Stanford School of Medicine

Surgical Pathology Criteria
http://surgpathcriteria.stanford.edu/

 use browser back button to return

Primary Myelofibrosis

Definition

  • Myeloproliferative neoplasm characterized by panmyelosis, clustered hyperchromatic megakaryocyte proliferation and development of bone marrow fibrosis

Alternate/Historical Names

  • Agnogenic myeloid metaplasia
  • Chronic idiopathic myelofibrosis
  • Myelofibrosis with myeloid metaplasia

Diagnostic Criteria

  • All three major and two minor criteria required for diagnosis
    • Major
      • Atypical densely clustered megakaryocytic hyperplasia with either:
        • Fibrosis (MF-2 or 3) (fibrotic phase) OR
        • Hypercellular marrow with granulocytic hyperplasia (cellular phase)
      • Does not meet criteria for PV, CML, MDS or other myeloid neoplasm
      • Jak2V617F or other clonal marker (MPL W515K/L), OR
    • Minor
      • Splenomegaly
      • Leukoerythroblastosis
      • Anemia
      • Increase in serum LDH
  • Cellular / prefibrotic phase is characterized by hypercellularity but absent or minimal reticulin fibrosis
    • MF-0 or 1 (European consensus grading system, Thiele 2005)
    • Peripheral blood may show only marked thrombocytosis
    • Hypercellular marrow
      • Prominent megakaryocytic hyperplasia with dense clustering
      • Increased M:E ratio
    • Pleomorphic megakaryocytes
      • Hyperchromasia and coarse lobulations
      • Increased N:C ratio
      • Anisocytosis
  • Fibrotic phase is characterized by marrow fibrosis
    • Leukoerythroblastic peripheral blood findings
      • RBC may show teardrops
      • Anemia with mild reticulocytosis and nucleated RBCs
      • Variable platelet count with giant hypogranular bizarre forms
        • Circulating megakaryocytes and/or bare nuclei can be seen
      • Leukocytosis, 15-30 x 103/μL
        • Left shift with 1-10% myeloblasts
        • Basophilia, eosinophilia in 10-30% of cases
      • Can present with isolated thrombocytosis
    • Marrow fibrosis
      • MF-2 or 3 (European consensus grading system, Thiele 2005)
      • May include collagen fibrosis
      • Loss of hematopoiesis, except for megakaryocytes
      • Osteosclerosis can be dramatic and occupy >50% of marrow
      • May lead to massive splenomegaly with extramedullary hematopoiesis
    • Dilated sinuses with intravascular hematopoiesis

Dita Gratzinger MD PhD
Tracy I George MD
Department of Pathology
Stanford University School of Medicine
Stanford CA 94305-5342

Original posting: 10/23/11

Supplemental studies

  • CBC
    • Blast count >9%
    • WBC >40%
  • Molecular
    • None are specific, morphologic and clinical correlation required
    • Rapidly evolving area, panel likely to change in near future
    • JAK2V617F mutations in 50%
      • MPL W515K/L mutations in 5%
    • ASXL1 mutations in 43%
      • 21% are JAK2V617F negative, ASXL1 positive
      • Also occurs in post polycythemia vera and essential thrombocythemia marrow fibrosis
  • Clonal cytogenetic abnormalities in 30%
    • None are specific, morphologic and clinical correlation required
    • Type of abnormality has prognostic implications
      • e.g. poor prognosis with monosomal karyotype
    • del(13q) or der(6)t(1;6) suggestive of PMF
    • del(20q), partial +1q, +9, +8 not specific
    • del (7q) and (5q) reported
      • May be due to prior cytotoxic therapy
    • Absence of Ph’ and BCR-ABL1

Differential Diagnosis

Common Myeloproliferative Neoplasms - Overview
  CML PV PMF ET
Tyrosine kinase ABL JAK2 JAK2 or MPL JAK2 or MPL
Blood ↑WBC with IG, basophils Normo or hypochromatic anemia, may have ↑platelets & basophils Leukoerythroblastic with teardrops ↑Platelets, often abnormal
Marrow ↑↑Myeloids Panmyelosis, ± erythroid hyperplasia, atypical megas Panmyelosis, atypical megas ↑↑Megas
Marrow fibrosis Varies ↑In spent phase ↑↑In fibrotic phase Minimal
Splenomegaly ++ ++ +++ ±
Clinical Presentation /Other B symptoms Hypertension, thrombosis, pruritus,↓EPO B symptoms, bleeding, gout Thrombosis, hemorrhage
CML = chronic myeloid leukemia; PV = polycythemia vera; PMF = primary myelofibrosis; ET = essential thrombocythemia; IG = immature granulocytes; Megas = megakaryocytes; EPO = erythropoietin

Essential Thrombocythemia vs Cellular Phase Primary Myelofibrosis vs CML
  Essential Thrombocythemia Cellular Phase Primary Myelofibrosis CML with p230
Cellularity Normal to moderately hypercellular Markedly hypercellular (cellular phase) Markedly hypercellular
Megas - Distribution Dispersed or loose clusters Tight clusters, touching each other Dispersed or loose clusters
Megas - Size Large and giant Pleomorphic Variable, may have dwarf forms
Megas - Nuclei Lobulated Bulbous, hyperchromatic Hypolobated
Megas - Cytoplasm Mature Variable, may have naked nuclei Mature
Granulopoietic Hyperplasia Infrequent, mild Moderate to marked in cellular phase Marked
Splenomegaly Infrequent Frequent Rare
JAK2V617I Allele burden <50% Allele burden >50%  
Megas = megakaryocytes

Hematolymphoid Disorders with Marrow Fibrosis (overview)
Disorder Distinguishing Feature(s)
Polycythemia Vera, Fibrotic Phase History of PV / JAK2+
Essential Thrombocythemia, Fibrotic Phase (rare) History of ET / may be JAK2+
CML, Fibrotic Phase History of CML / BCR-ABL1+
MDS with Fibrosis Dysplastic features in marrow
Acute Megakaryoblastic Leukemia Blasts, acute onset
Osteosclerotic Myeloma Plasma cells. light chain restricted
Acute Pan-myelosis with Myelofibrosis Bone pain, acute onset
Primary Myelofibrosis Clustered atypical megakaryocytic hyperplasia
Hairy cell leukemia Clonal B cells
MDS with Fibrosis = descriptive term that includes primary MDS (often RAEB2) with fibrosis and therapy related myeloid neoplasms with fibrosis

Secondary Marrow Fibrosis

  • Infections
  • Autoimmune diseases
  • Chronic inflammatory conditions
  • Hairy cell leukemia and other lymphoid neooplasms
  • Metastatic malignancy
  • Chronic toxic myelopathies

Clinical

  • 0.5-1.5 patients /100,000
  • Equal male and female incidence
  • Usually middle aged to elderly
  • 30-40% of patients asymptomatic at presentation
  • May have nonspecific signs and symptoms
    • Fever, weight loss, night sweats, fatigue, gout
  • Mortality due to:
    • Marrow failure
      • Infection, hemorrhage
    • Thromboembolic events
      • Portal hypertension
      • Cardiac failure
    • Transformation to AML in 5-30%
  • Median survival
    • Cellular phase 10-15 years
    • Fibrotic phase 3-7 years

Classification / Lists

WHO 2008 Classification of Myeloid Neoplasms

Myeloproliferative Neoplasms (MPN)

Myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB or FGFR1

Myelodysplastic/Myeloproliferative Neoplasms (MDS/MPN)

Myelodysplastic Syndromes (MDS)

Therapy Related Myeloid Neoplasms

 

Bibliography

  • Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, World Health Organization Classification of Tumours 2008
  • Anastasi J. The myeloproliferative neoplasms: insights into molecular pathogenesis and changes in WHO classification and criteria for diagnosis. Hematol Oncol Clin North Am. 2009 Aug;23(4):693-708.
  • George TI, Arber DA. Pathology of the myeloproliferative diseases. Hematol Oncol Clin North Am. 2003 Oct;17(5):110
    Tefferi A, Vardiman JW. Classification and diagnosis of myeloproliferative neoplasms: the 2008 World Health Organization criteria and point-of-care diagnostic algorithms. Leukemia. 2008 Jan;22(1):14-22.
  • Wadleigh M, Tefferi A. Classification and diagnosis of myeloproliferative neoplasms according to the 2008 World Health Organization criteria. Int J Hematol. 2010 Mar;91(2):174-9. 1-27.
  • Sawyers CL. Chronic myeloid leukemia. N Engl J Med. 1999 Apr 29;340(17):1330-40.
  • Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR, Tichelli A,  Cazzola M, Skoda RC. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med. 2005 Apr 28;352(17):1779-90.
  • Baxter EJ, Scott LM, Campbell PJ, East C, Fourouclas N, Swanton S, Vassiliou GS, Bench AJ, Boyd EM, Curtin N, Scott MA, Erber WN, Green AR; Cancer Genome Project. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet. 2005 Mar 19-25;365(9464):1054-61. Erratum in: Lancet. 2005 Jul 9-15;366(9480):122.
  • James C, Ugo V, Le Couédic JP, Staerk J, Delhommeau F, Lacout C, Garçon L, Raslova H, Berger R, Bennaceur-Griscelli A, Villeval JL, Constantinescu SN, Casadevall N, Vainchenker W. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature. 2005 Apr 28;434(7037):1144-8.
  • Thiele J, Kvasnicka HM, Schmitt-Graeff A, Zankovich R, Diehl V. Follow-up examinations including sequential bone marrow biopsies in essential thrombocythemia (ET): a retrospective clinicopathological study of 120 patients.  Am J Hematol. 2002 Aug;70(4):283-91.
  • Cools J, DeAngelo DJ, Gotlib J, Stover EH, Legare RD, Cortes J, Kutok J, Clark J, Galinsky I, Griffin JD, Cross NC, Tefferi A, Malone J, Alam R, Schrier SL, Schmid J, Rose M, Vandenberghe P, Verhoef G, Boogaerts M, Wlodarska I, Kantarjian H, Marynen P, Coutre SE, Stone R, Gilliland DG. A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. N Engl J Med. 2003 Mar 27;348(13):1201-14.
  • Gotlib J, Cools J, Malone JM 3rd, Schrier SL, Gilliland DG, Coutré SE. The
    FIP1L1-PDGFRalpha fusion tyrosine kinase in hypereosinophilic syndrome and chronic eosinophilic leukemia: implications for diagnosis, classification, and management. Blood. 2004 Apr 15;103(8):2879-91.
  • Thiele J, Kvasnicka HM, Facchetti F, Franco V, van der Walt J, Orazi A. European consensus on grading bone marrow fibrosis and assessment of cellularity. Haematologica. 2005 Aug;90(8):1128-32.
  • Ricci C, Spinelli O, Salmoiraghi S, Finazzi G, Carobbio A, Rambaldi A. ASXL1 mutations in primary and secondary myelofibrosis. Br J Haematol. 2011 Sep 19. doi: 10.1111/j.1365-2141.2011.08865.x. [Epub ahead of print]
  • Finazzi G, Carobbio A, Thiele J, Passamonti F, Rumi E, Ruggeri M, Rodeghiero F, Randi ML, Bertozzi I, Vannucchi AM, Antonioli E, Gisslinger H, Buxhofer-Ausch V, Gangat N, Rambaldi A, Tefferi A, Barbui T. Incidence and risk factors for bleeding in 1104 patients with essential thrombocythemia or prefibrotic myelofibrosis diagnosed according to the 2008 WHO criteria. Leukemia. 2011 Sep 16. doi: 10.1038/leu.2011.258.
  • Tefferi A, Jimma T, Gangat N, Vaidya R, Begna KH, Hanson CA, Van Dyke DL, Caramazza D, Pardanani A. Predictors of greater than 80% two-year mortality in primary myelofibrosis: a Mayo Clinic study of 884 karyotypically-annotated patients. Blood. 2011 Aug 31. [Epub ahead of print]
Printed from Surgical Pathology Criteria: http://surgpathcriteria.stanford.edu/
© 2010  Stanford University School of Medicine