16. Lymphoid Malignancies

Question 1

Major underlying principles of malignant lymphocytes (1)

Answer 1

1. Malignant lymphoid cells arise from normal cells and so they share most of their characteristics with normal lymphocytes
2. Since normal lymphocytes pass through a range of developmental stages the malignant cells tend to resemble cells at a particular stages of normal developmental stage
3. However the cells are “malignant” so while resembling a normal lymphoid cells they also behave a little differently – generally simply because there are too many of them!

Question 2

Major underlying principles of malignant lymphocytes (2)

Answer 2

There are basically four stages of normal lymphocyte development that malignant cells can resemble:

Phase 1: initial formation – proliferative cells committed to forming many more lymphocytes. occurs in bone marrow as all lymphocytes made in bone marrow. controlled process - make as many as we need then stop

Phase 2: responding to antigen – meeting antigen then proliferating before making maturing into effector cells. after wondering round the body they encounter an antigen and react to it, undergoing a secondary proliferative phase. Occurs in lymph nodes

Phase 3: cells that have met antigen and are performing an action e.g. cytotoxic T cells or antibody producing plasma cells. mature into a cell that reacts to the antigen eg antibody or toxic t cell or helper cell. Ie effector cells, these are not very proliferative, they do things. When antigens disappear from the body so do these as no longer required

Phase 4: memory – after an antigen is successfully eliminated memory cells persist to allow the body to respond rapidly in future. immunological memory

Question 3

stages in picture form see slide 5

Answer 3

stage 1 is production in bone marrow
stage 2 is response to antigen (lymph node)
stage 3 destroying antigen eg antibody production
stage 4 is memory cells, migrate widely

Question 4

phase 1 of normal development

Answer 4

Normal lymphocytes undergo an initial wave of proliferation
These cells develop in bone marrow

1. Because large numbers are needed, the cells are highly proliferative, growing in bone marrow until they mature and are released into blood.
2. In normal cells this process is highly controlled – there should not be too many or too few cells formed

cell has no fatures of maturation , consists of only a nucleus and nucleolus

Question 5

appearance of phase 1 cells

Answer 5

have features of rapidly growing cells
The nucleus has chromatin that is unwound from histones protein so it can be transcribed into mRNA to make proteins. It therefore looks “unravelled” and “lace-like”.
There are pale round nucleoli present to support the processing and export of RNA to transcribe protein
The cytoplasm is blue because it is packed with ribosomes transcribing mRNA into protein

Question 6

malignant cells tha develop from phase 1

Answer 6

acute lymphoblastic leukaemias
“acute” reflects their rapid appearance and development

“lympho” refers to their lymphocyte origin

“blastic” is an old term that refers to their capability to make rapid divisions

“leukaemia” another old term “white blood” reflects their tendency to spill over from bone marrow into blood in large numbers

Question 7

initial behaviour of malignant cells from phase I

Answer 7

The cells resemble normal lymphocytes proliferating in bone marrow
Lymphocytes develop on the edge of bone marrow next to the bony support. At early stages they resemble normal cells. get all nutrition
bony skeleton of bone marrow provides support whilst fat filled spaces provide energy

Question 8

later behaviour of malignant cells of phase 1

Answer 8

The difference is that they grow rapidly and do not mature
As they increase their number the malignant lymphocytes begin to fill the bone marrow
They supress normal cells
Eventually they fill marrow entirely and move out to other areas, appear in blood
The bone marrow is packed and entirely replaced by abnormal cells
normal cells wiped out so don’t make rbc or platelets

Question 9

eventual behaviour of malignant cells of phase I

Answer 9

The acute lymphoblastic leukaemia are eventually seen in blood – this is usually the point where people become ill

Question 10

Acute lymphoblastic leukaemia symptoms

Answer 10

bleeding
infection
lack of rbc
pain

Question 11

ALL bleeding

Answer 11

The lack of normal platelets means that very small vessel trauma cannot be plugged so patients experience tiny points of bleeding (petechei). These may be simply unsightly on leg, but can be fatal (brain)
haemorrhages eg when standing due to hydrostatic pressure

Question 12

ALL infection

Answer 12

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. E.g. yeast in mouth. Later infection is the major cause of death

Question 13

ALL lack of rbc

Answer 13

People become pale, lack energy, become short of breath. This can be reversed by transfusion.

Question 14

ALL other symptoms

Answer 14

The infiltration of bone marrow is sometimes felt as pain as the number of cells restricts oxygen availability and tine areas of cell death occur!
Microthrombosis – death of bits of bone

Question 15

ALL clinical features

Answer 15

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

Other symptoms relate to the effects of this the rapid growth in bone marrow – causing bone pain; and by an excess number of cells accumulating in blood or other sites

Question 16

phase 2 of normal development

Answer 16

Normal cells go to lymph node where they recognise and respond to antigen
Normal cells go to lymph node where they recognise and respond to antigen
After they meet antigen normal lymphocytes begin to proliferate

the proliferating population matures into cells with particular features.

Question 17

phase 2 lymph node phase normal

Answer 17

Small resting cells, solid look to nucleus as DNA tightly bound to histones
But later unravel their chromosome for transcribing and synthesising protein
The cells of this phase are also very variable in appearance
Cells that have not yet met antigen tend to be small mature and proliferate slowly and resemble normal lymphocytes
to Later cells are very proliferative and resemble bone marrow cells (but in lymph node)

Question 18

outcome of phase 2 - normal and malignant

Answer 18

is always similar
A normal lymph node has a varied appearance and structure and is small (less than 1cm in size)
A lymph node in lymphoma becomes filled with malignant lymphocytes – the normal structure is lost and the node becomes very large – often from 10-20cm in size.

Question 19

phase 2 malignant cells

Answer 19

Like their normal
lymphomas
counterparts the types can be very variable and can be slow or fast growing, but grow mainly in lymph node

“lymph” refers to their lymphoid nature

“oma” refers to their growing in a solid lump

Question 20

clinical features of lymphomas

Answer 20

Patients usually discover one or more enlarged lymph glands
Unlike normal nodes that can become enlarged during and infection then get better these nodes carry on growing
Like the normal cells at this stage of development the lymphomas can vary a lot in how fast or how slowly they grow

Question 21

phase 2 lymph node phase a

malignant

Answer 21

Here is a rapidly growing lymphoma affecting the lymph glands of the neck.

Generally these will arise in one gland and rapidly enlarge – spreading to other connected lymph glands. So initially the appearances are asymmetrical.

Can spread to other glands
As they start just in one place can treat them locally eg radiotherapy

Question 22

PET scan for lymphoma

Answer 22

Later they may spread throughout the body (shown here on a PET scan which uses a “tracer” to highlight nodes that have lymphoma). These cells may be treated the right side image is post treatment – the nodes have been cured there is now only a small amount of the “tracer” being eliminated in kidney and bladder!

Question 23

phase 3 normal cells

Answer 23

Mature “effector” cells e.g. antibody secreting plasma cells
Mature lymphocytes performing functions in the body: These cells do not grow quickly and have different characteristics that reflect their mature function and can be very different to lymphomas or leukaemias.

In this lecture we will use the example of antibody producing plasma cells that make large amounts of antibody

we know its a plasma cell as nucleus has popped off to one side of the cell due to massive Golgi body - where mRNA passes thorugh its interactioin with ribosome before protein is made
plasma cells are antibody producing cells
highly developed protein translative and exportive system
cytoplasm is blue
nucleus is only transcribing one gene so will look quite mature

Question 24

phase 3 effector cell example plasma cell

Answer 24

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

Chromatin tightly bound round histone proteins as only transcribing one gene – antibody
mRNA produced is popping out of golgi body, synthesis in ribosomes pop antibodies out in serum for good

Question 25

phase three leaving lymph node

Answer 25

these mature post antigen cells now leave the lymph node
Depending on their final function, these cells may occupy different sites within the body.

E.g. Plasma cells are formed in the lymph nodes but then move into blood before eventually becoming resident in marrow.

Plasma cell develops at end of the antigen response in the lymph gland, passes into blood and very rapidly passes from blood to bone marrow and settle. Its in bone marrows in clumps and make antibodies, this is where they get their nutrients and supporting cytokines which help them to grow and accessory cells which help them develop. These help establish control
Antibodies made. supporting cells die by apoptosis.

Question 26

phase three malignant cell

Answer 26

myeloma
These behave very differently – the problem is not usually the number of abnormal cells. The problem is what the abnormal cells do to the body!

“myel” refers to their growth mainly in bone marrow

“oma” refers to their growing in solid lumps

Question 27

myeloma plasma cells

Answer 27

Malignant plasma cells look very much like normal plasma cells and do similar things – moving to bone marrow, making room for themselves, producing antibody ………………..

There are simply too many of them and they are no longer controlled. This causes a particular set of problems.

Question 28

multiple myeloma

Answer 28

How mature cell function determines clinical disease:
plasma cells cause “multiple myeloma”

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

Excess antibody production – large amounts of a single antibody are produced, large amounts of identical proteins can precipitate . This can block kidneys, make plasma too thick or be deposited in organs

Cytokines produced by plasma cells stimulate break down of bone – causing holes in bones leading to fracture and raised calcium levels in blood. If you break down enough protein tis increases the calcium levels in the blood. Can make you loopy, lead to calcium stones in the kidney and can cause severe pain of normal bodily function. Bones, stones, moans and abdominal groans

Question 29

myeloma: patients complain of

Answer 29

Bone pain and eventually fractures as a result of bone loss
Kidney failure as the large amount of excess antibody affects kidneys
Effects of slow circulation caused by excess antibody
Infections caused by suppression of normal antibody producing cells

Question 30

effect of myeloma on bones

Answer 30

Myeloma forearm
Note the holes caused by the “lumps” of plasma cells
Thick outer cortex and inside spongy medulla
Some holes breaking the cortex which ruins the strength
Bone can regrow if we get rid of the myeloma

Skeletal survey – take multiple xrays

Question 31

effect of myeloma on kidneys

Answer 31

Sometimes the disease first comes to light as severe kidney failure

Question 32

effect of myeloma on antibodies

Answer 32

Sometimes the loss of normal antibody responses means that diseases of childhood are reactivated. In this case a severe and widely spreading shingles infection.
Immunosuppressed , those dormant viruses can recur
Eg chicken pox lies dormant in nerves of spinal cord

Question 33

phase 4 normal cells

Answer 33

Memory cells following elimination of antigen
Once the effector cells have successfully eliminated antigen and are not needed:

Many cells die
Others persist as memory cells

Question 34

phase 4 memory B cell

Answer 34

The function is to do nothing unless they meet an antigen that they have previously encountered. So they appear as a “resting cell” that migrates widely between nodes, blood and tissues looking for antigen.
The cells appear small round and unexciting with no features of activation or increased proliferation
Dark purple nucleus – chromatins tightly wrapped around histones, no golgi bodies. Not doing anything just moving round circulation
Migrate widely

Question 35

phase 4 memory cells

Answer 35

patrol widely, immune surveillance
leave the lymph gland to bone marrow out the bone marrow and so on
spend their life in movement
These cells spend their time “patrolling the body” moving in and out of blood, node, marrow throughout their life looking for antigen.

Question 36

phase 4 malignant cell

Answer 36

chronic lymphocytic leukaemia
The problem with this disease is not fast growth or effects of the cells (they do very little) it is simply their slow and progressive increase in number
“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”

can have more rbc than wbc

Question 37

CLL lymphocyte

Answer 37

The CLL lymphocyte looks like a resting cell –the 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.
The main problem is that they are malignant and uncontrolled – they have a slow progressive proliferation and a tendency to survive in excessive number – the cells very slowly increase in number. Like the “parent cell” they migrate widely so from the time of diagnosis they are already present throughout the body!
Numbers slowly increase, long lived malignancy . Just doesn’t die – not told to die

Question 38

CLL patients complain of

Answer 38

1. Because this is a slow disease, most commonly CLL is diagnosed when a raised numbers of abnormal lymphocytes are detected in blood on a routine blood test

But people may present with effects of cell accumulation:

2. Widespread enlargement of lymph glands
3. Bone marrow failure as the CLL cells take over the marrow
4. Immune deficiency as normal lymphocytes are supressed

Question 39

phase 4

1. Increased numbers of abnormal lymphocytes in blood

Answer 39

CLL cells in blood: 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

Question 40

phase 4

2. lymphocytes accumulating in lymph nodes

Answer 40

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
Occur on both sides of body as these cells grow everywhere

Question 41

3. eventual accumulation and replacement of bone marrow

Answer 41

mass of CLL cells in marrow
Eventually the CLL cells accumulate in the marrow often as “lumps”. Ulitimately this can cause failure of the marrow function.

Question 42

main problem of CLL

Answer 42

The main problem though is Immune suppression and “autoimmune” effects
The CLL lymphocyte shares many features with the normal B lymphocyte

1. The normal immune system becomes supressed with increased infection rate and chronic ill health the most common cause of death in CLL.
2. The cells also interfere with the function of the normal immune system and can cause unwanted activity against the bodies own cells – autoimmune destruction of red cells is the most common

Part of normal immune system so can knock down immunity and interfere with function of immune system so we get autoimmune disorders. Cells which attack ur own body
Eg making antibodies against own red cells

Question 43

CLL also causes

Answer 43

anaemia
Immune destruction can damage red cells causing their rapid destruction and a severe anaemia
The damaged cells lose membrane and become small dense and round
Can be rapid process
Daily blood transfusions
Immunosuppression
Key treatment is to get rid of cll
If we kill cll cells makes immune dysfunction worse,
Eventually abnormal cells go away and haemolysis settles down

Question 44

cachexia

Answer 44

Chronic cell accumulation and persistent infections can take their toll………….
Lack of nutrition and muscle bulk
Lose weight, become frail