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PathY5 > Lymphoma 1: MDT > Flashcards

Lymphoma 1: MDT Flashcards

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1
Q

What is Lymphoma?

A

The term ‘lymphoma’ means a neoplastic (malignant) tumour of lymphoid cells.

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2
Q

Where are lymphomas usually found?

A

Lymphomas 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)

Rarely “anywhere” (breast kidney){*Immune privilege sites CNS, occular, testes}

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3
Q

What is the incidence of Lymphoma (Incl. HL and NHL)?

A

There are approximately 200 new cases per year for every million of the population (around 10,000 new cases a year in the UK).
Non-Hodgkin’s Lymphomas 80%
Hodgkin Lymphoma 20%

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4
Q

What are precursor malignancies?

A

Precursor cell neoplasia of B or T cell lineage:

Precursor B cell lymphoblastic leukaemia

Precursor T cell lymphoblastic leukaemia

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5
Q

What are mature B cell malignancies?

A

NHL

HL

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6
Q

What are mature T cell malignancies?

A

T cell or NK cell NHL

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7
Q

What are lymphoma RFs?

A

Most lymphoma subtypes/cases are sporadic with no known risk factors

Some lymphoma subtypes have specific risk factors immune diseases acquired or iatrogenic

Associated specific infections or inflammation

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8
Q

How does the limited instability of DNA become problematic in lymphoma?

A
  1. Lymphocytes undergo DNA changes in development:
    Potential for recombination errors and new point mutations
  2. Rapid cell proliferation in the germinal centre
    Allows rapid response to infection
    Rapid cell division = increased risk of DNA replication errors
  3. Dependent on apoptosis
    Exquisite antibody specificity & eliminates self reactive clones
    Apoptosis is “switched off” in germinal centre
    Consequences of mutation ins in apoptosis regulating genes
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9
Q

What is VDJ recombination?

A

Occurs in BM
Key enzymes: RAG1+2
TdT

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10
Q

What do B cells undergo?

A

Class switch recombination
Somatic hypermutation
Key enzyme: Adenosine induced Deaminase

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11
Q

What are immune gene recombination errors and lymphoma linked translocations?

A

Lymphoma/recombination associated translocations
Involves the Ig Locus (IgH, K or l loci)
Ig promoter highly active in B cells
Bring intact oncogenes close to the Ig promoter
Oncogenes may be anti apoptotic, proliferative.
bcl2
bcl6
Myc
cyclinD1

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12
Q

What are the 3 main groups of rare NHL subtypes?

A
  1. Constant antigenic stimulation- bacteria/ AI
  2. Viral infection (direct viral integration of lymphocytes)
  3. Loss of T cell function and EBV infection (B cell) - Loss of T cells (HIV), iatrogenic immunosuppression
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13
Q

What are the bacterial or AI driven causes of rare NHL (chronic inflammation)?

A

B cell Non Hodgkin Lymphoma Marginal zone sub type (MZL)
H.Pylori : Gastric MALT (mucosa associated lymphoid tissue) (MZL of stomach)
Sjogren syndrome : MZL of salivary glands
Hashimoto’s : MZL of thyroid

Enteropathy associated T-Cell
Non Hodgkin lymphoma (EATL)
Coeliac disease/Gluten: small intestine EATL

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14
Q

How does direct viral integration and lymphomagenesis occur?

A

HTLV1 retrovirus infects T cells by vertical transmission
Caribbean, Japan (and world wide) endemic infection
Risk of Adult T cell leukaemia lymphoma is 2.5% at 70 years
ATLL is a subtype of T cell Non Hodgkin Lymphoma

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15
Q

How does loss of T cell function occur?

A

HIV (in uncontrolled infection there is x60 increased incidence of B NHL )
Iatrogenic (transplant immunosuppression)
PTLD (post transplant lymphoproliferative disorder)

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16
Q

How does EBV infection result in lymphoma?

A

EBV infects B lymphocytes, healthy carrier state post glandular fever.

EBV driven proliferation of B cells is associated with surface expression of EBV antigens.

Proliferating B cells targeted and killed by EBV specific cytotoxic T cell response

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17
Q

How do CTLs cause EBV to cause havoc?

A

Loss of cytotoxic T cell function can cause failure to eliminate EBV driven proliferation of B cells

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18
Q

How do you make a haemato-oncology diagnosis?

A 
Morphology (Cytology/ cytochemistry/ histo) 
Immunophenotye (Flow cytometry, immunohistochemistry)
Cytogenetics (Conventional karyotyping, FISH)
Molecular genetics (Sequencing, PCR, gene profiling, whole genome sequencing)
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19
Q

How many types of lymphoma are there?

A

> 60

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20
Q

How do we do diagnosis and staging?

A

Histological diagnosis

Anatomical stage (CT/ MRI/ PET/ BM biopsy)

Prognostic factors (LDH, beta2 mic, albumin, kidney or BM function)

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21
Q

What cells are specific to HL/ NLPHL?

A

Reed Sternberg cells

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22
Q

How many Lymphomas are HL?

A

15% (NHL = 85%)

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23
Q

What are the mature B and T cell lymphomas?

A

Mature B cell neoplasm
DLBCL, Follicular NHL, CLL etc

Mature T and NK neoplasm
PTCL, Anaplastic, Cutaneous

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24
Q

What is the epidemiology of HL?

A

1% of all cancer, 3:100,000 population
HL is more common in males than females.
Bimodal age incidence
Most common age 20-29, young women NS subtype
Second smaller peak affecting elderly >60 years old

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25
What are the S/S of HL?
Painless enlargement of lymph node/nodes. May cause obstructive symptoms/signs Constitutional symptoms; fever, night sweats weight loss (the B symptoms) and pruritis may be present. Rarely alcohol induced pain
26
What is the classification of HLs?
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
27
How common is NLPHL?
Nodular Lymphocyte predominant HL 5% (disorder of the elderly multiple recurrences)
28
How do you stage HL?
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
29
What is the staging system?
``` Stage I; one group of nodes II; >1 group of nodes same side of the diaphragm III; nodes above and below the diaphragm IV; extra nodal spread Suffix A if none of below, B if any of below Fever Unexplained Weight loss >10% in 6 months Night sweats ```
30
How is chemo used?
Chemotherapy is often given as a combination of drugs which affect the malignant cells in different ways Radiotherapy: HL is highly responsive to radiotherapy, can be given at end of chemo as an Involved field a small area only targeting diseased nodes (less toxicity to normal tissue) Combined modality uses both chemo and radiotherapy
31
What is the chemo used for HL?
``` ABVD- 4 weekly intervals Adriamycin Bleomycin Vinblastine DTIC ```
32
Why is ABVD good?
Effective treatment Preserves fertility (unlike MOPP the original chemo) Can cause (long term): Pulmonary fibrosis cardiomyopathy
33
How is radiotherapy used for HL?
Modern practice involved field RT only Low/negligible risk of relapse within field Risk of damage to normal tissue: 1. Ca breast (risk 1:4 after 25 years) 2. Leukaemia/mds (3% at 10y) 3. Lung or skin cancer Combined modality greatest risk of second degree malignancy (two mechanisms of DNA damage)
34
What is the treatment for HL?
Chemotherapy required for all cases (ABVD) ABVD 2-6 cycles (depending on stage) +/- Radiotherapy PET CT Interim: post x2 cycles, response assessment End of Treatment: Guides need for radiotherapy Relapse High dose salvage chemotherapy Autologous PB stem cell transplant as salvage
35
What is the outcome of therapy/ prognosis?
Outcome of therapy: Older patients generally do less well as do those with lymphocyte-depleted histology. ``` Prognosis: This depends principally on stage. 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 ```
36
What are the treatment dilemmas?
HL is a curable disease overall approx 80% 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!
37
What are the parts of the lymphoreticular system?
Generative LR tissue Bone marrow and thymus Function - generation/maturation of lymphoid cells Reactive LR tissue Lymph nodes and spleen Function - development of immune reaction Acquired LR tissue Extranodal lymphoid tissue E.g. Skin, stomach, lung Function - development of local immune reaction
38
What are the cells of the lymphoreticular system?
B lymphocytes Express surface immunoglobulin Antibody production T lymphocytes Express surface T cell receptor Regulation of B cell and macrophage function Cytotoxic function Antigen presenting cells Macrophages Connective tissue cells
39
Where do B cells bind to antigen epitopes?
Germinal center (B cells, Antigen presenting cells) This is where B cells which bind antigen epitopes are selected and activated
40
What is the T cell area?
Comprises T cells Antigen presenting cells High endothelial vessels This is where T cells which bind antigen epitopes are selected and activated
41
How do we identify different types of lymphocytes?
Identify lymphocyte subtypes and different stages of development by the different types of cell surface receptors expressed by the cells These are called CD markers - over 100! They can be detected in tissue samples using immunohistochemistry
42
What is the site of lyphoma?
Arise in and involve lymphoid tissues (including acquired lymphoid tissue - extranodal lymphomas)
43
What is the pathogenesis of lymphoma (clonal neoplasia)?
Mutation in genes to allow uncontrolled cell growth Normal lymphocytes undergo controlled genomic “instability” of lymphoid cells - mistakes in this process produce neoplastic mutations Inherited disorders – inherited disorder resulting in increased/abnormal genomic instability Viral agents – EBV, HTLV-1 Environmental agents – mutagens, chronic immune stimulation (e.g H pylori) Iatrogenic causes – radiotherapy, chemotherapy ALSO immunosuppression (infection + loss of surveillance)
44
What is the WHO classification of lymphoma?
HODGKIN LYMPHOMA Classical Lymphocyte predominant ``` NON-HODGKIN LYMPHOMA B cell Precursor B cell neoplasms Peripheral B cell neoplasms Low grade High grade T cell Precursor T cell neoplasms Peripheral T cell neoplasms ```
45
What are the basic principles of lymphoma?
B cell Non-Hodgkin lymphomas most common type (80-85 %) Can arise at different stages of lymphocyte development and activation Therefore in certain lymphomas the neoplastic lymphoid cell resembles a normal counterpoint both in morphology and in the pattern of CD markers expressed. Neoplastic lymphoid cells circulate in blood Hence often disseminated at presentation (although this may be sub-microscopic). Exception is Hodgkin lymphoma and some very early NHL Lymphoid neoplasms may disrupt normal immune system Therefore patients may develop immunodeficiencies
46
What are diagnostic tools pathologists can use?
Morphology Cytology: Look at single cells aspirated from a lump ``` Histology: look at tissue sections Architecture Nodular Diffuse Cells Small round Small cleaved Large (centroblastic, immunoblastic, plasmablastic) ```
47
How is immunohistochemistry used?
Used to identify proteins on/in cells in tissue sections Use labelled antibody to cell surface receptor Dye label is visible under light microscope in tissue sections
48
How can we differentiate cell types with immuno?
``` T = CD3, CD5 B = CD20 ```
49
What can you see on immunophenotyping?
Cell type Cell distribution Loss of normal surface proteins E.g. neoplastic T cells Abnormal expression of proteins (often secondary to specific chromosomal/ gene abnormalities) E.g Cyclin D1 Clonality of B cells Light chain expression
50
Which molecular tools are available?
FISH (chromosome translocations) e.g. anaplastic large cell lymphoma t(2:5) PCR (translocations, clonal TCR or Ig gene rearrangement)
51
What can be used in PCR for diagnosis and prognosis?
Diagnostic E.g 11;14 Mantle cell lymphoma Prognostic E.g. 2;5 Anaplastic large cell lymphoma
52
What are common B cell NHL lymphomas?
Low grade Follicular lymphoma CLL (Small lymphocytic lymphoma/chronic lymphocytic leukaemia) Marginal zone lymphoma High grade Diffuse large B cell lymphoma Intermediate Burkitt’s lymphoma Aggressive Mantle cell lymphoma (disseminated at presentations)
53
What is follicular lymphoma?
Clinical: Lymphadenopathy. MA/elderly Histopathology: Follicular pattern, Germinal centre cell origin CD10, bcl6+ Molecular: t(14;18) - bcl-2 gene Indolent but can transform to high grade lymphoma
54
What would immunohistochemistry show in follicular lymphoma?
Detection of bcl-2 expression by neoplastic B cells in follicles
55
What is CLL (small lymphocytic lymphoma)?
Clinical: MA/elderly; nodes or blood Histopathology: Small lymphocytes, Naïve or post-germinal centre memory B cell, CD5, CD23 + Molecular,: Multiple genetic abnormalities Indolent, but can transform to high grade lymphoma (Richter transformation)
56
What is MALT lymphoma?
Arise mainly at extranodal sites (many sites, e.g. gut, lung, spleen) Thought to arise in response to chronic antigen stimulation (e.g. by Helicobacter in stomach) Post germinal centre memory B cell Indolent but can transform to high grade lymphoma Can treat low grade disease with non-chemotheraputic modalities - i.e. remove antigen E.g Helicobacter eradication
57
What is mantle cell lymphoma?
Clinical: MA male predominence, Lymph nodes, GI tract, Disseminated disease at presentation, Med survival 3-5 years Histopathology: Located in mantle zone, Pre-germinal centre cell, Aberrant CD5, cyclin D1 expression Molecular: t(11;14)- Cyclin D1 over expression AGGRESSIVE: Median SR 3-5 yrs
58
What is Burkitt's Lymphoma?
Clinical: Jaw or abdominal mass children/young adults Types: Endemic (children/ YA), (Adults) Sporadic, Immunodeficiency, EBV associated Histopathology: Germinal center cell origin, “starry-sky” appearance Molecular: t(8:14, 2:8, 8;22) - C-myc Aggressive disease
59
What is the presentation/ pathology of Diffuse large B cell lymphoma?
Clinical: MA/elderly, Lymphadenopathy Histopathology: Germinal center or post-germinal center B cell, Sheets of large lymphoid cells, Germinal center phenotype = good prognosis p53 positive, high proliferation fraction = poor prognosis
60
What are T cell lymphomas?
Rarer NHLs - Peripheral T cell lymphoma NOS Clinical: MA/elderly, Lymphadenopathy and extranodal sites Hist/cyto: Large T lymphocytes, Often with associated reactive cell population, esp eosinophils Aggressive
61
What are special forms of T cell lymphoma?
Adult T cell leukaemia/lymphoma Caribbean and Japan Associated with HTLV-1 infection Enteropathy associated T cell lymphoma Some patients with long standing coeliac disease Cutaneous T cell lymphomas E.g. mycosis fungoides - more indolent Anaplastic large cell lymphoma
62
What is anaplastic large cell lymphoma?
Clinical: Children/young adults, Lymphadenopathy Histopathology: Large “epithelioid” lymphocytes, T cell or null phenotype Molecular t(2;5) - Alk-1 protein expression Aggressive Alk-1 positive better prognosis CD30 positive
63
Summarise HL and NHL
Hodgkin Lymphoma More often localised to a single nodal sit Spreads contiguously to adjacent lymph nodes Non-Hodgkin Lymphoma More often involves multiple lymph node sites Spreads discontinuously
64
What is the difference between classical HL and NLPHL?
``` Classical Several subtypes Nodular sclerosing Mixed cellularity Lymphocyte rich and lymphocyte depleted ``` Lymphocyte predominent Some relationship to non-Hodgkin’s lymphoma
65
What is the presentation of classical lymphoma?
Clinical: Young and MA, Often involves just single lymph node group, EBV associated Staining: Thought to be germinal center/post germinal center B cell origin, CD30+, CD15+, CD20- Histopathology: Sclerosis, mixed cell population in which scattered Reed-Sternberg and Hodgkin cells with eosinophils Moderately aggressive
66
What is the presentation of NLPHL?
Clinical: Isolated lymphadenopathy, Germinal centre B cell (positive for some germinal centre B cell markers), No association with EBV Markers: CD20, CD30-, CD15- Histopathology: B cell rich nodules with scattered L&H cells, Indolent Can transform to high grade B cell lymphoma
67
Which of these is common: CLL, myeloma, hairy cell leukaemia
CLL and myeloma
68
How do lymphocytes uphold DNA instability normally?
DNA molecules are 1) cut and recombined 2) subjected to deliberate DNA mutagenesis (somatic hypermutation) Generates immunoglobulin and T cell receptor diversity and Ig class switching
69
How many lymphocytes die in the germinal centre?
(90% of normal lymphocytes die in the Germinal centre!)
70
Give an example of a translocation that may cause cancer in B cells
t(8:14) - c-myc oncogene for Ig molecules- proto-oncogene and oncogenesis
71
What happens in the lymphoid follicle?
Mantle zone Naïve unstimulated B cells Germinal center B cells Antigen presenting cells This is where B cells which bind antigen epitopes are selected and activated
72
What does starry sky represent in Burkitt's lymphoma?
Stars- Macrophages which are full of debris Sky- Tightly packed little cytoplasm lymphoma cells

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