Immunoproliferative disorders
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Immunoproliferative disorders

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Immunoproliferative disorders Immunoproliferative disorders Presentation Transcript

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