3. • In an adult, all blood cells are produced
in the red marrow.
• Restricted to the bones of the axial
skeleton (vertebrae, ribs, sternum, skull,
sacrum, pelvis and femur).
• In fetal life, the major haemopoietic
tissues are:
• Yolk sac (before 6 weeks).
• Liver and spleen (6 weeks to 6-7 months).
• In disease, the liver and spleen can again
become haemopoietic, even in adult life
(extramedullary haemopoiesis).
4. • The same basic pathological mechanism underpins a large number of
haematological malignancies.
• Essentially, a haemopoietic stem cell in the BM acquires genetic
mutations which disrupt the normal differentiation and maturation
of its progeny.
• The resulting disease depends on how these mutations affect the
differentiation pathway.
5. Undifferentiated
Differentiated
Normal Abnormal
differentiation differentiation
Lymphomas
7. • Characterised by the presence of large numbers of
undifferentiated blood cells (blasts) in the BM.
• These immature cells rapidly overwhelm the normal
developing blood cells and spill out into the
peripheral blood.
• Clinical features reflect the consequences of bone
marrow failure.
• Highly aggressive and rapidly fatal without treatment
(6-12 weeks).
• Sudden onset of marrow failure
• Types: (pancytopenia).
- Fatigue and lethargy (↓RBCs)
• ALL - acute lymphoblastic leukaemia - Infections (↓WBCs)
• AML - acute myeloid leukaemia - Bleeding, bruising and purpura (↓Plts)
• Bone pain (esp. in children)
• Diagnosis requires the presence of > 20% blasts in • Lymphadenopathy
the blood or bone marrow.
• Splenomegaly
8. • ALL (acute lymphoblastic leukaemia):
• Commonest childhood cancer (peak incidence
at age 2-4 years)
• Modern treatment has improved prognosis
significantly (4 stages - induction, consolidation,
CNS prophylaxis, and maintenance)
• Male gender and age > 10 years represent
negative prognostic factors.
• AML (acute myeloid leukaemia):
• Sudden onset of marrow failure
• May occur at any age, but becomes increasingly
(pancytopenia).
common in older people.
- Fatigue and lethargy (↓RBCs)
• Down’s syndrome = 400x greater incidence. - Infections (↓WBCs)
- Bleeding, bruising and purpura (↓Plts)
• Poor prognosis, patients over the age of 70 • Bone pain (esp. in children)
rarely survive beyond 1 year.
• Lymphadenopathy
• Splenomegaly
9. • Commonest leukemia in adults.
• Characterised by the accumulation of small mature
B lymphocytes in the BM and peripheral blood
(smear cells).
• Unknown aetiology.
• Peak incidence 60-80 years; male 2:1 female.
• A watch and wait policy is usually appropriate for
many patients.
• Around 10% develop a high-grade non-Hodgkin • Slow and indolent, many asymptomatic
at diagnosis
lymphoma, which is refractory to treatment and
• Isolated lymphocytosis (↑WBCs)
carries a very poor prognosis (Richter’s syndrome). • Anaemia (tiredness and fatigue)
• Recurrent infections
• Autoimmune phenomena (AIHA, ITP)
• Lymphadenopathy (late)
• Bone marrow failure (late)
10. • A group of neoplastic disorders characterised by the
overproduction of normal myeloid cells.
• Occur mostly in the elderly.
• Caused by a genetic abnormality which bestows a
proliferation advantage to one or more myeloid cell
lineages.
• Types:
• Chronic myeloid leukaemia (↑neutrophils)
• Polycythaemia vera (↑RBCs)
• Essential thrombocythaemia (↑Plts)
• Primary myelofibrosis (↑Megakaryocytes)
• Diagnosis is difficult as blood cell overproduction can
often be a normal physiological response.
11. • CML is the most common myeloproliferative
disorder.
• Very rare in children; incidence increases with age.
• Examination of the peripheral blood reveals large
numbers of neutrophils and neutrophil precursors.
• Associated with the Philadelphia chromosome.
• 95% possess the t(9;22) translocation.
• The translocation produces an abnormal fusion
gene, BCR-ABL, which generates a protein with • Pallor
excessive tyrosine kinase growth signaling • Night sweats
properties. • Fatigue, weight loss and anorexia.
• Massive splenomegaly
• Tx. imatinib (tyrosine kinase inhibitor - not curative). • Begins with a ‘chronic’ phase (5
years) which then spontaneously
transforms into a ‘blast’ crisis with
fulminant bone marrow failure.
12. • Increased production of RBCs.
• Excess proliferation of other myeloid lineages is
usually seen (↑neu ↑plts).
• Rarely presents before age 40.
• 90% of cases associated with a mutation in the
erythropoietin signaling pathway (JAK-2).
• The key to diagnosis is the exclusion of a secondary
physiological erythrocytosis.
• Chronic hypoxia (e.g. lung disease) • Plethora (red face)
• Erythromelalgia (burning red skin)
• ↑EPO secretion (e.g. RCC, PCKD) • Pruritus (particularly after hot baths)
• Thrombosis is a serious risk. • Hepatosplenomegaly
• Headache, dizziness and stroke (↑
• With treatment (venesection), patients often survive blood viscosity).
10 years; most die from thrombosis / haemorrhage. • Mesenteric, portal or splenic vein
thrombosis.
14. • Increased production of platelets (megakaryocyte
cell line).
• Platelet count > 600 x 109/L (normal = 150-400)
• Difficult to differentiate from reactive causes of
thrombocytosis (e.g. infection, malignancy).
• 50% possess JAK-2 mutation.
• Usually affects older patients; presents with
thrombotic or bleeding complications.
• An indolent condition with a median survival of • Many asymptomatic (25%)
• Erythromelalgia and digital ischaemia
12-15 years.
(intense burning and pain)
• Rarely transforms into an acute leukaemia. • Stroke
• Recurrent abortions and fetal growth
retardation
• Hepatic and portal vein thrombosis
(e.g. Budd-Chiari syndrome)
15. • Overproliferation of megakaryocytes which release
fibroblast-stimulating factors (e.g. platelet-derived
growth factor).
• Usually presents age 50+
• These factors stimulate marrow stromal cells to lay
down fibrous tissue in the BM.
• The marrow space becomes obliterated resulting in
extramedullary haematopoiesis.
• Immature nucleated RBCs and neutrophils enter the • Hepatosplenomegaly and pallor
peripheral blood (leukoerythroblastosis). • Splenic pain
• Constitutional symptoms (weight
• Distorted RBCs (teardrop cells) and a ‘dry tap’ on loss, night sweats, fever)
trephine needle biopsy are typical. • Anaemia symptoms (SOB, fatigue,
palpitations)
• Very poor prognosis, 3-5 years.
• Gout (increased cell turnover =
hyperuricaemia)
16. • A malignant disease of plasma cells in the BM.
• Unknown aetiology.
• Generalised BM involvement; although areas of
greatest haematopoietic activity (vertebrae, ribs and
skull) are predominantly affected.
• Malignant plasma cells produce a single non-
functioning monoclonal immunoglobulin
(paraprotein) in large quantities.
• The abnormal plasma cells also produce free
immunoglobulin light chains, which are readily filtered
and excreted by the kidneys (Bence-Jones protein).
17. • Clinical features:
• Bony destruction: proliferating plasma cells
stimulate osteoclast activity (lytic lesions).
• Immunosuppression: production of normal
immunoglobulins is impaired, leading to immune
paresis (recurrent infections).
• Renal failure: free light chains produced by the
malignant cells become trapped in the renal
tubules resulting in kidney damage.
• Diagnosis: • Peak age 50-60 years.
• Bone destruction / pain
• Serum electrophoresis (serum paraprotein) • Renal failure
• Urine electrophoresis (Bence-Jones protein) • Bone marrow failure
• Bone marrow aspirate (demonstrates plasma cell • Immunodeficiency
infiltration).
• Hypercalcaemia
• Amyloidosis (peripheral neuropathy,
cardiomyopathy etc)
18. • The same basic pathological mechanism underpins a large number of
haematological malignancies.
• Using knowledge of haematopoiesis, the haematological malignancies
can be categorised into:
• Acute leukaemias
• Chronic leukaemias
• Myeloproliferative disorders
• Others (e.g. myeloma)
• In part two of this series, we will be covering the topic of lymphoma.
20. (1)A 63 year old female presents to her GP with general fatigue and lethargy of 6 months
duration. She suffers from HTN, but is otherwise well. A FBC reveals ↑WBCs and ↓Hb
(iron, B12 and folate are normal). The doctor orders a blood film.
Examination of the blood film reveals large reticulocytes and damaged red cells. The
presence of characteristic smear cells is also noted.
What is the most likely diagnosis?
a) Acute myeloid leukaemia
b) Multiple myeloma
c) Iron deficiency anaemia
d) Chronic lymphocytic leukaemia
e) Essential thrombocythaemia
21. (2)A 4 year old boy presents with his mother. His mother explains he has had a widespread
rash for 7 days and that he has been ‘somewhat lethargic’ for the last 2 weeks. O/E: he is
pale, with a widespread purpuric rash but there is no fever or meningism; generalised non-
tender lymphadenopathy and splenomegaly are also noted. A FBC reveals ↓WCC, ↓Hb,
↓Plts and a blood film is ordered.
Examination of the blood film reveals blast cells.
What is the most likely diagnosis?
a) Bacterial meningitis
b) Acute myeloid leukaemia
c) Acute lymphoblastic leukaemia
d) Chronic lymphocytic leukaemia
e) Essential thrombocythaemia
22. (3)A 65 year old man presents to his GP with intermittent headache and dizziness of 6 months
duration. He has also noted an unpleasant burning sensation in his hands and feet, especially
when he is in the shower. O/E: both his big and first toes of his right foot are dusky in colour
and tender to touch.
What single pathological process is most likely to account for his symptoms?
a) Bone marrow failure
b) Plasma cell proliferation
c) Chronic haemolysis
d) Chronic lymphocytic leukaemia
e) Myeloproliferation
23. (4)A 58 year old farmer presents with severe upper arm pain having suffered a trivial fall at
home. He also complains of lower back pain and significant lethargy for the last 6 months.
O/E: he is notably pale with a pulse of 120 bpm, with a visibly inflamed and painful upper left
arm. He is also considerably kyphotic. Urinalysis is +++ for protein.
What is the most likely haematological diagnosis?
a) Multiple myeloma
b) Grave’s disease
c) Chronic lymphocytic leukaemia
d) Primary myelofibrosis
e) Essential thrombocythaemia