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Chronic Myeloid Neoplasms

Myeloproliferative neoplasms (MPN)

Polycythemia vera


Reviewer: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 12 August 2011, last major update August 2011
Copyright: (c) 2001-2011, PathologyOutlines.com, Inc.

Clinical features
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● Also called polycythemia rubra vera
● Clonal, neoplastic proliferation of multipotent myeloid stem cells (panmyelosis)
● RBC production increases independent of the mechanisms that normally regulate erythropoiesis
● Prevalence of 2-3 per million (Am J Hematol 2008;83:359)
● Median age 60 years, uncommon in children
● Etiology unknown
● Genetic predisposition reported by some
● 3 clinical phases: (a) pre-polycythemic (previously called latent PV) with borderline increase in RBC mass; (b) overt polycythemic with significant RBC increase; and (c) ‘spent’ or post-polycythemic with ineffective hematopoiesis, marrow fibrosis, extramedullary hematopoiesis causing splenomegaly, and peripheral cytopenia
● Most symptoms are due to polycythemia (increased hematocrit) with associated increased total blood volume, vascular distention and stasis; mild hepatosplenomegaly due to extramedullary hematopoiesis
● Patients are plethoric, cyanotic and hypertensive with headache, dizziness, gastrointestinal symptoms, pruritis or ulcers, possibly from basophilic histamine
● May have hyperuricemia or gout due to increased cell turnover
● 25% have thrombotic episodes (stroke, deep venous thrombosis, myocardial infarction) due to abnormal blood flow and possibly abnormal platelet function; also Budd-Chiari syndrome (hepatic vein thrombosis), bowel infarction, hemorrhagic strokes due to thrombosis of venous sinuses of brain, life threatening hemorrhage in 10%
● May have iron deficiency due to bleeding, which corrects the hematocrit to normal

Prognosis
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● Spent phase with marrow fibrosis and marked cytopenias in 15% after 10 years, death in months if no treatment
● Acute myeloid leukemia in 2% with phlebotomy but 15% with alkylating agents or radioactive phosphorus (no longer used)
● Acute lymphocytic lymphoma is rare

Case reports
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● 77 year old man who also developed variant hairy cell leukemia (Arch Pathol Lab Med 2003;127:e209)
● Transformation to AML-M7 (Arch Pathol Lab Med 2000;124:1389)
● Transformation to CML (Arch Pathol Lab Med 2007;131:1719)

Laboratory
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● Elevated red cell mass, white blood cell count and platelet count
● Marked increase in hemoglobin and hematocrit
● Abnormal aggregation of platelets, normal or increased LAP score, no CML translocation, decreased erythropoietin (EPO), EPO-independent erythroid colony (EEC) growth formation in vitro

Diagnosis (WHO 2008)
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● Requires major criteria #1 and #2 plus one minor criterion, OR major criterion #1 plus 2 minor criteria:
Major criterion #1: Hgb > 18.5 g/dl for men or 16.5 g/dl for women OR Hgb or Hct > 99th percentile of reference range for age, sex or altitude of residence, OR Hgb > 17 g/dl men or 15 g/dl women if associated with a sustained increase of 2 g/dl or more from baseline that cannot be attributed to correction of iron deficiency OR elevated red cell mass > 25% above mean normal predicted value
Major criterion #2: Presence of JAK2 V617F or functionally similar mutation like JAK2 exon 12 mutation
Minor criterion #1: bone marrow trilineage myeloproliferation (panmyelosis)
Minor criterion #2: subnormal serum erythropoietin level (EPO) below the reference range for normal
Minor criterion #3: endogenous erythroid colony (EEC) growth in vitro (Table, WHO 2008 diagnostic algorithm)

Criteria for diagnosis of post-PV myelofibrosis (‘spent’ phase):
● Required criteria – established diagnosis of PV, and marrow fibrosis 2 – 3 (European consensus system on a 0 – 3 scale)
● Additional criteria (at least 2 required) – anemia or peripheral cytopenia, leukoerythroblastic peripheral blood picture, progressive splenomegaly, or constitutional symptoms like fever, night sweats

● Diagnosis (WHO 2001): polycythemia (increased red blood cell mass) with nonelevated erythropoietin levels; Table - not used anymore

Treatment
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● Median survival of 10 years with phlebotomy
● High risk patients (for thrombosis) get cytoreductive therapy (hydroxyurea) and low dose aspirin (N Engl J Med 2004;350:114)
● Possibly interferon (Cancer 2006;107:451)

Micro description
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Peripheral blood: increased erythrocytes, leukocytes, platelets, basophils; large platelets
Bone marrow: Mean 80% cellularity (range 37-100%), panmyelosis (helps distinguish from ET)
● Usually marked erythroid hyperplasia although may be subtle
● Increased megakaryocytes (PAS stain can help identify), megakaryocytes are often larger and more polymorphic than normal, some may have bulbous nuclei, they form loose clusters or lie close to the bone trabeculae; increased vascularity, modestly increased reticulin (particularly near megakaryocytes), reduced storage iron
● Late changes are fibrotic marrow observed with reticulin stain, megakaryocytes then start to cluster and have hyperchromatic and dysmorphic nuclei

Micro images
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Peripheral blood:

38 year old woman with Hb of 19 g/dL, WBC of 12.8, platelet count of 555K, splenomegaly and increased RBC mass

   
Left: spent phase with three erythroid precursors and mild to moderate anisopoikilocytosis; right: spent phase with blast, micromegakaryocyte and hypolobulated neutrophil

Bone marrow biopsy:
   
Markedly hypercellular marrow with prominent megakaryocytes


Patients with JAK2 exon 12 mutations


Various images

   

Post-treatment with myelofibrosis due to metastatic prostate carcinoma

Bone marrow biopsy-spent phase:
       
Left two images: predominance of immature cells, some erythroid precursors have dysplastic features; right: marked increase in coarse reticulin fibers (reticulin stain)

Positive stains
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● High expression of VEGF, but not used for diagnosis (Am J Clin Pathol 2007;128:966)

Negative stains
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● c-Mpl (thrombopoietin receptor) on megakaryocytes (usually moderate/strong), but this is not used for diagnosis

Molecular description
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● JAK2 V617F mutation in up to 97% (Blood 2006;108:1865, Hum Pathol 2006;37:1458)
● JAK2 V617F JAK2 exon 12 mutations (N Engl J Med 2007;356:459)
● These mutations are observed in erythroid, as well as granulocytic and megakaryocytic populations

Differential diagnosis
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● Secondary polycythemia due to dehydration, smoking, high altitude (these have increased erythropoietin levels)
● Gaisock syndrome: associated with hypertension, obesity, anxiety or other causes; normal megakaryocytes, less cellular marrow, no increase in reticulin, more normal iron stores, normal or high erythropoietin levels
● CML: no erythroid hyperplasia

Additional references
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Arch Pathol Lab Med 2006;130:1126, eMedicine #1, #2, American Family Physician, Wikipedia

End of Chronic Myeloid Neoplasms > Myeloproliferative neoplasms (MPN) > Polycythemia vera


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