Plasma Cell Disorders Flashcards
Plasma cell
terminally differentiated, non dividing cell representing final stage of B cell lymphocyte
requires antigen dependent maturation
Main fucntion: production of antibodies (immunoglobin)
Life span: approx. 1 month
Plasma cell strutcure
- round, eccentric nucleaus with coarse chromatin (may have clock face)
- Abundant basophilic cytoplasm
- Prominent perinuclear hof (clearing)
immunoglobin structure and function
Composed of 2 homologous heavy chains and 2 homologous light chains
Heavy chains of immunoglobin
gamma (IgG, alpha(IgA), mu(IgM), delta(IgD), episilon (IgE)
light chains
kappa or lambda
immunoglobin overproduction is
hallmark of plasma cell disorders
serum protein contains:
Albumin ( majority)
Alpha Globulins
- a1 - antitrypsin (small amt)
- a2 - macroglobulin
Beta Globulun
- beta-lipoprotein and transferring (small amt)
Gamma globulin - immunoglobin (remaining amt)
Serum preotein and albumin measurement allow us to approximate immunoglobin (Ig fraction)
estimated Ig Fraction =
total serum protein - albumin
Electrophoresis
Seperates the serum proteins into albumin, alpha, beta and gamma globulin
increased immunoglobin -> gamma region
a1 - antitrypsin TGB
a1
a2
haptoglobin
ceruloplasmin
a2- macroglobulin
monoclonal
Abs derived from single anestral cell
polyclonal
Abs derived from more than one Ab producing cell
spikes in electophoresis caused by monoclonal Ig
monoclonal spike or M-spike
further identification of the M-spike protein is carried out by
immunofixation
immunofixation
- Migrate 5 seperate lanes, mono-specific Ab (toward heavy or light chain) are added
- Mono-specific antibodies bind to antigen of serum antibodies (heavy or light chain and complex)
- complexes precipitate and are measured
An M spike is characterized by a combinaiton of
- sharp, well defined band associated with a single heavy chain
- sharp, well defined band associated with a specific light chain
plasma cell disorders display
monoclonal spike
Ig classes are quantitated by
rate nephleometry
patient serum is mixed with specific
reagent to create Ag-Ab complexes
Ag-Ab causes
light scatter which is measured
helps us accurately quantitate Ig, but does NOT assess monoclonality
nephelometry is useful in combination with
electrophoresis, in following plasma cell disorders
Ig light chains in urine
Bence-Jones Proteinuria
imbalanced Ig production most frequently yields
excess free light chains (FLC)
increased FLC
leads to filtration in urine
- called Bence-Jones proteinuria
FLC can deposit in
kidney
- lead to more leakage of protein into the urine
- severe – kidney failure
Use 24 hr urine collections to perform to perform a precipitation or electrophoresis assay for determination.
Excess monoclonal immunoglobin can lead to
- Hyperviscosity
- Decreased production of normal immunoglobin
- Cryoglobins
Hyperviscosity syndrome
Excess immunoglobin causes blood to become viscuos
- higher resitance to flow in bood vessels
- decreased blood flow in small vessels of vital organs
- increased workload on the heart
Leads to symptoms of
- confusion
- headache
- dementia
- distrubances of conciousness
- stroke
- and/or coma
Plasma exchange (Plasmapheresis) is an emergency therapy for symptomatic patients
plasmapheresis
plasma exchange
Decreased produciton of normal immunoglobin
Pateints have decreased levels of normal immunoglobin
- from suppression of normal plasma cells
Low “normal” Ig level leads to increased susceptibility to infections, especially respiratory infections such as
- sinusitis
- bronchitis
- pneumonia
Seen in multiple myeloma and waldenstrom’s macroglobinemia
- infection is the leading cause of death in multiple myeloma patients
IV infusions of Ig can help decrease frequency of these infections.
Cryoglobulins
Serum immunoglobins that precipitate reversibly on exposure to cold temps
Can affect organs, but usually patient suffers with painful extremeities exposed to cold
In severe cases, may result in vasculitis and kidney damage
Multiple Myeloma (MM)
Most common plasma cell dyscrasia
Older patients (media = 67 yrs old)
Plasma cells generally stay localized in BM until late in disease
- then we begin to see in PB - leading to plasma cell leukemia
MM Major symptoms
Anemia, bone pain, increased infections
MM survival
varies ..
a few months - 15 years
MM pathophysiology
- plasma cell population expansioon
- BM stroma interaction
- Osteoclast activation
- Bone disease
- Hypercalcemia
MM plasma cell expansion
Single cell establishes a malignant clone
Malignant cell proliferates into plasma cell colonies
Begins gradually replacing normal BM leding to pancytopenia
- 1st anemia = decrease in RBCs
- 2nd thrombocytopenia - decrease in platelets
- 3rd neutropenia - decrease in neutrophils
MM interaction with BM stroma
BM microenvironment plays important role in supporting the malignant plasma cell (myeloma cells)
- promotes growth and prevents apoptosis
Myeloma cells adhere to stromal cells inducing cytokine secretion which mediate the disease
- Bone destruction (activating osteoclasts)
- Tumor cell proliferation
- drug resistance
MM osteoclast Activation
Osteoclast activating cytokines stimulate tumor necrosis factor-related induced cytokine (TRANCE)
- usually it is blocked by Osteoprotegrin (OPG), but OPG becomes trapped by myeloma cells and overwhelmed/unbalanced.
TRANCE activates
osteoclasts, which absorbs bone
MM bone disease
Results from disturbed balance of bone formation and absorption
Increased bone absorption due to increased osteoclasts activation
MM bone disease causes
- lytic bone lesions
- osteoprosis with fractures and/or spinal cord compression
- vertebral collapse
MM hypercalcemia
increased bone turn over leads to calcium being released in the blood
- constipation (intestine motility)
- increased urination
- dehydration
- muscle weakness
- kidney stones/ kidney failure (increased failure)
calcium balance
plays ciritical role in regulation of cellular function
MM hypercalcemia
mental status
confusion
MM lab findings
- decreased RBC (normocytic, normochromic RBCs)
- decreased WBC
- decreased PLT
Rouleaux
- due to excess Ig in plasma
Circulating plasma cells
- late in disease - poor prognosis
- can transition to Plasma Cell Leukemia
MM ESR
Increased Sedimentation Rate (ESR)
- due to rouleaux and increased Ig in plasma
MM chemistry studies
increased calcium
- due to bone destruction and low albumin
Possible increased LDH (Lactate Dehydrogenase)
- non-specific for tissue breakdown
Monitor BUN (blood urea nitrogen) and Creatinine
- asssesses kidney function
M-spike
- monoclonal peak in gamma region
- immunoglobin IgG
Reduced albumin
production inhibited by cytokines secreted
MM BM examination
10-30% plasma cells
Types of cells:
- flame cells
- Mott cells
- Russel Bodies
flame cell (MM)
abundant glycoprotein and ribosomes give cell intense staining
Mott cells (MM)
contains multiple Russell bodies
Russel bodies (MM)
inclusions containing immunoglobulins
MM cytogenetics
Chromosomal abnormaltities found in 40% of patients
Chromosomes 14 band q32 are the most common
- site of immunoglobin heavy chain locus
MM diagnostic criteria
BM clonal plasma cells
Monoclonal protein (M-spike); serum or urine
Related organ or tissue impatiment (CRAB)
Calcium
Renal
Anemia
Bone
C (CRAB)
Calcium
Ca > 11mg/dL
R (CRAB )
Renal
Creatinine >2mg/dL
A (CRAB)
Anemia
Hgb<10g/dL
B (CRAB)
Bone
Lytic lesions/osteoprosis
other diagnostic criteria MM
recurrent bacterial infection, hyperviscosity, amyloidosis
Plasma cell leukemia
rare multiple myeloma variant (2-3%)
Definde as:
- circulating plasma cells >2000/uL
- plasma cells more than or equal to 20% peripheral WBC
Panocytopenia - decrease: WBC, RBC, PLT
Hyperfammaglobulinemia
- IgD and IgE moslty
Can be found in advanced multiple myeloma - usually terminal event
Organomegaly, anemia, bleeding
Waldenstrom’s Macroglobulinemia
malignant lymphoproliferative disorder of plasma cytoid lymphocytes
IgM monoclonal immunoglobulins
- coat platelets impeding their function and causing complicagions
Found often in older males
Waldenstroms macroglobulinemia
symptoms
fatigue, bleeding, weakness
PB smear
Waldenstroms Macroglobulinemia
rouleaux, small lymphs with plasmacytoid features
Serum protein electrophoresis
Waldenstroms Macroglobulinemia
monoclonal peak - increased IgM
Waldenstrom macroglobulinemia
incresed blood viscosity
increased cryoglobulins
monoclonal gammopathy of undetermined significance (MGUS)
Previously known as benign monoclonal gammopathy
small M-spike with normal levels of uninvolved Ig
Fewer than 10% plasma cells on BM aspirate
No related organ impairment
20% will develop malignancy, such as multiple myeloma, lymphoma, or chronic lymphocytic leukemia
No treatment needed, but must be monitered for life