HAEMATOLOGY - LEUKAEMIA Flashcards
What are the 4 main types of leukaemia?
Acute myeloid leukaemia
Acute lymphoid leukaemia
Chronic myeloid leukaemia
Chronic lymphoid luekaemia
Which leukaemia diseases are most common in childhood and which in the elderly?
Childhood - ALL
Elderly - CLL
What risk factors are associated with leukaemia?
Radiation
Chemicals e.g. benzene
Previous chemo
Inherited bone marrow failure conditions
Down’s syndrome
What conditions can predispose you to leukaemia?
fanconi anaemia
Down’s syndrome
Myelodysplastic syndrome
Myeloproliferative disorders
li-fraumeni syndrome
ataxia-telangiectasia
What chemicals and drugs can predispose you to leukaemia?
Benzene can cause marrow damage
Chemotherapy drugs such as alkylating agents and topoisomerase 2 inhibitors - linked to AML
What viruses are associated with leukaemia?
Human T-lymphocyte virus
HIV
Whats the difference between leukaemias and lymphomas?
Leukaemias are mutated white cells in the blood
Lymphomas are malignancies of the lymphoid system
Whats the difference in age demographic between acute myeloid and acute lymphoid leukaemia?
Acute myeloid as a median age of presentation of 65
Acute lymphoid has a substantially lower age of presentation and is the most common maliganncy in childhood
What are the symptoms of leukaemia?
Breathlessness, fatigue, angina and claudication = Anaemia
Infections = neutropenia
Bleeding and bruising = thrombocytopenia
Breathlessness, headache, confusion, visual problems = leucostasis
Bone pain = marrow infiltration
Headache = CNS infiltration
Gout = hyperuricaemia
What are the signs of leukaemia?
Pallor, cardiac flow murmur = anaemia
Fever, mouth ulcers, septic focus = neutropenia
Petechia, bleeding gums, fundal haemorrhage = thrombocytopenia
Hypoxia, pulmonary infiltrates, reduces GCS, retinal dilation, papilloedema, fundal haemorrhage = leucostasis
Hepatospelnomegaly = liver and spleen infiltration
Lymphadenopathy = lymph node infilatration
Cranial nerve palsies = cns infiltration
Renal stones/trophi = hyperuricaemia
What are some signs specific to AML?
Gum hypertrophy = gum infiltration
Granulocytic sarcomas = skin infiltration
What are some signs specific to ALL?
Testicular enlargement = testes infiltration
Mediastinal mass = mediastinum infiltration
How do you confirm a diagnosis for acute leukaemia?
Blood count - Hb and Plt low, WBC raised
Blood film - blast cells
Bone marrow aspirate - increased cellulairyt, reduced erythropoeisis, reduced megakaryocytes
Chest X-ray - mediastinal widening is often present in T-lymphoblastic leukaemia
CSF examination - risk of CNS involvement is high in ALL
Coagulation profile - to exclude presence of disseminated intravascular coagulation which is particularly associated with acute promyelocytic leukaemia
When should you refer an adult with suspected leukaemia?
Consider a very urgent FBC (within 48 hrs) to assess leukaemia in adults with any of the following:
Pallor, persistent fatigue, unexplained fever, unexplained persistent/recurrent infection, generalised lymphadenopathy, unexplained bruising, unexplained bleeding, unexplained petechia, hepatosplenomegaly
How do we define acute leukaemia?
proliferation of immature white blood cells that comprise more than 20% of the cells of the bone marrow or peripheral blood stream
Outline the pathology of Acute leukaemia?
Myeloid blast cells LOs their ability to differentiate and divide uncontrollably in the bone marrow which crowds out of normal cells. This leads to a loss of cells in the bone marrow (pancytopenias). Eventually blasts build up so much they spill out into the blood stream. Some blast cells settle down in organs causing them to enlarge
What would you see on a blood smear for AML?
> 20% myeloblasts (large cells with nuclei containing fine chromatin and prominent nucleoli)
Low amount of cytoplasm
Presence of myeloperoxidase (done by cytoplasmic staining or you can look for auer rods)
What are auer rods?
Crystallised versions/aggregates of myeloperoxidase
What are the subtypes of AML?
M1 - AML with minimal maturation
M2 - AML with maturation
M3- APL (acute promyelocytic)
M4 - Myelomonocytic
M5 - Monocytic
M6 - Acute erythroid leukaemia
M7 - acute megakaryblastic leukaemia
What is acute promyelocytic leukaemia?
Leukaemia arising from promyelocytes (more mature than blast cells)
Caused by translocation of 15;17 which produced a fusion gene PML/RAR alpha which disrupts the retinoic acid receptor alpha gene which usually regulates cell division
Why is acute promyelocytic leukaemia a medical emergency?
These cells have a lot of auer rods which increase the coagulation risk, making it a medical emergency from disseminated intravascular coagulation
How do you treat acute promyelocytic leukaemia?
All transretinoic acid - a derivative of vitamin A which binds to disrupted retinoic acid receptor and causes the blasts to mature into neutrophils to lift some leukaemia burden
Followed by chemotherapy
Which leukaemia can cause swollen gums?
Acute Monoblastic leukaemia
Which type of AML has an association of Down’s syndrome before the age of 5?
Acute megakaryoblastic leukaemia -
Which leukaemia has Down syndrome as a risk factor?
Acute megakaryoblastic leukaemia before the age of 5
ALL
Which conditions can lead to AML?
Myelodysplastic syndrome
Myelodysplasia
What can a haematopoetic stem cell differentiate into?
Common myeloid progenitor and common lymphoid progenitor
What can a common myeloid pregenitor differentiate into?
Erythrocyte, thrombocyte or a myeloblast
What can a common lymphoid pregenitor cell differentiate into?
Lymphoblast
What can a lymphoblast differentiate into?
T cell
B cell
NK cell
What are the leukocytes?
Neutrophil, basophil, eosinophil, monocyte, B lymphocytes, T lymphocytes and NK cell
What are the 2 common chromosomal translocations that cause ALL?
T(12;21) and t(9;22) which result in the production of abnormal cell proteins which affects cells function and division
What are the 2 types of ALL?
B cell ALL (70-80% of cases)
T cell ALL
What is ‘AML with a background of myelodysplasia’?
When you have myelodysplastic syndrome causing a build up in blast cells and eventually the disease progresses and blast percentage may go over 20%
Why is Down syndrome associated with AML and ALL?
Due to an extra copy of chromosome 21 and common causes of leukaemia are due to translocations involving this chromosome
Which 2 symptoms are more likely in ALL than AML but can be seen in both?
Feeling of abdominal fullness - hepatosplenomegaly
Lymphadenopathy
This is because lymphoblasts are more likely to deposit in the spleen, liver and lymph nodes
What would you see on a blood smear for ALL?
> 20% lymphoblastic (smaller cells with coarse chromatin and small nucleoli)
Very little cytoplasm with glycogen granules
How can we use immunophenotyping to diagnose Acute Leukaemia?
TdT is a DNA polymerase that is only present in nuclei of lymphoblastic
CD10 is a surface marker for pre-B cells
How do we treat acute leukaemia?
Chemotherapy
Biological therapy
Stem cell transplants
Bone marrow transplants
What is chronic leukaemia?
A slowly progressing cancer that starts in blood-forming tissues such as the bone marrow, and causes large numbers of partially matured white blood cells to be produced and enter the blood stream.
Different from acute leukaemias as cells don’t mature at all
What causes CML?
Chromosomal transflocation that affects granulocytes
What causes CLL?
A variety of chromosomal mutations that affect lymphocytes, particularly B cells
Outline the pathophysiology of chronic leukaemia?
Mutations in myeloid and lymphocyte cells mean that cells mature only partially and so cannot work effectively
In CML cells divide too quickly
In CLL the cells don’t die as they should
In both situations we have loads of premature cells accumulating in the bone marrow and eventually they spill out into the blood. These can settle in organs or remain in the blood
Healthy cells get crowded out and its tough to survive with extra competition for nutrients - cytopenias.
Whats the most common cause of CML?
T(9;22)
Forms the Philadelphia chromosome (modified chromosome 22). This BCR gene sits next to ABL gene = BCR-ABL gene = BCR-ABL protein - this is a constitutionally active tyrosine kinase
This means myeloid cells keep dividing as the switch is always on
What is a blast crisis and why can CML develop into it?
The final stage of CML which appears and behaves like AML
It happens because of this constant cell division, there is a high chance that further genetic mutations can happen
Often caused by a trisomy of chromosome 8 or doubling of the Philadelphia chromosome.
What are the 3 stages of CML?
Chronic phase
Accelerated phase - blood samples 15-30% blasts, new chromosome changes, very low Plt, basophils make up 20% or more of blood
Blast phase - blast cells have spread to tissues and organs
What is the pathophysiology of chronic lymphocytic leukaemia?
A mutation means that B cells start to interfere with pathways of B cell receptors which should only be signalled during infection to activate specific tyrosine kinase
Interference with some tyrosine kinases prevents maturation and cell death so blast cells build up
In the bone marrow and eventually spill out into the blood
They move to the lymphatic system and form lymphomas
What are common surface proteins on blast cells?
CD5
CD19
CD23
What is Richters syndrome?
a rare complication of CLL where there is progression into a significantly more aggressive form of nonHodgkin lymphoma, usually diffuse large cell lymphoma.
Why can CLL cause autoimmune haemolytic anaemia?
CLL cells may process red blood cell antigens and act as antigen presenting cells, inducing a T-cell response and the formation of polyclonal antibodies by normal B cells, thus indirectly provoking autoimmune hemolytic anemia.
Why can CLL cause hypogammaglobulinaemia (a problem with the immune system that prevents it from making enough antibodies called immunoglobulins)?
The cells don’t produce enough gammaglobulins
How is chronic myeloid leukaemia diagnosed?
Blood smear shows increased granulocytes and monocytes
Genetic testing for the Philadelphia chromosome
How is CLL diagnosed?
Blood smear shows smudge cells (immature B cells broken during smear)
Genetic testing for chromosomal defects
Whats the treatment for Chronic leukaemia?
Biological therapy with a tyrosine kinase inhibitor - aims to stop cell division caused by BCR-ABL protein (this is less effective for CLL)
Chemotherapy
Stem cell transplants
Bone marrow transplants
Which leukaemias are associated with the Philadelphia chromosome?
CML
ALL
What are some complications of CLL?
Infections
Richters transformation
Autoimmune cytopenias - particularly autoimmune haemolytic anaemia
Second cancers
What causes immune dysfunction in CLL patients?
Dysfunction in cell mediated immunity
Hypogammaglobulinaemia
Neutropenia from marrow infiltration
Splenectomy
How does richters transformation commonly present?
New B symptoms in CLL
Usually happens at a median of 2-4 years post-diagnosis of CLL
What are some cancers that can come secondary to CLL?
Malignant melanoma
Larynx cancer
Lung cancer
CNS cancer in men
Stomach cancer in women
What is tumour lysis syndrome?
when tumor cells release their contents into the bloodstream, either spontaneously or in response to therapy, leading to metabolic and electrolyte abnormalities. These can progress to clinical toxic effects, including renal insufficiency, cardiac arrhythmias, seizures, and death due to multiorgan failure.
What causes tumour lysis syndrome?
The rapid breakdown of large numbers of cancer cells and subsequent release of large amounts of intracellular content into the blood stream, overwhelming normal haemostasis mechanisms
What electrolyte and metabolic abnormalities are seen in tumour lysis syndrome?
hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia
Which cancers is tumour lysis syndrome most commonly associated with?
Acute leukaemias with high WBC counts
Those with high-grade lymphomas
What is leukostasis?
a pathologic diagnosis in which white cell plugs are seen in the microvasculature. It’s a medical emergency. Aka hyperviscocity
Characterised by an extremely elevated blast cell count and symptoms of decreased tissue perfusion (dyspnoea, hypoxia, confusion coma etc)
Which leukaemia is leukostasis most commonly associated with?
AML
Whats the management for CML?
First line in Imatinib - tyrosine kinase inhibitor for Philadelphia chromosome positive cases
Hydroxyurea is second line
Interferon gamma
Bone marrow transplant
What are the common chromosomal changes in CLL?
Del 13q (deletion of long arm on chromosome e 13)
Or del 17p
Which type of autoimmune haemolytic anaemia is CLL associated with?
Warm
Which symptoms indicate Ritchers transformation?
Lymph node swelling
Unexplained fever and night sweats
Weight loss
Nausea
Abdominal pain
Which gene mutations in AML is associated with a worse prognosis?
FLT3
What are granulocytic sarcomas? Whats the most likely cause
Extramedullary tumours of immature granulocytic cells - solid tumours of myeloblasts
AML
Whats the most frequent cause of death in acute promyelocytic leukaemia and why?
Haemorrhage
Because there is fibrinogenolysis -
Heavily associated with disseminated intravascular coagulation
What chemotherapy treatment is used for AML?
Anthracycline or cytarabine arabiniside
Outline the prognosis of AML?
For those <40, more than 50% will survive 5 years
For those over 80 only 2% will survive 5 years
What chemo is used for ALL?
Methotrexate
When do you treat CLL?
If symptomatic or very progressive disease
No benefit for early treatment
Whats the prognosis for CML?
70-75% 5 year survival
Whats the management for CLL?
Fludarabine, cyclophosphamide and rituximab (FCR)
Which leukaemia causes massive splenomegaly?
CML
What are the chromosomal translocations in acute myeloid and acute lymphoid leukaemia?
AML - 15;17
ALL 12;21 and 9;22
What is hair cell leukaemia?
Rare type of CLL
Linked to a mutation in the BRAF gene which regulates cell survival
Affected B cells have hair-like projections. They build up in the bone marrow leading to fibrosis and therefore pancytopenia
Also found in large quantities in the spleen leading to severe splenomegaly
Which acute leukaemia causes thymus enlargement and what symptoms can this cause?
T cell ALL (as T cells migrate to thymus usually)
It can compress mediastinal structures leading to sympotms…
SVC - superior vena cava syndrome
Oesophagus - dysphagia
Trachea - dyspnoea and stridor
Whats the normal value of blast cells in bone marrow?
1-2%
How do myeloblasts and lymphoblastic look different?
Myeloblasts are large cells that have fine chromatin, prominent nucleolus and auer rods
Lymphoblastic are relatively small cells with coarace chromatin, scant nucleoli and little cytoplasm which contains glycogen granules
How can you distinguish between myeloblasts and lymphoblasts?
Blood stained smear
Immunophenotyping
How can immunophenotyping distinguish between myeloblasts and lymphoblastic?
TdT is a DNA polymerase only found in the nucleus of a lymphoblast
Also…
B cells express CD20 and CD19
T cells variably express CD1, 2, 3, 4, 5, 6, 7, 8
What is leukemoid reaction? How can you differentiate between this and CML?
an increase in the white blood cell count, which can mimic leukemia. The reaction is actually due to an infection or another disease and is not a sign of cancer
Differentiate by measuring leukocyte alaklaline phosphate (LAP) score. This will be low in CML due to low activity of maligannt neutrophils as they are non functioning
In leukemoid reaction there will be a normal or increased LAP score as the neutrophils are functional
What percentage of blasts will be seen on bone marrow biopsy in CML?
<10%
Unless blast crisis when it might be >20%
What proteins do abnormal B cells express in CLL?
CD5, CD20 and CD23
How do you diagnose hair cell leukaemia?
Blood smear will show cells with filamentous, hair-like projections
Aspiration of bone marrow will be a dry tap (as bone marrow is hypocellularity and cells are replaced by fibrous stroma)
Flow cytomegalovirus immunophenotyping to look for CD20, CD22, CD11C and CD25
What staging system do we use in the UK for CLL?
Binet staging system
Outline the Binet staging system?
stage A – you have fewer than 3 groups of swollen lymph nodes (likely to not have symptoms)
stage B – you have 3 or more groups of enlarged lymph nodes (likely to have no sympotms other than fatigue)
stage C – you have a low number of red blood cells or platelets (symptms!)
