2.02 - Malignant Haematology Flashcards
What are the broad types of haematological malignancies?
- leukaemia
- lymphoma
- myeloma
- myelodysplastic syndromes
- myeloproliferative syndromes
Broadly, what is the pathophysiology of haematological malignancy?
Loss of normal tight controls of haemopoiesis:
- too many cells proliferating
- cells don’t apoptose
- cells don’t differentiate
What are the myeloid malignancies?
- acute myeloid leukaemia (AML)
- chronic myeloproliferative neoplasms (MPNs)
What are the lymphoid malignancies?
- acute lymphoblastic leukaemia (ALL)
- chronic lymphocytic leukaemia (CLL)
- lymphoma
General presentation of haematological malignancy.
Symptoms of bone marrow failure:
- anaemia (tired, SOB, dizziness)
- thrombocytopenia (abnormal bruising or bleeding)
- neutropenia (recurrent infection)
Symptoms of disease involvement:
- lumps
- hepatosplenomegaly
Constitutional symptoms:
- weight loss
- drenching night sweats
- fevers
- intense pruritis
Symptoms of hypercalcaemia.
- fatigue
- abdominal pain
- N+V
- constipation
- confusion
- headaches
- polydipsia
- polyuria
Hypercalcaemia of unknown cause is investigated as…
Myeloma
Symptoms of hyperviscocity.
Can occur in any haematological malignancy.
- headaches
- visual disturbance
- sleepiness
- ischaemic events
Routine bloods to investigate haematological malignancy.
- FBCs
- U&Es
- LFTs
- CRP
- Ca2+
- haematinics
- retics
- blood film
Special bloods to investigate haematological malignancy.
- LDH & urate (cell turnover)
- serum free light chains
- flow cytometry
Imaging to investigate haematological malignancy.
- CT NeckCAP
- PET scan
- MRI spine/pelvis
Invasive investigations for haematological malignancy.
- core tissue biopsy
- bone marrow aspirate and trephine
What is flow cytometry?
Identifies classes of cells based upon the pattern of protein expression.
Malignant cells have different protein expressions, therefore will be highlighted on flow cytometry.
What is leukaemia?
A malignancy of the bone marrow causing an increase in the number of leukocytes.
How is leukaemia classified?
- myeloid vs lymphoid
- acute vs chronic
What is acute lymphoblastic leukaemia (ALL)?
The acute proliferation of lymphoid blast cells (B or T cells).
Presentation of ALL.
Pancytopenia:
- anaemia sx
- thrombocytopenia sx
- neutropenia sx
Bone pain (esp. younger pts)
Lymphadenopathy.
Age distribution of ALL diagnosis.
Peak age 0-4 years.
Investigations of ALL.
- FBCs
- blood film (lymphoblasts)
- bone marrow biopsy
- cytogenetics
- flow cytometry
Role of lumbar puncture in ALL.
ALL can migrate to the CSF.
LP can be used to diagnose and introduce chemotherapy into the CSF.
Management of ALL.
Multi-drug chemotherapy.
Associations of ALL.
- Down’s syndrome
- Philadelphia mutation (<20%)
What is acute myeloid leukaemia (AML)?
The acute proliferation of the myeloid stem cell or myeloid blast cell.
Precursor of AML.
- polycythaemia vera
- myelofibrosis
Blood film / bone marrow biopsy findings of AML.
- myeloblasts
- Auer rods in cytoplasm
Presentation of AML.
Pancytopenia:
- anaemia sx
- thrombocytopenia sx
- neutropenia sx
Treatment of AML.
Intensive chemotherapy.
Allogenic stem cell transplant.
What is the age distribution most commonly affected by AML?
Over 60s.
What are the three phases of chronic myeloid leukaemia (CML)?
- chronic phase
- accelerated phase
- blast phase
Presentation of CML.
- leukocytosis (incl. basophilia)
- splenomegaly
Otherwise usually asymptomatic at time of diagnosis.
Genetic mutation associated with CML.
Philadelphia mutation - activates tyrosine kinase pathway.
Results in uncontrolled cellular proliferation.
Chronic phase of CML.
- asymptomatic
- pts diagnosed after incidental leukocytosis
- can last several years
Accelerated phase of CML.
- blast cells infiltrate bone marrow and blood (<20%)
- patients become symptomatic (anaemia, thrombocytopenia, neutropenia)
Blast phase of CML.
- higher proportion (>20%) of blast cells in the blood
- severe symptoms (pancytopenia)
- often fatal
Management of CML.
Tyrosine kinase inhibitors can induce remission and give normal life expectancy.
Some patients remain in remission OFF medication - potentially curable.
What is chronic lymphocytic leukaemia (CLL)?
The slow clonal expansion of a single well-differentiated lymphocyte (usually B lymphocyte).
Presentation of CLL.
- asymptomatic
- age > 60 years
Complications of CLL.
- autoimmune haemolytic anaemia
- immune thrombocytopenic purpura
What is Richter’s transformation?
The rare transformation of CLL into high-grade B-cell lymphoma.
Blood film findings associated with CLL.
- smear / smudge cells
Management of CLL.
- chemotherapy
- targeted immune treatments
What are myeloproliferative neoplasms (MPNs)?
The uncontrolled and chronic proliferation of myeloid stem cells.
MPNs examples.
- primary myelofibrosis (PMF)
- polycythaemia vera (PV)
- essential thrombocythaemia (ET)
Proliferating cell line in
a) PMF
b) PV
c) ET
a) haematopoietic stem cells
b) erythroid cells
c) megakaryocytes
FBC consistent with PMF.
- anaemia
- high or low WCC
- high or low platelet count
FBC consistent with PV.
- elevated haematocrit
FBC consistent with ET
- thrombocytosis
Mutations associated with MPNs.
- JAK2 (most commonly)
- MPL
- CALR
Presentation of essential thrombocythaemia.
Thrombosis sx:
- headaches
- blurred vision
- erythromelalgia
Haemorrhage.
Splenomegaly.
Risks of ET.
Transformation to:
- myelofibrosis
- AML
Treatment for ET.
- low dose aspirin
- chemotherapy targeting platelets
- immunotherapy
What is polycythaemia vera (PV)?
JAK2 mutation causes uncontrolled production of red cells in bone marrow, despite EPO production being switched off.
Presentation of PV.
Thrombosis sx:
- headaches
- blurred vision
- erythromelalgia
Pruritis after a bath.
Plethoric complexion.
Risks of PV.
- leukaemic transformation
- myelofibrosis
Investigations for PV.
- FBC
- cytogenetics (JAK2)
- bone marrow biopsy
Treatment of polycythaemia (low risk of thrombosis).
- venesection
- low dose aspirin
Treatment of polycythaemia (high risk of thrombosis).
- chemotherapy
- JAK2 inhibitors
- allopurinol
Rationale of allopurinol in polycythaemia vera.
High RBC turnover increases uric acid release.
Allopurinol lowers the amount of uric acid in the blood, and prevents gout.
Secondary causes of thrombocytosis.
- bleeding
- iron deficiency
- inflammation
- infection
- post-surgical
- splenectomy
Secondary causes of polycythaemia.
- chronic hypoxia
- smoking
- obstructive sleep apnoea
- altitude
- renal / hepatic tumours (EPO secreting)
- congenital heart disease
Clinical signs of polycythaemia.
- red face
- conjunctival plethora
- splenomegaly
- hypertension
Causes of myelofibrosis.
- primary myelofibrosis
- polycythaemia vera
- essential thrombocythaemia
What is myelofibrosis?
Proliferation of a single cell line leads to bone marrow fibrosis.
Fibrosis affects the production of blood cells and leads to:
- anaemia
- thrombocytopenia
- leukopenia
Sites of extramedullary fibrosis.
- liver (hepatomegaly)
- spleen (splenomegaly)
- spine (spinal cord compression)
Blood film typical of myelofibrosis.
- teardrop-shaped red blood cells
- anisocytosis (varying sizes of red blood cells)
- blast cells
Risks of myelofibrosis.
Leukaemic transformation.
Management of myelofibrosis.
- supportive care
- JAK2 inhibitor
- splenectomy
- bone marrow transplant
What is lymphoma?
The clonal proliferation of lymphoid cells, ultimately resulting in lymphadenopathy.
What are the types of lymphoma?
- Hodgkin’s lymphoma
- Non-Hodgkins lymphoma
Microscopic findings in Hodgkin’s lymphoma.
Reed Sternberg cells
Risk factors for Hodgkin’s lymphoma.
- HIV
- Epstein-Barr virus
- autoimmune conditions (e.g. RA, sarcoidosis, SLE)
- family history
Age distribution of Hodgkin’s lymphoma.
20-25 years
then
80 years.
Types of non-Hodgkin’s lymphoma.
- diffuse large B cell lymphoma
- Burkitt lymphoma
- MALT lymphoma
Features of diffuse large B cell lymphoma.
Rapidly growing painless mass, in older patients.
Features of Burkitt lymphoma.
Associated with Epstein-Barr virus and HIV.
Features of MALT lymphoma.
Affects mucosa-associated lymphoid tissue, around the stomach.
Risk factors for non-Hodgkin’s lymphoma.
- HIV
- Epstein-Barr virus
- H. pylori
- HBV / HCV
- exposure to pesticides
- family history
Presentation of lymphoma.
Lymphadenopathy:
- non-tender
- firm
- rubbery
B symptoms:
- fever
- weight loss
- drenching night sweats
Non-specific symptoms:
- fatigue
- itching
- cough
- SOB
- abdominal pain
- recurrent infections
Investigations for lymphoma.
- immunohistochemistry
- flow cytometry
- cytogenetics
- karyotyping
- lymph node biopsy
CD antigens associated with:
a) T-cell lymphoma
b) B-cell lymphoma
a) CD20 and CD79a
b) CD3, CD4 and CD8
What is the lymphoma paradox?
How is lymphoma classified?
Ann Arbor / Lanugo classification - emphasises whether the affected nodes are above or below the diaphragm.
Treatment of Hodgkin’s lymphoma.
- chemotherapy
- radiotherapy
Management of non-Hodgkin’s lymphoma.
Depends on the type and stage:
- watchful waiting
- chemotherapy
- monoclonal antibodies
- radiotherapy
- stem cell transplantation
What is myeloma?
A bone marrow malignancy resulting in clonal proliferation of plasma cells.
What are paraproteins?
The clonal proliferation of a plasma cell results in the large quantities of a specific paraprotein, which is an abnormal antibody or part of an antibody.
What is multiple myeloma?
Where the myeloma affects multiple bone marrow areas in the body.
What is monoclonal gammopathy of undetermined significance (MGUS)?
Production of a specific paraprotein without other features of myeloma or cancer.
It is an incidental finding in an otherwise healthy person.
Risk of progression to myeloma for MGUS.
1%
What is smouldering myeloma?
Abnormal plasma cells and paraproteins, but no organ damage or symptoms.
Risk of progression to myeloma for smouldering myeloma.
10%
Pathophysiology of myeloma.
A genetic mutation in the bone marrow results in the clonal expansion of a single type of plasma cell.
This plasma cell produces a specific paraprotein:
- IgA
- IgG
- IgM
- IgD
- IgE
- kappa light chain
- lambda light chain
Presentation of myeloma.
Pathophysiology of anaemia of myeloma.
Bone marrow infiltration results in the suppression of other blood cell lines, leading to:
- anaemia
- leukopenia
- thrombocytopenia
What is myeloma bone disease?
Abnormal plasma cells release cytokines that promote osteoclast activity, and suppress osteoblast activity.
This results in bone resorption, AKA osteolytic lesions. These lesions are at risk of pathological fractures.
It also causes hypercalcaemia.
What is a plasmacytoma?
Individual tumours formed by cancerous plasma cells, occurring in bones or soft tissue.
What are the common sites of myeloma bone disease?
- skull
- spine (vertebral fracture)
- long bone
- ribs
What are the causes of renal disease in myeloma?
- paraprotein deposition in the kidneys
- hypercalcaemia
- dehydration
- glomerulonephritis
- medications used to treat the condition
What defines myeloma?
Risk factors for myeloma.
- older age
- male
- black ethnic origin
- family history
- obesity
What is hyperviscocity syndrome?
Clonal expansion of paraproteins increases plasma viscocity, causing a haematological malignancy.
It can cause complications:
- bleeding
- visual symptoms
- retinal haemorrhages
- neurological complications (e.g. stroke)
- heart failure
Laboratory investigations for myeloma.
- FBC (anaemia / leukopenia)
- calcium (raised)
- ESR (raised)
- plasma viscocity (raised)
- U&Es (?renal impairment)
Specialist laboratory investigations for myeloma.
- serum protein electropheresis
- serum free light chain assay
- urine protein electropheresis
What is the role of serum protein electropheresis in the diagnosis of myeloma?
Detects paraproteinaemia.
ie. heavy chains (IgA, IgG, IgM, IgD or IgE)
What is the role of serum-free light-chain assay in the diagnosis of myeloma?
Detects abnormally abundant light chains.
What is the role of urine protein electropheresis in the diagnosis of myeloma?
Detect Bence-Jones protein
What light chains do plasma cells produce?
Give the normal ratio.
Kappa:Lambda
2:1 ratio
Diagnostic test for myeloma.
Bone marrow biopsy.
Imaging used in myeloma.
- whole-body MRI
- whole-body low-dose CT
NB: NOT skeletal survey.
X-ray findings consistent with myeloma.
- well-defined lytic lesions
- diffuse osteopenia
- abnormal fractures
Raindrop skull / pepper-pot skull refers to multiple lytic lesions seen in the skull on an x-ray.
What is amyloidosis?
The extracellular tissue deposition of fibrils - commonly affects renal, liver, heart, gastrointestinal tract or peripheral nerves.
Management of myeloma.
Chemotherapy to induce remission.
Stem cell transplant may be an option for fitter patients.
Define stem cell transplant
a) autologous
b) allogenic
a) using the person’s own stem cells
b) using stem cells from a healthy donor
Management of myeloma bone disease.
- bisphosphonates
- radiotherapy
- orthopaedic surgery
- cemental augmentation
Complications of myeloma.
- infection
- bone pain
- fractures
- renal failure
- anaemia
- hypercalcaemia
- peripheral neuropathy
- MSCC
- hyperviscocity syndrome
- venous thromboembolism
What are myelodysplastic syndromes?
A form of cancer caused by a mutation in the myeloid cells in the bone marrow, resulting inadequate haematopoiesis.
Progression of myelodysplastic syndromes.
Risk to transform into AML.
Presentation of myelodysplastic syndrome.
Patients may be asymptomatic and diagnosed after incidental findings on a FBC.
They may present with symptoms of:
- anaemia (fatigue, SOB, pallor)
- neutropenia (frequent or severe infections)
- thrombocytopenia (bleeding and purpura)
Diagnosis of myelodysplastic syndromes.
- FBC (anaemia, thrombocytopenia, neutropenia)
- blood film (blast cells)
- bone marrow biopsy
Management of myelodysplastic syndromes.
- watchful waiting
- supportive treatment (e.g. blood or platelet transfusion)
- erythropoietin (anaemia)
- G-CSF (neutropenia)
- chemotherapy
- targeted therapies
- allogenic stem cell transplant
