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Cancer > Cancer as a disease: Leukaemia > Flashcards

Cancer as a disease: Leukaemia Flashcards

1
Q

What is the literal meaning of leukaemia

A

Cancer of the blood

Means white blood

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2
Q

Describe the epidemiology of Leukaemia

A

In the UK approximately 60 people every day are diagnosed with a cancer of the blood
Blood cancers are the most common cancers in men and women aged 15‒24
They are the main cause of cancer death in people aged 1‒34 years

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3
Q

How many people in the UK will die of a leukaemia, lymphoma or myeloma

A

One in 45 of the UK population will die of leukaemia, lymphoma or myeloma

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4
Q

Why do we call cancers of the blood leukaemia

A

Leukaemia means ‘white blood’
The name was given because the first cases of leukaemia recognized had a marked increase in the white cell count which made the blood look whiter
Leukaemia is actually a bone marrow disease and not all patients have abnormal cells in the blood

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5
Q

Where exactly does the problem exist in Leukaemia

A

Leukaemia is actually a bone marrow disease and not all patients have abnormal cells in the blood
Therefore the problem exists in the bone marrow- but you can get overspill into the blood

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6
Q

What does Leukaemia result from

A

Leukaemia results from a series of mutations in a single lymphoid or myeloid stem cell

One mutation is not enough

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7
Q

What is the ultimate consequence of these mutations in Leukaemia

A

These mutations lead the progeny of that cell to show abnormalities in proliferation, differentiation or cell survival leading to steady expansion of the leukaemic clone

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8
Q

Outline the schemata for the production of the different blood cells

A

Pluripotent haematopoietic stem cell – Lymphoid stem cell or myeloid stem cell

Lymphoid stem cell- Pre B Lymphocytes/ Pro T Lymphocytes

Myeloid stem cells- Erythroblasts, myeloblasts, monoblasts,megakaryoblasts

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9
Q

In which cells can mutations arise in Leukaemia

A

Pluripotent haematopoietic stem cell- mutations in this cell type can give rise to mixed phenotype leukaemia- where there are lymphoid and myeloid cells present

Myeloid stem cell- myeloid leukaemias

Lymphoid stem cell- B/T/NK cell leukaemias/lymphomas

Pre B lymphocyte

Pro T lymphocyte

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10
Q

When we centrifuge blood and put it into a capillary tube, how may the white cells be visualised

A

White column
Referred to as the buffy-coat- slightly off-white

This layer will be increased in patients with leukaemia- reflecting the increase in WBC

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11
Q

Describe how a leukaemia can arise

A

Mutation in one of the cells- this mutation does not normally produce any noticeable changes in the cells but it can be detected using molecular and genetic methods.
This will give its progeny a survival advantage, either by:
proliferation (more of them)
differentiation (produce abnormal mature cells)
loss of cell survival (more of them)
susbequent mutations then occur in the progeny- leading to the emergence of a leukemic clone

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12
Q

Describe how leukaemia differs from most other cancers

A

Most cancers exist as a solid tumour
However, it is uncommon for patients with leukaemia to have tumours
More often they have leukaemic cells replacing normal bone marrow cells and circulating freely in the blood stream
So, essentially, leukaemia is diffuse infiltration of the bone marrow- with overspill into the blood.

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13
Q

Describe how leukaemia behaves differently to other cancers

A

Leukaemia is different from other cancer because haemopoietic and lymphoid cells behave differently from other body cells
Normal haemopoietic stem cells can circulate in the blood and both the stem cells and the cells derived from them can enter tissues
Normal lymphoid stem cells recirculate between tissues and blood (through lymphatics)

A epithelial cell isn’t going to move anywhere- it will stay in the epithelium.

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14
Q

Differentiate between the terms ‘invasion’ and ‘metastasis’

A

Invasion- local expansion and penetration into local tissues.
Metastasis- when the tumour moves to a distant site via the blood or lymphatics.

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15
Q

Why can’t the terms invasion and metastasis apply to leukaemias and how does this impact their classification into chronic and benign tumours

A

The concepts of invasion and metastasis cannot be applied to cells that normally travel around the body and enter tissues
We have to have other ways of distinguishing a ‘benign’ condition from a ‘malignant’ condition and haematologists usually use different words for these concepts

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16
Q

Describe the classification of benign and malignant leukaemia

A

Leukaemias that behave in a relatively ‘benign’ manner are called chronic—that means the disease goes on for a long time
Leukaemias that behave in a ‘malignant’ manner are called acute—that means that, if not treated, the disease is very aggressive and the patient dies quite rapidly

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17
Q

Summarise the classification of leukaemia

A

It follows from what has been said that leukaemia can be acute or chronic
Depending on the cell of origin, it can also be lymphoid or myeloid
Lymphoid can be B or T lineage ( or NK lineage)
Myeloid can be any combination of granulocytic, monocytic, erythroid or megakaryocytic- can get multiple lineages affected, or where one lineage predominates.

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18
Q

State the different classifications of leukaemia

A

Acute lymphoblastic leukaemia (ALL)
Acute myeloid leukaemia (AML)
Chronic lymphocytic leukaemia (CLL)
Chronic myeloid leukaemia (CML)

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19
Q

Explain the significance of the terms acute lymphoBLASTIC leukaemias and chronic lymphoCYTIC leukaemias

A

In ALL the cells are immature – they are lymphoblasts

IN CLL the cells are mature lymphocytes

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20
Q

Summarise the two key classes of mutations that may occur which explains why people get leukaemias

A

Leukaemia results from a series of mutations in a single stem cell
Some mutations result from identifiable (or unidentifiable) oncogenic influences
Others are probably random errors—chance events—that occur throughout life and accumulate in individual cells

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21
Q

In what percentage of leukaemia patients do we know the cause of their leukaemia

A

<10%

However, we understand a lot about the mechanisms

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22
Q

Describe the important leukaemogenic mutations that have been recognised

A

Mutation in a known proto-oncogene (cells that give rise to oncogenes but also any normal gene with oncogenic potential).
Creation of a novel gene, e.g. a chimaeric or fusion gene (as a result from chromosomal translocation)
Dysregulation of a gene when translocation brings it under the influence of the promoter or enhancer of another gene ( so the gene is structurally normal- but a promoter or enhancer region of another gene has been translocated onto it which turns it on/off inappropriately).

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23
Q

What is the difference between a fusion and a chimaeric gene

A

Chimeric genes (literally, made of parts from different sources) form through the combination of portions of two or more coding sequences to produce new genes. These mutations are distinct from fusion genes which merge whole gene sequences into a single reading frame and often retain their original functions.

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24
Q

What other factors can lead to the development of leukaemias

A

Loss of function of a tumour-suppressor gene can also contribute to leukaemogenesis—this can result from deletion or mutation of the gene (this can often transform the leukaemia from chronic to acute, as the tumour-suppressor gene was giving the patient some control until it became mutated).

If there is a tendency to increased chromosomal breaks, the likelihood of leukaemia is increased

In addition, if the cell cannot repair DNA normally, an error may persist whereas in a normal person the defect would be repaired

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25
Q

State some inherited or constitutional abnormalities that can lead to leukaemogenesis

A

Inherited or other constitutional abnormalities can contribute to leukaemogenesis, e.g.
Down’s syndrome
Chromosomal fragility syndromes (fragile X syndrome)
Defects in DNA repair (Fanconi anaemia, Werner syndrome, xeroderma pigmentosum).
Inherited defects of tumour-suppressor genes

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26
Q

State some identifiable causes of leukaemogenic mutations

A

Irradiation
Anti-cancer drugs (can induce mutations which lead to leukaemias)
Cigarette smoking
Chemicals—benzene

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27
Q

How can Leukaemia be described

A

Leukaemia, like cancer in general, can be seen as an acquired genetic disease, resulting from somatic mutation

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28
Q

Differentiate between mutations in germ cells and somatic mutations

A

Mutation in germ cells may bring favourable, neutral or unfavourable characteristics to the species
Somatic mutation may be beneficial*, neutral or harmful
* A rare occurrence but can lead to reversion to normal phenotype in some cells in individuals with an inherited abnormality, e.g. an immune deficiency or bone marrow failure syndrome

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29
Q

Describe the philosophical interpretation of why people get leukaemias and cancers in general

A

Since some mutations that contribute to leukaemogenesis appear to be random events rather than caused by an exogenous influence, they may result from the nature of the human genome

Leukaemia may thus be, in part, the inevitable result of the ability of mankind to change through evolution

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30
Q

What happens in AML

A

In AML, cells continue to proliferate but they no longer mature so there is
A build up of the most immature cells— myeloblasts or ‘blast cells’—in the bone marrow with spread into the blood
A failure of production of normal functioning end cells such as neutrophils, monocytes, erythrocytes, platelets - BECUASE THIS LEUKAEMIC CLONE WILL CROWD OUT THE BONE MARROW AND PREVENT THE NORMAL PRODUCTION OF MATURE MYELOID CELLS.

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31
Q

Why else may the platelet count be low in acute leukaemias (as well as AML)

A

One type of acute leukaemia exists where there are complications of DIC- so the platelets are consumes in the vasculature.

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32
Q

What mutations take place in AML

A

In AML, the responsible mutations usually affect transcription factors so that the transcription of multiple genes is affected
Often the product of an oncogene prevents the normal function of the protein encoded by its normal homologue (so it’s acting in a dominant manner)
Cell behaviour is profoundly disturbed (due to the effects on transcription factors).

33
Q

What mutations occur in CML

A

In CML, the responsible mutations usually affect a gene encoding a protein in the signalling pathway between a cell surface receptor and the nucleus
The protein encoded may be either a membrane receptor or a cytoplasmic protein
Unlike AML, this doesn’t profoundly influence cell behaviour, but it can result in innappropiate activation of the cell.

34
Q

What are the consequences of the mutations of CML

A

In CML, cell kinetics and function are not as seriously affected as in AML
However, the cell becomes independent of external signals, there are alterations in the interaction with stroma and there is reduced apoptosis so that cells survive longer and the leukaemic clone expands progressively

35
Q

How can we distinguish between AML and CML

A

Whereas in AML there is a failure of production of end cells, in CML there is increased production of end cells

AML and CML blood films may both show anaemia- but in CML you will see evidence of maturation and differentiation of myeloid cells and stem cells.

36
Q

What is the key difference between ALL and CLL

A

Acute lymphoblastic leukaemia has an increase in very immature cells— lymphoblasts—with a failure of these to develop into mature T and B cells
In chronic lymphoid leukaemias, the leukaemic cells are mature, although abnormal, T cells or B cells

37
Q

What does the accumulation of immature cells in ALL result in

A

Accumulation of abnormal cells leading to
Leucocytosis, bone pain (if leukaemia is acute), hepatomegaly, splenomegaly lymphadenopathy (if lymphoid), thymic enlargement (if T lymphoid), skin infiltration

Bone pain is a common presentation of ALL in children- due to white cells infiltrating bone marrow.

38
Q

How does the skin of a patient with ALL appear

A

Papular lesion infiltrates

39
Q

What is leukaemia cutis

A

leukaemia of the skin (skin infiltration)- will cause gross thickening of the skin- can be treated.

40
Q

Describe the metabolic effects of increased leukaemic cells

A

Metabolic effects of leukaemic cell proliferation—hyperuricaemia and renal failure, weight loss, low grade fever, sweating

Hyperuricaemia (due to breakdown of DNA from dying leukaemic cells)- can cause renal failure if uric acid is deposited in the kidneys.

Weight loss- metabolism being directed to proliferating white cells.

Low grade fever and sweating- due to increased metabolic rate.

41
Q

What are the effects of increased leukaemic cells on other blood cells

A

Crowding out of normal cells leading to

anaemia, neutropenia, thrombocytopenia

42
Q

Which type of leukaemia increases the risk of a fatal intraventricular haemorrhage

A

Acute promyelocytic leukaemia (APML) – this is associated with DIC so the platelet count and fibrinogen are low leading to increased risk of fatal haemorrhage

Will also present with small bruises

Blood shows as white on CT of brain.

43
Q

What are the effects of acute myeloid leukaemia (particularly of the monocytic lineage) on the gums

A

Monocytes attracted by chemotactic stimuli to the gums and consequently infiltrate the gums:
Infiltration of leukaemic cells and monocytes can lead to inflammation of the gums (swelling of the gums)
There will be small haemorrhages due to thrombocytopenia

This will not happen in patients without any teeth.

44
Q

What is a potential key feature of CLL

A

Loss of normal immune function as a result of loss of normal T cell and B cell function—a feature of chronic lymphoid leukaemia
As the cells are abnormal- it gives a propensity to infection.

45
Q

What is important to remember about the epidemiology of ALL

A

Acute lymphoblastic leukaemia is largely a disease of children
Peak incidence is between 2-5
Also another peak in middle age, but this is a genetically different ALL (due to translocation of chromosomes 9 and 22- which is also the translocation in CML, but this time it occurs in a lymphoid stem cell- so you get a lymphoid leukaemia).

46
Q

What does the data regarding the epidemiology of ALL suggest

A

Epidemiology suggests that B-lineage ALL may result from delayed exposure to a common pathogen or, conversely, that early exposure to pathogens protects
Evidence relates to family size, new towns, socio-economic class, early social interactions, variations between countries
A study in Taiwan suggested that enterovirus infection gave protection

47
Q

Explain the factors that may protect against ALL

A

Essentially, anything that would stimulate your immune system early in life
Low socio-economic class- more early exposure to pathogens- kindergartens- more social interactions
New towns built on edges of cities= protective- less likelihood of introduction of an unencountered pathogen
New town built in countryside= harmful- mixing of people from different cities brining unknown pathogens.

48
Q

Describe some leukogenic factors for ALL in children

A

Epidemiology also suggests that some leukaemias in infants and young children result from
Irradiation in utero
In utero exposure to certain chemicals ? Baygon, ? Dipyrone
? Epstein–Barr virus infection
Rarely ALL results from exposure to a mutagenic drug- tends to be AML.

49
Q

How can we classify the symptoms of ALL

A

Those as a result of the accumulation of abnormal cells

Those as a result of crowding out of the bone marrow.

50
Q

List the complications of ALL related to the accumulation of abnormal cells

A 
Bone pain
Hepatomegaly
Splenomegaly
Lymphadenopathy
Thymic enlargement
Testicular enlargement
51
Q

How may a lymphadenopathy present in the patient

A

Swelling of the lymph nodes

Most obvious in the neck.

52
Q

How will thymic enlargement show on a CXR

A

Will increase the cardiac shadow

53
Q

Describe the complications of ALL resulting from the crowding out of cells in the bone marrow

A

Fatigue, lethargy, pallor, breathlessness (caused by anaemia)
Fever and other features of infection (caused by neutropenia)- particularly bacterial infections.
Bruising, petechiae, bleeding (caused by thrombocytopenia)

54
Q

What is meant by petechiae

A

Small pin-point haemorrhages in the skin

55
Q

If a child comes in with bruises all over the body, as well as investigating abuse, what else should you consider

A

ALL

Perform a blood count immediately.

56
Q

What are the haematological features of ALL

A

Leucocytosis with lymphoblasts in the blood
Anaemia (normocytic, normochromic) - no Fe or folic acid deficiencies- just crowded out
Neutropenia
Thrombocytopenia
Replacement of normal bone marrow cells by lymphoblasts

57
Q

What investigations should be performed to diagnose ALL

A 
Blood count and film
Check of liver and renal function and uric acid
Bone marrow aspirate 
Cytogenetic/molecular analysis
Chest X-ray
58
Q

How will the blood film a patient with ALL show

A

Lots of lymphoblasts- with increased nuclear:cytoplasmic ratio, delicate chromatin condensations, larger
No platelets.

59
Q

Describe how a bone marrow film of a patient with ALL will appear

A

Lots of lymphobasts- same as blood film

60
Q

What is the purpose of immunophenotyping

A

To determine the lineage involved in the leukaemia

61
Q

Describe how immunophenotyping works

A

Pass cells single file through a detector- which picks up fluorescence due to antibody being bound to an antigen.
CD10 is common ALL antigen- commonly expressed on B lineage ALL
TDT (terminal deoxynucleotidyl transferase)- marker of cell immaturity- so blast cells tend to express this.

X-axis -TDT- so further right= more blast cells
Y-axis- CD10- so higher up- more B cells

Can also look at CD19 for B cell lineage

62
Q

How can you quickly tell from the blood film that it is a myeloid lineage

A

Granules of mast cells.

63
Q

Describe the importance of cytogenetic and molecular genetic analysis

A

Cytogenetic/molecular genetic analysis is useful for managing the individual patient because it gives us information about prognosis
Cytogenetic/molecular genetic analysis advances knowledge of leukaemia because it has permitted the discovery of leukaemogenic mechanisms

64
Q

Describe how cytogenetic analysis of bone marrow aspirates can dictate the treatment course given

A

Hyperdiploidy—good prognosis- so need less aggressive treatments
t(4;11)—poor prognosis- so need more aggressive treatments

65
Q

Describe the potential consequences of the formation of a fusion gene

A

Formation of a fusion gene
Dysregulation of a proto-oncogene by juxtaposition of it to the promoter of another gene, e.g. a T-cell receptor gene
Point mutation in a proto-oncogene

66
Q

Describe reciprocal translocations

A

Bits of chromosomes are swapped
Two detached fragments from two non-homologous chromosomes are switched.
Two fusion genes- of which only one tends to be active.

67
Q

Describe the use of FISH in cytogenetics to detect chromosomal translocations

A

This can be detected by two fluorescent probes, a green probe for ETV6 and a red probe for RUNX1; when a fusion gene is formed the two colours fuse to give a yellow fluorescent signal
This technique is called fluorescence in situ hybridization —FISH
Used over cytogenetics of bone marrow aspirate when these cells don’t go into mitosis.

68
Q

What is a common translocation in T cell lymphomas

A

t(10;14)(q24;q11)—the TCL3 gene is dysregulated by proximity to the TCRA gene

Proto-oncogene brought close to TCR- dysregulation- not a fusion gene!

69
Q

Summarise the treatment for ALL

A

Supportive
Red cells- anaemia
Platelets- thrombocytopenia
Antibiotics/anti-fungals- neutropenia

Systemic chemotherapy- leukaemia is widespread
Intrathecal chemotherapy/ systemic drug that can cross BBB- otherwise-patient will enter remission- residual leukaemic cells which will reactivate in CNS.

70
Q

What has been happening to childhood survivial rates with ALL

A

Increasing gradually.

§ Overall survival has been gradually been getting better:
o Approx. 10-year survival was 10% in 60s, now it is 95%.
§ Event free survival shows a similar pattern -5%

This is due to advances in chemotherapy and better supportive care.

71
Q

What is the difference between overall survival and event free survival

A

EFS- don’t have disease and alive

OS- just alive (so may have disease)

72
Q

What are the disease characteristics of leukaemia due to

A

Disease characteristics are due to (i) proliferation of leukaemic cells (ii) loss of function of normal cells

73
Q

Why does the treatment for leukaemias need to be systemic

A

Unlike other cancers, leukaemia is disseminated from very early in the disease process
Treatment must therefore be systemic

74
Q

Describe the relationship between prognosis and treatment for leukaemias

A

It is the molecular genetic events that determine the disease phenotype including the prognosis
This in turn determines the optimal treatment for individual patients
Increasingly, identification of the precise genetic events underlying the leukaemia indicates the best treatment for an individual patient

75
Q

What other form of treatment may be used in ALL

A

In poor prognosis cases, bone marrow (or other haemopoietic stem cell) transplantation may be needed.
About three-quarters of children with ALL can now be cured.

76
Q

Describe how ALL may cause cranial nerve palsies

A

Meningeal infiltration

77
Q

What may give rise to CLL

A

Family predisposition

78
Q

Describe the common results of cytogenetic analysis seen in ALL

A 
o Hyperdiploidy = GOOD prognosis 
o t(4:11) = BAD prognosis 
o t(12:21)(p12:q22) = ETV6-RUNX1 - fusion gene 
o t(10:14)(q24:q11) – TCL3 gene is dysregulated by proximity to the TCRA gen
79
Q

Describe the different proportions of the different lineages of ALL

A

· ALL:
o 75% - B cell lineage
o 25% - T cell lineage

Cancer (15 decks)

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