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Year 2 - Cancer > Leukaemia > Flashcards

Leukaemia Flashcards

1
Q

…..

A
  • Leukaemia is cancer of the blood (5% of all cancers are cancers of the blood)
  • 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
  • One in 45 of the UK population will die of leukaemia, lymphoma or myeloma
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2
Q

What is the difference between lymphoma and myeloma?

A

Lymphoma: tumour of lymphoid cells

Myeloma: neoplasma of plasma cells

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3
Q

What is leukaemia?

A

Leukaemia is actually a bone marrow disease and not all patients have abnormal cells in the blood, not all patients have circulating tumour cells

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4
Q

How does leukaemia occur?

A
  • Leukaemia results from a series of mutations in a single lymphoid or myeloid stem cell
  • It isn’t sufficient to have a single mutation (normally at least two)
  • These mutations lead the progeny of that cell to show:
    abnormalities in proliferation, abnormalities in differentiation or cell survival
    -This leads to steady expansion of the leukaemic clone
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5
Q

What can a pluripotent haematopoietic stem cell differentiate into?

A
  • We start off with a pluripotent haematopoietic stem cell
  • It can give rise to both myeloid and lymphoid cells
  • These differentiate into specific stem cells (either myeloid or lymphoid SCs)
  • Lymphoid SCs give rise to B lymphocytes and T lymphocytes
  • Myeloid SCs give rise to cells of the erythroid lineage and other cells
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6
Q

Describe how a stem cell mutation can lead to leukaemia

A
  • An initial mutation occurs in a stem cell, giving it a growth advantage
  • There is uncontrolled and increased expansion of this stem cell, crowding out the normal polyclonal cells
  • A second mutation in one of the cells provides it with even more aggressive behaviour
  • There can be an interval of years between the first and second mutations
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7
Q

What is different about leukaemia compared to other cancers?

A
  • Leukaemia is different from other cancers
  • Most cancers exist as a solid tumour
  • However, it is uncommon for patients with leukaemia to have tumours
  • They have leukaemic cells replacing normal bone marrow cells and circulating freely in the blood stream
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8
Q

What can solid tumours do?

A
  • Invasion and metastasis
  • Invasion: local spread
  • Metastasis: distant spread
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9
Q

Why can we not use invasion and metastasis to classify benign and malignant for haematopoietic and lymphoid cells?

A

They travel around the body normally and enter tissues

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10
Q

What is the difference between chronic and acute 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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11
Q

How can leukaemias be classified?

A
  • Chronic or acute
  • Myeloid and lymphoid
  • Lymphoid can be B/T cell
  • Myeloid can be granulocytic, monocytic, erythroid or megakaryocytic
  • In cancers involving lymphoid cells, we use different terms: lymphoblastic (acute) and lymphocytic (chronic)
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12
Q

Give examples of types of leukaemias

A
  • Acute lymphoblastic leukaemia (ALL)
  • Acute myeloid leukaemia (AML)
  • Chronic lymphocytic leukaemia (CLL)
  • Chronic myeloid leukaemia (CML)
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13
Q

How do people get leukaemia?

A
  • Leukaemia results from a series of mutations in a single stem cell
  • Some mutations results from identifiable (or unidentifiable) oncogenic influences
  • Others are probably random errors
  • Many types of leukaemia increase steadily in incidence with the age of individuals
  • This may be because of steady accumulation of mutations, some of which are harmful
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14
Q

Give examples of important leukaemogenic mutations

A
  • Mutation in a known proto-oncogene
  • Creation of a novel gene, e.g. a chimeric or fusion gene
  • Translocation may bring a normal gene under the influence of the promoter/enhancer of another gene
  • Loss of function of a TSG
  • If there is a tendency to increased chromosomal breaks, the likelihood of leukaemia is increased
  • If cells cannot repair DNA normally, an error may persist (may be the result of an inherited conditions)
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15
Q

Give examples of inherited abnormalities that can lead to leukaemogenesis

A

Down’s syndrome – associated with an increased propensity to ALL and AML

Chromosomal fragility syndromes

Defects in DNA repair

Inherited defects of TSG

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16
Q

What are some causes of leukaemogenic mutations?

A
  • Irradiation
  • Anti-cancer drugs are themselves leukaemogenic
  • Cigarette smoking
  • Chemicals e.g. benzene
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17
Q

What are beneficial and neutral mutations?

A

BENEFICIAL MUTATION: 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.

NEUTRAL: there is a mutation, but it doesn’t give the cell any particular growth or survival advantage, and therefore it doesn’t give rise to leukaemia.

18
Q

The genome, mutation, evolution and leukaemia

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
  • The human genome is prone to mutation, leading to evolution of the species
  • It may be that a side effect of the ability to evolve is that genetic changes may lead to cancer
19
Q

What is seen in terms of cells and maturation in AML? (how is AML different to CML)

A

In AML, cells continue to proliferate but they no longer mature so there is:

  • A build up of the most immature cells (myeloblasts) in the BM with spread into the blood
  • A failure of production of normal functioning end cells such as neutrophils, monocytes, erythrocytes, platelets (this can result in anaemia)
  • In acute myeloid leukaemia, there is a failure of production of the end cells, whereas in chronic myeloid leukaemia, there is increased production of end cells.
20
Q

Why might there be a low platelet count in leukaemia?

A
  1. Due to failure of production of normal functioning end cells
  2. Pathological process called disseminated intravascular coagulation (clotting occurs within circulation)
21
Q

What is the difference between acute and chronic lymphoid leukaemia?

A
  • Acute lymphoblastic leukaemia has an increase in very immature cells (lymphoblasts)
  • There is a failure of these lymphoblasts to develop into mature T and B cells
  • In chronic lymphoid leukaemias, the leukaemic cells are mature, although abnormal
  • So in CLL, we see mature T cells or B cells, but they may not be very functional
22
Q

How does leukaemia cause the characteristics of the disease?

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

Metabolic effects of leukaemic cell proliferation:

  • Hyperuricaemia: uric acid in the blood is high due to increased breakdown of DNA
  • Renal failure: as a result of uric acid depositing in the kidneys
  • Weight loss
  • Low grade fever
  • Sweating

Crowding out of normal cells, leading to:

  • Anaemia
  • Neutropenia
  • Thrombocytopenia

Loss of normal immune function as a result of loss of normal T cell and B cell function

  • There is a high incidence of shingles and herpes zoster in individuals with CLL
  • These patients are susceptible to viral, fungal and bacterial infections
23
Q

How does leukaemia affect the immune system?

A

Loss of normal immune function as a result of loss of normal T cell and B cell function:

  • This is a feature of chronic lymphoid leukaemia
  • In its advanced stages, CLL has quite a profound immunological deficit
  • The number of T cells are also reduced, and responses are poor
  • There is a high incidence of shingles and herpes zoster in individuals with CLL
  • These patients are susceptible to viral, fungal and bacterial infections
24
Q

Who is affected by acute lymphoblastic leukaemia?

What does this mean in term of acquiring mutations?

A
  • It is largely a disease of children
  • The peak incidence of ALL in childhood is between 2 and 8 years
  • Many of these children have been shown to have a first mutation occurring in utero
  • A second mutation occurs just before the development of leukaemia
  • We know about in utero mutations from the sots of dried blood from the umbilical cord
25
Q

How does the risk of acute lymphoblastic leukaemia change with age?

A
  • The incidence of ALL decreases with age and stays relatively low after the age of 20
  • The peak incidence in childhood reduces
  • From the age of 50 onwards, there is a slow rise again
  • There is a second, lower peak in old age
  • The genetic abnormalities underlying the childhood type are different from those underlying the type in middle-aged people and elderly people
26
Q

Clinical features of acute lymphoblastic leukaemia (due to abnormal cell accumulation)?

A
  • Bone pain is common (particularly in the legs)
  • Hepatomegaly
  • Splenomegaly
  • Lymphadenopathy
  • Thymic enlargement (if T lineage)
  • Testicular enlargement (due to infiltration of testes

Many clinical features of ALL result from crowding out of normal cells:

  • Fatigue, lethargy, pallor, breathlessness (caused by anaemia)
  • Fever and other features of infection (caused by neutropenia)
  • Bruising, petechiae, bleeding (caused by thrombocytopenia)
27
Q

What are the haematological features of acute lymphoblastic leukaemia?

A
  • Leucocytosis with lymphoblasts in the blood (sometimes they are just in the bone marrow)
  • Anaemia (normocytic, normochromic)
  • Neutropenia
  • Thrombocytopenia
  • Replacement of normal bone marrow cells by lymphoblasts
28
Q

What investigations are done into acute lymphoblastic leukaemia?

A
  • Before starting investigations, we want a clinical and familial history, and a physical examination
  • Blood count and film
  • Check of liver and renal function (may be impaired by infiltration) and uric acid measurement
  • Bone marrow aspirate – for cytogenetic analysis
  • Cytogenetic/molecular analysis
  • Chest X-ray: look for thymus enlargement, and to look for evidence of pneumonia
29
Q

What is immunophenotyping?

A
  • Recognising the antigens expressed on the surface of cells
  • It tells us whether cells are of T-lineage or B-lineage
  • Within each lineage, we can recognise different stages of maturation of blast cells (which is of some prognostic importance)
  • We can tell from the markers on the cell surface which type of lymphocyte they are
  • E.g. if CD19 is expressed on the cell surface, it is a B cell
  • TDT expressed on the surface: this tells us that the cell is an immature blast cell
30
Q

What is the importance of cytogenic and molecular genetic analysis in leukaemia?

A
  • Cytogenetic/molecular genetic analysis is useful for managing the individual patient
  • This is because it gives us information about prognosis
  • It helps us to identify oncogenes, and to study their effects
  • Cytogenetic/molecular genetic analysis advances knowledge of leukaemia
  • This is because it has permitted the discovery of leukaemogenic mechanisms
  • When we see hyperdiploidy (a lot more chromosomes than there should be in a diploid cell), this is often associated with a good prognosis
  • A reciprocal translocation of chromosomes is associated with a bad prognosis
31
Q

Leukaemogenic mechanisms in acute lymphoblastic leukaemia

A
  • Formation of a fusion gene – this may result from translocation of chromosomes
  • 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
32
Q

Cytogenetics of acute lymphoblastic leukaemia - what are the changes in the chromosome

How can these changes be detected?

A
  • Normal chromosomes 12 and 21 carry the ETV6 gene and RUNX1 gene respectively
  • Following translocation, there is a fusion ETV6- RUNX1 gene on chromosome 12
    t(12;21)(p12;q22) leading to a ETV6-RUNX1 fusion gene
  • Another example: t(10;14)(q24;q11)—the TCL3 gene is dysregulated by proximity to the TCRA gene
  • 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
33
Q

How is acute lymphoblastic leukaemia treated?

A
  • Supportive treatment: red cell transfusion (anaemia), platelets (thrombocytopenia) and antibiotics
  • Systemic chemotherapy (orally or intravenous)
  • Intrathecal chemotherapy (lumbar puncture, injection of drugs into the CSF)
  • Leukaemic cells cross into the CSF
  • Giving only systemic chemotherapy cures systemic disease, but there can be relapse from CSF disease
34
Q

How has the survival rates from leukaemia changed over time and why?

A
  • Survival in the 1960s was 3%
  • It is getting higher and higher (over 80% in 1996)
  • This results from better supportive care, better drugs and better prognostication
35
Q

What is event free survival?

A

This is survival, in which there is no relapse of the leukaemia. Overall survival refers to whether the patient is alive or not

36
Q

What causes the disease characteristics of leukaemia?

A
  • Proliferation of leukaemic cells

- Loss of function of normal cells

37
Q

Why must leukaemia treatment be systemic?

A
  • Unlike other cancers, leukaemia is disseminated from very early in the disease process
  • Treatment must therefore be systemic
38
Q

….

A
  • Acute lymphoblastic leukaemia results from mutation in a T- or B-lineage lymphoid stem cell
  • ALL is not a single disease or even two diseases
  • There are multiple different leukaemogenic mechanisms giving different disease phenotypes
39
Q

In CML what is mutated and what effect does this have?

A
  • The product of an oncogene prevents normal function of the protein encoded by its normal homologue
  • Cell behaviour is therefore profoundly disturbed
  • In CML, the responsible mutations usually affect a signalling protein gene
  • This gene encodes 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
  • 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
  • There is reduced apoptosis so that cells survive longer and the leukaemic clone expands progressively
40
Q

What does epidemiology suggest about leukaemia and what is associated with it?

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, and variations between countries
  • A study suggested that enterovirus infection gave protection
  • Epidemiology also suggests that some leukaemias in infants and young children result from:
    Irradiation in utero may be leukaemogenic, in utero exposure to certain chemicals
  • EBV may be causative, but the evidence is not very strong
  • Rarely, ALL results from exposure to a mutagenic drug

Year 2 - Cancer (9 decks)

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