Chronic Myeloid Neoplasms
Myeloproliferative neoplasms (MPN)
Primary myelofibrosis

Author: Nikhil Sangle, M.D. (see Authors page)

Revised: 8 March 2017, last major update August 2011

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PubMed Search: Primary myelofibrosis [title]

Cite this page: Primary myelofibrosis. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/myeloproliferativemyelofibrosis.html. Accessed July 28th, 2017.
Diagrams / tables

Images hosted on other servers:

PMF table



Nature images

WHO 2008 diagnostic algorithm

Clinical features
  • 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 × 109/L, constitutional symptoms (fever, night sweats, weight loss), circulating blasts ≥ 1%, platelet count < 100 × 109/L or absolute monocyte count ≥ 1 × 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)

Diagnosis
  • 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. prefibrotic 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
  • 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 (Arch Pathol Lab Med 2006;130:1133)
Laboratory
  • 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
Case reports
Treatment
Microscopic (histologic) description
  • 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
Microscopic (histologic) images

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Images hosted on PathOut server:

Peripheral blood:

Moderate anisopoikilocytosis with dacrocytes and elliptocytes

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

Cell intermediate
between
megakaryoblast and
micromegakaryocyte



Initial hypercellular phase:

Granulocytes and clusters of megakaryocytes

Numerous, markedly distorted megakaryocytes

Marked increase in reticulin fibers (reticulin stain)

Granulocytes in all
stages of maturation
and streaming effect
due to reticulin fibrosis


Fibrotic phase:

Intrasinusoidal hematopoiesis



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

Bone marrow biopsy shows marked osteomyelosclerosis



Other:

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



Images hosted on other servers:

Initial hypercellular phase:

 

Marrow with excess megakaryocytes



Fibrotic phase:

Various images



Other:

Lung parenchyma extramedullary hematopoiesis

Lung vasculature

Stomach

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



Nature Images

Microvascular density (H&E and stains)

Spleen

Positive stains
Molecular / cytogenetics description
Molecular:
Cytogenetics:
  • 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
Differential diagnosis