Myeloma Flashcards
What are B cells derived from?
Derived from pluripotent haematopoietic stem cells in the bone marrow
What system are B cells part of?
The adaptive immune system
‘think AB’
B cells have a _____ role.
Dural
What is the dual role of B cells?
- Antibody production.
2. Acting as antigen presenting cells.
What are immunoglobulins?
Antibodies produced by B cells and plasma cells
Describe the structure of immunoglobulins.
Proteins made up of (κ or λ) 2 heavy (μ, α, δ, γ, ε) and 2 light chains
What does each antibody in the body do?
Recognises a specific antigen
The type of antibody is determined by the type of ______ chain used
Heavy
Of the 5 types of immunoglobulins, which are:
i) monomers
ii) dimers
iii) pentamers?
i) IgD, IgE, IgG.
ii) IgA.
ii) IgM.
Name the 5 immunoglobulins found in the body.
IgD, IgE, IgG, IgA, IgM
What differentiates immunoglobulins?
The type of heavy chain used
Where does initial production and development of B cells occur?
In the bone marrow
What is B cell development under the control/influence of?
The microenvironment
What is the Ig variable element generated from?
V-D-J region recombination early in development
What are removed during B cell development?
Self-reactive cells
What do immature B cells have on their surface?
Immunoglobulin (Ig).
What happens to immunoglobulins when they leave the surface of B cells?
They exit bone marrow, ready to meet their target
What can B cells undergo once they have left the bone marrow?
Class switching by switching heavy chains
Once B cells leave the bone marrow, and travel tot the periphery, where do they go?
The follicle germinal centre of the lymph node
What do B cells do in the follicle germinal centre of the lymph node?
They identify the antigen and improve the fit by somatic mutation, or be deleted
Lymph nodes are the site where …
Immature B cells are exposed to antigens
Once B cells have been exposed to antigens in the lymph node, what do they do?
Either return to the marrow as a plasma cell, or circulate as a memory cell.
What is a plasma cell also known as?
A factory cell
What do plasma cells do?
Pump out antibodies
Describe the characteristic features on microscopy, of plasma cells pumping out antibodies.
- Eccentric ‘clock face nucleus’ on H+E.
* Open chromatin
Why does plasma cells pumping out antibodies look like an eccentric clock face nucleus on microscopy?
- Plentiful blue cytoplasm.
- Laden with protein.
- Pale perinuclear area.
- Golgi apparatus.
Describe the appearance of a bone marrow aspirate in multiple myeloma.
Typical ‘fried egg’ appearance, with nucleus off to one side and large, pale cytoplasm.
Healthy individuals will have a POLYCLONAL appearance
T
Malignancy reveals a monoclonal appearance
T
If a polyclonal increase of immunoglobulins is seen, what does this tell us about how the immunoglobulins were produced?
Many different plasma cells
Polyclonal means that many different plasma cells have many immunoglobulins
T
What is polyclonal immunoglobulins usually indicative of?
A reactive problem
Give examples of reactive problems which could cause polyclonal immunoglobulins.
- Infection.
- Autoimmune.
- Malignancy – reaction of the host to the malignant clone.
- Liver disease.
What are ALL immunoglobulins derived from when a monoclonal rise in immunoglobulins is seen?
Clonal expansion of a single B-cell
Describe the antibodies produced by clonal expansion of a single B cell.
They are identical in structure and specificity (size and charge
What other name is used for ‘monoclonal immunoglobulin’?
Paraprotein
What is a monoclonal rise in immunoglobulins a marker of?
Underlying clonal B cell disorder
What method is used to detect immunoglobulins?
Serum electrophoresis
What does serum electrophoresis do?
Separates proteins into distinct bands or zones
Proteins move at different rates, determined by …
Their size and charge
What molecule is closest to the anode? Why?
Albumin – it is the most negatively charged molecule.
If electrophoresis looks suspicious for a paraprotein, what should you do?
Serum immunofixation
Why is serum immunofixation done?
To classify the abnormal protein band
What are Bence Jones proteins?
Immunoglobulin light chains
How are Bence Jones proteins detected?
Urine electrophoresis
Why is it only immunoglobulin light chains (BJP’s) that are detected in urine electrophoresis?
Intact antibodies are too big to get through the kidney, but light chains can
What is the normal free light chain production by plasma cells?
0.5g/day
What happens if free light chains are produced in excess?
Excess can leak into the urine as BJP
There is always a little bit of light chain over-production, but this isn’t usually detectable.
T
What is the i) 1st ii) 2nd most common cause of paraproteinaemia?
i) Monoclonal Gammopathy of Uncertain Significance (MGUS).
ii) Myeloma.
What can the effects of myeloma on the body be grouped into?
- Direct tumour effects
* Paraprotein effects
What are the direct tumour effects in Myeloma?
- Bone lesions.
- Increased calcium.
- Bone pain.
- Replace normal bone marrow - marrow failure.
What are the paraprotein-mediated effects in myeloma?
- Renal failure.
- Immune suppression.
- Hyperviscosity.
- Amyloid.
How is myeloma classified?
By the type of immunoglobulin produced
What is the i) 1st ii) 2nd iii) 3rd most common classification of myeloma?
- IgG
- IgA
- Bence Jones - free light chains
Describe the appearance of lytic bone disease seen in multiple myeloma.
Multiple ‘punched-out’ lytic lesions in the skull in myeloma
Why do people with myeloma get lytic bone disease?
Myeloma cells produce cytokines which activate osteoclasts (bone destruction) and inhibit osteoblasts (bone construction)
The balance between bone production and construction is skewed.
Why does hypercalacaemia occur?
Because of breakdown of bone in lytic bone disease
What are the common manifestations of hypercalcaemia?
- Stones.
- Bones.
- Abdominal groans.
- Psychiatric moans.
- Thirst.
- Dehydration.
- Renal impairment.
What % of myeloma patients have renal failure at diagnosis?
30%
List the causes of renal failure in myeloma paitients.
- Tubular cell damage by light chains.
- Light chain deposition - cast nephropathy.
- Sepsis.
- Hypercalcaemia and dehydration.
- Drugs – NSAIDs.
- Amyloid.
- Hyperuricaemia.
Light chains can cause renal failure by tubular cell damage and cast nephropathy. Explain this.
- Free light chains are small enough to be filtered through the glomerular pores.
- They do not simply pass into the urine however, because a specific function of the kidneys is to prevent the loss of small proteins such as light chains.
- If the proximal tubules are overwhelmed by large amounts of light chain or damaged in some other way, then light chains can pass through into the loop of Henle.
- In the thick ascending limb of the loop of Henle, Tamm-Horsfall protein is produced and this can combine with free light chains to produce insoluble casts which block the nephron.
- Renal failure is a frequent feature of multiple myeloma and cast nephropathy is the most common cause in these patients.
What is the most common cause of renal failure in multiple myeloma patients?
Cast nephropathy
Is cast nephropathy damage reversible?
Possibly, with prompt treatment
What is the treatment for cast nephropathy?
Steroids/chemo to switch off light chain production.
What is the median age of diagnosis of multiple myeloma?
65
What is the survival like of someone with multiple myeloma?
5-8 years for younger pts, with more effective therapy.
Give examples of drugs/methods used to treat myeloma.
- Corticosteroids; dexamethasone or prednisolone (high dose = toxic to plasma cells)
- Alkylating agents eg cyclophosphamide, melphalan
- ‘Novel agents’ like thalidomide, bortezomib and lenalidomide
- Many more becoming available even monoclonal antibodies against plasma cells!
- High dose chemo/autologous stem cell transplant in fit patients
What is used to monitor response to treatment in multiple myeloma patients?
Paraprotein level
What drug is used to manage pain in multiple myeloma patients?
Opiates
What should NOT be used to manage pain in multiple myeloma patients?
NSAID’s
What is used to manage pain and spinal cord compression in multiple myeloma patients?
Local radiotherapy
What is used to manage hypercalcaemia and bone pain in multiple myeloma patients?
Bisphosphonates
What is vertebroplasty?
Inject sterile cement into a fractured bone to stabilise it
What is Monoclonal Gammopathy of Uncertain Significance (MGUS)?
Patient who has paraproteins but not myeloma
MGUS becomes more common as people get older
T
Outline the features which define MGUS.
- Paraprotein <30g/l
- Bone marrow plasma cells <10%
- No evidence of myeloma end organ damage;
- Normal calcium
- Normal renal function
- Normal Hb
- No lytic lesions
- No increase in infections
What is AL amyloidosis?
Immunoglobulin light chain amyloidosis
AL amyloidosis is common/rare
Rare
Describe the pathology of AL amyloidosis.
- A small plasma cell clone.
- Mutation in the light chain leads to altered structure.
- And precipitates arise in tissues as an insoluble beta pleated sheet.
Is AL amyloidosis a cancer?
NO
Why can AL amyloidosis result in problems?
Because accumulation of the insoluble beta pleated sheet in tissues can cause organ damage.
AL amyloidosis is a …..
SLOWLY PROGRESSIVE, MULTISYSTEM DISEASE.
What is the prognosis of AL amyloidosis like?
Poor – especially if cardiac amyloid
Outline the organ damage which may occur in AL amyloidosis.
- Kidney – nephrotic syndrome.
- Heart – cardiomyopathy.
- Liver – organomegaly, deranged LFT’s.
- Neuropathy – autonomic, peripheral.
- GI tract – malabsorption.
What is the gold standard diagnostic test for AL amyloidosis?
Organ biopsy, confirming Al amyloid deposition.
Congo red stain !!! - +ve result
What may be done if there is a HIGH clinical suspicion of AL amyloidosis?
Rectal or fat biopsy – less invasive
What is also looked for when diagnosing someone with AL amyloidosis? How?
Evidence of deposition of amyloid in other organs:
- SAP scan.
- Echocardiogram.
- Heavy proteinuria.
What stain is used to show amyloid deposition in AL amyloidosis?
Congo red
How does amyloid deposition appear in a congo red stain under polarised light?
‘apple-green’ birefringence
What is Waldenstrom’s Macroglobulinaemia?
IgM paraprotein
think the ‘W’ in Waldenstrom’s is an upside down M
Is Waldenstrom’s Macroglobulinaemia a neoplasm?
Yes
What type of neoplasm is Waldenstrom’s Macroglobulinaemia?
LYMPHOPLASMACYTOID neoplasm.
- Clonal disorder of cells intermediate between a lymphocyte and a plasma cell.
- Characteristic IgM paraprotein.
What are the TUMOUR EFFECTS in Waldenstrom’s Macroglobulinaemia?
- Lymphadenopathy.
- Splenomegaly.
- Marrow failure.
What are the PARAPROTEIN EFFECTS in Waldenstrom’s Macroglobulinaemia?
- Hyperviscosity.
* Neuropathy.
Why are the problems in Waldenstrom’s Macroglobulinaemia different to in Myeloma?
Because IgM is a pentamer, so is 5x the size of IgG.
What are the clinical features of WM?
- Hyperviscosity Syndrome*
- Fatigue, visual disturbance, confusion, coma.
- Bleeding.
- Cardiac failure.
B symptoms; night sweats; weight lossLOT
Lots of IgM makes the blood more viscous
T
How is WM treated?
- Chemotherapy.
* Plasmapheresis – removes the patients IgM paraprotein from the circulation and replace with donor plasma
