Lymphoid malignancies Flashcards
Leukaemias can be classified by:
- How rapidly they progress
- The cell line that is affected
This makes 4 main types. What are they?
- Acute myeloid leukaemia
- Acute lymphoblastic leukaemia
- Chronic myeloid leukaemia
- Chronic lymphocytic leukaemia
What is the pathogenesis of haematological malignancies?
- Multi step process
- Acquired genetic alterations/mutations in a long lived cell from exposure to radiation for example
- Proliferative/survival advantage to that mutated cell over normal cells
- This produces a malignant clone
- The malignant clone grows to dominate the tissue - see image - red cells dominate causing leukaemia
- (e.g bone marrow or lymph nodes)
What is meant by the term stem cell self-renewal?
Hematopoietic stem cells are unique in that they have the ability to replenish themselves through self-renewal and give rise to differentiated cell lineages.
What are the main groups of lymphoid malignancies?
- Acute lymphoblastic leukemia (ALL) - proliferation but no differentiation - more common in childhood
- Chronic lymphocytic leukemia - proliferation and differentiation
- Lymphomas - proliferation and differentiation
- Multiple myeloma - proliferation and differentiation
Describe briefly the pathogenesis of acute lymphoblastic leukaemia (ALL)
- Mutations occur in the haematopoietic stem cell population
- These mutations cause proliferation but block maturation in the lymphoid lineage
- Results in rapid proliferation of immature blast cells (lymphoid progenitor cells) within the bone marrow
- These cells usually stay within the bone marrow but they can go anywhere and this is how you get variation in presentation between patients
Epidemiology of ALL
- Incidence = 1-2/100,000 population/year - not that common
- 75% cases occur in children < 6 years old
- 75-90% cases are of B-cell lineage (as opposed to T-cell ALL)
What is a typical presentation of ALL?
- Present with 2-3 week history of bone marrow failure (anaemia, SOB, fatigue etc) or bone/joint pain (tissue infiltration)
- Blood count will usually show anaemia, marked high WCC and thrombocytopenia
- The bone marrow biopsy will commonly show 90% B-lymphoblasts - B-cell ALL
How can immunophenotyping be used to determine disease for example ALL?
Immunophenotyping is when you put the cells through a machine that can tell the difference between disease (i.e myeloid/lymphoid) on the basis of the types of markers or antigens present on the cell’s surface. Because you cannot tell by just looking through a microscope.
The 2 key markers in ALL:
- CD19 - expressed on all B-cells
- CD34, TDT - markers of very early haematopoietic stem cells - these are very quickly lost in normal circumstances so if you see them then you know they are immature cells. They haven’t had the chance to differentiate yet.
Treatment of ALL
Standard treatment:
- Induction chemotherapy to obtain remission (kill off the leukaemic cells and allow normal bone marrow to form again)
- Consolidation therapy - vital for curation
- CNS directed treatment - intrathecal (directly into the CSF) - high risk of acute leukaemias or high-grade lymphomas involving the CNS
- Maintenance treatment for 18 months
Stem cell transplantation (if high risk i.e their risk of relapse is high).
New therapies = Blinatumumab and CAR - don’t need to know really
What factors put you at higher risk of a poor outcome with ALL?
- Increasing age - risk of relapse goes up with age
- Increased WCC - lymphoblasts spill into peripheral blood
- The patient’s cytogenetic/molecular genetics - t(9;22), t(4;11)
- How slow/poor the patient’s response is to the treatment
Describe briefly the pathogenesis of Chronic lymphocytic leukaemia (CLL), lymphomas and multiple myeloma
- These are all mature lymphoid malignancies meaning…
- Mutations either occur in the haematopoietic stem cell population or in the lymphoid progenitor cells
- These cells proliferate and differentiate into B-cells, T cells or plasma cells.
- They usually resemble normal, well-behaved lymphocytes meaning they grow slowly (or not at all) and carry many of the normal markers that B-cells have.
What does the lymphocyte count have to be to define it as CLL?
Lymphocyte count has to be >5
- Normal = <4
- You can find small populations of CLL cells in normal, healthy individuals and these cells just sit in the background but don’t progress to disease
What is the difference in meaning between Leukaemia and Lymphoma? (historical)
These terms are very old descriptive terms with no biological meaning. They describe the distribution of disease in the body:
- If predominantly in blood/bone marrow = leukaemia
- If predominantly in lymph nodes or other organs i.e liver = lymphoma
However, in modern times we realise that these diseases can behave similarly.
Give examples of where the terms Leukaemia and Lymphoma overlap (don’t need to know these inside out just be aware that the terms are flexible)
In day to day use clinicians tend to use the term for how the disease most commonly presents, however, there are sometimes exceptions to this:
- Take Acute Lymphoblastic Leukaemia for example – ALL most commonly develops in bone marrow/blood but occasionally it can be found in lymph nodes - in this case it is called lymphoblastic lymphoma
- Chronic Lymphocytic Leukaemia causes an increase in malignant lymphocytes (CLL cells) in the blood but sometimes there can be patients that present with a normal blood count and swollen lymph nodes – LN biopsy shows exact same disease –in this case it is called small cell lymphocytic lymphoma
- Burkitt’s lymphoma is the most aggressive lymphoma – often presents with swollen lymph nodes but you occasionally see it presnt as exact same disease as Acute Lympoblastic Leukaemia so then you call it Burkitt’s leukaemia
Different lymphocyte populations reside in different areas of the lymph node. Where do you find:
- T cells?
- B cells?
- Plasma cells?
- T cells are found in the paracortex
- B cells are in the Germinal centre within B cell follicles
- Plasma cells are found in the medulla
Describe the process of B-cell maturation and why this is important in relation to B-cell lymphoma?
- The B-cell is made in the bone marrow and released from there into the blood
- It makes its way into lymph nodes and moves into the germinal centre within
- Here the B-cells are exposed to antigens and then they rearrange/learn to recognise the antigen and attack it
- The B-cell then presents an anitbody on its surface that can bind this antigen and if it does this successfully it emerges from the germinal cell into the blood to fight the infection etc
- If it doesn’t do this successfully, it dies
Why is this important? B cell maturation is a high demand process that requires a lot of genetic rearrangement. If this goes wrong it results in B-cell lymphoma (the commonest type of lymphoma)
Describe the disease process in Acute Lymphoblastic Leukaemia (ALL):
- Where does it take place?
- What happens?
- In the bone marrow - early stage of lymphoid cell development
- There is a build up of lymphoblasts that fill up the bone marrow, some may spill over into the peripheral blood
Describe the disease process in Chronic Lymphocytic Leukaemia (CLL) and lymphoma:
- Where does it take place?
- What happens?
- After early lymphoid cell development in the bone marrow, cells spill out into the peripheral blood. These cells move into lymph nodes, into the germinal centres and look for antigens.
- If you have a malignant transformation at this stage it tends to arise in the lymph nodes.
Where do multiple myelomas form?
In the bone marrow as plasma cells tend to move back into the bone marrow
Look
This is roughly how common the lymphoid malignancies are in clinics. From more common to less common.
- High-grade NHL
- Low-grade NHL
- Hodgkin’s lymphoma
- CLL
- ALL
Binet staging for CLL
Stage is based on answers to the following:
- Do they have abnormal blood count?
- And Do they have enlarged lymph nodes?
Stage A, B or C
How are lymphomas staged?
The Ann Arbor staging system
- Stage 1 – 1 nodal site
- Stage 2 – 2 separate nodal sites either above or below diaphragm but not both
- Stage 3 – multiple nodal sites above and below the diaphragm
- Stage 4 – extranodal involvement i.e liver or bone
A - absence of B symptoms
B - b symptoms present such as fever, night sweats, weight loss
