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MBBS IV - Junior Clerkship WCS > JC44 (Medicine) - MPN > Flashcards

JC44 (Medicine) - MPN Flashcards

1
Q

Components and functions of lymphatic system

A

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:

  1. Excess interstitial fluid drainage
  2. Immune response
  3. Dietary lipid and lipid-soluble vitamin transport and absorption
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2
Q

Spleen

  • Functions (4)
  • General structure
A

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
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3
Q

Main causes of splenomegaly *****

A

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

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4
Q

Causes of vascular congestion causing splenomegaly

A
  • 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
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5
Q

Malignancies that cause splenomegaly

A
  1. Chronic Leukaemia: CML, CLL
  2. Acute leukaemia: ALL
  3. Myeloproliferative neoplasm:
    - Primary myelofibrosis
    - Polycythaemia vera
    - Essential thrombocythaemia
  4. Lymphoma
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6
Q

History taking for Splenomegaly

A

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)

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7
Q

Physical exams for splenomegaly

A

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

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8
Q

Ddx splenomegaly by size

A

Massive: CML, Myelofibrosis

Moderate: Portal hypertension, haematological malignancies

Minimal: Haemolytic anaemia (Thal. intermedia, HbH disease), Autoimmune cytopenia (ITP, AIHA), Infective causes

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9
Q

D/dx splenomegaly by incidence

A

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

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10
Q

First line investigations for splenomegaly

A

Investigations:

  • CBC with diff.
  • Clotting profile
  • LFT
  • HbsAg
  • Imaging of abdomen: USG, CT, PET-CT
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11
Q

Post-splenectomy/ Hyposplenism features on PBS

A

Howell-Jolly bodies + nucleated RBC

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12
Q

Outline the transition of normal hematopoietic stem cell to myeloid malignancies

A
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13
Q

AML

  • Genetic cause
  • Peripheral blood changes
  • BM exam findings
A
  • 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
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14
Q

MPN

  • Genetic cause
  • Peripheral blood changes
  • BM exam findings
  • Examples
A
  • 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)

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15
Q

MDS

  • Genetic cause
  • Peripheral blood changes
  • BM exam findings
A
  • Loss-of-fx mutations in terminal differentiation
  • Pancytopenia, Morphology dysplastic
  • Hypercellular marrow, Ineffective haemopoiesis with aberrant differentiation, N/↑ blasts <20%
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16
Q

MDS/ MPN

  • Genetic cause
  • Peripheral blood changes
  • BM exam findings
A
  • 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
17
Q

MPN

  • Definition
  • Key features
A

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)

18
Q

Complications of MPN

A

Transformation into AML

Other transformation: into MDS, develop myelofibrosis

Thrombohaemorrhagic complications: most pronounced in PV and ET

Overwhelming Post-splenectomy Infection (OPSI) medical emergency

19
Q

CML

  • Key genetic mutation
  • Defining features
  • AML risk
A

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

20
Q

Polycythaemia vera

  • Key genetic mutation
  • Defining features
  • AML risk
A

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

21
Q

Polycythaemia vera

  • Clinical definition
  • Epidemiology
  • Clinical features
A

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
22
Q

Polycythaemia vera:

  • Diagnostic criteria
  • Major ddx to exclude
  • Treatment
  • Transformations
A

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)
23
Q

Primary myelofibrosis

  • Key genetic mutation
  • Defining features
  • AML risk
A

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%

24
Q

Essential throbocythaemia

  • Key genetic mutation
  • Defining features
  • AML risk
A

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%

25
Q

Essential thrombocythaemia

  • Clinical definition
  • Epidemiology
  • Diagnostic criteria
  • Prognosis and transformations
A

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
26
Q

Essential thrombocythaemia

  • Clinical presentation
  • Treatment
A

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

27
Q

Myelofibrosis

  • subtypes and definitions
A

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

28
Q

Primary myelofibrosis

  • Defining features
  • Epidemiology
  • Pathogenesis
A

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
29
Q

primary myelofibrosis

Clinical course and S/S, CBC in each stage

A

Clinical course: divided into two phases

  1. Cellular (prefibrotic) phase (pre-PMF): megakaryocyte atypia only without significant fibrosis
    S/S:
    - Mild anaemia only with Leukocytosis/thrombocytosis
    - no blasts, no splenomegaly
  2. 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
30
Q

Primary myelofibrosis

Clinical presentation
Treatment
Prognosis

A

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

31
Q

Overwhelming post-splenectomy infection (OPSI)

  • Causative pathogen
  • Prevention methods
A

Causative agents: Encapsulated bacteria

Prevention:

  • Pre-operative vaccination against streptococcal pneumoniae, Haemophilus influenzae, Neisseria meningitidis
  • Post-op antibiotic prophylaxis with penicillin
  • Patient education

MBBS IV - Junior Clerkship WCS (131 decks)

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