Intro to lymphoid malignancies Flashcards
What is ALL? What is it characterised by? What is the corresponding normal cell?
Acute lymphoblastic leukaemia
- Infiltration of blood and bone marrow
- B-cell precursors in the bone marrow
- T-ALL is T-cell precursors
What is CLL? What is it characterised by? What is the corresponding normal cell?
Chronic lymphocytic leukaemia
- Infiltration of blood and bone marrow
- Mature circulating B cells
What are lymphomas? What is it characterised by? What is the corresponding normal cell?
- Tumours of lymph nodes and other secondary lymphoid organs
- B cells in secondary lymphoid organs
- T-cell lymphoma = T cells in secondary lymphoid)
What is myeloma? What is it characterised by? What is the corresponding normal cell?
- Foci of malignant cells in the bone marrow
- Ig secreting plasma cells in the bone marrow
What are the two pathways that can be taken from HSCs?
- Common myeloid progenitor -> neutrophils, red cells, platelets etc
- Common lymphoid progenitor -> Pre-T and Pre-B
Where are lymphocytes produced?
- All lymphocytes start in the bone marrow
- Pre-T cells then go to the thymus where they mature and undergo TCR gene rearrangement. They then go to the secondary lymphoid organs
- Pre-B cells stay in the bone marrow longer, here they can undergo Ig gene rearrangement. When they are mature, they go to the secondary lymphoid organs
- in the lymph nodes, you have follicles with resting lymphocytes and germinal centres with proliferating ones
What are secondary lymphoid organs?
- Lymph nodes
- Spleen
- Peyers patches
What is light chain restriction?
- Normal B cells have Ig with heavy and light chains
- The light chains are either kappa or lambda
- Because malignancies are clonal disease, if a cell with lambda light chains becomes malignant, all the descendants will also be lambda
How does ALL present?
- Usually non-specific symptoms of bone marrow suppression
- Will get symptoms of organ filtration in advanced disease
What is the epidemiology of ALL?
- Commonest leukaemia in children under 10
- Majority of patients are over 40
How do we investigate and diagnose ALL?
- Bone marrow morphology - infiltration by undifferentiated blasts
- Immunophenotyping - B-cell surface markers (T for T-ALL); light chain restriction; TdT (terminal deoxynucleotidyl transferase) positive
- Cytogenetics - look at flow cytometry
How do we treat ALL?
- Chemotherapy - induction, intensification, CNS directed chemo, maintenance
What is the prognosis for ALL?
- Children - cure more than 90%
- Adults - much lower survival because of different cell of origin, different oncogene mutations and older patients dont tolerate intensive treatment
What is Hodgkin’s lymphoma?
- Enlarged lymph nodes from accumulation of lymphocytes
- Presence of large Reed-Sternberg cells - malignant B-cells
- Typically 99% of cells are reactive non-malignant cells
- Peak incidence in young adults and possibly associated with EBV
- treated with chemo/radiotherapy
- 5 year survival ~50-90% dependent on age, stage and histology
What are the different types of NHL?
- Low grade
- High grade
- T-cell lymphoma
- EBV driven lymphoma in immunosuppressed patientss
What happens when there are chromosomal translocations in lymphoma?
- Each Ig gene has a powerful tissue specific enhancer near to the constant segment
- They activate the promoter of the rearranged V segment
- If a chromosome translocation brings another gene close to the Ig enhancee, it will increase the expression of the gene
- So if it gets closer to the BCL-2 gene, there will be increased production of BCL-2 (which inhibits apoptosis)
- So follicular lymphoma is caused by cells failing to die rather than increased proliferation
What happens in some cases of high grade lymphoma?
- Some cases carry t(8:14)(q24;32)
- This brings together the myc gene on chr18 with the IgH locus on chr14
- Myc is a powerful oncogene - so cell has fast replication of cells, which also fail to die
How does low grade NHL present?
- enlarged lymph nodes
- Normal tissue architecture partially preserved
- Normal cell of origin recognisable
How do we diagnose low grade NHL?
- Histology
- Immunocytochemistry - take a section of the tumour, stain it, see that kappa cells stain - shows clonal and malignant
- Cytogenetics
- Light chain restriction
- PCR
How do we use PCR to look at NHL?
- Look at the Ig genes
- Do PCR between the V and J regions - gives different sized bands
- Would usually see a smear do to the polyclonal response
- However if it is malignant and clonal, there will be separate bands
How do we treat low grade NHL?
- Chemo
- Glucocorticoids - can induce death of lymphocytes
- Radiotherapy
- MoAb therapy - rituximab (anti-CD20)
What is the prognosis for low grade NHL?
- Doesnt proliferate much
- Responds well to therapy
- But hard to cure
What is different about high grade NHL?
- Low grade - relatively normal cells
- High grade - undifferentiated, abnormal cells
What is the main risk factor for acute t-cell leukaemia/ lymphoma?
- Infection with retrovirus HTLV-1
human T-cell leukaemia/lymphoma virus 1
How does EBV cause lymphomas?
- EBV (HHV4) directly transforms B-lymphocytes in culture
- This is caused by the viral oncogene LMP-1
- Over half of all normal indivuiduals carry latent EBV, but dont develop lymphomas due to immune surveillance by CTLs
- So causes lymphoma in highly immunosuppressed individuals
What is paraproteinaemia?
- Presence of a single monoclonal Ig in the serum
- If you take plasma, allow it to clot to get serum, and then run electrophoresis, you will see a series of bands
- Bands will be albumin, alpha globulins, beta globulins and then a fuzzy band of gamma globulins
- Usually it would be a faint blur of gamma globulins (polyclonal)
- In malignancies, it will show a dark, thick bands as the clonal cells will produce a single type of Ig
What is the most common disease that you find paraprotein?
Multiple myeloma
What three aspects of myeloma give rise to different clinical features?
- Suppression of normal bone marrow, blood cells and immune cell function
- Bone resorption and release of calcium
- Pathological effects of the paraprotein
What does the blood cell/ immune suppression cause?
- Anaemia
- Recurrent infections
- Bleeding tendency
What causes the bone resorption?
- Myeloma produces cytokines - especially IL-6
- These stimulate bone marrow stromal cells to release RANKL
- This activates osteoclasts, causing lytic lesions of bone, bone pain, and fractures
- The calcium released from the bone causes hypercalcaemia -> mental disturbance
What is the effect of the paraprotein?
- Precipitates in the kidney tubules and causes renal failure
- Deposited as amyloid in many tissues
- 2% of cases develop hyperviscosity syndrome leading to stroke and heart failure
How do we diagnose MM?
- Serum electrophoresis for paraprotein
- urine electrophoresis - Bence-Jones protein represents free monoclonal light chains
- Increased plasma cells in the bone marrow
- ESR (very high due to rouleaux formation) - RBCs stack together due to high protein
- Radiological investigation of skeleton for lytic lesions
How do we treat myeloma?
- Chemo - cytotoxic drugs, glucocorticoids, thalidomide analogues, Bortezomib
- Allogenic bone marrow transplant
