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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
Q

What typical sites of infiltration of AML blasts?

A

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
Q

What Clinical Features of AML can be see due to Bone Marrow failure

A
  1. Anaemia (tired)
  2. Neutropenia: Infections/ Sepsis, DIC
  3. Thrombocytopenia: Bleeding
27
Q

Why do Patients with AML get DIC?

A
  1. Due to sepsis –> Neutropenoa
  2. Due to release of factors that trigger DIC
28
Q

What Investigations are done to diagnose AML?

A
  • FBC and Film (Blast cells) and high WCC
  • BM aspirate**
  • Immunophenotyping
  • Cytogenic Analysis
  • Molecular studies (If cytogenetic analysis normal, genetic prognostif fcators are needed )

FIlm and BM aspirate can be done with or without Cytochemistry
BM might be needed if no peripheral blasts present

29
Q

What are the symptoms of ALL due to local inflitration?

A

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
Q

Which tissue do most B-lineage ALL usually start?

A

In the Bone Marrow

31
Q

In what tissue does a T lineage ALL usually start?

A

Can start in the thymus, thymus may be enlarged

32
Q

What is the prognosis for ALL?
What factors carry a good prognosis?

A

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
Q

What are the Leukaemogenic mechanisms for ALL vs AML?

A

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
Q

How is ALL diagnosed?

A
  • 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
Q

What is More common: B cell lineage or T cell lineage ALL?

A

Bcell 85% vs T cell 15%

36
Q

What is the Treatment of ALL?

A

Chemotherapy for 2-3 years

Specific therapy
systemic chemotherapy
CNS-directed therapy
* CNS infiltration is common
Supportive care

37
Q

Why is the treatment for ALL longer in Boys than in Girls?

A

Due to testicular infiltration of Lymphoblasts (century side for Lymphoblasts –> longer treatment needed)

38
Q

What are the main short term and long-term toxicisites of treatment of ALL?

A

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
Q

What is a mixed lineage leukaemia? Why does it occur?

A

Leukaemia with both Myeloid blasts and lymphoblasts (due to the fact that mutations occur in pluripotent haematopoietic stem cells)

40
Q

What is the effects of chromosomal tranlocation and inversion in AML pathogenesis?

A

Altering of DNA sequence

  • new fusion genes (AML + ALL)
  • abnormal regulation of genes (ALL)
41
Q

What role do transcription factors play in acute leukaemia pathogenesis?

A

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
Q

What is the treatment principle of AML?

A
  1. Supportive: Blood products, ABX, Allupurinol)
  2. Medical
    * (combinaiton) Chemotherapy (Daunorubicin, cytarabine) –> aggressive regimen
  • BM transplant (if poor prognosis)
43
Q

What picture of cells would you expect in a Bone Marrow aspirate of CML?

A

General Many Myelocytes in different states of differentiation (incl. Fully differenatiated neutrophils etc)

44
Q

What is the Philadelphia Chromosome?

A

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
Q

What malignancies are associated with the presence of the Philadelphia chromosome?

A

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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