Myeloproliferative Neoplasms Overview

MPNs are slow-growing cancers of the bone marrow that involve an overproduction of mature blood cells.
The affected cells are mature, meaning they lack immature or dysplastic features.

Polycythemia vera (PV): Most frequent MPN, characterized by an increased red blood cell count, often linked to the JAK-2 mutation.
Primary myelofibrosis (PMF): The most severe form of MPN, often involving bone marrow fibrosis and associated with various mutations like JAK-2, CALR, or MPL. It leads to a high risk of transformation into acute myeloid leukemia (AML).
Essential thrombocytosis (ET): A benign form of MPN with an increased platelet count. It is less likely to transform into other MPNs or AML compared to PV or PMF.
Chronic myeloid leukemia (CML): A distinct type of leukemia characterized by a BCR-ABL translocation, not directly classified as MPN.
Chronic neutrophilic leukemia (CNL): MPN with a CSF3R mutation, causing an overproduction of neutrophils.
Chronic eosinophilic leukemia (CEL): MPN with a PDGFRA mutation resulting in excess eosinophils.
Juvenile myelomonocytic leukemia (JMML): MPN primarily affecting children, featuring myelomonocytic proliferation in the blood and bone marrow.

Extramedullary hematopoiesis: The production of blood cells occurs outside the bone marrow, primarily in the spleen (splenomegaly) and can occur in the liver and skin.
Hyperviscosity symptoms: High white blood cell count can lead to hyperviscosity, resulting in headaches, dizziness, and tinnitus.
Cytokine release: Increased cytokines can cause fatigue, thrombosis, and endothelial damage.
Systemic mastocytosis: A mast cell disease with a c-kit mutation, not classified as an MPN.

Caused by a decrease in plasma volume, leading to a higher concentration of red blood cells (e.g., dehydration, post-viral infections).
Red blood cell mass is normal.
Total leukocyte count and platelet count are also within normal limits.

Marked by an increased red blood cell mass.
Primary (PV): Erythropoietin levels are normal to low, total leukocyte count and platelet count are elevated.
Secondary: Erythropoietin levels are increased, while total leukocyte count and platelet count are normal..

Hypoxia: Chronic obstructive pulmonary disease (COPD), obstructive sleep apnea syndrome, high altitude, carbon monoxide poisoning, hepatopulmonary syndrome.
Renal artery stenosis
Paraneoplastic Conditions: Renal carcinoma, cerebellar hemangioblastoma, meningioma, pheochromocytoma, uterine fibroids, hepatoma.

JAK-2 mutation: Found in 50% of cases.
Calreticulin (CALR) mutation: 30-40% of cases.
MPL mutation: 10-20% of cases.
Triple negative PMF: Lack of the above mutations, indicating a poorer prognosis.
Deletion 13q: A chromosomal abnormality associated with PMF.
Megakaryocytes in PMF are dysplastic lacking CXCR4 receptors, leading to production of TGF-β and PDGF (platelet-derived growth factor) contributing to fibrosis in the bone marrow.
Pancytopenia emerges due to premature cell release and bone marrow fibrotic replacement.

Most PMF cases present in the fibrotic stage.
Age of onset: 50-70 years old.
Thrombosis: Increased risk, especially compared to ET.
B-symptoms: Occur in 20% of cases, including fever, night sweats, and weight loss.
Anemia: Most common reported symptom.
Bleeding: May occur due to pancytopenia.
Gout: Commonly develops during the proliferation phase.
Extramedullary hematopoiesis: Frequently observed.
Osteosclerosis: Possible in the bone marrow.
Skin: Febrile neutrophilic dermatosis (Sweet syndrome) may manifest.
Massive splenomegaly (75% of cases) and hepatomegaly (leading to portal hypertension).

Diagnosis: Three major criteria or one major plus one minor criteria from the World Health Organization (WHO) criteria.
Major criteria:
- Hemoglobin levels: 7-16.5 g/dL in men and >16 g/dL in women.
- Hypercellular bone marrow.
- JAK-2 mutation.
Minor criteria: Subnormal serum erythropoietin level.

Low-risk (<60 years of age): Weekly phlebotomy to maintain hemoglobin levels between 13-14 g/dL, aspirin therapy.
High-risk (760 years of age, history of thrombosis): Combined therapy with phlebotomy, aspirin (75mg), and JAK inhibitors like ruxolitinib (10mg twice daily) or hydroxyurea (0.5-2 g/day).

Red blood cells, white blood cells: Normal.
Platelet count: 74.5 lakhs.
Bone marrow biopsy:
- Megakaryocyte hyperplasia, few dysplastic megakaryocytes.
- Staghorn cells: Large cells with mature cytoplasm and hyperlobulated nuclei.

Peripheral smear:
- Leukoerythroblastosis.
- Anisopoikilocytosis (variation in red blood cell size and shape) with teardrop-shaped red cells (dacryocytes).
- Cloud-like megakaryocytes due to thrombocytosis.
Serum type-III procollagen peptide: Elevated.
Bone marrow aspirate: Dry tap.
Bone marrow biopsy:
- Reticulin fibrosis and collagen fibrosis upon silver impregnation.
- Fibrosis with hypercellular marrow.

JAK-2 mutation: Present in 100% of cases.
- Exon 14 mutation (95%): V617F mutation.
- Exon 12 mutation (5%).

Erythrocytosis:
- Hyperviscosity symptoms.
- Thrombosis: Arterial (e.g., stroke in young adults) more common than venous (e.g., Budd-Chiari syndrome, deep vein thrombosis).
- Microvascular thrombosis leading to erythromelalgia (burning pain of hands and feet).
- Hypertension.
Granulocytosis:
- Neutrophilia.
- Basophilia (causing histamine release): Can lead to aquagenic pruritus (pruritus after bathing).
- Mature granulocytes: Increased transcobalamin-1, increasing vitamin B12 binding capacity.
Thrombocytosis
- Increased dysfunctional platelets: Bleeding (esp. epistaxis) due to acquired Von Willebrand disease.
Erythromelalgia:
- Burning pain of hands and feet due to microvascular thrombosis.
Moderate splenomegaly.
Hyperuricemia: Resulting from increased cell turnover.

Diagnosis: Sustained platelet count 74.5 lakhs and exclusion of reactive thrombocytosis (normal RBC and WBC).
Management:
- Low-risk ( <60 years old): Aspirin 75 mg/day.
- High-risk ( 760 years old, history of thrombosis, platelets 71.5 x 10^9: Aspirin therapy, combined with hydroxyurea, interferon, or anagrelide.