5. Lymphoma 1 - Multidisciplinary Flashcards
(138 cards)
1
Q
What is the definition of lymphoma?
A
neoplasm of the lymphoid cells
2
Q
Where is lymphoma usually found?
A
- Lymph nodes, bone marrow and/or blood (lymphatic system)
- Lymphoid organs: spleen or gut-associated lymphoid tissue
- Skin (often T cell disease)
- Rarely ‘anywhere’ (CNS, ocular, testes, breast)
3
Q
What percentage are Non-Hodgkin vs Hodgkin lymphoma?
A
80% = Non-Hodgkin and 20% = Hodgkin
4
Q
How many types of lymphomas are there and why?
A
There are > 60 different types of lymphoma because they all originate from different points in the maturation of lymphocytes. B cells go through several stages when they are developing. You get different types of lymphoma/leukaemia based on the point at which the tumour arises.
5
Q
How does immunoglobulin and T cell receptor gene recombination allow antibodies to recognise a huge number of different antigens?
A
- We have a set of germ line genes that we can recombine to make a diverse variety of different antibodies and T cell receptors
- This recombination (know as VDJ recombination) will occur in the bone marrow
- Within the germinal centre, there is a second stage of DNA alteration which involves class switching and the insertion of nucleotide point mutations at the sites of VDJ recombination (known as somatic hypermutation) to generate even more diversity
- These phenomena make it possible for antibodies to recognise a huge number of different antigens
6
Q
What is the downside of an adaptive immune system?
A
- The process of VDJ recombination and somatic hypermutation runs the risk of causing recombination errors and new point mutations
- Lymphocytes are reliant on apoptosis to keep their massive proliferation under control (90% of lymphocytes will die in the germinal centre)
- This ensures antigen specificity and prevents autoimmune disease
- If mutations turn off apoptosis, it can lead to malignancy
- Rapid cell proliferation in the germinal centre increases the risk of DNA replication error
7
Q
Why are Ig promotors in B cells highly active?
A
Because they are designed to be able to produce loads of immunoglobulins
8
Q
If, by some error, you translocate an oncogene downstream of the promoter, then you get malignant genes being expressed, such as:
A
Bcl2, Bcl6, Myc, cyclinD1
9
Q
What are known risk factors for lymphoma, and what is the risk factor identified in the majority?
A
Majority have NO identifiable risk factor.
Know risk factors: Constant antigenic stimulation, infection (direct viral infection of lymphocytes), loss of T cell function
10
Q
Can lymphomas be caused by constant antigenic stimulation?**
A
Yes - This is initially antigen-dependent, but then becomes autonomous?
11
Q
What can H pylori infection lead to?
A
Gastric MALT marginal zone NHL of the stomach
12
Q
What can Sjogren syndrome lead to?
A
Marginal zone NHL of parotid lymphoma
13
Q
What can Coeliac disease lead to?
A
Small bowel T cell lymphoma, EATL (enteropathy-associated T cell non-Hodgkin lymphoma)
14
Q
What viruses can cause lymphoma?
A
E.g. HTLV1, EBV
15
Q
What virus is associated with lymphoma by direct viral integration?
A
HTLV1
16
Q
How does HTLV1 cause lymphoma?
A
Infects T cells by vertical transmission
17
Q
Who tends to carry HTLV1?
A
Caribbean and Japanese carriers
18
Q
What virus may lead to developing adult T cell leukaemia lymphoma? And why?
A
HTLV1. This is very aggressive. This is caused by a virus integrating into the T cell genome, driving proliferation and transforming the cells
19
Q
Why virus causes lymphoma by immunosuppresion?
A
EBV
20
Q
How does EBV cause lymphoma?
A
EBV infects B lymphocytes and when the EBV is quiescent, it is doing nothing to the B cells. The healthy carrier state is maintained by cytotoxic T cells killing EBV antigen expressing B cells. Loss of T cell function leads to risk of EBV-driven lymphomas. T cell function can be lost due to HIV or iatrogenic (organ transplant immunosuppression) - later leads to post-transplant lymphoproliferative disorder (PTLD)
21
Q
What types of lymphoreticular tissues are there as part of the lymphoreticular system?
A
Generative LR tissue, reactive LR tissue, acquired LR tissue
22
Q
Where is generative LR tissue found?
A
Bone marrow and thymus
23
Q
Where is reactive LR tissue found?
A
Lymph nodes and spleen
24
Q
Where is acquired LR tissue found?
A
Extra-nodal lymphoid tissue (e.g. skin, stomach, lung).
25
What is the function of generative LR tissue?
Generation/maturation of lymphoid cells
26
What is the function of reactive LR tissue?
Development of immune reaction
27
What is the function of acquired LR tissue?
Development of local immune reaction
28
What are the cells of the lymphoreticular system?
B and T lymphocytes, and accessory cells
29
What is the purpose of B lymphocytes (in the context of the lymphoreticular system)?
Express surface Ig, responsible for antibody production
30
What is the purpose of T lymphocytes (in the context of the lymphoreticular system)?
Express surface T cell receptor, regulation of B cells and macrophage function, cytotoxic function
31
What types of cells are accessory cells?
Antigen-presenting cells, macrophages, connective tissue cells
32
What is normal lymph node histology?
- The rounded areas are the B cell follicles
- In between the B cell follicles you have the T cell areas
- The medulla is the central area where mature B cells eventually end up
(See notes)
33
What is the mantle zone?
In a lymphoid follicle, the crescent shaped region is the mantle zone where naive unstimulated B cells are located
34
What is the germinal centre?
B cells will then migrate into the paler round area (germinal centre) where they encounter antigen-presenting cells and undergo activation and selection.
35
What is a predisposing factor for lymphoma in the germinal centre?
There is a lot of cell turnover in this area
36
What does the T cell area of a lymph node contain?
Consists of lots of T cells, antigen-presenting cells and high endothelial vessels
37
What happens in the T cell area of the lymph node?
This is where T cells that bind antigen epitopes are selected and activated
38
How can we detect and identify lymphocytes?
Lymphocytes can be identified based on their type and stage of maturation by looking at the different types of cell surface receptors expressed by the cells.
There are > 100 CD markers. They can be detected using immunohistochemistry.
39
What are the main markers to identify B and T lymphocytes?
CD20 for B cells and CD3 and CD5 for T cells
40
What is the (histological) definition of lymphoma?
Neoplastic proliferation of lymphoid cells forming discrete tissue masses
41
What site are lymphomas found in?
Arise in and involve lymphoid tissues (including acquired lymphoid tissue - extranodal lymphoma)
42
What is the basic WHO classification of lymphoma?
Hodgkin Lymphoma: classical and lymphocyte predominant.
Non-Hodgkin Lymphoma: B cell (more common) - precursor B cell neoplasms, peripheral B cell neoplasms (Low grade, High grade); T cell (rarer) - precursor T cell neoplasms, peripheral T cell neoplasms.
43
How is lymphoma classified?
Lymphoma is classified using a combination of clinical, histological, immunohistochemical and molecular data resulting in well-defined entities with distinct behaviour. This has implications on treatment and prognosis.
44
Why does immunosuppression lead to lymphoma?
Immunosuppression increases the risk of lymphoma because it predisposes to infection and also leads to a loss of surveillance of cell replication
45
What is the most common type of lymphoma? And what % of cases?
B Cell Non-Hodgkin Lymphoma is the MOST COMMON type (80-85%)
46
What stage of lymphocyte development and activation do lymphomas form?
Can arise from different stages of lymphocyte development and activation. (So, in some lymphomas the neoplastic lymphoma cells will look pretty similar to the normal counterpart in terms of morphology and the pattern of CD markers)
47
Where do you tend to find neoplastic lymphoid cells? and what is the exception?
Neoplastic lymphoid cells circulate in the blood (this is why it is often disseminated at presentation). NOTE: Hodgkin's lymphoma is an exception because it tends to only affect one or two lymph node groups.
48
How may patients develop immunodeficiencies as a result of lymphomas?
Lymphoid neoplasms can disrupt the normal immune system
49
What type of B cell lymphomas are there from the bone marrow?
Precursor B lymphoblastic lymphoma(/leukaemia), small lymphocytic lymphoma, chronic lymphocytic leukaemia
50
What types of T cell lymphoma is there from the thymus?
Precursor T lymphoblastic lymphoma (/leukaemia)
51
What type of B cell lymphoma is there from the mantle zone of lymph nodes?
Mantle cell lymphoma
52
What types of B cell lymphomas are there from the germinal centre?
Follicular lymphoma, Burkitt lymphoma, diffuse large B cell lymphoma, Hodgkin lymphoma
53
What types of B cell lymphomas are there from the post germinal centre?
Diffuse large B cell lymphoma, marginal zone lymphoma, small lymphocytic lymphoma, chronic lymphocytic leukaemia
54
What types of T cell lymphomas are there from the post germinal centre?
Peripheral T cell lymphoma
55
What type of B cell lymphoma is there from after the lymph node?*
Multiple myeloma
56
What are pathologists' diagnostic tools in lymphoma?
Cytology, histology, immunophenotyping, and molecular tools such as FISH and PCR
57
How can we use cytology to diagnose lymphoma?
Look at single cells aspirated from a lump
58
How can we use histology to diagnose lymphoma?
Look at the tissues.
Architecture: nodular, diffuse
Cells: small round; small cleaved; large (centroblastic, immunoblastic, plasmablastic) - note this is suggestive of high grade lymphoma
59
How can we use immunophenotyping as a diagnostic tool in lymphoma?
Immunohistochemistry is used to identify proteins on/in the cells.
Things to look at: cell distribution, loss of normal surface proteins, abnormal expression of proteins (e.g. cyclin D1 is suggestive of Mantle cell lymphoma), clonality of B cells (light chain expression - a normal clonal proliferation will show roughly event amounts of kappa and lambda light chains).
60
How can we use FISH to diagnose lymphomas?
Identify chromosome translocations
61
How can we use PCR to diagnose lymphomas?
Identify chromosome translocations, clonal T cell receptor or Ig gene rearrangement
62
Give an example where diagnostic tools such as PCR and FISH can be diagnostic
11;14 = Mantle cell lymphoma
63
Give an example where diagnostic tools such as PCR and FISH can be prognostic
2;5 = anaplastic large cell lymphoma
64
What are examples of common B cell Non-Hodgkin lymphomas that are low grade?
Follicular lymphoma, small lymphocytic lymphoma/chronic lymphocytic leukaema, marginal zone lymphoma, mantle zone lymphoma
65
What are examples of common B cell Non-Hodgkin lymphomas that are high grade?
Diffuse large B cell lymphoma
66
What are examples of common B cell Non-Hodgkin lymphomas that are intermediate?
Burkitt's lymphoma
67
What is the presentation of follicular lymphoma?
Lymphadenopathy in the middle-aged or elderly
68
Describe the follicular pattern in the histopathology of follicular lymphoma
These follicles are neoplastic, they are not normal. Often these follicles spread out of the node into the adjacent tissues. (See notes for pictures)
69
Considering histopathology of follicular lymphoma, how is the germinal centre cell origin demonstrated?
Demonstrated by showing positive staining for CD10 and bcl-6
70
On a molecular level of lymphoma, what genes are involved?
14;18 translocation involving bcl-2 gene. (Usually indolent, but can transform into high grade lymphoma)
71
On a molecular level of lymphoma, what can we used to show these neoplastic follicles?
Immunohistochemistry can be used to show that these neoplastic follicles express bcl-2 whereas normal follicles do not
72
What is the presentation of small lymphocytic lymphoma/chronic lymphocytic leukaemia?
Middle-aged or elderly, detected in the lymph nodes or blood.
73
Describe the histopathology of small lymphocytic lymphoma/chronic lymphocytic leukaemia. What markers are seen?
Small lymphocytes, arises from naïve B cells or post-germinal centre memory B cells. These cells are CD5 and CD23 positive. They replace the entire lymph node so that you no longer see follicles or T cell areas. (see notes for pictures)
74
Describe small lymphocytic lymphoma/chronic lymphocytic leukaemia on a molecular level
Multiple genetic abnormalities, indolent, but can transform into a higher grade lymphoma (Richter transformation)
75
Where does marginal zone lymphoma/MALT lymphoma arise from?
Arise mainly at extranodal sites (e.g. gut, lung, spleen).
| Arise from post-germinal centre memory B cells.
76
What is marginal zone lymphoma/MALT lymphoma thought to arise in response to?
Chronic antigenic stimulation (e.g. H pylori). • Indolent, but can transform into a high grade lymphoma.
77
How can we treat low grade disease of marginal zone lymphoma/MALT lymphoma?
Can treat low-grade disease with non-chemotherapeutic modalities (e.g. removing the antigen (such as eradicating H. pylori))
78
What is the presentation of mantle cell lymphoma?
Typically occurs in middle-aged males, affects lymph nodes and the GI tract, often present with disseminated disease
79
Considering histopathology, where is mantle cell lymphoma located?
Located in the mantle zone of the lymph node. (See pictures)
80
Where does mantle cell lymphoma arise from?
Arise from pre-germinal centre cells
81
Which markers do mantle cell lymphoma cells express?
They will show aberrant expression of CD5 and cyclin D1
82
What chromosomes and gene is involved in mantle cell lymphoma?
11;14 translocation. Cyclin D1 over-expression.
83
What is the prognosis of mantle cell lymphoma?
Median survival: 3-5 years
84
What is the presentation of Burkitt's lymphoma?
Jaw or abdominal mass in children/young adults; it can be endemic, sporadic or associated with immunodeficiency; associated with EBV
85
Describe the histopathology of Burkitt's lymphoma
Arises from germinal centre cells and has a starry-sky appearance (see notes)
86
What chromosome translocation is involved in Burkitt's lymphoma?
C-myc translocation (8;14, 2;8, 8;22)
87
What is the prognosis of Burkitt's lymphoma?
Poor; it is an aggressive disease
88
What is the presentation of diffuse large B cell lymphoma?
Middle-aged and elderly, present with lymphadenopathy
89
Describe the histopathology of diffuse large B cell lymphoma. Where do they arise from?
Arise from germinal centre or post-germinal centre B cells. There are LARGE lymphoid cells. The lymph node is effaced so it is not possible to identify germinal centres and follicles.
90
What is the prognosis of diffuse large B cell lymphoma?
Having a germinal centre phenotype is associated with a GOOD prognosis. p53 positive and high proliferation fraction is associated with a POOR prognosis.
91
What is the presentation of T cell lymphomas?
Middle-aged and elderly. Presenting with lymphadenopathy and extranodal sites
92
Histopathology of T cell lymphomas
Large T lymphocytes (see notes)
93
Which type of lymphoma is often found with an associated reactive cell population (especially eosinophils)?
T cell lymphoma
94
What is the prognosis for T cell lymphomas?*
Aggressive*
95
What are special forms of T cell lymphomas?
Adult T cell leukaemia/lymphoma, enteropathy-associated T cell lymphoma, cutaneous T cell lymphoma
96
Which populations is adult T cell leukaemia/lymphoma found in and what is it associated with?
Prevalent in the Caribbean and Japan. Associated with HTLV-1 infection
97
Which patients does enteropathy-associated T cell lymphoma occur in?
Occurs in some patients with long-standing Coeliac disease
98
What is the most common for of cutaneous T cell lymphoma?
Mycosis fungoides
99
How does anaplastic large cell lymphoma present?
Presents in children and young adults. Lymphadenopathy.
100
What is the histopathology of anaplastic large cell lymphoma?
Large epithelioid lymphocytes, T cell or null phenotype (i.e. anaplastic) (see notes)
101
Which chromosome and gene expression is involved in anaplastic large cell lymphoma?
2;5 translocation, Alk-1 protein expression - this is associated with better prognosis
102
What is the prognosis of anaplastic large cell lymphoma?
Aggressive
103
What are key differences between Hodgkin and non-Hodgkin lymphoma?
- Hodgkin is more localised (usually only one nodal site)
- Hodgkin spreads contiguously to adjacent lymph nodes
- NHL tends to involve multiple lymph node sites and spreads discontinuously
104
What are the characteristics of classical Hodgkin lymphoma?
Nodular sclerosing, mixed cellularity, lymphocyte rich/depleted
105
What are the two main types of Hodgkin lymphoma?
Classical Hodgkin lymphoma and lymphocyte predominant Hodgkin lymphoma
106
Which type of Hodgkin lymphoma has some relationship to Non-Hodgkin lymphoma?
Some relationship to non-Hodgkin lymphoma
107
What is the presentation of classical Hodgkin lymphoma?
Young and middle-aged, often involves just a single group of lymph nodes
108
Where does classical Hodgkin lymphoma arise from?
Arises from the germinal centre and post-germinal centre cells
109
Which type of Hodgkin lymphoma is associated with EBV?
Classical Hodgkin lymphoma, as nodular lymphocyte predominant Hodgkin lymphoma has NO association with EBV
110
What is the histopathology of classical Hodgkin lymphoma?
Sclerosis, mixed cell population with Reed-Sternberg/Hodgkin cells, lymphoma cells are relatively few in number and tend to be scattered around, eosinophils (see notes)
111
What is the prognosis of classical Hodgkin lymphoma?
Moderately aggressive
112
What are diagnostic markers for Hodgkin lymphoma?
CD30, CD15
113
What is the presentation of nodular lymphocyte predominant Hodgkin lymphoma?
Isolated lymphadenopathy
114
Where does nodular lymphocyte predominant Hodgkin lymphoma arise from?
Arise from germinal centre B cells (will stain positive for some germinal centre B cell markers)
115
Describe the histopathology of Nodular Lymphocyte Predominant Hodgkin Lymphoma
B cell rich nodules, scattered around L&H cells,
the reactive population in the background will just be small lymphocytes, you do NOT see eosinophils or macrophages like you would with classical Hodgkin.
116
What can nodular lymphocyte predominant Hodgkin lymphoma transform into?
Can transform to high grade B cell lymphoma (so it can transform into a non-Hodgkin lymphoma)
117
What are key markers of nodular lymphocyte predominant Hodgkin lymphoma?
NEGATIVE for CD30 + CD15 (which is seen in classical Hodgkin); POSITIVE for CD20
118
Lymphoma in practice: what three steps are involved in diagnosis and staging?
1. Histological diagnosis.
2. Anatomical stage (CT, MRI, PET scans, BM biopsy)
3. Prognostic factors (LDH, B2 microglobulin, albumin, kidney/BM function)
119
Lymphoma in practice: what two steps are involved in treatment and prognosis?
1. Prognosis
| 2. Correct therapy: curative or supportive/palliative
120
Who is Hodgkin lymphoma more common in and at what age?
More common in males, bimodal age incidence: 20-29 years, 60+ years
121
What are typical features of Hodgkin lymphoma?
Presents with painless enlarging lymph nodes. The nodes may cause obstructive signs and symptoms. Constitutional symptoms may be present (B symptoms: fever, night sweats, weight loss) and pruritus. Alcohol-induced pain is a classic but rare symptom.
122
What are constitutional symptoms of Hodgkin lymphoma?
B symptoms: fever, night sweats, weight loss
123
Describe staging in lymphoma
Stage I: one group of nodes. Stage II: >1 group of nodes same side of diaphragm. Stage III: nodes above and below the diaphragm. Stage IV: extra nodal spread. Suffix A if none of the following, B if any of the following: fever, unexplained weight loss > 10% in 6 months, night sweats
124
What is used to stage Hodgkin lymphoma?
FDG-PET/CT scan; consider biopsy of other sites (e.g. liver) if possibly infiltrated; REMEMBER: the diaphragm is key for staging.
125
How is Hodgkin disease treated?
ALL patients with Hodgkin lymphoma should receive chemotherapy (ABVD - 2-6 cycles depending on stage). Radiotherapy is also often given because Hodgkin lymphoma is highly responsive to radiotherapy. It can be given at the end of chemotherapy to target any remaining nodes that may have some lymphoma cells. PET CT will be done during the chemotherapy (after 2 cycles) to assess response to treatment and at the end of treatment to guide the need for radiotherapy. Combined modality is when radiotherapy and chemotherapy are used.
126
Which drugs are used in chemotherapy of Hodgkin lymphoma?
ABVD: adriamycin, bleomycin, vincristine and DTIC (dacarbazine). NOTE: this is given at 4-weekly intervals, 2-6 cycles depending on stage
127
ABVD is an effective treatment but does not preserve fertility - true or false?
False - ABVD is an effective treatment that preserves fertility
128
What are the long term consequences of ABVD?
Pulmonary fibrosis and cardiomyopathy
129
How does radiotherapy for Hodgkin disease work?
Modern practice involves irradiating very specific areas. It is highly uncommon for lymphoma to recur in the area that has been irradiated.
130
What are the risks of radiotherapy for Hodgkin disease?
There is a risk of damage to normal tissues (collateral damage). It is associated with an increased risk of breast cancer, leukaemia/ myelodysplastic syndromes, lung or skin cancer.
131
What could be done if a patient with Hodgkin disease presents years later with a relapse?
They may be treated with high-dose chemotherapy or an autologous stem cell transplant.
132
What is the prognosis of Hodgkin disease?
Older patients do NOT do quite as well. It is a highly curable disease. The prognosis depends on stage
133
What percentage of stage I and II Hodgkin disease patients are cured?
Over 80%
134
What percentage of stage IV Hodgkin disease patients are cured?
50% of stage IV are cured
135
What percentage will be long term survivors of Hodgkin lymphoma?
80%
136
What percentage of Hodgkin disease patients will die of a relapse within 10 years?
10%
137
What percentage of Hodgkin disease patients will die from long-term treatment complications after 10 years?
10%. KEY POINT: after around 5 years, patients are more likely to die of a secondary malignancy or cardiovascular complications.
138
What are the main treatment dilemmas in Hodgkin disease, in terms of reducing and intensifying therapy?
Reduce therapy: chemotherapy only -> reduce risk of secondary malignancy but increased HL relapse and 10% die of HL.
Intensify therapy: chemo/+radiotherapy -> decrease HL relapse but increased secondary malignancy of breast, skin and bone marrow, and 10% die of therapy complication
