Malignancy Flashcards
1
Q
How can we identify normal, mature non-lymphoid cells
A
Morphology - major one
Cell surface antigens
Enzyme expression
2
Q
How can we identify normal progenitors/stem cells
A
Cell surface antigens (immunophenotyping)
Cell culture assays
3
Q
What characterises malignant haemopoiesis
A
Increased numbers of abnormal and dysfunctional cells
Loss of normal activity
4
Q
What causes malignant haemopoiesis
A
Increased proliferation
Lack of differentiation
Lack of maturation
Lack of apoptosis
5
Q
What is the cause of acute myeloid leukaemia
A
Proliferation of abnormal progenitors
with block in differentiation/maturation
Excess of immature cells
6
Q
What is the cause of chronic myeloid leukaemia
A
Proliferation of abnormal progenitors,
but NO differentiation/maturation block
7
Q
What causes haematological malignancies
A
Genetic, epigenetic, environmental interaction - multiple factors
Somatic mutations in regulatory genes
8
Q
Is malignant haemopoiesis usually polyclonal or monoclonal
A
Usually monoclonal
Meaning most of the cells have come from the same parent cell
9
Q
What is the role of driver mutations in the development of cancer
A
They confer growth advantage on the cancer cells and are selected during the evolution of the cancer
They can select specific clones to develop
10
Q
How can you classify haematological malignancies
A
By lineage - myeloid or lymphoid
By developmental stage
By site involved - blood vs lymph node
11
Q
What is a leukaemia
A
Haem malignancy with blood involvement
12
Q
What is a lymphoma
A
Lymph node involvement with lymphoid malignancy
13
Q
Which type of malignancy are usually more aggressive
A
Acute leukaemias & high-grade lymphomas are histologically and usually clinically more aggressive
Will have rapid symptom progression
Cells will be large, high nuclear-cytoplasmic ratio, prominent nucleoli, rapid proliferation
14
Q
What is myeloma
A
Plasma cell malignancy in marrow
15
Q
What is acute lymphoblastic leukaemia
A
ALL is a malignant disease of primitive lymphoid cells (lymphoblasts)
Most common childhood cancer
16
Q
What is the definition of an acute leukaemia
A
Defined as an excess of ‘blasts’ (≥20%) in either the peripheral blood or bone marrow
Rapidly progressive clonal malignancy of the marrow/blood with maturation defect(s)
17
Q
How does ALL present
A
Anaemia, infections and bleeding due to marrow failure
Bone pain
leukemic effects: high count with obstruction of circulation which affects other sites - CNS, testis
18
Q
Describe acute myeloid leukaemia
A
A cancer of the myeloid line of blood cells
More common in the elderly (>60 years)
May be ‘de novo’ or secondary
19
Q
How does AML present
A
Similar to ALL
Feeling tired, shortness of breath, easy bruising and bleeding, and increased risk of infection
May present with DIC or gum infiltration in subtypes
20
Q
How would you investigate acute leukaemia
A
Blood count and film - would see fewer normal cells and more abnormal blasts
Coagulation screen
Bone marrow aspirate - look at morphology and immunophenotype the cells
Can do genetic tests on samples - may suggest prognosis
21
Q
What test is required for a definitive diagnosis for acute leukaemia (specific type)
A
Immunophenotyping
Allows you to determine the lineage and see if it is AML or ALL
22
Q
What is the treatment for ALL
A
Multi-agent chemotherapy
Can last up to 2-3 years with multiple phases of treatment
May be able to give targeted treatment
Allogeneic stem cell transplantation in select patients
23
Q
What is the treatment for AML
A
Multi-agent chemotherapy Normally intensive Between 2-4 cycles of chemotherapy Requires prolonged hospitalisation May be able to give targeted treatment Allogeneic stem cell transplantation in select patients
24
Q
What are the consequences of marrow suppression
A
Anaemia
Neutropoenia - infections
Thrombocytopaenia - bleeding
25
What are some of the complications of multi-agent chemotherapy
Nausea and vomiting
Hair loss
Tiredness
Liver, renal dysfunction
Tumour lysis syndrome
Infections - particularly fungal and gram -ve bacteria
Late effects - loss of fertility, cardiomyopathy, lung damage
26
What are some of the symptoms of lymphoma
```
Lymphadenopathy
Night sweats
Weight loss
Itch without a rash
Alcohol induced pain
Fatigue
```
27
Which types of infection lead to generalised lymphadenopathy
Viral
28
Which types of infection lead to regional lymphadenopathy
Bacteria
29
How does a lymph node feel in infections
```
Tender
Hard
Smooth surface
Bacterial may have inflamed skin (v not)
Viral may be tethered (b not)
```
30
How does a lymph node feel in lymphoma
```
Non-tender
rubbery and soft
Smooth surface
No inflamed skin
Not tethered
```
31
How does a lymph node feel in metastatic
```
Non-tender
Hard
Irregular surface
No inflamed skin
Tethered
```
32
How would you investigate a suspected lymphoma
Surgical biopsy of the lymph node
| FNA or core biopsy often insufficient - need a large sample
33
How do you analyse a lymph node biopsy sample
Histology-microscopic appearances.
Immunohistochemistry on the solid node - subclassifies cancer by looking at surface proteins
Immunophenotyping of the blood/marrow
Genetic analysis.
Molecular analysis - assesses pattern of gene expression
34
What are reed Sternberg cells a sign of
Hodgkin's Disease
| They are highly abnormal B cells
35
For which cancers is immunophenotyping useful
Leukaemia's
| Lymphomas involving the marrow - Burkitt's
36
What are the main subtypes of lymphoma
```
Hodgkin’s Lymphoma.
High grade B cell NHL.
Low grade B cell NHL.
Burkitt’s Lymphoma.
Mantle cell Lymphoma.
Marginal Zone NHL.
```
37
What are some of the direct tumour effects of myeloma
```
Bone lesions - lytic
Increased calcium
Bone pain
Fractures
Replaces normal bone marrow leading to marrow failure
```
38
What are some of the paraprotein mediated effects of myeloma
Renal failure
Immune suppression
Hyperviscosity
Amyloid
39
How is myeloma classifies
By the type of antibody it produces - e.g. IgG, IgA
40
What is the most common type of antibody produced in myeloma
IgG
41
What are the symptoms of hypercalcaemia
```
Stones
Bones
Abdominal groans
Psychiatric moans
Thirst
Dehydration
Renal impairment
```
42
How can myeloma affect the kidneys
```
Leads to renal impairment
Tubular cell damage by light chains
Light chain deposition; cast nephropathy
Sepsis
Hypercalcemia and dehydration
Hyperuricaemia
Amyloid
```
43
How do you treat cast nephropathy
Hydration, stop nephrotoxic drugs
| Switch off light chain production with steroids/chemo
44
How do you treat myeloma
Combination chemotherapy the mainstay
Corticosteroids; dexamethasone or prednisolone
Alkylating agents eg cyclophosphamide
'Novel agents' like thalidomide
In fit patients you can give high dose chemo then a autologous stem cell transplant
45
How do you monitor treatment response in myeloma
Monitor paraprotein level
46
What is a paraprotein
Abnormal immunoglobulins produced by clonal plasma cells
| Can be intact immunoglobulins or bits of them (e.g. light chains)
47
What is an autologous stem cell transplant
When the patient is given their own stem cells by infusion
Give pre-treatment to stimulate stem cell release
Collect the stem cells from the blood and freeze them
Give high dose chemo to remove the immune system
Infuse the stem cells back into the patient and give supportive treatment as the immune system rebuilds
48
Are patients with myeloma likely to relapse
Yes it is inevitable
| Survival is 5-10 years
49
How can you manage the symptoms of myeloma
Opiate analgesia (avoid NSAIDs)
Local radiotherapy - good for pain relief or spinal cord compression
Bisphosphonates - corrects hypercalcaemia and bone pain
Vertebroplasty – inject sterile cement into fractured bone to stabilise
50
What is Monoclonal gammopathy of undetermined significance
Condition where abnormal antibodies are produced by plasma cells
Similar to myeloma but levels are lower and don't get the end organ damage
Paraprotein <30g/l
Bone marrow plasma cells <10%
51
What is Waldenstrom’s macroglobulinaemia
Cancer of the B cells (between lymphocyte and plasma cells)
| Produces an IgM paraprotein (abnormal antibody)
52
What are some of the clinical effects of Waldenstrom’s macroglobulinaemia
```
Lymphadenopathy
Splenomegaly
Marrow failure
Hyperviscosity
Neuropathy
```
53
What are the signs of hyperviscosity syndrome (seen in Waldenstrom’s macroglobulinaemia)
Fatigue, visual disturbance, confusion, coma
Bleeding
Cardiac failure
54
How do you treat waldenstrom
```
Chemotherapy
Plasmapheresis (removes paraprotein from the circulation)
```
55
What type of cell death does low dose chemo or Rt cause
Triggers apoptosis - cell breaks apart and bodies are phagocytosed
Fewer side effects
56
What type of cell death does high dose chemo or Rt cause
Triggers necrosis
Membranes rupture and the cellular lysis causes inflammation
More side effects
57
Why do lymphoma/CLL and acute leukaemia respond better than most other cancers to chemo and RT
Lymphocytes are already keen to undergo apoptosis in the normal lymph node
Therefore they are readily triggered by chemo and RT
In acute leukaemia the cells divide quickly so are very susceptible
58
What supportive therapy may be needed during chemo or radiotherapy
Prompt treatment of neutropenic fever/infection with broad spectrum
antibiotics
Red cell and platelet transfusion
Growth Factors (GCSF).
Prophylactic antibiotics and antifungals to prevent infection occurring
59
What targeted therapies are available of haem cancers
Monoclonal antibodies - rituximab, ofatumunab
Biological agents - used in multiple myeloma
Molecularly targeted treatments - specific to cancer cell
60
Which monoclonal antibody is used in Hodgkin's disease
Brentuximab Vedotin
Has a chemo drug tagged onto it so that you target the cells
Binds to the CD30 protein on the Hodgkin's cells
61
How do proteosome inhibitors
The proteosome
breaks down old proteins in cells into amino acids for recycling.
Blocking this allows accumulation of toxic proteins in cell causing apoptosis
62
When are proteasome inhibitors used
Used in some low grade NHL (Waldenstrom’s)
63
When are IMIDs used
Can produce remission in some patients with low grade NHL and CLL no longer responding to chemo.
Slightly better in combination with chemotherapy for mantle cell
64
What are the side effects of IMIDs
nerve damage
risk to foetus.
effect on blood counts.
other cancers.
65
In which cancer are tyrosine kinase inhibitors used
Chronic myeloid leukaemia
| Well tolerated and very successful
66
How can B cell signalling pathways be used to treat cancers
CLL and lymphoma cells have abnormally active signalling mechanisms inside cell
Blockage of these signalling proteins can cause apoptosis, even if P53 is abnormal
67
Name 2 drusg used in the treatment of cancers that affect B cell signalling pathways
Ibrutinib- being approved for NHL
| Idelalisib - used in CLL
68
What are the side effects of idelalisib
diarrhoea, rash, fatigue, liver abnormality, fever
69
What are the side effects of ibrutinib
fever, low platelets, anaemia, shortness of breath
70
Give an example of a checkpoint inhibitor
Nivolumab
71
How does nivolumab work
Cancer cells avoid cells of the immune system by producing chemicals that bind to immune system receptors
When receptor is stimulated the immune system cell is switched off and ‘ignores’ the tumour
Nivolumab sticks to this chemical and stops it binding to the immune cell.
The immune system therefore remains switched on and attacks the cancer cell
72
In which cancers is nivolumab used
Used in malignant melanoma
| Even more effective in lymphoma (especially Hodgkin's)
73
How does an allogenic bone marrow transplant work in cancer
T cells from the donor cause immune attack on cancer
| However, there is also an immune attack on normal cells - graft vs host
74
How do you classify cytotoxic drugs
Cell cycle specific
Non-cell cycle specific
75
What are the general characteristics of cell cycle specific agents
```
Tumour specific (relatively)
Duration of exposure more important than dose
```
76
What are the general characteristics of non-cell cycle specific agents
Non-tumour specific; damage normal stem cells
| Cumulative dose more important than duration
77
List examples of cell cycle specific agents
Antimetabolites- methotrexate, hydroxyurea and 6-Mercaptopurine / Cytosine arabinoside / Fludarabine
Mitotic spindle inhibitors - Vinca alkaloids, Taxotere (Taxol)
78
How do antimetabolites work as cytotoxic agents
Impair nucleotide synthesis / incorporation
79
List examples of non-cell cycle specific agents
Alkylating agents - chlorambucil / melphalan
Platinum derivatives - Cis-platinum / carboplatin
Cytotoxic antibiotics - anthracyclines
80
How do alkylating agents work as non-cell cycle specific cytotoxic drugs
Bind covalently to bases of DNA (adducts)
| Produces DNA strand breaks (mutation) by free radical production
81
How do cytotoxic antibiotics work as non-cell cycle specific cytotoxic drugs
DNA intercalation: reversible
impairs RNA transcription
strand breaks in DNA
82
What are the immediate side effects of cytotoxic drugs
Affects the rapidly dividing organs
| Get bone marrow suppression, gut mucosal damage and hair loss
83
Neuropathy is a side effect of which cytotoxic drugs
Vinca alkaloids
84
Cardiotoxicity is a side effect of which cytotoxic drugs
Anthracyclines - cytotoxic antibiotics
85
Nephrotoxicity is a side effect of which cytotoxic drugs
Cis-platinum
86
What are some of the long term side effects of alkylating agents
Infertility
| Secondary malignancy
87
Why can chemotherapy fail
Slow tumour doubling time
Tumour “sanctuaries”
Drug resistance mechanisms
88
How can you safely intensify chemo regimes
use haematopoietic growth factors
combine myelosuppressive / non-myelosuppressive agents
intensify doses of active drugs and stem cell rescue
89
Where can you get stem cells for transplantation
Blood or bone marrow
| Can be autologous (from patient) or allogenic (from relative or unrelated donor)
90
What is a myeloproliferative neoplasm
Clonal haemopoietic stem cell disorders with an increased production of one or more types of
haemopoietic cells
Maturation is relatively preserved
91
What is meant by the term myelo-
Refers to the myeloid bone marrow lineages
| This includes granulocytes, red cells & platelets and their precursors
92
How does acute leukaemia appear on microscopy
Lots of large blue/purple cells
93
What are the subtypes of myeloproliferative neoplasm
Primary myelofibrosis
Essential thrombocythaemia - overproduction of platelets
Polycythaemia vera - overproduction of red cells
Chronic myeloid leukaemia - overproduction of granulocytes
94
What are the signs of a myeloproliferative neoplasm
```
High Granulocyte count
+/-
High Red cell count / haemoglobin
+/-
High Platelet count
+/-
Eosinophilia/basophilia
```
Splenomegaly
Thrombosis in an unusual place
All with no reactive explanation
95
Describe the disease process of chronic myeloid leukaemia
Chronic phase with intact cell maturation for around 3-5 years
Then develops into a 'blast crisis' where there is a maturation defect (similar to AL)
96
What is the prognosis for chronic myeloid leukaemia
Fatal without stem cell/bone marrow transplantation in the chronic phase
97
What are the clinical features of chronic myeloid leukaemia
```
Can be asymptomatic
Splenomegaly
Hypermetabolic symptoms
Gout
Priapism - painful erections
```
98
What are the lab features of chronic myeloid leukaemia
Normal or ↓Hb
Leucocytosis with neutrophilia and myeloid precursors (myelocytes), eosinophilia, basophilia
thrombocytosis
99
The Philadelphia chromosome is the hallmark of which malignancy
Chronic myeloid leukaemia
| It is a translocation between 9 and 22
100
What does the Philadelphia chromosome produce
A new chimaeric gene - BCR-ABL1
| This gene produces a tyrosine kinase which causes abnormal phosphorylation
101
Which myeoproliferative neoplasm are BCR-ABL1 positive
Chronic myeloid leukaemia
102
Which myeoproliferative neoplasm are BCR-ABL1 negative
Polycythaemia Vera (PV)
Essential thrombocythaemia (ET)
Primary Myelofibrosis
103
What are the common features of the myeoproliferative neoplasms
```
Can be asymptomatic
Increased cellular turnover (gout, fatigue, weight loss, sweats)
Symptoms/signs due to splenomegaly
Marrow failure
Thrombosis
```
104
What are the lab features of polcythaemia vera
High haemoglobin/haematocrit accompanied by erythrocytosis (increase in red cell mass)
May have excess production in other lineages
105
What can cause secondary polycythaemia
chronic hypoxia
smoking
erythropoietin-secreting tumour
106
What can cause pseudopolycythaemia
Dehydration
Diuretic therapy
Obesity
107
What are the clinical features of polcythaemia vera
Common MPN symptoms
Headache
Fatigue
Itch
108
Which mutation is present in most patients with polcythaemia vera
JAK2 mutations
| This results in a loss of auto-inhibition in erythropoiesis = more RBC
109
What investigations are done for polycythaemia
FBC and film
Investigation for secondary/pseudo causes (CXR, O2 saturation/arterial blood gases, drug history)
JAK2 analysis
110
How do you treat polycythaemia vera
Vensect to haematocrit <0.45
Aspirin
Cytotoxic oral chemotherapy (eg Hydroxycarbamide)
111
What is essential thrombocytopaenia
Uncontrolled production of abnormal platelets
| Abnormal function can lead to thrombosis or at high levels bleeding through acquired VW disease
112
What are the clinical features of essential thrombocytopaenia
Clinical features common to MPN (particularly vasoocclusive complications)
Bleeding (unpredictable risk especially at surgery)
113
How do you diagnose essential thrombocytosis
Exclude reactive thrombocytosis - blood loss, inflammation, malignancy etc
Exclude CML
Genetic tests
Bone marrow tests - characteristic appearance
114
How do you treat essential thrombocytosis
Anti-platelets - aspirin
| Cytoreductive therapy to control proliferation - hydroxycarbamide etc
115
What can lead to myelofibrosis
Can be idiopathic
Post-polycythaemia
Essential thrombocytopaenua
116
What are the pathological features of idiopathic myelofibrosis
```
Marrow failure (variable degrees)
Bone marrow fibrosis
Extramedullary hematopoiesis
Leukoerythroblastic film appearances
Teardrop-shaped RBCs in peripheral blood
```
117
What are the clinical features of myelofibrosis
Anaemia, bleeding and infections as a result of marrow failure
Splenomegaly - LUQ pain
Hypercatabolism
Common MPD features
118
How do you diagnose myelofibrosis
Typical blood film (tear-drop shaped RBC and leucoerythroblastic)
Dry aspirate
Fibrosis on marrow trephine biopsy
JAK2, CALR, MPL mutations
119
How do you treat myelofibrosis
Supportive care (blood transfusion, platelets, antibiotics)
Allogeneic stem cell transplantation in a select few
JAK2 inhibitors
Splenectomy - controversial
