Haematological Malignancy 1 Flashcards
Define haematological malignancy
Cancer of the blood and bone forming tissue (bone marrow, lymph nodes, spleen)
Leukaemia, lymphoma and plasma cell myeloma
Likely to get progressively worse and lead to death if not treated
Define leukaemia
(2)
A malignant disease of haematopoietic tissue characterised by replacement of normal bone marrow elements with abnormal (neoplastic) blood cells.
Abnormal cells are also seen in peripheral blood
Define lymphoma
Abnormal proliferation of lymphoid cells within the lymphatic tissue or lymph nodes, results in a solid tumour
What happens in leukaemia
A stem cell in the bone marrow develops into a malignant cell
All progeny from this cell will be a malignant cell
Clone takes over
Write about where you would see leukaemia
Arise in bone marrow (seen in biopsy)
Cells found in circulating blood
Found in CSF when advanced
What are the two classifications of leukaemia
Myeloid and lymphoid
How is leukaemia diagnosed
Morphology
Immunophenotype - flow cytometry
Cytogenetics and molecular characteristics
What are lymphomas
Solid tumours of lymphocytes
Arise in many sites
Present as tumorous masses in lymphoid organs (lymph nodes, tonsilitis, spleen, lymphoid tissue of GIT)
Investigative sample may be fluid, FNA, biopsy or lymph node
How are lymphomas diagnosed
Morphology
Flow cytometry
IHC
Molecular Genetics
How are lymphomas classified
Hodgkin and Non-Hodgkin lymphoma
Why is there a push for lymphoma awareness
Patients wait quite long before seeking medical help
Most people wait about 6 months
Lymph node swelling is key symptom
What are some common signs and symptoms of lymphoma
Painless swelling in a lymph node
Chils/temperature swings
Recurrent fevers and excessive sweating a tnight
Unintentional weight loss
Loss of appetite
Persistent tiredness and lack of energy
Breathlessness and coughing
Persistant itch all over the body without cause
General fatigue
Enlarged tonsils
Headache
What percentage of leukaemia patients survive?
60%
What is acute leukaemia
The onset is usually rapid, the disease is very aggressive and the cells involved are usually poorly differentiated with many blasts
Myeloid and lymphoid
What is chronic leukaemia
Onset is insidious, the disease is usually less aggressive and the cells involved are usually more mature cells
Write about ALL and prognosis
Really good prognosis as a child
Really poor prognosis as an adult
How do leukaemias arise
Somatic mutation of a single haematopoietic stem or progenitor cell
Causes unlimited self-renewal of the cancer-initiating cell
Defect in maturation of white blood cells
As the mutant cell line predominates, normal haematopoiesis is inhibited causing malignant cells to spill into peripheral blood
May involve a block in differentiation and/or a block in apoptosis
Transformation events involve acquired genetic changes
Initiating events unclear
Chromosomal abnormalities (translocations, deletions) implicated in many forms of Blood Cancer
What hypothesis was proposed for how leukaemia arises
The two hit hypothesis
What is the two hit hypothesis
Involves multiple mutations
Class I mutation in a kinase coding gene such as RAS, KIT or FLT3
Class II mutation targeting transcription of nuclear factor such as NPM1, RUNX1 or CEBPA
What evidence is there for mutations surrounding leukaemia
(2)
Evidence that there is also a temporal component to leukaemogenesis: mutations have to occur at a particular point in cell development, and in a particular order, to allow for leukaemic transformation
Research highlights novel mutations in genes that are related to epigenetic control of the genome (DNA methylation and histone modification)
What are some symptoms of leukaemia
Swollen lymph nodes
Fever
Night sweats
Nose bleeds
Severe infections
Bleeding easily
Bone pain
Red spots on skin
Weight loss
What are some clinical signs of leukaemia
Anaemia
Infection
Bleeding episodes occurring as frank haemorrhages
Petechiae or ecchymoses
Bone pain due to marrow expansion
Weight loss
Hepatosplenomegaly
Occassional lymphadenopathy and organomegaly (more common in chronic)
Compare acute versus chronic leukaemia
(Acute = 11)
Acute
- all ages
- 2-5years for ALL
- 40+ years for AML
- sudden
- 6 month or less course (untreated)
- immature >20% blasts
- anaemia
- thrombocytopenia
- variable WBCC
- mild lymphadenopathy
- mild splenomegaly
Compare acute versus chronic leukaemia
(Chronic 9)
Affects usually adults
Insidious onset
2-6 years course (untreated)
More mature cells
Mild anaemia
Mild thrombocytopenia
Increased WCC
Prominant lymphadenopathy
Prominent splenomegaly
What leukaemia has the worst prognosis
Acute lymphocytic leukaemia in adults
What leukaemia has the best prognosis
Chronic myeloid leukaemia
ALL in children
Chronic lymphocytic leukaemia
Why was classification brought in by WHO
Without it, clinical trial results could not be compared between countries
Research results could not be evaluated collectively
Epidemiological studies would be impossible
Its the basis of cancer science internationally
What is the WHO classification based on
Morphology
Genetic features
Cytochemistry
Immunophenotyping
Immunohistochemistry
Molecular features
Write about the WHO classification system
Emphasis on therapeutically and/or prognostically actionable biomarkers
Genetic basis is sought where possible, but classification strives to keep practical worldwide applicability in perspective
Result is an enhanced, contemporary, evidence-based classification of myeloid and histiocytic/dendritic neoplasms, rooted in molecular biology and an organisational structure that permits future scalability as new discoveries continue to inexorably inform future efitions
What are the four groupings of classified disease
Acute leukaemias
Lymphoproliferative disorders
Myeloproliferative disorders
Lymphomas
Give an example of a lymphoproliferative disorder
Chronic lymphocytic leukaemia
Give an example two myeloproliferative disorders
Chronic myeloid leukaemia
Essential thrombocythaemia, polycythemia vera, myelofibrosis
What is a myeloblast
In normal bone marrow 4% of cells are myeloblasts
They should not be apparent in peripheral blood
They have a high nucleocytoplasmic ratio (really big nucleus)
They have a fine open lacy chromatin pattern accompanied by prominent nucleoli
Cytoplasm stains a light blue
How does a myeloblast look
They have a high nucleocytoplasmic ratio (really big nucleus)
They have a fine open lacy chromatin pattern accompanied by prominent nucleoli
Cytoplasm stains a light blue
What does myeloblasts in peripheral blood indicate
Increasing numbers can suggest myeloid leukaemia
What do myeloblasts develop into
Promyelocytes
Write about promyelocyte
Promyelocytes are significantly larger than myeloblasts
They demonstrate a lower nuclear cytoplasmic ratio and occasional nucleoli
The cytoplasm has a deep blue colouration in comparison to the paler myeloblast, and contains primary granules
Primary granules are retained in nuetrophils, eosinophils and basophils
The nucleus of the promyelocyte is also slightly indented
Promyelocytes should not be present in the peripheral blood
What does increased promyelocytes mean
An increase in the number of cells in the absence of other intermediate stages of maturation is associated with a subtype of AML called acute promyelocytic leukaemia
Write about myelocyte
Myelocytes are smaller than promyelocytes
Show evidence of chromatin clumping and nucleoli are no longer visible
Secondary granules are present throughout the cytoplasm
Secondary granules are so called because they are produced after the primary granules and possess a cell-specific function
The myeloblast, promyelocyte and myelocyte stages of maturation are all mitotic stages
At each stage, daughter cells are produced, so the larger the number of cells entering the cell cycle at the myeloblast stage, the greater the number of cells will become effector (mature) cells
Write about metamyelocytes
Contain distinctive primary and secondary granules
The nucleocytoplasmic ratio is much lower in metamyelocytes and the nucleus is kidney shaped
As the metamyelocyte matures, the nucleus becomes increasingly curved so that it almost resembles a horseshoe
The cells are now called “band forms”
Finally the nucleus becomes segmented and the mature features of the effector cell, the neutrophil, eosinophil or basophil, become apparent
Comment on exposure to very high levels of radiation
Very high levels of ionising radiation can be caused by:
- Atomic bomb explosions e.g. Horoshima
- Nuclear power plant accidents e.g. Chernobyl
- Medical treatment e.g. Xrays or CT scan
- Radiation therapy for cancer (can increase risk of leukaemia e.g. AML)
- receiving radioactive iodine therapy for hyperthyroidism or thyroid cancer -> risk of AML 80% higher, 3.5 times more likely to get CML
- air and spacetravel -> the leukaemia risk from space travel due to galactic cosmic rays
- radioactive materials -> uranium mining as an occupation increase risk of leukaemia
- exposure to radioactive material in tobacco products, which pick up these materials in the soil where they are grown
Write about working with chemicals and leukaemia risk
Working with benzene and formaldehyde are at greater risk of developing leukaemia
Increased incidence of malignancy in petrol pump attendants
Smokers at higher risk of AML
Herbicides and pesticides associated with MDS and AML
Radon increases risk of CLL
Write about chemotherapy and risk
Risk begins to increase two years after treatment and peaks between five and 10 years after treatment
Commonly associated with monosomies (when one Ch lacks its homolog) or deletion of Ch7 and 5
What medical conditions increase risk of leukaemia?
(5)
MDS (up to 30% develop AML)
Severe Aplastic, Anaemia (BM failure) associated with treatment with immunosuppressive agents (Cylosporin A, Cyclophosphamide and/or G-CSF therapy) have a 20% risk of developing MDS or AML
PNH also risk of developing MDS or AML
Inflammatory Bowel Disease
Autoimmune disorders (RA, SLE, Coeliac, pernicious anaemia)
Write about down syndrome and leukaemia
20% increase of AML M7
Approximately 10% have TAM at birth, 30% will develop AML M7 within 5 years
Although TAM can closely mimic leukaemia, most neonates who survive 4 to 8 weeks show complete remission
Trisomy 21? Role in leukamogenesis - but notably TAM and AML M7 share somatic mutations of GATA 1 transcription factor in almost all cases
GATA1 is a lineage-restricted TF that is central to the correct differentiation, proliferation and apopotosis or erythroid and megakaryoctic cells - so mutation can assist in AML occurring
However, studies have shown that truncating mutations in GATA1 are not sufficient to cause leukaemia in people, and have suggested that trisomy 21 may have an essential leukaemogenic function in cooperation with GATA1 mutation in DS
Write about infection and Leukaemia
Infection with T-cell leukaemia virus (HTLV-1) increases the risk of leukaemia
No direct evidence of viral genomic inclusions within leukaemia cells
Maternal infection a risk factor
Breast feeding and attendance at a creche during first year of life decreases risk
No evidence of vaccinations causing an increased risk
Seasonal variations noted - even in Ireland! September/October highest
Prevalence of childhood leukaemia noted? Back to school
Virus involvement in 15% of all cancer (notably Burkitt lymphoma, cervical cancer etc)
Small peaks in ALL have been associated with outbreaks of influenza
Increase in ALL incidence post strep throat -> possible bacterial link
Write about genetics and leucaemia
(4)
ALL does not appear to run in families, with the exception being identical twins
People who have a first-degree family member who has had CLL (parent, sibling or child) have more than twice the risk of developing the disease themselves
Siblings of children with AML have up to a four times higher risk of developing the disease, with the risk in identical twins being around 20 percent. In contrast, children who have a parent who has adult-onset leukaemia do not appear to be at a higher risk
Family history has no role in CML
