Histopathology of myeloma Flashcards
What is a plasma cell myeloma?
malignant tumour arising from plasma cells in BM
made up on monoclonal plasma cells
one of the most common haematological cancers
incidence: 10/100,000
median age @ Dx is 68yo
What is a plasma cell?
formed after B cell activation when it fully differentiates
Plasma cells are the final stage of B cell differentiation
(however, not all B cells will differentiate into plasma cells)
How are plasma cells formed?
B cell exposed to specific Ag
Clonal activation of B cell mediates transdifferentiation into plasma cell
Somatic hypermutation of plasma cell aids generating a highly specific binding site @ the F-Ab
Secreted Ig molecules released in mass (kg) by plasma cells
What is meant by a polyclonal immune response generated against one pathogen?
One pathogen is made up of a number of Ag
But one single B cell/plasma cell can only generate Ig specific to one of these Ag epitopes
Therefore, for that one pathogen there must be multiple clones of B cells produced (each targeting a distinct Ag epitope on that pathogen)
This ensures an efficiency immune response and elimination
Which clinical and radiological features may raise suspicion of myeloma?
- bony pain
- anaemia
- recurrent infections
- renal impairment
- hypercalcaemia
- raised ESR
What further testing is used in the Dx of myeloma (additional to clinical and radiological features)
serum/urine electrophoresis
bone marrow biopsy (aspirate and trephine)
How can identification of Ig markers (class and light chain type) be important in Dx of myeloma?
important in distinguishing malignancy from a reactive condition of BM
How does ‘cellular pathology’ inform Dx of myeloma?
- BM infiltration by (dysplastic) plasma cells
- Abnormal if plasma cells make up >30% of the BM cellularity (normally it would only be 2-3%)
- Dx made in conjunction with other clinical evidence
Are dysplastic plasma cells always present in the BM biopsy in myeloma?
No
plasma cell abundance may be elevated (>30%) but cells may not be dysplastic
Infiltration itself is a warning sign that this may soon occur though
(hence why Dx is not based solely on BM trephine)
What 3 blood cell lineages are present in a normal BM aspirate?
- RBC
- WBC
- Megakaryocyte
How do megakaryocytes become platelets?
cytoplasmic blebs present in megakaryocyte are released and become platelets/thrombocytes
How does the cellularity in BM change with a reactive condition?
There may be slight elevations in plasma cells
but abundance would not exceed 30%
unlike myeloma
How is cellularity in BM related to age?
Low cellularity associated with older age
Cellularity = 100 - age (yr)
What do plasma cells look like with H&E stain?
contains eccentric nucleus (not centrally placed)
this produces a ‘clock face’ caused by chromatin condensation
Also may be able to observe a perinuclear blob, where there is a slightly paler patch of cytosol surrounding the nucleus
What is the normal ratio of kappa: lambda light chains present in healthy individuals (in BM)?
2-3 kappa: 1 lambda
How do light chains look in a slide section following staining?
plasma cells producing monoclonal light chain will stain brown
Nuclei from normal cells stain as blue/purple
What is light chain restriction?
in myeloma, neoplastic plasma cells will preferentially one type of light chain over the other
this skews the ratio between normal and abnormal ratios
This would not occur in reactive conditions and can be a strong indicator of a malignant neoplasm
When looking at kappa and lambda light chains, why is a neoplastic rather than inflammatory process?
neoplastic plasma cells are making only one type of light chain
in reactive processes, a large number of Ig are secreted from multiple cells and would have included both lambda and kappa
neoplasms are clonal, that is they are derived from a single mutated parent cell
What are the major criteria used for Dx of myeloma?
- marrow plasmacytosis >30% (normal is 2-3% max)
- plasmacytoma (biopsy)
- M-component
serum: IgG most common then IgA
urine: Bence-Jones protein (1g/24hr)
Which genetic markers may be investigated in plasma cells in myeloma?
CD56
Cyclin D1
What are the minor criteria used for Dx of myeloma?
- marrow plasmacytosis (10-30%)
- M-component present but less than above
- lytic bone lesions
- reduced normal Ig (< 50% of normal)
What are the main mechanisms by which myeloma affects patient health?
- lytic lesions: impaired bone health
- pancytopenia: caused by replacement of BM
- paraprotein: secretory product of neoplastic plasma cells
What is the pathogenesis of lytic lesions in myeloma? What are the consequences?
Appears as punched out appearance on X ray films. ‘pepper pot’ appearance when multiple lytic lesions on skull
inflammatory cytokines (IL-1B and IL-6) stimulate osteoclast activity (and inhibit osteoblast)
Promotes bone resorption, release Ca2+ (hypercalcaemia) and bone thinning
causes pain, pathological #, vertebral collapse and wedge fractures
Where are osteoclasts derived from?
derived from BM monocytes
these proliferate and fuse to form MULTINUCLEATE OSTEOCLASTS
Where are osteoblasts derived from?
derived from periosteum or BM stromal cells
What signals released by osteoclasts trigger concomitant bone deposition by osteoblasts in physiology?
Ca2+
TGF (act on osteoblasts to promote bone deposition)
What is pancytopenia?
comprises:
- resultant immunosuppression
- thrombocytopenia
- anaemia
How does paraprotein/mutated Ig mediate damage in myeloma?
M-component = monoclonal gamma globulin
Bence-Jones proteins in urine (75% of cases)
High [bence-jones] can mediate precipitation in renal tubules -> ATN -> AKI
How does renal impairment in myeloma result in an acutely unwell patient?
hypercalcaemia -> dehydration (osmotic pressure differences)
Acute RF
Amyloid AL (deposits)
hyperviscosity syndromes (caused by paraprotein which makes blood sticky, increased ESR)
What are the 4 main mechanisms by which renal failure occurs in myeloma?
- Bence-Jones proteins: filtered through glomerulus and form protein casts in DCT causing AKI/ATN
- free light chains can cause amyloid (AL) deposits (nephrotic syndrome)
- hypercalcaemia (dehydration)
- NSAIDs taken for bony pain
What are the complications of myeloma protein/amyloid in kidneys?
can cause sloughing of tissue
formation of granulomas
Functional deficit to GFR etc
What is amyloid?
- any protein that has abnormally folded into a beta-pleated sheet
- makes protein very insoluble
- Body not able to break down amyloid
- amyloid deposits in the extracellular spaces -> cell necrosis
What are common sites of amyloid deposit?
heart
blood vessels
functional deficits: ischaemia ?
What is amyloidosis?
group of conditions where there is excess deposition of amyloid tissues
body has no inflammatory/reactive response to amyloid
What are the 4 main types of amyloid protein?
Amyloid AA
precursor: serum amyloid A
Amyloid A beta
precursor: amyloid precursor protein
e. g. tau protein in Alzheimer’s
Amyloid AL
Precursor: Ig light chain
most common type, seen in myeloma (caused by light chain fragments)
Amyloid ATTR
precursor: transthyretin
more commonly seen in inherited/genetic conditions. Driven by constitutive amyloid expression
What is systemic amyloidosis?
generalised deposition of amyloid in multiple organs
leads to gradual organ failure
often undiagnosed until patients are really unwell (when organ damage starts)
most important organs affected: kidney, heart, GI tract,
What are the most common types of amyloidosis?
Amyloid AA (complication of chronic inflammation) Amyloid AL (poor prognosis, observed in plasma cell disorders e.g. MGUS)
What kind of staining can be used to visualise amyloid?
H&E: difficult to see, nodular deposition of pink amorphous material observed
Congo red: salmon pink coloured deposits of amyloid
Can take Congo red stained section and POLARISE under UV to observe amyloid as apple green bifringence
Polarised congo red (apple green staining) is a diagnostic marker of myeloma
What is the prognosis of myeloma generally?
poor
