Plasma cell disorders Flashcards
1
Q
Human genome basics
A
- 3 billion base pairs
- 25K-30K genes
- People differ from each other by 1 bp in 1000
- Most sensitive method to detect minimal residual disease (MRD) is PCR
2
Q
Development of plasma cells
A
- VDJ rearrangement occurs in the BM for stem cells and pre-B cells
- Somatic hypermutation occurs in germinal centers of follicles for mature B cells
- Once the cell exits the GC as a plasma cell it expresses CD138 (typical PC marker)
3
Q
Ab structure
A
- 2 Light chains (K or L) + 2 heavy chains (G, A, E, M, D)
- Both the heavy and light chains have hyper variable regions
- Clonal Igs (what myeloma PCs produce) are exactly identical (clonal proliferation from a single mutant plasma cell)
- These are not capable of responding to infections
- M protein (paraprotein): monoclonal Ig Ab secreted from myeloma PCs (IgA and IgG are most common)
4
Q
Morphology of myeloma PCs
A
- Look largely like normal PCs (large w/ round dark nucleus)
- But they have bubbles in the cytoplasm from expanded ER (due to producing and secreting lots of Abs)
- They also have a punched out nucleolus
5
Q
BM microenvironment in supporting MM 1
A
- Stomal (BM fibroblasts) cells bind to PCs in BM and release IL1 and IL6, which prompts the PC to release cytokines (MIP1, VEGF)
- IL6 is the driving cytokine for growth of plasma cells and final differentiation of B cells to plasma cell
- MIP1 causes bone resorption by stimulating osteoclasts
- MM PCs also produce molecules that inhibit osteoblast differentiation and function: DKK1
6
Q
BM microenvironment in supporting MM 2
A
- Osteoclasts also stimulated to resorb bone by binding of RANKL to the osteoclast receptor RANK
- RANKL is present on osteoblasts and MM PCs, and when these two cells bind to RANK on osteoclasts they initiate bone resorption
- RANKL is usually inhibited from binding to RANK by OPG (thus OPG decreases bone resorption to allow for bone deposition)
- However in MM there is a decreased production of OPG by stromal cells, and the MM PCs degrade the OPG present
- This leads to a large increase in bone resorption which is not counteracted by bone deposition
- Over all leads to fragile bones w/ tendency to fracture along w/ lytic lesions
7
Q
Malignant PCs
A
- Replace normal BM causing anemia thrombocytopenia, possible neutropenia
- Cause lytic lesions of bone, leading to pain and fractures
- Secrete monoclonal Abs, depositing in heart and kidney
- Depress growth of normal B cells leading to decreased Ig and propensity to infection
- Classic presentation: vertebral or rib fracture
8
Q
Serum protein electrophoresis (SPEP)
A
- Separates serum protein by charge/size and identifies excess concentration of the uniform protein (in gamma region- Abs are gamma globulins)
- Use to Dx the disease
9
Q
Serum immunoelectrophoresis (SIEP)
A
- Runs parallel wells w/ reagents against the various heavy and light chains (g, a, m, k, l) to identify the monoclonal protein (such as IgG,L)
- Use to identify and quantify the M protein to follow disease response
10
Q
Requirements for MM Dx
A
- The pt must have polyclonal hypogammaglobulinemia (low amounts of normal Abs in blood) and one other criteria below
- This means that there is something interfering w/ normal PC function and implies MM
- Due to decrease in normal PC number but also b/c MM PCs interact w/ monocytes and T cells and down-regulate the immune response feedback system
- Most MM pts also have monoclonal hypergammaglobulinemia (high amounts of abnormal Abs in blood)
- But some simply have an increase in free light chains in their blood
- Pts must have >10% PCs in BM along w/ the above
11
Q
Distribution of monoclonal gammopathies
A
- Majority (62%) are MGUS (monoclonal gammopathy of unknown significance), which is generally benign but can progress to MM (all MM started as MGUS)
- MM is 15%, amyloidosis is 10%
- SMM (smoldering MM) is asymptomatic MM and is 3.5%
- Waldenstrom’s (monoclonal gammopathy of IgM) is 3%
12
Q
Amyloidosis
A
-Amyloid light chain (AL) deposits in kidney, liver, heart, nerves causing symptoms of fatigue, nephrotic syndrome, heart failure
13
Q
Waldenstom’s macroglobulinemia (WM)
A
- Hyper secretion of IgM monoclonal Ab
- Pentamer (large) and causes hyperviscosity
- Is a low-grade lymphoma (CD20+)
- Present w/ increase blood volume, anemia, fatigue, neurlogic Sx, bleeding (platelets can’t adhere and don’t activate), CHF
- Also can have retinal changes (sausaging of retinal veins, hemorrhages or exudates)
14
Q
Epidemiology of MM
A
- Median age of onset for me: 62, for women: 61
- Median survival from Dx: 3 yrs
- Remains mostly incurable
- Rx base on stage of disease, pt status, cytogenetics, and medical complications
15
Q
MM clinical manifestations
A
- Malignant PCs replace BM cells and lead to cytopenias (anemia, thrombocytopenia). This can lead to fatigue and bleeding. If neutropenia is present can be more susceptible to bacteria
- Increase in bone resorption leads to lytic lesions, pain, and easy fractures (spontaneous fracture= pathologic fracture)
- Secrete monoclonal Abs that are deposited in kidney leading to renal failure (high serum creatinine or low GFR)
- Lack of production of normal Ab leads to infection
