Haematology JC044: Splenomegaly: Common Causes Of Splenomegaly, Myeloproliferative Diseases Flashcards
Revision: Spleen anatomy
- 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
Normal structural organisation of spleen
Function:
1. Blood pool
- store blood
- 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
Normal function of spleen
- 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 - 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) - Blood pool
- 5% red cell mass
- 30-50% WBC margining pool
- 20-40% total platelet mass (splenectomy in treatment of ITP) - Haematopoiesis (only in fetus)
- shift to axial skeleton except in extra-medullary haematopoiesis in Thalassaemia major / Primary myelofibrosis
How do we know that spleen is performing Filtration
Seen in blood films in Post-splenectomy / Hyposplenism:
- Howell-Jolly bodies
- basophilic nuclear remnants (clusters of DNA) in circulating RBC - Nucleated RBC
- may be mistaken by machine in CBP test as WBC —> “Spurious Leukocytosis” - Spherocytes (in AIHA)
- RBC marked by autoimmune RBC Ab —> macrophages “pit” RBC membrane —> ↓ SA/V ratio
How to examine for Splenomegaly
- LUQ mass
- Moves down with respiration along Gardner’s line
- Cannot get above it (no subcostal gap)
- Dull to percussion (∵ anterior organ)
- Splenic notch (medial border)
***Major causes of Splenomegaly
-
**Congestive (most common)
- Pre-hepatic: Thrombosis of portal / hepatic / splenic veins
- Intra-hepatic: **Cirrhosis (Hep B, Alcohol etc.)
- Post-hepatic: ***Heart failure - Malignancy
- **Lymphoma
- **Acute / Chronic Leukaemia
- **PV, ET, PMF
- Multiple myeloma (not cause Splenomegaly except Splenic plasmacytoma / **Amyloidosis)
- Primary / Metastatic tumour - Infection
- Bacterial
- Viral
- Parasitic
- Fungal
- IE - Inflammation
- Sarcoidosis
- SLE
- RA (Felty syndrome)
- Serum sickness - Infiltration by non-malignant disease (Rare, can only seen by Imaging +/- Biopsy)
- Gaucher disease
- Niemann-Pick disease
- Amyloid - 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
- Congestive cause of Splenomegaly
- Pre-hepatic
- Portal vein thrombosis
- Splenic vein thrombosis - Intra-hepatic
- Cirrhosis - Post-hepatic
- Budd Chiari syndrome
- IVC obstruction
- RH failure
Hypersplenism
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
Clinical features of Splenomegaly
***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
History taking in Splenomegaly
- Age, gender, race
- Residence, travel history
- Alcohol abuse
- ***Bleeding tendency (end result)
- ***Constitutional symptoms: Fever, LOW, Night sweat (find out cause)
- ***Family history of liver / blood diseases: Hep B, Thalassaemia (find out cause)
Physical examination of Splenomegaly
- Size of spleen
- Associated Hepatomegaly, Lymphadenopathy
- Stigmata of chronic liver disease, jaundice
- Fever / other signs of infection
- Cardiac murmur / splinter haemorrhage —> IE as a cause
***Diagnosis of Splenomegaly
- Size of Splenomegaly
- Massive: **CML, **Myelofibrosis
- Moderate: **Portal hypertension, **Haematological malignancies
- Minimal: ***Haemolytic anaemia (Thalassaemia intermedia, HbH disease), Autoimmune cytopenia (ITP, AIHA) - Geographical location
- determine possible infective causes of splenomegaly e.g. Malaria
Investigations of Splenomegaly
- CBP
- ***Cytopenia
- abnormal cells - Clotting profile
- if suspected liver disease - LFT
- if suspected liver disease - HbsAg
- Hep B common in HK
Imaging
5. USG
6. CT
7. PET-CT
- look for space-occupying lesions
Haematological diseases in Splenomegaly
***Blood film to differentiate
Example:
1. CML
- Leukocytosis
- **Bimodal distribution of Neutrophils + Myelocytes
- BM examination: small hypolobated megakaryocytes (*Dwarf megakaryocyte)
- Cytogenetics: Philadelphia chromosome +ve
- CLL
- ***Smear / Smudge cells (squashed abnormal CLL cells) - PMF
- **Teardrop RBC
- **Leukoerythroblastic (LE) blood picture
- BM examination: ***↑ Reticulin - Others
- e.g. Hairy cell leukaemia (a type of lymphoma), Large granular lymphocyte leukaemia, Splenic marginal zone lymphoma with villous lymphocytes
Chronic myeloid leukaemia
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
- Accelerated phase
- **New cytogenetic abnormalities
- **15-30% blasts
- ↑ tiredness, LOW, enlarged spleen - Blastic crisis
- ↑ genomic instability
- ↑ BM blasts proportion + Constitutional symptoms
Diagnosis of CML
- Blood film
- BM exam
- ***Small hypolobated megakaryocytes (Dwarf megakaryocyte) on BM exam - ***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)
Treatment of CML
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)
Chronic lymphocytic leukaemia
- 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
Diagnosis of CLL
No need BM exam to make definitive diagnosis
- but patterns of BM involvement have prognostic significance (diffuse involvement have worse prognosis)
-
**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
Treatment of CLL
- 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)
Prognosis determination of CLL
- BM exam
- FISH
- poor prognosis: del 11q23, trisomy 12, del 13q14, del 13q34, del 17p
Myeloproferative neoplasm (MPN) (formerly known as Myeloproliferative disease)
WHO classification 2017 of MPN:
1. Philadelphia chromosome +ve / BCR-ABL1 +ve
- CML
- Philadelphia chromosome -ve / BCR-ABL1 -ve
- PV
- ET
- PMF - Others
- Chronic neutrophilic leukaemia
- Chronic eosinophilic leukaemia
- MPN unclassified
Pathogenesis of MPN
-
**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 - JAK2 mutation on unknown receptor
- Epo receptor —> ↑ RBC
- MPL receptor —> ↑ Megakaryocyte
- G-CSF receptor —> ↑ Granulocyte
Diagnostic flowchart for Polycythaemia
Polycythaemia: ↑ Hb
- Relative Polycythaemia
- blood concentration secondary to dehydration
- red cell mass is normal - 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)
