Lecture 14/15 - Lymphoid malignancies Flashcards
Malignant lymphoid cells: where do they arise from and how are they typically distinguished from ‘normal’ cells?
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
Malignant cells arising from the initial lymphocyte production stage
Will be highly proliferative cells in bone marrow
Malignant cells arising from cells responding to antigen
Rapidly proliferating cells found in lymphoid tissues
Malignant cells arising from cells that have met antigen
Will often perform actions e.g. antibody production
Malignant cells arising from memory cells
Will tend to perform actions involving migration and tissue invasion
If malignant cells are so similar how can we tell a difference?
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
Hairy cell leukaemia: what is it caused by, what causes its phenotype, and where can it be found?
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.
Blast cells: where do they develop, are they proliferative, and what are their key features?
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
Why do blast cells typically have bigger, lighter nuclei?
DNA is constantly replicated, these proliferative cells don’t typically have their DNA wrapped in histones
Acute
Rapid appearance/development
Lympho
Refers to lymphocyte origin
Blastic
Refers to the capability to make rapid divisions
Leukaemia
White blood - reflects the tendency to spill from the bone marrow into blood in large numbers
Acute lymphoblastic leukaemia name meaning
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
Bone marrow: where do lymphocytes grow and what aspects does the bone marrow have?
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)
Later malignant cell behaviour: what do they do and how do they interact with normal cells?
- 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
Why do people become ill: what are the main symptoms and how do they cause illness?
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
ALL mutations: how do they act in children, what can they carry, and how do they act in the elderly?
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
Normal vs malignant lymphoma
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
Burkitt lymphoma: how specific is it, how does it occur, what is it caused by, and how severe is it?
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
Glandular fever: what is it and what is it caused by?
Never goes away, just suppressed by the immune system - ggle
Caused by EBV
Plasma cells: what does it look like when activated?
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
Normal plasma cell movement
Post-antigen cells moves from the lymph nodes into the blood then into the marrow where it grows
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?
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
Malignant lymphocytes symptoms
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
What happens to memory cells following target elimination
Many cells die
Others persist as memory cells
Round and unexciting “resting cell” that migrates widely between nodes, blood and tissues looking for antigens
Chronic lymphocytic leukaemia: what are they, what do they look like, and how do they form?
“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
CLL diagnosis: why is CLL diagnosis typically hard to do, what ways may it be detected by, and
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
CLL: immune system effects
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)
Cachexia
The effect of the body fighting persistent infections and having chronic cell accumulation and eventually resulting in an aged-looking body
