lymphoma 1 Flashcards
definition of lymphoma
a neoplastic (malignant) tumour of lymphoid cells.
where are lymphomas usually found
lymph nodes, bone marrow and/or blood (the lymphatic system)
lymphoid organs; spleen or the gut-associated lymphoid tissue
Skin (often T cell disease)
Rarely “anywhere” (breast kidney){*Immune privilege sites CNS, occular, testes} ie sanctuary sites
incidence of lymphoma
10,000 new cases a year in the UK
Non-Hodgkin’s Lymphomas 80%
Hodgkin Lymphoma 20%
what are the lymphoid malignancies
Precursor malignancies (bone marrow pre-germinal centre) - B or T cell lineage
Mature B cell malignancies - Non Hodgkin Lymphoma Or Hodgkin Lymphoma
Mature T cell malignancies T cell or NK cell Non Hodgkin Lymphoma
what are the lymphoma risk factors
most are sporadic
some specific RFs:
* immune disorders acquired or iatrogenic
* Associated specific infections or inflammation
why is the immune system at risk of ca
to have adaptive immune system - need limited DNA instability
Immunoglobulin (Ig) and T cell receptor genes (TCR):
1) cut and recombined (VDJ)
2) subjected to deliberate DNA mutagenesis (somatic hypermutation)
-> Ig and TCR diversity and Ig class switching
Potential for recombination errors and harmful point mutations
Rapid cell proliferation in the germinal centre ->
* rapid response to infection
* Rapid multiple cell divisions = increased chance of DNA replication errors
depends on apoptosis - eliminate self reactive or ineffective Ig clones
Apoptosis is “switched off” in germinal centre
Consequences of mutations in apoptosis regulating genes
summarise VDJ recombination
Occurs in BM
Key enzymes: RAG1+2
TdT
summarise class switch recombination
Somatic hypermutation
Key enzyme: Adenosine induced
Deaminase
how can generation of Ab go wrong
in normal rearranged Ig gene - get VDJ rearrangement
how can generation of Ab go wrong
in normal rearranged Ig gene - get VDJ rearrangement downstream of Ig promotor which is highly active - drive production of Ig gene
if recombination or class switching goes wrong -> translocation of a cell growth reg gene (ie oncogene) downstream of the Ig promotor
Ig promotor can be IgH, K or l loci
oncogene may be anti apoptotic, proliferative.
* bcl2
* bcl6
* Myc
* cyclinD1
NHL risk factors
Constant antigenic stimulation
* Bacterial infection (chronic)
* Auto immune disorders (chronic)
Viral Infection of lymphocytes via vertical transmission, breastfeeding (direct viral integration of lymphocytes)
Retrovirus (HTLV1)
EBV infection in a scenario of loss of T cell function – chronic EBV
* Loss of T cells (HIV infection )
* Iatrogenic immunosuppression
what NHL does chronic antigen stimulation lead to
bacterial or autoimmune -> Lymphocytic infiltration – can evolve from polyclonal response – to produce malignant clones
B cell Non Hodgkin Lymphoma Marginal zone sub type (MZL)
* H.Pylori : Gastric MALT (mucosa associated lymphoid tissue) (MZL of stomach)
* Sjogren syndrome : MZL of parotid gland
* Hashimoto’s Thyroiditis: MZL of thyroid
Enteropathy associated T-Cell Non Hodgkin lymphoma (EATL)
* Coeliac disease/Gluten: small intestine EATL
how does direct viral integration lead to lymphoma
HTLV1 retrovirus infects T cells by vertical transmission
Caribbean, Japan (and world wide) endemic infection
-> adult T cell leukaemia lymphoma (ATLL) - type of T cell NHL
tropical spastic paraparesis
how does EBV cause lymphoma
EBV infects B lymphocytes - healthy carrier state post glandular fever
EBV driven proliferation of B cells -> surface expression of EBV antigens. -> Proliferating B cells targeted and killed by an EBV specific cytotoxic T cell
however if:
loss of T cell function eg HIV or Iatrogenic (transplant immunosuppression)/steroids , PTLD (post transplant lymphoproliferative disorder)
-> cant eliminate EBV driven proliferation of B cells due to absence of cytotoxic T cells
