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Cancer > Haematological malignancies > Flashcards

Haematological malignancies Flashcards

1
Q

What is cell culture?

A

Procedure used to grow cells under controlled conditions

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2
Q

What is cell harvest?

A

Procedure used to collect cells from the specimen

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3
Q

Of FISH and karyotype which is the specific and which is the global test?

A 
FISH = specific
Karyotype = global
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4
Q

Which test has a higher sensitivity FISH or karyotype?

A

FISH

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5
Q

Which test can be performed more quickly FISH or karyotype?

A

FISH

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6
Q

Do you require metaphase or interphase for karyotype?

A

Metaphase spreads

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7
Q

Do you require metaphase or interphase for FISH?

A

Can be performed on both

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8
Q

What are the two cell lineages that can arise from haematopoeitic stem cells?

A

Myeloid and lymphoid

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9
Q

Examples of cells in the myeloid lineage

A

Anything that’s not T cells, B cells or NK cells e.g. platelets, red blood cells (erythrocytes), granulocytes, basophills etc.

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10
Q

Three reasons why we test for haematological malignancies?

A

Diagnosis
Prognosis
Monitoring

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11
Q

Prognosis of complex karyotypes?

A

Bad

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12
Q

Prognosis of balanced translocation?

A

Good

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13
Q

In which haematological malignancies can BCR-ABL1 be found?

A

Most common in CML
ALL
AML

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14
Q

What are blast cells?

A

Immature cells in either the myeloid or lymphoid lineage e.g. a myeloid blast can become all the myeloid cells but not lymphoid ones

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15
Q

In leukaemias why is bone marrow a better choice of starting material than blood?

A

Because bone marrow will have more immature white blood cells than blood (in normal individuals blood shouldn’t contain immature white cells but in affected individuals it will)

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16
Q

What is leukaemia?

A

Cancer of white blood cells where changes occur in the bone marrow

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17
Q

Symptoms of leukaemia?

A

Fatigue, easy bruising, proneness to infection

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18
Q

What does acute mean?

A

Occurs quickly

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19
Q

What does chronic mean?

A

Occurs over a long period of time

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20
Q

Different types of leukaemia?

A

AML (acute myeloid leukaemia)
ALL (acute lymphoblastic leukaemia)
CML (chronic myeloid leukaemia)
CLL (chronic lymphocytic leukaemia)

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21
Q

What is more aggressive “lymphoblastic” or “lymphocytic”

A

Lymphoblastic because these blast cells are less differentiated and therefore more aggressive

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22
Q

What is more aggressive ALL or CLL?

A

ALL

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23
Q

What cells are overproduced in AML??

A

Myeloid cells

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24
Q

Standard rearrangements in AML

A

t(15;17) PML;RARA
t(8;21) RUNX1T1;RUNX1
inv(16) CBFB-MYH11
All make chimeric fusion proteins

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25
Q

t(15;17) is characteristic of what?

A

APML - acute promyelocytic leukaemia

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26
Q

What treatment is APML sensitive to?

A

Retinoic acid and arsenic

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27
Q

Are APML and APL the same thing?

A

Yes

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28
Q

How are rearrangements in AML identified?

A

Can use karyotype, FISH, RT-PCR or multiplex PCR

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29
Q

If you have a suspected APML what analysis method would you use for a rapid analysis?

A

FISH or RT-PCR - can get result very quickly

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30
Q

If you have suspected AMPL should rapid analysis be performed?

A

Yes

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31
Q

If you have a cytogenetically normal AML what test could you use to look for mutations in FLT3 and NPM1?

A

Multiplex PCR - amplify up and look at size on gene marker. Controls run alongside with known size that these fragments should be

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32
Q

Prognosis of t(15;17) PML;RARA in AML

A

Favourable

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33
Q

Prognosis of t(8;21) RUNX1T1;RUNX1 in AML

A

Favourable

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34
Q

Prognosis of inv(16) CBFB-MYH11 in AML

A

Favourable

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35
Q

Prognosis of FLT3 internal tandem duplications in AML

A

Poor prognosis

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36
Q

Prognosis of NPM1 mutations in AML

A

Favourable

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37
Q

What would you use multiple PCR for in AML

A

To look for mutations in NPM1 and FLT3 if was cytogenetically normal

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38
Q

Why is APML worse than AML?

A

APML tend to have serious bleeding abnormalities due to low platelet count and clotting factors - at increased risk of bleeding in their brain

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39
Q

What is myelodysplastic syndrome (MDS)?

A

Affects the production of myeloid cells, causing cytopenias (reduction in mature blood cell)

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40
Q

How does MDS progress?

A

Can progress slowly but can rapidly convert into AML

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41
Q

Loss of Y or 15+ is problematic why?

A

Often occurs in elderly people with no haematological disease but may also be markers of neoplastic myeloid clones (MDS/AML)

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42
Q

What is CML?

A

Myeloproliferative neoplasm (MPN)

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43
Q

What cells are overproduced in CML?

A

Myeloid cells

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44
Q

CML is well managed in what phase?

A

Chronic phase

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45
Q

What are the three phases of CML?

A

Chronic
Aggressive
Blast

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46
Q

What happens when CML switches into “blast crisis”?

A

It resembles acute leukaemia which is difficult to treat

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47
Q

Testing available for CML diagnosis

A

Karyotype
FISH
RT-PCR

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48
Q

Translocation found in almost all cases of CML

A

t(9;22)(q34;q11) on derivative 22 (Philadelphia chromosome)

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49
Q

Does t(9;22) in CML create a chimeric fusion protein?

A

Yes, BCR-ABL1. This has enhanced tyrosine kinase activity resulting in increased proliferation

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50
Q

Drug treatment that can be used in individuals with Ph+ CML

A

Imatinib (TKI)

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51
Q

In terms of monitoring what haematological malignancies can we monitor for?

A

Can do for all, but in Glasgow only do for CML (two transcripts) all other monitoring is sent down south

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52
Q

Does “blast crisis” in CML have a high mortality rate?

A

Yes

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53
Q

When does “blast crisis” occur in CML

A

When >30% of cells in blood/bone marrow are immature blood cells (blast cells)

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54
Q

When is MRD done?

A

When the patient is in remission

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55
Q

When is monitoring done?

A

At certain time periods after the patient has received a diagnosis and while they are receiving treatment

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56
Q

How is monitoring performed for CML?

A

RT-PCR to determine transcript and then QRT-PCR to determine level

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57
Q

Imatinib resistance can be primary or secondary, explain

A

Primary - failure to achieve a response

Secondary - acquired resistance

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58
Q

What are the three myeloid disease categories?

A

MDS
MPN
Myeloid leukaemia

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59
Q

Examples of myeloproliferative neoplasms

A

CML
Polycythaemia vera
essential thrombocythaemia

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60
Q

Genes mutations generally seen in MPN

A

JAK2, CALR, MPL

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61
Q

What cells are overproduced in ALL

A

Lymphoid cells

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62
Q

What age group is ALL mostly seen in

A

Young children

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63
Q

Is ALL generally a T-cell proliferation or a B-cell

A

B-cell

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64
Q

Translocation seen in 25% of ALL cases

A

t(12;21) ETV6;RUNX1

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65
Q

What is the prognosis for t(12;21) in ALL

A

Favourable

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66
Q

In ALL if children are diagnosed early whats the cure rate

A

Above 90%, if diagnosed early respond well

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67
Q

Is BCR-ABL found in ALL?

A

Yes, found in adults (11-30%) and in children (2-4%) has a poor prognosis in both

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68
Q

Does ALL have a high mortality rate in adults?

A

Yes

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69
Q

Poor prognosis abnormalities in ALL children

A 
iAMP21
t(17;19)
MLL translocations
low hypodiploidy
t(9;22)
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70
Q

Poor prognosis abnormalities in ALL adults

A

iAMP21
MLL translocations
low hypodiploidy
t(9;22)

71
Q

What cells are overproduced in CLL

A

Lymphoid cells (generally B)

72
Q

Does CLL affect old or young

A

Most common in old

73
Q

How does CLL progress?

A

1/3 regress, 1/3 don’t progress and 1/3 progress to acute leukaemia

74
Q

Good prognostic abnormality in CLL

A

-13q4

75
Q

Intermediate prognostic abnormality in CLL

A

Trisomy 12

76
Q

Poor prognostic abnormalities in CLL

A

-17p (or mutation of TP53)

Deletion of segment of ATM (chr11)

77
Q

What is lymphoma?

A

Cancer of white blood cells where changes occur in the lymph nodes and other lymphoid tissues (spleen, GALT)

78
Q

Symptoms of lymphoma

A

Lumps, night sweats, fever

79
Q

If individuals said to have a Ph+ variant translocation in CML what does this mean

A

They have a translocation involving chromosomes 9;22 and other chromosome(s)

80
Q

What percentage of individuals with CML have a Ph+ variant translocation

A

5-10%

81
Q

What referrals come from haematology?

A

Leaukaemias and myelomas

82
Q

What do haematology base their ?diagnosis on?

A

Patient demographics
Symptoms
Full blood count
What cells look like on blood film

83
Q

Is FLT3 a good marker for monitoring of AML?

A

No because it can disappear when patient is in remission

84
Q

What are good markers for AML monitoring?

A

NPM1 and the fusions

85
Q

What leukaemias are classed as urgent referrals?

A

Diagnostic acute leukaemia and CML

86
Q

What is the time frame for urgent diagnostic acute leukaemia and CML results to go out

A

14 calendar days - could do rapid test by FISH/PCR in three working days and then karyotype within the 14

87
Q

Routine referrals for the leukaemias turn around time

A

21 days

88
Q

What is myeloma?

A

When changes occur in activated plasma cells (B-cells that make antibody)

89
Q

Symptoms of myeloma?

A

Bone fractures, kidney injury

90
Q

What is the commonest haematological malignancy?

A

Myeloma

91
Q

Is myeloma curable?

A

It is treatable but not curable

92
Q

Genetic testing offered for myeloma

A

FISH

93
Q

Genetic testing offered for lymphoma

A

FISH

Sometimes B/T cell clonality

94
Q

Starting material for leukaemia

A

Preferably bone marrow but can use blood

95
Q

Starting material for lymphoma

A

FFPE FISH slides

96
Q

Starting material for myeloma

A

Preferably bone marrow but can use blood

97
Q

Where do referrals for lymphoma come from?

A

Pathology

98
Q

Where do referrals for myeloma come from?

A

Haematology

99
Q

Where do referrals for leukaemia come from?

A

Haematology

100
Q

Poor prognosis karyotypes in myeloma

A

t(4;14)
-13q
t(11;14)
Deletion of TP53

101
Q

When do we offer chimerism testing?

A

For leukaemia bone marrow transplantation patients

102
Q

What is a chimera?

A

A single organism composed of cells with distinct genotypes

103
Q

When are bone marrow transplantation’s carried on in individuals with leukaemia

A

When other treatments have failed
If have very poor prognosis
In kids with ALL

104
Q

What does chimerism testing monitor?

A

Engraftment

105
Q

What does 100% chimerism mean?

A

No recipient cells can be found

106
Q

How is chimerism testing performed?

A

Chemo to get rid of malignant cells, QF-PCR to look at microsatellites from donor and recipient to see if recipient cells have engrafted in donor

107
Q

What can you do if leukaemia returns after transplant?

A

Give T cells from donor which attack leukaemia cells

108
Q

What is MYC and where is it located?

A

Proto-oncogene, chromosome 8, role in cell cycle progression and apoptosis

109
Q

What type of haematological malignancy is MYC generally mutated in?

A

Lymphoma

110
Q

Different types of FISH probes available and what they detect?

A 
Enumeration probes (copy number)
Break apart probe (gene rearrangement) 
Dual fusion (specific translocations)
111
Q

Why do we try and diagnose type of lymphoma someone has?

A

Different types are treated differently depending on how aggressive they are.

112
Q

Different classes of lymphoma

A

Hodgkins and Non-Hodgkins lymphoma

113
Q

Difference between Hodgkins and Non-Hodgkins lymphoma

A

Hodgkins always have Reed Sternberg cells (B lymphocytes), while Non-Hodgkins can be B or T cell

114
Q

Characteristics of Burkitt lymphoma

A

highly aggressive B cell lymphoma, fast growing and high grade, rare. Most common abnormality t(8;14) MYC;IGH

115
Q

Characteristics of Follicular lymphoma

A

2nd most common NHL, B cell, most common abnormality t(14;18) IGH;BCL2. Sometimes IGH;BCL6

116
Q

What is the most common type of NHL

A

Diffuse large B cell (aggressive), no specific abnormality associated

117
Q

Most common BCR-ABL1 transcripts

A

e13a2 and e14a2 (MAJOR transcripts) produce 210kDa protein and e1a2 (MINOR transcript) produce 190kDa protein

118
Q

Most common BCR-ABL1 transcript in CML

A

Ones that produce 210kDa protein

119
Q

Most common BCR-ABL1 transcript in ALL

A

One that prodcues 190kDa protein

120
Q

What mitogen can be used to stimulate B cells

A

PMA

121
Q

What mitogen can be used to stimulate T cells

A

PHA

122
Q

Do clinicians prefer ISCN or words

A

They prefer words describing how many chromosomes youve got

123
Q

What does hypodiploid mean?

A

35-46 chromosomes

124
Q

What does hyperdiploid mean?

A

47-57 chromosomes

125
Q

What does pseudodiploid mean?

A

46 chromosomes (abnormal)

126
Q

What does near triploid mean?

A

Number close to 69 (3n)

127
Q

In ISCN what is // used for

A

To represent a chimera - separate cells from host and donor

128
Q

In ISCN what is [*] used for

A

To detail the number of cells in that cell line

129
Q

In ISCN are normal cells presented at beginning or end?

A

End

130
Q

Three different types of karyotype

A

Normal
Abnormal
Complex

131
Q

Categories of acquired genetic disease

A

Formation of chimeric fusion protein
Gain or amplification of gene or gene product
Deletion/loss of function of a gene

132
Q

If you see a +8 what do you think it is

A

A myeloid disorder (MDS or AML)

133
Q

What is the tumour suppressor affected in retinoblastoma

A

RB1

134
Q

Deletion of chromosome 5 is common in what type of disease?

A

MDS

135
Q

What is the percentage for no response in monitoring?

A

96-100%

136
Q

What is the percentage for minimal response in monitoring?

A

66-95%

137
Q

What is the percentage for minor response in monitoring?

A

36-65%

138
Q

What is the percentage for partial response in monitoring?

A

1-35%

139
Q

What is the percentage for complete response in monitoring?

A

o%

140
Q

For CML once found abnormality monitor using what kind of test

A

QRT-PCR (but they will send cytogenetic sample at intervals because you can get other abnormalities cropping up in Ph- cells)

141
Q

Name some abnormalities in the poor prognosis risk group for AML

A

-5
-7
del(5q)
complex abnormality

142
Q

In AML what is an abnormal karyotype defined as?

A

4 abnormalities or more

143
Q

Is high hyperdiploidy a good or bad prognosis in ALL

A

Good

144
Q

What is iAMP21

A

> 5 copies of RUNX1 = amp = iAMP21

145
Q

Does pyrosequencing look at short or long fragments?

A

Short

146
Q

If you have a sex mismatch donor and recipient for a bone marrow transplant what other testing could you do other than QF-PCR for microsatellite analysis

A

FISH for X/Y

147
Q

Screening for those with BRCA1/2 mutation

A

Mamography or MRI

148
Q

Screening for those with mutations in MMR genes/APC/MUTYH

A

Colonoscopy

149
Q

Factors that increase risk of breast/ovarian cancer

A 
Increasing age
Higher body mass index
Late menopause
Pill
Breast density
150
Q

Ethical issues of testing someone for breast cancer

A

Issues regarding health insurance, employment
Confidentiality - will have to ask about other family members etc
If do have a mutation, concerns regarding child bearing issues

151
Q

Down syndrome is a risk factor for what haematological malignancy?

A

Acute leukaemia

152
Q

Environmental risk factors of cancer?

A

Radiation
Chemotherapy and radiotherapy
Epstein Barr Virus - Burkitt’s lymphoma

153
Q

What is a major cytogenetic response in CML?

A

More than 65% Ph-ve

154
Q

What is a complete cytogenetic response in CML?

A

100% Ph-ve

155
Q

What FISH tests do we offer for myeloma?

A

TP53
IGH-FGFR3
IGH-MAF
CDKN2C

156
Q

Do they use interphase or metaphase FISH for haematological specimens?

A

Both interphase and metaphase

157
Q

Do specimens require culturing to get metaphases?

A

Yes

158
Q

Do specimens require culturing to get interphases?

A

No, can get interphases from a straight harvest

159
Q

For say ?BCR-ABL/PML-RARA samples what kind of FISH would be done on these fast turn around samples?

A

Interphase FISH because would get a straight harvest, no culturing

160
Q

For haematological malignancies when would you use interphase FISH

A

If you were looking for a standard rearrangement for which probes were available/fast turn around

161
Q

For haematological malignancies when would you use metaphase FISH

A

If you saw something unusual (say 3 way t) on a karyotype and you wanted to know location of it/needed help in working out breakpoints would do metaphase FISH

162
Q

If you saw a marker chromosome what would you do?

A

If experienced staff have an idea what it is FISH for that chromosome. If hard to tell consider standard rearrangements for that diagnosis or ?. If have no idea just report as “marker1/2/3” in ISCN

163
Q

Prognosis of unbalanced translocation

A

Depends on the level of imbalance

164
Q

Why is ISCN important?

A

As an international standard it enables cytogeneticists across the world to understand the exact nature of the chromosome constitution in an individual

165
Q

Sibling donors for bone marrow transplant - what considerations need to be taken in analysis of engraftment (QF-PCR of markers)

A

May struggle to get enough informative markers because siblings share 50% of genes

166
Q

What % of donor cells need to be present for bone marrow transplant to have worked?

A

90%

167
Q

If you see an abnormality on karyotype of an individual with ?leukaemia/myeloma, what do you need to consider about this abnormality

A

Is it clonal? Can you see it in almost every abnormal cell?

168
Q

In which myeloproliferative neoplasm do you find JAK2 variants? And are these acquired or inherited?

A

Polycythemia vera, and they are acquired

169
Q

Most common JAK2 variants in PV?

A

c.1849G>T, p.(Val617Phe) 90-95% cases

Variants in JAK2 exon 12 2-4% cases

170
Q

How is JAK2 analysis performed?

A

Allele specific PCR for c.1849G>T variant and exon 12 deletion, followed by GeneMarker for analysis. For the deletion you get an extra peak 3 bp smaller than the WT and for the variant will get a peak in the “positive” bin

171
Q

Are there sanger sequencing best practice guidelines available?

A

Yes

172
Q

What is “improving outcomes guidance”?

A

Guidelines put in place by NICE, looks at haematological cancers and how we can use things like integrated reporting, MDTs, staffing levels and facilities to improve care for these patients

173
Q

What does NICE stand for?

A

National Institute for Health and Care Excellence

174
Q

What does NICE do?

A

Provides national guidance and advice to improve health and social care

Cancer (9 decks)

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