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2.2 Haematology > Haematological Malignancy 1 > Flashcards

Haematological Malignancy 1 Flashcards

1
Q

Define haematological malignancy

A

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

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2
Q

Define leukaemia
(2)

A

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

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3
Q

Define lymphoma

A

Abnormal proliferation of lymphoid cells within the lymphatic tissue or lymph nodes, results in a solid tumour

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4
Q

What happens in leukaemia

A

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

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5
Q

Write about where you would see leukaemia

A

Arise in bone marrow (seen in biopsy)
Cells found in circulating blood
Found in CSF when advanced

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6
Q

What are the two classifications of leukaemia

A

Myeloid and lymphoid

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7
Q

How is leukaemia diagnosed

A

Morphology
Immunophenotype - flow cytometry
Cytogenetics and molecular characteristics

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8
Q

What are lymphomas

A

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

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9
Q

How are lymphomas diagnosed

A

Morphology
Flow cytometry
IHC
Molecular Genetics

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10
Q

How are lymphomas classified

A

Hodgkin and Non-Hodgkin lymphoma

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11
Q

Why is there a push for lymphoma awareness

A

Patients wait quite long before seeking medical help

Most people wait about 6 months

Lymph node swelling is key symptom

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12
Q

What are some common signs and symptoms of lymphoma

A

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

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13
Q

What percentage of leukaemia patients survive?

A

60%

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14
Q

What is acute leukaemia

A

The onset is usually rapid, the disease is very aggressive and the cells involved are usually poorly differentiated with many blasts

Myeloid and lymphoid

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15
Q

What is chronic leukaemia

A

Onset is insidious, the disease is usually less aggressive and the cells involved are usually more mature cells

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16
Q

Write about ALL and prognosis

A

Really good prognosis as a child

Really poor prognosis as an adult

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17
Q

How do leukaemias arise

A

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

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18
Q

What hypothesis was proposed for how leukaemia arises

A

The two hit hypothesis

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19
Q

What is the two hit hypothesis

A

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

20
Q

What evidence is there for mutations surrounding leukaemia
(2)

A

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)

21
Q

What are some symptoms of leukaemia

A

Swollen lymph nodes
Fever
Night sweats
Nose bleeds
Severe infections
Bleeding easily
Bone pain
Red spots on skin
Weight loss

22
Q

What are some clinical signs of leukaemia

A

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)

23
Q

Compare acute versus chronic leukaemia
(Acute = 11)

A

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

24
Q

Compare acute versus chronic leukaemia
(Chronic 9)

A

Affects usually adults
Insidious onset
2-6 years course (untreated)
More mature cells
Mild anaemia
Mild thrombocytopenia
Increased WCC
Prominant lymphadenopathy
Prominent splenomegaly

25
Q

What leukaemia has the worst prognosis

A

Acute lymphocytic leukaemia in adults

26
Q

What leukaemia has the best prognosis

A

Chronic myeloid leukaemia
ALL in children
Chronic lymphocytic leukaemia

27
Q

Why was classification brought in by WHO

A

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

28
Q

What is the WHO classification based on

A

Morphology
Genetic features
Cytochemistry
Immunophenotyping
Immunohistochemistry
Molecular features

29
Q

Write about the WHO classification system

A

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

30
Q

What are the four groupings of classified disease

A

Acute leukaemias

Lymphoproliferative disorders

Myeloproliferative disorders

Lymphomas

31
Q

Give an example of a lymphoproliferative disorder

A

Chronic lymphocytic leukaemia

32
Q

Give an example two myeloproliferative disorders

A

Chronic myeloid leukaemia

Essential thrombocythaemia, polycythemia vera, myelofibrosis

33
Q

What is a myeloblast

A

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

34
Q

How does a myeloblast look

A

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

35
Q

What does myeloblasts in peripheral blood indicate

A

Increasing numbers can suggest myeloid leukaemia

36
Q

What do myeloblasts develop into

A

Promyelocytes

37
Q

Write about promyelocyte

A

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

38
Q

What does increased promyelocytes mean

A

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

39
Q

Write about myelocyte

A

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

40
Q

Write about metamyelocytes

A

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

41
Q

Comment on exposure to very high levels of radiation

A

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

42
Q

Write about working with chemicals and leukaemia risk

A

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

43
Q

Write about chemotherapy and risk

A

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

44
Q

What medical conditions increase risk of leukaemia?
(5)

A

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)

45
Q

Write about down syndrome and leukaemia

A

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

46
Q

Write about infection and Leukaemia

A

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

47
Q

Write about genetics and leucaemia
(4)

A

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

2.2 Haematology (38 decks)

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