20. Intro to Lymphoid Malignancies Flashcards
What is the difference between a lymphoma and leukaemia?
- Lymphoma – cancer in the lymph/ nodes etc. ~ ‘lump’
- Leukaemia – cancer in the blood/bone marrow
Describe the lymphocyte development in the bone marrow.
- Haematopoietic stem cell (HSC) -> common myeloid progenitor (CMP) ~ neutrophils, red cells, platelets etc.
- HSC -> Common lymphoid progenitor (CLP) -> T-cell precursors (Pre-T)
- HSC-> CLP -> B-cell precursors (Pre-B) -> immature B-cell
- From Pre-B to Imm-B = immunoglobulin gene rearrangement
For the following conditions, list the corresponding normal cells:
- Acute lymphoblastic leukaemia (ALL)
- T-ALL
- Lymphoma
- T-cell lymphoma
- Chronic lymphocytic leukaemia (CLL)
- Myeloma
- ALL: B-cell precursos in the bone marrow
- T-ALL: T-cell precursors in teh bone marrow or thymus
- Lymphoma: B-cells in secondary lymphoid organs
- T-cell lymphoma: T-cells in the secondary lymphoid organs.
- CLL: Mature circulating B-cells
- Myeloma: Ig-secreing plasma cells in the bone marrow
Describe the presentation and epidemiology of ALL
Presentation
- Usually non-specific symptoms of bone marrow suppression
- Symptoms of organ infiltration more often in advanced disease
Epidemiology
- Commonest leukaemia in children <10yo
- But majority of patients >40 yo
What are some different ways to investigate and diagnose ALL?
- Bone marrow morphology
- Infiltration by undifferentiated blast cells
- Immunophenotyping
- B-cell surface markers (or T markers for T-ALL)
- Light chain restriction
- TdT positive
- At the join some nucleotides randomly removed by exonuclease
- Some nucleotides randomly added by terminal deoxynucleotidyl transferase (TdT)
- Cytogenetics
What is treatment of ALL?
Chemotherapy
- Induction
- Intensification
- CNS directed chemotherapy
- Maintenance
- (Radiotherapy to CNS)
What is the prognosis of ALL?
Children >90% cure
Adults much lower survival, because
- Different cell of origin
- Different oncogene mutations
- Older patients do not tolerate intensive treatment
Describe the presentation and epidemiology of Hogkin’s lymphoma.
Presentation- enlarged lymph node(s)
Epidemiology-
- Peak incidence in young adults
- Possible association with Epstein Barr Virus (EBV) aka Human Herpes Virus 4 (HHV4)
Describe the histopathology of Hogkin’s lymphoma.
- It is a clonal B-cell malignancy that develops within the lymphatic system.
- The malignant Reed-Sternberg cell typically has a bi-lobed nucleus that gives an owl’s eyes appearance.
- You would diagnose it via an excisional lymph node biopsy.
- It spread in an orderly fashion to adjacent nodes
Describe the treatment and prognosis of Hodgkin’s lymphoma.
Treatment-
- Chemotherapy +/- radiotherapy
Prognosis
- 5 year survival ~50-90% depending on age, stage and histology
- Especially good results in young adults
Describe non-hodgkin’s lymphomas.
• Can be divided into 4 categories
- Low grade
- High grade
- T-cell lymphomas
- EBV (HHV4) driven lymphomas in immunosuppressed patients
What is the relation between chromosome translocations and lymphomas?
- Many lymphomas carry chromosome translocations involving the Ig heavy chain or light chain loci
- Ig genes are highly expressed in B-cells
- Each Ig gene has a powerful tissue specific enhancer near to the constant (C) segment
- In lymphomas, we get these translocations (as expected) but they don’t happen as they should,
What is the most common chromosomes translocation in lymphomas?
Most cases of follicular lymphoma carry t(14;18)(q32;q31).
This juxtaposes the BCL-2 gene on chromosome 18 with the IgH locus on chromosome 14.
This causes the overexpression of the BCL-2 protein.
BCL-2 is an apoptosis inhibitor
What is another chromosome translocation that high-grade lymphomas can carry?
Some cases of high grade lymphoma carry t(18;14)(q24;q32).
This juxtaposes the MYC gene on chromosome 18 with the IgH locus on chromosome 14.
MYC is a powerful oncogene.
We can also get MYC of BCL-2 translocations to one of the Ig light chain loci
Describe the presentation and histology of a low grade non-Hogkin’s lymphoma (NHL)
Presentation- enlarged lymph node(s)
Histology
- Normal tissue architecture partially preserved
- Normal cell of origin recognisable
How would you diagnose low grade NHL?
- Histology
- Immunocytochemistry
- Cytogenetics
- Light chain restriction
- PCR:
- For clonal Ig gene rearrangement
- For chromosome translocations e.g. t(14;18) Ig : Bcl-2
Describe the treatment and prognosis of low grade NHL
Treatment- - Chemotherapy - Glucocorticoids (e.g. prednisolone) - Radiotherapy - Monoclonal Ab therapy Rituximab (anti-CD20)
Prognosis
- Relatively indolent (slowly growing)
- Respond well to therapy
- But hard to cure
Describe the presentation and histology of high grade NHL.
Presentation- enlarged lymph node(s)
Histology
- Loss of normal tissue architecture
- Normal cell of origin hard to determine
How would you diagonse high grade NHL?
(similar to low grade) •Histology •Immunocytochemistry •Cytogenetics •Light chain restriction • PCR - For clonal Ig gene rearrangement - For chromosome translocations
How would you treat high grade NHL?
- Chemotherapy
- Glucocorticoids
- Radiotherapy
- Monoclonal Ab therapy
- Rituximab- anti CD20
What is the prognosis of high grade NHL?
- Variable depending on type, stage and other factors
- Overall long term survival ~65%
Describe T-cell lymphomas
- Rare
- Usually CD4 cells
- Often present with skin infiltration e.g. Sezary syndrome and Mycosis Fungoides
Describe acute T-cell leukaemia/lymphoma
- Found in Japan, Caribbean and UK citizens of Caribbean origin
- Associated with retrovirus HTLV-1 (human T-cell leukaemia/lymphoma virus 1) infection
Describe EBV driven lymphomas
•Epstein Barr Virus
•EBV or Human Herpes Virus 4 (HHV4) directly transforms B-lymphocytes in culture
Due to viral oncogene LMP-1
- Over half of all normal individuals carry latent EBV infection
- Do not develop lymphomas due to effective immune surveillance by cytotoxic T-cells
•However, in highly immunosuppressed individuals:
- the endogenous latent EBV may transform B-cells
- No longer eliminated by cytotoxic T-cells
- Develop high grade lymphoma
Who typically gets EBV driven lymphomas?
•Transplant patients on cyclosporine
- Lymphoma usually regresses on withdrawal of immunosuppression
- But patient may lose the graft
•AIDS patients
- Lymphoma may regress on successful HAART (highly active antiretroviral therapy)
Describe the presentation of chronic lymphocytic leukaemia (CLL)
•Most often as incidental finding on fbc
•Persistent infection(s)
- due to immunosuppression
- Low IgG, suppression of normal •B cells
•Lymph node enlargement
•Symptoms of bone marrow suppression
Describe the epidemiology and diagnosis of CLL
Epidemiology
•85% of cases >50yo
Diagnosis •FBC: Lymphocytosis •Immunophenotyping - Cell surface markers - Light chain restriction •Cytogenetics
Describe the three aspects of myeloma that give rise to its different clinical features.
1) Suppression of normal bone marrow, blood cell and immune cell function
2) Bone resorption and release of calcium
3) Pathological effects of the paraprotein –(single monoclonal Ig in the serum- high levels – malignancy))
Describe blood cell/immune suppression in myelomas
- Anaemia
- Recurrent infections
- Bleeding tendency
Describe bone resorption in myelomas
- Myeloma cells produce cytokines (esp. IL-6)
- Which stimulate bone marrow stromal cells to release the cytokine RANKL
- Which activates osteoclasts
• Leads:
- Lytic lesions of bone
- Bone pain
- Fractures
•Calcium released from bone causes hypercalcaemia ~ Multiple symptoms including mental disturbance
Describe the effects of paraprotein in myelomas
- Precipitates in kidney tubules cause renal failure
- Deposited as amyloid in many tissues
•2% of cases develop hyperviscosity syndrome
- Increased viscosity of blood leading to
- Stroke
- Heart failure
How would you diagnose myeloma?
•Serum electrophoresis for paraprotein
•Urine electrophoresis
-Bence-Jones protein represents free monoclonal light chains
•Increased plasma cells in bone marrow
•ESR (very high due to rouleaux formation)
• Radiological investigation of skeleton for lytic lesions
Describe the treatment of myelomas
•Chemotherapy (not curative)
- Cytotoxic drugs
- Glucocorticoids
- Thalidomide analogues
- Bortezomib
• Allogeneic bone marrow transplant
- Only available for a small number of younger patients (<45yo, not too ill)
- Need to find an HLA (MHC) matched donor
- But potentially curative
Describe the Ig gene PCR electrophoresis.
- Normally would get a smear because so much variation in the B-cells and so you will not have a single band produced.
- If clonal B-cell = fixed band. ~ Position of the band will tell you the type of translocation that has occurred
