18.06.18 Genetics of Lymphoma

Question 1

Give a brief overview of lymphoma.

Answer 1

1) 5th most common cancer in UK
2) Caused by malignant B or T cells that accumulate in lymph nodes to form tumours and clinical features of lymphadenopathy. Uncontrolled and anti-apoptotic proliferation of lymphocytes.
3) Lymphocytes may spill into blood (leukaemia phase) or spleen/ other organs (extra-nodal disease)
4) Two broad types;. Hodgkin’s lymphoma and NHL

Question 2

What is the defining feature of Hodgkin’s lymphoma?

Answer 2

Presence of Reed-Sternberg (RS) cell in the tumour (B-cell lineage).

RS and associated abnormal mononuclear cells are neoplastic whereas infiltrating inflammatory cells are reactive.

Question 3

What proportion of HL patients have EBV genome present?

Answer 3

50% but it has an unknown role in pathogenesis

Question 4

What are the clinical features of HL?

Answer 4

1) Peak incidence in young adults, rare in children
2) 2:1 male predominance
3) Painless, non-tender, asymmetrical, firm, discrete and rubbery enlargement of superficial lymph nodes (commonly in neck)
4) Disease typically localised in a single LN region. Progression through contiguity of lymphatic syndrome
5) Widespread disease associated with fever, weight loss and sweating

Question 5

What is the prognosis of HL?

Answer 5

Good >85% survival rate

Question 6

Give an overview of non-Hodgkin’s lymphoma.

Answer 6

1) Clonal lymphoid tumours
2) 85% are B-cell, 15% are T-cell
3) Variable presentation and progression
4) Characterised by an irregular pattern of spread
5) Many patients develop extranodal disease
6) >50 types

Question 7

What proportion of patients have low grade or indolent NHL, what is the typical presentation and progression?

Answer 7

20-40% of NHL cases
Late presentation and slow progression
Compatible with long-life without treatment

Question 8

What proportion of patients have high grade or aggressive NHL, what is the typical presentation and progression?

Answer 8

60-70% of NHL
Early presentation and rapid progression
Fatal without treatment

Question 9

Name three different subtypes of NHL.

Answer 9

1) Burkitt’s lymphoma
2) Follicular lymphoma
3) Diffuse Large B-cell lymphoma
4) Mantle cell lymphoma
5) Marginal zone lymphoma
6) Anaplastic large cell lymphoma, ALK +ve (ALCL)

Question 10

In B-cell malignancies, what do the most common chromosomal rearrangements involve?

Answer 10

Reciprocal translocations involving the IG genes. Errors are presumed to occur during VDJ rearrangements of the IG in the BM.

Question 11

What are the common clinical features of lymphoma?

Answer 11

1) Enlarged lymph node - neck is most common, groin, axilla
2) Night sweats, unexplained weight loss, fever (B symptoms, used to stage lymphoma)
3) Fatigue
4) Bruising
5) Bone pain
6) Anaemia
7) Low wcc
8) Breathlessness
9) Persistent itching

Question 12

How many cases of Burkitt’s lymphoma are there each year? Is it more common in adults or children?

Answer 12

220 cases per year in UK
More common in children (1/3 of all lymphoma)
3-4% of adult lymphoma in Western countries and associated with immunodeficiency

Question 13

Which cell type does Burkitt’s lymphoma originate from?

Answer 13

IgM+ memory B-cell

Question 14

What genetic feature is the hallmark of Burkitt’s lymphoma?

Answer 14

MYC (8q24) rearrangement

Question 15

What is the treatment for Burkitt’s lymphoma?

Answer 15

Acute, very aggressive, high-grade NHL requiring high-intensity chemotherapy that targets the proliferating cells.

If treated promptly, many patients can be cured.

Question 16

How many forms of Burkitt’s lymphoma are there? What are they?

Answer 16

1) Sporadic - occurs globally and usually presents as abdominal masses
2) Endemic - occurs in equatorial Africa and predominantly affects the jaws and other facial bones
3) Immunodeficiency-related forms - most commonly seen in AIDS patients

Question 17

What are the most common rearrangements seen in patients with Burkitt’s lymphoma?

Answer 17

1) t(8;14)(q24;q32) MYC-IGH~85% of cases
2) t(8;22)(q24;q11) MYC-IGL ~10% of cases
3) t(2;8)(p12;q24) MYC-IGK ~5% of cases

IG genes next to MYC bringing about its constitutional expression.

Question 18

What is the role of MYC protein?

Answer 18

Regulation of cell proliferation, differentiation and apoptosis.

Question 19

In which ways can constitutive expression of the MYC oncogene achieved?

Answer 19

1) Juxtaposition to regulatory elements of the IG loci
2) Mutations in the MYC 5’ region
3) Missense mutations in exon 2

Question 20

How is Burkitt’s lymphoma diagnosed?

Answer 20

Karyotype and FISH - characterised by simple karyotype with absence of complex abnormalities.

Question 21

Give an overview of follicular lymphoma.

Answer 21

Most common low-grade lymphoma
20% of adult lymphoma in Western countries
1800 cases per year in UK
Peak incidence in 5th and 6th decades
Most patients have widespread disease at diagnosis - nodal and extranodal (BM) and PB.
Usually follows indolent disease
60-80% progress to DLBCL (high-grade)

Question 22

What is the treatment for follicular lymphoma?

Answer 22

Rituximab (immusuppression)
Monoclonal antibody against CD20+
Binds to CD20+ and triggers apoptosis
Kills normal and malignant cells

Question 23

What is the most common chromosomal rearrangement seen in follicular lymphoma?

Answer 23

~80% have t(14;18)(q32;q21) resulting in overexpression of BCL2 which prevents apoptosis.

Question 24

Other than the IGH-BCL2 translocation, give some other examples of chromosomal translocations that occur in follicular lymphoma.

Answer 24

Rare translocations involving IGK t(2;18)(p11;q21) and IGL (18;20)(q21;q11) with BCL2 have been described.

~15% 3q27 - t(3;14), t(3;22) or t(2;3)

~60% have 6q21del

20% have del(17)(p13p13) - TP53 deletion

Question 25

What proportion of normal, healthy adults have the t(14;18)(q32;q21)?

Answer 25

~70% (increasing with age)

Question 26

Give an overview of mantle cell lymphoma (MCL)?

Answer 26

~400 cases in UK per year, ~5% of NHL
Low-intermediate grade NHL
Most aggressive course of small lymphomas - important to diagnose quickly. Is often widespread at diagnosis. 
High relapse rate
Difficult to distinguish from CLL
Male predominance, median age 65
Median survival 3-4 years

Question 27

Which biomarker is highly specific for mantle cell lymphoma?

Answer 27

SOX11 transcription factor

Question 28

Which chromosomal translocation is commonly seen in mantle cell lymphoma?

Answer 28

95% cases t(11;14)(q13;q32)
Over expression of CCND1 which accelerates cells through G1 causing cells to divide before they are mature and functioning.
Best detected by FISH (only 75% karyotypically visible)

Question 29

What are the common secondary findings in Mantle cell lymphoma?

Answer 29

40-50% Del13q14 
20-45% del17p13
20-60% del11q23 (ATM)
40-75% mutations in ATM
Gains/rearrangements of MYC
Gains of 3q26
Del9p21

Question 30

Give an overview of diffuse large B-cell lymphoma.

Answer 30

High-grade, acute and aggressive lymphoma
Most common NHL - 4000 cases per year in UK
11-27% have bone marrow involvement
Treatment CHOP-R (Rituximab with cyclophosphamide, hydroxydaunorubicin, oncovin, prenisolone)
May cure 40-60% of cases depending on age and risk factors