In a patient with a myeloproliferative neoplasm (polycythemia vera, essential thrombocythemia, or primary myelofibrosis) presenting with cholestatic liver enzyme abnormalities and marked hepatosplenomegaly, what is the appropriate diagnostic work‑up and initial management?

Diagnostic Work-Up and Initial Management of MPN with Cholestasis and Hepatosplenomegaly

In a patient with myeloproliferative neoplasm presenting with cholestatic liver enzyme abnormalities and marked hepatosplenomegaly, immediately obtain bone marrow biopsy with cytogenetic analysis and molecular testing (JAK2, CALR, MPL mutations) to distinguish primary myelofibrosis from post-PV/post-ET myelofibrosis, as this distinction is critical for risk stratification and determines whether the patient requires urgent cytoreductive therapy or allogeneic stem cell transplant evaluation. 1

Diagnostic Work-Up

Immediate Laboratory Assessment

• Obtain complete blood count with differential looking specifically for leukoerythroblastosis (immature white and red blood cells in peripheral blood), which is a minor diagnostic criterion for primary myelofibrosis and indicates extramedullary hematopoiesis 1

• Measure serum lactate dehydrogenase (LDH), as elevation is a minor diagnostic criterion for PMF and reflects increased cell turnover 1

• Assess liver function tests including direct and indirect bilirubin to differentiate cholestasis from hemolysis, as mild hyperbilirubinemia can occur from intravascular hemolysis or extramedullary hematopoiesis in the liver 2

• Check for anemia (hemoglobin threshold varies by age/sex), which is a minor diagnostic criterion for PMF and affects prognostic scoring 1

Molecular and Cytogenetic Testing

• Perform JAK2 V617F mutation testing first, as it is present in ≥95% of PV and ~60% of ET/PMF cases 1

• If JAK2 V617F is negative, test for CALR and MPL mutations, as 60-80% of JAK2-negative ET/PMF patients harbor CALR mutations, and 3-8% have MPL mutations 1

• Order bone marrow biopsy with chromosome analysis (karyotype) because cytogenetic abnormalities are essential for risk stratification using DIPSS-plus, GIPSS, and MIPSS70+v2 prognostic scores in myelofibrosis 1

• If bone marrow aspirate fails due to fibrosis (common in myelofibrosis), use optical genome mapping (OGM) on peripheral blood to identify chromosomal aberrations, as this technique successfully characterized 10/21 cases with unsuccessful karyotypes in one series 1

Bone Marrow Morphology Assessment

• Evaluate bone marrow for reticulin and collagen fibrosis grading (MF-0 to MF-3 scale), as grade 2-3 fibrosis is a required criterion for diagnosing post-PV or post-ET myelofibrosis 1

• Assess megakaryocyte morphology: PMF shows clusters of megakaryocytes with hyperchromatic, bulbous, or irregularly folded nuclei, while post-PV/post-ET MF shows similar features but requires documentation of prior PV/ET diagnosis 1

• Look for hypercellularity versus hypocellularity, as hypocellularity is common in post-PV/post-ET myelofibrosis 1

Distinguishing Primary from Secondary Myelofibrosis

For post-PV myelofibrosis diagnosis, both required criteria must be met: (1) documented prior PV diagnosis per WHO criteria, and (2) bone marrow fibrosis grade 2-3, PLUS at least 2 additional criteria: anemia or loss of phlebotomy requirement, leukoerythroblastosis, increasing splenomegaly ≥5 cm from left costal margin, or constitutional symptoms 1

For post-ET myelofibrosis diagnosis, both required criteria must be met: (1) documented prior ET diagnosis per WHO criteria, and (2) bone marrow fibrosis grade 2-3, PLUS at least 2 additional criteria: anemia with hemoglobin decrease ≥2 g/dL from baseline, leukoerythroblastosis, increasing splenomegaly ≥5 cm, constitutional symptoms, or increased LDH 1

Hepatic-Specific Evaluation

• Exclude BCR-ABL1 fusion by FISH or RT-PCR if CML is clinically suspected, as Philadelphia-positive CML can also present with hepatosplenomegaly 1

• Screen for tyrosine kinase gene rearrangements (PDGFRA, PDGFRB, FGFR1, JAK2) if eosinophilia is present, as these have variable responsiveness to targeted drugs 1

• Consider liver biopsy only if cholestasis is severe and unexplained by extramedullary hematopoiesis, as marked hyperbilirubinemia responsive to ruxolitinib has been reported in PMF progression 2

Risk Stratification

For Primary Myelofibrosis

Apply the International Prognostic Scoring System (IPSS) at diagnosis using five risk factors: age >60 years, hemoglobin <10 g/dL, white blood cell count >25 × 10⁹/L, circulating blasts ≥1%, and constitutional symptoms 1, 3

Use Dynamic IPSS (DIPSS) for patients seen during disease course, which applies the same five factors but can be calculated at any time point 1

Incorporate cytogenetic risk into DIPSS-plus scoring, as abnormal karyotype (excluding sole abnormalities of 13q- or +9) adds one point and worsens prognosis 1

Assess transfusion dependency, as this is included in DIPSS-plus and identifies patients with median survival <5 years who should be evaluated for allogeneic stem cell transplantation 1

For Post-PV/Post-ET Myelofibrosis

Apply the same prognostic scoring systems (DIPSS-plus, MIPSS70+v2) as used for primary myelofibrosis, as karyotype has been suggested as a useful indicator in post-PV/post-ET MF 1

Initial Management

Cytoreductive Therapy Indications

Initiate hydroxyurea as first-line cytoreductive therapy for symptomatic splenomegaly, as it is the recommended first-line treatment of PMF-associated splenomegaly 1, 4, 5

Consider interferon-α or busulfan as second-line options if hydroxyurea is ineffective or not tolerated 1, 4, 5

Reserve ruxolitinib for severe protracted pruritus or marked splenomegaly unresponsive to hydroxyurea, as controlled studies are needed to confirm its role beyond symptom control 4, 5

Anemia Management

Use corticosteroids, androgens, erythropoiesis-stimulating agents, or immunomodulators to treat myelofibrosis-associated anemia 1

Splenectomy Indications

Consider splenectomy for symptomatic portal hypertension, drug-refractory painful splenomegaly, or frequent RBC transfusions, but recognize the high surgical risk in this population 1

Allogeneic Stem Cell Transplantation

Evaluate transplant-eligible patients for allogeneic stem cell transplantation if median survival is expected to be <5 years based on DIPSS-plus or MIPSS70+v2 scoring, as this is the only curative therapy 1, 6

Critical Pitfalls to Avoid

Do not assume cholestasis is unrelated to the MPN—marked hyperbilirubinemia can be a presenting sign of PMF progression and may respond to ruxolitinib 2

Do not rely solely on peripheral blood for cytogenetic analysis in myelofibrosis—bone marrow aspirate often fails due to fibrosis, and OGM on peripheral blood is now recommended to improve risk stratification 1

Do not overlook the distinction between ET and prefibrotic myelofibrosis—this morphological distinction is prognostically relevant and affects survival, with prefibrotic MF having worse outcomes than true ET 1, 4, 5

Do not delay molecular testing—approximately 17% of ET patients are triple-negative (JAK2/CALR/MPL), and these patients may have different prognoses and require alternative diagnostic approaches 4, 5

Do not forget to screen for acquired von Willebrand syndrome if platelets >1000 × 10⁹/L before administering aspirin, as extreme thrombocytosis increases bleeding risk 4, 5