Haem: Lymphoma MDT (Laz) Flashcards
Outline the difference in prevalence of Hodgkin’s lymphoma and Non-Hodgkin lymphoma.
- NHL = 80%
- Hodgkin = 20%
Outline the processes by which immunoglobulins and T cell receptors become capable of identifying a wide variety of antigens.
- The germline VDJ genes undergo recombination in the bone marrow to generate a wide repertoire of specificities.
- In germinal centres, a second stage of DNA alteration involving isotype switching and somatic hypermutation (point mutations) generates even more diversity.
Which proteins carry out VDJ recombination and somatic hypermutation
VDJ recombination: RAG1 and RAG2 combine to form RAG complex
SHM: activation induced cytidine deaminase
What is the main downside of the processes that generate variety in immunoglobulins and TCR during the adaptive immune response?
Recombination errors and new point mutations can occur
Lymphocytes are reliant on apoptosis to keep their massive proliferation under control (90% of lymphocytes die in the germinal centre)
- If a mutation turns off apoptosis, it can lead to malignancy or autoimmunity
Rapid proliferation within germinal centres - increased risk of DNA replication errors
Outline how chromosomal translocations in B cells can lead to malignancy.
- Immunoglobulin gene promoters in B cells are highly active because they are designed to produce loads of immunoglobulin
- If an error occurs and an oncogene is translocated downstream of the promoter, malignant genes can be expressed
List some oncogenes that are implicated in lymphoma/leukaemia.
- Bcl2
- Bcl6
- Cyclin D1
- c-Myc
List some risk factors that contribute to the aetiology of NHL.
- Constant antigenic stimulation
- Viral infection
- Loss of T cell function (immunosuppression)
List some examples of how constant antigenic stimulation can lead to lymphoma.
- H. pylori → gastric MALT - marginal zone NHL of the stomach
- Sjogren syndrome → marginal zone NHL of the parotid
- Coeliac disease → small bowel T cell lymphoma, enteropathy-associated T cell NHL
Give an example of how viral infections that can lead to lymphoma.
Direct viral integration: HTLV1
- HTLV1 infects T cells by vertical transmission
- Viral genome integrates into T cell genome and drives proliferation
- May cause adult T cell leukaemia/lymphoma (very aggressive)
Give an example of how loss of T cell function can lead to lymphoma
EBV infection and immunosuppression
- EBV established latent infection in B cells which is kept in check by cytotoxic T cell (kill EBV antigen-expressing B cells)
- Loss of T cell function (e.g. HIV, post-transplant immunosuppression) can lead to EBV-driven lymphoma
List some different types of tissues of the lymphoreticular system.
- Generative tissue: bone marrow and thymus (generates or matures lymphoid cells)
- Reactive tissue: lymph nodes and spleen (development of immune reaction)
- Acquired tissue: extra-nodal lymphoid tissue (e.g. skin, stomach, lung - responsible for developing a local immune response)
List the different cell types of the lymphoreticular system.
Lymphocytes
- B cells
- T cells
Accessory cells
- Antigen-presenting cells
- Macrophages
- Connective tissue cells
Describe the normal histological appearance of a lymph node.
Round areas full of B cells (B cell follicles)
- Mantle zone - a crescent-shaped region where naïve unstimulated B cells are found
- Germinal centre - where naïve B cells will eventually migrate, and mature B cells will end up in the medulla.
- Antigen presenting cells present antigens to B cells in germinal centre to activate them
Paracortical T cell zone - surrounds the B cell follicles
Describe the composition of T cell areas in lymph nodes.
- Consists of lots of T cells, antigen-presenting cells and high-endothelial venules
- This is the site where T cells bind to antigens and are selected/activated
What is the main technique used to identify different types of lymphocyte within a lymph node biopsy?
Immunohistochemistry
What are the main markers used for B and T cells?
T cell = CD3, CD5
B cell = CD20
Define lymphoma.
- Neoplastic proliferation of lymphoid cells forming discrete tissue masses
- They arise in and involve lymphoid tissues
Which factors are taken into account when classifying a lymphoma?
- Clinical
- Histological
- Immunohistochemical
- Molecular
Outline the WHO classification of lymphoma.
Hodgkin lymphoma
- Classical
- Lymphocyte predominant
- Abnormal B cells
Non-Hodgkin lymphoma
- B cell (MOST COMMON)
- Precursor B cell neoplasm
- Peripheral B cell neoplasm (low and high grade)
- T cell
- Precursor T cell neoplasm
- Peripheral T cell neoplasm
Why is non-Hodgkin lymphoma often disseminated at presentation?
Neoplastic lymphoid cells circulate in the blood leading to disseminated disease at presentation
NOTE: lymphoid neoplasms can disrupt normal immune functioning leading to immunodeficiencies
What are the diagnostic tools used by pathologists when investigating lymphoma?
- Cytology (from aspiration)
- Histology (architecture: nodular, diffuse; cells: small round, small cleaved, large)
- Immunohistochemistry
- Loss of normal surface proteins
- Expression of abnormal proteins (e.g. cyclin D1 an Mantle cell lymphoma)
- Light chain restriction
- Molecular tools
Which molecular tools are used when investigating lymphoma?
- FISH - identify chromosomal translocations
- PCR - identify chromosomal translocations transcripts (e.g. bcr-abl transcript in CML)
Give an example of a chromosomal translocation that is diagnostic of lymphoma.
11;14 = Mantle Cell Lymphoma
Give an example of a chromosomal translocation that is prognostic in lymphoma.
2;5 = anaplastic large cell lymphoma
List some types of low grade lymphoma.
- Follicular lymphoma
- Small lymphocytic lymphoma (CLL)
- Marginal zone lymphoma
Name 3 types of high grade lymphoma.
- Diffuse large B cell lymphoma
- Burkitt’s lymphoma
- Mantle cell lymphoma
How does follicular lymphoma typically present?
Lymphadenopathy in middle-aged or elderly patients
NOTE: it is usually indolent but can transform into a high-grade lymphoma
Describe the histological features of follilcular lymphoma.
- Follicular pattern - the follicles are neoplastic and spread from the node into adjacent tissues
- Cells have a germinal centre cell origin (positive staining for CD10 and Bcl2)
Which molecular feature is associated with follicular lymphoma?
14;18 translocation involving Bcl2 gene
Describe the typical presentation of small lymphocytic lymphoma.
Lymphadenopathy or high blood lymphocyte count in middle-aged or elderly patients
Outline the histological features of small lymphocyte lymphoma.
- Small lymphocytes
- Arise from naïve B cells or post-germinal centre memory B cells
- Cells are CD5 and CD23 positivie
- They replace the entire lymph node so that you can no longer identify follicles or T cell areas
What is the term used to describe the transformation of small lymphocytic lymphoma into a higher grade lymphoma/leukaemia?
Richter transformation
What is marginal zone lymphoma?
- Arise mainly in extra-nodal sites (e.g. gut, spleen)
- Thought to arise due to chronic antigenic stimulation
- Arise from post-germinal centre memory B cells
- Low-grade disease can be treated by non-chemotherapeutic methods (e.g. H. pylori eradication)
Outline the typical presentation of mantle cell lymphoma.
- Typically affects middle-aged males
- Affects lymph nodes and the GI tract (diarrhoea, abdominal pain)
- Often present with disseminated disease
NOTE: median survival = 3-5 years
Outline the key histological features of mantle cell lymphoma.
- Located in the mantle zone of the lymph node
- Arise from pre-germinal centre cells
- Show aberrant expression of cyclin D1 and CD5
- ‘anglular / clefted nuclei’
Which molecular features are characteristic of mantle cell lymphoma?
- 11;14 translocation
- Cyclin D1 overexpression
Outline the typical presentation of Burkitt’s lymphoma.
- Jaw or abdominal mass in children and young adults
- Associated with EBV
NOTE: this is very agressive
Outline the histological features of Burkitt’s lymphoma.
- Arises from germinal centre cells
- Starry sky appearance
Which molecular feature is associated with Burkitt’s lymphoma.
- c-Myc translocation (8;14, 2;8 or 8;22)
Outline the typical presentation of diffuse large B cell lymphoma.
Middle-aged and elderly patients with lymphadenopathy
Outline the histological features of diffuse large B cell lymphoma.
- Arise from germinal centre or pre-germinal centre B cells
- Large lymphoid cells
- Lymph node is effaced so follicles and germinal centres cannot be identified
List some prognostic association of diffuse large B cell lymphoma.
Good prognosis - germinal centre phenotype
Poor prognosis - p53-positive and high proliferation fraction
Outline the typical presentation of T cell lymphomas.
Middle-aged and elderly patients with lymphadenopathy
NOTE: these are aggressive
Outline some key histological features of T cell lymphomas.
- Large T lymphocytes
- Associated reactive cell population (especially eosinophils)
List some types of T cell lymphoma and their associations.
- Adult T cell leukaemia/lymphoma - HTLV1
- Enteropathy-associated T cell lymphoma - Coeliac disease
- Cutaneous T cell lymphoma (mycosis fungoides)
- Anaplastic large cell lymphoma
Outline the typical presentation of anaplastic large cell lymphoma.
Children and young adults with lymphadenopathy
NOTE: this is aggressive
Outline the key histological features of anaplastic large cell lymphoma.
- Large epithelioid lymphocytes
- T cell or null phenotype (anaplastic)
Which molecular features are associated with anaplastic large cell lymphoma?
- 2;5 translocation
- Alk-1 protein expression - BETTER prognosis
List some key differences between Hodgkin and Non-Hodgkin Lymphoma.
- Hodgkin is more localised (usually one nodal site)
- Hodgkin spreads contiguously to adjacent to adjacent lymph nodes
NOTE: NHL tends to involve multiple lymph node sites and spread discontinuously
Outline the typical presentation of classical Hodgkin lymphoma.
- Young and middle-aged patients with only a single group of lymph nodes involved
- Associated with EBV
Name 3 subtypes of classical Hodgkin’s lymphoma
- Nodular sclerosing
- Mixed cellularity
- Lymphocyte rich and lymphocyte depleted
Which type of Hodgkin’s lymphoma is related to NHL
Lymphocyte predominant Hodgkins
What is the difference between a Hodgkin cell and a Reed-Sternberg cells
Hodgkin cell: mononucleated abnormal lymphocyte
Reed-Sternberg cell: bi- or multinucleated abnormal lymphocyte
Outline some histological features of classical Hodgkin lymphoma.
- Nodular sclerosis
- Mixed cell population of Reed-Sternberg cells and Hodgkin cells
- Lymphoma cells are few in number and are scattered around
- Eosinophils present
- Arise from germinal centre or post-germinal centre cells
What are the diagnostic markers for classic Hodgkin lymphoma?
- CD15
- CD30
(CD20 negative)
Describe the typical presentation of nodular lymphocyte predominant Hodgkin lymphoma.
- Isolated lymphadenopathy
- NO association with EBV
Outline the key histological features of lymphocyte predominant Hodgkin lymphoma.
- B cell rich nodules with scattered around L&H cells
- Arise from germinal centres
- Reactive population in the background consisting of small lymphocytes
- NO eosinophils and macrophages
Which markers are key in the diagnosis of lymphocyte predominant Hodgkin lymphoma?
- Positive = CD20
- Negative = CD15, CD30 (unlike classical Hodgkin lymphoma)
What constitutional symptoms may be present in a patient with lymphoma?
B symptoms - fever, night sweats, weight loss
Pruritis
What are the stages of lymphoma?
1 = 1 group of nodes
2 = > 1 group of nodes on the same side of the diaphragm
3 = > 1 group of nodes above and below the diaphragm
4 = extranodal spread
Suffic ‘B’ if B symptoms are present
Which type of scan is often used to stage lymphoma?
FDG-PET/CT
Which treatment modalities are used in Hodgkin lymphoma?
- All patients receive chemotherapy
- Radiotherapy is often used because Hodgkin lymphoma is very responsive
- Referred to as ‘combined modality’ if both are used
Which chemotherapy regimen is usually used for Hodgkin lymphoma?
ABVD: Adriamycin, Bleomycin, Vinblastine, Dacarbazine
NOTE: this is usually given at 4-weekly intervals for 2-6 cycles
What are some possible long-term consequences of chemotherapy for Hodgkin lymphoma?
Pulmonary fibrosis
Cardiomyopathy
How might a relapse of Hodgkin lymphoma be treated?
High-dose chemotherapy with autologous stem cell transplant
NOTE: intensifying chemotherapy will lead to an increased cure rate but it will also lead to an increase in secondary cancers
Describe the curability of Hodgkin lymphoma.
Stage I and II: >80%
Stage IV: 50%
