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Year 5 Path Haematology > Acute Leukaemias > Flashcards

Acute Leukaemias Flashcards

1
Q

What are the characteristics of acute Leukaemia?

A
  • acute onset
  • Arise from myeloid or lymphoid stem cell (immature cells (blasts))
  • Leads to Bone Marrow failure: Aaemia, leukopenia, thrombocytopenia
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2
Q

Why can chronic leukaemias usually be survived years wihout treatment, and acute leukaemias not?

A

Different factors and clinical behaviours but main difference
1. Mature vs immature cells
Chronic = mature cells, just more of them vs.

in acute leukaemias often unfunctional blast cells, that can replace bone marrow –> bone marrow failure

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3
Q

What Haematological Stem cell does the mutation in CML usually occurs in?

A

Pluripotent haemopoietic stem cell (associated with philadelphia chromosome)

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4
Q

What Haematological Stem cell does the mutation in AML usually occurs in?

A

Can occur in

  • Pluripotent Haemopoietic Stem Cell
  • Multipotent Myeloid stem cell/progenitor cell
  • Granulocyte -monocyte progenitor
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5
Q

What Haematological Stem cell does the mutation in ALL usually occurs in?

A

In the B cell / T cell precursor lymphoid cells

–> heterogenous malignancy

–> in ALL 75-80% B-cell origin, only 20% T-cell

–> most common childhood malignancy

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6
Q

What are the Characteristics of a Myeloid Blast Cell?

A
  1. Increased Nuclear to Cytoplasmic Ratio
  2. Prominent Nucleoli
  3. Immature chromatin (small dots)
  4. Few/ no cytoplasmic granules
    (Auer Rods)
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7
Q

What is the epidemiology of AML?
What is the prognosis?

A

Incidence Increases with Age

Prognosis worsens with age
–> 5 year survival 20% but
5 year survival 25-45 years 60%

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8
Q

What are the most common chromosomal mutations/ abnormalities in AML?

A

Addition of Genetic Mateiral
* Often abberation in chromosome count or structure (e.g. translocation, inversion etc.)
* Associated wtih new fusion genes (ALL and AML)
* Associated with abnormal regulation of genes (ALL)

Loss of Genetic Material
* Chromosomal Deletion or Loss

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9
Q

What are common Chromosomal Duplication associated with AML?

A

Trisomy 8 and Trisomy 21 higher association with AML

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10
Q

Why are blasts usually the dominant cells type in Acute Myeloid Leukaemias?

A

There is a block in maturation of Myeloid precursor cells (Myeloblast)

–> Blast cells at different stages of maturation accumulate in BM + here might be some mature cells still from working haematopoietic stem cells

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11
Q

What are risk factors for the development of AML?

A

Mostly aetiology unknown

Familial/ Genetic predisposition (+ Down’s)
Irradiation
Anti cancer drugs
Benzene exposure
Cigarette Smoking

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12
Q

What is the difference betwen Type 1 and Type 2 genetic factors causing Acute Leukaemias?

A

Type 1: promote proliferation and survival
Type 2: block differentiation (often via transfusion factor abnormalities - AND blocked apoptosis)

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13
Q

What is the dominant negative effect?

A

A single mutation/faulty gene domintes the one normal copy, which can be sufficient in causing pathology. Often in Translocation factor abnormalities

Commonly seen in Leukaemias

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14
Q

What is APL?

A

Acute Promyelocytic Leukaemias

A rare subtype of acute myeloid leukemia in which myeloid cells proliferate but stop maturing when the cell is in the promyelocyte stage. Associated with t(15;17) translocations and responds to therapy with all-trans retinoic acid.

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15
Q

Where does the maturation of cell lineage in APL usually stop?

A

At the pro-Myelocytes (e.g. auer rods can be presents)

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16
Q

What leukaemia does a Translocation between chromosomes 15 and 17 predispose to?

A

Acute Promyelocytic Leukaemia

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17
Q

What are the clinical signs of APL?

Why is it important to identify early?

A

Excess of Promyelocytes causes DIC and bleeding –> if diagnosis takes longer catastrophic bleeding can occur

  1. Rapid progression + easily deadly
  2. good treatment avaialble
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18
Q

Why does APL cause bleding?

A

Due to
1. DIC (important differntial for DIC)
2. Fibronogenesis abnormalities

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19
Q

What is the treatment of APL?

What is the prognosis

A

Treated with All-trans- tretinoic acid (ATRA) and As2O3 (arsenig trioxide)

–> prompt pro-myelocytes to differentiate into neutrophils –> die

20
Q

What Role do Transcription factors play in genesis of AML?

A

Usually important, but not alone sufficient in causing AML.
Further Type 1 Mutations need to occur

21
Q

How do you clinically differentiate between AML and ALL?

(Signs and investigations)

A

Can be hard
Clinically

  • CNS involvement, fever and lymphadenopathy (+testicular/Thymic enlargement): more commonly seen in ALL
  1. Cytological Features (e.g. visible granules in myeloblast)
  2. Cytochemistry
  3. Immunophenotyping (antigens on cell surface) (Usually now needed for diagnosis)
22
Q

What is the epidemiolgoy of ALL?

What is the overall prognosis

A

Usually childhood (peak incidence 2-5)

Relatively good prognosis of 85% cure (good in children, gets worse with age)

Most common childhood malignancy

23
Q

What cytological features can differentiate between an AML blast and ALL blast ?

A

Indicators for Myeloid:

  1. Auer Rods
  2. Cytoplasmic Granules

Can never be certain

24
Q

Through which two mechanisms do you see clinical features in Acute Leukaemias?

A
  1. Bone Marrow Failure
  2. Local Infiltrations
25
What typical sites of infiltration of AML blasts?
Both AML and ALL: 2. Splenomegaly 2. Hepatomegaly More specific to AML 3. Skin: Leukaemia Cutis 4. Gum infiltration (if monocytic): hypergingiva 5. CNS (uncommon)
26
What Clinical Features of AML can be see due to Bone Marrow failure
1. Anaemia (tired) 2. Neutropenia: Infections/ Sepsis, DIC 3. Thrombocytopenia: Bleeding
27
Why do Patients with AML get DIC?
1. Due to sepsis --> Neutropenoa 2. Due to release of factors that trigger DIC
28
What Investigations are done to diagnose AML?
* FBC and Film (Blast cells) and high WCC * BM aspirate** * Immunophenotyping * Cytogenic Analysis * Molecular studies (If cytogenetic analysis normal, genetic prognostif fcators are needed ) ## Footnote FIlm and BM aspirate can be done with or without Cytochemistry BM might be needed if no peripheral blasts present
29
What are the symptoms of ALL due to local inflitration?
All acute Leukaemias * Splenomegaly * Hepatomegaly A bit more specific to ALL * B-symptoms * Lymphadenopathy (+/- thymic enlargement) (can lead to SVC syndrome/ SOB) * Testes (rare) * CNS (meningeal leukaemia) * Bone pain: avoid to weight bare in children
30
Which tissue do most B-lineage ALL usually start?
In the Bone Marrow
31
In what tissue does a T lineage ALL usually start?
Can start in the thymus, thymus may be enlarged
32
What is the prognosis for ALL? What factors carry a good prognosis?
Very dependent on genetic/cytogenetic sub-type Good: Generally: hyperdiploidy, t12,21 or t1,19 Poor: Hypodiploidy, (philadelphia chromosome --> more commom in adults, that's why prognosis is worse in adults)
33
What are the Leukaemogenic mechanisms for ALL vs AML?
Proto-oncogene dysregulation due to * chromosomal translocation * Fusion genes * Wrong gene promoter * Dysregulation by proximity to T-cell receptor (TCR) or immunoglobulin heavy chain loci Unknown – hyperdiploidy
34
How is ALL diagnosed?
* Clinical suspicion * Blood count and film (cytopenia + may show blast cells - can be abscent) * Bone marrow aspirate+ cytogenics * Immunophenotyping * Cytogenetic/molecular genetic analysis Needed for Baseline Treatment * Blood group, LFTs, creatinine, electrolytes, calcium, phosphate, uric acid, coagulation screen
35
What is More common: B cell lineage or T cell lineage ALL?
Bcell 85% vs T cell 15%
36
What is the Treatment of ALL?
Chemotherapy for 2-3 years Specific therapy systemic chemotherapy CNS-directed therapy * CNS infiltration is common Supportive care
37
Why is the treatment for ALL longer in Boys than in Girls?
Due to testicular infiltration of Lymphoblasts (century side for Lymphoblasts --> longer treatment needed)
38
What are the main short term and long-term toxicisites of treatment of ALL?
Short term (reversible) * BM suppression/ failure Long term (usually irreversible) * infertibily (esp after transplant) * mild cognitive impariement (cranial radiaion) * myocardial damage * increased risk of AML (damage to normal haematopoetic cells wih chemo)
39
What is a mixed lineage leukaemia? Why does it occur?
Leukaemia with both Myeloid blasts and lymphoblasts (due to the fact that mutations occur in pluripotent haematopoietic stem cells)
40
What is the effects of chromosomal tranlocation and inversion in AML pathogenesis?
Altering of DNA sequence * new fusion genes (AML + ALL) * abnormal regulation of genes (ALL)
41
What role do transcription factors play in acute leukaemia pathogenesis?
Mutation/ Alteration in Transcription factors often lead to the lack of differentiation of Blast cells --> higher blast cells count BUT Further hits (Type 1 and 2) needed to become malignant
42
What is the treatment principle of AML?
1. Supportive: Blood products, ABX, Allupurinol) 2. Medical * (combinaiton) Chemotherapy (Daunorubicin, cytarabine) --> aggressive regimen * BM transplant (if poor prognosis)
43
What picture of cells would you expect in a Bone Marrow aspirate of CML?
General Many Myelocytes in different states of differentiation (incl. Fully differenatiated neutrophils etc)
44
What is the Philadelphia Chromosome?
Translocation between chromosome 9 and 22 --> fusion genes of the ABL1 (chromosome 9) with BRC (22) --> formation of BCR-ABL gene Inhibits apoptosis and increased mitotic rate
45
What malignancies are associated with the presence of the Philadelphia chromosome?
9:22 translocation with formation of BCR-ABL CML: >90% of cases ALL: 20% of adults, 5% of children AML <2% of cases

Year 5 Path Haematology (18 decks)

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