Immunoproliferative disorders


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Immunoproliferative disorders

  1. 1. Immunoproliferative Disorders <ul><li>Neoplastic expansions of mature Ab-secreting plasma cells give rise to:- </li></ul><ul><ul><li>Multiple myeloma </li></ul></ul><ul><ul><li>Waldenstrom’s macroglobulinaemia </li></ul></ul><ul><ul><li>Monoclonal gammopathy of unknown significance </li></ul></ul><ul><ul><li>Heavy chain disease </li></ul></ul><ul><li>Tumors affecting plasma cells are often also referred to as plasma cell dyscrasias </li></ul>
  2. 2. Multiple Myeloma <ul><li>Is an abnormal proliferation of malignant plasma cells </li></ul><ul><li>typically characterized by excessive production of an immunoglobulin molecule of single heavy and light chain type  paraprotein </li></ul><ul><li>Most prevalent and clinically important plasma cell neoplasm </li></ul>
  3. 3. Multiple Myeloma <ul><li>Approx 4/100,000 of Western Europeans and North Americans are diagnosed per year </li></ul><ul><li>It is twice as common in black Americans than white Americans </li></ul><ul><li>Median age of onset 60 years </li></ul><ul><li>Men and women are equally affected </li></ul>
  4. 4. Multiple Myeloma <ul><li>Median survival from diagnosis is 3 years, with a range up to 10 years </li></ul><ul><li>Environmental factors presumed to have an influence on the development of disease </li></ul><ul><li>Agricultural workers and those exposed to benzene and radiation have a higher incidence </li></ul>
  5. 5. Multiple Myeloma <ul><li>Patients present with symptoms arising from lytic bone disease, anemia, renal failure or secondary Ab deficiency </li></ul><ul><li>20% of patients with MM are diagnosed by chance usually when liver function tests on a blood sample reveal an excessive concentration of total protein or gammaglobulins caused by excessive immunoglobulin production </li></ul>
  6. 6. Multiple Myeloma <ul><li>Diagnosis of MM and its remission </li></ul><ul><li>Major criteria </li></ul><ul><li>I. Plasmacytoma i.e. solid plasma cell tumor </li></ul><ul><li>II. Plasma cells in bone marrow >30% </li></ul><ul><li>III. Paraprotein level >35 g/l (IgG); >20 g/l (IgA), or Bence Jones proteinuria >1 g in 24 hrs </li></ul>
  7. 7. Multiple Myeloma <ul><li>Minor criteria </li></ul><ul><li>A. 10 – 30% plasma cells in bone marrow </li></ul><ul><li>B. Paraprotein present but less than in III above </li></ul><ul><li>C. Lytic bone lesions </li></ul><ul><li>D. Suppression of normal immunoglobulins (IgG <6 g/l, IgA <1 g/l or IgM <0.5 g/l) </li></ul>
  8. 8. Multiple Myeloma <ul><li>Diagnosis based on </li></ul><ul><li>I or II plus one of b, c, or d </li></ul><ul><li>III plus a, c or d </li></ul><ul><li>A and b with either c or d </li></ul><ul><li>Features of disease remission </li></ul><ul><li>Serum paraprotein reduced by 75% </li></ul><ul><li>Bence Jones proteinuria reduced by 95% </li></ul>
  9. 9. Multiple Myeloma <ul><li>Less than 5% plasma cells in bone marrow </li></ul><ul><li>Tests in the diagnosis and management </li></ul><ul><li>Test Interpretation </li></ul><ul><li>Serum Ig levels Evidence of immune paresis </li></ul><ul><li>Serum electrophoresis Identify and quantify paraprotein; paresis of other Ig isotypes </li></ul>
  10. 10. Multiple Myeloma <ul><li>Immunofixation Paraprotein type </li></ul><ul><li>Urine electrophoresis Bence Jones proteinuria </li></ul><ul><li>BM examination % plasma cells; plasma cell clonality </li></ul><ul><li>Skeletal radiology Lytic bone lesions </li></ul>
  11. 11. Multiple Myeloma <ul><li>Calcium, urea, Hypercalcemia; </li></ul><ul><li>electrolytes renal function </li></ul><ul><li>Levels of  2 Prognostic </li></ul><ul><li>microglobulin marker </li></ul><ul><li>Full blood count Anemia; leucopenia; thrombocytopenia; rouleaux; increased background staining </li></ul>
  12. 12. Multiple Myeloma <ul><li>Once the diagnosis is made, it is generally accepted that patients with symptoms should commence treatment </li></ul><ul><li>In asymptomatic patients, treatment is started in the presence of a large tumor burden or may be delayed until symptoms arise </li></ul>
  13. 13. Multiple Myeloma <ul><li>There is a popular misconception that the finding of a paraprotein or M band (M for myeloma) makes the diagnosis of MM </li></ul><ul><li>The presence of an M band alone is not diagnostic of MM and neither it is an absolute requirement to make the diagnosis </li></ul>
  14. 14. Multiple Myeloma <ul><li>In the majority of patients, there is excessive production of free Ig light chains (  or  ) by the malignant plasma cell, and these are of a sufficiently low molecular weight to be excreted in the urine  Bence Jones proteinuria </li></ul>
  15. 15. Multiple Myeloma <ul><li>Immunological features </li></ul><ul><li>Overproduction of a single Ig by a malignant plasma cell clone </li></ul><ul><li>>95% of patients will have evidence in the serum or urine </li></ul><ul><li> :  light chain ratio of paraproteins in patients reflects that of normal Ig (2:1) </li></ul><ul><li>In the majority of patients (>60%), malignant clone produce IgG, with 20% secreting IgA, and 2% IgD </li></ul>
  16. 16. Multiple Myeloma <ul><li>IgE myeloma is exceedingly rare </li></ul><ul><li>In some patients (15%), only free light chains are secreted </li></ul><ul><li>No paraprotein is detected in 0.5% </li></ul><ul><li>BM examination – an excess of plasma cells by conventional staining techniques </li></ul><ul><li>Can be stained using immunofluorescence with specific antisera to  or  light chains revealing monoclonality of plasma cell expansion </li></ul>
  17. 17. Multiple Myeloma <ul><li>Paraproteins are identified by serum electrophoresis </li></ul><ul><li>Urine electrophoresis should always be performed in parallel to identify light chains being excreted which are found in 50% of patients </li></ul><ul><li>The heavy and light chain type of a paraprotein are identified by immunofixation </li></ul>
  18. 18. Multiple Myeloma <ul><li> 2 microglobulin, the invariant part of the class I HLA molecule acts as an independent prognostic indicator </li></ul><ul><li>A rising level is also an index of deteriorating renal function </li></ul><ul><li>As severe renal failure is frequently a fatal complication, serum  2 microglobulin is one of the best prognostic markers </li></ul>
  19. 19. Multiple Myeloma <ul><li>Treatment </li></ul><ul><li>Intermittent courses of alkylating agents (melphalan, cyclophosphamide) and a corticosteroid such as prednisolone have been the mainstays of therapy </li></ul><ul><li>For younger patients, more aggressive cytotoxic regimens are used with combination chemotherapy (vincristine, adriamycin, methylprednisolone:VAMP) </li></ul>
  20. 20. Multiple Myeloma <ul><li>Remission is typically achieved in 40% of patients </li></ul><ul><li>Remission is maintained for a median of 2 years although some may remain disease free for 10 yrs or more </li></ul><ul><li>New therapies have been evaluated to include other cytotoxic agents and IFN-  , shown to prolong the plateau phase of disease </li></ul>
  21. 21. Multiple Myeloma <ul><li>BM ablation followed by allogeneic BM transplantation is only recommended for recipients under 50 yrs of age with an HLA compatible sibling as a donor </li></ul><ul><li>Mortality is high with 15 – 20% of transplanted pts dying in the first 3 mo. </li></ul><ul><li>Autologous BM transplantation </li></ul><ul><ul><li>Harvesting marrow in early remission followed by ablation therapy and reinfusing the original marrow cells </li></ul></ul>
  22. 22. Multiple Myeloma <ul><li>Several important life-threatening complications:- </li></ul><ul><li>Lytic lesions seen in 60% of pts are painful and may give rise to vertebral collapse with spinal cord damage or pathological fractures </li></ul><ul><li>Bone disease probably caused by IL-6, IL-1  and TNF-   hypercalcaemia </li></ul>
  23. 23. Multiple Myeloma <ul><li>Renal damage evident in 50% of pts at presentation, may be exacerbated by hypercalcaemia </li></ul><ul><li>Secondary Ab deficiency is common and gives rise to recurrent bacterial infections </li></ul><ul><ul><li>Prompt and prolonged use of antibiotics is the treatment of choice </li></ul></ul><ul><ul><li>Prophylactic IVIG replacement therapy </li></ul></ul>
  24. 24. Waldenstrom’s Macroglobulinaemia <ul><li>Malignant expansion of mature B cells at the stage of IgM secretion </li></ul><ul><li>Can also be described as a slow-growing small-cell lymphocytic lymphoma </li></ul><ul><li>Median age of onset is 60 years </li></ul><ul><li>Has a better prognosis than MM, with median survival of 5 – 10 yrs </li></ul>
  25. 25. Waldenstrom’s Macroglobulinaemia <ul><li>Typically small lymphocytes that stain IgM positive and express only a single light chain type are infiltrating the BM, LN and spleen </li></ul><ul><li>Being a pentamer, IgM has a high molecular weight, and high levels of circulating paraprotein produce a hyperviscosity syndrome </li></ul>
  26. 26. Waldenstrom’s Macroglobulinaemia <ul><li>This manifests itself as fatigue, headaches, dizziness, visual disturbance and confusion </li></ul><ul><li>Hyperviscosity is treated by removal of the patient’s plasma and replacement with donor plasma or albumin  plasmapheresis </li></ul><ul><li>Plasmapheresis may also be required if the paraprotein has the physicochemical properties of a cryoglobulin </li></ul>
  27. 27. Waldenstrom’s Macroglobulinaemia <ul><li>High levels of paraprotein can also interfere with the function of other plasma proteins such as those of the clotting cascade producing a coagulopathy, with nose bleeds and bruising being common signs at presentation </li></ul>
  28. 28. Waldenstrom’s Macroglobulinaemia <ul><li>Anemia is typically present and often more severe than in MM </li></ul><ul><li>Bence Jones proteinuria is only found in 10% of pts </li></ul><ul><li>Bone lesions are rare </li></ul>
  29. 29. Waldenstrom’s Macroglobulinaemia <ul><li>Therapy involves use of alkylating agents chlorambucil and cyclophosphamide, administered with corticosteroids and accompanied by regular monitoring of paraprotein levels </li></ul><ul><li>Younger pts may be suitable for more aggressive therapy, with autologous or allogeneic BM transplantation </li></ul>
  30. 30. Monoclonal Gammopathy of Unknown Significance <ul><li>Frequently, high levels of gammaglobulins or total protein detected in routine screening result in the identification of a paraprotein, but the diagnostic criteria for MM are not met </li></ul>
  31. 31. Monoclonal Gammopathy of Unknown Significance <ul><li>In these cases, a diagnosis of monoclonal gammopathy of unknown significance (MGUS) may be made if the patient is asymptomatic; the paraprotein levels are below 35 g/l for IgG and 20 g/l for IgA; there are no Bence Jones proteins in urine (<1g/24 hrs free light chains); there are <10% plasma cells in the BM; and there are no bone lesions </li></ul>
  32. 32. Monoclonal Gammopathy of Unknown Significance <ul><li>Frequency of MGUS goes as high as 3% of the population over the age of 50 yrs </li></ul><ul><li>In some cases, condition is pre-malignant and the conversion rate to frank myeloma is of the order of 1% of pts per yr </li></ul><ul><li>A similar proportion of pts will progress to WM or amyloidosis </li></ul>
  33. 33. Monoclonal Gammopathy of Unknown Significance <ul><li>Regular monitoring of these patients for evidence of marrow suppression, increasing level of paraprotein and depression of normal Ig production is advisable </li></ul>
  34. 34. Monoclonal Gammopathy of Unknown Significance <ul><li>One interesting complication is the presence of a monoclonal paraprotein with specificity for the peripheral nerve component myelin-associated glycoprotein giving rise to peripheral neuropathy </li></ul>
  35. 35. Heavy Chain Disease <ul><li>There are rare B lymphocyte lymphoproliferative disorders in which only heavy chains are produced by the malignant cells </li></ul><ul><li>Typically it is the Fc region alone that is produced and in the majority of patients described to date, this has been the  heavy chain </li></ul>
  36. 36. Heavy Chain Disease <ul><li>There are approximately 100 reported pts with  heavy chain disease and even fewer involving production of  chains </li></ul><ul><li>In most pts, the level of paraprotein is very low and the diagnosis difficult to make </li></ul>
  37. 37. Heavy Chain Disease <ul><li>The  heavy chain disease is the best characterized and appears to be a pre-malignant syndrome in which young pts of Mediterranean origin present with upper GI symptoms (pain, diarrhoea, fever and weight loss) </li></ul><ul><li>The condition may respond to antibiotics or may progress to a lymphomatous condition </li></ul>
  38. 38. Heavy Chain Disease <ul><li>A high degree of intestinal infestation with microorganisms has been suggested as the aetiological factor in this condition, but no single organism has been identified to date. </li></ul>