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Chronic Myeloid Neoplasms

Myeloproliferative neoplasms (MPN)

Primary myelofibrosis


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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● Previously called agnogenic (idiopathic) myeloid metaplasia, chronic idiopathic myelofibrosis (CIMF), myelofibrosis with myeloid metaplasia
● Mean age 60 years, rarely occurs in children (eMedicine)
● Incidence of 3 to 15 per 1 million annually
● Clonal stem cell defect characterized by panmyelopathy with intact maturation, progressive marrow fibrosis (from inception), extramedullary hematopoiesis in spleen, liver and lymph nodes, and marked splenomegaly up to 4 kg (eMedicine)
● Also anemia, other cytopenias, “B” symptoms (fever, weight loss > 10%, night sweats), gout, infections, thrombotic episodes, bleeding
● Rarely, extramedullary hematopoiesis forms masses (exclude myeloid sarcoma with CD34 immunostain) in breast (Am J Surg Pathol 1980;4:281), lung (Arch Pathol Lab Med 2008;132:99), prostate (Am J Surg Pathol 1991;15:486), retroperitoneum (Am J Surg Pathol 2000;24:51), spinal cord (J Korean Med Sci 2007;22:1090), or stomach (Arch Pathol Lab Med 2004;128:568)
● Fibrosis is due to neoplastic megakaryocytes releasing platelet derived growth factor, basic fibroblast growth factor, transforming growth factor beta or other cytokines, which causes nonneoplastic fibroblasts in marrow to deposit collagen
● 5% transform to AML
● May coexist with systemic mastocytosis (J Mol Diagn 2008;10:58)
● Survival 3.5 to 5.5 years
Atypical presentation: CD34+ cells in peripheral blood, circulating endothelial progenitor cells (Arch Pathol Lab Med 2006;130:1133)
Prognostic scoring systems (PSS): poor prognostic factors include Hb <10 g/dL, WBC <4 or >30 x 109/L, constitutional symptoms (fever, night sweats, weight loss), circulating blasts ≥ 1%, platelet count <100 x 109/L or absolute monocyte count ≥ 1 x 109/L
Cervantes PSS: uses Hb, constitutional symptoms and circulating blasts (Br J Haematol 1998;102:684)
Dupriez PSS: uses Hb and WBC count (Blood 1996;88:1013)
Mayo Clinic PSS: uses hemoglobin, platelet, leukocyte and monocyte counts (Cancer 2007;109:2083)

Primary myelofibrosis variant with rapid clinical course: see Acute panmyelosis with myelofibrosis in Leukemia-acute chapter

Case reports
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● Amyloidosis (Arch Pathol Lab Med 1987;111:525)
● Portal vein thrombosis (Arch Pathol Lab Med 2003;127:e385)
● Subsequent histiocytic sarcoma (Arch Pathol Lab Med 2004;128:1167)
● Subsequent granulocytic sarcoma (Hum Pathol 1996;27:417)

Laboratory
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● Initially normal or increased blood counts with immature granulocytes and atypical platelets
● Later cytopenias develop, more dysplastic cells, teardrop elliptocytes / dacrocytes
● Leukocyte (neutrophil) alkaline phosphatase (LAP) score is increased

Diagnostic criteria
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Diagnostic criteria (WHO 2008): must meet all 3 major criteria plus at least two minor criteria
Major criterion #1: megakaryocyte proliferation and atypia (small to large megakaryocytes with dense clustering, an aberrant N/C ratio and hyperchromatic and irregularly folded nuclei, often described as ‘cloud-like’ or ‘balloon-shaped’) accompanied by either reticulum or collagen fibrosis OR in the absence of reticulin fibrosis, the megakaryocyte changes must be accompanied by increased marrow cellularity, granulocytic proliferation and often decreased erythropoiesis (i.e. pre-fibrotic PMF)
Major criterion #2: not meeting WHO criteria for CML, PV, MDS or other myeloid neoplasm
Major criterion #3: demonstration of JAK2 V617F or other clonal marker (MPL W515K/L) or no evidence of reactive marrow fibrosis
Minor criterion #1: leukoerythroblastosis
Minor criterion #2: increased serum LDH
Minor criterion #3: anemia
Minor criterion #4: palpable splenomegaly

   
Table and WHO 2008 diagnostic algorithm

Diagnostic criteria (WHO 2001): not used now (Prefibrotic myelofibrosis, Fibrotic myelofibrosis)
European Clinical and Pathological criteria: important for prefibrotic disease with WHO 2001 - see Table 3

Treatment
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● Reduced intensity allogeneic stem cell transplant if intermediate to high risk, or palliation of extramedullary hematopoiesis and treatment of cytopenias (Leukemia 2008;22:474, Cancer J 2007;13:377)

Micro description
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Peripheral blood: leukoerythroblastosis (immature granulocytes and normoblasts in peripheral blood) is common in later phases; also dacrocytes (teardrop erythrocytes)
Bone marrow: prefibrotic stage: hypercellular with large, dysplastic, clustered (loose or tight) megakaryocytes and excess granulocytes; increased reticulin is present around clusters of megakaryocytes; megakaryocytes have aberrant N/C ratios and hyperchromatic, bulbous or irregularly folded nuclei; often bare megakaryocytic nuclei; megakaryocytic features are most useful to distinguish this stage of primary myelofibrosis from essential thrombocythemia
Intermediate phase: has alternating areas of hematopoiesis and fibrosis
Fibrotic phase: is hypocellular and diffusely fibrotic with atypical streaming megakaryocytes; marrow osteosclerosis with irregular, broad bony trabeculae; markedly dilated sinuses; associated with dry bone marrow taps
Spleen: red pulp sinuses contain megakaryocytes, granulocyte precursors, nucleated red cells; may be nodules of extramedullary hematopoiesis

Micro images
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Peripheral blood:

Moderate anisopoikilocytosis with dacrocytes and elliptocytes


Cell intermediate between megakaryoblast and micromegakaryocyte


Post-splenectomy patient has marked increase in normoblasts and large atypical, partially agranular platelets

Initial hypercellular phase:
Marrow with excess megakaryocytes #1


Marrow with excess megakaryocytes #2

           

Markedly hypercellular marrow #1 with granulocytes and clusters of megakaryocytes;
#2 with numerous, markedly distorted megakaryocytes;
#3 with granulocytes in all stages of maturation and streaming effect due to reticulin fibrosis;
#4 with marked increase in reticulin fibers (reticulin stain)



Microvascular density (H&E and stains)

Fibrotic phase:

Fibrosis

   

Intrasinusoidal hematopoiesis


Various images

Blast transformation:

Peripheral blood shows 4 immature cells, 3 with a blast nucleus, cell in lower left is a very small, late stage promegakaryocyte


Bone marrow biopsy shows marked osteomyelosclerosis


Bone marrow smear shows numerous blasts, several small promegakaryocytes with fine azurophilic granules

Other:

Liver-fig 1/2: liver thrombi, fig 3: recanalized liver thrombi, fig 4: hypercellular marrow with large, dysplastic, abnormally clustered megakaryocytes


Lung parenchyma-extramedullary hematopoiesis due to myelofibrosis


Lung vasculature

   

Lymph node: left-marked sinusoidal infiltration of megakaryocytes; right-many megakaryocytes are large with hyperlobulated nuclei


Spleen


Stomach

Virtual slides
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Chronic idiopathic myelofibrosis

Positive stains
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● VEGF (high expression, Am J Clin Pathol 2007;128:966)
● CD105 (to assess microvascular density, may have prognostic value, Mod Pathol 2004;17:1513)
● Naphthol-ASD-choracetate esterase (CAE) helps mark granulocytic proliferation in the prefibrotic (cellular) phase of PMF

Cytogenetics description
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● Abnormalities present in 56% (using FISH), but main recurrent chromosomal aberrations do not correlate with clinical features or prognosis (Cancer 2006;107:2801)
● No BCR-ABL fusion gene (or classify as CML); presence of del(13)(q12-22) or der(6)t(1;6)(q21-23;p21.3) is strongly suggestive of primary myelofibrosis

Molecular description
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● JAK2 V617F mutation present in 35-95% (Am J Clin Pathol 2006;125:625)
● Mutational status predicts progression to large splenomegaly and leukemic transformation (Blood 2007;110:4030)
● 8% have mutations in thrombopoietin receptor c-Mpl W515K/L /CD110 (J Transl Med 2006;4:41, Br J Haematol 2007;137:244)

Differential diagnosis
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● Other causes of leukoerythroblastosis or dry taps are granulomatous marrow disease, metastases to marrow (desmoplasia but no increased reticulin) or lymphoma
● Polycythemia vera (25%) and essential thrombocythemia (2%) may have marrow fibrosis
● Primary hyperparathyroidism rarely causes myelofibrosis and pancytopenia (Int J Lab Hematol 2007;29:464)

End of Chronic Myeloid Neoplasms > Myeloproliferative neoplasms (MPN) > Primary myelofibrosis


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