Myeloma & Plasma Dyscrasia Flashcards by Hannah Farquhar

What are immunoglobulins?

Antibodies - proteins produced by B cells and plasma

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Describe the structure of immunoglobulins

Two heavy and two light chains bound by a disulphide bond. Each have a specific antigen binding site

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Describe the different shapes of antibody

Monomer - IgD, IgE, IgG
Dimer - IgA
Pentamer - IgM

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Where are B cells produced?

Bone marrow

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How does the variable element of B cells arise?

V-D-J recombination

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What happens to B cells when they leave the bone marrow?

Immature B cells with Ig on surface leave and go onto meet their target antigen - IgM

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Where does the B cell encounter the antigen?

Follicle germinal centre of lymph node

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What happens to the B cell in the lymph node?

Identifies the antigen
Improve the fit by mutation or deletion
Class switching

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After the lymph node interactions what can happen to the B cell?

Return to the marrow as a plasma cell

Remain in circulation as memory B cell

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What is the function of plasma cells?

Produce antibodies

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Describe the appearance of plasma cells

Eccentric clock face nucleus on H and E stain
Open chromatin (synthesising mRNA)
Blue cytoplasm with lots of protein
Pale perinuclear area due to golgi apparatus

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What do plasma cells look like on bone marrow aspirate?

Fried Egg

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What is meant by polyclonal?

Lots of clones encounters specific antigen and ready to produce antibodies

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What does a polyclonal immunoglobulinopathy imply?

Reactive aetiology

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Name the causes of polyclonal immunoglobulinopathy

Infection
Autoimmune
Malignancy
Liver disease

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What do monoclonal immunoglobulinopathies produce?

Paraprotein

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How can monoclonal immunoglobulinopathies be investigated?

Serum electrophoresis
Immunofixation
Quantified by graph calculation

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Describe serum electrophoresis

Sample serum on gel and apply voltage different proteins move different distances
Ig found in gamma region and should be diffuse more distinct band will appear in the presence of paraprotein

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What does immunofixation do?

Mix with anti-sera that binds to heavy or light chains to classify Ig

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What protein can be identify by urine electrophoresis?

Bence Jones Protein

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What is BJP?

Excess light chains leak into the urine and precipitate

Name the causes of paraproteinaemia

MGUS 
Myeloma 
Amyloidosis 
Waldenstroms
Leukaemia/NHL

What is myeloma?

Cancer of plasma cells

Describe the progression to myeloma

Normal
MGUS
Asymptomatic
Overt myeloma

What are the direct tumour effects of myeloma?

Bone lesions, increased calcium, bone pain, marrow failure (pancytopenia)

How can bone lesions present?

Focal erosion of bone - pepper pot skull | Compression fractures in spine

What are the paraprotein mediated effects of myeloma?

Renal failure Immune suppression Hyperviscosity Amyloid

What is the commonest myeloma?

IgG

How does myeloma cause bone lesions?

Malignant cells produces cytokines that activate osteoclasts and suppress osteoblasts Osteoclasts produce cytokines which stimulate more myeloma cells

Describe hypercalcaemia

``` Stones Bones Groans Psych moans Thirst Dehydration Renal impairment ```

What is the effect of myeloma on the kidney?

``` Tubular damage by light chains Precipitate causing casts Risk of sepsis NSAIDs --> AKI Hyperuricaemia due to high cell turnover Amyloid ```

What are casts?

Solid aggregates - light chains bind to Tamm horsfall protein causing obstructive uropathy

How is obstructive uropathy due to casts treated?

Hydration, stop nephrotoxic drugs, switch off light chain production with steroids/chemo

What is the median age of myeloma diagnosis?

65 years old

How is myeloma treated?

``` Combination chemotherapy - corticosteroids - alkylating agents - novel agents - monoclonal antibodies Autologous stem cell transplant ```

How do you monitor response to myeloma treatment?

Measure paraprotein

Describe the symptom control of myeloma

Opiate analgesia Local radiotherapy Bisphosphonates Vertebroplasty

What does MGUS stand for?

Monoclonal gammopathy of undetermined significance

How is MGUS different to myeloma?

Paraprotein <30g/l Fewer faulty plasma cells <10% of bone marrow plasma No end organ damage Normal calcium, renal function, Hb, no lytic lesions, no increased infections

Describe the pathology of AL amyloidosis

Small plasma cell clone - faulty light chain has the potential to misfiled and aggregate to be insoluble - beta pleated sheets become amyloid fibril

What happens as fibrils accumulate>

Build up in tissues and cause organ damage

How is AL amyloidosis treated?

Chemotherapy

For each organ describe the damage AL amyloid causes

``` Kidney - nephrotic syndrome Heart - cardiomyopathy Liver - organomegaly, LFT abnormality Neuropathy - autonomic/peripheral GI - malabsorption ```

How is AL amyloid diagnosed?

Biopsy - bone marrow, fat, renal - congo red stain which apple green birefringence on microscopy

Name the indirect scans for AL amyloid

SAP scan Echo/MRI Nephrotic range proteinuria

What is Waldenstrom's Macroglobulinaemia?

Lymphoplasmactyoid neoplasm - clonal disorder of cells between lymphocyte and plasma

What are the tumour effects of Waldenstrom's Macroglobulinaemia?

Lymphadenopathy Splenomegaly Marrow failure

What paraprotein is in Waldenstrom's Macroglobulinaemia?

IgM

Describe the paraprotein effects of Waldenstrom's Macroglobulinaemia

Hyperviscosity | Neuropathy

How does hyperviscosity present?

High levels of IgM - fatigue - visual disturbance - confusion - bleeding - cardiac failure - coma - B symptoms

How is Waldenstrom's Macroglobulinaemia treated?

Chemotherapy | Plasmaphoresis - removes paraprotein and replaces with donor FFP