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JC WCS > Haematology JC044: Splenomegaly: Common Causes Of Splenomegaly, Myeloproliferative Diseases > Flashcards

Haematology JC044: Splenomegaly: Common Causes Of Splenomegaly, Myeloproliferative Diseases Flashcards

1
Q

Revision: Spleen anatomy

A
  • Intraperitoneal
  • LUQ
  • Below diaphragm
  • Longitudinal axis along 9th-11th rib
  • “Normal size” correlate with individual body build: Splenomegaly: 12 cm on USG

Blood supply:
- Splenic artery from Celiac artery
- Splenic vein (join with Superior mesenteric vein) —> ***Portal vein

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2
Q

Normal structural organisation of spleen

A

Function:
1. Blood pool
- store blood

  1. Secondary immune organ

White pulp (內):
- PALS (peri-arteriolar lymphoid sheath) (containing mainly CD4 T cells)
- Primary follicles (containing B cells)
- Marginal zone (containing Plasma cells)

Red pulp (外):
- Splenic sinuses (closed circulation)
- Splenic cords (open circulation) —> reticular fibres surrounding sinuses, contain macrophage to filter

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3
Q

Normal function of spleen

A
  1. Filtration
    - **Reticuloendothelial macrophages lining splenic sinusoids + Slow blood in narrow splenic sinusoids —> filter + remove “defective” **RBC + **pathogens
    - “defective” RBC: deformed ∵
    —> aging
    —> **    complement fixed
    —> opsonised (Ab coated)
    —> Howell-Jolly bodies (RBC with nuclear remnants)
    - occurs in cords of Billroth in red pulp
  2. Immunity
    - ***Secondary lymphoid organ
    - B + T cells, Plasma cells mature + resides in white pulp
    - Mature B cells interact with T cells in spleen on exposure to Ag (Ag dependent humoral immunity) —> Ab production (Humoral immune response)
  3. Blood pool
    - 5% red cell mass
    - 30-50% WBC margining pool
    - 20-40% total platelet mass (splenectomy in treatment of ITP)
  4. Haematopoiesis (only in fetus)
    - shift to axial skeleton except in extra-medullary haematopoiesis in Thalassaemia major / Primary myelofibrosis
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4
Q

How do we know that spleen is performing Filtration

A

Seen in blood films in Post-splenectomy / Hyposplenism:

  1. Howell-Jolly bodies
    - basophilic nuclear remnants (clusters of DNA) in circulating RBC
  2. Nucleated RBC
    - may be mistaken by machine in CBP test as WBC —> “Spurious Leukocytosis”
  3. Spherocytes (in AIHA)
    - RBC marked by autoimmune RBC Ab —> macrophages “pit” RBC membrane —> ↓ SA/V ratio
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5
Q

How to examine for Splenomegaly

A
  1. LUQ mass
  2. Moves down with respiration along Gardner’s line
  3. Cannot get above it (no subcostal gap)
  4. Dull to percussion (∵ anterior organ)
  5. Splenic notch (medial border)
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6
Q

***Major causes of Splenomegaly

A
  1. **Congestive (most common)
    - Pre-hepatic: Thrombosis of portal / hepatic / splenic veins
    - Intra-hepatic: **    Cirrhosis (Hep B, Alcohol etc.)
    - Post-hepatic: ***Heart failure
  2. Malignancy
    - **Lymphoma
    - **    Acute / Chronic Leukaemia
    - **PV, ET, PMF
    - Multiple myeloma (not cause Splenomegaly except Splenic plasmacytoma / **    Amyloidosis)
    - Primary / Metastatic tumour
  3. Infection
    - Bacterial
    - Viral
    - Parasitic
    - Fungal
    - IE
  4. Inflammation
    - Sarcoidosis
    - SLE
    - RA (Felty syndrome)
    - Serum sickness
  5. Infiltration by non-malignant disease (Rare, can only seen by Imaging +/- Biopsy)
    - Gaucher disease
    - Niemann-Pick disease
    - Amyloid
  6. Haematological disease causing / caused by Hypersplenic state
    - **Acute / Chronic Haemolytic anaemia (e.g. AIHA, Thalassaemia)
    - **    Sickle cell disease
    - Following use of recombinant human G-CSF
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7
Q
  1. Congestive cause of Splenomegaly
A
  1. Pre-hepatic
    - Portal vein thrombosis
    - Splenic vein thrombosis
  2. Intra-hepatic
    - Cirrhosis
  3. Post-hepatic
    - Budd Chiari syndrome
    - IVC obstruction
    - RH failure
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8
Q

Hypersplenism

A

Hypersplenism: ↑ Blood ***sequestration in enlarged spleen

4 diagnostic criteria:
1. **Pancytopenia
2. Splenomegaly
3. Evidence of **active marrow
4. Reversal of abnormal features on splenectomy (if performed)

NB:
- patients with abnormal marrow may develop pancytopenia due to splenomegaly
—> but should NOT be called hypersplenism

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9
Q

Clinical features of Splenomegaly

A

***Pressure symptoms from Enlarged spleen:
1. Abdominal fullness
2. Early satiety
3. Referred pain to left shoulder

Symptoms related to Pancytopenia:
1. **Bleeding
2. **Infection

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10
Q

History taking in Splenomegaly

A
  1. Age, gender, race
  2. Residence, travel history
  3. Alcohol abuse
  4. ***Bleeding tendency (end result)
  5. ***Constitutional symptoms: Fever, LOW, Night sweat (find out cause)
  6. ***Family history of liver / blood diseases: Hep B, Thalassaemia (find out cause)
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11
Q

Physical examination of Splenomegaly

A
  1. Size of spleen
  2. Associated Hepatomegaly, Lymphadenopathy
  3. Stigmata of chronic liver disease, jaundice
  4. Fever / other signs of infection
  5. Cardiac murmur / splinter haemorrhage —> IE as a cause
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12
Q

***Diagnosis of Splenomegaly

A
  1. Size of Splenomegaly
    - Massive: **CML, **Myelofibrosis
    - Moderate: **Portal hypertension, **Haematological malignancies
    - Minimal: ***Haemolytic anaemia (Thalassaemia intermedia, HbH disease), Autoimmune cytopenia (ITP, AIHA)
  2. Geographical location
    - determine possible infective causes of splenomegaly e.g. Malaria
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13
Q

Investigations of Splenomegaly

A
  1. CBP
    - ***Cytopenia
    - abnormal cells
  2. Clotting profile
    - if suspected liver disease
  3. LFT
    - if suspected liver disease
  4. HbsAg
    - Hep B common in HK

Imaging
5. USG
6. CT
7. PET-CT
- look for space-occupying lesions

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14
Q

Haematological diseases in Splenomegaly

A

***Blood film to differentiate

Example:
1. CML
- Leukocytosis
- **Bimodal distribution of Neutrophils + Myelocytes
- BM examination: small hypolobated megakaryocytes (*Dwarf megakaryocyte)
- Cytogenetics: Philadelphia chromosome +ve

  1. CLL
    - ***Smear / Smudge cells (squashed abnormal CLL cells)
  2. PMF
    - **Teardrop RBC
    - **    Leukoerythroblastic (LE) blood picture
    - BM examination: ***↑ Reticulin
  3. Others
    - e.g. Hairy cell leukaemia (a type of lymphoma), Large granular lymphocyte leukaemia, Splenic marginal zone lymphoma with villous lymphocytes
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15
Q

Chronic myeloid leukaemia

A

Clinical features:
1. Leukocytosis
- **Bimodal prominence of Neutrophils + Myelocytes
- Basophilia
2. Thrombocytosis
3. **Splenomegaly
4. ***Small hypolobated megakaryocytes (Dwarf megakaryocyte) on BM exam

Pathogenesis:
- **Philadelphia chromosome: **t(9;22)(q34.1;q11.2)
—> Translocation of ABL gene on chromosome 9 —> BCR gene on chromosome 22
—> Oncogenic **BCR-ABL fusion protein
—> **Constitutive activated tyrosine kinase
—> Phosphorylation of multiple substrates (e.g. JAK-STAT pathway)
—> Abnormal + Uncontrolled cell proliferation

Natural disease progression (3 phases):
1. Chronic phase
- BCR-ABL1 fusion —> **Expansion of myeloid compartment
- **10-15% blasts
- Asymptomatic

  1. Accelerated phase
    - **New cytogenetic abnormalities
    - **    15-30% blasts
    - ↑ tiredness, LOW, enlarged spleen
  2. Blastic crisis
    - ↑ genomic instability
    - ↑ BM blasts proportion + Constitutional symptoms
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16
Q

Diagnosis of CML

A
  1. Blood film
  2. BM exam
    - ***Small hypolobated megakaryocytes (Dwarf megakaryocyte) on BM exam
  3. ***Demonstration of Philadelphia chromosome
    - Karyotype
    - FISH (demonstration of BCR-ABL fusion gene)
    —> red: BCR
    —> green: ABL
    —> yellow: fusion
    - PCR (demonstration of BCR-ABL fusion gene)
17
Q

Treatment of CML

A

Past:
- Hydroxyurea
- Chemotherapy
- IFN
- Allogeneic HSCT

Now:
- **Tyrosine kinase inhibitors (Imatinib, Nilotinib, Dasatinib, Ponatinib (newest))
—> bind to **ATP-binding site of BCR-ABL protein
—> ***preventing phosphorylation of substrates
—> block downstream signaling
—> able to induce deep molecular remission (not only morphological remission)

Monitoring treatment response:
1. Measure BCR-ABL1 transcript in peripheral blood
- by quantitative RT-PCR
- 0.1: complete cytogenetic response
- ***0.01: major molecular response
- 0.0001: complete molecular response (undetectable disease)

New treatment of CML:
- Kinase domain mutation in BCR-ABL gene
—> Resistant to TKI
—> ***Asciminib: overcome resistance by Allosteric inhibition of BCR-ABL1 by binding to Myristoyl-binding site (no need bind to ATP-binding site)

18
Q

Chronic lymphocytic leukaemia

A
  • Disease of ***older patients
  • Incidental findings of ***Lymphocytosis: Slow-growing
  • May transform into **aggressive Large cell lymphoma —> **Richter transformation (difficult to treat)
  • ***Abnormal lymphocytes

Clinical presentation:
1. Constitutional symptoms: Fatigue, LOW
2. Lymphadenopathy
3. Hepatosplenomegaly

19
Q

Diagnosis of CLL

A

No need BM exam to make definitive diagnosis
- but patterns of BM involvement have prognostic significance (diffuse involvement have worse prognosis)

  1. **Immunophenotype (Flow cytometry) of **abnormal lymphocytes
    - detect **Ag on abnormal lymphocytes —> can differentiate from other chronic lymphoproliferative disease
    —> **    CD5 (T cell marker but now expressed on B cells)
    —> **CD23
    —> **    absent of FMC7
20
Q

Treatment of CLL

A
  • No single universal treatment, ***no treatment is curative
  • Depends on clinical staging + symptoms (***Rai + Binet staging system) + patients comorbidities
  • ***Watch + wait in asymptomatic patients with early stages

Young + Fit:
- Chemotherapy:
1. **Fludarabine (purine analogue)
+
2. **Cyclophosphamide (alkylating agent)
+
3. ***Rituximab (Anti-CD20 Ab)

Old + Frail:
- Chlorambucil + Anti-CD20 Ab

New small molecules:
- **Ibrutinib (BTK inhibitor)
- **Venetoclax (BCL2 inhibitor)

21
Q

Prognosis determination of CLL

A
  1. BM exam
  2. FISH
    - poor prognosis: del 11q23, trisomy 12, del 13q14, del 13q34, del 17p
22
Q

Myeloproferative neoplasm (MPN) (formerly known as Myeloproliferative disease)

A

WHO classification 2017 of MPN:
1. Philadelphia chromosome +ve / BCR-ABL1 +ve
- CML

  1. Philadelphia chromosome -ve / BCR-ABL1 -ve
    - PV
    - ET
    - PMF
  2. Others
    - Chronic neutrophilic leukaemia
    - Chronic eosinophilic leukaemia
    - MPN unclassified
23
Q

Pathogenesis of MPN

A
  1. **JAK2 mutation on erythropoietin receptor (Tyrosine kinase)
    - normally: Epo bind to erythropoietin receptor —> autophosphorylation of JAK2 kinase —> downstream cell signaling
    - JAK2-V617F mutation: **    Constitutively active Tyrosine kinase —> cell signaling ***without Epo —> Uncontrolled proliferation of RBC
  2. JAK2 mutation on unknown receptor
    - Epo receptor —> ↑ RBC
    - MPL receptor —> ↑ Megakaryocyte
    - G-CSF receptor —> ↑ Granulocyte
24
Q

Diagnostic flowchart for Polycythaemia

A

Polycythaemia: ↑ Hb

  1. Relative Polycythaemia
    - blood concentration secondary to dehydration
    - red cell mass is normal
  2. Absolute Polycythaemia
    - ↑ red cell mass
    —> Primary BM cause: PV
    —> **    Secondary BM cause (↑ EPO production): Appropriate (    Hypoxia: COPD, cyanotic heart, smoking, high altitude) / Inappropriate (Hepatoma, **Renal tumour)
25
Q

***Polycythaemia Vera (PV)

A

Clinical features:
1. **Hyperviscosity syndrome
- dizziness
- headache
2. **Pruritus (particularly after hot bath)
3. Risk of arterial + venous ***thrombosis

Investigations:
1. Peripheral blood: ↑ red cell mass
2. BM: ↑ red cell precursors + hyperlobated megakaryocytes
3. Reticulin stain of BM: not present (i.e. no fibrosis)
(4. EPO suppressed)

26
Q

***Diagnosis of PV

A
  1. Clinical criteria
    - ↑ Hb
    - ↑ Hct
    - ***↑ Red cell mass
  2. BM morphology
    - **Hypercellular BM
    - Prominent erythroid, granulocytic, megakaryocytic proliferation with **    pleomorphic mature megakaryocytes (differences in size)
    - ***記: 唯一一個MPN全部升
  3. Genetic mutation (Clonal gene marker)
    - **JAK2 V617F mutation
    or
    - **    JAK2 exon 12 mutation

Minor criteria
4. Suppressed serum Epo level

27
Q

Essential thrombocythaemia (ET)

A

Clinical features:
1. Asymptomatic (usually)
2. Headache, dizziness (∵ disturbance in microcirculation)
3. **Arterial > Venous thrombosis
4. **Paradoxical bleeding in very high platelet (∵ ***acquired VWD, consumption of VW factors due to ↑ platelet)

Investigations:
1. Peripheral blood: ↑ platelets
2. BM: ↑ megakaryocytes + pleomorphic
3. Reticulin stain of BM: not present (i.e. no fibrosis)

28
Q

***Diagnosis of ET

A

Mainly a diagnosis by exclusion (from other causes of thrombocytosis)

  1. Clinical criteria
    - ***↑ Plt >=450
  2. BM morphology
    - ***Proliferation of megakaryocyte lineage
    - ↑ no. of enlarged, mature megakaryocyte with hyperlobated nuclei
  3. Not meeting criteria of CML, PV, PMF, MDS, other myeloid neoplasms
  4. Presence of Clonal gene markers
    - JAK2 mutation
    - CALR mutation
    - MPL mutation
  5. No evidence for ***reactive thrombosis
29
Q

Treatment of ET and PV

A

**Thrombotic risk + Leukaemia transformation (PV 5%, ET 1%) + **Secondary myelofibrosis

Depends of risk of thrombosis:
1. History of thrombosis
2. Age
3. Presence of JAK2 mutation
4. Other CVS risk factors

No risk factors:
- Safely observe

With risk factors:
- ***Antiplatelets (low dose aspirin)

Intermediate / High risk diseases / thrombosis:
- **Cytoreduction (Hydroxyurea / IFN for younger, child-bearing age women)
- **Anticoagulants (in history of thrombosis)

All patients with PV require ***Phlebotomy (Venesection) to Hct <45%

30
Q

***Myelofibrosis (MF)

A

2 types:
- Primary (PMF)
- Secondary: Post-PV / Post-ET MF

  • Highest risk of leukaemic transformation (15%) among all MPN

Clinical features:
1. **Pancytopenia
2. **Leukoerythroblastic (LE) blood picture
3. ***Gross splenomegaly
4. Weight loss (disease induce hypercatabolic state)

Investigations:
1. Peripheral blood
- **Left shift in WBC
- ↑ Myeloid precursors in circulation
- Nucleated RBC
- **Teardrop poikilocytes

  1. BM
    - Distorted architecture
  2. Reticulin stain
    - ***↑ Reticulin in BM

NB:
- Fibroblasts in PMF are not clonal
- Abnormal **megakaryocytes release cytokines (PDGF, TGFβ) —> stimulate Fibroblast proliferation + Collagen deposition
- Fibrotic BM unable to function —> Myeloid precursors (HSC) move to spleen and liver (i.e. **Extramedullary haematopoiesis) (not contribute to significant haematopoiesis)

31
Q

Treatment of Myelofibrosis

A

Scoring based on:
1. Cytogenetics
2. Gene mutation profile

Very low risk disease:
- Asymptomatic without high risk gene mutations: Observation
- Symptomatic splenomegaly: **Hydroxyurea / **Ruxolitinib (JAK1/2 kinase inhibitor)

Intermediate risk disease:
- Drug therapy / Allogeneic HSCT

High risk disease:
- Allogeneic HSCT

***Splenectomy:
- sometimes performed to relieve pressure symptoms + ↓ transfusion requirement

***Allogeneic HSCT:
- only potentially curative procedure
- feasibility limited by age + comorbidities

Median survival for intermediate / high risk disease:
- 3-5 years

32
Q

Treatment for Splenomegaly

A

Splenectomy:
- generally not performed in most cases of splenomegaly

Indications:
1. Diagnostic purpose
- e.g. suspected splenic lymphoma

  1. Therapeutic
    - **Symptomatic relief in massive splenomegaly e.g. Myelofibrosis
    - **    Refractory ITP / AIHA
    - ***↓ Transfusion requirement in Thalassaemia major

Other non-surgical spleen reduction therapies:
1. ***Splenic irradiation
- in patients with haematological malignancy to relieve pressure symptoms + improve cytopenia

  1. ***Hydroxyurea / Ruxolitinib for PMF
33
Q

Complications of Splenectomy

A
  1. Overwhelming post-splenectomy infection (**OPSI)
    - medical emergency
    - caused by **    encapsulated bacteria
    - prevented by:
    —> **Pre-op vaccination: Strept. pneumoniae, Hib, N. meningitidis
    —> **    long term Post-op antibiotic prophylaxis with Penicillin
    —> patient education to watch out early signs of infection (e.g. fever) + seek early medical help

(From SpC Surg:
2. Thrombocytosis (cause stroke)
3. Portal vein thrombosis (cause liver failure))

34
Q

Summary

A

High white cell count:
1. Reactive causes are more common in daily clinical practice
2. Ascertainment of abnormal cell type
3. Leukaemia (Acute / Chronic) treatment depends on specific diagnosis, risk of disease, patient comorbidities
4. Look out for haematological emergencies in suspected / newly diagnosed leukaemia —> Neutropenic sepsis, TLS, Leukostasis
5. Allogeneic HSCT reserved for high risk cases / at relapse
6. HLA-matching is crucial in Allogeneic HSCT (probably except Haplo-identical transplantation)

Splenomegaly:
1. Many causes of Splenomegaly
2. Size + How common the diseases are can help narrow down DDx
3. Geographical location determines possible infective causes of Splenomegaly
4. Post-splenectomy infections requires urgent treatment
5. Refer to Haematology if abnormal cells seen on blood film

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