Bone marrow neoplastic

• Also referred to as polycythemia rubra vera, primary polycythemia and essential polycythemia
• BCR-ABL1 negative myeloproliferative neoplasm (MPN) characterized by peripheral erythrocytosis with or without leukocytosis or thrombocytosis

• WHO 2016 revision - PV criteria - diagnosis requires meeting either all 3 major criteria or the first 2 major criteria and the minor criterion (Blood 2016;127:2391, Am J Hematol 2017;92:94)
• Major criteria:
  1. Hemoglobin > 16.5 g/dL in men, > 16.0 g/dL in women, hematocrit > 49% in men, > 48% in women or increased red cell mass
     • More than 25% above mean normal predicted value
  2. Bone marrow biopsy showing hypercellularity for age with trilineage growth (panmyelosis) including prominent erythroid, granulocytic and megakaryocytic proliferation with pleomorphic, mature megakaryocytes (differences in size)
  3. Presence of JAK2 V617F or JAK2 exon 12 mutation
• Minor criterion:
  • Subnormal serum erythropoietin level (normal range of EPO: adults: 4.1 - 19.5 mU/mL)
• Major criterion 2 may not be required in cases with sustained absolute erythrocytosis:
  • Hemoglobin levels > 18.5 g/dL (hematocrit, 55.5%) in men or > 16.5 g/dL (hematocrit, 49.5%) in women, if major criterion 3 and the minor criterion are present
  • Of note, approximately 20% of PV patients' bone marrow biopsies show myelofibrosis, which may predict a more rapid progression to overt myelofibrosis (post PV MF)

Diagnostic criteria set by the Polycythemia Vera Study Group (PVSG)

• Requires all three Category A criteria be present or that criterion A1, A2 and any two Category B criteria are present
• Category A criteria:
  • A1. Total red blood cell mass ≥ 36 mL/kg in males or ≥ 32 mL/kg in females
  • A2. Arterial oxygen saturation ≥ 92%%
  • A3. Splenomegaly
• Category B criteria:
  • Thrombocytosis with platelet count > 400,000/μL
  • Leukocytosis with a white blood cell count > 12,000/μL
  • Leukocyte alkaline phosphatase (LAP) > 100 U/L in the absence of fever or infection
  • Serum vitamin B12 concentration > 900 pg/mL or binding capacity > 2,200 pg/mL

Other findings that may be present but are not necessary for diagnosis include:

• Subnormal erythropoietin (EPO) levels
• Endogenous erythroid colony (EEC) formation
• Detection of JAK2 V617F or functionally similar mutation (JAK2 exon 12)

• Median survival > 10 years
• Most patients die of thrombosis or hemorrhage (approximately 15%)
• Approximately 20% progress to post PV MF at 10 to 15 years
  • Due to increased red blood cell production independent of mechanisms that typically regulate erythropoiesis
  • 15% develop spent phase with marrow fibrosis and marked cytopenias after 10 years, death in months if no treatment
• Leukemic transformation rates at 20 years are estimated at < 10% for PV (Am J Hematol 2017 Jan;92:94)
  • 2% develop acute myeloid leukemia with phlebotomy treatment but 15% with alkylating agents or radioactive phosphorus (no longer used)
  • Risk of leukemic transformation (ALL) is rare, except in patients treated with cytotoxic regimens
• Therapeutic goals:
  • Decrease thrombosis without increasing bleeding
  • Prevent progression
  • Ameliorate symptoms
• Treatment guidelines (Ann Oncol 2015;26:v85, Blood 2014;124:3212, N Engl J Med 2004;350:114)
  • Low / intermediate risk for thrombosis:
    • First line: phlebotomy
    • Low dose aspirin
    • Intensive management of cardiovascular risk factors
  • High risk for thrombosis:
    • Cytoreductive therapy (hydroxyurea)
    • Adjunct phlebotomy
    • Low dose aspirin
  • Pregnant women:
    • First line: Phlebotomy
    • Low dose aspirin
    • Low molecular weight heparin in postpartum period

• Even in early pre polycythemic stage, the morphologic findings are sufficient to allow distinction of PV from secondary polycythemia and other subtypes of MPN
  
  

Bone Marrow (Pre polycythemic and overt polycythemic phases) (Figures A - C)

• Hypercellular (mean 80% cellularity, range 37 - 100%)
• Panmyelosis with notable predominance of erythroid and megakaryocytic lineages
• Complete and progressive maturation of all 3 hematopoietic lineages
• Abnormal megakaryocyte morphology and architecture (PAS stain can assist in identification); variably hyperlobulated; not as pronounced as in essential thrombocythemia (ET) or as pleomorphic as in primary myelofibrosis (PMF) (see ET and PMF images)
• Reticulin fibrosis tends to be minimal or absent or limited to a small focus
• Iron stores are decreased, often absent

Post PV / spent phase: (Figures D - G)
• Leukoerythroblastosis
• Overt bone marrow reticulin and collagen fibrosis
• Osteosclerosis usually prominent
• Blasts may increase but are less than 20%
• Dilated sinuses with intrasinusoidal hematopoiesis
• Decline in hematopoietic cells
• Overall picture may be indistinguishable from advanced PMF; need prior documentation of PV diagnosis

Contributed by Erika M. Baardsen, D.O. and Ling Zhang, M.D.

Contributed by Erika M. Baardsen, D.O. and Ling Zhang, M.D.

Which of the following is most reliable to establish a diagnosis of primary polycythemia?


1. Detection of JAK2 exon 12 mutation
2. Hemoglobin > 16.5 g/dL (men) or 16.0 g/dL (women)
3. Increased EPO level
4. Marrow fibrosis grade 3
5. Presence of BCR-ABL1 gene fusion product

A. JAK2 V617F and JAK2 exon 12 mutations are not only found in PV but detection is fairly sensitive and is identified in nearly all patients with PV (Am J Hematol 2017;92:94). Whereas answer choice B is a major criterion, elevated hemoglobin can be seen in other conditions and would not be the most reliable. Marrow fibrosis (answer D), especially grades 2 and 3, can represent the post polycythemic / spent phase but may also be found in other conditions, such as primary myelofibrosis (PMF) or secondary changes after direct exposure to radiation therapy. The presence of Philadelphia chromosome (BCR-ABL1 gene fusion product, answer E) is associated with CML and in some cases of AML. Increased EPO levels (answer C) are associated with secondary polycythemia or administration of EPO agonist for treatment of anemia.

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Reference: Polycythemia vera

A patient undergoes bone marrow biopsy. Reticulin staining of the core reveals myelofibrosis grade 3. Which of the following is the most reliable in differentiating post polycythemic / spent phase of PV from PMF?


1. Detection of JAK2 mutation
2. Detection of MPL mutation
3. Differentiation is not necessary because the prognosis and treatments are similar
4. Longstanding history of elevated hemoglobin and hematocrit levels and panmyelosis on previous bone marrow biopsies
5. Low EPO level

D. In addition to bone marrow fibrosis grade 2 or 3, documentation of a previous diagnosis of WHO defined PV is required to diagnose post polycythemic/spent phase and would be the most reliable in differentiating the post polycythemic / spent phase from primary myelofibrosis. JAK2 mutations (answer A) are detected in > 95% of PV patients; however, they can also be detected in other conditions such as PMF (approximately 50% of cases). Detection of MPL mutations (answer B) has been reported in up to 5% of PMF cases and some cases of essential thrombocythemia (ET) but has not been reported in PV (Leukemia 2017;31:2726). Low EPO levels (answer E) are characteristic of PV but can also be seen in several other conditions, including diseases associated with inherited EPO receptor mutations. The predictive factors, prognosis, natural disease progression and treatments are different for PV and PMF, making distinction between the two diseases important (answer C).

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Reference: Polycythemia vera