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Polycythemia vera

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polycythemia vera blood smear bone marrow JAK2

This diagnostic visual presents an [18F]FDG PET/CT scan of a 59-year-old male, illustrating advanced polycythemia vera (PV) with transformation to myelofibrosis. Panel A is a Maximum Intensity Projection (MIP) showing widespread, intense metabolic activity throughout the axial and appendicular skeleton. High FDG uptake is particularly localized in the bone marrow of the trunk (spine, ribs, pelvis) and the proximal long bones (humeri and femurs), characteristic of panmyelosis. Panel B displays three transversal PET/CT fusion slices corresponding to the abdominal and pelvic levels. These slices reveal massive splenomegaly, with the spleen extending from the upper abdomen into the pelvis. The splenic tissue demonstrates uniform and significantly elevated metabolic activity, reflecting extramedullary hematopoiesis and high cellular turnover. The combination of intense skeletal uptake and hypermetabolic splenomegaly in the absence of nodal or solid organ malignancy is highly suggestive of a myeloproliferative neoplasm in the 'spent phase' or fibrotic transformation. The image serves as an educational reference for nuclear medicine and hematology-oncology in identifying metabolic patterns associated with JAK2-positive myelofibrosis.

This diagnostic visual presents an [18F]FDG PET/CT scan of a 59-year-old male, illustrating advanced polycythemia vera (PV) with transformation to myelofibrosis. Panel A is a Maximum Intensity Projection (MIP) showing widespread, intense metabolic activity throughout the axial and appendicular skeleton. High FDG uptake is particularly localized in the bone marrow of the trunk (spine, ribs, pelvis) and the proximal long bones (humeri and femurs), characteristic of panmyelosis. Panel B displays three transversal PET/CT fusion slices corresponding to the abdominal and pelvic levels. These slices reveal massive splenomegaly, with the spleen extending from the upper abdomen into the pelvis. The splenic tissue demonstrates uniform and significantly elevated metabolic activity, reflecting extramedullary hematopoiesis and high cellular turnover. The combination of intense skeletal uptake and hypermetabolic splenomegaly in the absence of nodal or solid organ malignancy is highly suggestive of a myeloproliferative neoplasm in the 'spent phase' or fibrotic transformation. The image serves as an educational reference for nuclear medicine and hematology-oncology in identifying metabolic patterns associated with JAK2-positive myelofibrosis.

This infographic summarizes treatment recommendations for Myeloproliferative Neoplasms (MPN), specifically Polycythemia Vera (PV), Essential Thrombocythemia (ET), and Myelofibrosis (MF). The central panel illustrates the conditions: PV is shown with a cluster of erythrocytes; ET with light-colored thrombocytes; and MF with a histological bone marrow biopsy slide showing reticulin fibrosis. A red box for PV lists standard therapy (low-dose ASA, phlebotomy to Hct<45%) and high-risk options (hydroxyurea, pegylated IFṆ̑́, ruxolitinib). A blue box for ET outlines ASA use and high-risk treatments including hydroxyurea, pegylated IFṆ̑́, and anagrelide. The bottom green section displays management for MF stratified by risk: Low/Int-1 patients receive symptomatic therapy (transfusions, ESA), hydroxyurea, or JAK2 inhibitors; Int-2/High-risk patients are managed with JAK2 inhibitors and evaluation for allogeneic hematopoietic stem cell transplantation (allo-HSCT). This educational algorithm serves as a clinical guide for hematology-oncology professionals and students to differentiate subtype-specific therapeutic pathways based on patient risk stratification.

This infographic summarizes treatment recommendations for Myeloproliferative Neoplasms (MPN), specifically Polycythemia Vera (PV), Essential Thrombocythemia (ET), and Myelofibrosis (MF). The central panel illustrates the conditions: PV is shown with a cluster of erythrocytes; ET with light-colored thrombocytes; and MF with a histological bone marrow biopsy slide showing reticulin fibrosis. A red box for PV lists standard therapy (low-dose ASA, phlebotomy to Hct<45%) and high-risk options (hydroxyurea, pegylated IFṆ̑́, ruxolitinib). A blue box for ET outlines ASA use and high-risk treatments including hydroxyurea, pegylated IFṆ̑́, and anagrelide. The bottom green section displays management for MF stratified by risk: Low/Int-1 patients receive symptomatic therapy (transfusions, ESA), hydroxyurea, or JAK2 inhibitors; Int-2/High-risk patients are managed with JAK2 inhibitors and evaluation for allogeneic hematopoietic stem cell transplantation (allo-HSCT). This educational algorithm serves as a clinical guide for hematology-oncology professionals and students to differentiate subtype-specific therapeutic pathways based on patient risk stratification.

This diagnostic image displays a series of three whole-body Maximum Intensity Projection (MIP) 18F-FDG PET scans (1a, 2a, 3a) paired with age- and sex-matched controls (1b, 2b, 3b) for a comparative study of Polycythemia Vera (PV). The visual focuses on the metabolic activity of the bone marrow. Case 1a exhibits elevated, dispersed FDG uptake throughout the axial skeleton compared to control 1b, alongside incidental avid hepatic and esophageal lesions. Case 2a demonstrates diffuse heterogeneous uptake in both the axial and appendicular skeleton, notably more intense than control 2b, with focal uptake at the gastroesophageal (GE) junction and mediastinum. Case 3a shows more subtle visual differences from its control 3b, although the axial skeleton maintains increased metabolic activity. These images illustrate the hyper-metabolic state of bone marrow in myeloproliferative neoplasms and highlight the utility of functional imaging in identifying both disease-related marrow expansion and co-morbidities such as potential malignancies in secondary sites like the thyroid, lungs, or GE junction.

This diagnostic image displays a series of three whole-body Maximum Intensity Projection (MIP) 18F-FDG PET scans (1a, 2a, 3a) paired with age- and sex-matched controls (1b, 2b, 3b) for a comparative study of Polycythemia Vera (PV). The visual focuses on the metabolic activity of the bone marrow. Case 1a exhibits elevated, dispersed FDG uptake throughout the axial skeleton compared to control 1b, alongside incidental avid hepatic and esophageal lesions. Case 2a demonstrates diffuse heterogeneous uptake in both the axial and appendicular skeleton, notably more intense than control 2b, with focal uptake at the gastroesophageal (GE) junction and mediastinum. Case 3a shows more subtle visual differences from its control 3b, although the axial skeleton maintains increased metabolic activity. These images illustrate the hyper-metabolic state of bone marrow in myeloproliferative neoplasms and highlight the utility of functional imaging in identifying both disease-related marrow expansion and co-morbidities such as potential malignancies in secondary sites like the thyroid, lungs, or GE junction.

This diagnostic axial MRI image focuses on the pelvic region, specifically evaluating the prostate gland and surrounding musculoskeletal structures. Within the prostate, a black arrow highlights a small, localized nodule (approximately 5 mm) in the right peripheral zone characterized by abnormal signal intensity. The prostatic capsule appears continuous and intact, suggesting no extracapsular extension. Anatomically, the pelvic bone marrow (indicated by white arrows) exhibits a diffusely inhomogeneous signal intensity, which contrasts with the preserved integrity of the cortical bone structure. There is no evidence of localized lymphadenopathy in the immediate periprostatic area. This imaging is representative of clinical oncology and radiology, used to differentiate between localized primary prostatic adenocarcinoma and secondary hematologic or metastatic bone marrow involvement, such as that seen in myeloproliferative disorders like JAK2 mutation-positive polycythemia vera.

This diagnostic axial MRI image focuses on the pelvic region, specifically evaluating the prostate gland and surrounding musculoskeletal structures. Within the prostate, a black arrow highlights a small, localized nodule (approximately 5 mm) in the right peripheral zone characterized by abnormal signal intensity. The prostatic capsule appears continuous and intact, suggesting no extracapsular extension. Anatomically, the pelvic bone marrow (indicated by white arrows) exhibits a diffusely inhomogeneous signal intensity, which contrasts with the preserved integrity of the cortical bone structure. There is no evidence of localized lymphadenopathy in the immediate periprostatic area. This imaging is representative of clinical oncology and radiology, used to differentiate between localized primary prostatic adenocarcinoma and secondary hematologic or metastatic bone marrow involvement, such as that seen in myeloproliferative disorders like JAK2 mutation-positive polycythemia vera.

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Polycythemia Vera (PV)

Definition and Overview

Polycythemia vera is a clonal hematopoietic stem cell disorder (myeloproliferative neoplasm, MPN) in which phenotypically normal red cells, granulocytes, and platelets accumulate in the absence of a recognizable physiologic stimulus. It is the most common of the MPNs, with an incidence of 2.5 per 100,000 persons, rising to >10/100,000 with advancing age. Women under age 50 predominate among sporadic cases; familial transmission is rare.
  • Harrison's Principles of Internal Medicine 22E, p. 864
  • Robbins, Cotran & Kumar Pathologic Basis of Disease

Pathogenesis

JAK2 Mutation

The central molecular event is a point mutation in the autoinhibitory pseudokinase domain of JAK2 (the tyrosine kinase for erythropoietin and thrombopoietin receptors), replacing valine with phenylalanine at residue 617 (V617F). This causes constitutive kinase activation, making hematopoietic progenitors growth factor-independent. Consequences include:
  • Erythropoietin hypersensitivity and EPO-independent erythroid colony formation
  • Increased Bcl-X_L expression (apoptosis resistance)
  • Rapid terminal differentiation of erythroid progenitors
  • Low serum EPO (contrast with secondary polycythemia where EPO is high)
>95-97% of PV cases carry JAK2 V617F. Most remaining cases carry a JAK2 exon 12 mutation. Loss of heterozygosity at chromosome 9p (uniparental disomy) leads to homozygosity for JAK2 V617F in ~60% of PV patients - associated with higher WBC, more splenomegaly, symptomatic pruritus, and faster progression to spent-phase fibrosis.
JAK2 V617F is not the sole initiating lesion; other cooperating mutations (LNK, CALR, TET2, DNMT3A) exist. The GGCC JAK2 haplotype predisposes to acquiring JAK2 mutations.
  • Harrison's 22E; Robbins & Kumar Basic Pathology; Robbins, Cotran & Kumar Pathologic Basis of Disease

Morphology

FeatureFinding
Bone marrowHypercellular (panmyelosis) with residual fat; increased erythroid, granulocytic, and megakaryocytic precursors
ReticulinModerate-to-marked increase at diagnosis in ~10% of cases
Peripheral bloodElevated RBC, often leukocytosis, large/abnormal platelets, basophilia
Late "spent phase"Extensive marrow fibrosis, displaced hematopoiesis, prominent splenomegaly from extramedullary hematopoiesis
  • Robbins, Cotran & Kumar Pathologic Basis of Disease

Clinical Features

PV often presents incidentally with a high hemoglobin, hematocrit, or RBC count. Presenting features in 1,545 patients (Goldman-Cecil data) include:

Symptoms from Hyperviscosity

  • Headache, vertigo, tinnitus, visual disturbances, TIAs
  • Systolic hypertension
  • Fatigue, difficulty concentrating, lightheadedness

Characteristic Symptoms

  • Aquagenic pruritus - itching after a warm bath/shower (highly characteristic)
  • Erythromelalgia - burning, erythema, and pain in the extremities due to platelet-mediated small vessel occlusion; responds dramatically to aspirin
Erythromelalgia of the hands in a patient with polycythemia vera (JAK2 exon 12 mutation)

Examination Findings

  • Facial plethora, conjunctival injection, engorged retinal veins
  • Splenomegaly (more frequent than hepatomegaly) - from congestion early, extramedullary hematopoiesis later
  • Hypertension

Thrombosis and Bleeding

In a large international study of PV patients, arterial thrombosis, venous thrombosis, or major hemorrhage were noted prior to or at diagnosis in 16%, 7%, and 4% of patients, respectively.
  • Cerebral, cardiac, and mesenteric vessels are most commonly involved
  • Budd-Chiari syndrome (hepatic vein thrombosis) is particularly common in young women with PV - PV should be suspected in any woman who develops hepatic vein thrombosis
  • Portal vein thrombosis is more common in male PV patients
  • Bleeding can occur due to acquired von Willebrand disease (platelet-mediated proteolysis of high-MW vWF multimers when platelets >900,000/mL)

Metabolic

  • Hyperuricemia, secondary gout, uric acid stones
  • Gastrointestinal symptoms (epigastric discomfort, early satiety from splenomegaly)
  • Harrison's 22E, p. 863-864; Goldman-Cecil Medicine, p. 1751

Diagnosis

WHO 2022 Diagnostic Criteria for PV

Major criteria:
  1. Hemoglobin >16.5 g/dL (men) or >16.0 g/dL (women), OR hematocrit >49% (men) or >48% (women), OR elevated red cell mass
  2. Bone marrow biopsy showing age-adjusted hypercellularity with trilineage proliferation (panmyelosis) including prominent erythroid, granulocytic, and pleomorphic megakaryocytic proliferation
  3. Presence of JAK2 V617F or JAK2 exon 12 mutation
Minor criterion:
  • Subnormal serum EPO level
Diagnosis requires all 3 major criteria OR major criteria 1+3 + minor criterion.

Key Diagnostic Notes

  • An elevated hemoglobin/hematocrit is not sufficient alone - plasma volume expansion in PV can mask the elevated red cell mass, especially in women. Red cell mass and plasma volume determinations may be necessary.
  • Normal arterial oxygen saturation + JAK2 mutation provides strong evidence for PV
  • Differential includes: secondary erythrocytosis (high altitude, COPD, high-O2-affinity Hgb), relative erythrocytosis (dehydration, diuretics), other MPNs
  • Harrison's 22E; Goldman-Cecil Medicine

Treatment

Risk Stratification

Risk CategoryFeatures
Low riskAge <60 AND no prior thrombosis
High riskAge ≥60 OR prior thrombosis

Treatment Algorithm

MPN treatment algorithm: PV management by risk stratification
All patients:
  • Phlebotomy - target hematocrit <45% (proven to reduce thrombotic risk in the CYTO-PV trial)
  • Low-dose aspirin (75-100 mg/day) - reduces thrombotic risk; avoids in extreme thrombocytosis (>1,500,000/mL) due to bleeding risk
High-risk patients (add cytoreductive therapy):
  • Hydroxyurea (hydroxycarbamide) - first-line cytoreductive agent; reduces all blood cell lines, lowers thrombotic risk
  • Pegylated interferon alpha (pegIFN-alpha) - alternative first-line, preferred in younger patients and pregnant women; can induce molecular remissions (JAK2 allele burden reduction)
  • Ruxolitinib (JAK1/2 inhibitor) - for patients intolerant or resistant to hydroxyurea; also effective for pruritus and splenomegaly
  • Busulfan - low-dose oral option especially in elderly patients
Symptom-directed measures:
  • Pruritus: antihistamines, aspirin, interferon, ruxolitinib (most effective)
  • Hyperuricemia/gout: allopurinol
  • Erythromelalgia: aspirin (dramatic response)
  • Harrison's 22E; Goldman-Cecil Medicine

Disease Course and Complications

Transformation

PV follows a natural history with three phases:
  1. Prepolycythemic phase - subtle erythrocytosis, minimal symptoms
  2. Polycythemic phase - classic manifestations
  3. Spent phase / Post-PV Myelofibrosis - extensive marrow fibrosis, progressive anemia, massive splenomegaly; occurs in ~15-20% over 20 years
TransformationFrequency
Post-PV myelofibrosis~15-20% at 20 years
Transformation to AML~1-3% (higher with hydroxyurea treatment history, especially if alkylating agents used)
The JAK2 V617F allele burden >25% and homozygosity are associated with faster progression to spent phase.
  • Robbins, Cotran & Kumar Pathologic Basis of Disease; Harrison's 22E

Key Distinguishing Features vs. Secondary Erythrocytosis

FeaturePVSecondary Erythrocytosis
Serum EPOLowElevated
JAK2 mutationPresent (>95%)Absent
Leukocytosis/thrombocytosisCommonAbsent
SplenomegalyPresentAbsent
Aquagenic pruritusCharacteristicAbsent
Oxygen saturationNormalOften low (hypoxic causes)

Recent Evidence Update

A 2025 systematic review and meta-analysis in Annals of Hematology (PMID 41238945) confirmed the efficacy and safety of ropeginterferon alfa-2b in PV treatment, supporting its role as a first-line cytoreductive option. A 2024 meta-analysis (PMID 39658117) examined prevalence of JAK2 V617F among blood donors, highlighting subclinical clonal hematopoiesis considerations.
Sources: Harrison's Principles of Internal Medicine 22E (2025); Goldman-Cecil Medicine International Edition; Robbins & Kumar Basic Pathology; Robbins, Cotran & Kumar Pathologic Basis of Disease; PubMed PMIDs 41238945, 39658117.
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