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Haematology > Haematology 2 > Flashcards

Haematology 2 Flashcards

1
Q

Features of myelodysplastic syndrome that just affects RBCs

A
  • anisocytosis
  • poikilocytosis
  • hypochromic
  • pyknotic
  • basophilic inclusions (Pappenheimer bodies)
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2
Q

What’s a Perls stain used for?

A

If coloured Prussian blue then granules are siderotic (iron). These are normally ‘bitten’ out by macrophages in the spleen.

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3
Q

What does pyknotic mean?

A

Irreversible condensation of chromatin in the nucleus of a cell undergoing necrosis or apoptosis. It is followed by karyorrhexis, or fragmentation of the nucleus.

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4
Q

Myelodysplastic syndromes can progress to….

A

AML

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5
Q

MDS diagnosis is based on…

A
  • Abnormal blood count.
  • Dysplastic features on bone marrow aspirate and trephine.
  • Increased blast count.
  • Abnormal karyotype.
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6
Q

Things that cause dysplastic features

A
  • Chronic inflammatory conditions
  • Nutritional deficiency
  • Hepatic or renal impairment
  • Alcohol
  • Endocrine disorders – hypothyroidism
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7
Q

What’s a normal amount of blast cells to find in bone?

A

< 5%

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8
Q

Diagnostic tests for MDS

A 
• Blood count and blood film
• Biochemistry
• Liver function
• Thyroid function test
• CRP ESR
• Autoimmune screen
• HIV and virology
• Bone marrow aspiration
    – Search for dysplastic changes and count the proportion of blasts
    – Mandatory cytogenetics
    – Trephine
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9
Q

Clinical features of MDS

A
  • Anaemia
  • Mouth ulcer (neutropenia)
  • Purpura (thrombocytopenia)
  • Pneumonia (neutropenia)
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10
Q

Two ways in which AML can occur

A 
De Novo AML 
Secondary AML (previous  MDS, Myeloproliferative Disorders)
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11
Q

What proportion of acute leukaemias are AMLs?

A

80%

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12
Q

Clinical features of AML

A
  • Anaemia – Pale, tired
  • Thrombocytopenia – bleeding and bruising
  • Neutropenia – infection
  • Catabolic state – weight loss, fevers, sweats
  • Organ infiltration - hepatosplenomegaly, gingival hypertrophy, and CNS infiltration
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13
Q

Types of bruising

A

Petechiae < 2mm

Purpura 3-5 mm

Ecchymosis >5mm

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14
Q

Infections in AML

A
  • Pseudomonas pyocyanea
  • Candidal septicaemia
  • HSV
  • Candida plaques
  • Aspergillomas in brain
  • Toxoplasma
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15
Q

Classification of AML

A

> 20% myeloid blasts in bone marrow

  1. Morphology
  2. Cytogenetic abnormalities- bone marrow aspirate- major impact on clinical outcome.
  3. Genetic abnormalities
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16
Q

FAB classification

A

French American British classification for AML based on morphology

MO - no evidence differentiation (blasts with no granules)
M1 – minimal differentiation
M2 – myeloid (granulocytic), myeloid blasts with granules
M3 - Acute Promyelocytic Leukaemia (APL, APML), abnormal promyeloblasts, lots of granules and folded nuclei
M4 – Myelomonocytic
M5 - M5a – monoblastic M5b – monocytic
M6 – erythroleukaemia
M7 – megakaryoblastic

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17
Q

Flow panel for B lymphoid

A

CD19, cCD22, cCD79a, CD10, CD19, anti-κ, anti-λ

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18
Q

Flow panel for myeloid cells

A

CD13, CD117, anti-cMPO, CD14, CD33

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19
Q

AML blast flow cytometery phenotype

A
  • Express CD33, CD117, CD15 CD56 and cMPO

- Does not express CD3, CD7 (T-cell), nor B-lymphoid markers like CD19 and CD10

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20
Q

Therapy for fit AML patients

A
  1. Combination chemotherapy to achieve complete remission (marrow blast count ≤5% with normal blood counts).
  2. APL (AML M3): Rx with All Trans Retinoic Acid. Arsenic is also used.
  3. Occasionally we give antibodies directed against leukaemic cells (anti-CD33 Mylotarg).
  4. In some patients we consider bone marrow transplantation. There are several types of transplant depending on source of donor stem cells and the type of chemo/radio therapy given.
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21
Q

Therapy for unfit AML patients

A
  1. Supportive care. Survival is only 2-3 months.
  2. Low dose chemotherapy – palliative.
  3. New agents – Epigenetic therapy. Azacitidine (causes DNA hypermethylation) and HDAC inhibitors. Anti-CD47 trial in Oxford
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22
Q

Prognosis for AML patients

A
  1. Age – elderly do worse – can not tolerate RX and disease is less sensitive to Rx.
  2. Performance status at time of therapy.
  3. De novo AML does better than secondary AML.
  4. Relapsed and refractory disease does worse.
  5. Cytogenetics and molecular mutations.
  6. Prior therapy
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23
Q

Common mutations in AML

A 
NPM1
FLT3
TDK
CEBPA
ITD
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24
Q

ATRA

A

all-trans-retinoic acid

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25
Q

Mutations in signal transduction

pathways that promote proliferation.

A

JAK2
BCR-ABL
CALR
MPL

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26
Q

Types of s myeloproliferative

Neoplasms (MPNs)

A

White blood cells (myeloid)
Chronic myelogenous leukaemia, BCR-ABL1 positive

RBCs
Polycythemia vera

Megakaryocytes (secondary phenomenon - secondary scaring of bone marrow)
Primary myelofibrosis

Platelets
Essential thrombocythemia

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27
Q

Concept of clonal disorder of myeloid lineage

A

A mutation arising in a single stem cell eventually causes “clonal dominance” and emergence of MPN

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28
Q

Basic Leukaemia Classification

A

Acute Leukaemia:
Acute Myeloid Leukaemia (AML)
Acute Lymphoblastic Leukaemia (ALL)

Chronic Leukaemia:
Chronic Myeloid Leukaemia (CML)- Classified as a myeloproliferative neoplasm
Chronic Lymphocytic Leukaemia (CLL)

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29
Q

Laboratory Assessment of MPNs

A
  • Full blood count
  • Blood film examination
  • Bone marrow aspirate and trephine:
    • Morphological assessment including cytochemistry (Blast %, Assess different lineages – number and appearance)
    • Flow cytometry
    • Cytogenetics
  • Molecular analysis: Blood or bone marrow
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30
Q

AML

A

In marrow:

  • Auer rods (abnormal lysosomes)
  • Myeloblasts
  • Monoblasts
Blood:
Anaemia
Neutropenia
Thrombocytopenia
> 30% myeloblasts

Adults

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31
Q

CML

A

Marrow:

  • Hypercellular marrow
  • Elevated eosinophils and basophils (deep purple)

Blood:

  • WBC >200K-1000K
  • Some blast cells in blood
  • Increased eosinophils and basophils

Splenomegaly

Ages 20-50, rare in children

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32
Q

CLL

A

Smudge cells
Condensed chromatin
Scant cytoplasm

Sustained abs
Lymphocytosis >5000/uL
Low platelets in 20-30%

Most common leukemia in adults (2 x more common in men)

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33
Q

ALL

A

Condensed chromatin
Scant cytoplasm
Small nucleoli

Anaemia
Thrombocytopenia
Variable WBCs
> 30% lmphoblasts

Children

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34
Q

CML – Essential investigations

A

Full blood count with differential count

Bone marrow aspirate and trephine:

  • Cytogenetics (Philadelphia chromosome)
  • Real-time quantitative PCR (RQ-PCR)
  • Fluorescence in situ hybridization of 9;22 translocation
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35
Q

Phases of CML

A

Chronic
Accelerated
Blast transformation

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36
Q

Characteristics of Chronic phase CML

A 
20% asymptomatic
Systemic unwell
Abdominal discomfort
Leucocytosis
±thromobocytosis
Blood film
neutrophilia,
metamyelocytes,
basophilia,
Blasts <15%

BM exam
Blast count<15%
karyotype

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37
Q

Characteristics of Accelerated phase CML

A 
Blood count
Anaemia
Persistent thrombocytopenia
(<100 x 1^09
/L)

Blood film:
Basophilia (>20%)
Blasts seen (15-29%)

BM exam :
Blast count 15-29%
Karyotype

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38
Q

Characteristics of Blast transformation CML

A

Blood count
Anaemia
Thrombocytopenia

Blood film
Basophilia ++
Blasts

BM exam
Blast count ≥30%
Karyotype
70% AML
30% ALL
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39
Q

When is it good to be positive for philadelphia chromosome?

A

In CML

Poor prognosis if positive in PV, ET, PMF

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40
Q

Polycythaemia vera clinical presentation

A

Annual incidence 0.84/100000
 Most commonly routine fbc, May be asymptomatic
Symptoms that are not obviously related to MPD
Abnormal fbc: high Hb high HCT high Plt count (50%) High Wcc
Possible Symptoms: Headache, Dizziness, Visual disturbances, Parasthesias,
Pruritus, Erythromelalgia, Gout, Haemorrhage, Chorea
Median age 60 years
Common Signs: Plethora 70%, Splenomegaly 70%, Hepatomegaly 40%
Thrombosis in 25%, arterial or venous
Budd Chiari syndrome particularly associated with PV
Haemorrhage

Abnormal fbc: high Hb high HCT high Plt count (50%) High Wcc

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41
Q

Causes of Congenital erythrocytosis

A

Associated with reduced P50:
(partial pressure of oxygen at which 50% of haemoglobin is saturated with oxygen)
•High-oxygen-affinity hemoglobinopathy (usually autosomal dominant)
•2,3-Bisphosphoglycerate deficiency (usually autosomal recessive)
•Methemoglobinemia

Associated with normal P50:
•VHL mutations including Chuvash polycythemia (usually autosomal recessive)
•PHD2 mutations
•HIF2a mutations
•EPOR mutations (usually autosomal dominant)

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42
Q

Causes of Acquired erythrocytosis Clonal (polycythemia vera)

A

Hypoxia driven (Epo high):

  1. Chronic lung disease
  2. Right-to-left cardiopulmonary shunts
  3. High-altitude habitat
  4. Tobacco use/carbon monoxide poisoning
  5. Sleep apnea/hypoventilation syndrome
  6. Renal artery stenosis

Hypoxia independent

  1. Use of androgen preparations/erythropoietin injection
  2. Post-renal transplant
  3. Tumours: cerebellar, renal, liver

Apparent erythrocytosis
Not “true” polycythaemia
Stress, alcohol, obesity, smoking, diuretics

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43
Q

Essential thrombocytosis (incidence, presenting features, diagnosis)

A
  • Incidence: Annual incidence 1.03/100000
  • Median Age: ~60 yrs (middle age). There is a second peak in women ~30 yrs of age
  • Presenting features: ~60% asymptomatic
  • Rest complications of the disease e.g. erythromelalgia, thrombosis, haemorrhage
  • 40% splenomegaly
  • Sustained platelet count >450x10^9/L
  • It is a diagnosis of exclusion
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44
Q

Differential diagnosis of raised platelet count

A

1 . Reactive — infection, inflammation, malignancy, iron deficiency, haemorrhage
drugs e.g. corticosteroids
prior splenectomy
history, examination, CRP, ferritin

  1. Exclude mixed overlap MPD - PV/ET exclude primary myelofibrosis
  2. Exclude CML – clinical picture, blood count, blood film, karyotype bcr-abl testing
  3. Exclude MDS – rare overlap MDS/MPD, RARS, 5q- syndrome

Practice of doing a bone marrow for PV/ET varies widely through out the country- In a young patient worth doing to document degree of fibrosis

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45
Q

Complications and prognosis for ET and PV

A 
• Complications:
Venous and arterial thromboembolic events.
Haemorrhage
25-30% myelofibrosis
5-10% acute myeloid leukaemia

• Prognosis: median survival 10-15 years.

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46
Q

A patient has lab results showing increased haemoglobin, increased neutrophils, increased platelets, decreased EPO. On bone marrow biopsy, there was hypercellularity. Dx?

A

Polycythaemia vera

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47
Q

What would a bone marrow biopsy show in chronic myeloid leukaemia?

A

Hyperplastic marrow, with granulocytic proliferation

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48
Q

What is the treatment for myelofibrosis?

A

No treatment

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49
Q

How does transferrin respond to inflammation?

A

Decrease

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50
Q

How does albumin respond to inflammation?

A

Decrease

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51
Q

blood film shows a neutrophil with darker granules, vacuoles and a paler nucleus. What is the cause of this toxic change?

A

Infection

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52
Q

What procedure would be done in essential thrombocythaemia patients to reduce the risk of bleeding or clotting before surgery?

A

Platelet phoresis

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53
Q

A blood film has immature neutrophils with large nuclei and RBCs containing nuclei. What is the name of this picture?

A

Leukoerythroblastosis

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54
Q

Which disorder will have teardrop red cells evident on blood film?

A

Myelofibrosis

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55
Q

A patient with a high haemoglobin and a high EPO level has what condition?

A

Secondary polycythaemia

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56
Q

A patient with high haemoglobin and a low EPO level has what condition?

A

Polycythaemia vera

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57
Q

A patient has a high serum iron, high ferritin and a high transferrin saturation. What is the diagnosis?

A

Haemochromatosis

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58
Q

A patient has had a gradual onset of headache, dizziness, weakness and sweating. On examination, he has red skin, splenomegaly and hepatomegaly. What is the diagnosis?

A

Polycythaemia vera

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59
Q

What is the treatment for essential thrombocythaemia?

A

Aspirin
Hydroxyurea
Anagralide

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60
Q

What cell is CRP synthesised by?

A

Macrophages

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61
Q

A patient has a slow onset of anaemia, weight loss and night sweats, as well as a massively enlarged spleen. They also experience episodic severe pain in the left shoulder. Dx?

A

Myelofibrosis

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62
Q

A patient has a blood screen showing increased platelet count, abnormal platelet morphology, marked increase in megakaryocytes, a mild anaemia and normal white blood cell count. Dx

A

Essential thrombocythaemia

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63
Q

What is the treatment for polycythaemia vera?

A

Aspirin

Phlebotomy

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64
Q

An asymptomatic patient with elevated platelets has a bone marrow biopsy which shows many enlarged, mature megakaryocytes. What is the likely diagnosis?

A

Essential thrombocythaemia

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65
Q

A patient has a slow onset disease, with bruising, fatigue, weight loss and splenomegaly. A blood screen shows increased WBCs, increased platelets, anaemia and high uric acid. Dx?

A

CML

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66
Q

What will a bone marrow biopsy show in myelofibrosis?

A

Collagen fibrosis

Increased reticulin

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67
Q

Prognosis of myelofibrosis?

A

Worse than ET/PV

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68
Q

Primary myelofibrosis (incidence, presentation)

A

Incidence: 0.47/100000 per year

Clinical Picture: Primarily a disease of the elderly
Systemic symptoms – weight loss, night sweats low grade fever gout (often severe)
Abdominal discomfort – 90% splenomegaly – massive splenomegaly
50% hepatomegaly
Extra-medullary haemopoiesis

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69
Q

Blood film of primary myelofibrosis

A
  • tear drop poilkiocytes
  • bizarre platelet morphology - megakaryocyte fragments
  • leucoerythroblastic

Bone marrow exam is essential to make a firm diagnosis

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70
Q

Phases of myelofibrosis

A 
Cellular phase:
Hypercellular
Left shifted
Abnormal excessive mks -
clusters of mk
abnormal chromatin - cloud like, balloon shaped 
Fibrotic phase:
Variable cellularity
Abnormal Mks
Increased blasts number
Increased number and
dilation of sinusoids
New bone formation
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71
Q

Secondary myelofibrosis

A 
Post ET
Post PV
Other haematological malignancy
Malignancy
Drugs
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72
Q

Causes of leucoerythroblastic blood film

A

Causes of a leucoerythroblastic blood picture can generally be divided into three main groups:

Conditions in which the bone marrow is under severe
“stress” including:
• severe sepsis
• severe haemorrhage
• severe haemolysis
• advanced megaloblastic anaemia

Conditions in which the bone marrow is subject to abnormal infiltration including:
• metastatic carcinoma
• haemopoietic malignancies e.g. leukaemia
• Myelofibrosis
• osteopetrosis

Conditions associated with extramedullary haemopoiesis including
• advanced megaloblastic anaemia
• myelofibrosis

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73
Q

Prognostic factors in myelofibrosis

A 
Age > 65 years
Constitutional symptoms
Hb < 100 g/L
WBC > 25 x 10^9/L
Blast count >1% (blood)
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74
Q

Targeted treatment of JAK2

A

Ruxolitinib

However, not used to treat myelofibrosis as minimal survival effect shown. It does prevent splenomegaly.

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75
Q

If you have a raised platelet count what tests would you to do determine cause?

A

Mutational analysis (PCR) for the JAK2 V617F mutation and for BCR-ABL fusion gene may help exclude a primary myeloproliferative disorder, though a bone marrow biopsy may be needed.

General markers of inflammation (CRP, ESR) may be useful, as may serum ferritin (partly as it is an acute phase reactant, and partly because the platelet count will sometimes rise in iron deficiency). The remaining investigation will be determined by clinical history and examination.

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76
Q

What are the risks of an elevated platelet count?

A

Risks include thrombosis and, with marked elevated platelet counts, haemorrhage.

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77
Q

Which steps in the normal regulation of haemoglobin production can be disturbed to produce polycythaemia?

A

Hypoxia – patients with chronic hypoxaemia (e.g. cyanotic heart disease, chronic obstructive pulmonary disease) have a chronic stimulus to produce more erythropoietin and thus to promote erythrocytosis

Oxygen sensing – rare forms of polycythaemia may result from defects in the HIF O2 sensing pathway (conceptually important, but small print from a clinical perspective).

Erythropoietin excess – erythropoietin may be secreted in an unregulated fashion in patients with some renal tumours or polycystic kidney disease, resulting in polycythaemia

Erythropoeitin sensing – rare defects in the epo receptor may result in polycythaemia

Clonal bone marrow disorders – as in polycythaemia vera

78
Q

Suggest three possible complications of an elevated haematocrit.

A

Thrombosis
Haemorrhage
Hyperviscosity

79
Q

A 70-year-old woman with a ten-year history of polycythaemia vera is found no longer to require venesections
to keep her haematocrit under control.
- Suggest two possible complications that might give this picture.
- What further laboratory tests might help clarify things?

A
  1. Development of iron deficiency – great caution would be needed in replacing iron in this context as it might cause a rapid and uncontrolled increase in red cell mass.
  2. Transformation into a myelofibrotic picture (‘burnt out’ polycythaemia)

Suitable investigations would include inspection of the peripheral blood film (features of iron deficiency – microcytosis, pencil cells? Features of myelofibrosis – teardrop poikiocytes, nucleated red cells, occasional immature myeloid cells?), assessment of iron status (ferritin, serum iron and transferrin) and possibly a bone marrow aspirate and trephine.

80
Q

A 38-year-old woman presenting with a short history of fatigue, mouth ulcers and petechial haemorrhage is found to have numerous featureless blasts on her peripheral blood smear, suggesting a diagnosis of acute leukaemia.

  • What tests will determine whether this is myeloid or lymphoblastic?
A

Inspection of the peripheral blood and bone marrow aspirate to assess the morphology of the blasts may help in some cases (e.g. granulated blasts suggest myeloid leukaemia) - but here we are told that the blasts are featureless. Immunophenotyping by flow cytometry is the key test, using either peripheral blood or aspirated bone marrow. Specific CD markers will define whether the blasts are from the myeloid or lymphoid lineage. This is important, because the drugs used to treat myeloid and lymphoid acute leukaemias differ.

81
Q

If acute myeloid leukaemia is confirmed, what additional tests are needed to define her prognosis?

A

The key prognostic test is cytogenetic analysis/karyotyping. Additional molecular tests include investigation for FLT3 mutation status. Details of prognostication in AML is beyond the Lab Med
syllabus.

82
Q

This is the formation of stacks of RBCs observed in peripheral blood

A

Rouleaux

83
Q

Leukocyte Alkaline Phosphatase levels are elevated in….

A

Polycythemia vera

84
Q

Where is the marginal zone and what do B-cells here do?

A

The marginal zone is the region at the interface between the non-lymphoid red pulp and the lymphoid white-pulp of the spleen.
Protect against capsulated bacteria.

In humans the splenic marginal zone B cells have evidence of somatic hypermutation in their immunoglobulin genes, indicating that they have been generated through a germinal centre reaction to become memory cells.

Similar to B1 B cells, MZ B cells can be rapidly recruited into the early adaptive immune responses in a T cell independent manner.

85
Q

Where do naive B-cells go?

A

From bone marrow to spleen where they become transitional B-cells.

They then either stay in the spleen (MZ B-cells) or go to the lymphnodes (follicular B cells).

86
Q

Where is the mantle zone?

A

The mantle zone (or just mantle) of a lymphatic nodule (or lymphatic follicle) is an outer ring of small lymphocytes surrounding a germinal center.

It is also known as the “corona”.

87
Q

What are germinal centres and what happens?

A

Germinal centers or germinal centres (GCs) are sites within secondary lymphoid organs – lymph nodes and the spleen[1] where mature B cells proliferate, differentiate, and mutate their antibody genes (through somatic hypermutation aimed at achieving higher affinity), and switch the class of their antibodies (for example from IgM to IgG) during a normal immune response to an infection. They develop dynamically after the activation of follicular B cells by T-dependent antigen.

As they undergo rapid and mutative cellular division in the dark zone, B cells of the germinal center are known as centroblasts. Once these B cells have stopped proliferating, they migrate to the light zone where they are known as centrocytes, and are subjected to selection by follicular helper T (TFH) cells in the presence of follicular dendritic cells (FDCs). Germinal centers are an important part of the B cell humoral immune response, acting as central factories for the generation of affinity matured B cells specialized in producing improved antibodies that effectively recognize infectious agents, and for the production of durable memory B cells. Histologically, the GCs describe microscopically distinguishable parts in lymphoid tissues.

88
Q

What is a lymphoproliferative condition?

A

A Clonal Proliferation of Lymphocytes: T-cells or B-cells
Clonal - all cells derived from one precursor cell
May arise from a lymphocyte at any part of life cycle

Maybe either:
1. Lymphomas - present as solid lumps e.g. Hodgkin’s

  1. Leukaemias - presents with blood or bone marrow involvement e.g. ALL, CLL
89
Q

What’s the difference between CLL and SLL?

A

Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are the same disease, but in CLL cancer cells are found mostly in the blood and bone marrow. In SLL cancer cells are found mostly in the lymph nodes. Chronic lymphocytic leukemia/small lymphocytic lymphoma is a type of non-Hodgkin lymphoma.

90
Q

Classification of lymphomas

A

Lymphoma: Cancer of lymphocytes (T or B cells)

Hodgkin lymphoma (young/curative)

Non-Hodgkin Lymphoma (older people):

  • T-cell NHL
  • B-cell NHL (90%); high grade, low grade
91
Q

Classes of Hodgkin Lymphoma

A

Classical Hodgkin Lymphoma

Nodular sclerosing
Lymphocyte rich
Lymphocyte depleted
Mixed cellularity

92
Q

High grade B-cell NHLs

A

Diffuse Large B-cell (most common)
Burkitt
Lymphoblastic

93
Q

Low grade B-cell NHLs

A

CLL
Follicular
Marginal zone

94
Q

Features of high grade B-cell NHLs

A
  • Rapidly progressive
  • Increases with age but do see in children
  • Usually no cause - HIV is a risk factor
  • Without treatment, survival only months
  • Treated with combination chemotherapy +monoclonal antibodies
  • Fequently curable with chemotherapy
95
Q

Features of low grade B-cell NHLs

A
  • Slowly progressive
  • Increases with age -never seen in children
  • Usually no cause -H pylori in gastric MALT lymphoma
  • Without treatment,may live for many years
  • Generally watch and wait but treatment variable: mono-agent chemo, multiagent chemo, antibodies, radiotherapy
  • Generally NOT considered curable with chemotherapy
96
Q

Reed Sternberg cells

A

classical Hodgkin Lymphoma

97
Q

Hodgkin cell of origin

A

Germinal centre

98
Q

Ages of presentation of Hodgkin lymphoma

A

15-35 years

Second peak around 60 yrs

99
Q

Virus associated with cHL

A

EBV (50%)

100
Q

Presentation of Hodgkin lymphoma

A

Usually presents as a lump or with mediastinal mass
May have ‘B symptoms’: fever, weight loss, night sweats
Other symptoms: itch, alcohol-induced pain

101
Q

Staging of Hodgkin lymphoma

A

Called the Ann-Arbor Classification system - applies to most lymphomas

Stage I: single lymph node group
Stage II: more than one lymph node group SAME side of the diaphragm
Stage III: lymph node groups BOTH sides of the diaphragm (includes spleen)
Stage IV: Extranodal involvement e.g. liver, bone marrow
A or B added after to signify absence or presence of so-called B symptoms

102
Q

Treatment and prognosis of Hodgkin lymphoma

A

Treatment very successful
Combination chemotherapy +/- radiotherapy
Now > 80% cured

Concern now shifting towards late effects of treatment:
Increased 2nd cancers and heart disease.

103
Q

‘Diffuse infiltration by large, pleomorphic

lymphoid cells - stain positive for CD20’

A

Diffuse large B-cell lymphoma (CD20 positive)

104
Q

Cell of origin for DLBCL

A

Germinal centre or just after

105
Q

Where do plasma cells live?

A

Circulation and bone marrow

106
Q

Most common lymphoma subtype

A

DLBCL

107
Q

Where can DLBCL be found?

A

Nodal or Extra-nodal

Extra-nodal: brain, testis, breast, bone….anywhere!

108
Q

Risk factors of DLBCL

A

Age

HIV risk factor for CNS disease

109
Q

Prognosis of DLBCL

A 
Prognosis is variable - various factors identified which determine a worse prognosis. Together used to calculate the International Prognostic Index (IPI)
• Age > 60
• Stage III or IV
• LDH raised
• ≥ 2 extranodal sites
• Performance status > 2
110
Q

Treatment of DLBCL

A

Treatment is combination chemotherapy (usually CHOP) combined with the anti-CD20 monoclonal antibody rituximab

111
Q

What’s CHOP?

A

(C)yclophosphamide, an alkylating agent which damages DNA by binding to it and causing the formation of cross-links

(H)ydroxydaunorubicin (also called doxorubicin or adriamycin), an intercalating agent which damages DNA by inserting itself between DNA bases

(O)ncovin (vincristine), which prevents cells from duplicating by binding to the protein tubulin

(P)rednisone or (P)rednisolone, which are corticosteroids.

112
Q

What causes the starry sky appearance in Burkitts lymphoma?

A

Macrophages embedded
in monomorphic lymphoid
infiltrate

Black sky= burkitt cells
White stars= macrophages

113
Q

What’s unusual about Burkitts lymphoma?

A

Every single cell is cycling.

100% proliferation index

114
Q

What’s tumour lysis syndrome?

A

If chemo is very successful there’s a large amount of cell death and contents is dumped into cells.

Hyperkalemia
Hyperphosphatemia
Hypocalcemia
Hyperuricemia and hyperuricosuria (purine degradation)

The most common tumors associated with this syndrome are poorly differentiated lymphomas (such as Burkitt’s lymphoma), other Non-Hodgkin Lymphomas (NHL), acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myelogenous leukemia (CML).

115
Q

Most common childhood cancer

A

ALL

Numerous blast cells in bone marrow
Immunophenotype- lymphoid

116
Q

ALL cell of origin

A

hematopoietic progenitor cells

117
Q

Child presents with Presents with:
• pancytopenia, Anaemia, Thrombocytopenia, Leucopenia
• bone pain (limping with no obvious cause)
• Non-specifically unwell

A

ALL

118
Q

Poor prognostic factors of ALL

A
  • High WCC at presentation
  • Infant or adolescent
  • Specific cytogenetic abnormalities e.g. Ph chromosome
  • Slow response to chemotherapy
  • High ‘minimal residual disease’ at end of induction treatment
  • Male sex (testis act as a sanctuary)

Overall cure rate > 80%

Adult ALL much less common and survival much worse

119
Q

Peak age of ALL presentation

A

1-9 years

120
Q

Childhood ALL treatment

A
  • Long and complex - 2 years girls; 3 years boys
  • involves multi-agent chemotherapy
  • CNS directed Rx and important component
  • Maintenance treatment
  • A lot of steroids: psych disturbance, avascular necrosis
121
Q

Proportion of different lymphomas

A 
30% Large B cell
22% follicular 
14% Hodgkins
8% marginal zone
7% PTCL
6% mantle cell
6% SLL/CLL
6% mediastinal
2% anaplastic
122
Q

PTCL

A

Peripheral T-cell lymphoma

123
Q

Features of low grade B cell NHL

A
  • Slowly progressive Increases with age (never seen in children)
  • Usually no cause (H pylori in gastric MALT lymphoma)
  • Without treatment, may live for many years
  • Treatment variable: mono-agent chemo, multiagent chemo, antibodies, radiotherapy
  • Generally NOT considered curable with chemotherapy
  • Auto-immune phenomena
124
Q

Deletion of 11q

A

CLL

125
Q

CLL cell of origin

A

Transitional B cell or Marginal zone B cell

126
Q

Most common adult leukaemia in the Western world

A

CLL

(3-6/100,000); 15% of patients are diagnosed under the age of 65

127
Q

B-symptoms, lymphadenopathy, splenomegaly

A

CLL

128
Q

Complications of CLL

A

Complications:
– increased risk of infections mainly with encapsulated bacteria
– Autoimmune complications: ITP, AIHA

129
Q

Staging for CLL

A

Binet staging

stage A: (raised WBC count)

  • fewer than three areas of enlarged lymphoid tissue
  • no anaemia
  • no thrombocytopaenia
  • lymphadenopathy in the neck, axiallary, inguinal as well as the splenic invovement, are each considered as “one group,” whether unilateral (one-sided) or bilateral (on both sides)

stage B: (lymphadenopathy)

  • three or more areas of enlarged lymphoid tissue
  • no anaemia
  • no thrombocytopaenia

stage C: (marrow failure)
- patients have anaemia and/or thrombocytopaenia regardless of lymphadenopathy

130
Q

Prognosis for CLL

A

Stage A 11 years
Stage B 7 years
Stage C 3 years

CLL is incurable for most patients
1/3 of patients do not require treatment
Treatment is with chemo-immunotherapy
Focus on quality of life
Bone marrow transplantation for a minority of younger patients
131
Q

CLL treatment

A

There are a number of different medicines for CLL, but most people will take three main medications in treatment cycles lasting 28 days.

These medicines are:
fludarabine – usually taken as a tablet for three to five days at the start of each treatment cycle
cyclophosphamide – also usually taken as a tablet for three to five days at the start of each treatment cycle
rituximab – given into a vein over the course of a few hours (intravenous infusion) at the start of each treatment cycle

Fludarabine and cyclophosphamide can usually be taken at home. Rituximab is given in hospital, and sometimes you may need to stay in hospital overnight.

A number of different medicines can also be tried if you can’t have these medicines, you’ve tried them but they didn’t work, or your CLL has come back after treatment.
These include bendamustine, chlorambucil, ibrutinib, idelalisib, obinutuzumab, ofatumumab and prednisolone (a steroid medication).

132
Q

Fludarabine

A

Fludarabine is a purine analog, and can be given both orally and intravenously. Fludarabine inhibits DNA synthesis by interfering with ribonucleotide reductase and DNA polymerase. It is active against both dividing and resting cells. Being phosphorylated, fludarabine is ionized at physiologic pH and is effectually trapped in blood. This provides some level of specificity for blood cells, both cancerous and healthy.

133
Q

cyclophosphamide

A

The main effect of cyclophosphamide is due to its metabolite phosphoramide mustard. This metabolite is only formed in cells that have low levels of ALDH. Phosphoramide mustard forms DNA crosslinks both between and within DNA strands at guanine N-7 positions (known as interstrand and intrastrand crosslinkages, respectively). This is irreversible and leads to cell apoptosis.

134
Q

bendamustine

A

Bendamustine is a white, water-soluble microcrystalline powder with amphoteric properties. It acts as an alkylating agent causing intra-strand and inter-strand cross-links between DNA bases.

After intravenous infusion it is extensively metabolised in the liver by cytochrome p450. More than 95% of the drug is bound to protein – primarily albumin. Only free bendamustine is active. Elimination is biphasic with a half-life of 6–10 minutes and a terminal half-life of approximately 30 minutes. It is eliminated primarily through the kidneys.

135
Q

chlorambucil

A

Chlorambucil produces its anti-cancer effects by interfering with DNA replication and damaging the DNA in a cell. The DNA damage induces cell cycle arrest and cellular apoptosis via the accumulation of cytosolic p53 and subsequent activation of Bax, an apoptosis promoter.

Chlorambucil alkylates and cross-links DNA during all phases of the cell cycle, inducing DNA damage via three different methods of covalent adduct generation with double-helical DNA:

  1. Attachment of alkyl groups to DNA bases, resulting in the DNA being fragmented by repair enzymes in their attempts to replace the alkylated bases, preventing DNA synthesis and RNA transcription from the affected DNA.
  2. DNA damage via the formation of cross-links which prevents DNA from being separated for synthesis or transcription.
  3. Induction of mispairing of the nucleotides leading to mutations.

The precise mechanisms by which Chlorambucil acts to kill tumor cells are not yet completely understood.

136
Q

ibrutinib

A

Ibrutinib (Imbruvica) is a small molecule drug that binds permanently to a protein, Bruton’s tyrosine kinase (BTK), that is important in B cells; the drug is used to treat B cell cancers like mantle cell lymphoma, chronic lymphocytic leukemia, and Waldenström’s macroglobulinemia, a form of non-Hodgkin’s lymphoma.

Ibrutinib has been reported to reduce chronic lymphocytic leukemia cell chemotaxis towards the chemokines CXCL12 and CXCL13, and inhibit cellular adhesion following stimulation at the B cell receptor (BCR). Additionally, ibrutinib down-modulates the expression of CD20 (target of rituximab/ofatumumab) by targeting the CXCR4/SDF1 axis. Together, these data are consistent with a mechanistic model whereby ibrutinib blocks BCR signaling, which drives cells into apoptosis and/or disrupts cell migration and adherence to protective tumour microenvironments.

137
Q

idelalisib

A
  • Targeted, potent, highly selective, small-molecule, oral inhibitor of PI3Kδ
  • Inhibits proliferation and induces apoptosis in many B-cell malignancies
  • Inhibits homing and retention of malignant Bcells in lymphoid tissues, reducing B-cell survival
138
Q

obinutuzumab

A

humanized anti-CD20 monoclonal antibody

Obinutuzumab binds to CD20 on B cells and causes these cells to be destroyed by engaging the adaptive immune system, directly activating intracellular apoptosis pathways, and activating the complement system.

139
Q

ofatumumab

A

Ofatumumab (trade name Arzerra, also known as HuMax-CD20) is a fully human monoclonal antibody (for the CD20 protein) which appears to inhibit early-stage B lymphocyte activation. It is FDA approved for treating chronic lymphocytic leukemia that is refractory to fludarabine and alemtuzumab (Campath) and has also shown potential in treating follicular lymphoma, diffuse large B cell lymphoma, rheumatoid arthritis and relapsing remitting multiple sclerosis.

Ofatumumab is a humanised anti-CD20 monoclonal antibody whose epitope is distinct from that of rituximab. The CD20 antigen is expressed on solely B cell lymphocytes. Compared with rituximab, ofatumumab binds more tightly to CD20 with a slower off-rate. It causes cytotoxicity in the cells that express CD20 by means of complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC).

140
Q

56 year old man notices persistent lymph nodes in his
neck. He is otherwise well.
Initial investigations including a FBC are normal.
A CT scan reveals the presence of widespread
lymphadenopathy.

Lymphnode biopsy: Closely packed follicles with a mixture of centrocytes and centroblasts

A

Follicular Lymphoma

141
Q

Follicular Lymphoma-cell of origin

A

Germinal centre

142
Q

Features of follicular lymphoma

A

FL acounts for 20% of all lymphomas
Median age of presentation: 60
Mostly widespread disease at presentation
• Patients are often asymptomatic or present with painless lymphadenopathy
• Can transform into high grade diffuse large B-cell lymphoma
• Rising in incidence (4% per year)
• Median age of onset is 60
• Accounts for 70% of low grade lymphomas
• Slight female:male predominance
• Less common in Asian and African Americans

143
Q

Staging of follicular lymphoma

A
  • Staging according to Ann-Arbor Classification system
  • Histological grading (grade 1-3) depending on the number of centroblasts
  • About 80% of cases are positive for the t(14;18)(q32;q21) leading to overexpression of bcl-2
  • However: this t(14;18) is also found in normal population in low levels
144
Q

Prognosis of follicular lymphoma

A

International prognostic index

  • Age greater than 60 years
  • Stage III or IV disease
  • Elevated serum LDH
  • ECOG ( Eastern Cooperative Oncology Group) performance status of 2, 3, or 4
  • More than 1 extranodal site
  • Newer prognostic models incorporating clinical and genetic features

One point for each. More points is worse

145
Q

Follicular lymphomas express

A

Bcl2

146
Q

Grades of follicular lymphoma

A

Grade I: 0-5 centroblasts/HPF(high power field), “Small cleaved follicle cells”, Centrocytes

Grade II: 6-15 centroblasts/HPF, Mixed

Grade III: >15 centroblasts/HPF, “large blastic follicle cells”, Centroblasts

147
Q

Treatment for follicular lymphoma

A
  • Treatment is only required for symptomatic disease
  • Modern treatment is with chemoimmunotherapy (rituximab, CHOP)
  • High-grade ‘transformation’ is treated with more intensive therapies
148
Q

Acrocyanosis

A

Acrocyanosis is persistent blue or cyanotic discoloration of the extremities, most commonly occurring in the hands, although it also occurs in the feet and distal parts of face.

149
Q

A 75 year old lady is admitted via A&E with breathlessness and discoloration of her hands, feet and ear lobes.

Fundoscopy showing: Dilated veins, haemorrhages, Venous sausaging

Protein electrophoresis: Showing a monoclonal band
in gamma position

Bone marrow infiltration by lymphoplasmacytoid cells

A

Lymphoplasmacytic lymphoma (LPL)and Waldenström macroglobulinemia.

Waldenstrom describes the disease and problems relating to the IgM paraprotein problems.

The IgM paraprotein can have cryoglobulin activity and cause autoimmune symptoms, neuropathy and coagulopathy

150
Q

LPL/Waldenstrom cell of origin

A

Lymphoplasmacytoid cell (comes out of lymph node after class swithching)

151
Q

Features of LPL/Waldenstrom

A

Rare lymphoma of patient over the age of 60 years
Familial predisposition
About 80% of patients have a mutation in the MYD88 gene (L265P)
Association with HCV infection
Bone marrow involvement common

Patients present with:
Fatigue, anaemia, cryoglobulinaemia and hyperviscosity: breathlessness, headaches, visual disturbance, strokes, neuropathy

152
Q

cryoglobulinaemia

A

Ig precipitates at low temperatures and causes vasculitis.

153
Q

Treatment of LPL/Waldenstrom

A

Not all patients require treatment at diagnosis
Emergency treatment of hyperviscosity: plasma exchange
Chemo-immunotherapy, more novel targeted therapies
Antibody properties of IgM paraprotein

154
Q

A 65 year old man presents to his GP with chronic indigestion. More recently, he has experienced some upper abdominal pain after heavy meals. A full blood count shows a microcytic anaemia. The GP refers him for upper GI endoscopy.

Treatment

A

Urease positive (detect carbon dioxide when take urea capsule)

H. pylori causing MALT

Treat with 2 antibiotics and PPI

155
Q

MALT Lymphoma- cell of origin

A

Marginal zone

156
Q

Causes of MALT

A

Accumulation of MALT
Chronic inflammation
MALT lymphoma (t(11;18)

Infectious organism:
•H pylori (gastric)
•Chlamydia psittaci (ocular)
•Campylobacter jejuni (small intestine)
•Borrelia Burgdorferi (cutaneous)
Autoimmune diseases:
Sjogren Syndrome (salivary glands)
Hashimoto thyroiditis (thyroid)
157
Q

What’s an M-spike?

A

In myeloma, there is a loss of polyclonal immunoglobulins, and development of monoclonal immunoglobulins, which results in an “M-spike”

The loss of polyclonal immunoglobulins results in infectious complications

158
Q

What’s MGUS?

A

Monoclonal Gammopathy of Undetermined Significance

NOT CANCER, common in elderly

  • Monoclonal protein present, but < 3 g/dL
  • Monoclonal bone marrow plasma cells present, but < 10%
  • No features of symptomatic disease (“CRAB” features)
159
Q

What are CRAB features?

A

C: Calcium elevation > 11.5 mg/L or ULN
R: Renal dysfunction (serum creatinine > 2 mg/dL)
A: Anaemia (Hb < 10 g/dL or 2 g < normal)
B: Bone disease (lytic lesions or osteoporosis)

160
Q

What factors increase the risk of progression from MGUS to MM?

A
  • serum M-protein ≥15g/l
  • non-IgG subtype
  • abnormal SFLC ratio (<0.26 or >1.65)
20yr risk ofprogression(%):
Score 0 5%
Score 1 21%
Score 2 37%
Score 3 58%
161
Q

SFLC

A

Serum free light chains

162
Q

Criteria for Smouldering (asymptomatic) myeloma

A 
As for MGUS, but:
 Monoclonal protein level higher at > 3g/dL
AND/OR
 Monoclonal plasma cells present at a higher
percentage, at > 10%
BUT
 No symptoms attributable to myeloma
present (see CRAB features)

Cancer that doesn’t require treatment

163
Q

Stepwise progression of MGUS

A

MGUS
Smoldering MM
Active MM
Extra medullary

164
Q

Criteria of multiple myeloma diagnosis

A

 Increased monoclonal plasma cells in the bone marrow and/or biopsy proven plasmacytoma
AND
 Monoclonal protein present in the serum and/or urine
AND
 Symptoms related to 1 or more of CRAB criteria

165
Q

Clinical features of myeloma

A

 Bone pain: often with loss of height
 Constitutional: weakness, fatigue, and weight loss
 Anaemia
 Renal disease: renal tubular dysfunction
 Infections: neutropenia/hypogammaglobulinaemia
 Hypercalcaemia: myeloma cells secrete osteoclast-activating factors
 Hyperviscosity: 2% with myeloma; 50% with macroglobulinaemia
 Neurologic dysfunction: spinal cord or nerve root compression

166
Q

International staging system (ISS) for MM

A 
1 Serum ß2 microglobulin <3.5 mg/dL
\+
Serum albumin ≥ 3.5 g/dL
2 Not 1 or 3*
3 Serum ß2 microglobulin >5.5 mg/dL
167
Q

Example of IMiDs and side effects

A

Thalidomide (neuropathy, constipation, sedation, DVT)

Lenalidomide (myelosuppression, skin rash, DVT)

Pomalidomide

168
Q

Examples of protease inhibitors

A

Velcade
Bortezomib
Carfilzomib

169
Q

Manifestations of myeloma bone disease and treatment

A 
bone pain
fractures
osteoporosis
significant kyphosis
loss of height
  • Bisphosphonate therapy
  • Orthopaedic intervention
  • Vertebroplasty
  • Radiotherapy
170
Q

Myeloma renal disease

A

• “Myeloma kidney”
– Normal glomerular function
– Concentrated light chains precipitate in tubules
– Monoclonal light chains seen in UPEP with immunofixation

• Glomerular lesions
– Deposits of amyloid or light chain deposition disease
– Nonselective leakage of all serum proteins
– UPEP preponderance of albumin

171
Q

UPEP

A

Urine protein electrophoresis

172
Q

In MM where would you find casts and what are they composed of?

A

DCT
mainly consisting of immunoglobulin light chain known as Bence Jones protein, but often also contain Tamm–Horsfall protein.

173
Q

What’s THP?

A

Tamm–Horsfall glycoprotein (THP), also known as uromodulin

174
Q

What’s the most abundant protein excreted in ordinary urine?

A

Uromodulin

175
Q

Function of THP

A

THP is a GPI-anchored glycoprotein. It is not derived from blood plasma but is produced by the thick ascending limb of the loop of Henle of the mammalian kidney. While the monomeric molecule has a MW of approximately 85 kDa, it is physiologically present in urine in large aggregates of up to several million Da. When this protein is concentrated at low pH, it forms a gel. Uromodulin represents the most abundant protein in normal human urine (results based on MSMS determinations). It is the matrix of urinary casts derived from the secretion of renal tubular cells.

Uromodulin excretion in urine follows proteolytic cleavage of the ectodomain of its glycophosphatidylinositol-anchored counterpart that is situated on the luminal cell surface of the loop of Henle. Uromodulin may act as a constitutive inhibitor of calcium crystallization in renal fluids. The excretion of uromodulin in urine may provide defense against urinary tract infections caused by uropathogenic bacteria

176
Q

Co-factors for Acute Kidney Injury in Myeloma

A 
• Drugs
– NSAIDS
– Diuretics
• Hypercalcaemia
• Sepsis
• Volume depletion/dehydration
• Operative stress
177
Q

Solitary Plasmacytoma of Bone

A 
• ~3% of plasma cell neoplasms
• One isolated bony lesion of plasma cells
• Uninvolved marrow <5% plasma cells
• M-protein present ~25% cases
– Disappears following treatment
• Curable with local radiation therapy
– Median OS 10 years
– Multiple myeloma develops in 50-60%
178
Q

Extramedullary Plasmacytoma

A

• ~3% of plasma cell neoplasms
• Isolated plasma cell tumors of soft tissues
– Upper respiratory tract common
• Uninvolved marrow, negative skeletal survey
• M-protein present ~25% cases
– Disappears following treatment
• Curable with local radiation therapy/ surgery

179
Q

What’s amyloidosis?

A

Extracellular tissue deposition of low molecular weight fibrils. These fibrils are insoluble, linear, rigid and measures approximately 7.5 to 10mm in width.
– Beta-pleated sheets, bind Congo red
– Damage tissue structure and organ function

180
Q

Precursor proteins of amyloidosis

A

• Precursor proteins involved
– Monoclonal immunoglobulin light chains: Primary (AL)
Amyloidosis
– Serum amyloid A protein: Reactive or Secondary (AA)
Amyloidosis
– Beta-2 microglobulin: Dialysis (DA) Amyloidosis
– Transthyretin, apolipoprotein A-I, Alzheimer amyloid precursor protein, prion protein, Prolactin, Atrial natriuretic protein, Procalcitonin, Insulin, Keratin…

181
Q

Amyloidosis: Presentation

A

• Nephrotic syndrome
• Refractory CHF, Arrhythmia, Heart block
• Orthostatic hypotension, Peripheral neuropathy
• Bleeding diathesis (Raccoon eyes)
– Factor X deficiency, liver disease
• GI bleeding, Gastroparesis/Dysmotility, Malabsorption
• Macroglossia, Carpal tunnel syndrome, Organomegaly
• Skin thickening/waxy, easy bruising

182
Q

Prognosis of AL

A

Poor, cardiac involvement makes it worse

183
Q

What’s a SAP scan?

A
  • Serum Amyloid protein purified from normal people labelled with 123Iodine.
  • Given intravenously
  • Poor definition in GI tract and heart
  • Useful for staging and assessment for response
  • Only performed at the Royal Free Hospital
184
Q

Characteristics common to all amyloid subtypes

A
  • Hematoxylin and Eosin (HE) staining results in amorphous eosinophilic appearance when viewed on light microscopy.
  • Congo red staining results in bright green fluorescence/birefringe apple green color when viewed under polarized light.
185
Q

Waldenstrom’s macroglobulinaemia

A
  • Cells: lymphocytes, lymphoplasmacytoid cells, plasma cells, excess mast cells in association with lymphoid aggregates
  • BM: interstitial pattern with diffuse or nodular infiltrates, excess mast cells in association with lymphoid aggregates
  • LN/SP: diffuse pattern
186
Q

Clinical manifestations of WM

A 
↓HCT, ↓PLT, ↓WBC
Hyperviscosity Syndrome: Epistaxis, HA, Impaired  vision
>4.0 CP
IgM Neuropathy (22%)
Cryoglobulinaemia (10%)
Cold Agglutinaemia (5%)
Fatigue
Adenopathy
splenomegaly≤15%
187
Q

Adenopathy

A

Large or swollen lymph nodes

Synonymous with lymphadenopathy.

188
Q

Histological features of Follicular lymphoma

A

‘Follicles’ of centrocytes (cleaved follicle centre B-cells) of monomorphic appearance, surrounded by non-malignant lymphoid cells, often with little interfollicular tissue. This is a low grade lymphoma, so the proliferation rate of the malignant cells is low.

189
Q

What’s a paraprotein?

A

Production of a single immunoglobulin from a clone of lymphoid cells results in a strong narrow band on the electrophoresis strip – this is the paraprotein (also known as an M protein)

190
Q

A patient has a paraprotein. Explain what additional laboratory investigation this patient should have.

A

Investigation for end-organ damage:

  • FBC
  • renal function
  • calcium
  • skeletal survey for lytic lesions
  • Urine should be examined for Bence-Jones proteins (free light chains).
  • Free immunoglobin light chains in the peripheral blood can also be assayed, and are now often used in monitoring patients with myeloma.
191
Q

What is the underlying genetic basis of Waldenstrom’s macroglobulinaemia?

A

This is another example of how exome sequencing has enhanced our understanding of the pathophysiological basis of disease. The great majority of cases of WM are characterised by a somatic mutation in the MYD88 gene – a mutation that results in uncontrolled activation of two kinases (Interleukin-1 receptor associated kinase and Bruton’s tyrosine kinase) and subsequent NF-kB pathway activation. Although the molecular details here are beyond the requirements of the lab medicine course, it is important to recognise that a proper understanding of haematological diseases moves beyond the clinical picture and the
orphological appearance of the cells into an
appreciation of the genetic and biochemical disturbances in each cell. Emphasizing the clinical significance of these findings, Bruton’s tyrosine kinase has recently been exploited as a target for the treatment of some lymphomas.

192
Q

A 55-year-old woman presents with night sweats, a cough, and cervical lymphadenopathy. A lymph node biopsy demonstrates diffuse large B-cell lymphoma.
- What tests need to be performed to complete her staging investigations?

A

Bone marrow trephine biopsy and staging CT of neck, chest, abdomen and pelvis

Haematology (5 decks)

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