Flashcards in 18.06.18 Genetics of Lymphoma Deck (30):
Give a brief overview of lymphoma.
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
What is the defining feature of Hodgkin's lymphoma?
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.
What proportion of HL patients have EBV genome present?
50% but it has an unknown role in pathogenesis
What are the clinical features of HL?
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
What is the prognosis of HL?
Good >85% survival rate
Give an overview of non-Hodgkin's lymphoma.
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
What proportion of patients have low grade or indolent NHL, what is the typical presentation and progression?
20-40% of NHL cases
Late presentation and slow progression
Compatible with long-life without treatment
What proportion of patients have high grade or aggressive NHL, what is the typical presentation and progression?
60-70% of NHL
Early presentation and rapid progression
Fatal without treatment
Name three different subtypes of NHL.
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)
In B-cell malignancies, what do the most common chromosomal rearrangements involve?
Reciprocal translocations involving the IG genes. Errors are presumed to occur during VDJ rearrangements of the IG in the BM.
What are the common clinical features of lymphoma?
1) Enlarged lymph node - neck is most common, groin, axilla
2) Night sweats, unexplained weight loss, fever (B symptoms, used to stage lymphoma)
5) Bone pain
7) Low wcc
9) Persistent itching
How many cases of Burkitt's lymphoma are there each year? Is it more common in adults or children?
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
Which cell type does Burkitt's lymphoma originate from?
IgM+ memory B-cell
What genetic feature is the hallmark of Burkitt's lymphoma?
MYC (8q24) rearrangement
What is the treatment for Burkitt's lymphoma?
Acute, very aggressive, high-grade NHL requiring high-intensity chemotherapy that targets the proliferating cells.
If treated promptly, many patients can be cured.
How many forms of Burkitt's lymphoma are there? What are they?
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
What are the most common rearrangements seen in patients with Burkitt's lymphoma?
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.
What is the role of MYC protein?
Regulation of cell proliferation, differentiation and apoptosis.
In which ways can constitutive expression of the MYC oncogene achieved?
1) Juxtaposition to regulatory elements of the IG loci
2) Mutations in the MYC 5' region
3) Missense mutations in exon 2
How is Burkitt's lymphoma diagnosed?
Karyotype and FISH - characterised by simple karyotype with absence of complex abnormalities.
Give an overview of follicular lymphoma.
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)
What is the treatment for follicular lymphoma?
Monoclonal antibody against CD20+
Binds to CD20+ and triggers apoptosis
Kills normal and malignant cells
What is the most common chromosomal rearrangement seen in follicular lymphoma?
~80% have t(14;18)(q32;q21) resulting in overexpression of BCL2 which prevents apoptosis.
Other than the IGH-BCL2 translocation, give some other examples of chromosomal translocations that occur in follicular lymphoma.
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
What proportion of normal, healthy adults have the t(14;18)(q32;q21)?
~70% (increasing with age)
Give an overview of mantle cell lymphoma (MCL)?
~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
Which biomarker is highly specific for mantle cell lymphoma?
SOX11 transcription factor
Which chromosomal translocation is commonly seen in mantle cell lymphoma?
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)
What are the common secondary findings in Mantle cell lymphoma?
20-60% del11q23 (ATM)
40-75% mutations in ATM
Gains/rearrangements of MYC
Gains of 3q26