Haem: Lymphoma Flashcards
Lymphoma vs Leukaemia
Lymphoma –> usually originates in lymph nodes or the spleen and spreads through the lymphatic system - hence malignant blood cells are predominantely found in the lymph nodes.
Leukaemia –> tends to originate in bone marrow resulting in bone marrow infiltration and malignant cells spread through blood stream
This distinction is seen in early stages - at later stages of both cancers, malignant cell location becomes less distinctive.
Define lymphoma
Neoplastic tumour of lymphoid cells that arise in and involve lymphoid tissues. Malignant cells are usually found in:
- Lymph nodes and lymphatic system
- Lymphoid organs (spleen, gut-assocaited lymphoid tissue, bone marrow)
- Skin (often T cell disease)
Malignant lymphoid cells are rarely found elsewhere CNS, Ocular, testes, breast etc
Types of lymphoid malignancies
Acute lymphoblastic leukaemia (ALL)
Non-Hodgkin Lymphoma (B-cell lineage)
Non-Hodgkin Lymphoma (T-cell lineage)
Hodgkin Lymphoma
Differentiate between Hodgkin’s and Non-Hodgkin’s Lymphoma
If there is a presence of Reed Sternberg cells (abnormal form of a B lymphocyte) = Hodgkin’s Lymphoma
Hodgkins lymphoma tends to only affect one or two lymph node groups.
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.
What is the main downside of the processes that generate variety in immunoglobulins and TCR?
- Recombination errors and new point mutations can occur resulting in predisposition to malignancies
- 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
- There is rapid cell proliferation in germianl centres which increase risk of replication errors
Outline how chromosomal translocations in B cells can lead to malignancy.
a
List some oncogenes that are implicated in lymphoma/leukaemia.
- Bcl2
- Bcl6
- Cyclin D1
- c-Myc
These are anti-apoptotic or proliferative.
List some risk factors that contribute to the aetiology of lymphoma.
- Constant antigenic stimulation
- Infections
- Loss of T cell function
List some examples of how constant antigenic stimulation can lead to lymphoma.
- H. pylori → gastric MALT marginal zone B-cell NHL of the stomach
- Sjogren syndrome → marginal zone B-cell NHL of the parotid
- Coeliac disease → small bowel T cell lymphoma, enteropathy-associated T cell NHL
List two examples of viral infections that can lead to lymphoma.
Direct viral integration: HTLV1
- HTLV1 infects T cells by vertical transmission
- May cause adult T cell leukaemia/lymphoma (very aggressive)
- Caused by viral genome integrating into T cell genome and driving proliferation
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 (express surface Ig + Ab production)
* T cells (surface TCR, regulate B cells, Cytotoxic)
Accessory cells
* Antigen-presenting cells
* Macrophages
* Connective tissue cells
Describe the normal histological appearance of a lymph node.
- These are rounded areas full of B cells (B cell follicles)
- The mantle zone is a crescent-shaped region where naïve unstimulated B cells are found
- These naïve B cells will eventually migrate into the germinal centre, and mature B cells will end up in the medulla (middle of rounded follicles)
- T cells are found in T cell areas surrounding 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 = CD19, CD20
Which factors are taken into account when classifying a lymphoma?
- Clinical
- Histological
- Immunohistochemical
- Molecular
What constitutional symptoms may be present in a patient with lymphoma?
Painless enlargement of lymph nodes
B symptoms - fever, night sweats, weight loss
Pruritis
Outline the WHO classification of lymphoma.
Hodgkin lymphoma
- Classical
- Lymphocyte predominant
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. Hodgkins lymphoma is an exception because it tends to only affect one or two lymph node groups.
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 (identify proteins on/in cells - i.e. determine cell lineage)
* cell types (CD markers)
* Cell distribution
* Loss of normal surface proteins
* Expression of abnormal proteins (e.g. cyclin D1 indicative of Mantle cell lymphoma)
Cytogenetics
* FISH - identify chromosome translocations
* PCR - identify chromosome translocations, cloncal T cell receptor or Ig gene rearrangement
Which molecular tools are used when investigating lymphoma?
- FISH - identify chromosomal translocations
- PCR - identify chromosomal translocations, clonal T cell receptor of Ig gene rearrangement
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
Which type of scan is often used to stage lymphoma?
FDG-PET/CT
Key differences between HL and NHL
- Hodgkin is more localised (usually one nodal site)
- Hodgkin spreads contiguously to adjacent to adjacent lymph nodes while NHL tends to involve multiple lymph node sites and spread continuously
List the different types of HL
Classical HL:
- Nodular sclerosing (commonest)
- Mixed cellularity
Lymphocyte predominant
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
Outline some histological features of classical Hodgkin lymphoma.
- Nodular sclerosis
- Mixed cell population of Reed-Sternberg cells
- Lymphoma cells are few in number and are scattered around
- Eosinophils
- Arise from germinal centre or post-germinal centre cells
What are the diagnostic markers for Hodgkin lymphoma?
- CD15
- CD30
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.
Arise from germinal centre B cells (will stain positive for some germinal centre B cell markers)
- B cell rich nodules
- Scattered around L&H cells (popcorn cells)
- Reactive population in the background consisting of small lymphocytes
- NO eosinophils and macrophages (unlike Classical HL)
Which markers are key in the diagnosis of lymphocyte predominant Hodgkin lymphoma?
- Positive = CD20
- Negative = CD15, CD30 (unlike classical Hodgkin lymphoma)
Staging system for HL
Ann-Arbor Staging
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
Utilises FDG-PET / CT Scan for staging
Which treatment modalities are used in Hodgkin lymphoma?
- All patients receive chemotherapy
- Radiotherapy is often used after chemotherapy because Hodgkin lymphoma is very responsive to radiotherapy to clear up remaining cells
- Referred to as ‘combined modality’ if both are used
Which chemotherapy regimen is usually used for Hodgkin lymphoma?
ABVD: Adriamycin, Bleomycin, Vincristine, 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
Outline the treatment steps in HL
- Chemotherapy (ABVD)
- PET-CT to assess need for radiotherapy (irradiate very specific areas - highly uncommon to recur in area that has been irradiated)
What is a risk of radiotherapy for Hodgkin lymphoma?
Collateral damage to surrounding tissues
Increased risk of breast/lung/skin cancer, leukaemia/myelodysplasia
How might a relapse of Hodgkin lymphoma be treated?
- High-dose chemotherapy
- 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.
- Elderly patients do worse than the worst-prognosis of HL (lymphocyte depleted)
- It is a highly curable disease but prognosis depends on stage:
- 80% cured if Stage I or II
- 50% cured if Stage IV - 80% will be long-term survivors
- 10% will die from relapse within 10 years
- 10% will die from long term treatment complications after 10 years
Presentation of NHL
Painless lymphadenopathy
Compression symptoms from lymphadenopathy
B Symptoms - (fevers, night-sweats, weight loss)
Prognosis of NHL
Depends on type of NHL
Outline the basic management for NHL
1) Stage disease by WHO Classification:
- CT scan
- Bone marrow biopsy
- PET Scan
- Lumbar puncture (if risk of CNS involvement)
2) Prognostic markers and important tests:
- Prognosis (LDH - marker of cell turnover)
- Viral infections (HIV serology, HBV serology)
3) Plan therapy options (depending on type, etc)
What is the WHO Classification of NHL
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 Bcl6)
Which molecular feature is associated with follicular lymphoma?
14;18 translocation involving Bcl2 gene (Bcl2 = anti-apoptotic protein)
Median survival for follicular NHL
Incurable - median survival 12-15 years
Requires 2-3 chemotherapy schedules over this period
Treatment options for Follicular NHL
At presentation = watch and wait and only treat if clinically indicated (e.g. compression due to nodes in bowel, vena cava, ureter etc or massive painful nodes or recurrent infections)
Treatment = Combination immuno-therapy (R-CVP)
Describe the typical presentation of small lymphocytic lymphoma (CLL).
Lymphadenopathy or high blood lymphocyte count in middle-aged or elderly patients - indolent therefore only picked up incidentally in routine blood test.
Involves the proliferation of mature B cells
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 positive (normal mature B cells = CD19 +ve but CD5 -ve - vice versa for mature T cells)
- They replace the entire lymph node so that you can no longer identify follicles or T cell areas
Typical laboratory findings for Small lymphocytic Lymphoma (CLL)
Lymphocytosis (5-300x10^9/L)
Smear cells
Normocytic Normochromic Anaemia
Thrombocytopaenia
Bone marrow lymphocytic replacement of normal marrow elements
Prognostic factors for small lymphocytic lymphoma (CLL)
- Patients with unmutated VH (remember –> VH = variable heavy chain - the part that undergoes somatic hypermutation by VDJ recombination) - meaning malginant cells are arising from pre-germinal (as post-germinal cells are mutated) cells have worse prognosis
- Certain chromosomal abnormalities (screened for in FISH panel done for most lymphoma patients) (worse is deletion of 17p –> resulting in loss of p53 tumour suppressor gene)
What is the term used to describe the transformation of small lymphocytic lymphoma into a higher grade lymphoma/leukaemia?
Richter transformation
Clinical complications of patients with CLL
Treatment for patients with CLL
- Supportive (vaccination but no live vaccines, anti-infective prophylaxis)
- Leukaemia directed treatment (always tailored to patient’s demographics and disease status - indicative to treat in cacses of bone marrow failure, or progressive lymphocytosis, progression of systemic B symptoms)
- First line = chemotherapy
What is marginal zone lymphoma?
- A marginal zone NHL involving extra-nodal lymphoid tissue (e.g. MALT in gut or spleen).
- Thought to arise due to chronic antigenic stimulation:
- Sjogren’s syndrome —> parotid MZL
- H. pylori ——-> gastric MALToma
- Hashimotos –> thyroid MZL
- Psittaci infectin –> lacrimal gland MZL - Arise from post-germinal centre memory B cells
- Low-grade disease can be treated by non-chemotherapeutic methods (e.g. H. pylori eradication results in remission of 75% of patients )
Features seen in patients with Marginal Zone Lymphoma
- Median age: 55-60
- Most commonly arise in stomach –> epigastric pain, ulceration, bleeding
- B symptoms are uncommon
- Treatment of h.pylori —> remission in 75% of cases
Outline the typical presentation of mantle cell lymphoma.
- Typically affects middle-aged males
- Affects lymph nodes and the GI tract
- 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
Which molecular features are characteristic of mantle cell lymphoma?
- 11;14 translocation
- Cyclin D1 overexpression
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 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 T cell lymphomas.
Middle-aged and elderly patients with lymphadenopathy and extra nodal sites
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
