Haematology Tutorial

Aims of the session
• Brief overview of the haematological system
• Leukaemias
• Lymphomas
• Myelomas and other paraproteinaemias
• SBAs

http://library.med.utah.edu/WebPath/webpath.html
Webpath
•SBAs
•Tutorials
•Images
•Covers most major systems of the body

OSCE Scenario
• You are a GP and a 23-year old woman comes to
visit your clinic complaining of decreased energy
levels. Please take a history and attempt to
formulate an appropriate management plan
(5 minutes)

Key Differentials - TATT
• Hypothyroidism
• Infection
• Menorrhagia
• Lyphoma
• Other Malignancies
NB: DON’T FORGET: 1) General Proforma
2) Systemic Symptoms
3) ICE

Terminally differentiated cells vs Partially
differentiated
Hematopoiesis

Some definitions
• Blast cell
• Terminally differentiated
• Totipotent stem cell

Some definitions
• Blast cell – immature precursors of either lymphocytes
(lymphoblasts) or myeloid cells (myeloblasts). They do not
normally appear in peripheral blood. They can be recognized by
their large size, and primitive nuclei (ie. the nuclei contain
nucleoli).
• Terminally differentiated - cells which have specialized
properties and functions. They are also unable to undergo
cellular growth or multiplication.
• Totipotent stem cell – a cell that is capable of developing into
any cell type including extraembyronic tissue.

Terminally differentiated cells vs Blast cells
Terminally differentiated Blast cells
Unlikely to transform to other cell types
Slow rate of cell turnover (tumours of
terminally differentiated cells will take
time to accumulate – chronic
leukaemias
Low cell turnover means they are less
responsive to chemotherapy
Highly specialized cell
Ability to transform to many cell types
Rapidly replicating (tumours of blast
cells can accumulate quickly causing a
acute leukaemias)
High cell turnover means they are more
responsive to chemotherapy
Not very specialized

• Pluripotent stem cell
• Granulocyte
• Pancytopenia

• Pluripotent stem cell – a cell which has the ability to
differentiate into more than one cell type. Pluripotent stem cells
are derived from totipotent stem cells. Pluripotent stem cells can
develop into any cell type except for the extraembryonic tissue.
• Granulocyte - a circulating white blood cell which has
prominent granules in the cytoplasm and a nucleus of two or
more lobes. They are derived from the myeloid lineage and
including neutrophils, basophils and eosinophils
• Pancytopenia - a reduction in the number of red and white
blood cells, as well as platelets. It occurs due to a problem with
the bone marrow.

Classification of Leukaemias
Classified according to the cell lineage
that is affected ie. myeloid or lymphoid
Also classified according to speed of
onset ie acute due to accumulation of
blast cells or chronic due to
accumulation of a terminally
differentiated cell.

Disorders of the
myeloid lineage

differentiated
Acute myeloid
leukaemias

differentiated
Acute myeloid
leukaemias The myeloid stem cell can
differentiate into myeloid,
monocytic, or erythroid cells,
or into megakaryocytes

differentiated
Acute myeloid
leukaemias The myeloid stem cell can
differentiate into myeloid,
monocytic, or erythroid cells,
or into megakaryocytes
Therefore, AML can be derived from myeloblasts (MI-M2), promyelocytes
(M3), a mixture of myeloblasts and monoblasts (M4), monoblasts (M5),
erythroblasts (M6), or megakaryoblasts (M7).

Acute myeloid leukaemias
• Characterized by the rapid growth of abnormal white blood
cells that accumulate in the bone marrow and interfere
with the production of normal blood cells.
• The most common acute leukemia affecting adults.
• Two classification systems – WHO and the FAB
• FAB classification still widely used and clinically important

French American British (FAB) classification
of AML
Classified based upon type of precursor / blast cell which is predominant
Type Name Cytogenetics Associated features
M0 minimally differentiated acute myeloblastic leukemia
M1 acute myeloblastic leukemia, without maturation Gum hypertrophy
M2 acute myeloblastic leukemia, with granulocytic maturation
t(8;21)
(q22;q12), t(6;9) Auer rods
M3 promyelocytic, or acute promyelocytic leukemia (APL) t(15;17) DIC and Auer rods
M4 acute myelomonocytic leukemia
inv(16)(p13q22),
del(16q)
M4eo myelomonocytic together with bone marrow eosinophilia inv(16), t(16;16) Eosinophilia
M5 acute monoblastic leukemia (M5a) or acute monocytic leukemia (M5b)
del (11q), t(9;11),
t(11;19) Hypokalemia
M6
acute erythroid leukemias, including erythroleukemia (M6a) and very rare pure
erythroid leukemia (M6b)
M7 acute megakaryoblastic leukemia t(1;22) Downs syndrome

AML BLOOD FILM – WHAT CAN BE SEEN?

Bone marrow apsirate showing Auer rods
• Highly specific for AML
subtypes M2 and M3

AML – Presentation
• Patients present with pancytopaenia due to a hypercellular bone
marrow
– Symptoms of anaemia
– Infections
– Bleeding
Other signs: Splenomegaly, Hepatomegaly, Lymphadenopathy
• Death in 6-12 weeks if left untreated.
• Best initial test is blood smear
– Blast cells present (blasts have occupied all of the bone
marrow and are now spilling over into the blood)
– WCC can be low, normal or high

Treatment of acute leukaemia
Supportive:
Problem
Anaemia
Thrombocytopenia
DIC
Infection
Tumour lysis syndrome
Treatment

Supportive:
Problem
Anaemia
Thrombocytopenia
DIC
Infection
Treatment
Packed RBCs
Platelets (if <10)
FFP, cyroprecipitate
Antibiotics, reverse
barrier nursing
Allopurinol/rasburicase

Definitive treatment for AML
Chemotherapy:
• Induction 4-6w
• Consolidation
• Duanorubicin + Cytobarine
• Other
• Add in all-trans-retinoic-acid (ATRA) in PML (M3)
during induction
• Monoclonal Ab
• CNS radiotherapy
• BM transplantation

The importance of the t(15;17) translocation
• The t(15;17) translocation is associated with PML
(M3) and produces a PML-RARα fusion protein
which binds to the retinoic acid receptor element
in the promoters of several myeloid-specific genes
and inhibits myeloid differentiation
• Treatment with Retinoic acid thus stimulates
cellular differentiation and has a big impact on the
prognosis of PML

differentiated
Myeloproliferative
disorders

Myeloproliferative disorders
• A group of disorders which are due to over
proliferation of terminally differentiated cells of the
myeloid lineage.
• Are classified according to whether they are
Philadelphia chromosome positive or negative.
• Have the ability to transfrom into an acute myeloid
leukaemia
Philadelphia positive Philadelphia negative
Chronic myeloid leukaemia Polycythemia rubra vera
Essential thrombocytosis
Myelofibrosis

Pathophysiology
Two classes of mutations may be required:

differentiated
Chronic myeloid
leukaemias

Stepped-up production of granulocytes and their
precursors and failed apoptosis leads to insidious
progression towards a blast crisis.
Epidemiology
•Incidence= 0.6-2/100,000
•Can occur at any age but rare in children. Peak
incidence at 40-60
•Less common than AML, CLL
Chronic myeloid leukaemia

Pathophysiology
95% involve t(9;22)(q34;q11) translocation,
resulting in the Philadelphia chromosome. This
forms a fusion gene- BCR-ABL1 with constitutively
active tyrosine kinase activity.

Usually asymptomatic!
•Examination
-Splenomegaly- may be only feature at latent
phase, massive later on
•Bloods
-Anaemia- mild, worsens with progression
-WBCs- extremely high
-Smear- leukocytosis with granulocyte left-shift
Symptoms

Leukocytosis,
increased
numbers of
banded
neutrophils

•Imatinib
-Tyrosine kinase inhibitor, targets BCR-ABL1. Greatly
increases 5 year survival compared to older drug
therapies
-Initial treatment, continued indefinitely if optimal response.
Other:
•Monoclonals
•Surgery
-Splenectomy for splenomegaly or pancytopenia
•Radiotherapy
-Pallative for bulky LN or splenomegaly
Treatment of CML

Prognosis
• Median survival 5-6 years.
• Chronic  Accelerated  Blast Transformation

differentiated
Polycythemia
rubra vera

• Clinical features
– Night sweats
– Hyperviscosity symptoms
– Pruritus after a hot bath
– Plethoric face
– Splenomegaly
– Haemorrhage
– Hypertension
– Gout
• Increased proliferation of erythrocytes, and
sometimes thrombocytes. Rarely increased
proliferation of granulocytes

• Important lab features
– Increased Hb, HCT, Red cell mass
– Low serum EPO
– Increased platelet count
– JAK2 mutation in 95%
• Treatment
– Venesection
– Cytotoxic myelosuppression
• Hydroxyurea
• Busulphan
INCREASED RISK OF DEVELOPING ACUTE
MYELOID LEUKAEMIA

differentiated
Histiocytosis (too many
dendritic cells and
macrophages aka histiocytes)

differentiated
Mastocytosis (too
many mast cells)

Disorders of the
lymphoid lineage

differentiated
Lymphoproliferative
disorders

differentiated
Acute lymphoblastic
leukaemias

Acute lymphoblastic leukaemia
Also known as ‘lymphocytic’.
Presents acutely with a pancytopenia and hypercellular bone
marrow.
Epidemiology
•Incidence = 1/50,000. Slight male predominance.
•Commonest type of childhood leukaemia (70%)
•Peak age 2-5 years, but later increase >50.
•Prognosis is poor if <1 year of age or >10 years of age.

Pathophysiology
UNCONTROLLED PROLIFERATION
•Genetic Factors - dysregulation of proto-
oncogene e.g. TEL-AML1 (25%).
• Environmental Factors – X Rays + DOWN’S
85% are derived from B-cell precursors.
-T-cell ALL
-B-cell ALL

Findings specific for ALL
•Examination
-Lymphadenopathy
-Splenomegaly (10-20% presentation)
-CNS signs- more likely
•Bloods
-Anaemia- usually severe, signs present
-WBCs- variable, usually neutropenia
-Smear- smallish basophilic blasts, few
granules, hand-mirror cells
-Clotting- 10% ALL presents with DIC
•Imaging
-Mediastinal mass in some T cell ALL

Small basophilic
blasts with few
granules

Supportive:
Problem
Anaemia
Thrombocytopenia
DIC
Infection
CNS prophylaxis
Treatment
Packed RBCs
Platelets (if <10)
FFP, cyroprecipitate
Antibiotics, reverse
barrier nursing
Allopurinol/uricase
Intrathecal chemo e.g.
methotrexate, cytarabine

Definitive
Chemotherapy:
•Induction 4-6w
•Consolidation
•Maintenance (ALL only) 1-2y
-Longer in boys
Other
•Monoclonal Ab
•CNS radiotherapy
•BM transplantation
•5 year survival
-Children- 75%
-Adults- 40%

differentiated
Chronic lymphoid
leukaemia/ lymphoma

98% develop from B cells.
Epidemiology
•Incidence = 4.2/100,000. Slight male
predominance.
•Most common form of leukaemia in the West
•Usually >55, median age 72, rare <40.

Pathophysiology
Largely unknown with no specific
genetic abnormalities.

Symptoms specific for CLL
Usually asymptomatic!
• Examination
-Lymphadenopathy/splenomegaly present in
late disease.
• Bloods
-WBCs- extremely high
-Smear- lymphocytosis with ‘smudge/basketball
cells’
• Other
-Richter’s syndrome
-Prolymphocytic transformation

Smudge cells-
destruction of
fragile
lymphocytes
during smear

Treatment of CLL
• Watchful waiting with regular monitoring
• Chemotherapy. Indications:
– Severe systemic symptoms
– Non-pred-responsive AI anaemia/thrombocytopenia
– Progressive splenomegaly/lymphadenopathy
– Increased WBC/reduced ‘doubling time’
• Surgery
– -Splenectomy for splenomegaly or pancytopenia
• Radiotherapy
– -Pallative for bulky LN or splenomegaly

What is the difference between lymphoma
and CLL
• Are part of a continuum of disease
• Leukemia usually refers to a condition in which the
abnormal cells populate the blood
• But lymphoma usually initially populates LN,
spleen etc. to form a tumour mass.

Hodgkin’s lymphoma
Originates from B cells in the germinal centres of
lymphoid tissue and is characterised by orderly
spread from one LN group to another.
Epidemiology
•Incidence = 2.2/100,000, 30% of all lymphoma
•Bimodal distribution with peaks at 15-30 and >50
years
•Slight male predominance

Risk factors
•Acquired
-HIV/AIDS- increases with CD4 count
-Previous non-Hodgkin’s lymphoma
-Autoimmune conditions
•Inherited
-Immune defects
-Family history of H/non-H lymphoma, CLL

Pathogenesis
Some proliferation of malignant Reed-Sternberg
cells (probably of B cell lineage) and abnormal
mononucleocytes.

Presentation
•Painless non-tender rubbery enlarged LN
-Cervical involvement in 60-70%, axillary in 10-
15%, inguinal in 6-12%
-May increase/decrease in size spontaneously
-May become ‘matted’ and non-mobile
-Contiguous progression to nearby groups
-Alcohol-induced pain
•Systemic symptoms
-Especially fever (30%), may be cyclic
-And severe pruritis (25%)
•Other
-Early satiety due to splenomegaly

Investigations
•FBC
-Exclude leukaemia, mononucleosis
•ESR/CRP
•LFTs
•U&Es
•CXR
-Lymphadenopathy, mediastinal expansion
•CT
-Thorax, abdomen for staging
•BM biopsy
•Other
-HIV, Monospot, LDH, thoracentesis, PET, LP,
MRI

Ann-Arbour staging
Automatic stage IV if extranodal involvement.
Systemic symptoms = B, extranodal = E, >10cm =
X, splenic involvement = S

Treatment
Supportive
•Fertility
•Cardiac function
•Respiratory function
•Tumour lysis syndrome
•Others, as indicated (see leukaemias slide)

Treatment
Definitive
•IA/IIA
-Radiotherapy alone- affected nodes and
prophylatically
-Chemo with radiotherapy of affected nodes
•IB/IIB/III/IV
-Chemo
•BM transplant
-If still progressive despite chemo or after
induction of remission after relapse

Non-Hodgkin’s lymphoma
A heterogeneous group of lymphoid tumours,
mostly of B cell origin. Characterised by irregular
pattern of spread and common extranodal disease,
they vary in their aggressiveness.
Epidemiology
•Incidence = 17/100,000
•Median age is >50
•Diffuse large B cell and follicular commonest

Risk factors
•Acquired
-Infection e.g. EBV (Burkitt’s), HTLV-1 (T cell),
HCV, HHV8 (Castleman’s), H. pylori (gastric
MALT)
-Previous chemotherapy/Hodgkin’s
-Autoimmune disorders e.g. Sjogren’s,
Hashimoto’s, coeliac
-Immunodeficiency e.g. post-transplant, HIV/AIDS
•Inherited

Presentation
•Painless non-tender rubbery enlarged LN
-Non-contiguous progression
•Systemic symptoms
-Commoner in high-grade
•Rash
-Cutaneous involvement e.g. mycosis fungoides, anaplastic large-
cell etc.
•Abdominal pain, early satiety
-Splenomegaly but unusual as rarely massive
-Hepatomegaly
•Mass
-Testicular
-GI, symptoms of obstruction
•Shortness of breath, pleuritic chest pain, SVC syndrome
-Mediastinal mass in high grade
•Neurological
-Primary CNS lymphoma, commoner in immunosuppressed

Investigations
•FBC
-Anaemia, thrombocytopenia, neutropenia
-Thrombocytosis, lymphocytosis may occur
•ESR/CRP
•LFTs
•U&Es
-Obstructive nephropathy, hypercalcaemia
•Serology
-HIV, HTLV-1, HCV
•Imaging
-CXR-Intrathoracic lymphadenopathy, mediastinal expansion
-CT-Thorax, abdomen for staging
-Bone scan
-PET
-MRI- Brain, cord
-USS- Scrotum
•BM biopsy
-Should always be carried out

•Lymph node USS and excision biopsy

Treatment
•Low grade
-Localised (rare)- radiotherapy, surgery
-Disseminated- watch and wait or chemo when
symptomatic/organ dysfunction
-Gastric MALT- associated with H pylori,
antibiotic therapy curative in 90%
•High grade
-Aggressive chemo e.g. CHOP
-Maintenance not needed
-Allogenic stem cell transplantation
-CNS prophylaxis in very high grade e.g.
Burkitt’s

Prognosis of lymphoma
5 year survival rates
•Hodgkin’s- highly curable
-I/II- 90%
-IV- 65%
-Long-term sequelae of treatment
•Non-Hodgkin’s- vary widely (see IPI)
-Overall 63%
-Indolent follicular lymphoma I/II- 91% but may
not be curable
-DLBLC- curable with aggressive chemo

differentiated
Plasma cell neoplasm e.g. Multiple
myeloma and Waldenstrom’s
macroglobulinaemia

• Multiple Myeloma
• MGUS
• Waldenstrom’s macroglobulinaemia
• (Non-Hodgkin lymphoma)
• (CLL)

• Presdisposing factors
– Radiation
– Benzene
– Pesticides
• Epidemiology
– 4 per 100,000 per year
– Median age 66 years
• Pathophysiology
– Post germinal centre B cell proliferation
• Monoclonal antibody

• Hypercalcaemia
• Renal impairment
• Anaemia
• Bone disease
• Hyperviscosity
• Amyloidosis (AL)
• Infection (recurrent)

• Amyloid L – Ig light chains
– paraproteinaemias
• Amyloid A – Protein A
– Chronic inflammation
• Amyloid TTR – Transthyretin
– Transthyretin abnormality
• Polyneuropathy,
• Restrictive cardiomyopathy
• Amyloid B2M – Beta 2 microglobulin
– Occurs in dialysis
• Carpal tunnel
• Also associated with Alzheimer’s disease, Diabetes
Mellitus

• FBC and film
• ESR
• Urine dipstick
• 24 hour urine collection
• U&Es
• Urate
• Albumin, calcium, phosphate, ALP
• Serum and urinary electrophoresis
• Serum Ig
• X-ray
• (BM Biopsy –diagnostic rather than screening)

1. Production of a single monoclonal antibody
(paraprotein)
– ‘M’ band in γglobulin region on serum/ urine
electrophoresis
2.Increased clonal plasma cells in the bone
marrow
– >20% monoclonal plasma cells on bone marrow
biopsy
3. Evidence of organ damage (‘CRAB HAI’)

• Prognosis
– MM remains an incurable disease
– Mean survival 3-4 yrs from diagnosis
• Treatment
– Specific
– Supportive

• Intensive or non intensive
– Intensive if <65
– Non intensive if >65
• Intensive
– 4-6 cycles chemotherapy
• Cyclophosphamide, dexamethasone, thalidomide
– THEN autologous stem cell collection and
transplant
• Non-intensive
– Chemo: Melphalan and cyclophosphamide

• Renal disease
– rehydration – 3L/day
• Bone disease
– Bisphosphonates
– Radiotherapy to bony lesions
– Corticosteroids
• Anaemia
– Transfusion/ EPO
• Hyperviscosity
– Plasmapheresis
• Infection
– Broad spectrum Abx and antifungals

• Post germinal centre B cell proliferation
• Monoclonal antibody/ paraprotein production
– M Band
– BJP
• >20% monoclonal plasma cells in BM
• ‘CRAB HAI’
• Specific and supportive treatment
• Outcome still poor

• Often discovered incidentally in elderly
• Benign
• Characterised by:
– Low levels of paraprotein, normal levels of Ig
– <10% plasma cells in bone marrow
– Absence of lytic bone lesions
– Absent/minimal urinary BJP
– Absence of end organ damage associated with MM
• 1% per year develop MM

• Lymphoplasmacytoid proliferation
– Similarities with CLL
• IgM paraprotein
– Plasma viscosity
• Organomegaly and lymphadenopathy more
common than in MM
– No end organ damage (cf MM)

A 67 year old lady is found to have an Hb of
18.9g/dL. Her erythropoeitin level is markedly
raised. Which of the following is the least likely
diagnosis?
A) COPD
B) Eisenmenger’s syndrome
C) Polycythaemia vera
D) Renal cell carcinoma
E) Nepalese woman living at high altitude

Which one of the following is not consistent with a
diagnosis of MGUS?
A) normal urinalysis
B) normal renal function
C) 20% plasma cells in bone marrow
D) Normochromic, normocytic anaemia with
Rouleaux formations
E) Absence of lytic bone lesions

A patient has a sharp M band on serum
electrophoresis. Which of the following is least
consistent with this result?
A) IgG MM
B) Waldenstrom’ macroglobulinaemia
C) AA amyloidosis
D) MGUS
E) CLL

Which ONE of these is the most likely clinical
presentation of a child with acute lymphoblastic
leukaemia?
a) A 6 month history of fatigue and repeated upper
respiratory tract infection
b) Poor appetite and abdominal pain resulting from
swollen spleen
c) Swollen gums in the mouth
d) Recent history of bruising and tiredness
e) None- incidental finding

A blood smear of a patients shows increased
numbers of neutrophils, eosinophils and
basophils. In addition, there are increased
numbers of promyelocytes (but infrequent blast
cells). What is the optimum treatment for this
patient?
a)Allogenic stem cell transplantation
b)Combination chemo
c)Imatinib
d)Blood transfusion to relieve symptoms
e)Rifampicin and isoniazid

A 59 year old man receiving chemotherapy for
NonHodgkin’s Lymphoma develops painful
haematuria. Which of the following is the most
likely cause of his symptoms?
A) Rituximab
B) Cyclophosphamide
C) Adriamycin (doxorubicin/
hydroxydaunarubicin)
D) Vincristine (oncovin)
E) Prednisolone

A 50 year old woman is about to commence
chemotherapy for treatment of AML. Which of
the following medications should she be started
on prior to chemotherapy?
A) Colchicine
B) Dexamethasone
C) Diclofenac
D) Allopurinol
E) Hydroxychloroquine

A 6 year old boy from Kenya develops swelling of
the jaw. The mass responds rapidly to
chemotherapy. What is the most likely diagnosis?
a) Burkitt's lymphoma
b) Follicular lymphoma
c) Mycosis fungoides
d) Lymphoblastic lymphoma
e) Enteropathy-associated T cell lymphoma

A 22-year-old man presents with fever, sweating, particularly at
night, pruritus and weight loss.
O/E: palpable, painless cervical lymph nodes and no skin
manifestations. The most appropriate investigation would be:-
a) FBC
b) Lymph Node Biopsy
c) Chest Radiograph
d) CT scan of the neck and mediastinum
e) Mantoux Test

25-year-old woman presents with a single, non-tender, enlarged
cervical lymph node. She also complains of fever and night
sweats. Lymph node biopsy reveals infiltration with histiocytes
and lymphocytes and presence of cells with bilobed mirror-image
nuclei. The most likely diagnosis is:-
a) Non-Hodgkin’s lymphoma
b) Hodkin’s lymphoma
c) Sarcoidosis
d) Acute Lymphoblastic Leukemia (ALL)
e) TB

30-year-old man has had a progressively worsening productive
cough for one month. On physical examination, a few small non-
tender lymph nodes are palpable in the axillae, and the tip of the
spleen is palpable.
Hb 10.2 g/dl,
Hct 31.1%
MCV 90 fL,
WBC count 67 x 10 9
/ L
Platelet count 36 x 10 9
/ L.
Microscopic examination of his peripheral blood smear shows
many blasts with Auer rods. Which of the following is the most
likely diagnosis?
A) Leukemoid reaction
B) Acute myelogenous leukemia
C) Chronic lymphocytic leukemia
D) Acute lymphoblastic leukemia
E) Leukoerythroblastosis

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