Haematology - MPN Flashcards
Components and functions of lymphatic system
Components:
- Lymph
- Lymphatic vessels
- lymphatic trunks (Lumbar, intestinal, bronchomediastinal, subclavian, jugular)
- lymphatic ducts (thoracic duct, right lymphatic duct)
- Lymphatic organs (Primary - BM, Thymus; Secondary - LN, Spleen, MALT, GALT, Tonsils)
Functions:
- Excess interstitial fluid drainage
- Immune response
- Dietary lipid and lipid-soluble vitamin transport and absorption
Spleen
- Functions (4)
- General structure
Function:
- Hematopoiesis in fetal life
- Filter circulating blood: remove old/ abnormal RBC
- Immune response: Antibody production, antigenic stimulation
- Blood storage
General structure:
- Fibrous capsule with trabeculae extension
- Red pulp (periphery): Splenic sinuses and splenic cords (Billroth cords) remove old RBC and drain into splenic veins
- White pulp (central) - Follicles, periarterial lymphatic sheath (PALS), Marginal zone for proliferation and antigenic stimulation of B cells, APCs in marginal zone
Main causes of splenomegaly *****
Hemolysis
- Hereditary causes: spherocytosis, thalassaemia intermedia, HbH disease
- Autoimmune haemolytic anaemia
Infection:
- Malaria
- TB, infective endocarditis
- EBV, CMV, HIV
Immune-mediated:
- Felty syndrome (RA)
Vascular congestion
Malignant Infiltration
Storage disease: Gaucher disease
Causes of vascular congestion causing splenomegaly
- Blockage of flow and blood pooling in red pulp
- Cirrhosis or non-cirrhotic portal hypertension
Post-hepatic:
- Budd-Chiari syndrome
- IVC obstruction
- Right heart failure
Intra-hepatic
- Liver cirrhosis
Pre-hepatic
- Portal vein thrombosis
- Splenic vein thrombosis
Malignancies that cause splenomegaly
- Chronic Leukaemia: CML, CLL
- Acute leukaemia: ALL
- Myeloproliferative neoplasm:
- Primary myelofibrosis
- Polycythaemia vera
- Essential thrombocythaemia - Lymphoma
History taking for Splenomegaly
Basic particulars: Age, gender, race
Splenomegaly compressive S/S: Abdominal fullness, Early Satiety
Haematological malignancy S/S:
- Pancytopenia S/S: thrombocytopenia and bleeding tendency, anaemia S/S, frequent infections …etc
- Bone pain, pathological fractures
Residence and travel history (infective causes)
Constitutional symptoms (malignancies)
Family history (storage diseases)
Physical exams for splenomegaly
General:
Anemia: Pallor, jaundice, Tachycardia, cyanosis
Thrombocythemia: bruising, deep-seated bleeding, mucocutaneous bleeding in gum/ mouth
Constitutional/ CA: Lymphadenopathy (Epitrochlear nodes, Axillary nodes, Cervical nodes), cachexia/ muscle wasting, bony tenderness
Specific Etiologies:
- Infections: Rash, retinal lesions (CMV, toxoplasmosis)
- Autoimmune diseases: arthralgia due to Felty’s syndrome (due to RA), Gout (due to MPD), Connective tissue disease
- Leukemia: e.g. testicular/ mediastinal mass (ALL)
Splenomegaly:
- Size below costal margin
- Confirm spleen: LUQ mass, moves down with respiration, cannot get above it, Dull on percussion, splenic notch present
- Associated hepatomegaly, lymphadenopathy
- Stigmata of liver disease
Ddx splenomegaly by size
Massive: CML, Myelofibrosis
Moderate: Portal hypertension, haematological malignancies
Minimal: Haemolytic anaemia (Thal. intermedia, HbH disease), Autoimmune cytopenia (ITP, AIHA), Infective causes
D/dx splenomegaly by incidence
Common:
→ Haematological malignancy, eg. lymphoma, leukaemia, MPN
→ Portal hypertension, eg. cirrhosis, splenic v. obstruction
→ Haemolytic anaemia, eg. thal intermedia, HBH disease, AIHA, hereditary spherocytosis
Rare:
→ Chronic inflammatory or A/I disease
→ Infections, eg. IE, schistosomiasis, malaria
Extremely uncommon:
→ Certain CAs,eg. splenic lymphoma with villous lymphocytes, hairy cell leukaemia
→ Certain infections, eg. hepatosplenic candidiasis, chronic malaria infection
→ Storage diseases
First line investigations for splenomegaly
Investigations:
- CBC with diff.
- Clotting profile
- LFT
- HbsAg
- Imaging of abdomen: USG, CT, PET-CT
Post-splenectomy/ Hyposplenism features on PBS
Howell-Jolly bodies + nucleated RBC
Outline the transition of normal hematopoietic stem cell to myeloid malignancies
AML
- Genetic cause
- Peripheral blood changes
- BM exam findings
- Two-hit mutations: Somatic mutation of TET2, IDH1/ IDH2 confers proliferative advantage and impairs differentiation
- Pancyotpenia due to BM infiltration, Variable WBC levels, Myeloid blast cells
- BM infiltration by leukaemic blasts, reduced normal haemopoietic cells
MPN
- Genetic cause
- Peripheral blood changes
- BM exam findings
- Examples
- Gain-of-fx mutations in pro-growth signalling
Eg. BCR-ABL1, JAK2, MPL, CALR - Increase cell count in 1 or more lineages, non-dysplastic cells
- Hypercellular with ↑progenitor cells, Effective haemopoiesis with normal differentiation
- Examples:
CML (BCR-ABL Positive)
Polycythaemic vera, Essential thrombocythaemia, Primary myelofibrosis, CNL, CEL (BCR-ABL negative)
MDS
- Genetic cause
- Peripheral blood changes
- BM exam findings
- Loss-of-fx mutations in terminal differentiation
- Pancytopenia, Morphology dysplastic
- Hypercellular marrow, Ineffective haemopoiesis with aberrant differentiation, N/↑ blasts <20%
MDS/ MPN
- Genetic cause
- Peripheral blood changes
- BM exam findings
- Mixture of gain-of-function mutation in pro-growth signaling and loss-of-function in terminal differentiation
- Increase cell count, morphology dysplastic
- Hypercellular marrow, Features of aberrant differentiation present
MPN
- Definition
- Key features
Definition:
- clonal disease involving pluripotential haematopoietic stem cell of myeloid lineage
- Proliferation of all three haematopoietic lineages viz. erythroid, myeloid and megakaryocytic
(CBC may only show proliferation in one lineage doesn’t mean that the other lineages are normal)
- Potential to progress to myelofibrosis and blastic transformation
Key features:
□ Increased circulating cells
□ Hypercellular marrow
□ Absence of myelodysplastic features (cf MPN/MDS)
Complications of MPN
Transformation into AML
Other transformation: into MDS, develop myelofibrosis
Thrombohaemorrhagic complications: most pronounced in PV and ET
Overwhelming Post-splenectomy Infection (OPSI) medical emergency
CML
- Key genetic mutation
- Defining features
- AML risk
BCR-ABL1 (95% a/w t(9;22)
Presence of Philadelphia chromosome (karyotype) or BCR-ABL1 (FISH) or fusion mRNA transcript (RT-PCR)
> 90% if untreated
Polycythaemia vera
- Key genetic mutation
- Defining features
- AML risk
Cause:
somatic mutation in Janus kinase 2 (JAK2) in HSC: ↑proliferation of RBC series ± granulocyte and platelet series
Mutation: JAK2 V617F (95-97%), JAK2 exon 12 (3%)
(1) Otherwise unexplained polycythaemia (↑Hb or ↑Hct)
(2) Hypercellular marrow showing trilineage growth and megakaryocytic proliferation
(3) JAK2 V617F/exon 12 mutation
AML risk:
10% at 10y
25% at 25y
Polycythaemia vera
- Clinical definition
- Epidemiology
- Clinical features
Definition: RBC mass >125% that expected for body mass and gender
- Male >16.5g/dL
- Female >16g/dL
Demographics:
- median age 60y
- M>F = 2:1
- RARELY a/w FHx
Clinical features: Hyperviscosity, Hypervolaemia and Hypermetabolism
- Hyperviscosity: Headache, dizziness, loss of concentration, SOB
- Aquagenic pruritis**
- Erythromelalgia *(burning pain in hands/feet with color change) due to mircrovascular thrombosis
- Thrombohaemorrhagic: Arteriovenous thrombosis, Bleeding **
- Facial plethora (Ruddy cyanosis)
Others:
- Retinal venous engorgement
- GI symptoms: mucosal erosions, PUD
- Transient visual symptoms
Polycythaemia vera:
- Diagnostic criteria
- Major ddx to exclude
- Treatment
- Transformations
Major diagnostic criteria
1. High RBC volume by Hb or Hct
2. BM biopsy show hypercellularity for age with trilineage growth (panmyelosis) including prominent erythroid, granulocytic, and megakaryocytic proliferation with pleomorphic, mature megakaryocytes
3. JAK2 mutation: either V617F or exon 12 mutation
Minor criteria: serum EPO below reference
Rule out secondary causes of polycythaemia, exclude high EPO state:
- Chronic hypoxia e.g. COPD
- Abnormal EPO secretion e.g. Hepatoma
Rule out ET, EPO receptor mutations
Treatment:
- Hyperviscosity symptoms: Venesection/ Therapeutic phlebotomy + Cytoreduction by Hydroxyurea, peg-IFN-α or busulphan (suppress erythropoiesis)
- Thromboprophylaxis: Low-dose aspirin
Transformations:
- AML
- 10% Myelofibrosis (Post-PV myelofibrosis)
Primary myelofibrosis
- Key genetic mutation
- Defining features
- AML risk
JAK2 (60-65%), CALR (20-25%), MPL (7%)
(1) Megakaryocytic proliferation/atypia ± myelofibrosis
(2) Any clonal mutation (JAK2, CALR, MPL, other clonal markers) or no other cause of reactive fibrosis
(3) Does not meet CML, PV, ET, MDS criteria
AML risk: 6-18%
Essential throbocythaemia
- Key genetic mutation
- Defining features
- AML risk
JAK2 (60-65%), CALR (20-25%), MPL (3%)
(1) Thrombocytosis (PLT ≥450 × 109/L)
(2) Predominant megakaryocyte proliferation and no significant involvement of other lineages on BM
(3) Demonstration of JAK2, CALR or MPL mutation
AML risk: <5%
Essential thrombocythaemia
- Clinical definition
- Epidemiology
- Diagnostic criteria
- Prognosis and transformations
Definition: sustained ↑platelet count (>450 ×109/L) due to megakaryocyte proliferation resulting in overproduction of platelets
Demographics: median age 60y, peak at 30y for women, F>M = 2:1
Diagnostic criteria: 4 major or 3 major + 1 minor
Major criteria:
→ Platelet count ≥450×10^9/L
→ BM biopsy: proliferation of mainly megakaryocyte lineage with ↑numbers of enlarged, mature megakaryocytes with hyperlobulated nuclei AND no significant left shift in neutrophil granuopoiesis or erythropoiesis and very rarely minor (G1) increase in reticulin fibres
→ Not meeting criteria for other myeloid neoplasms incl CML, PV, PMF, MDS
→ Demonstrate of JAK2, CALR or MPL mutation
Minor criteria:
→ Demonstration of another clonal marker (ASXL1, EZH2, TET2, IDH1/IDH2, SRSF2, or SR3B1 mutation) OR no identifiable cause of thrombocytosis (eg, infection, inflammation, iron deficiency anemia)
Median survival: 10-15 years
Transformations:
- Post-ET Myelofibrosis
- AML
Essential thrombocythaemia
- Clinical presentation
- Treatment
Clinical presentation:
Asymptomatic: incidental finding
Vasomotor symptoms due to microvascular thrombosis
→ Neurological: headache, lightheadedness, syncope, TIA
→ Acral symptoms: acral paraesthesia, erythromelalgia
Mainly Arterial Thrombosis, eg. stroke, MI, superficial thrombophlebitis, DVT, PE, digital ischaemia
Paradoxical haemorrhage with extreme thrombocytosis (>1000×109/L) and acquired vWD
Treatment:
Low-dose Aspirin
Cytoreductive: Hydroxyurea, peg-IFNα-2a, platelet-pheresis
Cardiovascular risk modification: smoking cessation, weight loss
Myelofibrosis
- subtypes and definitions
Acute myelofibrosis:
- very rare form of AML
- characterized by rapid onset of severe BM fibrosis
- a/w fever, pancytopenia, tear-drop RBCs and leucoerythroblastic picture with no splenomegaly
Secondary myelofibrosis:
- from previous PV or ET
Other chronic myeloid disorders
- CML, MDS, MDS/MPN, PV…etc
Misc. haematological disorders: uncommon, eg. hairy cell leukaemia, lymphoma, multiple myeloma
Non-haematological disorders: rare, eg. metastatic BM infiltration, A/I disorders, 2o hyperPTH
Primary myelofibrosis
- Defining features
- Epidemiology
- Pathogenesis
Features:
- unexplained progressive generalized reactive BM fibrosis
- development of extramedullary haematopoiesis in spleen and liver
- Non-functional marrow
Epidemiology
- median age 67y, Increase incidence with aging
Pathogenesis: NOT a neoplasm of fibroblasts
- sporadic mutation in JAK2, CALR, MPL→ activation of growth factor signaling in megakaryocytes → proliferation of megakaryocytic lineage → elaboration of platelet-derived growth factor (PDGF) and TGT-B
- PDGF and TGT-B Stimulate Reactive fibroblast proliferation
→ BM fibrosis Leucoerythroblastic picture (left-shifting) + tear-drop RBCs, high reticulin
- HSC move to extramedullary sites for haematopoiesis
primary myelofibrosis
Clinical course and S/S, CBC in each stage
Clinical course: divided into two phases
- Cellular (prefibrotic) phase (pre-PMF): megakaryocyte atypia only without significant fibrosis
S/S:
- Mild anaemia only with Leukocytosis/thrombocytosis
- no blasts, no splenomegaly - Fibrotic phase (overt PMF): significant marrow fibrosis
S/S:
- pancytopenia (marrow replacement) with leukoerythroblastic blood picture
- Progressive anaemia with abnormal morphology: dacrocytes (teardrop RBCs), anisopoikilocytosis, polychromasia
- hepatosplenomegaly (extramedullary haematopoiesis)
- high LDH
- Dry tap on BM aspirate
Primary myelofibrosis
Clinical presentation
Treatment
Prognosis
Constitutional: severe fatigue (50-70%), low-grade fever, bone pain, night sweats, LOW/A
Anaemic S/S and thrombohaemorrhage events
Massive splenomegaly: hallmark of PMF
Hepatomegaly (40-70%) ± portal hypertension (increase intrahepatic obstruction from extramedullary hematopoiesis, increase splanchnic flow)
Musculoskeletal abnormalities: Osteosclerosis, Periostitis
Treatment:
- Ruxolitinib (JAK1/2 kinase inhibitor)
- Splenectomy
- Allogeneic HSCT
Prognosis: Worst non-CML MPN
median survival 6y
Overwhelming post-splenectomy infection (OPSI)
- Causative pathogen
- Prevention methods
Causative agents: Encapsulated bacteria
Prevention:
- Pre-operative vaccination against streptococcal pneumoniae, Haemophilus influenzae, Neisseria meningitidis
- Post-op antibiotic prophylaxis with penicillin
- Patient education
