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
