Myeloma, Lymphoma and CLL Flashcards
1
Q
What is myeloma?
A
- Incurable malignant disorder of clonal plasma cells (these are a type of B cell)
- One of a spectrum of plasma cell dyscrasias called the “paraproteinaemias”
2
Q
Epidemiology of myeloma?
A
- Annual incidence of 60-70 per millions in the UK, median age 70 years
- Higher incidence in Afro-Caribbean ethnic groups compared with Caucasians
3
Q
What is myeloma preceeded by in all patients?
A
Asymptomatic MGUS
4
Q
What is MGUS?
A
Monoclonal gammopathy of undetermined significance (MGUS) is a condition in which your body makes an abnormal protein in the bone marrow — known as monoclonal protein or M protein.
5
Q
Describe the development of B cells in the bone marrow?
A
- Pro B cells
- Pre B cells
- Immature B cells
- Leave bone marrow and either a) apoptose and die b) travel as naive B cells to lymphoid tissue (naive as have not been exposed to antigen)
6
Q
Where does B cell development occur prenatally?
A
In the foetal liver
7
Q
What do naive B cells express on their surface?
A
- IgM
- IgD
- Pan B-cell markers (CD 19, 20, 22, 40, 79a)
- Complement receptors
- CD23
- Some express CD5
8
Q
What immunoglobulins do naive B cells express?
A
IgM and IgD
9
Q
When encountering antigens, what immunoglobulins do B cells then express?
A
Naive B cells undergo class-switch recombination (CSR) from initially producing membrane-bound IgM and IgD to expressing more effective membrane-bound IgG, IgA, or IgE when encountering antigens.
10
Q
Location of lymphoid tissue around the body
A
11
Q
Describe stages of development of B cell once it enters the lymphoid tissue
A
- B cells enter lymphoid tissue and become centroblasts
- Exposed to antigens by cells such as dendritic cells
- Stages of development to become centrocytes
- Will leave lymphoid tissue as either memory B cell or plasma B cell
12
Q
Plasma cells have a separate stage of maturation. Describe the maturation route of a plasma cell
A
- NF-kB pathway upregulated when plasma cells developed
- Become plasmablasts
- Eventually form plasma cells
13
Q
If plasma maturation ceases and they remain as plasmablasts, what can occur?
A
Mutliple myeloma
14
Q
What are immunoglobulins? What are they produced by?
A
Glycoprotein molecules produced by plasma cells in response to an immunogen and function as antibodies
15
Q
What is the structure of immunoglobulins?
A
- Composed of 4 polypeptide chains, held together by covalent disulphide bonds
- 2 identical light chains
- 2 identical heavy chains
- Each chain has one variable and one constant region
16
Q
How are immunoglobulins classified?
A
Classified according to the amino acid sequence in the constant region
- Heavy chains are either: IgG, IgM, IgA, IgD, IgE
- Light chains are either: kappa or lambda
17
Q
What is protein electrophoresis?
A
- Protein electrophoresis is a test that measures specific proteins in the blood.
- Serum is placed in a gel and exposed to an electric current
- The test separates proteins in the blood based on their electrical charge.
- Five major fractions are normally identified:
- Serum albumin
- Alpha-1 globulins
- Alpha-2 globulins
- Beta blogulins
- Gamma globulins
- The protein electrophoresis test is often used to find abnormal substances called M proteins.
18
Q
What are the 5 major fractions normally identified in protein electrophoresis?
A
- Serum albumin
- Alpha-1 globulins
- Alpha-2 globulins
- Beta blogulins
- Gamma globulins (these are the immunoglobulins)
19
Q
What abnormal protein is protein electrophoresis used to detect?
A
Protein M (can indicate myeloma) - ‘M spike’
20
Q
What is M protein?
A
- Monoclonal immunoglobulin (paraprotein)
- A type of gamma globulin
21
Q
what is M protein produced by?
A
plasma cells
22
Q
If an ‘M spike’ occurs in protein electrophoresis, what is the next step?
A
Immunofixation
23
Q
What is immunofixation?
A
- Enables the detection and identification of monoclonal immunoglobulins
- Performed when “M-spike” seen on electrophoresis
- Serum or urine is placed on a gel and electric current is applied to separate the proteins
- Anti-immunoglobulin antisera is added to each migration lane
- If the immunoglobulin is present, a complex precipitated –> indicates which Ig is present
24
Q
What would the protein electrophoresis look like in a patient with sepsis?
A
If there was sepsis or any inflammatory disease, there would be an increase in all (benign, polyclonal increase) as all plasma cells are producing globulins.
25
What is a paraproteinaemia?
A group of related diseases characterised by an **unbalanced** or **disproportionate** **proliferation** of **Ig-producing cells**, usually from a single clone. These cells frequently secrete a structurally homogeneous immunoglobulin (**M-component)** and/or an abnormal immunoglobulin. E.g. myeloma is one
26
What is the spectrum of disease of myeloma?
Low burden of disease --\> MGUS
High burden of disease --\> plasma cell leukaemia
27
What is amyloidosis?
A **rare** type of paraproteinaemia.that occurs when an abnormal protein, called **amyloid**, builds up.
28
What is the diagnostic criteria for myeloma?
Requires
a) More than 10% clonal bone marrow plasma cells or extramedullary plasmacytoma (lump of plasma cells)
AND
b) Any one or more of:
–CRAB features
–MDEs
29
What are CRAB features?
Classical features of myeloma
* C: hypercalcaemia (\>2.75mmol/L)
* R: renal insufficiency (creat clearance \<40ml/min or serum creat \>177micromol/L)
* A: anaemia (Hb\<100g/L)
* B: bone lesions (one or more osteolytic lesions on skeletal radiography, CT, or PET/CT)
30
What are MDEs?
Myeloma-defining events (this allows for asymptomatic myeloma to be treated if it is worrying):
* Greater than **60% clonal plasma cells** on bone marrow biopsy
* **SFLC** ratio \>100mg/L provided the absolute level of the involved LC is \>100mg/L (if one of their light chains is raised \>100mg/L and if ratio of kappa:lamda or lamda:kappa \>100mg/L)
* **\>1 focal lesion** on MRI measuring \>5mm
31
When would MDEs be looked for?
If CRAB features are not present but think could be 'asymptomatic/smouldering' myeloma
32
What is the relationship between myeloma and the kidney?
* 20-25% of patients have renal insufficiency at diagnosis, 50% during disease course
* 50% will have persistent renal impairment despite therapy
* 2-12% will require RRT (renal replacement therapy)
33
Why can myeloma damage the kidney?
* The abnormal proteins made by the plasma cells in patients with multiple myeloma can damage block and damage the tubules --\> '**myeloma kidney'**
* Abnormal proteins can also lead to inflammatory reactions in the surrounding tissue
* Toxic effects of these abnormal proteins
34
What are the external factors that can cause kidney damage during myeloma?
1. **Renal** **vein** **thrombosis** (myeloma is a pro-thrombotic disease)
2. **Biphosphonates** (drugs used to treat bone damage caused by myeloma, but can cause toxicity in kidneys)
3. **Hypercalcaemia** (caused by myeloma, can damage nephrons)
4. **ACEi** (drugs commonly taken by elderly population, can be damaging to kidney)
5. **Dehydration**
6. **NSAIDs**
7. **CT** **contrast**
8. **Hyperviscosity** (myeloma can cause thickening of blood which can damage kidneys)
9. **Type** **1 cryoglobulinaemia** (can cause direct kidney injury)
35
Clinical features of myeloma?
Symptoms usually resulting from renal impairment, hypercalcaemia and bone impairment:
* Chest infections: neoplastic plasma cells take up room, so normal plasma cells cannot proliferate
* Loss of height due to pathological fractures of the spinal vertebrae
36
What are the actue complications of myeloma?
* Hyperviscocity
* Hypercalcaemia
* Acute kidney injury
* Spinal cord compression
* Due to bone lytic lesions that occur in spine
* Or due to plasmacytoma that can occur
* Sepsis
37
What is the most common cause of mortality in first 60 days of patient's journey with myeloma?
Sepsis
38
What is the cardinal sign of hyperviscocity?
Retinal vein dilatation/haemorrhage
39
What is plasmacytoma?
Plasmacytoma refers to a tumour consisting of abnormal plasma cells that grows within the soft tissue or bony skeleton.
40
What are bone lytic lesions?
Spots of bone damage that result from **cancerous plasma cells** building up in your bone marrow.
41
What blood investigations are done in myeloma?
* **_FBC_**: Hb, WBC, platelets and blood film
* **_U&Es_**: urea, creatinine, sodium and potassium
* **_Calcium_**
* **_C reactive protein_**
* **_Immunoglobulin levels_**
42
What would the FBC in myeloma be looking for?
FBC: Hb, WBC, platelets and blood film
* Anameia?
* Active infection?
* Degree of bone marrow infiltration? (by looking at white cells, low platelets if the plasma cells are taking up room)
* Rouleaux? (red cells stack on top of each other, showing high PSR)
* Plasma cells present? (Uncommon to find in peripheral blood)
43
What would the U&Es in myeloma be looking for?
U&Es: urea, creatinine, sodium and potassium
* Renal failure?
* Dehydration?
44
What would the calcium blood test in myeloma be looking for?
Hypercalcaemia
45
When would a C-reactive blood test be done in myeloma?
If suspected infection
46
Regarding immunoglobulin levels, what result of the blood test would make you suspicious of myeloma? What would you do next?
* One elevated immunoglobulin subtype with low levels of the others
* Next step --\> protein electrophoresis and immunofixation
* Paraprotein present?
* N.B. lf no paraprotein detected but clinical suspicion of myeloma then do **light chain analysis**
47
Why would light chain analysis be done?
If no paraprotein detected but clinical suspicion of myeloma as there are a small % of myeloma cases that don't produce Ig but just produce light chains.
48
What imaging would be done in the investigation of myeloma?
* Skeletal survey
* **Whole-body CT or MRI** (most common)
* PET-scan: rarely used as not all myelomas are PET positive
49
Acute kidney injury with suspected myeloma!!
Treatment???
This is a **medical emergency**:
* STEROIDS!!!
* Within 24 hours:
* Blood film (plasma cells??)
* Electrophoresis
* Immunofixation
* Bone marrow biopsy with flow cytometry
50
What are the simple measures in the treatment of myeloma?
* Hydration
* Avoid nephrotoxics
* Appropriate chemotherapy (attenuated dosing)
51
Does myeloma relapse?
Myeloma is chronic relapsing-remitting disease – there may be many months/years of a patient being disease and treatment free. Regular monitoring and intervention is useful.
52
_Clinical Case 1_
* Presents to GP with 6 month history of right hip pain
* Hypertension, peripheral vascular disease
* Hb 142 (NR: 130-180g/dL)
* Creat 103 (NR: 40-90mmol/L)
* Ca2+ 2.34 (NR: 2.20-2.60mmol/L)
* IgG kappa PP 4g/L
* IgM and IgA levels normal
* SFLC ratio normal
From the xray, what is the cause of the right hip pain?
Osteoarthritis - can operate!
53
What is MGUS defined as?
* Quite common, benign disorder
* Serum M-protein \<30g/L
* \<10% clonal plasma cells in the bone marrow
* Absence of end-organ damage (CRAB)
54
What is the epidemiology of MGUS?
* 3.2% of people \> 50 years
* 5.3% of people \> 70 years
* 8.9% of people \>80 years
* M\>F
55
What does MGUS have the potential to progess to?
* Can progress to myeloma (1% of cases per year, by 27% in one series)
* Waldenstorm’s macroglobulinaemia
* Primary AL amyloidosis
* Lymphoproliferative disorders
56
What does the risk of progression of MGUS depend on?
* High vs low M-proteins
* Lower paraprotein = less risk of progression
* If paraprotein \<15g/L then risk is minimal
* IgA/IgM more likely than IgG
* If there is an abnormal light chain ratio
* Normal SFLC then risk is less
57
_Clinical Case 2_
* Presents to GP with 2 month history of ankle swelling
* Hypertension, peripheral vascular disease
* Hb 142 (NR: 130-180g/dL)
* Creat 103 (NR: 40-90mmol/L)
* Ca2+ 2.34 (NR: 2.20-2.60mmol/L)
* **Albumin 18g/L (NR: 30-40)**
* IgG kappa PP 4g/L
* IgM and IgA levels normal
a) what should be your next investigation?
b)
a) Urinary PCR needed due to low albumin --\> if this is high, this would indicate that the kidneys are losing proteins (nephrotic range proteinuria)
58
When someone presents with very low albumin, what should your next investigation be?
Urinary PCR (protein:creatinine ratio)
59
If the urinary PCR is high, what should be done next?
kidney biopsy for presence of amyloid fibrils
60
What is AL amyloidosis?
* Amyloid light-chain (AL) amyloidosis
* Neoplastic plasma cells in MGUS and myeloma produce light chains/paraproteins which misfold and self-aggregate, depositing in **organs** as **beta-pleated fibrils******
* Heart (amyloid deposits) (30%)
* Liver (hepatomegaly) (30%)
* Kidneys (nephrotic syndrome) (1.5%)
* Nerves (peripheral neuropathy) (10%)
* Gut
61
If albumin is low and there is peripheral oedema, what could this could be a sign of?
amyloidosis
62
How does amyloidosis affect the kidneys?
* 1.5% of native kidney biopsies
* Nephrotic-range proteinuria
* Mainly albumin
* Small monoclonal light chain component therefore classical myeloma symptoms usually not present
* End stage renal failure in 40%
63
Why are the classical myeloma symptoms usually not present in AL amyloidosis?
Small monoclonal light chain component
64
Clinical features of amyloidosis?
* Similar to myeloma without bone symptoms
* Cardiac failure can occur
* Cardiac and liver involvement in 30%
* Peripheral neuropathy in 10%
65
What is lymphoma?
* Malignant proliferations of lymphocytes (B or T cells)
* Lymph nodes are predominantly affected but:
* In advanced stages there may be bone marrow involvement and other organ involvement (e.g. gut, skin, CNS sometimes seen in T cell lymphomas)
66
If there was skin and GI involvement, what type of lymphoma is more likely to be suspected?
T cell lymphoma
67
How are B cell lymphomas classified?
According to the presence or absence of Reed-Sternberg cells
68
If there are Reed-Sternberg cells present, what lymphoma is this then classified as?
Hogkins lymphoma
69
What age group is Hodgkin lymphoma more common in?
Bimodal age distribution, commoner in young people in 20 and 30s, or 60/70s
70
Symptoms/signs of Hogkin lymphoma?
* Lymphadenopathy
* Night sweats
* Weight loss
* Fatigue
* Bone marrow involvement uncommon
71
Is there bone marrow involvement in Hodgkin lymphoma?
Uncommon
72
Prognosis of Hogkin lymphoma?
Excellent (over 90%) cure rates
73
If Reed-Sternberg cells aren't present, what lymphoma can this be classified as?
This is either a T cell lymphoma (very rare) OR non-Hodgkin Lymphoma (B cell lymphoma)
74
What 2 categories can Non-Hodgkin Lymphomas be divided into?
1. Aggressive; e.g. DLBCL, Burkitt Lymphoma
2. Indolant e.g. follicular lymphoma, marginal zone lymphoma
75
How do aggressive Non-Hodgkin Lymphomas present?
* Classic B symptoms; fever, drenching night sweats and loss of more than 10 percent of body weight over 6 months
* Rapid onset lymphadenopathy
* Systemically unwell
76
Can aggressive Non-Hodgkin Lymphomas be cured?
yes
77
How do indolent Non-Hodgkin Lymphomas present?
* Insidious onset lymphadenopathy (less dramatic)
* Systemically well
78
Can indolent Non-Hodgkin Lymphomas be cured?
* Usually not curable, just monitor as long as asymptomatic. Overall survival of 10 years, usually doesn’t affect life expectancy unless diagnosed when young.
* Can be an incidental finding
79
What are 5 possible causes of a neck mass?
* Malignant: lymphoma, chronic lymphocytic leukaemia, metastatic cancer of the lung/breast/cervix
* Non-malignant: infective (bacterial, viral, mycobacterial), inflammatory (sarcoidosis), lipoma, fibroma, haemangioma
80
_Clinical Case 3_
* 81 year-old lady
* Presents to her GP with a 3-month history of left-sided neck lump
* COPD, type II DM
a) What other factors are important in the history here?
b) Further investigations?
a)
* –Nature of the lump – size, rate of change, tenderness, skin changes, history of trauma
* –Additional lumps/lesions elsewhere (particularly breast lumps)
* –History of weight loss and/or night sweats
* –History of breathlessness/cough/haemoptysis
* –Past medical history – particularly previous malignancies
* –Social history – smoking history particularly
* –Family history - ?of bone marrow disorders or malignancies
b)
* Bloods; FBC, U&Es, LFTs, Ca2+, LDH, Immunoglobulins and protein electrophoresis
* Imaging; Chest X-ray, Ultrasound scan of the neck lump, Fine needle aspirate and/or core needle biopsy
81
What are the malignant causes of a neck mass?
* Lymphoma
* Chronic lymphocytic leukaemia
* Metastatic cancer of the lung/breast/cervix
82
What are the non-malignant causes of a neck mass?
* Infective (bacterial, viral, mycobacterial)
* Inflammatory (sarcoidosis)
* Lipoma
* Fibroma
* Haemangioma
83
Normal appearance of lymph node
84
What is follicular lymphoma?
* Neoplastic disorder of lymphoid tissue
* Type of **non-Hodgkin lymphoma** characterised by slowly enlarging lymph nodes
* Accounts for approximately 15% of all non-Hodgkin lymphoma diagnoses
* Incidence rises with age
* M=F
85
Cause of follicular lymphoma?
Often due to an acquired **chromosomal translocation t(14;18)** which confers a survival advantage to the neoplastic lymphoid cells by **inhibiting apoptosis**
86
Prognosis for follicular lymphoma?
* Median survival 8-10 years
* Five-year overall survival 72-77%
87
The Follicular International Prognostic Index (FLIPI) can be used to prognosticate follicular lymphoma. What prognostic factors does this comprise?
1. –age \>60 years
2. –Ann Arbor stage III or IV
3. –LDH above the limit of normal at diagnosis
4. –Hb\<120g/L
5. –presence of more than four nodal sites of disease
88
_Clinical Case 4_
* 21 year-old
* Presented to GP with 6-week history of breathlessness
* No significant past medical history
a) What other factors in the history are important here?
b) What will your clinical examination focus on?
a)
–Nature of the breathlessness – rate and duration of onset, variability with activities, exacerbating and relieving factors
–Additional symptoms – cough, sputum production, ankle swelling, orthopnoea, PND, weight loss, night sweats
–Past medical history – childhood illnesses
–Social history – smoking, occupational and animal exposure
–Family history – any history of respiratory/cardiac problems
b)
–Chest and cardiovascular examination
–Lymphadenopathy
89
What is Hodgkin lymphoma characterised by? How can Hodgkin Reed-Sternberg (HRS) cells evade apoptosis?
* Presence of Hodgkin Reed-Sternberg (HRS) cells within a cellular infiltrate of non-malignant inflammatory cells eg: eosinophils
* HRS **fail to express surface immunoglobulin** and **evade apoptosis** through several mechanisms – eg: activation of NFkB, incorporation of EBV and latent membrane proteins (LMP1 and LMP2)
90
Leukaemias overview
* Acute vs chronic
* Lymphoid vs myeloid
91
Stem cell overview
92
What cells are involved in myeloid leukaemias?
Cells which develop into neutrophils, eosinophils, monocytes, basophils
93
What cells are involved in lymphoid leukaemias?
Cells which develop into lymphocytes
94
What is Chronic Lymphocytic Leukaemia (CLL)?
* A malignant disorder of **mature B-cells** (lymphocyte)
* The most common type of leukaemia in the UK: –1% of all cancers in the UK
95
What is the presentation of CLL?
Presentation ranges from:
* Incidental finding of lymphocytosis (picked up on routine FBC)
to
* Widespread lymphadenopathy, splenomegaly, bone marrow failure, systemic symptoms
96
How is CLL staged?
Binet system:
97
Different types of CLL depending on genetics. What is the effect of a;
1. 17p deletion
2. 13q deletion?
1. particularly bad prognosis
2. best prognosis
98
Investigations for CLL?
peripheral blood for flow cytometry, blood film
99
Management of CLL?
* Watch and wait if asymptomatic, could be months-years
* Needs active treatment if symptomatic
* Chemo-immunotherapy e.g. Bendamustine and Rituximab (monoclonal antibody treatment)
100
Complications of CLL?
* Transformation to high-grade lymphoma (DLBCL) = Richter’s transformation, occurs in less than 10% of cases. Poor prognosis, median survival is less than 9 months even with intensive chemo. Acute onset of symptoms:
* Drenching night sweats
* Abdominal swelling
* Rapid weight loss
* Fatigue
* Lymphadenopathy
* Recurrent infections secondary to reduced immunoglobulin production
* Autoimmune phenomenon
* ITP
* Haemolytic anaemia
* Pure red cell aplasia
* Autoimmune neutropenia
101
Lymphadenopathy has a wide differential. What should you take into account?
* Distribution
* Timing of onset
* Systemic symptoms (or lack of)
* Bloods (can be normal in lymphomas particularly)
102
Plasma cell disorders such as MGUS, myeloma and amyloidosis present in a variety of non-specific ways. What are these ways?
–Incidental finding (MGUS)
–Symptoms secondary to hypercalcaemia, anaemia and renal failure
–Bone pains
–Organ infiltration (amyloidosis)
