Intro to lymphomas and myeloma Flashcards
What is lymphoma?
Cancer of white blood cells (lymphocytes)
Affects mature blood cells, mostly B lymphocytes and also T lymphocytes
Heterogenous group
Many known to be due to specific genetic mutations and chromosomal translocations
What are the main functions of the lymphatic system?
Blood filtration/purification
Removal of excess fluids from tissue
Absorption and transport of lipids
Immune system activation – produces immune cells
What is lymph fluid?
Fluid that accumulates in tiny spaces between tissue cells, contains proteins, fats, lipids and lymphocytes.
Lymph filtered by network of lymph nodes, helps to remove microorganisms and foreign bodies.
What are the primary and secondary lymph organs?
Primary lymph organs: sites where stem cells can divide and become immunocompetent. Bone marrow and thymus.
Secondary lymph organs: sites where most of the immune responses occur. These are spleen, lymph nodes, appendix, Peyer’s patches, tonsils and adenoids.
How does lymphoma develop?
Chromosomal translocation/ mutation that affects lymphocytes in different maturation stages or mature lymphocytes
Causes uncontrolled division
Consequence: organs where lymphocytes are numerous increase in size.
Causes adenopathy (lymph node increases in size) and splenomegaly (other lymph organs increasing in size)
Lymphocytes can spread to other tissues through lymphatic system, most spread to liver, bone marrow and lungs
Infiltration into bone marrow makes it detectable in the blood and other organs
can also be caused by infections.
What are the two main groups lymphomas can be categorised into?
Non-hodgkin’s lymphomas, most common type - 83% of total lymphomas
- incidence increases with age, 6th most common cancer in UK
Hodgkin’s lymphomas - 17% of total lymphomas
- not common, accounts for less than 1% of all new cancer cases
What are the symptoms of lymphoma?
Fever
Swelling of the face and neck
Lump in the neck, armpit or groin
Excessive sweating at night
Unexpected weight loss
Itchiness
Breathlessness
Loss of appetite
Feeling of weakness
How is lymphoma diagnosed?
Lymph node biopsy, partial or total excision of lymph node to be examinder under microscope - histopathological features
Other tests to identify subtype
- FISH
- Flow cytometry
- NGS
- immunophenotyping
Staging PET, determines which areas of the body are affected
What are the different stages of PET?
S1 – only one single node region is affected
S2- involves 2 or more lymph node regions on the same side of diaphragm
S3 – lymph node regions on both sides of the diaphragm
S4- cancer involves 1 or more lymphatic organs
What is the aetiology of lymphoma?
Multifactorial disorder
- Malfunctioning of the body’s immune system
- Exposure to certain infections
Triggers are unknown but most of lymphomas occur when a B cell develops/acquires a mutation in its DNA.
What causes the mutation in DNA is unknown
What is the presentation of Hodgkin Lymphoma?
Clonal B-cell malignancy
Presentation – non-painful, enlarged lymph node/s
Half of the cases of Hodgkin Lymphoma are due to Epstein Barr virus infection
Other risk factors include family history of lymphoma or having HIV/AIDS
What is seen in lymph node biopsy of Hodgkin’s lymphoma?
Hodgkin’s cells - multinucleated red stem cells in lymph nodes
Can observe with light microscope, big.
Derived from B-lymphocytes, bi-lobe nucleus, ‘owl’ eye appearance.
also called Reed-Sternberg cell
How is Hodgkin lymphoma treated?
Treatment: Chemotherapy +/- radiotherapy. Stem cell transplant.
Prognosis: 5 year survival, 50-90% depending on age, stage and histology. Especially good results in young adults (97%)
What is the presentation of non-hodgkin lymphoma?
Enlarged lymph nodes. Some forms are slow others grow faster.
General lymphoma symptoms – weight loss, fevers, night sweats.
Enlarged lymph nodes may cause lumps that can be felt under the skin.
What is the cause of non-hodgkin lymphoma and the risk factors?
Chromosome translocations.
Risk factors:
virus infections e.g EBV (HHV4) in Burkitt’s lymphoma
Human T-cell leukaemia virus in adult t-cell lymphoma
Between what chromosomes does translocations occur in?
Ig heavy or light chain in chr14 and another chromosome
Ig genes highly expressed in B-cells
each Ig gene has powerful tissue specific enhancer (high expression levels), enhances expression of these genes
most cases of follicular lymphoma translocation between chr 14 and 18
What happens when chromosome translocation occurs?
How does it cause lymphoma?
Enhancer activates promoter or rearranged V segment of the Ig.
Enhances transcription of genes located in other chromosome fused with chr14
for example, chr18 has BCL-2 gene, apoptosis inhibitor.
BCL-2 overexpressed when under regulation of Ig enhancer after translocation
lower rate of apoptosis, inhibits cell proliferation and survival
How do we know that virus infections like EBV drive lymphomas in immunosuppressed patients?
It transforms B-lymphocytes in culture due to viral oncogene LMP-1 in immunosuppressed people
cytotoxic T cells can’t attack virus
no longer eliminated by cytotoxic T-cells, develop high grade lymphoma
What is a low grade non-hodgkin lymphoma?
Normal tissue architecture partially preserved – normal cell of origin recognisable
Divide slowly
May be present for many months before diagnosis
Behave in an indolent fashion
What is a high grade non-hodgkin lymphoma?
Loss of normal tissue architecture – normal cell of origin hard to determine
Divide rapidly
Present for matter of weeks before diagnosis
May be life threatening
How is non-hodgkin lymphoma diagnosed?
Immunophenotyping
Cytogenetics – FISH – for chromosome translocations
Light chain restriction - in reactive lymphoid population there is a mixture of kappa and lambda positive cells. Cells expressing kappa light chains outnumber cells expression lambda light chains. Can determine type of NHL
PCR – for clonal Ig gene rearrangement
How is NHL treated?
Chemotherapy
Radiotherapy
Stem cell transplant
Monoclonal Ab therapy – Rituximab (anti-CD20, targets CD20 cell surface molecules present in leukaemia and lymphoma B cells). Antibody sticks to all CD20 cell bodies it finds, immune system picks out the marked cells and kills them – Natural killer cells – 80% success rate
What is multiple myeloma?
What is its presentation?
What are the risk factors?
Tumour of the bone marrow, involves plasma cells (antibodies production), a type of leukocyte originate in BM and secrete large amounts of AB in response to antigen
Presentation:
absence of initial symptoms, later bone pain, bleeding, frequent infections and anaemia
Cause unknown, risk factors:
obesity, radiation exposure, family history, chemicals
What are paraproteins?
Abnormal plasma cells produce abnormal antibodies, paraproteins.
A monoclonal Ig, can be detected in blood or urine.
Characterised by homogenous electrophoretic migration by expression of single chain type - kappa or lambda.
What are the three clinical features that paraproteins give rise to?
- Suppression of normal bone marrow, blood cell and immune cell function. Causes anaemia, recurrent infections and bleeding tendency.
- Bone resorption and release of calcium
Myeloma cells produce cytokines e.g IL-6, activating release of RANKL cytokine from bm and stromal cells.
Osteoclast activation (lytic lesions of bone, bone pain, fractures). multiple myeloma cells also suppress OPG. Unbalance of normal RANKL and OPG drives osteoclastogenesis, the production of more osteoclasts. Osteoclasts promote bone resorption.
Patients start suffering lytic lesions of bone, bone pain and fractures
Consequence calcium is release from the bone, causing hypercalcaemia – multiple symptoms, including mental disturbance
- Pathological effects of the paraprotein - (single monoclonal Ig in the serum – high levels – malignancy ).
When paraprotein precipitates in kidney tubules it can cause renal failure
Deposited as amyloid in many tissues
2% of cases develop hyper viscosity syndrome
Increased viscosity of blood leading to
- Stroke
- Heart failure
How is multiple myeloma diagnosed?
Serum electrophoresis for paraprotein
Urine electrophoresis
Bone marrow biopsy for increased levels of plasma cells
Erythrocyte sedimentation rate (ESR)- high due to stacking of the RBC, rouleau, because of increase in plasma paraprotein concentration. - ESR can also be high in other conditions like inflammation, non-specific test
flow cytometry and cytogenetics to detect cause
Radiological investigation of skeleton for lytic lesion
How is MM treated?
Radiotherapy (recommended when myeloma is localised)
chemotherapy combinations (thalidomide, lenalidomide and bortezomib)
targeted therapies
immunotherapy (CAR-T) and allogeneic hematopoietic stem cell transplantation (ASCT) in young patients
Prognosis: Chemo +ASCT – overall 5-year survival rate 35%
