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Chronic Myeloid Neoplasms

Myeloproliferative neoplasms (MPN)

Essential thrombocythemia


Reviewer: Nikhil Sangle, M.D., University of Utah & ARUP Laboratories (see Reviewers page)
Revised: 8 August 2011, last major update August 2011
Copyright: (c) 2001-2011, PathologyOutlines.com, Inc.

Clinical features
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● See MDS/MDN-unclassifiable for refractory anemia with ringed sideroblasts plus essential thrombocythemia
● Prevalence of 2-3 per million (Am J Hematol 2008;83:359)
● Median age of 50-60 years at diagnosis, but may occur at any age; 2/3 female
● Rarely occurs in children (must rule out hereditary thrombocytosis)
● Closely related to polycythemia vera, but no increased red blood cell mass
● More than half of the cases are detected due to routine peripheral blood count
● Increased proliferation usually confined to megakaryocytes with platelet count > 450 x 109/ L
● Thrombosis and hemorrhage common, due to qualitative and quantitative abnormalities in platelets
● Indolent, long asymptomatic periods alternating with thrombotic or hemorrhagic crises; may rarely progress to myelofibrosis
● Median survival is 10-15 years, hence life expectancy is almost normal (Orphanet J Rare Dis 2007;2:3)
● Bone marrow examination necessary to exclude other myeloproliferative neoplasms (Arch Pathol Lab Med 1991;115:475)

Diagnostic criteria (WHO 2008): must meet all 4 major criteria
Criterion #1: sustained platelet count of 450 x 109 / L or more
Criterion #2: megakaryocyte proliferation with large and mature morphology, no or little granulocyte or erythroid proliferation
Criterion #3: does not meet WHO criteria for CML, PV, PMF, MDS or other myeloid neoplasm
Criterion #4: demonstration of JAK2 V617F or other clonal marker OR no evidence of reactive thrombocytosis

   
Table (left) and WHO 2008 diagnostic algorithm (right)

Diagnostic criteria (WHO 2001):
Not currently used: sustained platelet count >600K, marrow shows proliferation mainly of megakaryocytes with enlarged mature forms, no other causes of thrombocytosis (thus, is a diagnosis of exclusion), Table

Treatment
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● High risk patients (for thrombosis) get cytoreductive therapy (hydroxyurea) and low dose aspirin

Micro description
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Peripheral blood: abnormally large platelets and increased platelets; bizarre shapes, pseudopods and agranular forms
Bone marrow: mildly hypercellular, increased number and large forms of megakaryocytes with deeply lobulated or hyperlobulated nuclei (staghorn nuclear appearance), megakaryocytes dispersed throughout the marrow with occasional loose clusters; delicate reticulin fibers (myelofibrosis absent / minimal), but no overt fibrosis
● Increased angiogenesis (CD34+)
● Usually no dyserythropoiesis, dysgranulopoiesis, macrocytosis or monocytosis
● No increased trilineage proliferation; no highly bizarre / dysplastic megakaryocytes, no predominance of small megakaryocytes with monolobulated nuclei

Diagnostic criteria for post-ET myelofibrosis:
Required criteria: established diagnosis of ET per WHO criteria; and marrow fibrosis grade 2-3 (on 0-3 scale)
Additional criteria (2 required): anemia or decrease in Hb by 2 gm/dL from the baseline level; leukoerythroblastic peripheral blood; splenomegaly; rise in LDH levels; constituitional symptoms including fever, night sweats, >10% weight loss in 6 months

Micro images
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Peripheral blood:

Clusters of large platelets (platelet count is 1700K)

Bone marrow biopsy:
       

Increased megakaryocytes (many megakaryocytes are unusually large) in mildly hypercellular marrow of 66 year old woman with platelet count of 1200K

Bone marrow smear:

Increased megakaryocytes

Molecular description
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Adults - JAK2 V617F mutation in up to 75% (Blood 2006;108:1865)
● JAK2 mutant allele burden contributes to clinical phenotype (Haematologica 2008;93:41)
● Also W515L and W515K mutations in thrombopoietin receptor c-Mpl (J Transl Med 2006;4:41)
● May have del(20q) and unbalanced translocations between 1q and 7p
● Must rule out BCR-ABL1 fusion gene status
Children - usually have no JAK2 mutation

Molecular images
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Drawing of JAK2 mutation


Drawing of c-Mpl mutation

Differential diagnosis
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● Other myeloproliferative neoplasms
● An increase in erythroid / granulocytic population should raise suspicion of prodromal stage polycythemia vera (Acta Haematol 2005;113:213)
● Granulocytic proliferation with bizarre or dysplastic megakaryocytes is suggesive of prefibrotic stage of PMF
● Reactive thrombocythemia (inflammatory disorders, asplenism, infection, connective tissue disorders, metastatic cancer, lymphoproliferative disorders and iron deficiency: no JAK2 or c-Mpl mutations)

End of Chronic Myeloid Neoplasms > Myeloproliferative neoplasms (MPN) > Essential thrombocythemia


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