Lecture 14/15 - Lymphoid malignancies

Question 1

Malignant lymphoid cells: where do they arise from and how are they typically distinguished from ‘normal’ cells?

Answer 1

Normal cells - they share many of their characteristics with normal lymphocytes

Since normal lymphocytes pass through a range of developmental stages the malignant cells tend to resemble cells at a particular stage of normal developmental stage - this led to the concept that each type of malignant cell had a ‘normal’ counterpart that we could recognise

Question 2

Malignant cells arising from the initial lymphocyte production stage

Answer 2

Will be highly proliferative cells in bone marrow

Question 3

Malignant cells arising from cells responding to antigen

Answer 3

Rapidly proliferating cells found in lymphoid tissues

Question 4

Malignant cells arising from cells that have met antigen

Answer 4

Will often perform actions e.g. antibody production

Question 5

Malignant cells arising from memory cells

Answer 5

Will tend to perform actions involving migration and tissue invasion

Question 6

If malignant cells are so similar how can we tell a difference?

Answer 6

They behave a little differently – generally simply because there are too many of them, but also sometimes because of unusual features.

We can occasionally find malignancies where a normal counterpart is hard to identify, however

Question 7

Hairy cell leukaemia: what is it caused by, what causes its phenotype, and where can it be found?

Answer 7

Has a mutation in the BRAF gene – the normal counterpart is believed to be a normal small lymphocyte, but the mutated gene activates the cell cytoskeleton causing numerous “hairy” projections (amongst other things)

The disease does not affect lymph nodes but grows extensively in bone marrow and blood. It is very sensitive to a whole range of different treatments.

Question 8

Blast cells: where do they develop, are they proliferative, and what are their key features?

Answer 8

Develop in bone marrow

Because large numbers are needed, the cells are highly proliferative, growing in the bone marrow until they mature and are released into the blood

In normal cells this process is highly controlled – there should not be too many or too few cells formed

• Unwound chromatin
• Pale, round nuclei - processing/export of RNA
• blue cytoplasm - packed with ribosomes

Question 9

Why do blast cells typically have bigger, lighter nuclei?

Answer 9

DNA is constantly replicated, these proliferative cells don’t typically have their DNA wrapped in histones

Question 10

Acute

Answer 10

Rapid appearance/development

Question 11

Lympho

Answer 11

Refers to lymphocyte origin

Question 12

Blastic

Answer 12

Refers to the capability to make rapid divisions

Question 13

Leukaemia

Answer 13

White blood - reflects the tendency to spill from the bone marrow into blood in large numbers

Question 14

Acute lymphoblastic leukaemia name meaning

Answer 14

Acute - Rapid appearance/development
Lympho - Refers to lymphocyte origin
Blastic - Refers to capability to make rapid divisions
Leukaemia - White blood - reflects the tendency to spill from the bone marrow into blood in large numbers

Question 15

Bone marrow: where do lymphocytes grow and what aspects does the bone marrow have?

Answer 15

Early-stage malignant lymphocytes develop on the edge of the bone marrow next to the bony support

• Fat-filled spaces (provides energy)
• The bony skeleton (provides support)

Question 16

Later malignant cell behaviour: what do they do and how do they interact with normal cells?

Answer 16

• Malignant lymphocyte cells grow rapidly and do not mature - they increase in number and begin to fill the bone marrow
• They suppress the growth of normal cells - eventually filling the marrow entirely and spilling out to other areas

Question 17

Why do people become ill: what are the main symptoms and how do they cause illness?

Answer 17

The main symptoms are caused by the suppression of normal cells by the rapidly growing malignant cells: patients with acute leukaemia have low red cells, low white cells and low platelets:

• The lack of normal platelets means that very small vessel trauma is not plugged by platelets, so patients experience tiny points of bleeding (petechiae). These may be simply unsightly on the leg but can be fatal (brain) (uncommon)
• The lack of normal white cells makes responding to infection very difficult. Initially, this is simply an overgrowth of normal organisms that cause no problems in healthy people - later infection becomes the major cause of death
• Lack of red cells - People become pale, lack energy, and become short of breath - this can be reversed by transfusion

Other symptoms relate to the effects of this through the rapid growth in bone marrow – causing bone pain (abnormal cells restrict oxygen availability - necrosis - severe pain); and an excess number of cells accumulating in blood or other sites

Question 18

ALL mutations: how do they act in children, what can they carry, and how do they act in the elderly?

Answer 18

All these diseases are caused by mutations that allow them to grow in an uncontrolled way, but sometimes these genetic changes can make a great difference to behaviour:

In children, acute lymphoblastic leukaemia behaves very much like an adult disease, but the mutations are very different, and the outcome of treatment is much better - children are typically more robust so more aggressive treatments can be used

Sometimes acute lymphoblastic leukaemia carries the BCR/ABL mutation that is more often seen in myeloid leukaemia - in these cases, treatment can be very difficult - easier nowadays with new drugs and treatments

In the elderly, acute lymphoblastic leukaemia often has many different mutations and a very poor response to treatment

Question 19

Normal vs malignant lymphoma

Answer 19

The normal structure is lost and the node becomes very large – often from 10-20cm in size in contrast to the usual <1cm size

(Patients usually discover one or more enlarged lymph glands)

Normal nodes - enlarged only during infection
Malignant nodes - keep growing

(Like the normal cells at this stage of development, the lymphomas can vary a lot in how fast or how slowly they grow)

Lymph - lymphoid nature
Oma - growing in a solid bump

Question 20

Burkitt lymphoma: how specific is it, how does it occur, what is it caused by, and how severe is it?

Answer 20

Carries very specific mutations

Involves the MYC gene - this gene normally controls progression through cell division but it is continually expressed in Burkitt lymphoma leading to the abnormal cells being continually in a proliferative cell cycle, making Burkitt lymphoma one of the fastest growing malignancies – with cells dividing each 12-24 hours

Caused by EBV (Epstein-Barr virus)

Used to be lethal due to the aggressive growth; however, nowadays the rapid division can be used in treatment targeting to wipe out all of the malignant cells

Question 21

Glandular fever: what is it and what is it caused by?

Answer 21

Never goes away, just suppressed by the immune system - ggle

Caused by EBV

Question 22

Plasma cells: what does it look like when activated?

Answer 22

The nucleus has chromatin that is dense because most is inactive and wound around histone proteins. These cells basically make only one protein type an antibody.

There is a large golgi body where the antibody mRNA is processed for transcription

The cytoplasm is blue because it is packed with ribosomes transcribing mRNA into antibody

Question 23

Normal plasma cell movement

Answer 23

Post-antigen cells moves from the lymph nodes into the blood then into the marrow where it grows

Question 24

Myeloma: how many antibodies are present, what may happen to the plasma, how do the malignant cells affect normal APCs, and what happens to the bone?

Answer 24

Excess antibody production – large amounts of a single antibody (up to 100g/L (normal is ~30g/L)) are produced. This can block kidneys as they stick to things

Hyperviscosity - may make plasma too thick or be deposited in organs (ie kidneys), this may cause headaches

The abnormal plasma cells displace normal antibody-producing cells. Infections can become a problem

Cytokines produced by plasma cells stimulate the breakdown of bone – causing holes in bones leading to fracture and raised calcium levels in the blood

• “myel” refers to their growth - mainly in bone marrow
• “Oma” refers to - their growing in solid lumps

Question 25

Malignant lymphocytes symptoms

Answer 25

Bone pain and eventually fractures as a result of bone loss - holes in the bone caused by plasma cell lumps

Kidney failure as a large amount of excess antibodies affects the kidneys

Effects of slow circulation caused by excess antibody - hyperviscosity

Infections caused by suppression of normal antibody-producing cells - immunity suppressed

Question 26

What happens to memory cells following target elimination

Answer 26

Many cells die

Others persist as memory cells

Round and unexciting “resting cell” that migrates widely between nodes, blood and tissues looking for antigens

Question 27

Chronic lymphocytic leukaemia: what are they, what do they look like, and how do they form?

Answer 27

“chronic” refers to their slow growth

“lymphocytic” indicates that they resemble mature cells (lymphocytes) not immaure cells (lymphoblasts)

“leukaemia” indicates that they grow mainly in blood (“white blood”)

The CLL lymphocyte looks like a resting cell:
* Nuclear DNA is tightly wrapped around histone protein and looks “dense”, with no nucleolus.
* The cytoplasm has few ribosomes so is pale rather than dark blue

Their slow and progressive increase in number and aptitude at surviving even in large numbers

Question 28

CLL diagnosis: why is CLL diagnosis typically hard to do, what ways may it be detected by, and

Answer 28

Numbers can be very high but as the cells are mature and relatively inert, symptoms from them are often minimal and the disease may not change over time

CLL is often diagnosed when a raised number of abnormal lymphocytes are detected in blood on a routine blood test - but people may also show effects of cell accumulation:

• Widespread enlargement of lymph glands
• Bone marrow failure as the CLL cells take over the marrow
• Immune deficiency as normal lymphocytes are suppressed
• CLL cells in lymph nodes – the nodes undergo slow painless enlargement, occasionally nodes become very large although this is uncommon. Enlargement is usually symmetrical because the cells migrate widely
• Diminished bone marrow function - caused by eventual malignant accumulation and replacement of bone marrow

Question 29

CLL: immune system effects

Answer 29

The normal immune system becomes suppressed - increased infection rate and chronic ill health are the most common causes of death in CLL

Interfere with the function of the normal immune system – autoimmune destruction of the body cells (usually red cells) occurs (rapid destruction and severe anaemia - small and round)

Question 30

Cachexia

Answer 30

The effect of the body fighting persistent infections and having chronic cell accumulation and eventually resulting in an aged-looking body