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Biology of Cancer SSC > Leukaemia and Lymphoma > Flashcards

Leukaemia and Lymphoma Flashcards

1
Q

Where does normal B cell development start?

A

In the bone marrow

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2
Q

What is B cell production stimulated by?

A

Growth factor and cytokine production that initiates gene regulation commiting the common lymphocyte progenitor to B cell lineage

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3
Q

How does a progenitor B cell differentiate to a mature B cell?

A
  1. Rearrangement of Ig Heavy Chain Genes

2. Rearrangement of Ig Light Chain Genes

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4
Q

What chains are brought together to form the heavy chain?

A

Kappa and Lambda chains

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5
Q

What are most B cell lymphomas derived from?

A

Germinal Centre Cells

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6
Q

What are the 4 B cell lymphomas (most common to least common)?

A
  1. Diffuse Large B Cell Lymphoma
  2. Follicular Lymphoma
  3. Mantle Cell Lymphoma
  4. Burkitt’s Lymphoma
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7
Q

What is a germinal centre?

A

A site within secondary lymphoid organs (lymph nodes and the spleen) where mature B cells proliferate, differentiate

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8
Q

What surrounds the germinal centre?

A

Mantle zone

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9
Q

Where does mantle cell lymphoma arise from?

A

Naive B Cells in the mantle zone

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10
Q

What do BL, FL and DLBCL arise from?

A

Germinal centre B cells

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11
Q

What drives Burkitt Lymphoma?

A

Chromosomal translocation

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12
Q

What kinds of Burkitt Lymphoma can occur?

A

High grade amd low grade, Sporadic and Epidemic, Immunodeficieny associated

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13
Q

What is the name for the histological appearance classically seen with BL?

A

Starry Sky

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14
Q

How do lymphoma cells appear?

A

Large nucleus with very little cytoplasm. Vacuoles within the cytoplasm.

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15
Q

What are 2 examples of epidemic causes of Burkitt lymphoma?

A
  • Epstein Barr Virus

- Malaria

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16
Q

How does EBV cause BL?

A

Attaches to and activates B-lymphocytes CD21 receptor

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17
Q

Where is sporadic BL more common?

A

In the western world

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18
Q

Which chromosomes are translocated in BL?

A

8 and 14 (t(8;14))

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19
Q

What does the 8:14 translocation cause?

A

MYC brought into the antibody heavy chain locus so increased expression influenced by antibody HC enhancer element

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20
Q

Where does the translocation tend to occur within the body in sporadic BL?

A

Later, within the germinal centre

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21
Q

Where does the translocation tend to occur within the body in epidemic BL?

A

Within the bone marrow

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22
Q

What happens in cells with increased deregulated cMYC expression?

A

Cell cycle progression factors increase, allowing cell transformation and persistence of cells with decreased affinity (instead of apoptosis) -> tumorigenesis -> cancer

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23
Q

What can help distinguish BL from other lymphomas?

A

FISH - get red and green probes mixing -> orange fusion signal on the translocated genes

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24
Q

What is Follicular lymphoma?

A

B cell lymphoma where abnormal lymphocytes build up in the lymph nodes

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25
Q

Is FL generally lower or higher grade?

A

Lower, with a slower clinical course

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26
Q

How does FL present often?

A

Painless swelling in neck, armpit or groin

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27
Q

What chromosomal translocation causes FL?

A

t(14;18)

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28
Q

What does the t(14;18) cause?

A

The antibody HC gene enhancer element is brought to the bcl-2 gene area and incresases the bcl-2 expression

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29
Q

What does Bcl-2 have an important role in?

A

Apoptosis

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30
Q

Which types of Bcl-2 genes are amplified in FL?

A

Anti-apoptotic subfamily

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31
Q

What do these anti-apoptotic Bcl-2 proteins do?

A

Help stabilise the outer mitochondrial membrane, and prevent pro-apoptotic Bcl-2 proteins from binding.

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32
Q

What is diffuse large b-cell lymphoma?

A

The most common type of high-grade (fast‑growing) non-Hodgkin lymphoma, where the B cells are abnormally large and spread diffusely.

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33
Q

What is the median age of diagnosis with DLBCL?

A

66

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34
Q

What translocation commonly causes DLBCL?

A

3q27 translocation affecting the BCL6 gene

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35
Q

How does the 3q27 translocation affect the BCL6 gene?

A

It amplifies it and deregulates it

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36
Q

What does BCL6 normally do?

A

It is a transcription repressor of other genes (oncogenes and TSGs) to allow rapid B cell differentiation, especially in response to antigen-presentation

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37
Q

Where is BCL 6 normally only active?

A

Within the germinal centre

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38
Q

How does this BCL6 amplification/deregulation cause DLBCL?

A

Overexpressed BCL6 still represses tumour suppressor genes but mutated oncogenes escape regulation causeing aggressive lymphoma

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39
Q

How is LBCL classified?

A

Based on expression of 3 genes

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40
Q

What are the 3 genes?

A
  • CD10
  • BCL6
  • MUM1
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41
Q

What TSG is frequently disrupted in LBCL?

A

BLIMP1

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42
Q

Which viruses are indirectly involved in lymphoma?

A
  • HCV
  • HIV
  • EBV
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43
Q

Which viruses are directly involved in lymphoma?

A
  • HHV8/KSHV

- HTLV1

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44
Q

What is primary effusion lymphoma?

A

A rare NHL associated with HHV8

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45
Q

When is primary effusion seen?

A

In immunosuppressed patients (either HHV8 infected AIDS pts or transplant recipients recieving high doses of immunosuppression)

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46
Q

What is always present with primary effusion lymphoma?

A

HHV8-genome positive

47
Q

What else can HHV8 cause apart from primary effusion lymphoma?

A
  • Multi-centric Castleman’s Disease

- Kaposi’s Sarcoma

48
Q

How does a HHV8 infection lead to PEL?

A
  1. Latent infection of B lymphocyte pool
  2. Immune Supression
  3. Cellular genetic changes -> PEL
49
Q

How does a HHV8 infection lead to Multi-centric Castleman’s disease?

A
  1. Latent infection of B lymphocyte pool
  2. Immune suppression
  3. Additional Co-factors -> Multicentric Castleman’s disease
50
Q

How does a HHV8 infection lead to Kaposi’s Sarcoma?

A

HHV8 aka KSHV:

  1. Replicative infection of endothelial cells
  2. Rare latent infection in cells failing to replicate virus
  3. Immune suppression -> KS
51
Q

How does HHV8 affect signalling?

A

Causes the insertion of an HHV8 GPCR into the B cell membrane. This causes a signalling cascade that increases nuclear transcription.

52
Q

What is Adult T-cell Leukaemia Lymphoma?

A

A rare and aggressive lymphoma, found in the blood (leukemia), lymph nodes (lymphoma), skin, or multiple areas of the body.

53
Q

Where is Adult T-cell Leukaemia Lymphoma prevalent?

A

Southern Japan, Equitorial Africa, Malaysia, the Caribbean, South America, and the southern United States

54
Q

What is Adult T-cell Leukaemia Lymphoma caused by?

A

HTLV-1

55
Q

What % of people with HTLV-1 will develop Adult T cell lymphoma/leukaemia?

A

Less than 5%

56
Q

What is the most common route of spread of HTLV-1 infection?

A

Mother to baby via breast milk

57
Q

When does Adult T cell lymphoma/leukaemia manifest?

A

Latent period ie several decades after initial infection

58
Q

What promotes growth in the HTLV-1 infected cells?

A

Tax and other viral genes

59
Q

How is this growth normally suppressed?

A

Cytotoxic T cells work against Tax.

Tax expression suppressed by Rex, HBZ, and p30

60
Q

What occurs along the path of clonal proliferation?

A

Somatic alterations eg transcriptional changes

61
Q

What do mature ATL cells have?

A
  • Frequently loss of Tax expression

- Continuous expression of HBZ gene

62
Q

How is Primary Effusion Lymphoma unique clinically?

A

In presentation - usually arises in body cavities

63
Q

How is PEL treated?

A

Combination chemotherapy

64
Q

What combination chemotherapy is used on PEL?

A

Cyclophosphamide, doxorubicin, vincristine, and prednisolone

65
Q

What else is used if the Pt is HIV positive?

A

Anti-retroviral therapy

66
Q

What is the prognosis for PEL?

A

Poor - 6 month median survival

67
Q

How does the HHV8 genome exist in PEL cells?

A

As mono- or oligoclonal episomes

68
Q

How does HHV8 lead to PEL?

A

Infected cells undergo clonal expansion -> neoplastic transformation

69
Q

What commonly is seen in a blood test at presentation?

A

Lowered CD4+ count

70
Q

What do a significant proportion of PEL patients already have?

A

Kaposi’s sarcoma or MCD

71
Q

How do patients with PEL present?

A

Symptoms of malignant effusion e.g. dyspnoea (pericardial/pleural), abdominal distention

72
Q

Does PEL commonly metastasise?

A

Yes

73
Q

What causes death in PEL patients?

A
  • Opportunistic infections
  • HIV related complications
  • Progression of lymphoma
74
Q

How is PEL diagnosed?

A

Following virological, morphological, immunophenotypical and molecular criteria

75
Q

How do PEL neoplastic cells look morphologically?

A

Large, have round irregular nuclei, prominant nucleoli

76
Q

What is serology used for in PEL diagnosis?

A

HHV8 detection

77
Q

How is PEL evaluated?

A

Full blood count, including a serum lactate dehydrogenase (elevated serum lactate dehydrogenase associated with better prognosis)

78
Q

How is PEL staged?

A

All cases are Stage IV so Ann Arbor not used

79
Q

What should all PEL pts be encouraged to do?

A

Get involved in well-designed clinical trials if possible

80
Q

What is associated with better prognosis in PEL?

A

Use of HAART

81
Q

What is used to combat opportunistic infections?

A

Use of growth factors to avoid prolonged neutropenia associated with chemotherapy

82
Q

What is Burkitt Lymphoma associated with in immunosuppressed pts in non-endemic areas?

A

HIV infection

83
Q

What can intensive chemotherapy achieve in BL pts?

A

Excellent outcomes in children

Poor prognosis in adults/elderly

84
Q

What has shown promise in BL therapy?

A

Adjuvant monoclonal antiody therapy with rituximab

85
Q

Who is immunodeficiency BL typically seen in?

A

Pts with HIV

86
Q

When in HIV infection does BL most commonly occur?

A

In the early stages when CD4+ count is high (more than 200/microlitre)

87
Q

What does EBV do to B cells in culture?

A

Induces immortalisation

88
Q

What can EBV do to cells to promote BL?

A

Promote instability, disregulate telomere function, and induce DNA damage

89
Q

What is the suggested pathogenic mechanism for BL developing in HIV infected pts?

A

Chronic antigenic stimulation (as occurs in pts with high T cell count)

90
Q

How does sporadic BL commony present?

A

Abdominally - abdo pain, distention, N&V, GI bleeding

Next most commonly -H&N

91
Q

What are the symptoms of BL presenting in the H&N?

A

Lymphadenopathy, involvement of the naso- or oro-pharynx, tonsils or sinuses

92
Q

What % of BL patients get bone marrow infiltrated?

A

~20%

93
Q

How does epidemic BL commony present?

A

Jaw or periorbital swellings, or abdo involvement

94
Q

What do BL B cells contain?

A

Coarse chromatin and prominent basophilic nuclei

95
Q

Do chromosomal break points differ between different types of BL?

A

Yes, but some overlap can occur

96
Q

Where do epidemic BL breakpoints tend to occur?

A

Upstream of Myc. They occur within the Ig gene loci

97
Q

Where do sporadic BL breakpoints tend to occur?

A

Closer to Myc

98
Q

How is BL confirmed in a lab?

A

Microscopy and Immunocytological analysis of sample from superficial lymph node/malignant pleural fluid (most often)

99
Q

Which method of biopsy is prefered and why?

A

Excision, as fine-needle aspirate doesn’t collect enough tissue

100
Q

If BL is suspected, what tests should be performed?

A
  • FBC (differential and film)
  • ESR
  • Urea and electrolytes
  • LFTs
  • Serum LDH
  • Urate
  • EBV status
  • Chest imaging
101
Q

What chest imaging should be done?

A

CT - shows disease extent

102
Q

What common co-infections can be found with epidemic BL?

A

Malaria, Helminth infections

103
Q

What should happen before chemotherapy?

A

These co-infections should be treated

104
Q

What staging system is used for BL?

A

St. Jude’s / Murphy Classification

105
Q

What can be used to monitor BL throughout treatment?

A

The signal BL gives off with fluorodeoxyglucose PET

106
Q

How is BL initially managed? (cytoreduction)

A

With cyclophosphamide, prednisolone, and vincristine

107
Q

What follows inital management of BL?

A

Intensive chemotherapy in varying combinations

108
Q

How many cycles of moderately intensive chemo do children with completely surgically removed localised disease need?

A

2

109
Q

How many cycles of intensive chemo do children with residual or stage 3 disease need?

A

At least 4

110
Q

How many cycles of intensive chemo do children with CNS or bone marrow involvement need?

A

Up to 8 cycles

111
Q

What is the cure rate of sporadic BL in high income countries?

A

~90%

112
Q

What important side effects are there to the treatment of BL?

A
  • Long periods of haematological toxic effects
  • Mucositis
  • High risk of severe infection
113
Q

How do pts with Adult BL present?

A

With rapidly developing disease - common in the abdomen, weight loss, night sweats, unexplained fevers

Biology of Cancer SSC (16 decks)

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