Cancer as a disease: Leukaemia Flashcards
What is the literal meaning of leukaemia
Cancer of the blood
Means white blood
Describe the epidemiology of Leukaemia
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
How many people in the UK will die of a leukaemia, lymphoma or myeloma
One in 45 of the UK population will die of leukaemia, lymphoma or myeloma
Why do we call cancers of the blood leukaemia
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
Where exactly does the problem exist in Leukaemia
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
What does Leukaemia result from
Leukaemia results from a series of mutations in a single lymphoid or myeloid stem cell
One mutation is not enough
What is the ultimate consequence of these mutations in Leukaemia
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
Outline the schemata for the production of the different blood cells
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
In which cells can mutations arise in Leukaemia
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
When we centrifuge blood and put it into a capillary tube, how may the white cells be visualised
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
Describe how a leukaemia can arise
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
Describe how leukaemia differs from most other cancers
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.
Describe how leukaemia behaves differently to other cancers
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.
Differentiate between the terms ‘invasion’ and ‘metastasis’
Invasion- local expansion and penetration into local tissues.
Metastasis- when the tumour moves to a distant site via the blood or lymphatics.
Why can’t the terms invasion and metastasis apply to leukaemias and how does this impact their classification into chronic and benign tumours
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
Describe the classification of benign and malignant leukaemia
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
Summarise the classification of leukaemia
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.
State the different classifications of leukaemia
Acute lymphoblastic leukaemia (ALL)
Acute myeloid leukaemia (AML)
Chronic lymphocytic leukaemia (CLL)
Chronic myeloid leukaemia (CML)
Explain the significance of the terms acute lymphoBLASTIC leukaemias and chronic lymphoCYTIC leukaemias
In ALL the cells are immature – they are lymphoblasts
IN CLL the cells are mature lymphocytes
Summarise the two key classes of mutations that may occur which explains why people get leukaemias
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
In what percentage of leukaemia patients do we know the cause of their leukaemia
<10%
However, we understand a lot about the mechanisms
Describe the important leukaemogenic mutations that have been recognised
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).
What is the difference between a fusion and a chimaeric gene
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.
What other factors can lead to the development of leukaemias
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
State some inherited or constitutional abnormalities that can lead to leukaemogenesis
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
State some identifiable causes of leukaemogenic mutations
Irradiation
Anti-cancer drugs (can induce mutations which lead to leukaemias)
Cigarette smoking
Chemicals—benzene
How can Leukaemia be described
Leukaemia, like cancer in general, can be seen as an acquired genetic disease, resulting from somatic mutation
Differentiate between mutations in germ cells and somatic mutations
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
Describe the philosophical interpretation of why people get leukaemias and cancers in general
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
What happens in AML
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.
Why else may the platelet count be low in acute leukaemias (as well as AML)
One type of acute leukaemia exists where there are complications of DIC- so the platelets are consumes in the vasculature.
What mutations take place in AML
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).
What mutations occur in CML
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.
What are the consequences of the mutations of CML
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
How can we distinguish between AML and CML
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.
What is the key difference between ALL and CLL
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
What does the accumulation of immature cells in ALL result in
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.
How does the skin of a patient with ALL appear
Papular lesion infiltrates
What is leukaemia cutis
leukaemia of the skin (skin infiltration)- will cause gross thickening of the skin- can be treated.
Describe the metabolic effects of increased leukaemic cells
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.
What are the effects of increased leukaemic cells on other blood cells
Crowding out of normal cells leading to
anaemia, neutropenia, thrombocytopenia
Which type of leukaemia increases the risk of a fatal intraventricular haemorrhage
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.
What are the effects of acute myeloid leukaemia (particularly of the monocytic lineage) on the gums
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.
What is a potential key feature of CLL
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.
What is important to remember about the epidemiology of ALL
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).
What does the data regarding the epidemiology of ALL suggest
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
Explain the factors that may protect against ALL
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.
Describe some leukogenic factors for ALL in children
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.
How can we classify the symptoms of ALL
Those as a result of the accumulation of abnormal cells
Those as a result of crowding out of the bone marrow.
List the complications of ALL related to the accumulation of abnormal cells
Bone pain Hepatomegaly Splenomegaly Lymphadenopathy Thymic enlargement Testicular enlargement
How may a lymphadenopathy present in the patient
Swelling of the lymph nodes
Most obvious in the neck.
How will thymic enlargement show on a CXR
Will increase the cardiac shadow
Describe the complications of ALL resulting from the crowding out of cells in the bone marrow
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)
What is meant by petechiae
Small pin-point haemorrhages in the skin
If a child comes in with bruises all over the body, as well as investigating abuse, what else should you consider
ALL
Perform a blood count immediately.
What are the haematological features of ALL
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
What investigations should be performed to diagnose ALL
Blood count and film Check of liver and renal function and uric acid Bone marrow aspirate Cytogenetic/molecular analysis Chest X-ray
How will the blood film a patient with ALL show
Lots of lymphoblasts- with increased nuclear:cytoplasmic ratio, delicate chromatin condensations, larger
No platelets.
Describe how a bone marrow film of a patient with ALL will appear
Lots of lymphobasts- same as blood film
What is the purpose of immunophenotyping
To determine the lineage involved in the leukaemia
Describe how immunophenotyping works
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
How can you quickly tell from the blood film that it is a myeloid lineage
Granules of mast cells.
Describe the importance of cytogenetic and molecular genetic analysis
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
Describe how cytogenetic analysis of bone marrow aspirates can dictate the treatment course given
Hyperdiploidy—good prognosis- so need less aggressive treatments
t(4;11)—poor prognosis- so need more aggressive treatments
Describe the potential consequences of the formation of a fusion gene
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
Describe reciprocal translocations
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.
Describe the use of FISH in cytogenetics to detect chromosomal translocations
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.
What is a common translocation in T cell lymphomas
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!
Summarise the treatment for ALL
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.
What has been happening to childhood survivial rates with ALL
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.
What is the difference between overall survival and event free survival
EFS- don’t have disease and alive
OS- just alive (so may have disease)
What are the disease characteristics of leukaemia due to
Disease characteristics are due to (i) proliferation of leukaemic cells (ii) loss of function of normal cells
Why does the treatment for leukaemias need to be systemic
Unlike other cancers, leukaemia is disseminated from very early in the disease process
Treatment must therefore be systemic
Describe the relationship between prognosis and treatment for leukaemias
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
What other form of treatment may be used in ALL
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.
Describe how ALL may cause cranial nerve palsies
Meningeal infiltration
What may give rise to CLL
Family predisposition
Describe the common results of cytogenetic analysis seen in ALL
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
Describe the different proportions of the different lineages of ALL
· ALL:
o 75% - B cell lineage
o 25% - T cell lineage
