytometry, looking for light-chain (k or l) restriction on tumor cells. Because B cells rearrange both immunoglobulin heavy- and light-chain genes to produce unique immunoglobulin genes, the detection of non-germ-line DNA immunoglobulin gene fragments following digestion with restriction endonucleases has become a common research technique (see Chap. 83). Genomic DNA isolated from a suspected B-cell neoplasm is digested with one or more restriction endonucleases that each cut DNA at specific recognition sequences. If the DNA between these target sites has rearranged to join constant, joining, and variable regions from which a messenger RNA can be transcribed, the DNA will be of a different length compared to that of germ line sequences or the DNA encoding any other heavy- or light-chain mRNA (see Chap. 83). When the products of such a digestion are electrophoresed on a sizing gel and then labeled by hybridization with specific DNA probes, monoclonal bands may be identified. This technique is useful for evaluating B-cell lymphoproliferative disorders that secrete insufficient amounts of immunoglobulin to detect in the serum. Rearrangement of immunoglobulin heavy-chain genes occurs very early in B-cell development and may be detected even in cells that produce no M protein at all (see Chap. 83). Both monoclonal and oligoclonal rearrangements may be detected by the technique, making it particularly valuable in the diagnosis of lymphoproliferative disorders in immunodeficient hosts, where truly oligoclonal, life-threatening lymphoproliferations are now being observed.56,57 and 58
QUANTITATIVE IMMUNOGLOBULIN ASSAYS
Immunoglobulins in serum, urine, or CSF usually are measured by nephelometry. This technique is based on the observation that antigen-antibody complexes form cloudy precipitates. These precipitates can be detected photoelectrically. One incubates varying dilutions of the fluid in question with antibodies specific for any one of the different immunoglobulin heavy and light chains. After allowing precipitates to form, the amount of precipitate is determined through comparison with standard curves produced by precipitating immunoglobulins of known concentration. This now-automated technique has replaced the slow, labor-intensive, and semiquantitative technique of radial immunodiffusion.
b2-Microglobulin is the light chain of class I molecules of the major histocompatibility complex (MHC). Class I molecules are present on essentially all nucleated cells, including lymphocytes and plasma cells. In rapidly dividing cell populations, membrane turnover leads to shedding of many molecules, including class I MHC. Because b2-microglobulin is not covalently linked to its heavy chain, it is released into the extracellular fluid and the blood. Because its molecular weight is less than 12,000, it is filtered through the normal glomerulus. However, b2-microglobulin is reabsorbed by normal proximal renal tubules and does not appear in significant quantities in the urine. In patients with plasma cell neoplasms, however, b2-microglobulin increases in the serum due to increased neoplastic cell turnover. Also, as myeloma-protein-induced renal damage occurs, reduced glomerular filtration will increase serum b2-microglobulin levels. Renal tubular dysfunction increases serum levels even further. Serum b2-microglobulin therefore provides another parameter with which to monitor for neoplastic cell mass, cell turnover, effect on renal function, and response to treatment.59,60,61 and 62
Large molecules such as IgM pentamers or IgA dimers can increase serum viscosity significantly. Some IgG molecules, particularly those of the IgG3 subclass, also tend to aggregate and increase serum viscosity.63 In vivo this can cause sludging of capillary flow and disturbances of vision, other central nervous system abnormalities, and some clotting disorders (see “Waldenstrom Macroglobulinemia,” Chap. 108). In the laboratory, serum viscosity is measured as resistance to flow through standardized glass tubing compared to distilled water. The test is usually performed at room temperature, which is highly variable. If a patient has cryoglobulins, which aggregate increasingly at temperatures below 37°C (98.6°F), then serum viscosity measurements should be performed at 37°C (98.6°F) to obtain clinically relevant information. The relative viscosity of normal serum ranges up to 1.8 times that of water. Patients usually do not experience clinical symptoms with serum viscosities of 4 or less.
The type of amyloidosis associated with plasma cell neoplasms is caused by the deposition of light chains or light-chain fragments in tissues (see Chap. 107). The name amyloid, meaning “starchlike,” comes from the polysaccharide groups attached to immunoglobulin light- (and heavy-) chain molecules. Amyloid can deposit in any tissue and often has a predilection for packing in and around the walls of small blood vessels. Amyloid is best detected by tissue biopsy, often of the kidney, liver, rectum, oral cavity, heart, or skin. Tissue light-chain deposition has a regular order and binds dyes such as Congo red or Thioflavin B.64 Under polarized light, or with a fluorescent microscope, these lesions have a characteristic appearance that permits one to establish the diagnosis. Amyloidosis may severely impair organ function and is a potentially serious complication of plasma cell neoplasms. One should also keep in mind that tissue amyloid deposits may interfere with hemostasis and complicate needle biopsies of internal organs.65
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Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn