HAEM: Lymphoma Flashcards
1
Q
Define lymphoma. Where are they usually found?
A
- Lymphoma = neoplastic (malignant) tumour of lymphoid cells; usually found in:
- Lymph nodes, bone marrow and/or blood (the lymphatic system)
- Lymphoid organs; spleen or the gut-associated lymphoid tissue
- Skin (often T cell disease; e.g. Mycoses Fungoides)
- Rarely “anywhere” (CNS, ocular, testes, breast, etc.)
2
Q
How common is lymphoma? What are the types?
A
- Incidence = 200 per 1,000,000 per year (i.e. 10,000/year in UK)
- NHL = 80%
- HL = 20%
- Types of lymphoid malignancies:
- Acute Lymphoblastic Leukaemia (ALL)
- Non-Hodgkin Lymphomas (B-cell lineage)
- Non-Hodgkin Lymphomas (T and NK cell lineage)
- Hodgkin Lymphoma
3
Q
What are the consequences of having an adaptive immune system in increasing risk of lymphoma?
A
- The process of lymphoma – immune modulation and the costs of having modulation:
-
Recombination – DNA molecules cut and recombined (deliberate point mutations; somatic hypermutation)
- +ve = diversity in Ig (and Ig class switching) and TCR
- -ve = unwanted point mutations
-
Rapid cell proliferation in germinal centres
- +ve = rapid response to infection
- -ve = replication errors
-
Apoptosis dependency (90% lymphocytes die in germinal centres)
- +ve = antibody specificity, elimination of self-reactive clones
- -ve = apoptosis switched off in germinal centre, acquired DNA mutation in apoptosis-regulating genes
-
Recombination – DNA molecules cut and recombined (deliberate point mutations; somatic hypermutation)
4
Q
What is the molecular basis of adaptive immunity and what mutations can arise in each of the two stages?
A
Immunoglobulin & TCR gene recombination – 2 STAGES: the molecular basis of an adaptive immune response:
(1) VDJ recombination – creates a molecule that recognises an epitope:
- Occurs in bone marrow
- Involves enzymes: RAG1 and RAG2
(2) Class switch recombination –> more important for lymphoma genesis:
- Somatic hypermutation in germinal centre (heavy chain of Ig changed – i.e. IgM to IgG)
-
Involves enzyme: Adenosine induced Deaminase (AID)
- Ig promotor highly active in B-cells to drive AB production
- Recombination errors occur
- Oncogenes brought close to the promotor
- Oncogenes = anti-apoptotic or proliferative:
- Bcl2
- Bcl6
- (C-)MYC
- CyclinD1
5
Q
What are the risk factors for different NHL subtypes?
A
Can be split into two main types:
- Immune system diseases
- Loss of T cell function
6
Q
Give examples of how chornic bacterial infection/AI disorders can cause lymphoma.
A
Chronic bacterial infection** or **auto-immune disorders:
- B-cell NHL Marginal Zone Lymphoma sub-type (B-cell NHL, MZL)
- H. pylori à gastric MALT = MZL of stomach
- Sjogren’s syndrome = causes MZL of salivary glands
- Hashimoto’s thyroiditis (lymphocytic destruction) = MZL of thyroid
- Thyroiditis = de Quervain’s (viral), Reiter’s (IgG4-related), Hashimoto’s
- Enteropathy associated T-cell NHL (EATL)
- Coeliac disease = small intestine EATL (enteropathy-associated T cell lymphoma)
7
Q
Give examples of how viral infection can cause NHL development.
A
Viral infection (direct viral integration into genome of lymphocytes stimulates lymphoma genesis)
- HTLV1 retrovirus –> Adult T-cell Leukaemia Lymphoma (ATLL) = sub-type of T-cell NHL
- Caribbean, Japan endemic infection
- Risk of ATLL = 2.5% at 70 years
8
Q
Describe how EBV can cause NHL development.
A
- EBV infects B-cells –> stimulates proliferation –> B-cells expresses EBV-associated antigens on cell surface –> CTL attack EBV-expressing B-cells –> carrier state for years…
- EBV switches on at later life and drives proliferation (normally CTL will control this but if you have a low CTL due to (1) HIV or (2) immunosuppression, the EBV can drive a lymphoma)
9
Q
Describe how iatrogenic immunosuppression can increase risk of NHL.
A
- (1) Viral killing of T-cells (HIV) –> low CTL
- HIV –> B-cell NHL (60x increased incidence)
- (2) Iatrogenic immunosuppression / after HSCT –> low CTL
- Transplant immunosuppression –> Post-Transplant Lymphoproliferative Disorder (PTLD)
10
Q
What are the 3 parts of the lymphoreticular system?
A
- Generative LR tissue –> generation/maturation of lymphoid cells
- Bone marrow and thymus
- Reactive LR tissue –> development of immune reaction
- Lymph nodes and spleen
- Acquired LR tissue –> development of local immune reaction
- Extra-nodal lymphoid tissue (e.g. skin, stomach, lung)
11
Q
What are the cells of the lymphoreticular system?
A
- Lymphocytes
- B lymphocytes
- Express surface Ig
- Antibody production
- T lymphocytes
- Surface TCR
- Regulation of B cells and macrophage function
- Cytotoxic function
- B lymphocytes
- Accessory Cells:
- Antigen-presenting cells
- Macrophages
- Connective tissue cells
12
Q
Describe the lymph node histology.
A
- Rounded areas = B cell follicles
- Between B cell follicles = T cell areas
- Central medulla = where mature B cells eventually end up
13
Q
Describe each of these parts of the lymph node (B and T cell areas).
A
- B-cell area:
- Crescent shaped region is the mantle zone where naïve unstimulated B cells are located
- B-cells migrate into germinal centre where they encounter APCs and undergo activation and selection
- There is a lot of cell turnover in this area, which is a predisposing factor for lymphoma
- T-cell area – comprises:
- T-cells
- APCs
- High endothelial vessels
14
Q
What is the WHO classification of lymphoma?
A
15
Q
Describe the basic principles of lymphoma.
A
16
Q
Which investigations are used in lymphoma?
A
- Cytology
- Histology
- Architecture (nodular like in folllicular or HL, diffuse)
- Cells (small round [CLL], small cleaved [nuceli show irregularity grooving in follicular lymphomal, large (centroblastic, immunoblastic, plasmoblastic) – large cells are suggestive of a high-grade lymphoma)
- Immunophenotyping
- Cell types identified by CD markers
- Cell distribution e.g. in sheaths
- Abnormal expression of proteins
- Clonality of B cells (light chain expression – normal clonal proliferation –> even kappa and lambda)
-
Cytogenetics / molecular tools –> identify genetics:
- FISH – identify chromosome translocations
- PCR – identify chromosome translocations, clonal T cell receptor or Ig gene rearrangement
17
Q
Which lymphoma is cyclin D1 expression associated with?
A
Mantle cell lymphoma
18
Q
How can cytogenetic investigations provide prognostic information in lymphoma?
A
- DIAGNOSTIC – i.e. t (11; 14) = Mantle Cell Lymphoma
- PROGNOSTIC – i.e. t (2; 5) = Anaplastic Large Cell Lymphoma
19
Q
What are the common types of NHL B cell type?
A
- Common B-cell NHL include:
-
Low-grade:
- Follicular lymphoma
- Small lymphocytic lymphoma/chronic lymphocytic leukaemia (CLL)
- Marginal zone lymphoma (MALT)
-
High-grade:
- Diffuse large B cell lymphoma
- Mantle zone lymphoma
-
Aggressive:
- Burkitt’s lymphoma
-
Low-grade:
20
Q
Summarise the histopathological features of follicular lymphoma.
A
21
Q
Describe the histopathological features of small lymphocytic lymphoma.
A
22
Q
What are the histopathological features of margincal cell lymphoma?
A
23
Q
What are the histopathological features of mantle cell lymphoma?
A
24
Q
What are the histopathological features of Burkitt;s lymphoma?
A
25
What are the histopathological features of diffuse large B cell lymphoma?
26
What are the general features of T cell lymphomas?
27
List 4 types of T cell lymphoma? Name a risk factor for each.
* Anaplastic large cell lymphoma
* Adult T cell leukaemia lymphoma / ATLL (Caribbean and Japan; HTLV-1 infection)
* Enteropathy-associated T cell lymphoma / EATL (long-standing Coeliac disease)
* Cutaneous T cell lymphoma (i.e. mycosis fungoides)
28
What are the features of anaplastic large cell lymphoma?
29
What are the types of Hodgkin's lymphoma?
* Types of HL:
* **Classical Hodgkin Lymphoma**: **subtypes** are…
* Nodular sclerosing
* Mixed cellularity
* Lymphocyte rich/depleted
* **Lymphocyte Predominant**
* Some relationship to NHL
30
What are key differences between HL and NHL?
Hodgkin is more localised (usually only one nodal site)
Hodgkin spreads contiguously to adjacent lymph nodes (NHL involves multiple sites and spreads sporadically)
31
What are the features of classical HL?
32
What are the features of nodular LP Hodgkin's lymphoma?
33
What are the features of nodular lymphocyte predominant lymphoma?
34
Part 2
35
4 - HTLV-1 can infect at birth and cause a T cell driven leukaemia lymphoma later on in life
EBV infects B cells and T cells should recognise this. T cell function may be reduced e.g. by HIV or immunosuppresant drugs. Here you can get EBV driven lymphoproliferative disorder.
36
3
Chromosomal translocations occur - if the bit moved is an oncogene inserted into the promoter region of the IgH chain then you get lymphoma. BCR-ABL1 is the typical translocation seen in myeloid malignancy and is therefore the correct answer.
37
How does lymphoma present?
* Painless progressive lymphadenopathy - palpable node, extrinsic compression of any "tube" e.g. ureter, bile duct, vessel, bowel
* Infiltrate/impair an organ system e.g. skin rash, ocular, CNS, liver failure
* Recurrent infection
* Constitutional symptoms
* Coincidental e.g. FBC, imaging
38
Biopsy is used for classification of lymphoma subtype (WHO classification)
39
How do you fdiagnose and stage?
1. HIstological - remove a safe and representative lymph node
2. Anatomical stage - PET or CT or BM biopsy +/- LP
3. Blood tests, LDH, albumin, kidney/BM function, HIV, HepB, HTLV-1 serology
40
List the different types of lymphoid malignancies. Which is the most common?
41
Which age and gender is most affected by HL? How common is it? Overall which gender is most affected?
Peak in young women aged 20-29
But more common in men overall
3:100,000
42
What are the HL symptoms and signs?
B symptoms
43
How is HL staged?
* Staging: Following pathological diagnosis of a lymph node biopsy patients are ‘staged’ this has prognostic significance and also may determine the best approach for therapy.
* FDG-PET/CT scan
* Consider biopsy of other site if possibly infiltrated e.g. liver
NB cHL spreads contiguously (what does that mean for staging?)
44
Which HL have good/poor prognoses?
Classical HL
* Nodular sclerosing 80% Good prognosis (causes the peak incidence in young women)
* Mixed cellularity 17% Good prognosis
* Lymphocyte rich (rare) Good prognosis
* Lymphocyte depleted (rare) Poor Prognosis
Nodular Lymphocyte predominant HL 5% (disorder of the elderly multiple recurrences)
45
Note the staging.
46
What are the features of cHL nodular sclerosing?
* cHL nodular sclerosing sub type
* Young women(\>men) 20-29 years
* Neck nodes and mediastinal mass(may be massive and compress SVC or trachea)
* May have B symptoms
* Needs a Tissue diagnosis
47
What is ABVD? What is an advantage and disadvantage of this therapy?
ABVD
* Adriamycin
* Bleomycin
* Vinblastine
* DTIC
*ABVD, is given at 4-weekly intervals.*
* ABVD is Effective treatment
* **Preserves fertility** (unlike MOPP the original chemo)
Can cause (long term) SE
* Pulmonary fibrosis
* cardiomyopathy
48
What is mainstay chemotherapy regimen for cHL?
**Chemotherapy** (essential for cure) +/- Radiotherapy
* ABVD 2-6 cycles (depends:stage&interim response)
* PET CT
**Interim**: After x2 cycles, response assessment
**End of Treatment:** Guides need for additional radiotherapy
**Relapse** {salvage chemotherapy}
* High dose chemotherapy + Autologous PB stem cell transplant as support
49
What are the advantages and disadvantages of cHL radiotherapy?
Modern practice involved field only
Low/negligible risk of relapse within field
Risk of damage to normal tissue (collateral damage)
* Ca breast (risk 1:4 after 25 years)
* Leukaemia/mds (3%@10years)
* Lung or skin cancer
Combined modality (chemo + radio) greatest risk of 2o malignancy
50
What is the cure rate for cHL? What does cure rate mean in HL?
Outcome of therapy
* Older patients generally do less well as do those with lymphocyte-depleted histology.
Prognosis:
* Cure rate ranges from 50-90%.
* Over 80% of patients with stage I or II disease are cured
* Only 50% of stage IV patients are cured
What does cure mean ?
* Overall 80% are long term survivors (can we improve)
* 10% die from relapse of HL (first 10 years)
* 10% die from treatment complications (after 10 years)
* “Curing” cHL in a 25-year old woman using chemo plus radiotherapy does not guarantee long term survival !
51
What is the fastest proliferating malignancy?
NHL subtype Burkitt's lymphoma
52
Which NHL is antibiotic responsive?
Gastric MALT
53
What are the most common NHL subtypes?
54
How does histology predict clinical course of NHL?
Called v aggresive, aggresive or indolent
55
Which (aggressive or indolent) are curable?
Indolent cause longer survival but need constant chemotherapy as they recur.
You can CURE aggressive subtypes with chemotherapy but not indolent types.
56
How are very aggressive lymphomas treated?(1)
Like acute leukaemias - see lecture
57
How common is DLBCL and what grade is it?
high grade/aggressive (intermediate)
40-60% of all NHL
58
What index is used for prognosis and treatment detemination in DLBCL?
IPI (International Prognostic Index)
1. Age
2. Stage (Ann Arbor)
3. LDH
4. Extra-nodal disease sites
5. ECOG performance status
59
How is DLBCL treated?
Treated by x 6-8 cycles of R-CHOP (Rituximab-CHOP)
combination chemotherapy using a mixture of drugs usually including an anthracycline (e.g. doxorubicin).
Combination drug regimens e.g. CHOP
* Cyclophosphamide 750 mg/m2 i.v. D1
* Adriamycin 50 mg/m2 i.v. D1
* Vincristine 1.4 mg/m2 i.v. D1
* Prednisolone 40 mg/m2 p.o. D1‑D5
R is Immunotherapy using the anti CD20 monoclonal antibody Rituximab
Aim of therapy is **curative** (overall approx 50%)
Relapse: Autologous Stem Cell transplant salvage 25% of patients
60
List three types of indolent NHL.
1. Folliclar NHL
2. Small lymphocytic/**CLL**
3. Mucosa associated (MALT)
61
Which translocations is follicular NHL associated with?
t(14;18) --\> over-expression of BCL2 ---\> anti-apoptosis
62
What score is used to detemine prognosis of follicular NHL? Is follicular NHL curable? What is the median surival?
1. FLIPI score (modified IPI)
2. Incurable
3. Median survival 12-15 years. May require 2-3 different chemotherapy schedules over the 12-15 year period
63
When is the "watch and wait" startegy acceptable in lymphoma? When is it contraindicated in this lymphoma?
Follicular NHL can adopt watch and wait at presentation if clinically indicated
Not indicated if:
* nodal extrinsic compression e.g. bowel, bile duct, ureter, vena cava
* massive painful nodes or recurrent infections
64
What is the treatment for follicular NHL?
* combination immuno-chemotherapy R-COP or R-CHOP
* not curative and mau need 2/3 treatments
* median survival 13 years but ranges
65
Give some examples of MZL? What is the aetiology? Do you get constitutional symptoms? What age does it mostly present?
Marginal zone NHL involves extra-nodal lymphoid tissue eg **Gastric** mucosa-associated lymphoid tissue MALT/H.Pylori , **Parotid** MZL/Sjogren syndrome
Chronic antigen stimulation e.g. H.Pylori infection and H.Pylori eradication may cure 75% of patients
**Median age at presentation 55-60y**
**_‘B’-symptoms uncommon -_** Most commonly arise in stomach, usually present with epigastric pain, ulceration or bleeding
Usual presentation is Stage I
66
What is EATL?
Enteropathy associated T cell lymphoma most commonly seen in coeliac disease patients
Involves small intestine jejunum and ileum
67
Which cells are affected/found in EATL? What are the signs and symptoms? How do you prevent it?
* Mature T cells (not precursor)
* Has an **_aggressive clinical course_**
Presentation & Clinical course
* Chronic antigen stimulation i.e. gluten in a gluten sensitive individual (Coeliac)
* Abdominal pain, obstruction perforation, GI bleeding
* Malabsorption
* Systemic symptoms
If responds poorly to chemo then generally fatal
Prevention: Strict adherence to gluten free diet
68
Which patient demographic is almost exclusively affected by CLL? What are other risk factors?
Caucasian - commonest leukaemia in Western world
x7 risk if relative affected
Median age 72 at diagnosis (but 10% aged \<55yrs)
69
22yr old female with cHL, mediastinal mass most common likely subtype
* lymphocyte depleted
* nodular sclerosing
* mixed cellularity
* lymphocyte rich
2
70
PET CT showsn disease involving mediastinul spleen and liver. What Ann Arbor stage?
4 because non-lymphatic organs invovled below diaphragm
71
Monitoring only appropriate for asymptomatic small volume disease in this lymphoma subtype
* Burkitt's
* Gastric MALT
* Follicular
* DLBCL
3 - indolent and chemo is not curative so can watch and wait
72
What are the laboratory findings on CLL?
* Lymphocytosis (5-300 x10^9/L)
* Smear cells
* Anaemia
* Thrombocytopenia
* BM lymphocytic crowding
73
Which immunophenotypes are found in CLL? How is this assessed?
Assessment of peripheral blood by FLOW CYTOMETRY
1. Correct immunophenotypes include CD5+, CD23 +, FMC7 -, CD79b +/-, SmIg +/-
2. ...but should also have smear cells and lymhocytosis.
3. Normal T cells - CD5+ve/CD19-ve
74
Immunophenotype correspondance with development of B cells.
75
What is the immunophenotype of a normal B cell?
CD3 -ve
CD5-ve
CD19 +ve
76
What are 3 cell based prognostic factors in CLL?
* IgHV mutation status
* CLL FISH cytogenetic panel
* TP53 mutation status (Chr 17p delection and/or TP53 point mutation)
77
What clinical staging systems are used for CLL?
1. Clinical staging - Binet or Rai
2. CLL IPI score
78
Loss of what means bad prognosis in CLL?
loss of 17p
However presence of IgH V means better prognosis as it indicated that the B cells are mature.
79
What technique is used for detection of chromosomal abnormalities such as delection of 17p (TP53) in CLL?
* FISH cytogenetic panel including a 17p probe and a 12 centromere probe
* TP53 sequencing can also be used
80
What is the natural progression of CLL?
Highly variable natural history
Initially 5-10 years good health until progression to a 2-3 year terminal phase
Rapid progression to death within 2-3 years
In a disorder of elderly
* 1/3 never progress
* 1/3 Progress, respond to CLL Rx (death from unrelated disorder)
* 1/3 Progress, require multiple lines of Rx, refractory disease, death from CLL
81
What are prognostic factors for CLL?
Cell based prognostic factors
* IgHV mutation status
* CLL FISH cytogenetic panel
* TP53 mutation status (Chromosome 17p del and/or TP53 point mutation)
Clinical staging systems
* Binet or Rai (clinical staging)
* CLL IPI score
82
What are the complications of CLL?
83
What are the prophylactic/supportive treatment given to CLL patients to improve prognosis?
Sino-pulmonary infections
* Early Rx with antibiotics
* Pneumocystis prophylaxis (may also require zoster ppx)
* Recurrent infection + IgG \< 5g/l \> IVIG replacement therapy
Vaccinations
* Pneumococcal
* Covid19
* Seasonal flu
* Avoid live vaccines
84
What are the indications for treating CLL? Summarise the treatment options.
**_IwCLL criteria_**
Watch and wait mostly unless:
1. Progressive lymphocytosis \>50% up in 2 months
2. Progressive BM failure - Hb\<100, plt \<100, neut \<1
3. Lymphadenpathy/splenomegaly
4. B symptoms
5. AI cytopenias
**CLL therapy -** combination immuno/chemo therapy but is being replaced by targeted treatment
* _Targeted therapy_ e.g. **BCR kinase** inhibitor, **BCL2** inhibitors
* _Cellular therapy_ only for relapsed high risk cases i.e. allogeneic SCT, **CAR-T** therapy (experimental)
85
What types of treatment are these in CLL?
1. Ibrutinib
2. Idelalisib
3. Venetoclax
Ibrutinib and idelalisib = BCR kinase inhibitors
Venetoclax = BCL2 inhibitors which causes apoptosis of CLL cells but risk of tumour lysis syndrome (!!)
86
4 - because IgHV mutated means it has undergone development in germinal centre and is better prognosis
87
1 - BCL2 inhibitor
