Introduction to Lymphomas and Myeloma

Question 1

What is Lymphoma?

Answer 1

Lymphoma: cancer of the white blood cells (lymphocytes).
- Affects mature blood cells, mostly B lymphocytes but also T lymphocytes
It is a heterogenous group of diseases
Many known to be due to specific genetic mutations and chromosomal translocations.

Question 2

What are the main functions of the lymphatic system?

Answer 2

Main functions of the lymphatic system include:

a) blood filtration/purification
b) removal of excess fluids from tissues
c) absorption and transport of lipids
d) Immune system activation

Question 3

What are primary and secondary lymph organs?

Answer 3

Primary lymph organs: sites where stem cells can divide and become immunocompetent. (ie located in bone marrow and thymus)

• Secondary lymph organs: sites where most of the immune responses occur.( located eg in tonsils/spleen/appendix etc)

Question 4

How do lymphomas develop?

Answer 4

Affect lymphocytes in different maturation stages…

Uncontrolled division….

Organ size increase:
Lymph node (adenopathy)
Other lymph organs (splenomegaly)……

Spread to other tissues through lymphatic system…..

Might infiltrate in bone marrow (detectable in blood)
and/or other organs……

Question 5

What is the traditional classification for Lymphomas?

Answer 5

Lymphomas can be categorised into 2 groups:
Non-hodgkins (more common)
Hodgkins (less common)

Question 6

What are some warning signs of Lymphoma?

Answer 6

Warning signs of Lymphoma can include:
fever
swelling in head/neck
excessive sweating at night
unexpected weight loss
loss of appetite 
feelings of weakness
breathlessness

Question 7

What would you do to diagnose Lymphoma?

Answer 7

Take a lymph node biopsy and use various technologies to analyse this eg Flow Cytometry, FISH or NGS.

There are stages 1-4 with diagnosing lymphoma .

Question 8

What do we know about the aetiology of Lymphoma?

Answer 8

Multifactorial disorder:
Malfunctioning of the body’s immune system
Exposure to certain infections

The triggers are unknown but… most of lymphomas occur when a B cell develops/acquires a mutation in its DNA.

Question 9

What do we currently know about Hodgkin Lymphoma?

Answer 9

• Clonal B-cell malignancy.
  Presentation- non-painful enlarged lymph node(s).
• Risk factors: ~50% cases due to Epstein-Barr virus (EBV)- Classic form.
• Other risk factors: Family history and HIV/AIDS.
• Diagnosis: Excisional lymph node biopsy
• 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%)

Question 10

What do we currently know about non-Hodgkin Lymphoma?

Answer 10

• Presentation: enlarged lymph node(s). Some forms are slow and others grow faster. General lymphoma symptoms.
• Causes: Chromosome translocations
  Many lymphomas carry chromosome translocations involving the Ig heavy chain or light chain loci (chr14).
• Ig genes are highly expressed in B-cells.
• Each Ig gene has a powerful tissue specific enhancer (high expression levels).
• Risk factors: virus infections (e.g. EBV (HHV4) in Burkitt’s lymphoma; Human T-cell leukaemia virus in adult T-cell lymphoma)
• Risk factors: virus infections (e.g. EBV (HHV4) driven lymphomas in immunosuppressed patients):
  It directly transforms B-lymphocytes in culture. Due to viral oncogene LMP-1.
  Over half of all normal individuals carry latent EBV infection. They do not develop lymphomas due to effective immune surveillance by cytotoxic T-cells.

In highly immunosuppressed individuals the endogenous latent EBV may transform B-cells.

• No longer eliminated by cytotoxic T-cells.
• Develop high grade lymphoma.

Question 11

Chromosome translocations process

Answer 11

Normal role(of the enhancer): activating the promoter of the rearranged V segment(near the promoter) on the immunoglobulin

Most cases of follicular lymphoma carry translocations between chromosomes: (14;18)(q32;q21)

less apoptosis - BCL-2 is an apoptosis inhibitor

t(8;14)(q24;q32) is frequently observed in Burkitt’s lymphoma.

Question 12

How can we classify non-Hodgkin Lymphomas?

Answer 12

Low grade:
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

High grade
Loss of normal tissue architecture -normal cell of origin hard to determine
Divide rapidly
Present for a matter of weeks before diagnosis
May be life-threatening

Question 13

What can be used to diagnose non-Hodgkin Lymphomas?

Answer 13

Immunophenotyping
Cytogenetics –FISH
For chromosome translocations (e.g. t(14;18) Ig : Bcl-2)
Light chain restriction
PCR
For clonal Ig gene rearrangement

Question 14

What treatment options are there for non-Hodgkin Lymphomas?

And what is the prognosis for non-Hodgkin Lymphomas?

Answer 14

Treatment:
Chemotherapy
Radiotherapy
Stem cell transplant
Monoclonal Ab therapy -Rituximab (anti-CD20)

Prognosis:
Overall five-year survival rate ~70%

Question 15

What is multiple myeloma? How does it present? Do we know any causes/risk factors for it?

Answer 15

• Tumour of the bone marrow that involves plasma cells (antibodies production).

Presentation: Absence of initial symptoms. Later: bone pain, bleeding, frequent infections, and anaemia.

Unknown cause. Risk factors: obesity, radiation exposure, family history, and certain chemicals.

Question 16

Three aspects of myeloma give rise to different clinical features, what are they ?

Answer 16

1. Suppression of normal bone marrow, blood cell and immune cell function - leads to anaemia/recurrent infections/bleeding tendencies
2. Bone resorption and release of calcium.
   a) Myeloma cells produce cytokines (esp. IL-6) → bone marrow stromal cells to release the cytokine RANKL→ osteoclasts activation (lytic lesions of bone, bone pain, fractures).
   b) Calcium released from bone causes hypercalcaemia (multiple symptoms including mental disturbance).
3. Pathological effects of the paraprotein –(single monoclonal Ig in the serum- high levels – malignancy)
   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

Question 17

How can you begin to diagnose multiple myelomas?

Answer 17

Diagnosis:
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
Flow cytometry and cytogenetics to detect cause
Radiological investigation of skeleton for lytic lesions

Question 18

What does treatment currently include for multiple myelomas?

What is the prognosis for multiple myelomas?

Answer 18

Treatment: Radiotherapy, 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%

Question 19

Summarise the lecture

Answer 19

Leukaemia, lymphoma and myeloma are cancers of the blood cells.

Lymphomas are a group of heterogeneous cancers of the mature lymphocytes that develop in lymph organs.

Lymphomas are classified in two main types: Hodgkin (HL) and Non-Hodgkin lymphomas (NHL).

Chromosome translocations are commonly observed in NHL and virus infection (e.g. EBV (HHV4)) is one of the main risk factors of both HL and NHL types.

Multiple myeloma is a tumour of the bone marrow that affects plasma cells characterised by suppression of normal bone marrow, bone resorption and release of calcium and production of paraprotein.