immunoproliferative disorders

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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

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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

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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

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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

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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

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Multiple MyelomaDiagnosis of MM and its remissionMajor 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

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Multiple MyelomaMinor 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)

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Multiple MyelomaDiagnosis 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 dFeatures of disease remission Serum paraprotein reduced by 75% Bence Jones proteinuria reduced by

95%

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Multiple Myeloma Less than 5% plasma cells in bone

marrowTests in the diagnosis and managementTest Interpretation Serum Ig levels Evidence of

immune paresis Serum electrophoresis Identify and

quantify paraprotein; paresis of other

Ig isotypes

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Multiple Myeloma Immunofixation Paraprotein

type Urine electrophoresis Bence Jones

proteinuria BM examination % plasma

cells; plasma cell clonality

Skeletal radiology Lytic bone lesions

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Multiple Myeloma Calcium, urea, Hypercalcemia; electrolytes renal function Levels of 2 Prognostic

microglobulin marker Full blood count Anemia;

leucopenia; thrombocytopenia;

rouleaux; increased background staining

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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

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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

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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

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Multiple MyelomaImmunological 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

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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

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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

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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

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Multiple MyelomaTreatment 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)

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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

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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

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Multiple MyelomaSeveral 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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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.