Myeloma csbrp
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Myeloma csbrp
- 1. PLASMA CELL DYSCRASIASPLASMA CELL DYSCRASIAS & RELATED DISORDERSRELATED DISORDERS Dr.CSBR.Prasad, M.D.
- 2. This patient came with shoulder pain of 1month duration
- 3. This patient complained of generalized bone pain and weakness
- 4. This patient complained of loss of HEIGHT and bone pain
- 5. What is the main function of plasma cells?
- 6. • A group of disorders • Common feature: – Clonal proliferation of Ig producing cells • Plasma cells / lymphocytes • They produce single class of Ig – Monoclonal spike (M-protein) on electrophoresis The plasma cell dyscraias
- 7. Classification The most commonly recognized types are: 1-Multiple myeloma 2-Monoclonal gammopathy of undetermined significance (MGUS) 3-Waldenström macroglobulinemia (lymphoplasmacytoid lymphoma) 4-Heavy chain disease and 5-Primary amyloidosis
- 9. Multiple myeloma • Definition. A neoplastic clonal proliferation of plasma cells characterized by the production of a monoclonal immunoglobulin. The bone marrow is the site of origin of nearly all myelomas and in most cases there is disseminated marrow involvement. Other organs may be secondarily involved. • Due to neoplastic proliferation of plasma cells • Immunosecretory disorder • Involves BM in multiple sites • Only neoplasm of terminally differentiated cells- plasma cells • Secretes homogeneous product M-component
- 10. Multiple myeloma • Multifocal involvement of the skeleton –axial skeleton –vertebral column, ribs, skull, pelvis, femur, clavicle, and scapula • Disease of the elderly (65 to 70 years) Never diagnose Myeloma below the age of 40yrs
- 11. • 1% of all cancers & 10% of hematological malignancies • M:F = 3:2 • usually >70yrs. Rare <35yrs, not seen in children • Presenting symptom is bone pain • Loss of height due to vertebral collapse • Generalized BM involvement (sites: hemopoietically active areas) • Infections, renal failure, hypercalcemia • Anemia (replacement of marrow, <EPO production) Multiple myeloma
- 12. Diagnostic criteria The diagnosis of myeloma requires • one major and one minor or • Three minor criteria which must include 1&2 Major criteria: 1. Marrow plasmacytosis >30% 2. Plasmacytoma on biopsy 3. M-component (IgG >3.5, IgA>2) Minor criteria: 1. Marrow plasmacytosis <10% 2. M-component is present but, less than above 3. Lytic bone lesions
- 13. Clinical varients • Non-secretory myeloma • Smouldering myeloma (like MGUS, M- component as in MM, BM plasma cells 10-30%) • Indolent myeloma (same as MM but, M- component <7, bone lesions<3, normal HGB, Ca, creatinine) • Plasma cell leukemia MGUS: – M-component <MM – BM plasma cells <10% – No bone lesions – Asymtomatic
- 14. Plasma cell leukemia • Involvement of PB occurs in 2% of MM • Def: circulating plasma cells >20% or PB plasma cells >2000/cumm • Likely to be light chain only disease • Osteolytic lesions are less frequent • Renal failure is more frequent • Clinically aggressive
- 15. Etiology • 3-4x more common in cosmetologists, farmers & laxative users • Pesticides, petroleum products, rubber, plastics and wood products • Radiation (atomic bombs, radiologists, nuclear plant workers) • Chronic infections (ostemyelitis, RA) • HHV8, EBV
- 16. Molecular Pathogenesis • Ig genes in myeloma cells always show evidence of somatic hypermutation • the cell of origin is considered to be a post-germinal center B cell that homes to the bone marrow and has differentiated into a plasma cell • tumor originates in and is maintained by stem-like cells resembling small B lymphocytes that rely on signals generated by the “hedgehog” pathway for self-renewal • The proliferation and survival of myeloma cells are dependent on several cytokines, most notably IL-6
- 17. Molecular Pathogenesis • rearrangements involving the Ig heavy-chain gene on chromosome 14q32 • Common translocation partners include FGFR3 (fibroblast growth factor receptor 3) on chromosome 4p16 • cell cycle–regulatory genes cyclin D1 on chromosome 11q13 and • cyclin D3 on chromosome 6p21 • The gene for the transcription factor c-MAF on chromosome 16q23; and • The gene encoding the transcription factor MUM1/IRF4 on chromosome 6p25
- 18. Why bone destruction and hypercalcemia in MM? • MIP1α • modulators of the Wnt pathway • The net effect is a marked increase in bone resorption, which leads to hypercalcemia and pathologic fractures
- 19. Gross • Osteolytic lesions on gross, filled with soft gelatinous material, fish-flesh appearance or hemorrhagic tissue.
- 20. Micro • Plasma cells in BM >30% • Plasma cells occur in clusters and sheets • Myeloma cells vary from mature to immature forms and may be frankly anaplastic • Clock face/spoke wheel chromatin • Perinuclear HOF • Mott cells, Russel bodies, Dutcher bodies, flame cells, cytoplasmic crystals.
- 21. Immunophenotyping • Cytoplasmic Ig • No sIg • Malignat plasma cells : CD19/20 neg CD56/58 pos • Normal plasma cells: CD19/20 pos CD56/58 neg
- 22. Plasmacytoma • Localized myeloma • Can be osseous or extraosseous • In bone osteolysis –(vanishing bone disease) • 5% of all plasma cell neoplasms • BM in active hemopoietic sites • Bone pain / # • No M-component
- 23. Bence-Jones proteins • Light chains of Ig • Seen in MM, WSMG, lymphoma • >6gm in serum • BJ appear in urine • Diagnosis: heat coagulation test (40-60°- appear; on boiling 100°-disappears; reappear on cooling) immunofixation test • Damages the kidney
- 24. The "punched out" circular lytic lesions in the skull seen here are the result of multiple myeloma in a woman. The rounded lesions with central lucency are more subtle. These lesions consist of a neoplastic proliferation of plasma cells.
- 25. Multiple myeloma of the skull (lateral view). The sharply punched-out bone lesions (usually 1 to 4 cm in dia) are most obvious in the calvarium
- 26. The skull demonstrates the characteristic rounded "punched out" lesions of multiple myeloma. The plasma cell proliferation results in bone lysis to produce these lytic lesions. Such lesions can produce bone pain.
- 27. Round lesions filled with a soft reddish material are indicative of foci of myeloma in this section of vertebral bone.
- 28. Here is a smear of bone marrow aspirate from a patient with multiple myeloma. Note that there are numerous well-differentiated plasma cells with eccentric nuclei and a perinuclear halo of clearer cytoplasm. There is also an abnormal plasma cell with a double nucleus.
- 29. MULTIPLE MYELOMA CASE-1 BM
- 30. MULTIPLE MYELOMA CASE-2 BM
- 33. PLASMA CELL LEUKEMIA A blood smear from a 59-year-old man with plasma cell leukemia. The total blood leukocyte count was slightly elevated. There were 50 percent plasma cells. The monoclonal protein in this case was IgG kappa. (Wright-Giemsa stain)
- 34. INTRANUCLEAR INCLUSIONS Bone marrow smear from a patient with IgA myeloma. Large nuclear inclusions (Dutcher bodies) are present in two of the plasma cells.
- 35. Two of the cells contain large cytoplasmic crystals. (Wright-Giemsa stain)
- 36. In this bone marrow biopsy section at medium power, there are sheets of plasma cells of multiple myeloma that are very similar to normal plasma cells, but the cells may also be poorly differentiated.
- 37. A plasma cell has prominent cytoplasmic smooth endoplasmic reticulum, an eccentrically placed nucleus with prominent radially arranged chromatin, and a prominent perinuclear Golgi apparatus (not seen in this plane of sectioning).
- 41. Multiple myeloma (BM). Normal marrow cells are largely replaced by plasma cells, including forms with multiple nuclei, prominent nucleoli, and cytoplasmic droplets containing Ig.
- 42. Clinical features Due to: • The effects of plasma cell growth in tissues • The production of excessive Igs and • The suppression of normal HI Bone pain & Fractures Hypercalcemia Lethargy Weakness Constipation confusion Polyuria
- 43. Clinical features Due to: • The effects of plasma cell growth in tissues • The production of excessive Igs and • The suppression of normal HI Hyperviscosity
- 44. Clinical features Due to: • The effects of plasma cell growth in tissues • The production of excessive Igs and • The suppression of normal HI Infections
- 45. Kidney • BJ proteins accumulate • Resorption of BJ proteins by renal tubules with resultant damage to tubular cells > kidney damage • Known as myeloma kidney • Micro: tubules plugged with proteinaceous material with giant cell reaction.
- 48. E N DE N D
Notes de l'éditeur
- The plasma cell dyscrasias: A group of disorders having in common the proliferation of a single clone of immunoglobulin-producing cells generally recognizable as plasma cells or lymphocytes. These cells produce a single class of immunoglobulin, or a polypeptide subunit of a single immunoglobulin, that is detectable in the serum or urine as a monoclonal spike (M-protein) on electrophoresis; The term monoclonal gammopathy refers to only one of the manifestations of the plasma cell dyscrasias, the production of a monoclonal immunoglobulin, which may be found in both neoplastic and reactive disorders. REF: Brunning, RD and McKenna, RW. Tumors of the bone marrow. Atlas of Tumor Pathology, 3rd Series, Fascicle 9. Washington D.C.:Armed Forces Institute of Pathology, 1993. p.323
- Brunning, RD and McKenna, RW. Tumors of the bone marrow. Atlas of Tumor Pathology, 3rd Series, Fascicle 9. Washington D.C.:Armed Forces Institute of Pathology, 1993. p.323.
- Brunning, RD and McKenna, RW. Tumors of the bone marrow. Atlas of Tumor Pathology, 3rd Series, Fascicle 9. Washington D.C.:Armed Forces Institute of Pathology, 1993. p.323.
- Brunning, RD and McKenna, RW. Tumors of the bone marrow. Atlas of Tumor Pathology, 3rd Series, Fascicle 9. Washington D.C.:Armed Forces Institute of Pathology, 1993. pp.323-324.
- Many myelomas have rearrangements involving the Ig heavy-chain gene on chromosome 14q32.[38,][39] Common translocation partners include FGFR3 (fibroblast growth factor receptor 3) on chromosome 4p16, a gene encoding a tyrosine kinase receptor implicated in the control of cellular proliferation; the cell cycle–regulatory genes cyclin D1 on chromosome 11q13 and cyclin D3 on chromosome 6p21; the gene for the transcription factor c-MAF on chromosome 16q23; and the gene encoding the transcription factor MUM1/IRF4 on chromosome 6p25. As may be gathered from the involvement of two different D cyclin genes, dysreglation of D cyclins is a common feature.[38] The other most frequent karyotypic abnormalities are deletions of 13q. Consistent with the diversity of chromosomal aberrations, gene expression profiling studies suggest that myeloma is molecularly quite heterogeneous.
- Factors produced by neoplastic plasma cells mediate bone destruction, the major pathologic feature of multiple myeloma. Of particular importance, myeloma-derived MIP1α upregulates the expression of the receptor activator of NF-κB ligand (RANKL) by bone marrow stromal cells, which in turn activates osteoclasts.[36] Other factors released from tumor cells, such as modulators of the Wnt pathway, are potent inhibitors of osteoblast function. The net effect is a marked increase in bone resorption, which leads to hypercalcemia and pathologic fractures.[37]
- FIGURE 13-16 Multiple myeloma of the skull (radiograph, lateral view). The sharply punched-out bone lesions are most obvious in the calvarium.
- PLASMA CELL LEUKEMIA A blood smear from a 59-year-old man with plasma cell leukemia. The total blood leukocyte count was slightly elevated. There were 50 percent plasma cells. The monoclonal protein in this case was IgG kappa. (Wright-Giemsa stain) Brunning, RD and McKenna, RW. Tumors of the bone marrow. Atlas of Tumor Pathology, 3rd Series, Fascicle 9. Washington D.C.:Armed Forces Institute of Pathology, 1993. p.325.
- IgA MYELOMA WITH INTRANUCLEAR INCLUSIONS Bone marrow smear from a patient with IgA myeloma. Large nuclear inclusions (Dutcher bodies) are present in two of the plasma cells. (Wright-Giemsa stain) Brunning, RD and McKenna, RW. Tumors of the bone marrow. Atlas of Tumor Pathology, 3rd Series, Fascicle 9. Washington D.C.:Armed Forces Institute of Pathology, 1993. p.331.
- PLASMA CELL MYELOMA WITH CYTOPLASMIC CRYSTALS Bone marrow aspirate smear from a 68-year-old man with IgG myeloma showing four large pleomorphic plasma cells. Two of the cells contain large cytoplasmic crystals. (Wright-Giemsa stain) Brunning, RD and McKenna, RW. Tumors of the bone marrow. Atlas of Tumor Pathology, 3rd Series, Fascicle 9. Washington D.C.:Armed Forces Institute of Pathology, 1993. p.333.
- In this bone marrow biopsy section at medium power, there are sheets of plasma cells of multiple myeloma that are very similar to normal plasma cells, but the cells may also be poorly differentiated. Usually, the plasma cells are differentiated enough to retain the function of immunoglobulin production. Thus, myelomas can be detected by an immunoglobulin &quot;spike&quot; on protein electrophoresis as shown below, or the presence of Bence-Jones proteins (light chains) in the urine. Immunoelectrophoresis characterizes the type of monoclonal immunoglobulin being produced.
- Electrophoresis of serum from a patient with multiple myeloma (an immunoglobulin-secreting tumor) shows an abnormally narrow gamma-globulin band, indicating the presence of a monoclonal (and therefore abnormal) immunoglobulin. In this example the concentration of this protein is about 18 milligrams per ml, and the &quot;+&quot; on the printout indicates that this value is only slightly above normal for gamma-globulin (range 6-17 mg/ml). But this is nevertheless a clearly pathological pattern indicating the presence of a monoclonal protein, as the gamma-globulin peak is far narrower than the broad peak seen in a normal serum. In other cases such a monoclonal protein may be present at far higher than normal concentrations.
- FIGURE 13-18 M protein detection in multiple myeloma. Serum protein electrophoresis (SP) is used to screen for a monoclonal immunoglobulin (M protein). Polyclonal IgG in normal serum (denoted by the arrow) appears as a broad band; in contrast, serum from a patient with multiple myeloma contains a single sharp protein band (denoted by the arrowhead) in this region of the electropherogram. The suspected monoclonal Ig is confirmed and characterized by immunofixation. In this procedure, proteins separated by electrophoresis within a gel are reacted with specific antisera. After extensive washing, proteins that are cross-linked by antisera are retained and detected with a protein stain. Note the sharp band in the patient serum is cross-linked by antisera specific for IgG heavy chain (G) and kappa light chain (κ), indicating the presence of an IgGκ M protein. Levels of polyclonal IgG, IgA (A), and lambda light chain (γ) are also decreased in the patient serum relative to normal, a finding typical of multiple myeloma. (Courtesy of Dr. David Sacks, Department of Pathology, Brigham and Women&apos;s Hospital, Boston, MA.)
- FIGURE 13-17 Multiple myeloma (bone marrow aspirate). Normal marrow cells are largely replaced by plasma cells, including forms with multiple nuclei, prominent nucleoli, and cytoplasmic droplets containing Ig.
- (1) the effects of plasma cell growth in tissues, particularly the bones; (2) the production of excessive Igs, which often have abnormal physicochemical properties; and (3) the suppression of normal humoral immunity.
- (1) the effects of plasma cell growth in tissues, particularly the bones; (2) the production of excessive Igs, which often have abnormal physicochemical properties; and (3) the suppression of normal humoral immunity.
- (1) the effects of plasma cell growth in tissues, particularly the bones; (2) the production of excessive Igs, which often have abnormal physicochemical properties; and (3) the suppression of normal humoral immunity.