Week 3 - Lymphomas and Myelomas Flashcards
Non-Hodgkin Lymphoma
Nodal disease of B- and T-cell origin
Genetic mechanism of carcinogenesis
- chromosomal translocations involving genes that regulate variety of cellular functions; with immunoglobulin genes
Outcome: aberrant expression of genes
Function of B Cells
- Make antibodies against antigens
- Perform the role of antigen-presenting cells (APC’s) themselves
- Develop into memory B cells after activation by antigen interaction
- Release a large variety of cytokines
What Normally Happens when an Antigen is Detected?
When a matching antigen is detected, with T-helper cell involvement:
1. Differentiates into plasma B cells & memory B cells directly -> Ab production
OR
2. Undergoes another differentiation step in the germinal center -> somatic hypermutation in the variable region of the Ig -> class switching -> Ab production
Somatic hypermutation = extremely high rate of mutation ≥10⁵ - 10⁶ times
Mistargeted somatic hypermutations is a likely mechanism in the development of B-cell lymphomas
Incidence of Myeloma
1% of all cancers
~10% of all haematological malignancies
Med age at diagnosis = 69 yrs
Almost all patients with myeloma, evolve from MGUS
- monoclonal gammopathy of undetermined significance
Medical Conditions Associated with an Increased Risk of Non-Hodgkins Lymphoma (NHL)
Inherited immune deficiencies Genetic syndromes Immune disorders Chemical exposure Viruses e.g. EBV, HIV, hepatitis
Clinical Presentation of Lymphomas
Lymphadenopathy (swelling of lymph nodes) Peripheral blood cytopenia Immune destruction or marrow replacement Solid tumor Abdominal mass Systemic B symptoms
Presentation of Follicular Lymphoma (FL), Diffuse Large B Cell Lymphoma (DLBCL) and Myeloma
FL - increase in localised nodes - extra nodal rare - 50% BM involvement DLBCL - localised nodes +- - 50% extra nodal, CNS risk - rarely in BM Myeloma - symptomatic: CRAB - calcium elevation, renal problems, anaemia, bone damage - BM involvement
Natural History of Lymphoma Subsets
Follicular - clinical history: indolent (slow) - symptomatic for: years DLBCL - clinical history: aggressive - symptomatic for: months Burkitts - clinical history: acute leukaemia life - symptomatic for: weeks Myeloma - clinical history: MGUS, smouldering myeloma - symptomatic for: ?
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Follicular Lymphoma
Originates follicular germinal centre
Cell of origin: centroblasts/centrocytes
- have somatic hypermutation of Ig HV genes & ongoing mutations
- therefore Ig heavy and light chain genes rearranged
Immunophenotype:
- CD5-, CD10+, CD19+, CD20+, CD22+, sIg +, BCL2+
Cytogenetics of Follicular Lymphoma
t(14;18)(q32;q21) IGH::BCL2 Promoter regions of IGH taking control of BCL2 and overexpressing it BCL2 has 2 breakpoint cluster regions: 1. MBR - major breakpoint region 2. MCR - minor cluster region
Genetic Mechanism Associated with Chromosomal Rearrangement - Follicular Lymphoma
Promoter region of IGH takes control of BCL2 and overexpresses it
BCL2 (chros 18) regulatory mitochondrial protein that inhibits/stops cell death from happening
Outcome of over expression: increase in proliferation, imbalance of cells, accumulation of neoplastic cells
Diffuse Large B-Cell Lymphoma
Originates germinal or post-germinal centre - mostly centroblasts
- large transformed B-cells harbouring somatic hypermutations of Ig HV genes & ongoing mutations, Ig heavy and light chain genes rearranged (ongoing mutations in some cases)
Immunophenotype:
CD5-, CD10±, CD19+, CD20+, sIg +, BCL2 ±, BCL6±
Cytogenetics of DLBCL
t(14;18)(q32;q21) IGH::BCL2 TP53 mutations - make up 20% t(3;V)(q27;V) IGH::BCL6 10 - make up 30% t(8;14)(q24;q32) IGH::MYC - make up 10% V = variable
Genetic Mechanism Associated with Chromosomal Rearrangement - DLBCL
Promoter regions of IGH take control of BCL2/BCL6 leading to overexpression
BCL2 (chros 18) regulatory protein that inhibits/stops cell death from happening
- overexpression of BCL2 results in increased proliferation
BCL6 (chros 3) regulatory protein that represses/inhibits germinal B-cell differentiation & inflammation
Overexpression of BCL6 results in inhibition of differentiation and increased proliferation
Myeloma
Originates post-germinal centre;
- myeloma plasma cells - somatic
- hypermutation of Ig HV genes, Ig heavy and light chain genes rearranged.
- BM based disease >10% clonal malignant plasma cells
97% of patients will have a monoclonal or M-protein in serum and/or urine, which could be:
Abs produced:
- heavy chains: IgG (50%), IgA (20%), IgD,E,M (<10%)
- light chains: kappa or lambda (aka Bence Jones proteins)
Immunophenotype
- CD79a+, CD138+, CD38+, CD19- , CD56+ usually
FISH Probes for Myeloma
Non-hyperdiploid group - locus specific indicator probes: TP53 deletions, Ip del/1q amp - breakapart probes: IGH Once IGH has been determined: - t(4:14) IGH:FGFR3 -t(14:16) IGH:MAF - t(11:14) IGH:CCND1 - all of these are dual colour dual fusion probes
Genetic Mechanism Associated with Chromosomal Rearrangement - CDKN2C
CDKN2C at 1p is important in the process of B cells undergoing a proliferative response as they pass through the germinal centre before going through plasma cell differentiation
It’s biological function is as a cyclin-dependent kinase inhibitor
Heterozygous and homozygous deletions exist
Genetic Mechanism Associated with Chromosomal Rearrangement - Overexpression of CKS1B
1q amplification
CKS1B binds to and activates cyclin-dependent kinases in the cell cycle
Overexpression -> increased cell growth and a poor prognosis in various cancers
Genetic Mechanism Associated with Chromosomal Rearrangement - Hyperdiploidy
Gene dosage effects
Outcome: various genes de-regulated and production of oncogenic proteins
Genetic Mechanism Associated with Chromosomal Rearrangement - t(14:16) IGH:MAF and t(4:14) IGH:FGFR3 Fusion
Juxtaposition of FGFR3 and/or MAF and the regulatory regions of the IGH gene results in control of FGFR3 and/or MAF by IGH and over expression of FGFR3 and/or MAF
FGFR3 (chros 4) codes for fibroblast growth factor receptor 3 protein (tyrosine kinase receptor) involved in cell regulation, differentiation and wound healing
MAF (chros 16) proto-oncogene encodes for transcription factor
Outcome of over expression:
- increased proliferation & decreased differentiation
- increased adhesion to stroma in IGH::MAF
Genetic Mechanism Associated with Chromosomal Rearrangement - t(11:14) IGH:CCND1
CCND1 promotes progression through the G1-S phase of the cell cycle and is dependent on other cyclin dependent kinases
Cytogenic Results and Prognosis Overview - FL, DLBCL and Myeloma
Follicular
- indolent, advanced stages predominate.
- t(14;18)IGH::BCL2 rearrangement mostly valuable for diagnosis
DLBCL
- usually aggressive
- complex karyotype (> 4 changes) confers a shorter survival
Myeloma
- ‘smouldering’ or advanced stages
- t(4;14), t(14;16), TP53 deletion, 1p deletions/1q amplifications - high risk
- the absence of high risk features and presence of hyperdiploidy 5, 9, 15 - std risk
Staging for FL, DLBCL and Myeloma
Follicular - Ann Arbour staging - Follicular Lymphoma International Prognostic Index (FLIPI) DLBCL - Ann Arbour staging - International Prognostic Index (IPI) Myeloma - revised international staging system for myeloma (R-ISS)
Ann Arbor Staging
Stages I to IV and A/B,E,X,S
Dependent on the site in the body where the malignancy is located and on the systemic symptoms of the patient
