Harrison's 107 - Plasma cells Disorders Flashcards
1
Q
What diseases are called plasma cell disorders?
A
- Multiple myeloma (MM), SMM, MGUS
- Waldenstrom’s macroglobulinemia
- Heavy Chain diseases
- POEMS Syndrome
2
Q
What diseases are the synonyms for Heavy Chain diseases?
A
Monoclonal Gammopathies Paraproteinemias
Plasma cell Dyscrasias
Dysproteinemias
3
Q
What is the root common cause for plasma cell disorders?
A
B cell Transformation into adult defective plasma cell without sufficient antigenic stimulus.
4
Q
What 3 factors determines the clinical manifestation & symptoms of a plasma cell disorder?
A
Amount of tumor cells
Type of Secretion Product
Immune cells response
5
Q
What is the normal light chains excess produced by plasma cells and excreted renally?
A
10 mg/day max.
6
Q
What cell stage is missing in this hematopoietic lineage?
Pluripotent Stem cell Common Lymphoid Precursor cell Pro-B cell \_\_\_\_\_\_\_\_\_ Immature B cell Mature B cell Plasma cell
A
Pluripotent Stem cell Common Lymphoid Precursor cell Pro-B cell Pre- B cell Immature B cell Mature B cell Plasma cell
7
Q
What cell stage is missing in this hematopoietic lineage?
Pluripotent Stem cell Common Lymphoid Precursor cell \_\_\_\_\_\_\_\_\_ Pre- B cell Immature B cell Mature B cell Plasma cell
A
Pluripotent Stem cell Common Lymphoid Precursor cell Pro-B cell Pre- B cell Immature B cell Mature B cell Plasma cell
8
Q
What cell stage is missing in this hematopoietic lineage?
\_\_\_\_\_\_\_\_\_\_ Common Lymphoid Precursor cell Pro-B cell Pre- B cell Immature B cell Mature B cell Plasma cell
A
Pluripotent Stem cell Common Lymphoid Precursor cell Pro-B cell Pre- B cell Immature B cell Mature B cell Plasma cell
9
Q
What cell stage is missing in this hematopoietic lineage?
Pluripotent Stem cell \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ Pro-B cell Pre- B cell Immature B cell Mature B cell Plasma cell
A
Pluripotent Stem cell Common Lymphoid Precursor cell Pro-B cell Pre- B cell Immature B cell Mature B cell Plasma cell
10
Q
What cell stage is missing in this hematopoietic lineage?
Pluripotent Stem cell Common Lymphoid Precursor cell Pro-B cell Pre- B cell \_\_\_\_\_\_\_\_\_\_\_\_\_ Mature B cell Plasma cell
A
Pluripotent Stem cell Common Lymphoid Precursor cell Pro-B cell Pre- B cell Immature B cell Mature B cell Plasma cell
11
Q
What cell stage is missing in this hematopoietic lineage?
Pluripotent Stem cell Common Lymphoid Precursor cell Pro-B cell Pre- B cell Immature B cell \_\_\_\_\_\_\_\_\_\_\_ Plasma cell
A
Pluripotent Stem cell Common Lymphoid Precursor cell Pro-B cell Pre- B cell Immature B cell Mature B cell Plasma cell
12
Q
What cell stage is missing in this hematopoietic lineage?
Pluripotent Stem cell Common Lymphoid Precursor cell Pro-B cell Pre- B cell Immature B cell Mature B cell \_\_\_\_\_\_\_\_\_\_
A
Pluripotent Stem cell Common Lymphoid Precursor cell Pro-B cell Pre- B cell Immature B cell Mature B cell Plasma cell
13
Q
What is the classic description of a serum electrophoresis in a state of a plasma cell disorder?
A
M-Component - Additional Peak of γ Globulins
14
Q
Where are B cells formed? Matured?
A
Bone Marrow
Bone Marrow
15
Q
BCR - which Igs?
A
IgM and IgD
16
Q
Processes of the Development of B cells after Antigen meeting?
Ending in a Plasma cell
A
Activation
Affinity Maturation
Differentiation
Isotypes Switch
17
Q
Negative Selection of B cells - Outcomes
A
1- Apoptosis of Auto-reactivity B cells
2 - Central tolerance:
Receptor Modification,New Light chain expression
Ultimately - No auto-reactivity
18
Q
Classical B cells in Lymph Node Cortex Follicles - which response kind?
A
TD - Require T cells
For Protein antigens
Long Lived Plasma cells, Isotype switched
19
Q
Lymph Node Marginal area B cells response - what kind?
A
TI - No T cell
Lipids and Polysaccharides antigens
Short lived plasma cells - IgM
20
Q
What are the co-stimulatory molecules on TH2 and B cells?
TD, B cell Activation - 3 By order
A
BCR+Antigen - TCR
CD40 - CD40L
IL21R - IL21
21
Q
Isotype (Class) Switch - Signals leading to which Antibody constant regions by B cell
A
IFN gamma - IgG
IL5 - IgA
IL4/IL13 - IgE
22
Q
Serum electrophoresis in a state of a plasma cell disorder - Quantitative / Qualitative?
A
Quantitative
23
Q
Immunoelectrophoresis in a state of a plasma cell disorder - Quantitative / Qualitative?
A
Qualitative
24
Q
Immunoelectrophoresis
What does it show?
A
Check the Ig Type and if Monoclonal
Presents Heavy or Light Chain
25
In 20% of Multiple Myeloma Cases there is Light Chain Secretion that will turn out as ____ ______ Protein in Urine.
In 20% of Multiple Myeloma Cases there is Light Chain Secretion that will turn out as Bence Jones Protein in Urine.
26
In Extramedullary Plasmacytoma or Solitary Bone Plasmacytoma only third of Patient will present __________ on serum electrophoresis.
In Extramedullary Plasmacytoma or Solitary Bone Plasmacytoma only third of Patient will present M-Component on serum electrophoresis.
27
In what other Neoplasms will we see a M-Component on serum electrophoresis?
CML, CLL, Breast and Colon Cancer
28
In what Non-neoplastic states will we see a M-Component on serum electrophoresis?
```
Cirrhosis
Sarcoidosis
Gaucher's Disease
Parasitic Infections
Pyoderma gangrenosum
```
29
In what Autoimmune Diseases will we see a M-Component on serum electrophoresis?
Rheumatoid Arthritis
Myasthenia Gravis
Cold Agglutinin Disease
30
Multiple Myeloma - Definition
Monoclonal Plasma cell Malignant Proliferation
31
Multiple Myeloma - Risk factors
Radiation, Pesticides, also Leather, Wood and Crude oil at Workplace
32
Multiple Myeloma - Typical Chromosomal Aberrations
Hyperdiploidy ,13q14 deletion, 17p13 deletion
33
Multiple Myeloma - Typical Chromosomal Translocations
t(11;14)(q13;q32), t(4;14)(p16;q32), t(14;16) , 1q amplification or 1p deletion
34
Activation
Affinity Maturation
Differentiation
Isotypes Switch
Which process was found to damaged in MM ?
Isotypes Switch
35
What are some Mutations common in MM (not determined as causative) ?
K-ras
N-ras
B-raf
36
What Interleukin is suspected to have a role in malignant proliferation in MM ?
IL6
37
What hematologic malignancies lab test is usually useless in Multiple myeloma? Why?
Peripheral Blood Smear
| Monoclonality is Undetectable
38
Multiple Myeloma incidence rises with -
older age, rare to encounter under 40
39
Multiple Myeloma Median diagnostic age is -
70
40
Multiple Myeloma is more common in Men/Women ?
Men
41
Multiple Myeloma is twice as common in African-Americans/Caucasians?
African-Americans > x2 Caucasians
42
What is the common mediterranean subtype of Multiple Myeloma?
Immunoproliferative small intestinal disease
| IPSD
43
What are the clinical manifestations of Multiple Myeloma? "CRAB"
Calcemia (Hyper) - CNS & Clotting disorders
Renal Injury
Anemia & Infections
Bone Lytic lesions
44
What is the most common symptom in MM ? What does in arise from ?
```
Bone Pain (70%)
Osteoclast Activating Factors formed by Tumor cells and Subsequent Pathological Fractures
```
45
What are the consequences of the lytic bone lesions in MM ?
Hypercalcemia with complications such as spinal cord compression, weakness, retinopathy, radicular pain.
46
Infections is the second most common symptom (after bone pain) in MM. What does in arise from ?
Hypogammaglobulinemia if M-Component is excluded T17 rise and Terg Malfunction
Granulocyte Lysosomal depletion with slow migration
Complement Malfunctions
Immunosuppressive treatments
47
What are the most common infections locations in MM?
Pneumonia and Pyelonephritis
48
What are the most common pathogens in MM ?
Strep. Pneumo, Staph. Aureus, Klebsiella Pneumo.
| E. Coli in Pyelonephritis
49
AKI will appear in __% of patients and ESRD will occur in __% of patients of MM.
Renal Injury will appear in 50% of patients and ESRD will occur in 25% of patients of MM.
50
What are the causes for AKI in patients with MM ? (8)
```
Hypercalcemia
NSAIDs
CIN
Hyperuricemia
Reccurent Infections
Amyloid Deposits
Bisphosphonates
Myeloma Tumor cells Infiltration
```
51
Tubular damage will almost always arise in MM due to -
Light Chain Deposition
52
What are the Normal Physiological processes that light chains go through in the kidney and Later on?
Filtration
Reabsorption
Catabolism
53
What is the indirect effect of Light Chain Deposition that enhances the toxic direct tubular damage?
Intracellular Lysosomal Enzymes Releases
54
What is the earliest manifestation of AKI as result of MM ? What is the most common cause of AKI here?
Adult Fanconi Syndrome - RTA type 2, Glucose and AA loss.
| Hypercalcemia!
55
What is unique about the proteinuria in MM ?
Without Hypertension. Mostly Light Chains - "Bence Jones Protein".
56
What is the glomerular effect of MM ?
Usually no effect - Correct Albumin levels
57
Patients with MM may have a _______ anion gap because M-Component is ______- leading to Chloride Retention.
Patients with MM may have a decreased anion gap because M-Component is Cationic - leading to Chloride Retention.
58
What does the high Antibodies concentration leads to on blood test presentation?
Pseudohyponatremia
59
What is the cause of ESRD in MM ?
Amyloid Nephropathy - AL amyloid from Light Chains
60
What can exacerbate AKI in MM patients?
Dehydration
| Medications such as Bisphosphonates or NAIDS
61
What neurological symptoms does hypercalcemia cause in MM ?
Lethargy, Weakness, Depression
62
What neurological symptoms does hyperviscosity syndrome cause in MM ?
Headaches, Vertigo, Blurred Vision and Retinopathy
| Coma
63
What neurological symptoms does lytic bone lesions cause in MM ?
Spinal Cord Compression, Radicular Pain, Incontinence
64
What neurological symptoms does amyloid deposition cause in MM ?
Carpal Tunnel Syndrome with Sensory Polyneuropathy
65
Sensory Polyneuropathy in MM - what can cause that, apart from Amyloid ?
Treatment: Bortezomib or Lenalidomide
66
What are the emergencies that can arise from MM ?
```
Spinal Cord Compression
Pathological Fracture
Hyperviscosity Syndrome
Sepsis
Severe Hypercalcemia
```
67
Diagnosis of Multiple Myeloma
1. __%< CD138+ Plasma cell level with Kappa/Lambda Monoclonality.
2. M Component in Serum or Urine
3. Myeloma Defining Event
Diagnosis of Multiple Myeloma
1. 10%< CD138+ Plasma cell level with Kappa/Lambda Monoclonality.(30 g/L)
2. M Component in Serum or Urine
3. Myeloma Defining Event - Pathological Fractures i.e
68
Diagnosis of Multiple Myeloma
1. 10%< CD138+ Plasma cell level with Kappa/Lambda Monoclonality.
2. ________ in Serum or Urine
3. Myeloma Defining Event
Diagnosis of Multiple Myeloma
1. 10%< CD138+ Plasma cell level with Kappa/Lambda Monoclonality. (30 g/L)
2. M Component in Serum or Urine
3. Myeloma Defining Event - Pathological Fractures i.e
69
Diagnosis of Multiple Myeloma
1. 10%< CD138+ Plasma cell level with Kappa/Lambda Monoclonality.
2. M Component in Serum or Urine
3. ________________
Diagnosis of Multiple Myeloma
1. 10%< CD138+ Plasma cell level with Kappa/Lambda Monoclonality.(30 g/L)
2. M Component in Serum or Urine
3. Myeloma Defining Event - Pathological Fractures i.e
70
What are the Diseases on the DD of MM ?
Smoldering Multiple Myeloma
| Monoclonal Gammopathy of Unknown Significance
71
Monoclonal Gammopathy of Unknown Significance
| Risk Factor for transition to MM ?
Non-IgG Subtype
Abnormal Kappa/Lambda Ratio (Not 60%-40%)
Serum M-Component above 15 g/L
72
Smoldering Multiple Myeloma
| Risk Factor for transition to MM ?
10%< CD138+ Plasma cell level
Abnormal Kappa/Lambda Ratio (Not 60%-40%)
Serum M-Component >30 g/L
73
What are the common variants of MM ?
Solitary Bone Plasmacytoma
| Solitary Extramedullary Plasmacytoma
74
Solitary Extramedullary Plasmacytoma
Lesions of lymphatic tissue of nasopharynx or paranasal sinuses
75
What is the physical examination principles for checking for MM ?
Looking for Masses and Tender Bones
76
What is purpose of each Imaging test in MM ?
X-Ray: Lytic Bone Lesions of Skull
MRI: Spinal cord Compression or Vertebral Lesions
PET/CT: Follow up of MM and Diagnosis of Solitary Bone Plasmacytoma
77
What are the lab tests from MM ?
CBC for Pancytopenia
ESR for Inflammatory state
Chemistry - Calcium, Urate, Creatinine, BUN
ALP - to rule out Paget Disease
78
M-Component - How is it recognized?
Protein Electrophoresis
| 24 hour Bence Jones in Urine
79
Which light chain usually has worse prognosis ?
Lambda
80
What is the risk in patients with an IgM related MM ? tx?
Hyperviscosity Syndrome
| Plasmapheresis!
81
What is the strongest prognostic factor in MM ? Why?
B2 Microglobulin
| Present on MHC-1 released by Tumor cells evade immune surveillance / cell turnover
82
ISS - What are the lab values taken into account?
B2 Microglobulin & Albumin
83
What are other prognostic factors apart from B2 Microglobulin ?
LDH
Microalbumin/B2 Microglobulin (80% Renal involv.)
Cytogenetic Variations
Patient disabilities
84
What is the treatment for High risk transition type MGUS ?
Twice yearly - Electrophoresis for M component +
| Observation: CBC, Creatinine and Calcium
85
What is the most important question one has to ask after diagnosing MM ? What does it depend on? Why is it Important during MM medical care?
Transplant ineligible? - age above 70 and co-morbidities
If Eligible - Usage of Melphalan will prevent ASCT!
86
What is the treatment of MM in Transplant ineligible patients?
Melphalan! , Prednisone and Bortezomib
| Lenalidomide as maintenance later
87
What is the treatment of MM in Transplant eligible patients?
Lenalidomide, Dexamethasone and Bortezomib
| Lenalidomide as maintenance later
88
What is maintenance therapy of MM ? What is the Adverse Effect? What is the prevention?
Lenalidomide, May lead to DVT, Prevention with Low-dose Aspirin
89
What is the name of the proteasome inhibitor treatment for MM ? what is the Adverse effect?
Bortezomib - Immunosuppression - Herpes Zoster Flares
90
What are the Osteoblast inhibitor & Osteoclast activators set out from malignant plasma cells in MM ?
Osteoblast inhibitor - DKK-1
| Osteoclast activators - IL1 & IL6 lead to RANKL↑
91
What kind of malignancy is yielding cells releasing specifically IgMs ?
Waldenstrom's Macroglobulinemia
92
What is the most common syndrome associated with WM ?
Hyperviscosity Syndrome
93
What is the DD of WM?
MM
CLL
Marginal Zone Lymphoma
94
What is the median age of WM ? what is the dominant sex?
64
| Men
95
What is the difference from MM, when examining WM bone involvement ?
10%< CD138+ Plasma cell level with Kappa/Lambda Monoclonality.(30 g/L) in BM BUT - not Lytic Bone Lesions therefore no Hypercalcemia and no AKI usually.
96
In 80% of WM the light chain in the IgM will be -
Kappa
97
What is the diagnostic test that allows differentiation of WM from MM(IgM8) , CLL and Marginal Zone Lymphoma?
Somatic Mutation of MYD88 in L265P position.
98
What will we see in WM patient with MAG IgM? What is MAG?
MYELIN ASSOCIATED GLOBULIN
| NEUROPATHY
99
What are the common symptoms of WM and MM ?
Recurrent Infections
Weakness
Lethargy
100
What are the symptoms unique for WM and less appearing on MM ?
Hyperviscosity Syndrome - Epistaxis, Blurry Vision, Neuropathy.
Hepatosplenomegaly.
Raynaud Phenomenon
101
What are lab results unique for WM and less appearing on MM ?
Rouleaux Formations (ESR)
Positive Coombs test
Malignant Lymphocytes (Peripheral Blood Smear)
10% are Pure Cryoglobulins (leading to Raynaud)
102
Parameters for high risk WM ?
Older age
Male
Symptomatic WM with Cytopenia
103
What is the treatment for Hyperviscosity Syndrome leading to Paralysis or Loss of Consciousness? Why?
Plasmapheresis - 80% of IgM is Intravascular
104
First Line Treatment for WM ?
No specific defined treatment - tailor for each patient:
| Ibrutinib - BTKi, Rituximab , Cyclophosphamide. Bortezomib
105
What is Amyloid?
Misfolded protein deposits in extracellular spaces that causes tissue damage.
106
What is the biochemical form of an Amyloid?
Beta-Pleated Sheet
107
What is the staining used in Amyloidosis? What other Laboratory may reveal it?
Congo Red on Histology
| Apple Green Birefringence in Polarized light
108
What are the clinical findings of Systemic Amyloidosis?
Nephrotic Syndrome; Ascites & Edema
RCM -Distant Heart sound, S4 & S3 and Arrhythmia
Glossomegaly and Hepatosplenomegaly
Carpal Tunnel Syndrome
109
What are the subtypes of Systemic Amyloidosis?
Primary Amyloidosis
| Secondary Amyloidosis
110
What kind of Amyloidosis is derived from elevated Serum Amyloid A (SAA) in Chronic Inflammatory Diseases or Malignancies?
Secondary Amyloidosis
Possibly in FMFm Brucella, TB, HCV, RA, IBD, etc..
111
What kind of Amyloidosis is derived from elevated Amyloid Light Chain (AL) in Plasma cell Dyscrasias?
Primary Amyloidosis
112
What are the organ specific/localized Amyloidosis subtypes?
Senile Cardiac Amyloidosis
Familial Amyloid Cardiomyopathy
T2DM related Amyloidosis
Alzheimer's Disease
113
What are the organ specific/localized Amyloidosis subtype that is related to elevated Serum Transthyretin?
Senile Cardiac Amyloidosis
114
What are the organ specific/localized Amyloidosis subtype that is related to elevated Mutated Serum Transthyretin?
Familial Amyloid Cardiomyopathy
115
What are the organ specific/localized Amyloidosis subtype that is related to elevated Serum Amylin?
T2DM
116
What are the organ specific/localized Amyloidosis subtype that is related to elevated Serum A-beta Amyloid?
Alzheimer's Disease
117
What kind of diseases are leading to Amyloidosis derived from elevated Amyloid Light Chain (AL)?
Multiple Myeloma
Waldenstrom's Macroglobulinemia
CLL
Lymphoma
118
What is the typical Light chain present in Primary Amyloidosis?
Lambda
119
What is the Most common organ damage resulting from Primary Amyloidosis? Characteristic Features?
Renal - Nephrotic Syndrome (80%)
| Proteinuria, Hypoalbuminemia, Hyperlipidemia and Edema with possible Anasarca.
120
Primary Amyloidosis - What is the course of the disease?
Rapidly Progressing Disease
121
What is the Second Most common organ damage resulting from Primary Amyloidosis? Characteristic Features? What is the DD ?
Cardiac - Hypertrophy and following Restrictive Disease. Low Voltage ECG.
Diagnosed with TEE/TTE, the DD is Hemochromatosis or Sarcoidosis.
122
What are the classical Neuropathy signs for Primary Amyloidosis?
Sensory and Motor Neuropathy are present bu Autonomic is the more specific - Neurogenic Bladder, Gastroparesis and Orthostatism.
123
What is the Rare yet Pathognomonic Sign for Primary Amyloidosis?
Macroglossia (10%)
124
Facial Features of Primary Amyloidosis?
| Why is it present?
```
Periorbital Ecchymosis ("Raccoon Eyes") with Alopecia
Easy Bruising - Deposition with Factor X binding.
```
125
Primary Amyloidosis leads to ALP↑, GGT↑ and Direct Bilirubin↑.
Why is it present?
Cholestasis with Hepatosplenomegaly
| Obstructive Hepatitis by Amyloid deposits
126
What are the diagnostic work-up steps in suspicion of Primary Amyloidosis?
1. Urine/Blood Collection of Monoclonal Light Chains.
2. Non-Invasive Biopsy
3. Invasive Biopsy
127
Non-Invasive Biopsy - suspicion of Primary Amyloidosis, What are the collection sites?
Peritoneal
Rectal
Areolar
Vaginal
128
Invasive Biopsy - suspicion of Primary Amyloidosis, What are the collection sites?
Renal
Cardiac
Liver
Spleen
129
Easy Bruising is caused by Primary Amyloidosis Deposition with Factor X binding, this leads to higher risk for DVT, what else might lead in this case to a higher risk for DVT?
Amyloid Nephrotic Syndrome leads to higher loss of Antithrombin, Protein C and S - Hypercoagulable State
130
What are the different heavy chain diseases?
Alpha Heavy Chain disease
Gamma Heavy Chain disease
Miu Heavy Chain disease
131
What is the most common heavy chain disease? Symptoms and Treatment?
Alpha Heavy Chain Disease
Chronic Diarrhea, Weight Loss, Mesenteric and Para-aortic Lymphadenopathy.
Chemo with Antibiotics.
132
What heavy chain disease will most probably lead to Palate Inflammation? Other Symptoms and Treatment?
Gamma Heavy Chain disease
May also cause Lymphadenopathy, Hepatosplenomegaly, Fever, Anemia, Myalgia.
Tx in Symptomatic Disease - Chemo with Rituximab
133
What does POEMS Syndrome involve? (POEMS)
```
Polyneuropathy
Organomegaly
Endocrinopathy
Monoclonal-protein
Skin Changes
```
134
What does POEMS Syndrome includes in Polyneuropathy?
Sensory Neuropathy with Sclerotic Lesions in bone
135
What does POEMS Syndrome includes in Organomegaly?
Lymphadenopathy
Hepatomegaly
Splenomegaly
136
What does POEMS Syndrome includes in Endocrinopathy?
Hyperprolactinemia
DM1/2
Adrenal Insufficiency
Hypothyroidism
137
What does POEMS Syndrome includes in Skin Changes?
Hyper-pigmentation
Hypertrichosis
Skin Thickening
Clubbing
138
What is the classical Treatment for POEMS Syndrome?
Lenalidomide, Dexamethasone and Bortezomib
Plasmapheresis is NOT EFFECTIVE
Radiation of Sclerotic Lesions.
139
What is the supportive treatment for Anemia resulting from Multiple Myeloma or Waldenstrom's macroglobulinemia? What is the Type of Anemia is present ?
EPO, Iron, Folic Acid and Vitamin B12
| For Normocytic Normochromic Anemia of MM or WM.
140
What is a unique electrolyte abnormality present in MM? Why?
Pseudohyponatremia
| Elevated proteins in serum cause that (M Component)
141
What is an important immunological treatment for MM induced URTI or UTI? What is a side effect and response to it?
IVIG for Infections in MM
| Side effect - Aseptic Meningitis: LP for Pressure release is needed.
142
MM Parameters for Prognostic Stage - Stage I ?
B2M<3.5 & ALB>=3.5
143
MM Parameters for Prognostic Stage - Stage II ?
B2M<3.5 & ALB<3.5
OR
B2M = 3.5-5.5
144
MM Parameters for Prognostic Stage - Stage II ?
B2M > 5.5
145
What is the actual process of Plasmapheresis?
Removal and Filtration of 15% of Plasma
