Leukemia (19.02.2020) Flashcards
(41 cards)
1
Q
What is leukemia?
A
- Cancer of the blood
- literally “white blood”
- 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
- bone marrow disease and not all patients have abnormal cells in the blood
2
Q
Leukemia statistics
A
- 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
3
Q
What causes this cancerous white cell expansion?
A
- results from a series of mutations in a single lymphoid or myeloid stem cell
- 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
- new mutation in a single cell giving it a growth or survival advantage
- emergence of a leukaemia clone
4
Q
Which cells can be involved in leukemia?
A
pluripotent heamatopoietic stem cell
- myeloid stem cell (gives rise to myeloid leukemias)
- lymphoid stem cell
- Pre-B lymphocye
- Pre-T lymphocyte
- NK
- leukemias and lymphomas
5
Q
What is different about leukaemia?
A
- different from 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
- Dif 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
6
Q
Benign and malignant leukemias
A
- concepts of invasion and metastasis cannot be applied to cells that normally travel around the body and enter tissues
- other ways of distinguishing a ‘benign’ condition from a ‘malignant’ condition and haematologists usually use different words for these concepts
- relatively ‘benign’ manner: called chronic—that means the disease goes on for a long time
- behave in a ‘malignant’ manner : called acute—that means that, if not treated, the disease is very aggressive and the patient dies quite rapidly
7
Q
chronic and acute leukemias - what is the implication?
A
- chronic behave in a more ‘‘benign’’ manner
- acute behave more in a ‘‘malignant’’ manner
8
Q
How is leukaemia classified?
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
- Myeloid can be any combination of granulocytic, monocytic, erythroid or megakaryocytic
9
Q
Leukemia types
A
Acute lymphoblastic leukaemia (ALL)
Acute myeloid leukaemia (AML)
Chronic lymphocytic leukaemia (CLL)
Chronic myeloid leukaemia (CML)
Note: lymphoblastic
lymphocytic
10
Q
Why do people get leukaemia?
A
- arises 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
- acquired genetic disease, resulting from somatic mutation
- 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
- Leukaemia may thus be, in part, the inevitable result of the ability of mankind to change through evolution
11
Q
What can cause leukemia?
A
- Irradiation
- Anti-cancer drugs
- Cigarette smoking
- Chemicals—benzene
12
Q
What is the difference between acute and chronic myeloid leukaemia?
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 (for 2 reasons)
- AML: responsible mutations usually affect TFs 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
- Cell behaviour is profoundly disturbed
- CML: 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
- cell kinetics and function are not as seriously affected as in AML
- cell independent of external signals, alterations in the interaction with stroma and reduced apoptosis -> cells survive longer and the leukaemic clone expands progressively
13
Q
2 meanings of myeloid
A
- generic term for all myeloid cells
- can also refer to granulocytes
14
Q
What is the difference between acute and chronic lymphoid leukaemias?
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
15
Q
How does leukaemia cause the disease characteristics?
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 and renal failure
- weight loss
- low grade fever (die to higher metabolic rate)
- sweating (higher metabolic rate)
Crowding out of normal cells leading to
- anaemia
- neutropenia
- thrombocytopenia (bruising, can cause haemorrhages, swelling and hameorhage of the gums)
Loss of normal immune function as a result of loss of normal T cell and B cell function—a feature of chronic lymphoid leukaemia
16
Q
leukemia cutis
A
- infiltration of neoplastic leukocytes or their precursors into the epidermis, the dermis, or the subcutis, resulting in clinically identifiable cutaneous lesions.
- may follow, precede or occur concomitantly with the diagnosis of systemic leukemia
17
Q
Acute myeloid leukaemia—abnormalities in the mouth
A
- swollen gums due to infiltration
- gum haemorrhages due to low platelets
18
Q
Acute lymphoblastic leukaemia—epidemiology
A
- Acute lymphoblastic leukaemia is largely a disease of children
- rises a bit in older age (because of 9:22 translocation)
- in children that translocation does not occur, it is different
19
Q
Why do children get ALL?
A
- a lot of research done
- 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 (working class are less likely to get leukemia), early social interactions (e.g. going to kindergarten is protective), variations between countries
- exposure to the pathogen later may be leukomegenic
- A study in Taiwan suggested that enterovirus infection gave protection
- 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
20
Q
ALL clinical features
A
Resulting from accumulation of abnormal cells
- Bone pain
- Hepatomegaly
- Splenomegaly
- Lymphadenopathy
- Thymic enlargement (makes chest x-ray look different)
- Testicular enlargement
Resulting 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 e.g. from mucosal surfaces (caused by thrombocytopenia)
- Leucocytosis with lymphoblasts in the blood
- Anaemia (normocytic, normochromic)
- Neutropenia
- Thrombocytopenia
- Replacement of normal bone marrow cells by lymphoblasts (if BMbiopsy is done)
21
Q
DD if a child is bruised
A
- accidental injury
- non-accidental injury, abuse
- leukemia
- bleeding disorders
22
Q
Investigations to do in ALL
A
- Blood count and film (high nucelocutoplasmic ratio, lack of platelets,
- Check of liver and renal function and uric acid
- Bone marrow aspirate
- Cytogenetic/molecular analysis
- Chest X-ray
23
Q
normal vs ALL blood film
A
normal
- different cells
- thrombocytes
- differentiated leukocytes
ALL
- many lymphoblasts
- high nucleocytoplasmic ratio
- chromatin condensed
- thrombocytopenia
24
Q
immunophenotyping
A
-> used to classify the leukemia by looking at antigens found in these cells (the graph shows ‘clusters’ of how much of a certain AG there is)
- CD10 - common ALL antigen
- TdT is a marker of immaturity
- CD-19 is a b-cell maker
25
Acute lymphoblastic leukaemia—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
- Hyperdiploidy—good prognosis
- t(4;11) - poor prognosis
26
Hyperdiploidy in ALL
-> good prognosis
27
t(4;11) in ALL
- poor prognosis
- gives rise to a very leukemogenic gene (formation of a fusion gene)
- reciprocal gene
28
ALL - leukemogenic mechanisms
- Formation of a fusion gene (e.g. translocation)
- 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
29
Acute lymphoblastic leukaemia — treatment
Supportive
- Red cells
- Platelets
- Antibiotics
Systemic chemotherapy
Intrathecal chemotherapy (LP and injecting drug into CSF). -> many leukemia drugs don't cross BBB
Treatment must be systemic!
30
ALL survival
- 1960s: 3%
| - 1990s: 80%
31
Types of leukemogenic mutations
- Mutation in a known proto-oncogene
- Creation of a novel gene, e.g. a chimaeric or fusion gene
- Dysregulation of a gene when translocation brings it under the influence of the promoter or enhancer of another gene
- Loss of function of a TS gene can also contribute to leukaemogenesis—this can result from deletion or mutation of the gene
- 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
32
Inherited or other constitutional abnormalities can contribute to leukaemogenesis
Down’s syndrome
Chromosomal fragility syndromes
Defects in DNA repair
Inherited defects of tumour-suppressor genes
33
What are myeloid stem cells precursors for?
- erythroblasts
- megakaryoblasts
- myeloblasts
- monoblasts
34
ALL — 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
35
What are some translocations known in ALL? what is their effect on the prognosis?
- t(4;11) -> worsens prognosis
- t(9;22)
- t(1;19)
- t(10;14) - the TCL3 gene is dysregulated by proximity to the TCRA gene, common mechanism in lymphoblastic leukemia
- t(12;21) (p12;q22) leading to a ETV6-RUNX1 fusion gene
36
t(10;14) in ALL
t(10;14)(q24;q11)—the TCL3 gene is dysregulated by proximity to the TCRA gene
37
What causes disease characteristics of leukemia?
(i) proliferation of leukaemic cells
| (ii) loss of function of normal cells
38
Is ALL a single disease?
- NO
- ALL is not a single disease or even two diseases
- There are multiple different leukaemogenic mechanisms giving different disease phenotypes
- It is the molecular genetic events that determine the disease phenotype including the prognosis
39
Multiple myeloma
cancer of plasma cells
40
ALL and CLL
Acute LYMOHOBLASTIC leukemia
Chronic LYMPHOCYTIC leukemia
41
Why do you check uric acid as a part of ALL investigation?
Secondary hyperuricemia
- Certain cancers, or chemotherapy agents may cause an increased turnover rate of cell death. This is usually due to chemotherapy, but high uric acid levels can occur before chemotherapy is administered.
- After chemotherapy, there is often a rapid amount of cellular destruction, and tumor lysis syndrome may occur. You may be at risk for tumor lysis syndrome if you receive chemotherapy for certain types of leukemia, lymphoma, or multiple myeloma, if there is a large amount of disease present.
source: Cleveland Clinic
