Document pBjm6gaKqY9Kwwapq5EYo0eVX

1410 PART TEN DISORDERS OF THE IMMUNE SYSTEM, CONNECTIVE TISSUE. AND JOINTS Treatment of the lymphoid neoplasms should follow guidelines of therapy for non-AIDS patients (see Chap. 302). Since these tumors generally follow a more aggressive course in AIDS patients. response rates and duration of responses are less favorable than in a non-AIDS population. A number of attempts at immune reconstitution have been undertaken. These have included bone m a m w transplantation. especially between identical twins when one of the pair has AIDS; infusion of histocompatible lymphocytes; and administration of soluble mediators such as interleukin 2 and interferon gamma. Temporary partial reconstitution of the immune response has been noted in some cases. There is no cure for AIDS, and no antiretroviral regimen is capable of eliminating HIV completely from infected individuals. As a consequence. the prognosis for infected individuals, particularly those that have advanced to symptomatic disease. is grave. Nonetheless, at least one drug (zidovudine) causes limited prolongation of survival in AIDS patients and a delay in the progression of disease in infected individuals. It is generally felt that the ultimate chemotherapeutic regimen for HIV infection. which it is hoped will lead to it becoming a chronic manageable disease. will be a combination of several antiretroviral agents acting at different phases of the HIV life cycle together with an immunoenhancing agent. PREVENTION Education. counseling. and behavior modification are the cornerstones of prevention of HIV infection. Widespread voluntary testing for HIV infection together with counseling of infected individuals should prove helpful in behavioral modification programs among infected individuals who would otherwise be unaware of their HIV status and who could potentially infect sexual partners. In addition, infected individuals may benefit from early therapeutic intervention even if they are asymptomatic. The incidence of new infections per year among homosexual and bisexual men in certain high-prevalence cities such as San Francisco has decreased dramatically from the early years of the epidemic. This has resulted, at least in part. from behavioral modifications regarding the number of sex partners and safe sexual practices. Several studies indicate that condom use decreases the risk of HIV transmission. Screening of the blood supply for antibodies to HIV has almost eliminated infections among transfusion recipients and hemophiliacs who require replacement of plasma components. Continuing high rates of new infections among intravenous drug users. their heterosexual partners, and children born to intravenous drug users or to the female sexual partners of intravenous drug users will require intensive efforts aimed at treatment of drug abuse together with behavioral modification. Health care workers should practice universal precautions when handling blood and body fluids and follow all guidelines for the prevention of transmission of HIV and hepatitis B virus that have been issued by the Centers for Disease Control (see Chap. 83). The development of a vaccine to prevent infection and/or disease with HIV will be an important tool in the strategy for world-wide containment of the AIDS epidemic. Several candidate vaccines are undergoing early phase I testing in humans. In the'monkey model of simian immunodeficiency virus (SIV). immunization with whole killed SIV is effective in protecting animals from challenge with live virus by preventing either infection or the development of disease following infection. These studies lend optimism to the feasibility of developing a safe and effective vaccine for HIV in the future. REFERENCES CENTERS FOR DISEASE CONTROL: Classification system for human T-lymphotropic virus type Illllymphadenopathy-associatedinfections. Morb Mon Week Rep 35334. I986 -: Revision of the CDC surveillance case definition for acquired immunodeficiency syndrome. Morb mor^ Week Rep 36:IS. 1y87 -: Guidelines for prevention of transmission ut' human immunodeticiency virus and hepatitis B virus to health-care and public safety workers. Morb Mon Weeh Rep 38:s-6. 1989 CURRANJW et at: Epidemiology of HIV infection and AIDS in the United States. Science 239610. 1988 FAUCAI S: The human immunodeficiency VINS: lnfectivtty and mechantsms of patho. genesis. Science 239:617. 1988 FIKHLMA et al: The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double-blind. placebo-controlledtrial. N Engl J Med 317:185. 1987 CALLORC. MONTAGNILE:RAIDS in 1988. Sci Am 25Y:JI. 1988 Ho DD et al: The acquired immunodeficiency syndrome (AIDS)dementia complex. Ann Intern Med 111:400. 1989 KNOWLES DM et al: Lymphoid neoplasia associated with the acquired immunodeficiency syndrome (AIDS). Ann Intern Med 108:744. 1988 LANE HC et al: Anti-retroviral effects of interferon-a in AIDS-associated Kaposi's sarcoma. Lancet 21218. 1988 PHAIRJ et al: The risk of Pnrumoc.vs:is carinii pneumonia among men infected with human immunodeficiency virus type I . N Engl J Med 322:161. 1990 plzzo PA et al: Acquired immune deficiency syndrome in children. Current problems and therapeutic considerations. Am J Med 85:tSuppl 2A) 195. 1988 PRICERW et al: The brain in AIDS: Central nervous system HIV-I infection and AIDS dementia complex. Science 239586. 1988 ROSENBERGZF.FAUUAS: The immunopathogenesis of HIV infection. Adv lmmunol 46377. 1989 SELWVNPA et al: A prospective study of the risk of tuberculosis among inwavenous drug users with human 1989 265 PLASMA CELL DISORDERS DAN L. LONG0 GENERAL PRINCIPLES The plasma cell disorders are monoclonal neoplasms related to each other by virtue of their development from common progenitors in the B-lymphocyte lineage. Multiple myeloma, Waldenstrom's macroglobulinemia. primary amyloidosis (see Chap. 266). and the heavy chain diseases comprise this group and may be designatcd by a variety of synonyms such as monoclonal gammopathies. paraprotcinemias. plasma cell dyscrasias. and dysproteinemias. A schema for the normal development of B lymphocytes is depicted in Fig. 265- I . Mature B lymphocytes destined to produce IgG. bear surface immunoglobulin molecules of both M and G heavy chain isotypes with both isotypes having identical idiotypes (variable regions). Under normal circumstances. maturation to antibodysecreting plasma cells is stimulated by exposure to the antigen for which the surface immunoglobulin is specific: however, in the plasma cell disorders the control over this process is lost. The clinical manifestations of all the plasma cell disorders relate to the expansion of the neoplastic cells. to the secretion of cell products (immunoglobulin molecules or subunits. lymphokines), and to some extent to the host's response to the tumor. There are three categories of structural variation among immunoglobulin molecules that form antigenic determinants. and these are used to classify immunoglobulins (Chap. 13). Isotypes are those determinants that distinguish among the main classes of antibodies of a given species and are the same in all normal individuals of that species. Therefore. isotypic determinants are by definition recognized by antibodies from a distinct species (heterologous sera) but not by antibodies from the same species (homologous sera). There are five heavy chain isotypes (M. G. A. D. E) and two light chain isotypes (kappa. lambda). Allotypesare distinct determinants that reflect regular small differences between individuals of the same species in the amino acid sequences of otherwise similar immunoglobulins. These differences are determined by allelic genes. and by definition they are detected by antibodies made in the same species. Idio/ym are the third category of antigenic determinants. They are unique to the molecules produced by a given clone of antibody-producing cells. Idiotypes are formed by the unique structure of the antigen binding portion of the molecule. - -Antibody molecules (see Fig. 265-2) are composed of two heavy chains (mol wt 50.000) and two light chains (mol wt 25.000)5 Each chain has a constant portion (limited amino acid sequence variability) and a variable region (extensive sequence variability). UI t Inu CHAPTER 265 PLASMA CELL DISORDERS Burkin's DWDL CLL NPDL DPDL DHL t 7.7 B1+ 1411 la - CALLA - Lymphoid Stem Cell la + CALLA + 84 + la + CALLA + 84 + B1 + Early BCells la + Cr + CALLA + 84+ B1 + slg + slg + la + la + 84 + 84 + 81 + B1 + 82 + Intermediate BCells Follicular Center BCells Waldenstroms Multiple 81 + 82 + Mature BCell 1 ski + B4+1- B1+ PC-1 + Secretory BCells I Antigen-Independent Differentiation I Antigen-Driven Differentiation FIGURE 265-1 Schematic representation of the pathway of differentiation of normal B cells. CALLA, B I . 82. B4. la. K-I. and slg (surface immunoglobulin) are cell markers used to distinguish discrete stages of development. Terminal transferase (TdT)is a cellular enzyme. The stage of differentiation arrest for each lymphoproliferative disorder is shown. The following abbreviationsare used: ALL. acute lymphoblastic leukemia: DWDL. diffuse well-differentiatedlymphocytic lymphoma: CLL. chronic lymphocytic leukemia: NPDL, nodular poorly differentiated lymphocytic lymphoma: DPDL, diffuse poorly differentiated lymphocytic lymphoma; DHL, diffuse histiocytic or large-cell lymphoma. The light and heavy chains arc linkcd by disulfide bonds and arc aligncd so thcir variablc rcgions arc adjacent to one anothcr. This variable rcgion forms the antigen recognition sitc of the antibody molcculc; its uniquc structural featurcs form a particular sct of detcrminants callcd idiotypcs that arc reliable markcrs for a particular clonc of cclls bccausc cach antibody is formed and sccrctcd by a singlc clonc. Each chain is spccificd by distinct gcncs. synthcsizcd separatcly. and asscmblcd into an intact antibody molcculc aftcr translation (SCC Fig. 265-3). Bccausc of the mechanics of thc gcnc rearriangemcnts ncccssary to spccify the immunoglobulin variable regions (VDJ joining for thc heavy chain. VJ joining for thc light chain; sec Fig. 265-3). a particular clone rearranges only onc of thc two chromosomcs to producc an immunoglobulin molcculc of only onc light chain isotypc and only one allotype (allclic cxclusion). After cxposurc to antigen. thc variable rcgion may bccomc associatcd with a ncw heavy chain isotypc (class switch). Each clonc of cclls performs thcsc scqucntial gene arrangcmcnts in a uniquc way. This rcsults in cach clone producing a uniquc immunoglobulin molcculc. In most cclls, light chains are synthcsizcd in slight cxccss. arc sccrctcd as frcc light chains by plasma cells. and arc clcarcd by thc kidncy. but less than IO mg of such light chains is excrctcd pcr day. Electrophorctic analysis of components of thc scrum protcins permits determination of thc amount of immunoglobulin in thc scrum (Fig. 265-4). The variety of immunoglobulins move hctcrogcncously in an electric field and form a broad pcak in the gamma rcgion. Thc gamma globulin region of the clectrophorctic pattcrn is usually increased in the serum of patients and animals with plasma ccll tumors. There is a sharp spike in this rcgion callcd an M componcnt FIGURE 265-2 Schematic depiction of an IgG molecule. Each molecule consists of two heavy and two light chains linked by disullide bonds. There are two types of light chains, kappa (genes on chromosome 2) and lambda (chromosome22). each containing two domains. There are 10 types of heavy chains: 4 types of G (GI to G4). 2 of A ( A l . A2). 2 of M ( M I . M2). and 1 each of D and E (all on chromosome 14). each with four domains. A domain is 100 to 110 amino acids in length. Within each domain is an intrachain disulfidebond that produces a loop. V,, (variable domain of the heavy chain) and V,. (variable domain of the light chain) form an antigen binding site whose unique determinants form an idiotype. Immunoglobulins of the same isotype (e.g., IgG IK)differ between individuals. The determinants that distinguish them are called allotypic determinantsand are located o n C,. (constant domain of the light chain) and C, (second constant domain of the heavy chain).C,,? is also the main site of glycosylation (CHO)and complement binding. Papain cleaves the molecule into antigen-binding (Fab) and crystallizable (Fc) components. The portion of the heavy chain in an Fab fragment is called the Fd piece. Fc receptors on cells bind to the C,, domain. IgM and IgA occur as polymers and each unit of two heavy and two light chains is connected by a J (joining) chain. The heavy chain isotypes determine the function of the antibody. Antigen Binding Site (idiotype) Fab -PAPAIN CLEAVAGE Fc HINGE REGION wI Determines biologic activity; contains allotype and heavy chain class and subclass determinates 1412 CELL TYPES NONLYMPHOID CELLS UNCOMMITTED B CELL PRECURSORS B lymphocytes prior to antigen exposure PART TEN DISORDERS OF THE IMMUNE SYSTEM. CONNECTIVE TISSUE. AND JOINTS GENE ORDER Rearrangementsjuxtapose V3 D2 J1 p and V3 D2 J 1 6 gems V3D21Ji P a 73 71 0 1 72 74 C O2 GENE PRODUCT None C b u swilch reanengemantbrings V3 D2Jt mx1 to anoIhef heavy Chain Osne B lymphocytes atter antigen exposure 2'3" J l O l 72 1 4 V3 D2 J, 0 , Secreted Ig FIGURE 265-3 Schematic diagram of the organization and translocation of immunoglobulin genes. Immunoglobulin heavy chains are encoded by four distinct genetic elements. variable (Igh-V). diversity (Igh-D).joining (lgh-J). and constant (Igh-C)genes. The variable region of the immunoglobulinheavy chain is encoded by the V. D. and J genes. The same variable region may be associated with any of the IO heavy chain constant region genes. In the germline genome (all cells except B cells) the V, D, and J genes are widely separated and there are numerous forms of each. Once a cell becomes committed to B-cell differentiation, a single V gene and a single D gene translocate to a single J gene. and the intervening genetic material is excised. This is called VDJ joining. The newly formed VDJ gene is transcribed into a single message along with either an M or D isotype C gene. Upon exposure to antigen. another rearrangement may occur so that the VDJ gene may be associated with a G. A or E isotype C gene. In light chain genes. there appear to be no D genes. and thus. light chain variable regions are formed by VJ joining. ( M for monoclonal). Less commonly the M component may appear measure of the tumor burden. This makes the M component an in the beta, or alpha, globulin region. The antibody must be present excellent tumor marker; yet it is not specific enough to be used to at a concentration of at least 5g/L (0.5 g/dL) to be detectable by this screen asymptomatic patients. In addition to the plasma cell disorders. method. This corresponds to approximately IO9 cells producing the M components may be detected in other lymphoid neoplasms such antibody. Contirmation that such an M component is truly monoclonal as chronic lymphocytic leukemia and lymphomas of B- or T-cell relies on the use of immunoelectrophoresis that shows a single light origin; nonlymphoid neoplasms such as chronic myelogenous leu- and heavy chain type. Hence, immunoelectrophoresis and electro- kemia, breast and colon cancer; a variety of nonneoplastic conditions phorcsis provide qualitative and quantitative assessment of the M such as cirrhosis, sarcoidosis, parasitic diseases, Gaucher's disease. component. respcctively. Once the presence of an M Component has and pyoderma gangrenosum; and a number of autoimmune conditions. been confirmed, clcctrophoresis provides the more practical infor- including rheumatoid arthritis. myasthenia gravis. and cold agglutinin mation for managing patients with monoclonal gammopathies. In a disease. A very rare skin diseasc known as lichen myxcdcmatosus given patient, the amount of M component in the serum is a reliable or papular mucinosis is associated with a monoclonal gammopathy. Highly cationic IgGX is deposited in the dermis of patients with this FIGURE 265-4 Representative electrophoreticpatterns of serum and urine. The upper panel illustrates the normal pattern of serum and urine protein on electrophoresis. Since there are many different immunoglobulinsin the serum, their differing mobilities in an electric tield produce a broad peak. The lower panel illustrates the patterns of serum and urine proteins in a patient with myeloma. The predominance of a product of a single cell is reflected by a "church spire" sharp peak. The presence of free light chains in the urine is reflected in a peak. as well. Serum -Urine disease. It is unclear whether this organ specificity reflects the specificity of the antibody for some antigenic Component of the dermis. The nature of the M component is variable. It may be an intact antibody molecule of any heavy chain subclass, or it may be an altered antibody or fragment. Isolated light or heavy chains may be produced. In some plasma cell tumors such as extramedullary or solitary bone plasmacytomas. less than a third of patients will have an M component. In about 20 percent of myelomas, only light chains are produced and in most cases are secreted in the urine as Bence Jones proteins. The frequency of myelomas of a particular heavy alb chain class is roughly proportional to the serum concentration. SO that IgG myelomas are more common than lgA and IgD myelomas. In some cases, the antigen specificity of the monoclonal antibody is known. MULTIPLE MYELOMA Definition Multiple myeloma repre- sents a malignant proliferation of plasma cells. The terms multiple myeloma and myeloma may be used interchangeably. The disease results from the uncontrolled proliferation of plasma cells derived from a single clone. The tumor. its products, and the host response NORMAL to it result in a number of organ dysfunctions and symptoms of bone alb Y pain or fracture, renal failure, susceptibility to infection, anemia. hypercalcemia. and occasionally clotting abnormalities. neurologic Light Chains A' IBenceJones Droteins) alb symptoms. and vascular manifestations of hyperviscosity. Etiology The etiology of myeloma is not known. Myeloma was found to occur with increased frequency in those exposed to the radiation of nuclear warheads in World War I1 after a 20-year latency. Although there is no direct evidence implicating oncogenes in human myeloma. the observations of c - m y and b - l y oncogenes in Burkitt's lymphoma. the high incidence of chromosomal translocations in hur Pia be pla' evil to 1 Ch of a PE' a si all0 libr con that cell surf are don of d stim to d mor ll the I diag inch of C( affec whit 100, P pain near ribs, at nil local fract Clinic 2_ Hype! logic corn bone pwo Renal hem lofectl Neuro ii7 Ebi P CHAPTER 265 PLASMA CELL DISORDERS 1413 human B-cell tumors. and the role of type C RNA viruses in murine formation suggest that cells of the B-cell lineage may be susceptible to growth deregulation by such stimuli. The murine plasmacytoma models are particularly interesting in that there is evidence that the induction of plasmacytomas may require exposure to foreign antigens as well as a cellular event. This suggests that chronic antigenic stimulation may play a role in the transformation of a particular B-cell clone. There is also some evidence for a genetic predisposition to myeloma in humans. Patients with myeloma have a significantly higher incidence of expressing the Glm(x) heavy chain allotype marker, and there is a weak but significant linkage disequilibrium that shows the HLA-B5 determinant being expressed more commonly than expected in myeloma patients. There is the possibility that the neoplastic event in myeloma may involve cells earlier in Bcell differentiation than the plasma cell. Circulating B cells bearing surface immunoglobulin that share the idiotype of the M component are present in myeloma patients. It is possible that the malignant clone escapes normal control mechanisms at a pre-plasma cell stage of differentiation and the chronic exposure to a particular antigenic stimulus drives the cell to terminal differentiation. It remains difficult to distinguish benign from malignant plasma cells on the basis of morphologic criteria in all but a few cases. Incidence and prevalence Myeloma is primarily a disease of the elderly and increases in incidence with age. The median age at diagnosis is 64 years. The disease is rare under age 40. The yearly incidence is around 3 per 100,OOO and remarkably similar in a variety of countries throughout the world. Males are slightly more commonly affected than females and blacks have nearly twice the incidence of whites. In the age group over 25 years of age the incidence is 30 per 1OO.OOO. Pathogenesis and cllnlcai manifestations (Table 265- I ) Bone pain is the most common symptom in myeloma and is present in nearly 70 percent of patients. The pain usually involves the back and ribs. and unlike the pain of metastatic carcinoma which often is worse at night. the pain of myeloma is precipitated by movement. Persistent localized pain in a patient with myeloma usually signifies a pathologic fracture. The bone lesions of myeloma are caused by thc proliferation TABLE 265-1 Pathogenesis and clinical manifestations of multiple myeloma of the tumor cells and the activation of osteoclasts which destroy the bone. The osteoclasts respond to osteoclast activating factors (OAF) made by the myeloma cells (OAF activity can be mediated by several cytokines including interleukin I , lymphotoxin. and tumor necrosis factor). However, production of these factors stops following administration of corticosteroids or interferon-gamma. The bone lesions are lytic in nature and are rarely associated with osteoblastic new bone formation; therefore, radioisotopic bone scanning is less useful in diagnosis than plain radiography. The bony lysis results in substantial mobilization of calcium from bone, and serious acute and chronic complications of hypercalcemia may dominate the clinical picture (see below). Localized bone lesions may expand to the point that mass lesions may be palpated, especially on the skull (Fig. 265-5). clavicles, and sternum, and the collapse of vertebrae may lead to symptoms of spinal cord compression. The next most common clinical problem in patients with myeloma is susceptibility to bacterial infections. The most common infections are pneumonias and pyelonephritis. and the most frequent pathogens are Streptococcuspneurnoniae. Sraph$ococcus aureus. and Klebsiella pneumoniae in the lungs and Escherichia coli and other gram-negative organisms in the urinary tract (Chap. 82). In about 25 percent of patients recurrent infections are the presenting features, and over 75 percent of patients will have a serious infection at some time in their course. The susceptibility to infection has several contributing causes. First. patients with myeloma have diffuse hypogammaglobulinemia if the M component is excluded. The hypogammaglobulinemia is related to both decreased production and increased destruction of normal antibodies. Moreover. some patients generate a population of circulating regulatory cells in response to their myeloma that can suppress normal antibody synthesis. In the case of IgG mycloma. normal IgG antibodies are broken down more rapidly than normal because the catabolic rate for IgG antibodies varies dircctly with the serum concentration. The large M component results in fractional catabolic rates of 8 to 16 percent instead of thc normal 2 percent. These patients have very poor antibody responses. espccialiy to polysaccharide antigens such as those on bacterial cell walls. Such responses are normally T-cell-independent. Most measures of T-cell function in myeloma arc normal but a subset of CD4 + cells may be decreased. Granulocyte lysozyme contcnt is low and granulocytc migration is not as rapid as normal in patients with myeloma. probably Clinical linding Hypercalcemia. pathologic fractures. cord compression, lytic bone lesions. ostco- porosis. bone pain Renal failure Anemia Infection Neurologic symptoms Bleeding Mass lesions Underlying cause Skeletal destruction Light chain proteinuna, hypercalcemia. urate nephropathy. amyloid glomerulopathy (rare) Pyelonephritis Myelophthisis. decreased production. increased destruction Hypogammaglobulinemia. decreased neu- trophil migration Hyperviscosity. cryo- globulins. amyloid deposits Hypercalcemia. cord compression Interference with clotting factors. amyloid damage of endothelium. platelet dysfunction Pathogenic mechanism Tumor expansion: production of osteoclast activating factors (OAF) by tumor cells Toxic effects of tumor products: light chains. OAF. DNA breakdown products: Hypogammaglobulinemia Tumor expansion: pro- duction of inhibitory factors and autoantibodies by tumor cells Decreased production due to tumor-induced suppression: increased IgG catabolism Products of tumor: properties of M com- ponent: light chains OAF Products of tumor; antibodies to clotting factors: light chains; antibody coating of platelets Tumor expansion FIGURE 265-5 Bony lesions in multiple myeloma. The skull demonstrates the typical "punched out" lesions characteristic of multiple myeloma. The lesion represents a purely osteolyticlesion with little or noosteoblastic activity. (Courtesv of Dr. Geraldine Schechrer.) 1414 PART TEN DISORDERS OF THE IMMUNE SYSTEM. CONNECTIVE TISSUE. AND JOINTS the result of a product of the tumor. There are also a variety of abnormalities in complement functions in myeloma patients. All of these factors contribute to the immune deficiency of these patients. Renal failure occurs in nearly 25 percent of myeloma patients. and some renal pathology is noted in over half. There are many contributing factors. Hypercalcemia is the most common cause of renal failure'. Glomerular deposits of amyloid, hyperuricemia. recurrent infections, and occasional infiltration of the kidney by myeloma cells all may contribute to renal dysfunction. However, tubular damage associated with the excretion of light chains is almost always present. Normally. light chains are filtered, reabsorbed in the tubules and catabolized. With the increase in amount of light chains presented to the tubule. the tubular cells become overloaded with these proteins. and tubular damage results either directly from light chain toxic effects or indirectly from the release of intracellular lysosomal enzymes. The earliest manifestation of this tubular damage is the adult Fanconi syndrome (a type 2 proximal renal tubular acidosis) with increased loss of glucose. amino acids, and defects in the ability of the kidney to acidify and concentrate the urine. The proteinuria is not accompanied by hypertension, and the protein is nearly all light chains. Generally, there is very little albumin in the urine because glomerular function is usually normal. When the glomeruli are involved, the proteinuria is nonselective. Patients with myeloma also have a decreased anion gap 1i.e.. sodium minus (chloridc plus bicarbonate)] because the M component is cationic, rcsulting in retention of chloride. This is often accompanicd by hyponatrcmia that is felt to be artificial (pscudohyponatremia) because each volume of serum has less water as a result of the incrcascd protcin. Anemia occurs in about 80 percent of myeloma patients. It is usually normocytic and normochromic and rclated both to the replacement of normal marrow by expanding tumor cells and to thc inhibition of hematopoiesis by factors made by the tumor. In addition, mild hemolysis may Contribute to the anemia. A larger than cxpccted fraction of paticnts may havc megaloblastic ancmia duc to cithcr folate or vitamin B,: deficiency. Granulccytopcnia and thrombocytopenia are very rire. Clotting abnormalities may be seen duc to the failure of antibody-coated platelets to function properly or to the interaction of the M componcnt with clotting factors 1, I I , V. VII. or VIII. Raynaud's phcnomcnon and impaircd circulation may rcsult if the M componcnt forms cryoglobulins. and hypcrviscosity syndromes may dcvclop dcpcnding on the physical propcrties of thc M Component (most common with IgM. lgG3. and IgA paraprotcins). Hyperviscosity is defined on the basis of the relative viscosity of Serum as compared to water. Normal relative Serum viscosity is I .8 (i.e.. serum is normally almost twice as viscous as water). Symptoms of hyperviscosity occur at a level of 5 to 6. a level usually reached at paraprotein conccntrations of around 40 g/L (4 g/dL) for IgM, 50 glL (5 @dL) for lgG3. and 70 glL (7 g/dL) for IgA. Although neurologic symptoms occur in a minority of patients. they may have many causes. Hypercalcemia may produce lethargy. weakness, depression, and confusion. Hyperviscosity may lead to headache, fatigue, visual disturbances. and retinopathy. Bony damage and collapse may lead to cord compression, radicular pain, and loss of bowel and bladder control. Infiltration of peripheral nerves by amyloid can be a cause of carpal tunnel syndrome and other sensorimotor mono- and polyneuropathies. Many of the clinical features of myeloma. e.g.. cord compression, pathologic fractures. hyperviscosity. sepsis. and hypercalcemia, can Present as medical emergencies. Despite the widespread distribution of Plasma cells in the body. tumor expansion is dominantly within bone and bone marrow and, for reasons unknown, rarely causes enlargement of spleen, lymph nodes, or gut-associated lymphatic tissue. Dlagnosls and staging The classic h a d of myeloma is marrow plasmacytosis (>IO percent). lytic bone lesions. and a serum and/or urine M component. The diagnosis may be made in the absence of bone lesions if the plasmacytosis is associated with a progressive increase in the M component over time or if extramedullary mass lesions develop. There arc two important variants of myeloma, solitary bone plasmacytoma and extramedullary plasmacytoma. These lesions are associated with an M component ;n less than 30 percent of the cases, they may affect younger individuals. and both are associated with median survivals of I O or more years. Solitary bone plasmacytoma is a single lytic bone lesion without marrow plasmacytosis. Extramedullary plasmacytomas usually involve the submucosal lymphoid tissue of the nasopharynx or paranasal sinuses without marrow plasmacytosis. Both tumors are highly responsive to local radiation therapy. If an M component is present, it should disappear after treatment. Solitary bone plasmacytomas may recur in othcr bony sites or evolve into myeloma. Extramedullary plasmacytomas rarely recur or progress. The most difficult differential diagnosis in paticnts with n1ycloma involves their scparation from people with benign monoclonal gammopathies or monoclonal gammopathies of uncertain significance (MGUS). MGUS is vastly more common than myeloma. occurring in 1 percent of the population over age 50 and in up to I O pcrccnt over age 75. Patients with MGUS usually havc fewer than 20 g/L (2 g/dL) of M components. no urinary Bence Jones protein. lcss than 5 percent marrow plasmacytosis, and no anemia, renal failure. lytic bone lesions, or hypercalcemia. When bone marrow cells are cxposed to radioactive thymidine in order to quantitate dividing cells, paticnts with MGUS always have a labcling index lcss than I pcrccnt and patients with myeloma always havc a labcling index greater than 1 perccnt. Othcr discriminators includc plasma ccll acid phosphatase and P-glucuronidasc, both of which arc low in MGUS paticnts. and the salmon calcitonin stimulation tcst. which is positivc only in patients with activc ongoing bonc dcstruction. Only about I I pcrccnt of patients with MGUS go on to dcvclop mycloma. Typically. paticnts with MGUS require no therapy. The clinical evaluation of paticnts with mycloma includes a carcful physical examination searching for tcndcr bones and masscs. It is paradoxic that only a small minority of paticnts havc an cnlargcmcnt of the spleen and lymph nodcs. the physiologic sitcs of antibody production. Chest and bonc radiographs may rcvcal lytic Icsions or diffusc ostcopcnia. A complctc blood count with differential may reveal anemia. Erythrocytc scdimcntation ratc is elevated. Vcry rare patients (-2 pcrccnt) may havc plasma ccll lcukcmia with more than 2000 plasma cells pcr microliter. This may be seen in disproportionate frequency in IgD (- 12 pcrccnt) and IgE (-25 pcrccnt) myclomas. Serum calcium. urea nitrogen, creatinine. and uric acid may be elevated. Protein electrophoresis and measurcmcnt of scrum immunoglobulins are useful for detecting and characterizing M spikes. supplemented by immunoelcctrophorcsis. which is especially scnsitive for identifying low concentrations of M Components not dctcctable by protein electrophoresis. A 24-h urine spccimen is ncccssary to quantitate protein excrction and a concentrated aliquot is uscd for electrophoresis and immunological typing of any M component. Serum alkaline phosphatase is usually normal even with cxtcnsive bone involvement because of the absence of ostcoblastic activity. It is also important to quantitate serum beta, microglobulin (sec below). The serum M component will be lgG in 53 percent of patients. lgA in 25 percent. lgD in I percent, and 20 percent of patients will have only light chains in serum and urine. Dipsticks for detecting proteinuria are not reliable at identifying light chains. and the heat test for detecting Bence Jones protein is falsely negative in about 50 percent of patients with light chain myeloma. Fewer than I percent of patients have no identifiable M component. and these are usually light chain myelomas in which renal catabolism has made them undetectable in the urine. About two-thirds of patients with serum M components also have urinary light chains. The light chain isotyF may have an impact on survival. Patients secreting lambda light chains have a significantly shorter overall survival than those secretink' kappa light chains. It is not clear whether this is due to some genetically important determinant of cell proliferation or because lambda light chains are more likely to cause renal damage and fofl amyloid than are kappa light chains. The heavy chain isotype mas haw with 4Pe mYe fom lead, conc 'I syste and tumc upon invol (stag 11. 0. x I( on th if >: years is a I regioi histoc cell. I of su micra 43 m montt histoll Tic loma PWrC antitui @L (: solitar & -Stage 1 I1 UI CHAPTER 265 PLASMA CELL DISORDERS 1415 have an impact on patient management as well. About half of patients with IgM paraproteins develop hyperviscosity compared to only 2 to 4 percent of patients with IgA and IgG M components. Among IgG myelomas, it is the IgG3 subclass that has the highest tendency to form both concentration- and temperature-dependent aggregates, leading to hyperviscosity and cold agglutination at lower serum concentrations. The staging system for patients with myeloma is a functional system for predicting survival and is based on a variety of clinical and laboratory tests, unlike the anatomic staging systems for solid tumors. Details of the staging system are given in Table 265-2. Based upon the hemoglobin, calcium, M component, and degree of skeletal involvement, the total-body tumor burden is estimated to be low (stage 1, <0.6 X IOu2cells per square meter), intermediate (stage 11.0.6 to 1.2 X IOu1cells per square meter), or high (stage Ill, > I . 2 x IO'? cells per square meter). and the stages are further subdivided on the basis of renal function (A if serum creatinine <2 mg/dL. B if >2). Patients in stage IA have a median survival of more than 5 years and those in stage IIIB about 15 months. Beta, microglobulin is a protein of 1I .OOO mol wt with homologies with thc constant region of immunoglobulins that is the light chain of the class I major histocompatibility antigens (HLA-A, -B. -C) on the surface of every cell. Serum bcta, microglobulin is the single most powerful predictor of survival and can substitutc for staging. Paticnts with bcta, microglobulin levels less than 0.004 g/L have a mcdian survival of 43 months and those with levels highcr than 0.004 glL only 12 months. It is also felt that oncc thc diagnosis of mycloma is firm. histologic fcaturcs of atypia may also cxcrt an intlucncc on prognosis. Treatment and course About 10 pcrccnt of paticnts with myc- loma will havc an indolcnt coursc dcmonstrating only vcry slow progrcssion of discasc ovcr many ycars. Such paticnts only rcquirc antitumor therapy whcn thc scrum mycloma protein riscs abovc 50 giL ( 5 g/dL) or progrcssivc bonc lesions dcvclop. Paticnts with solitary bonc plasmacytomas and cxtramcdullary plasmacytomas may TABLE 265-2 Myeloma staging system ~~ Stapc Criteria Estimated tumor hurdcn ( x IO'? cclldni3 I All of the following: I Hemoglobin >I 0 0 g/L ( I O g/dL) 2 Serum calcium <I2 nig/dL 3 Normal bonc x-ray or solitary 4 lLeoswionM-component production <0.6 (low) (I IgG levcl <50 g/L ( < 5 g/dL) h IgA lcvel <30 g/L ( < 3 g/dL) c Urine light chain <4 a124 h I 11 Fitting neither I nor 111 0.6-1.20 (intcrmcdiate) 111 Onc or more of the following: I Hemoglobin <85 g/L(<8.5g/dL) 2 Serum calcium (>12 mg/dL) 3 Advanced lytic bone lesions 4 High M-component production >I .20 (high) (I IgG level >70 g/L (>7 g/dL) b lgA level >50 g/L ( > 5 g/dL) c Urine light chains >12 g/24 h 1't.I \ S S l b l ( ' \ i T ( l \ l l s l I1O N S I K1 31 ( ' H I . \ l l N l X i . : I . ( . \ 1.1.5 Level A <2 mg/dL B >? mg/dL Stage IA 1IA.B IllA IlIB Median survival. months 61 55 30 15 be expected to enjoy prolonged, disease-free survival after local radiation therapy to a dose of around 40Gy. There is a low incidence of occult marrow involvement in patients with solitary bone plasmacytoma. Such patients are usually detected because their serum M component falls slowly or disappears initially only to return after a few months. These patients respond well to systemic chemotherapy. The vast majority of patients with myeloma require therapeutic intervention. In general. such therapy is of two sorts: systemic chemotherapy to control the progression of myeloma and symptomatic supportive care to prevent serious morbidity from the complications of the disease. All patients with stage I1 or 111 disease and stage I patients exhibiting Bence Jones proteinuria, progressive lytic bone lesions, vertebral compression fractures, recurrent infections. or rising Serum M component should be treated with systemic combination chemotherapy. Although there are no reported cases of long-term disease-free survival (i.e., cured patients), there is no doubt that therapy can prolong and improve the quality of life for mycloma patients. The standard treatment has consisted of intermittent pulses of an alkylating agent [L-phenylalanine mustard (L-PAM, melphalan). cyclophosphamide. or chlorambucil] and prcdnisonc administcrcd for 4 to 7 days cvcry 4 to 6 weeks. Thc alkylating agcnts appear to be roughly equally activc. but resistance to onc agcnt is oftcn accompanied by resistance to the others. The usual doscs arc as follows: melphalan, 8 mg/m, body surface area pcr day: cyclophosphamide. 200 mg/m2 pcr day: chlorambucil, 8 mg/m' pcr day: prcdnisonc. 25 to 60 mg/m, pcr day. Bccausc of their near cquivalcncc in antitumor efficacy, we favor cyclophosphamide as the alkylating agcnt bccausc it is lcss toxic to thc marrow stcm ccll compartmcnt and rcsults in a lowcr incidcncc of acutc myclodysplastic syndromcs than do thc othcr alkylating agcnts. Doscs may nccd adjustment bascd o n marrow tolcrancc. Howcvcr, thcrc arc fcw constraints on the dosc of thc stcroid pulsc and it appcars that morc is bcttcr. Rcccnt cvidcncc suggests that highcr dosc-intcnsity of the stcroid (i.c.. mg/m? pcr wcck) is associatcd with signilicantly longcr survival. Paticnts rcsponding to thcrapy gcncrally havc a prompt and gratifying rcduction in bonc pain. hypcrcalccmia. and ancmia. and oftcn havc fcwcr infcctions. Thc scrum M componcnt lags substantially bchind the symptomatic improvcmcnt. oftcn taking 4 to 6 wccks to fall. This fall dcpcnds upon thc ratc of tumor kill and thc fractional catabolic ratc of immunoglobulin. which in turn dcpcnds upon thc scrum conccntration (for IgG). Light chain cxcrction. with a functional halflifc of approximatcly 6 h. may fall within the first wcck of trcatmcnt. Howcvcr, sincc urinc light chain lcvcls may rclatc to renal tubular function. they arc not a rcliablc mcasurc of tuniorccll kill. Calculations of tumor ccll kill arc madc by cxtrapolation of the scrum M-componcnt lcvel and rely heavily on thc assumption that cvcry tumor ccll produccs immunoglobulin at a constant ratc. Thc data on which this assumption is bascd arc rcasonablc, but rcccntly it has bccn possible to alter the rate of immunoglobulin production of a mycloma in vitro with calcium channel blockers. a linding that may havc clinical utility, for cxamplc. in patients with hypcrviscosity. Thus. it is possible that a treatment might affcct immunoglobulin production without killing the tumor ccll. a situation that would rcsult in an overestimation of the antitumor cffccts of the treatment if currcnt criteria for response were applied. About 60 percent of patients will achieve at least a 75 perccnt rcduction in serum M-component lcvcl and tumor cell mass in response to an alkylating agcnt and prcdnisonc. Although this is a tumor reduction of lcss than one log, clinical responses may last many months. Efforts to improve the fraction of patients responding and the degrcc of response havc involved adding other active chemotherapeutic agents to the trcatmcnt program. Patients with more advanced disease may benefit most from such an approach, but 3- to 5-drug therapy is experimental at this time. The ideal duration of therapy has not been determined. Most physicians treat every 4 to 6 weeks for I or 2 years. Ccssation of therapy is followed by relapse, usually within a year. Rctreatmcnt may be associated with a second responsc in up to 80 perccnt of 1416 PART TEN DISORDERS OF THE IMMUNE SYSTEM, CONNECTIVE TISSUE, AND JOINTS patients. Maintenance therapy may prolong the duration of response, but no study has demonstrated this to result in prolonged survival. The regrowth rate of the tumor during relapse accelerates with each relapse. Patients primarily resistant to initial therapy have a median survival of less than a year. High-dose pulsed steroids used alone (200 mg prednisone every other day or 1 g/m2 per day methylprednisolone for 5 days) or VAD combination chemotherapy (vincristine, 0.4 mg per day 4-day continuous infusion; doxorubicin, 9 mg/mz per day in a 4-day continuous infusion; dexamethasone, 40 mg per day for 4 days per week for 3 weeks) may offer useful palliation in patients resistant to primary therapy. About 15 percent of patients die within the first 3 months after diagnosis, and subsequently the death rate is about 15 percent per year. The disease usually follows a chronic course for 2 to 5 years before developing an acute terminal phase usually marked by the development of pancytopenia with a cellular marrow that is refractory to treatment. Widespread organ infiltration by myeloma cells occurs and survival is less than 6 months. About 46 percent of patients die in the chronic phase of disease from progressive myeloma (16percent) and renal failure (10percent). sepsis (14 percent), or both (6 percent). Death in the acute terminal phase (26 percent) is chiefly from progressive myeloma (I3 percent) and sepsis (9 percent). Five percent of patients die of acute leukemia. myeloblastic or monocytic, and although it has been debated that this is related to the primary disease, it appears more likely to be the result of chronic therapy with alkylating agents. Nearly 23 percent of patients die of myocardial infarction, chronic lung disease, diabetes, or strokes, all intercurrent illnesses related more to the age of the patient group than the tumor. Supportive care directed at the anticipated complications of the disease may be as important as primary antitumor therapy. The hypercalcemia generally responds well to corticosteroid therapy, hydration. and natriuresis. Calcitonin may add to the inhibitory effects of steroids on bone resorption. Dichloromethane diphosphonate has also been shown to reduce osteoclastic bone resorption. Treatments aimed at strengthening the skeleton, like fluorides, calcium. and vitamin D with or without androgens. have been suggested but are not of proven efficacy. Iatrogenic worsening of renal function may be prevented by the use of allopurinol during chemotherapy to avoid urate nephropathy and by maintaining a high fluid intake to help excrete light chains and calcium. In the event of acute renal failure, plasmapheresis is approximately 10 times more effective at clearing light chains than peritoneal dialysis, and acutely reducing the protein load may result in functional improvement. Urinary tract infections should be watched for and treated early. Chronic dialysis probably should not be initiated in patients who have failed to respond to antitumor therapy. Plasmapheresis may be the treatment of choice for hyperviscosity syndromes. Although the pneumococcus is a dreaded pathogen in myeloma patients. they do not respond to pneumococcal polysaccharide vaccines. The advent of intravenous gamma globulin preparations raises some hope that prophylactic administration may prevent some serious infections, but this has not been tested. Chronic oral antibiotic prophylaxis is probably not warranted. Patients developing neurologic symptoms in the lower extremities. severe localized back pain, or problems with bowel and bladder control may need emergency myelography and radiation therapy for palliation. Most bone lesions respond to analgesics and chemotherapy. but certain painful lesions may respond most promptly to localized radiation. The chronic anemia may respond to hematinics (iron. folate. cobalamin) and some have responded to androgens. The pathogenesis of the anemia should be established and specific therapy instituted. where possible. WALDENSTROM'S MACROGLOBULINEMIA In 1948, Walden- strom described a malignancy of lymphoplasmacytoid cells that secreted IgM. In contrast to myeloma, the disease was associated with lymphadenopathy and hepatosplenomegaly. but the major clinical manifestation was the hyperviscosity syndrome. The disease resembles the related diseases chronic lymphocytic leukemia, myeloma, and lymphocytic lymphoma. Waldenstrom's macroglobulinemia and IgM myeloma both follow a similar clinical course. The diagnosis of lgM myeloma is usually reserved for patients with lytic bone lesions and is important only because of the hazard of pathologic fractures. The etiology of macroglobulinemia is unknown. The disease is similar to myeloma in being slightly more common in men and occurring with increased incidence with age (median, 64 years). There have been reports that the IgM in some patients with macroglobulinemia may have specificity for myelin-associated glycoprotein (MAG), a protein that has been associated with demyelinating disease of the peripheral nervous system and may be lost earlier and to a greater extent than the better known myelin basic protein in patients with multiple sclerosis. There is a surface antigen on natural killer cells that is cross-reactive with the MAG, and coincidentally, natural killer cells are decreased in multiple sclerosis. Sometimes patients with macroglobulinemia develop a peripheral neuropathy before the appearance of the neoplasm. There is speculation that the whole process begins with a viral infection that may elicit an antibody response that cross-reacts with a normal tissue component. Like myeloma, the disease involves the bone marrow, but unlike myeloma, it does not cause bone lesions or hypercalcemia. Like myeloma, a serum M component is present in the serum in excess of 30 g/L (3 g/dL), but unlike myeloma, the size of the IgM paraprotein results in little renal excretion and only around 20 percent of patients excrete light chains. Therefore, renal disease is not common. The light chain isotype is kappa in 80 percent of the cases. Patients present with weakness, fatigue, and recurrent infections, similar to myeloma patients, but epistaxis, visual disturbances, and neurologic symptoms like peripheral neuropathy, dizziness, headache, and transient paresis are much more common in macroglobulinemia. Physical examination reveals adenopathy and hepatosplenomegaly, and ophthalmoscopic examination may reveal vascular segmentation and dilatation of the retinal veins characteristic of hyperviscosity states. Patients may have a normocytic, normochromic anemia. but rouleaux formation and a positive Coombs' test are much more common than in myeloma. Malignant lymphocytes are usually present in the peripheral blood. About 10 percent of macroglobulins are cryoglobulins. These are pure M components and are not the mixed cryoglobulins seen in rheumatoid arthritis and other autoimmune diseases. Mixed cryoglobulins are composed of IgM or IgA complexed with IgG, for which they are specific. In both cases, Raynaud`s phenomenon and serious vascular symptoms precipitated by the cold may occur, but mixed cryoglobulins are not commonly associated with malignancy. Patients suspected of having a cryoglobulin based on history and physical examination should have their blood drawn into a warm syringe and delivered to the laboratory in a container of warm water to avoid errors in quantitating the cryoglobulin. Control of serious hyperviscosity symptoms like an altered state of consciousness or paresis can be achieved acutely by plasmapheresis because 80 percent of the IgM paraprotein is intravascular. Aside from this, management is identical to that of myeloma. About 80 percent of patients respond to chemotherapy and their median survival is over 3 years. The absence of other serious organ toxicities results in a longer life span of patients with macroglobulinemia compared to those with myeloma. HEAVY CHAIN DISEASES The heavy chain diseases are rare lymphoplasmacytic malignancies. Their clinical manifestations varY with the heavy chain isotype. They secrete a defective heavy chain that usually has an intact Fc fragment and a deletion in the Fd region. Gamma, alpha, and mu heavy chain diseases have been described, but no reports of delta or epsilon heavy chain diseases have appeared. Molecular biologic analysis of these tumors has revealed structural genetic defects that may account for the aberrant chain secreted. Gamma heavy chain disease (Franklin's disease) This disease affects people of widely different age groups and countries of origin. It is characterized by lymphadenopathy. fever, anemia, malaise, hepatosplenomegaly, and weakness. Its most distinctive symptom is palatal edema, resulting from node involvement of Waldeyer's ring, and this may progress to produce respiratory compromise. The CHAPTER 266 LIMYLODOSIS 1417 diagnosis depends upon the demonstration of an anomalous serum M component [often 4 0 g/L (<2 g/dL)] that reacts with anti-lgG but not anti-light chain reagents. The M component is typically present in both serum and urine. Most of the paraproteins have been of the gamma, subclass, but other subclasses have been seen. The patients may have thrombocytopenia, eosinophilia, and nondiagnostic bone marrow. Patients usually have a rapid downhill course and die of infection; however, some patients have survived 5 years with chemo- therapy. Alpha heavy chain disease (Setigmann's disease) This is the commonest of the heavy chain diseases. It is closely related to a malignancy known as Mediterranean lymphoma. a disease that affects young people in parts of the world such as the Mediterranean. Asia, and South America in which intestinal parasites are common. The disease is characterized by an infiltration of the lamina propria of the small intestine with lymphoplasmacytoid cells that secrete truncated alpha chains. Demonstrating alpha heavy chains is difficult because the alpha chains tend to polymerize and appear as a smear instead of a sharp peak on electrophoretic profiles. Despite the polymerization. hyperviscosity is not a common problem in alpha heavy chain disease. Without J-chain-facilitated dimerization. viscosity does not increase dramatically. Light chains are absent from serum and urine. The patients present with chronic diarrhea. weight loss. and malabsorption and have extensive mesenteric and paraaortic adenopathy. Respiratory tract involvement occurs rarely. Patients may vary widely in their clinical course. Some may dcvclop diffuse aggressive histologies of malignant lymphoma. Chemotherapy may produce long-term remissions. Rare patients appear to have responded to antibiotic therapy, raising the question of the ctiologic role of antigenic stimulation perhaps by some chronic intestinal infection. Mu heavy chain disease The sccrction of i d a t c d mu heavy chains into the serum appcars to occur in a very rare subset of patients with chronic lymphocytic leukemia. The only features that may distinguish patients with mu heavy chain discasc are the prescncc of vacuoles in the malignant lymphocytes and thc excretion of kappa light chains in the urine. Thc diagnosis requires ultracentrifugation or gel liltration to confirm thc nonreactivity of the paraprotein with the light chain reagents because some intact macroglobulins fail to interact with these serums. Thc tumor cells seem to have a defect in the assembly of light and heavy chains because they appcar to contain both in thcir cytoplasm. Thcrc is no evidence that such paticnts should bc treated diffcrcntly from other patients with chronic lymphocytic Icukemia. ALEXANIANR et al: Pmgnosis of asyniptomatic multiple myeloma. Arch Intern Med 148: 1963. 1988 BELCH A et al: A randomized trial of maintenance versus no maintenance melphalan and prednisone in responding multiple myeloma patients. Br J Cancer 57:94. lY88 CHAKLY et al: Solitary plasmacytoma of bone: Treatment. progression and survival. J C h Oncoi 5:181 I . 1987 DURIEBGM et ai: pretreatment tumor mass. cell kinetics and prognosis in mulliple myeloma. Blood 59364. 1980 FARHANG1 M (ed):Plasma cell myeloma and the myelomaproteins. Semin OnCol I3:259. 1986 GRlEPP PR et al: Value of beta-2-microglobulinlevel and plasma cell labeling indices as Prognostic factors in patients with newly diagnosed myeloma. Blood 72219. 1988 KYLE RA: Monoclonal gammopathy of undetermined significance. Natural history in *41 Cases. Am J Med 64:814. 1978 KYLE RA (ed): Myeloma and related disorders. in Neoplostir Disroses of the Blood. New York. Churchill Livingstone. 1985. pp 385-676 P4LMER M et al: Doseintensity analysis of melphalan and prednisone in multiple J Natl Cancer lnst 80414. I988 nLARSKl LM et al: he-B cells in peripheral blood of multiple myeloma patients. B!ood M:416. 1985 SALMON SE et al: Altemaring combination chemotherapy and levamisole improves in multiple myeloma: A Southwest Oncology Group study. J Clin Oncol I:453. 1983 SHEEH4N T el al. The efficacy and toxicity of VAD in the treatment of myeloma and disorders. Scand J Haematol 37:4?6. 1986 266 AMYLOIDOSIS ALAN S. COHEN DEFINITION AND CLASSIFICATION Amyloidosis may be defined as the extracellular deposition of the fibrous protein amyloid in one or more sites of the body. It was named by Virchow in 1854 on the basis of its color after staining with iodine and sulfuric acid. This protein has unique ultrastructural, x-ray diffraction. and biochemical characteristics. It can be deposited locally where it has no clinical consequences or may involve virtually any organ system of the body leading to severe pathophysiologic changes. or the disease may fall between these two extremes. The natural history of amyloidosis is poorly understood, and the clinical diagnosis is often not made until the disease is far advanced. It is now clear that there are multiplc clinically and biochemically different forms of amyloid. that are so classified because of the unique fibrous structure that they all possess. The following classification is clinically the most useful: ( I ) primary (AL type) amyloidosis (no evidence for preexisting or coexisting disease); (2) amyloid associated with multiple myeloma (also AL type); (3) secondary or reactive (AA type) amyloidosis associated with chronic infectious diseases (e.g.. ostcomyclitis. tuberculosis. leprosy) or chronic inflammatory diseases (e.g., rhcumatoid arthritis); (4) heredofamilial amyloidosis. a varicty of ncuropathic [AF transthyretin (prealbumin) typcl, renal, cardiovascular. and other syndromes, plus the amyloidosis associated with familial Mediterranean fever (AA type): (5) local amyloidosis (focal. oftcn tumorlike. deposits which occur in isolatcd organs. often endocrine. without evidence of systemic involvement): (6)amyloidosis asstxiatcd with aging, especially in the heart and in the brain. and (7)amyloid associated with long-term hemodialysis. These clinical forms and their current biochemical classification are listed in Table 266- I . PATHOLOGY AND STRUCTURE Amyloid is amorphous. cosinophilic. extracellular, and ubiquitous in distribution. The involvcd organs may have a rubbery consistency and a waxy, pink or gray .appearance. Organ enlargement. especially of the liver, kidncy spleen, and heart, may be prominent. Microscopically, amyloid stains pink with thc hematoxylin-eosin stain and shows metachromasia with crystal violct. The Congo rcd stain imparts a unique green birefringence when sections arc vicwcd in the polarizing microscope. This is the single most useful prcxcdurc for establishing the presence of amyloid. Amyloid deposits may bc focal in almost any area of the body but are most often perivascular. The heart may show focal or diffuse interstitial deposits in the myocardium, endocardium. or pericardium. In the aged heart, thc atrium is usually focally involved or there may occur morc diffuse lesions of the atria and ventricles. In the kidney, the glomerulus is primarily affected, although intcrstitial. peritubular, and vascular amyloid occur. In early lesions. small nodular or diffuse deposits appear near the basement membrane and, as the disease progresses. the glomerulus may be massively laden with amyloid. and its capillary bed will be occluded. In the gastrointestinal tract, there may be perivascular deposits only, or irregular or diffuse deposits may be found in the submucosa. in the muscularis mucosa, or subserosa. The amyloid may appear at any level or portion of the gastrointestinal tract including the gallbladder and pancreas. In the nervous system. amyloid has been described along peripheral nerves, in autonomic ganglia, and in senile plaques. in neurofibrillary tangles, as well as blood vessels ("congophilic angiopathy") of the central nervous system. It may be found in any portion of the orbit including the vitreous humor and cornea. In summary, there is virtually no area of the body that is spared. This ubiquitous distribution elicits a wide variety of clinical symptoms and signs. All types of human amyloid consist of fine, nonbranching rigid fibrils that in tissue sections measure approximately IO x IO"m ( I 0 0 A) in diameter. Isolated amyloid fibrils have a delicate. thin.