A 64-year-old woman comes to the physician for her routine health maintenance examination. She feels well. She had cervical cancer and received radiotherapy 8 years ago. Her vital signs are within normal limits. On percussion, the spleen size is 15 cm. Otherwise, the physical examination shows no abnormalities. The laboratory test results are as follows: Hemoglobin 10 g/dL Mean corpuscular volume 88 μm3 Leukocyte count 65,000/mm3 Platelet count 500,000/mm3 Two images of the peripheral blood smear are shown on the image. Which of the following is the most appropriate next step in management?

Allogeneic stem cell transplantation

BCR-ABL fusion gene is MOST CHARACTERISTICALLY seen in?

Chronic Lymphocytic Leukemia (CLL)

Acute Lymphoblastic Leukemia (ALL)

In polycythemia vera all are true except

Increased leukocyte alkaline phosphatase

Decreased levels of erythropoietin

Before the advent of tyrosine kinase inhibitors, the most effective treatment of chronic myeloid leukemia was:

Allogeneic bone marrow transplant

Haploidentical bone marrow transplant

Which of the following is the most common hematologic malignancy associated with Neurofibromatosis-1 (NF-1) in a child?

Juvenile Myelomonocytic Leukemia (JMML)

Acute Lymphoblastic Leukemia (ALL)

All of the following are seen in polycythemia rubra vera except :

Increased Vit B12 binding capacity (>9000 micromols/dL)

Myeloproliferative Neoplasms for FMGE: High-Yield Pathology Lessons

MPN Overview & Classification - Proliferation Powerhouse

⭐ MPNs are clonal hematopoietic stem cell disorders characterized by proliferation of one or more myeloid lineages, often with a relatively mature phenotype.

Hallmark: Autonomous proliferation of myeloid cells.
WHO Classification (Major):
- Chronic Myeloid Leukemia (CML): BCR-ABL1 positive.
- Polycythemia Vera (PV): ↑ RBCs.
- Essential Thrombocythemia (ET): ↑ Platelets.
- Primary Myelofibrosis (PMF): Marrow fibrosis, splenomegaly.
- Chronic Neutrophilic Leukemia (CNL)
- Chronic Eosinophilic Leukemia, NOS (CEL, NOS)
Key Pathogenesis: Tyrosine kinase activation (e.g., JAK2 V617F, CALR, MPL).
Clinical: ↑ Blood counts, organomegaly, thrombosis/bleeding risk.

Chronic Myeloid Leukemia (CML) - Philly's Chromosome Tale

MPN: Dysregulated production of mature/maturing granulocytes.
Pathogenesis:
- ⭐ > The Philadelphia chromosome, t(9;22)(q34.1;q11.2), resulting in the BCR-ABL1 fusion oncogene, is the pathognomonic molecular lesion in CML.
- BCR-ABL1: Constitutively active tyrosine kinase.
Clinical Phases (📌 CAB):
- Chronic: <10% blasts. Most common.
- Accelerated: 10-19% blasts, basophilia ≥20%, worsening splenomegaly/cytopenias.
- Blast Crisis: ≥20% blasts (myeloid/lymphoid). Like acute leukemia.
Diagnosis:
- PBS: Marked leukocytosis, left shift, basophilia, eosinophilia.
- BM: Hypercellular, ↑M:E ratio.
- t(9;22) or BCR-ABL1 (Cytogenetics/FISH/PCR). Philadelphia chromosome OR CML peripheral blood smear with marked leukocytosis, left shift, basophilia)
Treatment:
- Tyrosine Kinase Inhibitors (TKIs) e.g., Imatinib.

PV, ET, & PMF - The JAK/CALR/MPL Crew

⭐ JAK2 V617F mutation is the most common driver mutation in BCR-ABL1 negative MPNs, present in >95% of Polycythemia Vera cases and ~50-60% of Essential Thrombocythemia and Primary Myelofibrosis cases.

Feature	Polycythemia Vera (PV)	Essential Thrombocythemia (ET)	Primary Myelofibrosis (PMF)
Defining	↑ RBC mass (Hb >16.5/16 g/dL), Panmyelosis	Sustained ↑ Platelets (≥450,000/μL), no reactive cause	BM fibrosis, Extramedullary hematopoiesis (EMH), cytopenias
Mutations	JAK2 V617F (>95%), JAK2 Exon 12	JAK2 V617F (50-60%), CALR (25-35%), MPL (~5-10%)	JAK2 V617F (50-60%), CALR (25-35%), MPL (~5-10%)
Key Labs	↓ Serum EPO; ↑WBC, ↑Platelets often; ↑LDH, ↑Uric acid	Normal/↑ EPO; Platelets ≥450,000/μL	Anemia (often severe); Leukoerythroblastosis; Teardrop RBCs
Bone Marrow	Hypercellular (panmyelosis); Pleomorphic megakaryocytes	↑ Megakaryocytes (large, staghorn clusters); No/minimal fibrosis	Fibrosis (reticulin/collagen); Dry tap; Osteosclerosis
Clinical	Plethora, aquagenic pruritus, splenomegaly, thrombosis, gout	Thrombosis/hemorrhage, erythromelalgia, mild/no splenomegaly	Massive splenomegaly, B-symptoms, bone pain, cachexia
Progression	Myelofibrosis (MF) (~10-15%), Acute Myeloid Leukemia (AML) (~2-5%)	MF (<10%), AML (~1-2%)	AML (~5-20%)

MPN Complications & Progression - Trouble Brewing

Thrombotic/Hemorrhagic Events: Arterial (MI, CVA), venous (DVT, PE); often due to abnormal platelet function or count.
Hyperuricemia & Gout: Result of ↑ cell turnover.
Progressive Splenomegaly: Common, from extramedullary hematopoiesis.
Disease Progression:
- Myelofibrosis (Spent Phase / Post-PV/ET MF)
- Acute Myeloid Leukemia (AML) transformation (poor prognosis)

⭐ The major long-term risks across MPNs include thrombotic and hemorrhagic events, progression to myelofibrosis (spent phase), and transformation to acute myeloid leukemia (AML).

High‑Yield Points - ⚡ Biggest Takeaways

JAK2 V617F mutation is a common driver in PV, ET, and PMF.

Polycythemia Vera (PV): ↑RBC mass, ↓EPO, and characteristic aquagenic pruritus.

Essential Thrombocythemia (ET): Marked thrombocytosis, with thrombotic/hemorrhagic risks.

Primary Myelofibrosis (PMF): Features bone marrow fibrosis, extramedullary hematopoiesis, and dacrocytes.

CML: BCR-ABL1 fusion (Philadelphia chromosome) is pathognomonic; treat with TKIs.

MPNs can transform to AML or progress to myelofibrosis (spent phase).

CALR and MPL mutations are significant in JAK2-negative ET/PMF.

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Myeloproliferative Neoplasms