Introduction to Lymphoma and Myeloma Flashcards

1
Q

What are the lymphoid malignancies?

A

Lymphoma
Myeloma
Lymphoid leukaemia

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2
Q

What are the primary lymphoid organs?

What are the secondary lymphoid organs?

A

Primary lymphoid organs:

  • Bone marrow
  • Thymus

Secondary lymphoid organs:

  • Spleen
  • Lymph nodes
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3
Q

Define and outline Lymphoma

A

Lymphoma: A cancer of white blood cells (lymphocytes)

  • Affects mature WBCs - mostly B-lymphocytes, but also T-lymphocytes
  • Heterogeneous group of diseases
  • Many are due to specific genetic mutations, chromosomal translocations
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4
Q

Which cells are affected in Lymphomas?

A
  • (Small lymphocyte ->)B-cells + T-cells

- NK cell (large granular lymphocyte)

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5
Q

What is lymph?

A

Lymph: Fluid that accumulates in tiny spaces b/w cells. Contains proteins, lipids, lymphocytes.

Functions of Lymphatic System:

  • Blood filtration /purification
  • Removal of excess fluids from tissues
  • Absorption and transport of lipids
  • Immune system activation
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6
Q

What are the lymph nodes ?

A

Lymph nodes: Glands that filter lymph(clear fluid that circulates through the lymphatic system).
Remove microorganisms+foreign matter.
All throughout body, but ↑ in neck, arms, elbows, chest, abdomen

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7
Q

What are lymph organs ?

A

Primary lymph organs: Sites where stem cells can divide and become immunocompetent

  • Bone Marrow
  • Thymus

Secondary lymph organs: Sites where most of the immune responses occur

  • Spleen
  • Lymph nodes
  • Appendix
  • Peyer’s Patches
  • Tonsils + Adenoids
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8
Q

How do Lymphomas develop?

A

Mutation/Chr translocation affects mature lymphocytes (not stem cells) which leads to uncontrolled division .

Organ size increase due to ↑ lymphocytes:

  • Lymph node - Adenopathy = enlarged lymph nodes due to infection/autoimmune disease/Lymphoma
  • Other lymph organs - Splenomegaly

Mutated lymphocytes then spread to other tissues through the lymphatic system

Mutated lymphocytes may infiltrate bone marrow(=can detect the altered lymphocytes in blood) and other organs

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9
Q

How is Lymphoma classified ?

A
  • Hodgin’s Lymphoma - adolescence, 75-79yo

- Non Hodgkin’s Lymphoma (more common) - 80-84yo. Incidence of NHL ↑ with age

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10
Q

Presentation of Lymphoma

A
Large, usually painless lymph nodes
Fever 
Swelling on face 
Lump in neck,armpit or groin 
Excessive sweating at night
Unexpected weight loss
Loss of appetite
Weakness
Breathlessness
Itchiness
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11
Q

How is lymphoma diagnosed ?

A

Lymph node biopsy using a biopsy needle. Examine partial/total lymph node under microscope. Indicates lymphoma.

Then do further tests to identify lymphoma subtype:
Flow cytometry
FISH
NGS
Immunophenotyping
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12
Q

What is the staging of Lymphoma ?

After diagnosis, stage the lymphoma - same system for HL + NHL

A

A series of tests carried out by PET to identify which body regions affected .

Stage 1: Localised disease , 1 lymph node region/1 single organ

Stage 2: 2 or more lymph node regions on the same side of the diaphragm

Stage 3: 2 or more lymph nodes regions above and below diaphragm

Stage 4 : Widespread disease, Multiple organs with/without lymph node involvement, cancer has disseminated - spread to extralymphatic organs

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13
Q

What is the aetiology of Lymphoma ?

A

Multifactorial disorder:

  • Malfunctioning of the body’s immune system
  • Exposure to certain infections

Most lymphomas occur when a B cell develops/acquires a mutation in its DNA

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14
Q

What is the traditional classification of Lymphoma ?

A

Hodgkin’s and Non Hodgkin’s (larger group)

Non Hodgkin’s -
Diffuse / Follicular

Hodgkin’s

Lymphoma Classification:
HL/NHL
Affected cell: T-cell/B-cell
Site at which the cell arises

  • Mature B-cell neoplasms
  • Mature T-cell + NK cell neoplasms
  • Hodgkin’s lymphoma

slide 18

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15
Q

What is Hodgkin lymphoma?

Outline the disease and its presentation

A

Hodgkin’s Lymphoma = A Clonal B-Cell malignancy
Presentation: Non-Painful, enlarged lymph node(s)

Risk factors : Epstein Barr virus (EBV,HHV4), Family History of HL, HIV/AIDS

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16
Q

How can we diagnose Hodgkin’s Lymphoma ?

A

Lymph node biopsy:
-Observe Hodgkin cell (multinucleated Reed-Sternberg cell) in lymph node which are derived from normal B lymphocytes. Using light microscope bc v. big cells w/ a bilobed nucleus .

These cells are only present in Hodgkin’s lymphomas

17
Q

What is the Treatment of Hodgkin’s Lymphoma ?

A
  • Chemotherapy/Radiotherapy, Stem Cell Transplant

- Prognosis: 5 year survival. Good treatment results in young adults

18
Q

What are Non-Hodgkin’s Lymphomas?

A

Non-Hodgkin’s Lymphomas = All lymphomas aprt from Hodgkin’s lymphoma.

19
Q

Outline Non-Hodgkins Lymphoma - Presentation, Cause, Risk Factors

A

Presentation : Enlarged lymph nodes. General lymphoma symptoms.

Cause: Chromosome translocations

Risk factors : Virus infections - EBV(HHV4) in Burkitt’s lymphoma , Human T-cell leukaemia virus in adult T-cell lymphoma.

20
Q

What are the chromosome translocations which occour in Non-Hodgkins Lymphoma ?

A

Chromosome translocations involving Ig heavy chain/light chain loci (chr14)

  • Ig genes are highly expressed in B-cells
  • Each Ig gene has a powerful tissue-specific enhancer (high expression levels)

Identify chr translocation using lymph node biopsy, then FISH

21
Q

What are the consequences of these chromosome translocations in Non-Hodgkin lymphoma ?

A

Normal role of Ig enhancer: Activates the promoter of the rearranged V segment of the Ig

Due to the translocation b/w chr14 + other chr, the enhancer starts enhancing transcription of other genes of the chr fused to chr14.

= Overexpression of the BCL-2 gene (an apoptosis inhibitor) on chr18

Most Follicular Lymphoma cases carry t(14:18) (q32:q21)

Chr Translocation = Ig enhancer regulates promoter of the new adjacent gene. = overexpress BCL-2 gene = ↓ apoptosis, ↑ cell survival+proliferation

22
Q

Where does the Ig V segment gene reside?

A

chr 14

23
Q

What is Follicular Lymphoma ?

A

Follicular lymphoma is a type of non-Hodgkin lymphoma

24
Q

What is the translocation observed in Burkitt’s lymphoma ?

A

Burkitt’s lymphoma = NHL
t(8;14)(q24;q32)
Balanced translocation; brings together Ig enhancer(chr14) + c-myc gene.
c-myc = a potent proto-oncogene.
translocation fusion = converts c-myc (proto-oncogene) →oncogene. now highly expressed due to highly expressed Ig on chr14

25
Q

What are the risk factors of Non-Hodgkin lymphoma ?

A

Virus infections(EBV)

  • Virus directly transforms B-lymphocytes in culture. Due to viral oncogene LMP-1.
  • Many ppl carry latent EBV but don’t develop lymphomas due to effective immune surveillance by cytotoxic T-cells.
26
Q

If over half of normal individuals carry the latent EBV virus why do some people develop lymphoma ?

A

In highly immunosuppressed individuals (HIV/organ transplant), the endogenous latent EBV may transform B-cells.
= EBV is no longer eliminated by cytotoxic T-cells
= Develop high grade lymphoma

27
Q

What is the classification of Non-Hodgkin Lymphoma ?

A

Low grade Lymphoma :

  • Normal tissue architecture is partially preserved - normal cell of origin is recognisable
  • Divides slowly
  • May be present for many months before diagnosis
  • Behave in an indolent fashion

High grade Lymphoma :

  • Loss of normal tissue architecture - difficult to determine normal cell of origin
  • Divide rapidly
  • Present for a matter of weeks before diagnosis - clear obvious symptoms
  • May be life threatening
28
Q

How is Non-Hodgkin lymphoma diagnosed ?

A

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

29
Q

How is Non-Hodgkin lymphoma treated ?

A

-Chemotherapy
-Radiotherapy
-Stem cell transplant
-Monoclonal Ab therapy-Rituximab (anti-CD20).
Targets CD20 cell surface molecules which are present in Leukaemia + Lymphoma B cells. Ab will bind to all the CD20 proteins and NK cells kill these tumour cells by releasing cytotoxins

30
Q

What is multiple myeloma ?

A

Multiple Myeloma = A tumour of the bone marrow that involves plasma cells.
Plasma (B) cells =a type of leukocyte which secrete antibodies. activated B-cells
Plasma cells originate in bone marrow

31
Q

Presentation, Cause, Risk factors of Multiple Myeloma

A

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

Unknown cause (genetics, DNA damage occurs in BM)

Risk factors:

  • Obesity
  • Radiation exposure
  • Family history
  • Certain chemicals
32
Q

What is the difference between healthy bone marrow and bone marrow in myeloma ?

A

Bone marrow produces white blood cells (B cells).
B-cells secrete antibodies and become plasma cells.

Bone Marrow in Myeloma:
Damaged white blood cell, becomes myeloma cell and secretes paraprotein (M component)

Abnormal plasma cells produce abnormal antibodies (paraproteins)
Paraprotein = Monoclonal Ig (only light chain) detected in blood/urine. Homogeneous electrophoretic migration + express 1 gene type (kappa/lambda)

33
Q

What 3 aspects of myeloma give rise to clinical features?

A
  1. Suppression of normal bone marrow , blood cells and immune cell function, causing :
    - Anaemia
    - Bleeding tendency
    - Recurrent infections

2.Bone reabsorption + Ca2+ release:
-Myeloma cells produce cytokines (IL-6) → BM stromal cells release RANKL → activates osteoclasts (bone fractures, bone lytic lesions)
Multiple myeloma cells also suppress OPG (osteoprotogene) in BM. RANKL:OPG imbalance = osteoclastogenesis
Osteoclasts promote bone resorption = bone enters circulation = lytic lesions of bone, bone pain and fractures
Calcium released from bone = hypercalcaemia (mental disturbance)

3.Pathological effects of the paraprotein - single monoclonal Igs accumulate in serum

34
Q

Outline the pathological effects of the paraprotein in Multiple Myeloma

A

Single monoclonal Ig gamma in the serum -high levels =malignancy

  • Paraprotein Precipitates in kidney tubules = renal failure
  • Deposited as amyloid in many tissues
  • Hyperviscosity syndrome: ↑ blood viscosity = stroke + heart failure
35
Q

How can we diagnose Multiple Myeloma ?

A
  • Serum electrophoresis for paraprotein
  • Urine electrophoresis for paraprotein
  • Bone Marrow biopsy to detect ↑ levels of plasma cells
  • Erythrocyte sedimentation rate (ESR) ↑ due to stacking of the RBC (Rouleaux) due to ↑ plasma paraprotein conc.
  • Flow cytometry and cytogenetics to detect cause + characterise the origin of the myeloma
  • Radiological investigation of skeleton for lytic lesions
36
Q

Outline the treatment of Multiple Myeloma

A
  • Radiotherapy (for localised myeloma)
  • Chemotherapy combinations (thalidomide ,lenalidomide and bortezomib) (when dissemination)
  • Targeted therapies - deacetylase inhibitors, HSP inhibitors, monoclonal antibodies
  • Immunotherapy (CAR-T) and allogenic hematopoietic stem cell transplantation (ASCT) young patients