PLASMA CELL DISORDERS. Dr Mere Kende MBBS, Mmed (Path),MACTM, MAACB, MACRRM Lecturer: SMHS

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1 PLASMA CELL DISORDERS Dr Mere Kende MBBS, Mmed (Path),MACTM, MAACB, MACRRM Lecturer: SMHS

2 Terms/Antigenic Determinants Isotypes: Ig molecules that form antigenic determinants, and these are used to classify immunoglobulins E.g., five heavy chains (IgG, IgM, IgA, IgD, IgE) and two light chains (kappa & lambda). It is species specific and the same in one species. Allotypes are 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; by definition, they are detected by antibodies made in the same species. E.g., IgG1-4 Idiotypes are the third category of antigenic determinants. They are unique to the molecules produced by a given clone of antibodyproducing cells. Idiotypes are formed by the unique structure of the antigen-binding portion of the molecule.

3 Composition of Ab Two heavy chains (IgG, M, D, A, E) (mol wt ~ 50,000) Two light chains (lamba & kappa)- (mol wt ~ 25,000). Each chain has a constant portion (limited amino acid sequence variability) and a variable region (extensive sequence variability). The light and heavy chains linked by disulfide bonds Variable regions (antigen recognition) are adjacent to one another. Each chain is specified by distinct genes, synthesized separately, and assembled into an intact antibody molecule after translation. In most cells, free light chains are synthesized in slight excess, and are cleared by the kidney, but <10 mg of such light chains is excreted per day.

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5 Plasma cell disorders (monoclonal gammopathies, paraproteinemias, plasma cell dyscrasias, and dysproteinemias. are monoclonal neoplasms related to each other by virtue of their development common progenitors in the B lymphocyte lineage. Normal: Maturation to antibody-secreting plasma cells is stimulated by exposure to the antigen for which the surface immunoglobulin is specific; Plasma cell dyscrasias: the control over this process is lost.

6 Examples of plasma cell disorders Multiple Myeloma, Waldenström's macroglobulinemia (IgM), Primary amyloidosis & Heavy Chain diseases

7 Pathogenesis/Clinical Manifestation Expansion of the neoplastic cells Secretion of cell products (immunoglobulin molecules or subunits, lymphokines), To some extent to the host's response to the tumour Effects of Monoclonal protein (M protein)

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9 M-protein Electrophoretic analysis- detected if >5glL) Reliable measure of the tumour burden M component is an excellent tumour marker, (lack specificity)

10 M components may be detected in other lymphoid neoplasms CML Lymphomas CML Breast/Colon CA Nonneoplastic conditions such as cirrhosis, sarcoidosis, parasitic diseases, Gaucher disease, and pyoderma gangrenosum; Autoimmune conditions, including rheumatoid arthritis, myasthenia gravis, and cold agglutinin disease.

11 Multiple Myeloma Definition Multiple myeloma represents a malignant proliferation of plasma cells derived from a single clone. The terms multiple myeloma and myeloma may be used interchangeably. The tumour, its products, and the host response to it result in a number of organ dysfunctions

12 Etiology Cause? Exposure to radiation (WW II) Chromosomal abnormalities (deletions/translocations) Deletions: 13q14 deletions, 17p13 deletions, and 11q abnormalities predominate. Translocation: t(11;14)(q13;q32) and t(4;14)(p16;q32), and evidence is strong that errors in switch recombination the genetic mechanism to change antibody heavy chain isotype participate in the transformation pathway. Overexpression of myc or ras genes has been noted in some cases. Mutations in p53 and Rb-1 have also been described, but no common molecular pathogenesis has yet emerged.

13 High incidences in farmers, wood workers, leather workers, and those exposed to petroleum products.? Role of interleukin 6 may play a role in driving myeloma cell proliferation; a large fraction of myeloma cells exposed to IL-6 in vitro respond by proliferating.

14 Characteristic morphologic features of plasma cells, round or oval cells with an eccentric nucleus composed of coarsely clumped chromatin, a densely basophilic cytoplasm, and a perinuclear clear zone (hof) containing the Golgi apparatus. Binucleate and multinucleate malignant plasma cells can be seen.

15 Incidence and Prevalence In USA 19,900 cases of myeloma were diagnosed in 2007 & 10,790 people died Incidences increases in incidence with age Median age -68 years; it is uncommon under age 40. The yearly incidence is around 4 per 100,000 and remarkably similar throughout the world. Males > females, Blacks > twice the incidence of whites.

16 Myeloma accounts for ~1% of all malignancies in whites and 2% in blacks; 13% of all hematologic cancers in whites and 33% in blacks. Incidence: highest in African-American and Pacific islanders; intermediate in Europeans and North American Caucasians; and lowest in developing countries including Asia The higher incidence in more developed countries may result from the combination of a longer life expectancy and more frequent medical surveillance.

17 Pathogenesis and Clinical Manifestations

18 Pathogenesis of multiple myeloma. Multiple myeloma cells interact with bone marrow stromal cells and extracellular matrix proteins via adhesion molecules, triggering adhesionmediated signalling as well as cytokine production. This triggers cytokine-mediated signalling that provides growth, survival, and anti-apoptotic effects as well as development of drug resistance. HSP, heparin sulfate proteoglycan.

19 Clinical Features symptoms of bone pain or fracture, Renal failure Susceptibility to infection, Anaemia, Hypercalcemia, Occasionally clotting abnormalities, Neurologic symptoms, Manifestations of hyperviscosity (IgM).

20 Bone Pain back and ribs most common symptom in MM affecting nearly 70% of patients. Precipitated by movement Persistent localized pain ----pathologic fracture. Bone lesion- caused by the proliferation of tumor cells, activation of osteoclasts that destroy bone, and suppression of osteoblasts that form new bone.

21 Bony lesions in multiple myeloma. The skull demonstrates the typical "punched out" lesions characteristic of multiple myeloma. The lesion represents a purely osteolytic lesion with little or no osteoblastic activity. (Courtesy of Dr. Geraldine Schechter; with permission.)

22 Figure Cervical compression fracture. Lateral cervical x-ray showing an adequate image of the complete cervical spine from C1 to the top of T1. The arrows denote a compression fracture with loss of the vertebral body height of the fifth cervical vertebral body secondary to multiple myeloma. Note the sclerotic margins of the superior portion of the fifth vertebra, indicating this is a chronic lesion. There are other lesions in the third and fourth cervical vertebra as well.

23 Activation of Osteoclast by Osteoclast activating factors (OAF) OAF activity influenced by several cytokines, including IL-1, lymphotoxin, VEGF, receptor activator of NF-B (RANK) ligand, macrophage inhibitory factor (MIP)-1, and tumour necrosis factor (TNF)]. Glucocorticoids or interferon (IFN) decrease these cytokines. Result lytic bone lesion (No Bone Formation) Increased bone tissue resorption, lack of new bone formation, leaching of calcium ----increased serum levels & Normal ALP Localized bone lesions may expand to the point that mass lesions may be palpated, especially on the skull, clavicles, and sternum, and the collapse of vertebrae may lead to spinal cord compression.

24 Increased susceptibility to infection Pneumonias and pyelonephritis, and the most frequent pathogens are Streptococcus pneumoniae, Staphylococcus aureus, and Klebsiella pneumoniae in the lungs and Escherichia coli and other gram-negative organisms in the urinary tract. Decreased production and increased destruction of normal antibodies Impaired Neutrophil activity

25 Renal failure (~25%) Hypercalcemia Hyperuriceamia Increased light chain damage NSAID used to control pain Infections

26 Anaemia ~80% Normocytic and normochromic Replacement of normal marrow by expanding tumor cells and to the inhibition of hematopoiesis by factors made by the tumor. Mild hemolysis may contribute to the anemia. Associated megaloblastic anemia due to either folate or vitamin B 12 deficiency.

27 Clotting abnormalities may be seen due to the failure of antibody-coated platelets to function properly or to the interaction of the M component with clotting factors I, II, V, VII, or VIII. Deep venous thrombosis is also observed with use of thalidomide or lenalidomide in combination with dexamethasone.

28 Raynaud's phenomenon and impaired circulation may result if the M component forms cryoglobulins, and hyperviscosity syndromes may develop depending on the physical properties of the M component (most common with IgM, IgG3, and IgA paraproteins. Symptoms of hyperviscosity (normal 1.8) occur at a level of 5 6, a level usually reached at paraprotein concentrations of ~40 g/l (4 g/dl) for IgM, 50 g/l (5 g/dl) for IgG3, and 70 g/l (7 g/dl) for IgA.

29 Neurology 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

30 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 & marrow and, for reasons unknown, rarely causes enlargement of spleen, lymph nodes, or gut-associated lymphatic tissue.

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32 Diagnosis and Staging MM classic Triad: Marrow plasmacytosis (>10%), Lytic bone lesions, & A serum and/or urine M component. (electrophoresis/immunoelectrophoresis)

33 Plasma Cells Large cells with eccentric nuclei, bi-nucleated/ multinucleated, clumped chromatin, mitotic figures

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37 Differentials Monoclonal Gammopathy of Unknown Significance (MGUS) Solitary Plasmacytoma Extramedullary plasmacytoma

38 MGUS are vastly more common than myeloma, occurring in 1% of the population over age 50 and in up to 10% individuals over age 75. M protein <30g/L Require no therapy. Their survival is ~2 years shorter than age-matched controls without MGUS. Non-IgG subtype, abnormal kappa/lambda free light chain ratio, & serum M protein > 15 g/l (1.5 g/dl) are associated with higher incidence of progression to MM.

39 Solitary bone plasmacytoma & Extramedullary plasmacytoma Variants of MM Both are associated with an M component in <30% of the cases May affect younger individuals, Both are associated with median survivals of 10 years. Both tumors are highly responsive to local radiation therapy. If an M component is present, it should disappear after treatment.

40 Solitary bone plasmacytoma is a single lytic bone lesion without marrow plasmacytosis. May recur in other bony sites or evolve into myeloma.

41 Extramedullary plasmacytomas usually involve the submucosal lymphoid tissue of the nasopharynx or paranasal sinuses No Marrow plasmacytosis. No related organ or tissue impairment (no end organ damage other than solitary bone lesion) a Rarely recur or progress Normal skeletal survey (and MRI of spine and pelvis if done)

42 Diagnostic Criteria for MM Variants, and MGUS Monoclonal gammopathy of undetermined significance (MGUS) M protein in serum < 30 g/l Bone marrow clonal plasma cells < 10% No evidence of other B cell proliferative disorders No myeloma-related organ or tissue impairment (no end organ damage, including bone lesions) a Asymptomatic myeloma (smouldering myeloma) M protein in serum 30 g/l and/or Bone marrow clonal plasma cells 10% No myeloma-related organ or tissue impairment (no end organ damage, including bone lesions) a or symptoms

43 Symptomatic multiple myeloma M protein in serum and/or urine Bone marrow (clonal) plasma cells b or plasmacytoma Myeloma-related organ or tissue impairment (end organ damage, including bone lesions) Non-secretory myeloma No M protein in serum and/or urine with immunofixation Bone marrow clonal plasmacytosis 10% or plasmacytoma Myeloma-related organ or tissue impairment (end organ damage, including bone lesions) a

44 MM % IgG in 53% of patients, IgA in 25%, and IgD in 1%; 20% of patients will have only light chains in serum and urine. (50% BJP negative) Dipsticks for detecting proteinuria are not reliable at identifying light chains,

45 Other Laboratory features Normal ALP & hypercalcemia High ESR >20 Hyperuriceamia Azotaemia (increased urea/creat)

46 Treatment Systemic therapy to control the progression of myeloma Symptomatic supportive care to prevent serious morbidity from the complications of the disease. Therapy can significantly prolong survival and improve the quality of life for myeloma patients.

47 Cytotoxics/Dexamethasone Transplant Manage complications: hypercalcemia/hydration/renal failure/bone Pain/Fractures

48 References emedicine.medscape.com Harrison s Text Book of Medicine 17 th Edition

49 Myeloma Review Multiple Myeloma classic Triad: Marrow plasmacytosis (>10%), Lytic bone lesions, (x-ray) and A serum and/or urine M component. (electrophoresis/immunoelectrophoresis)

50 Clinical Features Mean Age: 65 Anaemia Hypercalcemia Renal failure Recurrent Infections Splenomegay/Lympadenopathy--RARE

51 Investigation Serum/Urine Electrophoresis (Monoclonal band) Bone Marrow Aspirate Skeletal X-ray

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53 Bony lesions in multiple myeloma. The skull demonstrates the typical "punched out" lesions characteristic of multiple myeloma. The lesion represents a purely osteolytic lesion with little or no osteoblastic activity. (Courtesy of Dr. Geraldine Schechter; with permission.)

54 Characteristic morphologic features of plasma cells, round or oval cells with an eccentric nucleus composed of coarsely clumped chromatin, a densely basophilic cytoplasm, and a perinuclear clear zone (hof) containing the Golgi apparatus. Binucleate and multinucleate malignant plasma cells can be seen.

55 Brief Monoclonal Gammapathy of Unknown Significance (MGUS)-asymptomatic, no treatment required Solitary plasmacytopma-single bone lesion Extramedullary plasmacytomas -lympadenopathy, no BM plasmacytosis

56 Other Plasma Cell Dyscrasias Waldenstrom s Macroglobulinaemia Primary Amyloidosis Heavy Chain Diseases

57 Waldenström's Macroglobulinemia Essentials of Diagnosis Symptoms nonspecific; splenomegaly common on examination. Monoclonal IgM paraprotein. Infiltration of bone marrow by plasmacytic lymphocytes. Absence of lytic bone disease.

58 General Considerations Waldenström's macroglobulinemia is a malignant disease of B cells/plasma cells. Secrete IgM paraprotein, Clnical manifestations of the disease are related to this IgM macroglobulin.

59 Symptoms and Signs Age: 60s or 70s. Fatigue related to anemia. Hyperviscosity Syndrome Coagulation disorder -engorged vessels & PLT dysfunction (Mucosal and GIT bleeding) Neurological Symptoms: nausea, vertigo, and visual disturbances, stupor, coma or peripheral neuropathy (Demyelination)

60 Exam Findings hepatosplenomegaly or lymphadenopathy. Pallor Engorged retinal Veins +/-Purpura No Bone tenderness

61 Laboratory Findings Anemia is nearly universal (related in part to expansion of the plasma volume by % due to the presence of the paraprotein. Rouleaux formation is common. Other blood counts are usually normal.

62 Increased Plasma cells in BM Electrophoresis IgM monoclonal band Coomb s Test may be positive (cold agglutinin disease) Normal Bone x-rays No sign of Kidney Failure/hypercalcemia

63 Differential Diagnosis MGUS (no BM plasma cell increase) CLL & Multiple Myeloma (IgM spike/also on clinical grounds).

64 Treatment Plasmapheresis Drugs: fludarabine and rituximab BM transplant (younger patients with more aggressive disease).

65 Prognosis Median survival rate of 3 5 years. Patients may survive 10 years or longer.

66 Amyloidosis Deposition of abnormal insoluble protein (amyloid protein/fibrils) in various vascular beds and organ system

67 General Considerations Clinical Syndromes based on organ affected Can be primary or secondary to other chronic diseases In primary amyloidosis (AL), the protein fibrils are monoclonal immunoglobulin light chains, whereas in secondary amyloidosis (AA), protein deposits are derived from acute phase reactant apolipoprotein precursors. Familial forms have been reported Over 20 types of fibrils have been identified in amyloid deposits. Amyloidosis due to deposition of 2 -microglobulin in carpal ligaments occurs in long-term hemodialysis patients.

68 Symptoms and Signs Symptoms and signs of primary amyloidosis are due to amyloid infiltration. For example, nephritic syndrome and renal failure, cardiomyopathy and cardiac conduction defects Alzheimer's disease, intestinal malabsorption pseudo-obstruction,

69 carpal tunnel syndrome, macroglossia, peripheral neuropathy, end-organ insufficiency of endocrine glands, respiratory failure, capillary damage with ecchymosis).

70 Secondary amyloidosis is more often limited to the liver, spleen, and adrenals. Familial syndromes commonly cause infiltrative neuropathies.

71 Laboratory Tests Diagnosis of Primary amyloidosis clinical suspicion Serum electrophoresis Aspirate of abdominal fat pad or biopsy of rectal or gingival mucosa In systemic disease, rectal or gingival biopsies show a sensitivity of about 80%, bone-marrow biopsy about 50%, and abdominal fat aspiration between 70% and 80%.

72 Differential Diagnosis Multiple myeloma, Hemochromatosis, sarcoidosis, Waldenström's macroglobulinemia, Metastatic tumors, and Other cause of nephrotic syndrome, such as lupus nephritis.

73 Treatment Localised- surgical excision No effective treatment available for systemic amyloidosis Supportive treatment /hemodialysis Treat primary cause

74 Heavy Chain Diseases The clinical presentation is more typical of lymphoma than multiple myeloma, and there are no destructive bone lesions Rare lymphoplasmacytic malignancies. Clinical manifestations vary with the heavy chain isotype. Secretion of 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.

75 Gamma Heavy Chain Disease (Franklin's Disease) Characteristics :lymphadenopathy, fever, anemia, malaise, hepatosplenomegaly, and weakness. Its most distinctive symptom is palatal oedema, resulting from involvement of nodes in Waldeyer's ring, and this may progress to produce respiratory compromise. The diagnosis depends on the demonstration of an anomalous serum M component [often <20 g/l (<2 g/dl)] that reacts with anti-igg but not anti-light chain reagents. The M component is typically present in both serum and urine.

76 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 chemotherapy.

77 Alpha Heavy Chain Disease (Seligmann's Disease) This is the most common of the heavy chain diseases. Affects young persons in parts of the world where intestinal parasites are common, such as the Mediterranean, Asia, and South America. The disease is characterized by an infiltration of the lamina propria of the small intestine with lymphoplasmacytoid cells that secrete truncated alpha chains. Associated with GIT symptoms (Diarrhoea/ malabsorption)

78 Mu Heavy Chain Disease Occurs in a rare subset of patients with CLL. Presence of vacuoles in the malignant lymphocytes and the excretion of kappa light chains in the urine. Treatment is the same as other heavy chain disease

79 Figure Cervical compression fracture. Lateral cervical x-ray showing an adequate image of the complete cervical spine from C1 to the top of T1. The arrows denote a compression fracture with loss of the vertebral body height of the fifth cervical vertebral body secondary to multiple myeloma. Note the sclerotic margins of the superior portion of the fifth vertebra, indicating this is a chronic lesion. There are other lesions in the third and fourth cervical vertebra as well.

80 References emedicine.medscape.com Harrison s Text Book of Medicine 17 th Edition