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HIS > HIS21 HIS22 White Cell Disorders And Their Investigation I + II > Flashcards

HIS21 HIS22 White Cell Disorders And Their Investigation I + II Flashcards

1
Q

White cell disorders framework

A
  1. Reactive
    - response of haemopoietic system to other abnormalities
    - mainly Quantitative changes in normal white cell types (most common explanation for quantitative white cells disorders)
    - Qualitative changes possible e.g. atypical lymphocytosis, appearance of immature cells in PB
  2. Malignant
    - primary abnormality of haemopoietic system
    - both Quantitative + Qualitative changes
  3. Functional
    - primary abnormality of haemopoietic system
    - rare in practice
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2
Q

***White cell disorders investigations

A

記: CMCICM —> 3C, 2M, 1I (CBC, Cytochemistry, Cytogenetics, Morphology, Molecular genetics, Immunophenotype)

  1. CBC
    - WBC
    - Differential count (Machine vs Manual count)
    - Machine: cannot distinguish abnormal cell types (e.g. blasts) —> need manual
  2. Morphology
    - PB smear
    - BM aspiration
    - Trephine biopsy (BM examination)
  3. Cytochemistry
    - Myeloid lineage —> Myeloperoxidase, Sudan Black B
    - Lymphoid lineage —> Immunophenotyping
  4. Immunophenotype
    - Flow cytometry
    - Immunohistochemistry
  5. Cytogenetics
    - Karyotyping —> for PB/BM aspiration
    - Fluorescence in-situ hybridisation —> for Trephine biopsy
  6. Molecular genetics
    - PCR

Other investigations:

  1. CXR
  2. LN biopsy
  3. Inflammatory / Autoimmune markers
  4. Tumour markers
  5. Fe profile
  6. PT/APTT + Platelet count for bleeding tendency
  7. Drug history
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3
Q

Morphology

A
  1. PB smear:
    - confirm nature of cytopenia / increased WBC count
    - detect abnormal cell types / abnormal morphology
  2. BM aspirate (i.e. BM blood):
    - determine **cellularity
    - detect abnormal cell types / dysplastic morphology
    - ascertain activities of trilineage **    haemopoiesis
  3. Trephine biopsy:
    - preserved BM architecture i.e. aspirate
    —> **Bone structure
    —> **    Marrow cellularity
    —> **Pattern of involvement by abnormal cells
    —> Marrow fibrosis
    - permit immunophenotyping by immunohistochemistry
    - **    less sensitive than aspirate for assessing cytological detail (e.g. dysplastic features)
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4
Q

Cytochemistry

A
  • performed on PB / BM aspirate
  • detect Dye / Reaction product in cells-of-interest using microscopy
  • Myeloid lineage cytochemical markers: Myeloperoxidase / Sudan Black B (show that cells have commit to Myeloid lineage)
  • Lymphoid lineage: Immunophenotyping
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5
Q

Immunophenotyping

A
  • Determine cell lineage
  • by detecting antigens on cells-of-interest

Myeloid lineage:

  • Myeloperoxidase
  • CD117, CD13, CD33 (x rmb)

Lymphoid lineage:

  • B-Acute Lymphoblastic Leukaemia: CD19, CD79a, CD22
  • T-Acute Lymphoblastic Leukaemia: CD3

2 ways:

  1. Flow cytometry (only for **liquid)
    - performed on **    PB / BM aspirate
    - investigate co-expression of antigens on a cell
    - use Anti-Ag Ab with ***fluorochromes —> wash away unbound Ab —> shine light on fluorochrome —> read colour signal —> know which Ag on cell —> know which cell
  2. Immunohistochemistry
    - performed on **Trephine biopsy
    - difficult to demonstrate co-expression of antigens on single cell
    - use Anti-Ag Ab with **    dyes —> read positive cells on biopsy specimen
    - also see ***spatial relationships between cells (e.g. clustering)
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6
Q

Cytogenetics

A

Many haematological malignancies harbour certain characteristic chromosomal abnormalities

Use: Diagnosis, ***Prognostication, Selection of treatment

  1. Karyotyping
    - study of chromosomes at Metaphase (when chromatin highly condensed and chromosome morphology is well-defined)
  2. Fluorescence in-situ hybridisation (FISH)
    - Single-stranded DNA probes (labelled by Fluorophores to allow detection by fluorescence microscopy) + Complementary DNA sequences on subject
    —> form hybrid double-stranded complexes
    —> wash away unbound probe
    —> shine light on fluorochrome
    —> read colour signal
    —> know which **DNA sequence present / determine ↑/↓ in copy of number of genes / whether there is **fusion of genes
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7
Q

Molecular genetics

A
  • Determine ***sequence changes in DNA/RNA (different diseases have different characteristics of sequence changes)
  • Detection of ***genetic mutations in specific genes
  • Usually ***PCR-based
  • Multiple types of end-point detection, tailored for the expected sequence changes to be observed
    —> Point mutation
    —> Insertion / Deletion
    —> Fusions

Use: Diagnosis, ***Prognostication, Selection of treatment

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8
Q

Framework of clinical approach

A

“Handle” —> Causes —> “Further Interrogate” —> Diagnosis

  1. Understand clinical problems
    - History taking (symptoms)
    - Physical examination (signs)
    - Investigations
    —> decide on “diagnostic handle”
  2. Consider causes of the “diagnostic handle”
    - require prior knowledge
    - generate differential diagnoses
    - prioritise according to likelihood
  3. Goal-directed history taking, physical examination, investigations to rule in / out causes
    - require prior knowledge
  4. Arrive at final diagnosis
  5. Direct history taking, physical examination / investigations to guide further management
    - look for complications
    - prognosis
    - treatment
  6. Treat the condition
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9
Q

Case 1a:

  • 63 yo male
  • ex-smoker
  • not on medication
  • cough and blood-stained sputum for 2 weeks
  • no lymphadenopathy
  • no cyanosis
  • hyperinflated chest
  • reduced breath sounds
  • no adventitious sounds
  • abnormal blood count
A 
Total WBC: ↑↑
RBC: ↓
Platelet: Normal
Neutrophil: ↑↑
Monocyte: ↑
Eosinophil: ↑↑
Basophil: ↑
Lymphocyte: Normal

Steps:
1. History taking

  1. Physical examination
    - Infection: cough, blood-stained sputum, but no fever
    - Inflammation: none
    - Solid tumours / haemic malignancies: blood-stained sputum, favouring factors: ex-smoker, obstructive lung disease (∵ hyperinflated chest)
    - Drug history: none
  2. Investigations (for Infection / Malignancies)
    - CBC: Leukocytosis (**Neutrophilia, Monocytosis, **Eosinophilia, Basophilia)
    - PB smear
    - Microbiological investigations: -ve sputum culture, Acid-Fast Bacilli (AFB) smear and culture
    - Imaging: CXR -ve, CT thorax with contrast: 5cm spiculated mass in left lower lobe of lung —> Lung biopsy: Adenocarcinoma
    - Tumour markers
    - Marrow exam if indicated
  3. Conclusion
    - Lung adenocarcinoma

Haematological diagnosis:

  • Myeloid leukaemoid (look like leukaemia) reaction secondary to lung adenocarcinoma (*reactive response to non-haematological abnormality)
    1. Eosinophilia, Monocytosis —> part of leukaemoid reaction
    2. Anaemia —> secondary to anaemia of chronic disease (less likely BM infiltration by metastasis)
    3. Neutrophilia —> can be multiple causes (e.g. pneumonia due to airway obstruction by lung adenocarcinoma)
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10
Q

***Clinical approach to Leukocytosis

A
  1. Confirm Leukocytosis
    - spurious causes possible e.g. circulating nucleated RBC mistaken
  2. Ascertain which WBC subtype that ↑
    - machine count not reliable in other cell types other then neutrophils, lymphocytes, monocytes, eosinophils, (basophil: not very accurate either)
  3. When in doubt always request manual PB smear review
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11
Q

***Clinical approach to Neutrophilia

A

Causes:
1. Infections
- ***Bacterial (esp. pyogenic)
—> check for signs/symptoms of infection (fever, cough, sputum, diarrhoea, dysuria)
—> further microbiological investigations directed against suspected infections

  1. Inflammation
    —> check for signs/symptoms of inflammation (skin rash, photosensitivity, joint pain)
    —> further investigations for inflammatory markers (ESR, CRP), autoimmune markers
  2. Malignancy
    - Solid tumours
    —> S/S + Imaging
    - Haematological
    —> ***Myeloproliferative neoplasms (esp. Chronic myeloid leukaemia, Myelofibrosis)
    —> S/S
    —> PB smear +/- BM exam, tumour markers
  3. Drugs
    - Steroids (demargination of neutrophils on blood vessels)
    - Growth factors
    —> check for drug history
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12
Q

Case 1b:

  • history of renal cell carcinoma with nephrectomy done
  • malaise, early satiety
  • splenomegaly down to umbilicus
A

“Handle”:
- Splenomegaly: find out causes

“Further interrogation”:

  1. CBC, PB smear:
    - ↑ WBC (Marked Leukocytosis) —> Bimodal distribution of Myelocytes + Neutrophils
    - ↑↑ Neutrophil, Myelocytes
    - ↑↑ Basophils (***Basophilia)
    - Thrombocytosis
    - BM: ↑ Granulopoiesis, ↑ Myeloid cells, Megakaryocytes (with abnormal pathology)
  2. Cytogenetics:
    - translocation **(chromosome 9;22) in over 95%
    - other variant subtypes may require FISH to confirm —> **    BCR-ABL1 fusion (normally BCR, ABL signals are separate ∵ genes located on separate chromosomes)
  3. Molecular genetics:
    - PCR: all harbour BCR-ABL1 fusion (Philadelphia chromosome) by definition

Diagnosis:
- Neutrophilia + Splenomegaly
—> Myeloproliferative neoplasms
—> ***Chronic myeloid leukaemia

Treatment:
Targeted therapy:
- ***Tyrosine kinase inhibitors (now standard treatment for CML)
—> Molecular monitoring of disease level (standard practice in CML)

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13
Q

***Causes of Splenomegaly

A

4 Categories: Increased function, Immune hyperplasia, Abnormal blood flow, Infiltration

  1. Haematological
    - **Malignancy: **Myeloproliferative neoplasms (massive in CML, MF), Leukaemia, Lymphoma
    - **Removal of defective RBC: Thalassaemia intermedia / major
    - **    Immune hyperplasia: Haemolytic anaemia (AIHA)
  2. Portal hypertension
  3. Some infections
    - infectious mononucleosis
    - infective endocarditis
    - malaria
    - schistosomiasis
    - leishmaniasis
  4. Autoimmune diseases
  5. Storage diseases (in paediatrics)
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14
Q

***Clinical approach to Thrombocytosis

A
  1. Reactive
    - ***Bleeding, Fe deficiency —> check Fe profile
    - Inflammation, Autoimmune disease —> check inflammatory markers
  2. Malignant
    - ***Myeloproliferative neoplasms —> check PB smear, marrow exam, molecular genetics
    - Solid tumours
  3. ***Hyposplenism
    - most commonly post-splenectomy
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15
Q

Case 2:

  • 57 yo female
  • Type 1 DM
  • on insulin
  • epigastric discomfort
  • mild epigastric tenderness
  • no hepatosplenomegaly
  • no lymphadenopathy
  • noted deranged liver function
A

CBC:

  • Leukocytosis
  • Eosinophilia
  • Megakaryocytic hyperplasia

Eosinophilia: History / Physical examination:

  • Drug history —> OTC health supplement 1 month
  • Allergic symptoms / history —> None
  • Autoimmune features (e.g. skin rash, joint pain) —> None
  • Travel history (parasitic infestations) —> None
  • Lymphadenopathy —> None

Further investigations:
1. PB smear: look for features of MPN, blasts, abnormal lymphoid cells
—> Eosinophilia

  1. Autoimmune markers
    —> -ve
  2. Microbiological screening: Stool culture, Ova / cysts (for parasites)
    —> -ve
  3. CXR (for solid tumours / lymphoma): Lung, mediastinal mass
    —> Normal CXR
  4. BM examination (if suspected haematological malignancies): may need cytogenetics / molecular testing
    —> Granulocytic + Megakaryocytic hyperplasia, with Eosinophilia
    —> No evidence of haematological malignancies
    —> Cytogenetics: 46, XX (normal)
  5. LN biopsy (if suspected lymphadenopathy/lymphoma)
    —> No lymphadenopathy

Diagnosis:
- Eosinophilia reactive to OTC medication (most likely, not definitive)

Progress:

  • Eosinophilia subsiding after cessation after medication
  • liver function normalised gradually (deranged liver function probably drug-related)
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16
Q

***Clinical approach to Eosinophilia

A

Eosinophilia: PB smear: look for features of MPN, blasts, abnormal lymphoid cells

  1. Drug reactions —> Drug history
  2. Allergic conditions —> Allergic symptoms / history
  3. Autoimmune diseases —> Autoimmune features (e.g. skin rash, joint pain), Autoimmune markers
  4. Infections esp. parasitic infestations
    —> Travel history (parasitic infestations)
    —> Microbiological screening: Stool culture, Ova / cysts (for parasites)
  5. Malignancies
    - Lymphomas (T cell lymphoma, Hodgkin lymphoma) —> LN biopsy
    - Myeloproliferative neoplasms
    - Solid malignancies (Leukaemoid reactions)
    —> Lymphadenopathy: **LN biopsy
    —> **    CXR (for solid tumours / lymphoma): Lung, mediastinal mass
    —> ***BM examination (if suspected haematological malignancies): may need cytogenetics / molecular testing
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17
Q

Case 3a:

  • 44 yo male
  • good past health
  • gum bleeding for 3 days after tooth extraction
  • fever
  • no petechiae
  • no retinal haemorrhage
  • unremarkable physical exam otherwise
A

CBC:

  • Pancytopenia (WBC, RBC, PLT) esp. ***Thrombocytopenia
  • Blast in PB
  • Abnormal promyelocytes with Auer rods (Faggot cell)

PT/APTT:

  • normal
  • normal fibrinogen
  • D-dimer slightly ↑

Diagnosis:
- Acute Promyelocytic leukaemia (APL) (synonym: APML, M3)

Diagnostic evaluation of Acute leukaemia:

  1. Morphology, including cytochemistry
    - Abnormal promyelocytes with Auer rods (Faggot cell)
    - Strongly +ve for Myeloperoxidase and Sudan Black B
  2. Immunophenotyping
  3. Cytogenetics and molecular genetics
    - t(15;17)

Treatment:
- Chemotherapy
- **All-trans retinoic acid (ATRA) —> allow promyelocytes to **differentiate
- **Arsenic trioxide
—> ATRA, Arsenic trioxide targets PML-RARa protein
—> **PML-RARa protein degradation

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18
Q

Clinical approach to Bleeding tendencies

A
  • Bleeding symptoms
  • Prior history of bleeding challenges
  • Family history

1st line investigation:

  • CBC (***platelet count)
  • ***PT/APTT
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19
Q

***Clinical approach to Pancytopenia

A

Marrow causes (Production causes):

  1. Megaloblastic anaemia —> diet history, CBC, PB smear, folate/B12 levels
  2. Aplastic anaemia —> BM exam
  3. Myelodysplastic syndrome (MDS) —> BM exam
  4. Marrow infiltration —> BM exam
  5. Leukaemia —> BM exam
  6. Inherited (rare) —> clinical features, special test, usually require genetic testing

Peripheral / non-marrow causes (Consumptive causes):

  1. Infections —> symptomatology, microbiological workup
  2. Autoimmune —> symptomatology, autoimmune markers
  3. Drug-induced —> drug history
  4. Splenomegaly (pooling effect) —> physical examination, imaging
20
Q

***Cytopenia

A

Common manifestation of haematological malignancies

  • Leukopenia / Leukocytosis (depends balance between Normal cell ↓/ Abnormal cell ↑)
  • **Anaemia, **Thrombocytopenia usually
  • ***Neutropenia (Neutrophil will ↓ regardless)

WBC count may ↑/↓ in haematological malignancies:

  • Normal count ↓ (e.g. neutropenia)
  • Abnormal cells ↑
21
Q

***Diagnostic evaluation of Acute Leukaemia

A
  1. Morphology, including Cytochemistry —> determine cell lineage
    - >=20% blasts in PB / BM
    - Myeloid (AML) / Lymphoid (ALL)
    - Morphology alone: difficult to distinguish myeloblasts from lymphoblasts
    —> ***Auer rod: Pathognomonic feature of Myeloid neoplasms (e.g. AML, MDS)
    —> AML: further sub-classification based on morphology
  2. Immunophenotyping
  3. Cytogenetics and molecular genetics
22
Q

***Diagnosis of Acute Promyelocytic leukaemia

A

APL a subtype of AML, though now treated as a distinct entity due to clinical emergency

  1. Clinical features:
    - Anaemic symptoms
    - Bleeding tendencies
  2. Blood count:
    - ***Pancytopenia (classical)
  3. Clotting profile:
    - ***Disseminated intravascular coagulation (DIC) (characteristic!!!) —> D-dimer ↑
  4. Morphology:
    - ***Faggot cells (characteristic)
  5. Cytochemistry:
    - Strongly positive for Myeloperoxidase and Sudan Black B (show that cells committed to Myeloid lineage)
  6. Cytogenetics:
    - ***t(15;17) (由17 translocate去15)
  7. Molecular genetics:
    - Fusion gene of ***PML-RARa detected by PCR / FISH
23
Q

APL: medical emergency

A
  • Fatal intracranial bleeding secondary to **thrombocytopenia and **DIC
  • On-call pathology service in place
  • Urgent treatment with ***all-trans retinoic acid (ATRA)
    —> induce cells to differentiate to lessen damaging effects
  • May need ***supportive infusion esp. platelets, plasma (to prevent DIC)
24
Q

Case 3b:

  • 51 yo male
  • history of nasopharyngeal carcinoma
  • anaemic symptoms: SOB, pale
  • no bleeding symptoms
A

CBC:

  • ***Pancytopenia (low WBC, neutrophil, RBC, platelet)
  • Neutropenia
  • Few blasts in PB

PB smear:
- Neutrophil hypolobated, lacks granules in cytoplasm (hypogranularity)
—> Dysplastic Neutrophils

BM exam:

  • ***Hypercellular
  • ***Focal prominence of blasts (<20%)
  • Increased + ***Dysplastic erythroid precursors and megakaryocytes

Conclusion:
- Myelodysplastic syndrome (secondary to previous chemotherapy)

Cytogenetics:
- complex karyotype including del(5q) + monosomy 7
—> poor prognosis (require more aggressive treatment)

25
Q

***Clinical approach to Neutropenia

A
  1. Infection —> symptomatology, microbiological workup
    - ***Viral (e.g. CMV, HIV, EBV, hepatitis, parvovirus)
  2. Autoimmune —> symptomatology, autoimmune markers
  3. Drug-induced —> drug history
  4. Marrow causes —> BM exam
    - Marrow infiltration
    - Leukaemia
    - Aplastic anaemia
    - Myelodysplastic syndrome (MDS)
  5. Inherited (very rare) —> clinical features, special test, usually require genetic testing
26
Q

***Myelodysplastic syndrome

A

Features:

  1. Cytopenia(s) in PB
  2. Hyperplastic marrow
  3. Dysplastic features in Myeloid, Erythroid, and/or Megakaryocytic lineage(s)
27
Q

***Diagnostic evaluation of MDS

A
  1. CBC
    - ***Cytopenia
    - Red cell macrocytosis
  2. Morphology of PB and BM
    - **Cellularity of marrow
    - Blast percentage
    - **    Dysplastic features in Myeloid, Erythroid, and/or Megakaryocytic lineage(s)
  3. Cytogenetics
    - Determine prognosis
28
Q

Case 4a:

  • 2 yo boy
  • good past health
  • fever 1 month
  • unremarkable physical examination
A

CBC:

  • Leukocytosis
  • Lymphocytosis
  • ***Blasts in PB
  • Mild anaemia
  • Thrombocytopenia

Suggestion:
- Acute leukaemia

Further investigation:
- BM exam
- Cytochemistry —> -ve for Myeloperoxidase and Sudan Black B —> Lymphoid lineage
- Immunophenotyping (Flow cytometry) for lymphoid lineage
—> -ve CD3 (T cell marker), +ve CD19 (B cell marker), -ve MPO (myeloid marker), +ve CD79a (B cell marker)
—> B cell lineage

Diagnosis:
- B Acute lymphoblastic leukaemia (BALL)

Cytogenetics to Determine prognosis
- Hyperdiploid karyotype (>46 chromosomes) (characteristic of B-ALL)
—> favourable prognosis

29
Q

***Clinical approach to Lymphocytosis

A
  1. ***Reactive
    - Lymphocytosis: Infections, Autoimmune disease
    - Atypical lymphocytosis: Viral infections, Autoimmune disease
    —> Symptomatology, Microbiological workup, Autoimmune markers
  2. ***Malignant (Haematological malignancies)
    - Acute: ALL
    - Chronic: CLL, Other Leukaemic phase of lymphomas
    —> CBC, PB smear, Cytochemistry, Immunophenotyping (Flow cytometry)

(1. Morphology, including cytochemistry —> determine cell lineage
- >=20% blasts in PB / BM
- Myeloid (AML) / Lymphoid (ALL)
- Morphology alone: difficult to distinguish myeloblasts from lymphoblasts
—> ***Auer rod: Pathognomonic feature of Myeloid neoplasms (e.g. AML, MDS)
—> AML: further sub-classification based on morphology
2. Immunophenotyping
3. Cytogenetics and molecular genetics)

30
Q

Atypical (Reactive) Lymphocytosis

A

Lymphocytosis with increased atypical lymphocytes

Causes:

  • Prototype: ***Infectious mononucleosis
  • but many viral infections can give rise to Atypical Lymphocytosis as well
  • autoimmune disease possible

NOT to be mistaken as blasts / lymphoma cells when reading report

31
Q

Case 4b:

  • 63 yo female
  • good past health
  • bilateral neck lumps
  • no fever, weight loss, night sweats
  • no other symptoms
  • multiple bilateral cervical lymphadenopathy
  • no hepatosplenomegaly
A

CBC:

  • Lymphocytosis
  • Abnormal lymphoid cells

Immunophenotyping:
- Typical CLL immunophenotype by flow cytometry

Diagnosis:
- CLL

32
Q

***Clinical approach to Lymphadenopathy

A
  1. ***Infection
    - Pyogenic
    - Viral
    - TB
    —> symptomatology, CBC, microbiological workup, CXR
  2. ***Autoimmune diseases / Inflammatory diseases
    —> symptomatology, CBC, autoimmune markers
  3. Malignancies
    - Haematological: **Lymphoma (most common), Leukaemia (possible)
    - **    Solid tumour: Carcinoma (with metastasis to LN)
    —> symptomatology, CBC, PB smear, imaging, LN biopsy
33
Q

***Diagnostic evaluation of CLL/Lymphoma

A
  1. Morphology
    - PB smear
    - BM exam
    - LN biopsy
  2. Immunophenotyping
    - Diagnostic classification —> Lymphoid / Myeloid lineage
  3. Cytogenetics / FISH
    - Prognosis determination
34
Q

***Causes of Monocytosis

A
  1. Infections
    - esp. ***TB
    - bacterial infections
  2. Autoimmune diseases
  3. ***Chronic myelomonocytic leukaemia (CMML)
    - MDS/MPN neoplasm (a bit of both)
35
Q

***Causes of Basophilia

A

Uncommon in clinical setting

  1. **Myeloproliferative neoplasms (most probably)
    - esp. **    CML
  2. Autoimmune diseases (uncommon)
  3. Allergic conditions (uncommon)
36
Q

CLL, CML, Myeloproliferative neoplasms, Plasma cell myeloma

A

CLL:
- B lymphocyte acquired mutation —> proliferate (more downstream, ∴ no blasts)

CML:
- HSC acquired mutation —> proliferate and differentiate more to Myeloid lineage (more up stream, ∴ can still see blasts although small no. compared to Acute leukaemia)

Myeloproliferative neoplasms:
- Chronic myeloid leukaemia
- Essential thrombocytopenia (ET) —> Megakaryocytes
- Polycythemia Vera (PV) —> RBC
- Primary myelofibrosis (PMF)
—> Common myeloid progenitor acquired mutation
—> uncontrolled proliferation + retain ability of differentiation

Plasma cell / Multiple myeloma:
- Plasma cell accumulation

37
Q

Myeloproliferative neoplasm

A

Philadelphia chromosome +ve:
- Chronic myeloid leukaemia

Philadelphia chromosome -ve:

  • Essential thrombocythemia
  • Polycythaemia Vera
  • Myelofibrosis
38
Q

Acute vs Chronic leukaemia

A

Distinguished by disease tempo

Acute: Rapid progression and fatal if not treated

  • Usually caused by Immature cell types (AML, ALL)
  • Blasts >=20% in PB/BM

Chronic: Slower progression

  • Usually caused by Mature cell types (Mature B cell lymphoma, Mature T cell lymphoma, NK cell lymphoma, Hodgkin lymphoma)
  • some mature entities progress rapidly e.g. Burkitt lymphoma, diffuse large B cell lymphoma etc.
39
Q

Immature vs Mature

A

Distinguished by maturation stage of malignant cells (by Morphology, Immunophenotype)

Immature:

  • Acute myeloid leukaemia
  • B lymphoblastic leukaemia/lymphoma
  • T lymphoblastic leukaemia/lymphoma

Mature:

  • B cell lymphoma
  • T cell lymphoma
  • NK cell lymphoma
  • Hodgkin lymphomas
40
Q

Leukaemia vs Lymphoma

A

Leukaemia: disease primary involves/originate from ***BM / blood
(AML, APL, ALL, CML, CLL)

Lymphoma: disease primary involves/originate from LN, spleen, lymphoid tissue, other tissues (e.g. nasopharynx, GI tract)

—> 2 conditions are NOT mutually exclusive

Examples:
Acute / Chronic myeloid leukaemia: almost entirely leukaemia
Acute lymphoblastic / Chronic lymphocytic leukaemia: depends on site of malignancy —> can be leukaemia / lymphoma

Follicular lymphoma: mainly in lymphoid tissue —> lymphoma —> but if severe enough to involve BM/blood —> Follicular lymphoma in leukaemic phase

Same principles apply to other lymphoma:
xxx lymphoma —> severe enough to involve BM/blood —> xxx lymphoma in leukaemic phase

41
Q

MDS vs MPN vs MDS/MPN

A

Mutations for proliferation —> Uncontrolled proliferation
- more towards MPN

Mutations for differentiation —> Impaired differentiation
- more towards MDS

Mutations for both coexist

  • MDS/MPN (some features of MPN while have dysplastic morphology)
  • esp. CMML

—> Disease phenotype depends on pattern of mutations in a particular patient
—> Rmb NOT clear cut!!!

42
Q

Miscellaneous concept: Massively Parallel Sequencing for DNA

A

Massively parallel sequencing performs millions of DNA sequencing in parallel (at the same time)

  1. Whole genome sequencing
    - still not used in clinical setting
  2. Whole exome sequencing
    - ALL exons of protein-coding genes
    - Diagnosis of rare inherited diseases
  3. Targeted sequencing
    - Selection of genes
    - Increasingly common in cancer testing
43
Q

Summary of White cell disorders

A

Reactive: MOST common in clinical practice
- infections, inflammation, non-haemic malignancy, drug

Intrinsic abnormalities
- Malignant white cell disorder: uncommon but important to recognise
- Inherited white cell disorder: rare
—> numerical vs functional

Diagnosis requires

  • Ascertainment of abnormal cell type
  • Pursue corresponding causes after taking into account all clinical features and investigational findings using the steps of clinical approach highlighted
  • Recognise patterns for features of diseases
44
Q

Summary of cases

A

Case 1a: Leukaemoid reaction
- Myeloid leukaemoid reaction secondary to lung adenocarcinoma —> reactive response to non-haematological abnormality

Case 1b: CML

  • Clinical presentation
  • morphology
  • cytogenetics + FISH —> t(9;22) + BCR-ABL1 fusion
  • molecular

Case 2: Eosinophilia secondary to drug reaction

Case 3a: APL

  • morphology, cytochemistry, cytogenetics + FISH, molecular —> t(15;17), PML-RARa fusion
  • medical emergency
  • treatment

Case 3b: MDS

  • morphology —> Pancytopenia, Neutropenia
  • cytogenetics

Case 4a: B-ALL

  • Leukocytosis, Lymphocytosis, Blasts in PB, Anaemia, Thrombocytopenia
  • flow cytometry —> B cell markers: CD19 +ve, CD79a +ve
  • cytogenetics + FISH —> Hyperdiploid karyotype (>46 chromosomes) (characteristic of B-ALL)
  • molecular

Case 4b: CLL

  • clinical
  • morphology
  • immunophenotype FISH
  • concept of lymphoma in leukaemic phase
45
Q

***Summary of clinical approaches

A
  1. Leukocytosis
    Clonal
    - Blasts >20% —> AML / ALL
    - Blasts <20% —> Other myeloid malignancy (MDS, MPN, CMML)
    - No leukaemic blasts but abnormal lymphoid cells present (e.g. B-CLL)
Reactive (“Leukaemoid”) —> ***BUT won’t be sky high (rarely >50)
- search for underlying cause
—> infection
—> inflammatory / autoimmune
—> paraneoplastic
—> reactive to solid organ tumours
  1. Leukopenia
  2. Neutrophilia
    - Solid tumours
    - MPN (esp. CML, MF)
  3. Eosinophilia
    - Lymphoma (T cell lymphoma, Hodgkin lymphoma)
    - MPN
    - Solid tumour
  4. Basophilia
    - MPN (esp. CML)
  5. ***Pancytopenia
    - APL
    - Megaloblastic anaemia
    - Aplastic anaemia
    - MDS
    - Marrow infiltration
  6. Neutropenia
    - Aplastic anaemia
    - MDS
    - Marrow infiltration
    - Leukaemia
    - Viral infection
  7. Lymphocytosis
    - Acute: ALL
    - Chronic: CLL, leukaemic phase of lymphoma —> Lymphadenopathy
    - Reactive (Infectious mononucleosis)
  8. Monocytosis
    - CMML
    - TB
  9. Thrombocytosis
    - Bleeding / Fe deficiency
    - MPN (ET)
    - Hyposplenism
  10. Lymphadenopathy
    - Infection
    - Autoimmune
    - Lymphoma
    - Solid tumour
  11. Splenomegaly
    - Increased function: Thalassaemia intermedia / major
    - Immune hyperplasia: Haemolytic anaemia (AIHA), Infectious mononucleosis
    - Abnormal blood flow: Portal hypertension
    - Infiltration: MPN, Leukaemia, Lymphoma

(Leukaemia, MDS: Cytopenia
MPN: Cytosis)
Cytosis: 可以係Reactive
Cytopenia: 唔會Reactive)

46
Q

***Summary of Leukaemia

A

Acute Leukaemia (最怕Bleeding tendency)

  • Treatment: Induction, Consolidation, Maintenance, HSCT
  • Treatment of Tumour lysis syndrome
  • Blood product support
  • Treat any infection
AML:
Acute myeloid leukaemia
- Leukocytosis
- Blasts
- Anaemia
- Thrombocytopenia
APL:
Acute promyelocytic leukaemia (t(15;17), PML-RARa fusion)
- Pancytopenia
- Anaemia
- Bleeding tendencies
- DIC
- Faggot cell
ALL (B-ALL / T-ALL):
Acute lymphoblastic leukaemia
- Lymphocytosis
- Blasts
- Anaemia
- Thrombocytopenia

MDS:
Myelodysplastic syndrome (Ineffective haematopoiesis —> Premature apoptosis)
- Pancytopenia
- Hyperplastic BM (Blasts but <20%)
- Dysplastic features in Myeloid, Erythroid, and/or Megakaryocytic lineage(s)
- RBC Macrocytosis
- Treatment
1. Supportive (e.g. transfusion)
2. Erythropoietin-stimulating factors (ESA)
3. G-CSF (for Granulopoiesis)
4. Hypomethylating agents (Azacitidine, Decitabine)

CML:
Chronic myeloid leukaemia (t(9;22), BCR-ABL1 fusion)
- Leukocytosis
—> Bimodal prominence of Neutrophils (Neutrophilia) and Myelocytes
—> Basophilia
(—> Eosinophilia)
- Anaemia
- Thrombocytosis
- Splenomegaly
- Tyrosine kinase inhibitor —> Imatinib

MPN:
Myeloproliferative neoplasms (最怕Thrombosis)
- CML —> Anaemia, ↑ WBC (Bimodal), ↑ Plt
- Polycythaemia Vera (JAK2 V617F) —> ↑ RBC, ↑ WBC, ↑ Plt
- Essential Thrombocythaemia (JAK2, CALR, MPL) —> ↑ Plt
- Primary Myelofibrosis (JAK2, CALR, MPL) —> Anaemia, ↑ WBC, ↑ Plt, Hypercytokinemia, Leukoerythroblastic picture
- Treatment:
1. Antiplatelet for managing risk
2. Cytoreduction (Hydroxyurea and IFN)
3. PV: Phlebotomy (Venesection)
4. ET: Monitor for acquired vWD + Anagrelide
5. PMF: JAK/STAT inhibition (Ruxolitinib)

CMML:
Chronic myelomonocytic leukaemia (CMML)
- Leukocytosis
- Monocytosis
- +/- Anaemia (Dysplastic change in Erythroid lineage)
- +/- Thrombocytopenia (Dysplastic change in Megakaryocyte lineage)

CLL:
Chronic lymphocytic leukaemia
- Lymphocytosis
- Abnormal lymphoid cells

Lymphoma:
- B / T cell
- Myeloid cell rarely
- Treatment:
1. Multi-agent cytotoxic chemotherapy
—> Rituximab (Anti-CD20)
—> Brentuximab vedotin (Anti-CD30 with MMAE, Immunoconjugate)
—> Pembrolizumab (Anti-PD1, Check-point inhibitor)
2. Multiple cycles
47
Q

***Summary of investigation

A

基本:

  1. CBC with manual blood film review + differential count (D/C)
  2. Diagnostic BM aspiration, Trephine biopsy
  3. CXR
  4. LFT, RFT
  5. Serum electrolytes (K, PO4)
  6. LDH, urate levels

其他:

  1. Clotting profile, d-dimer, fibrinogen (***APL)
  2. Serum protein electrophoresis, ESR, β2 microglobulin, Whole body PET-CT (Lymphoma)
Diagnostic:
BM examination:
1. Morphology on PB/BM
2. Cytochemistry
3. Immunophenotype
4. Cytogenetics
5. Molecular genetics

Pre-treatment investigations:

  1. ECG, transthoracic echocardiogram
  2. Lung function
  3. Hepatitis B, C serology
  4. HIV serology
  5. G6PD assay
  6. HLA-typing of patients, siblings for allogeneic HSCT

HIS (30 decks)

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