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Haematology > Malignancy > Flashcards

Malignancy Flashcards

1
Q

How can we identify normal, mature non-lymphoid cells

A

Morphology - major one
Cell surface antigens
Enzyme expression

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2
Q

How can we identify normal progenitors/stem cells

A

Cell surface antigens (immunophenotyping)

Cell culture assays

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3
Q

What characterises malignant haemopoiesis

A

Increased numbers of abnormal and dysfunctional cells

Loss of normal activity

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4
Q

What causes malignant haemopoiesis

A

Increased proliferation
Lack of differentiation
Lack of maturation
Lack of apoptosis

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5
Q

What is the cause of acute myeloid leukaemia

A

Proliferation of abnormal progenitors
with block in differentiation/maturation
Excess of immature cells

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6
Q

What is the cause of chronic myeloid leukaemia

A

Proliferation of abnormal progenitors,

but NO differentiation/maturation block

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7
Q

What causes haematological malignancies

A

Genetic, epigenetic, environmental interaction - multiple factors
Somatic mutations in regulatory genes

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8
Q

Is malignant haemopoiesis usually polyclonal or monoclonal

A

Usually monoclonal

Meaning most of the cells have come from the same parent cell

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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

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10
Q

How can you classify haematological malignancies

A

By lineage - myeloid or lymphoid
By developmental stage
By site involved - blood vs lymph node

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11
Q

What is a leukaemia

A

Haem malignancy with blood involvement

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12
Q

What is a lymphoma

A

Lymph node involvement with lymphoid malignancy

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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

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14
Q

What is myeloma

A

Plasma cell malignancy in marrow

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15
Q

What is acute lymphoblastic leukaemia

A

ALL is a malignant disease of primitive lymphoid cells (lymphoblasts)
Most common childhood cancer

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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)

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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

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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

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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

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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

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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

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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

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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
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24
Q

What are the consequences of marrow suppression

A

Anaemia
Neutropoenia - infections
Thrombocytopaenia - bleeding

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25
Q

What are some of the complications of multi-agent chemotherapy

A

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

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26
Q

What are some of the symptoms of lymphoma

A 
Lymphadenopathy
Night sweats 
Weight loss 
Itch without a rash 
Alcohol induced pain 
Fatigue
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27
Q

Which types of infection lead to generalised lymphadenopathy

A

Viral

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28
Q

Which types of infection lead to regional lymphadenopathy

A

Bacteria

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29
Q

How does a lymph node feel in infections

A 
Tender 
Hard 
Smooth surface 
Bacterial may have inflamed skin (v not) 
Viral may be tethered (b not)
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30
Q

How does a lymph node feel in lymphoma

A 
Non-tender 
rubbery and soft 
Smooth surface 
No inflamed skin 
Not tethered
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31
Q

How does a lymph node feel in metastatic

A 
Non-tender 
Hard 
Irregular surface 
No inflamed skin 
Tethered
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32
Q

How would you investigate a suspected lymphoma

A

Surgical biopsy of the lymph node

FNA or core biopsy often insufficient - need a large sample

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33
Q

How do you analyse a lymph node biopsy sample

A

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

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34
Q

What are reed Sternberg cells a sign of

A

Hodgkin’s Disease

They are highly abnormal B cells

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35
Q

For which cancers is immunophenotyping useful

A

Leukaemia’s

Lymphomas involving the marrow - Burkitt’s

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36
Q

What are the main subtypes of lymphoma

A 
Hodgkin’s Lymphoma.
High grade B cell NHL.
Low grade B cell NHL.
Burkitt’s Lymphoma.
Mantle cell Lymphoma.
Marginal Zone NHL.
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37
Q

What are some of the direct tumour effects of myeloma

A 
Bone lesions - lytic 
Increased calcium
Bone pain
Fractures 
Replaces normal bone marrow leading to marrow failure
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38
Q

What are some of the paraprotein mediated effects of myeloma

A

Renal failure
Immune suppression
Hyperviscosity
Amyloid

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39
Q

How is myeloma classifies

A

By the type of antibody it produces - e.g. IgG, IgA

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40
Q

What is the most common type of antibody produced in myeloma

A

IgG

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41
Q

What are the symptoms of hypercalcaemia

A 
Stones
Bones
Abdominal groans
Psychiatric moans
Thirst
Dehydration
Renal impairment
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42
Q

How can myeloma affect the kidneys

A 
Leads to renal impairment 
Tubular cell damage by light chains  
Light chain deposition; cast nephropathy   
Sepsis
Hypercalcemia and dehydration
Hyperuricaemia
Amyloid
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43
Q

How do you treat cast nephropathy

A

Hydration, stop nephrotoxic drugs

Switch off light chain production with steroids/chemo

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44
Q

How do you treat myeloma

A

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

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45
Q

How do you monitor treatment response in myeloma

A

Monitor paraprotein level

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46
Q

What is a paraprotein

A

Abnormal immunoglobulins produced by clonal plasma cells

Can be intact immunoglobulins or bits of them (e.g. light chains)

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47
Q

What is an autologous stem cell transplant

A

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

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48
Q

Are patients with myeloma likely to relapse

A

Yes it is inevitable

Survival is 5-10 years

49
Q

How can you manage the symptoms of myeloma

A

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
Q

What is Monoclonal gammopathy of undetermined significance

A

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
Q

What is Waldenstrom’s macroglobulinaemia

A

Cancer of the B cells (between lymphocyte and plasma cells)

Produces an IgM paraprotein (abnormal antibody)

52
Q

What are some of the clinical effects of Waldenstrom’s macroglobulinaemia

A 
Lymphadenopathy
Splenomegaly
Marrow failure
Hyperviscosity
Neuropathy
53
Q

What are the signs of hyperviscosity syndrome (seen in Waldenstrom’s macroglobulinaemia)

A

Fatigue, visual disturbance, confusion, coma
Bleeding
Cardiac failure

54
Q

How do you treat waldenstrom

A 
Chemotherapy
Plasmapheresis (removes paraprotein from the circulation)
55
Q

What type of cell death does low dose chemo or Rt cause

A

Triggers apoptosis - cell breaks apart and bodies are phagocytosed
Fewer side effects

56
Q

What type of cell death does high dose chemo or Rt cause

A

Triggers necrosis
Membranes rupture and the cellular lysis causes inflammation
More side effects

57
Q

Why do lymphoma/CLL and acute leukaemia respond better than most other cancers to chemo and RT

A

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
Q

What supportive therapy may be needed during chemo or radiotherapy

A

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
Q

What targeted therapies are available of haem cancers

A

Monoclonal antibodies - rituximab, ofatumunab

Biological agents - used in multiple myeloma

Molecularly targeted treatments - specific to cancer cell

60
Q

Which monoclonal antibody is used in Hodgkin’s disease

A

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
Q

How do proteosome inhibitors

A

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
Q

When are proteasome inhibitors used

A

Used in some low grade NHL (Waldenstrom’s)

63
Q

When are IMIDs used

A

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
Q

What are the side effects of IMIDs

A

nerve damage
risk to foetus.
effect on blood counts.
other cancers.

65
Q

In which cancer are tyrosine kinase inhibitors used

A

Chronic myeloid leukaemia

Well tolerated and very successful

66
Q

How can B cell signalling pathways be used to treat cancers

A

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
Q

Name 2 drusg used in the treatment of cancers that affect B cell signalling pathways

A

Ibrutinib- being approved for NHL

Idelalisib - used in CLL

68
Q

What are the side effects of idelalisib

A

diarrhoea, rash, fatigue, liver abnormality, fever

69
Q

What are the side effects of ibrutinib

A

fever, low platelets, anaemia, shortness of breath

70
Q

Give an example of a checkpoint inhibitor

A

Nivolumab

71
Q

How does nivolumab work

A

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
Q

In which cancers is nivolumab used

A

Used in malignant melanoma

Even more effective in lymphoma (especially Hodgkin’s)

73
Q

How does an allogenic bone marrow transplant work in cancer

A

T cells from the donor cause immune attack on cancer

However, there is also an immune attack on normal cells - graft vs host

74
Q

How do you classify cytotoxic drugs

A

Cell cycle specific

Non-cell cycle specific

75
Q

What are the general characteristics of cell cycle specific agents

A 
Tumour specific (relatively)
Duration of exposure more important than dose
76
Q

What are the general characteristics of non-cell cycle specific agents

A

Non-tumour specific; damage normal stem cells

Cumulative dose more important than duration

77
Q

List examples of cell cycle specific agents

A

Antimetabolites- methotrexate, hydroxyurea and 6-Mercaptopurine / Cytosine arabinoside / Fludarabine

Mitotic spindle inhibitors - Vinca alkaloids, Taxotere (Taxol)

78
Q

How do antimetabolites work as cytotoxic agents

A

Impair nucleotide synthesis / incorporation

79
Q

List examples of non-cell cycle specific agents

A

Alkylating agents - chlorambucil / melphalan
Platinum derivatives - Cis-platinum / carboplatin
Cytotoxic antibiotics - anthracyclines

80
Q

How do alkylating agents work as non-cell cycle specific cytotoxic drugs

A

Bind covalently to bases of DNA (adducts)

Produces DNA strand breaks (mutation) by free radical production

81
Q

How do cytotoxic antibiotics work as non-cell cycle specific cytotoxic drugs

A

DNA intercalation: reversible
impairs RNA transcription
strand breaks in DNA

82
Q

What are the immediate side effects of cytotoxic drugs

A

Affects the rapidly dividing organs

Get bone marrow suppression, gut mucosal damage and hair loss

83
Q

Neuropathy is a side effect of which cytotoxic drugs

A

Vinca alkaloids

84
Q

Cardiotoxicity is a side effect of which cytotoxic drugs

A

Anthracyclines - cytotoxic antibiotics

85
Q

Nephrotoxicity is a side effect of which cytotoxic drugs

A

Cis-platinum

86
Q

What are some of the long term side effects of alkylating agents

A

Infertility

Secondary malignancy

87
Q

Why can chemotherapy fail

A

Slow tumour doubling time
Tumour “sanctuaries”
Drug resistance mechanisms

88
Q

How can you safely intensify chemo regimes

A

use haematopoietic growth factors
combine myelosuppressive / non-myelosuppressive agents
intensify doses of active drugs and stem cell rescue

89
Q

Where can you get stem cells for transplantation

A

Blood or bone marrow

Can be autologous (from patient) or allogenic (from relative or unrelated donor)

90
Q

What is a myeloproliferative neoplasm

A

Clonal haemopoietic stem cell disorders with an increased production of one or more types of
haemopoietic cells

Maturation is relatively preserved

91
Q

What is meant by the term myelo-

A

Refers to the myeloid bone marrow lineages

This includes granulocytes, red cells & platelets and their precursors

92
Q

How does acute leukaemia appear on microscopy

A

Lots of large blue/purple cells

93
Q

What are the subtypes of myeloproliferative neoplasm

A

Primary myelofibrosis
Essential thrombocythaemia - overproduction of platelets
Polycythaemia vera - overproduction of red cells
Chronic myeloid leukaemia - overproduction of granulocytes

94
Q

What are the signs of a myeloproliferative neoplasm

A 
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
Q

Describe the disease process of chronic myeloid leukaemia

A

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
Q

What is the prognosis for chronic myeloid leukaemia

A

Fatal without stem cell/bone marrow transplantation in the chronic phase

97
Q

What are the clinical features of chronic myeloid leukaemia

A 
Can be asymptomatic
Splenomegaly
Hypermetabolic symptoms
Gout
Priapism - painful erections
98
Q

What are the lab features of chronic myeloid leukaemia

A

Normal or ↓Hb
Leucocytosis with neutrophilia and myeloid precursors (myelocytes), eosinophilia, basophilia
thrombocytosis

99
Q

The Philadelphia chromosome is the hallmark of which malignancy

A

Chronic myeloid leukaemia

It is a translocation between 9 and 22

100
Q

What does the Philadelphia chromosome produce

A

A new chimaeric gene - BCR-ABL1

This gene produces a tyrosine kinase which causes abnormal phosphorylation

101
Q

Which myeoproliferative neoplasm are BCR-ABL1 positive

A

Chronic myeloid leukaemia

102
Q

Which myeoproliferative neoplasm are BCR-ABL1 negative

A

Polycythaemia Vera (PV)

Essential thrombocythaemia (ET)

Primary Myelofibrosis

103
Q

What are the common features of the myeoproliferative neoplasms

A 
Can be asymptomatic
Increased cellular turnover (gout, fatigue, weight loss, sweats)
Symptoms/signs due to splenomegaly
Marrow failure
Thrombosis
104
Q

What are the lab features of polcythaemia vera

A

High haemoglobin/haematocrit accompanied by erythrocytosis (increase in red cell mass)
May have excess production in other lineages

105
Q

What can cause secondary polycythaemia

A

chronic hypoxia
smoking
erythropoietin-secreting tumour

106
Q

What can cause pseudopolycythaemia

A

Dehydration
Diuretic therapy
Obesity

107
Q

What are the clinical features of polcythaemia vera

A

Common MPN symptoms
Headache
Fatigue
Itch

108
Q

Which mutation is present in most patients with polcythaemia vera

A

JAK2 mutations

This results in a loss of auto-inhibition in erythropoiesis = more RBC

109
Q

What investigations are done for polycythaemia

A

FBC and film
Investigation for secondary/pseudo causes (CXR, O2 saturation/arterial blood gases, drug history)
JAK2 analysis

110
Q

How do you treat polycythaemia vera

A

Vensect to haematocrit <0.45
Aspirin
Cytotoxic oral chemotherapy (eg Hydroxycarbamide)

111
Q

What is essential thrombocytopaenia

A

Uncontrolled production of abnormal platelets

Abnormal function can lead to thrombosis or at high levels bleeding through acquired VW disease

112
Q

What are the clinical features of essential thrombocytopaenia

A

Clinical features common to MPN (particularly vasoocclusive complications)

Bleeding (unpredictable risk especially at surgery)

113
Q

How do you diagnose essential thrombocytosis

A

Exclude reactive thrombocytosis - blood loss, inflammation, malignancy etc
Exclude CML
Genetic tests
Bone marrow tests - characteristic appearance

114
Q

How do you treat essential thrombocytosis

A

Anti-platelets - aspirin

Cytoreductive therapy to control proliferation - hydroxycarbamide etc

115
Q

What can lead to myelofibrosis

A

Can be idiopathic
Post-polycythaemia
Essential thrombocytopaenua

116
Q

What are the pathological features of idiopathic myelofibrosis

A 
Marrow failure (variable degrees)
Bone marrow fibrosis 
Extramedullary hematopoiesis 
Leukoerythroblastic film appearances 
Teardrop-shaped RBCs in peripheral blood
117
Q

What are the clinical features of myelofibrosis

A

Anaemia, bleeding and infections as a result of marrow failure
Splenomegaly - LUQ pain
Hypercatabolism
Common MPD features

118
Q

How do you diagnose myelofibrosis

A

Typical blood film (tear-drop shaped RBC and leucoerythroblastic)
Dry aspirate
Fibrosis on marrow trephine biopsy
JAK2, CALR, MPL mutations

119
Q

How do you treat myelofibrosis

A

Supportive care (blood transfusion, platelets, antibiotics)
Allogeneic stem cell transplantation in a select few
JAK2 inhibitors
Splenectomy - controversial

Haematology (8 decks)

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