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Year 5 - Pathology > HAEM: Lymphoma: MDT, CLL, NHL, lymphoproliferative disorder > Flashcards

HAEM: Lymphoma: MDT, CLL, NHL, lymphoproliferative disorder 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.)
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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
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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
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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
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5
Q

What are the risk factors for different NHL subtypes?

A

Can be split into two main types:

  1. Immune system diseases
  2. Loss of T cell function
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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)
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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
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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)
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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)
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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)
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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
  • Accessory Cells:
    • Antigen-presenting cells
    • Macrophages
    • Connective tissue cells
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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
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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
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14
Q

What is the WHO classification of lymphoma?

A
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15
Q

Describe the basic principles of lymphoma.

A
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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
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17
Q

Which lymphoma is cyclin D1 expression associated with?

A

Mantle cell lymphoma

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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
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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
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20
Q

Summarise the histopathological features of follicular lymphoma.

A
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21
Q

Describe the histopathological features of small lymphocytic lymphoma.

A
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22
Q

What are the histopathological features of margincal cell lymphoma?

A
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23
Q

What are the histopathological features of mantle cell lymphoma?

A
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24
Q

What are the histopathological features of Burkitt;s lymphoma?

A
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25
Q

What are the histopathological features of diffuse large B cell lymphoma?

A
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26
Q

What are the general features of T cell lymphomas?

A
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27
Q

List 4 types of T cell lymphoma? Name a risk factor for each.

A
  • 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)
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28
Q

What are the features of anaplastic large cell lymphoma?

A
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29
Q

What are the types of Hodgkin’s lymphoma?

A
  • Types of HL:
    • Classical Hodgkin Lymphoma: subtypes are…
      • Nodular sclerosing
      • Mixed cellularity
      • Lymphocyte rich/depleted
    • Lymphocyte Predominant
      • Some relationship to NHL
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30
Q

What are key differences between HL and NHL?

A

Hodgkin is more localised (usually only one nodal site)

Hodgkin spreads contiguously to adjacent lymph nodes (NHL involves multiple sites and spreads sporadically)

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31
Q

What are the features of classical HL?

A
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32
Q

What are the features of nodular LP Hodgkin’s lymphoma?

A
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33
Q

What are the features of nodular lymphocyte predominant lymphoma?

A
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34
Q

Part 2

A
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35
Q
A

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
Q
A

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
Q

How does lymphoma present?

A
  • 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
Q
A

Biopsy is used for classification of lymphoma subtype (WHO classification)

39
Q

How do you fdiagnose and stage?

A
  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
Q

List the different types of lymphoid malignancies. Which is the most common?

41
Q

Which age and gender is most affected by HL? How common is it? Overall which gender is most affected?

A

Peak in young women aged 20-29

But more common in men overall

3:100,000

42
Q

What are the HL symptoms and signs?

A

B symptoms

43
Q

How is HL staged?

A
  • 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
Q

Which HL have good/poor prognoses?

A

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
Q

Note the staging.

46
Q

What are the features of cHL nodular sclerosing?

A
  • 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
Q

What is ABVD? What is an advantage and disadvantage of this therapy?

A

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
Q

What is mainstay chemotherapy regimen for cHL?

A

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
Q

What are the advantages and disadvantages of cHL radiotherapy?

A

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
Q

What is the cure rate for cHL? What does cure rate mean in HL?

A

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
Q

What is the fastest proliferating malignancy?

A

NHL subtype Burkitt’s lymphoma

52
Q

Which NHL is antibiotic responsive?

A

Gastric MALT

53
Q

What are the most common NHL subtypes?

54
Q

How does histology predict clinical course of NHL?

A

Called v aggresive, aggresive or indolent

55
Q

Which (aggressive or indolent) are curable?

A

Indolent cause longer survival but need constant chemotherapy as they recur.

You can CURE aggressive subtypes with chemotherapy but not indolent types.

56
Q

How are very aggressive lymphomas treated?(1)

A

Like acute leukaemias - see lecture

57
Q

How common is DLBCL and what grade is it?

A

high grade/aggressive (intermediate)

40-60% of all NHL

58
Q

What index is used for prognosis and treatment detemination in DLBCL?

A

IPI (International Prognostic Index)

  1. Age
  2. Stage (Ann Arbor)
  3. LDH
  4. Extra-nodal disease sites
  5. ECOG performance status
59
Q

How is DLBCL treated?

A

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
Q

List three types of indolent NHL.

A
  1. Folliclar NHL
  2. Small lymphocytic/CLL
  3. Mucosa associated (MALT)
61
Q

Which translocations is follicular NHL associated with?

A

t(14;18) –> over-expression of BCL2 —> anti-apoptosis

62
Q

What score is used to detemine prognosis of follicular NHL? Is follicular NHL curable? What is the median surival?

A
  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
Q

When is the “watch and wait” startegy acceptable in lymphoma? When is it contraindicated in this lymphoma?

A

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
Q

What is the treatment for follicular NHL?

A
  • combination immuno-chemotherapy R-COP or R-CHOP
  • not curative and mau need 2/3 treatments
  • median survival 13 years but ranges
65
Q

Give some examples of MZL? What is the aetiology? Do you get constitutional symptoms? What age does it mostly present?

A

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
Q

What is EATL?

A

Enteropathy associated T cell lymphoma most commonly seen in coeliac disease patients

Involves small intestine jejunum and ileum

67
Q

Which cells are affected/found in EATL? What are the signs and symptoms? How do you prevent it?

A
  • 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
Q

Which patient demographic is almost exclusively affected by CLL? What are other risk factors?

A

Caucasian - commonest leukaemia in Western world

x7 risk if relative affected

Median age 72 at diagnosis (but 10% aged <55yrs)

69
Q

22yr old female with cHL, mediastinal mass most common likely subtype

  • lymphocyte depleted
  • nodular sclerosing
  • mixed cellularity
  • lymphocyte rich
70
Q

PET CT showsn disease involving mediastinul spleen and liver. What Ann Arbor stage?

A

4 because non-lymphatic organs invovled below diaphragm

71
Q

Monitoring only appropriate for asymptomatic small volume disease in this lymphoma subtype

  • Burkitt’s
  • Gastric MALT
  • Follicular
  • DLBCL
A

3 - indolent and chemo is not curative so can watch and wait

72
Q

What are the laboratory findings on CLL?

A
  • Lymphocytosis (5-300 x10^9/L)
  • Smear cells
  • Anaemia
  • Thrombocytopenia
  • BM lymphocytic crowding
73
Q

Which immunophenotypes are found in CLL? How is this assessed?

A

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
Q

Immunophenotype correspondance with development of B cells.

75
Q

What is the immunophenotype of a normal B cell?

A

CD3 -ve

CD5-ve

CD19 +ve

76
Q

What are 3 cell based prognostic factors in CLL?

A
  • IgHV mutation status
  • CLL FISH cytogenetic panel
  • TP53 mutation status (Chr 17p delection and/or TP53 point mutation)
77
Q

What clinical staging systems are used for CLL?

A
  1. Clinical staging - Binet or Rai
  2. CLL IPI score
78
Q

Loss of what means bad prognosis in CLL?

A

loss of 17p

However presence of IgH V means better prognosis as it indicated that the B cells are mature.

79
Q

What technique is used for detection of chromosomal abnormalities such as delection of 17p (TP53) in CLL?

A
  • FISH cytogenetic panel including a 17p probe and a 12 centromere probe
  • TP53 sequencing can also be used
80
Q

What is the natural progression of CLL?

A

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
Q

What are prognostic factors for CLL?

A

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
Q

What are the complications of CLL?

83
Q

What are the prophylactic/supportive treatment given to CLL patients to improve prognosis?

A

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
Q

What are the indications for treating CLL? Summarise the treatment options.

A

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
Q

What types of treatment are these in CLL?

  1. Ibrutinib
  2. Idelalisib
  3. Venetoclax
A

Ibrutinib and idelalisib = BCR kinase inhibitors

Venetoclax = BCL2 inhibitors which causes apoptosis of CLL cells but risk of tumour lysis syndrome (!!)

86
Q
A

4 - because IgHV mutated means it has undergone development in germinal centre and is better prognosis

87
Q
A

1 - BCL2 inhibitor

Year 5 - Pathology (89 decks)

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