Chronic myeloid neoplasms
Myeloproliferative neoplasms (MPN)
Primary myelofibrosis


Topic Completed: 26 September 2019

Revised: 26 September 2019

Copyright: 2002-2019, PathologyOutlines.com, Inc.

PubMed Search: Primary myelofibrosis[TI] review[ptyp]

Hatem Kaseb, M.D., Ph.D., M.P.H.
Stanley David Hudnall, M.D.
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Cite this page: Kaseb H, Hudnall SD. Primary myelofibrosis. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/myeloproliferativemyelofibrosis.html. Accessed December 11th, 2019.
Definition / general
  • Primary myelofibrosis is an uncommon myeloproliferative neoplasm characterized by a proliferation of predominantly abnormal megakaryocytes and granulocytes in the bone marrow, which in fully developed disease is associated with reactive deposition of fibrous connective tissue and extramedullary hematopoiesis
Essential features
  • Shows a stepwise evolution from an initial prefibrotic / early stage to overt fibrotic stage
  • Is a clonal stem cell defect characterized by:
    • Impaired medullary hematopoiesis
      • Granulocytic and megakaryocytic proliferation in the bone marrow
      • Gradual increase in bone marrow reticulin and collagen fibrosis
    • Extramedullary hematopoiesis in the spleen, liver and other organs
Terminology
  • Chronic idiopathic myelofibrosis, myelofibrosis / sclerosis with myeloid metaplasia, agnogenic myeloid metaplasia, megakaryocytic myelosclerosis, idiopathic myelofibrosis, myelofibrosis with myeloid metaplasia, myelofibrosis as a result of myeloproliferative disease (Swerdlow: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th Edition, 2017)
  • Myelofibrosis refers to the increase in the amount and density of reticulin fibers in the bone marrow (can be caused by infections, inflammatory, neoplasms, etc)
ICD coding
Epidemiology
  • Least common of all myeloproliferative neoplasms
  • Estimated annual incidence of overt phase is 0.5 - 1.5 cases per 100,000 population
  • Prefibrotic / early phase accounts for 30 - 50% of all cases
  • Increasing prevalence due to earlier diagnosis (pre-primary myelofibrosis)
  • Equal gender predisposition
  • Disease of older adults (mean age 60 years)
  • Extremely rare in children; however, some childhood cases may be inherited and associated with other anomalies (Jaffe: Hematopathology, 2nd Edition, 2016)
  • Increased incidence in Ashkenazi Jews (Hsi: Hematopathology - Foundations in Diagnostic Pathology, 3rd Edition, 2017)
Pathophysiology
  • Clonal stem cell defect
  • 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
    • Myelofibrosis and osteosclerosis are secondary changes due to the abnormal release of growth factors and fibrogenic cytokines
  • Prominent angiogenesis in the bone marrow and spleen due to increased serum levels of vascular endothelial growth factor
  • Teardrop red blood cells and leukoerythroblastosis are caused by extramedullary hematopoiesis
Clinical features
  • Presentation
    • Asymptomatic (30%)
    • Symptomatic (70%)
      • Splenomegaly (90%): often considered a hallmark
      • Hepatomegaly (50%): portal hypertension can develop as a complication of hepatomegaly and may precede the onset of the disease (Gastroenterology 1988;94:1063)
      • Constitutional symptoms such as fatigue, dyspnea, weight loss, night sweats, low grade fever and cachexia
        • Fatigue is the most common presenting symptom
      • Anemia
      • Leukocytosis or thrombocytosis is common; leukopenia or thrombocytopenia is less common
      • Gouty arthritis and renal stones
      • Marked thrombocytosis may lead to thrombosis or hemorrhagic episodes
      • Uncommon symptoms include pruritus and pulmonary hypertension (Am J Hematol 2012;87:136, Leukemia 2008;22:646)
  • 2 phases (Swerdlow: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th Edition, 2017):
    • Prefibrotic:
      • Usually presents with thrombocytosis
      • No blasts
      • No / borderline anemia
      • No / borderline splenomegaly
      • Normal or borderline increased lactate dehydrogenase
      • Misdiagnosis of essential thrombocythemia is possible if the bone marrow biopsy is not carefully examined
    • Overt:
      • Thrombocytopenia
      • Leukoerythroblastosis
      • Anemia
      • Splenomegaly
      • Increased lactate dehydrogenase
      • Increased myeloblasts can be seen (< 20%)
      • Transformation to acute myeloid leukemia occurs in ~5 - 20% at a median of 3 years after the diagnosis of the overt phase (Jaffe: Hematopathology, 2nd Edition, 2016)
        • 2 factors at the time of diagnosis are considered predictors of leukemic transformation: circulating blasts ≥ 3% and platelet count < 100,000/μL (Cancer 2008;112:2726)
  • Extramedullary hematopoiesis can form masses
  • May coexist with systemic mastocytosis (J Mol Diagn 2008;10:58)
  • Survival 3.5 - 5.5 years
Diagnosis
  • Diagnostic criteria for primary myelofibrosis, prefibrotic / early stage: must meet all 3 major criteria plus at least 2 minor criteria (Swerdlow: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th Edition, 2017)
    • Major
      • Major criterion 1: megakaryocyte proliferation and atypia in the absence of reticulin fibrosis, accompanied by increased marrow cellularity, granulocytic proliferation and often decreased erythropoiesis
      • Major criterion 2: not meeting WHO criteria for other myeloproliferative neoplasms or myelodysplastic syndromes
      • Major criterion 3: demonstration of JAK2, CALR or MPL mutation OR other clonal marker OR no evidence of reactive marrow fibrosis
    • Minor
      • Minor criterion 1: leukoerythroblastosis
      • Minor criterion 2: increased serum lactate dehydrogenase
      • Minor criterion 3: anemia
      • Minor criterion 4: palpable splenomegaly
    • Comparing WHO 2017 to WHO 2008, only minor changes to the diagnostic criteria; the change involved the addition of CALR or MPL mutations in addition to the JAK2 mutation
  • Diagnostic criteria for primary myelofibrosis, overt fibrotic stage: all 3 major criteria and at least 1 minor criterion must be confirmed in 2 consecutive determinations (Swerdlow: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th Edition, 2017)
    • Major
      • Major criterion 1: megakaryocytic proliferation and atypia, accompanied by reticulin or collagen fibrosis grades 2 or 3
      • Major criterion 2: not meeting WHO criteria for other myeloproliferative neoplasms or myelodysplastic syndromes
      • Major criterion 3: demonstration of JAK2, CALR or MPL mutation OR other clonal marker OR no evidence of reactive marrow fibrosis
    • Minor
      • Minor criterion 1: anemia not attributed to a comorbid condition
      • Minor criterion 2: leukocytosis
      • Minor criterion 3: palpable splenomegaly
      • Minor criterion 4: increased serum lactate dehydrogenase
      • Minor criterion 5: leukoerythroblastosis
Laboratory
  • Complete blood count / peripheral blood smear
    • Prefibrotic:
      • Initially normal or increased blood counts
        • Mild neutrophilia with a left shift
        • Thrombocytosis (mild / moderate)
      • No / borderline anemia
      • No myeloblasts
      • No leukoerythroblastosis
    • Overt:
      • Thrombocytopenia with bizarre abnormal large platelets with altered granulation; in addition, fragmented megakaryocytes can be seen on the peripheral smear
      • Leukoerythroblastosis and anemia
      • Myeloblasts (usually > 5%)
  • Lactate dehydrogenase
    • Prefibrotic: normal or borderline increased lactate dehydrogenase
    • Overt: increased lactate dehydrogenase
  • Alkaline phosphatase, uric acid, leukocyte alkaline phosphatase and vitamin B12 are increased (Leuk Lymphoma 1996;22:303)
  • Bone marrow aspirate / biopsy
    • Prefibrotic:
      • Hypercellular bone marrow with granulocytic and atypical megakaryocytic proliferations
        • Usually morphologically more variable in size, atypical and bizarre than other myeloproliferative neoplasms
        • Bulbous hypolobated nucleus
      • Erythropoiesis is reduced
      • Absent or only slight reticulin fibrosis
    • Overt:
      • Hypocellular bone marrow with usually alternating cellular and hypocellular regions
      • Atypical megakaryocytes can form clusters or sheets
        • More variable in size, atypical and bizarre than other myeloproliferative neoplasms
        • Bulbous hypolobated nucleus
      • Marked reticulin or collagen fibrosis
      • New bone formation and osteosclerosis
    • Bone marrow aspirate is often difficult (dry tap)
  • See also Molecular description
Prognostic factors
  • Has the least favorable prognosis among the myeloproliferative neoplasms
  • Patients are at risk of death due to disease progression, leukemic transformation, thrombohemorrhagic complications and infections
  • Survival
    • Prefibrotic: 10 - 15 years
    • Overt: 3 - 5 years
  • Dynamic International Prognostic Scoring System (DIPSS plus) (Swerdlow: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th Edition, 2017)
    • Includes 8 predictors of inferior survival:
      • Patient age > 65 years
      • Red blood cell transfusion dependency
      • Unfavorable karyotype
      • Hemoglobin < 10 g/dL
      • White blood cells > 25 × 109/L
      • Constitutional symptoms (fever, night sweats, weight loss)
      • Circulating blasts ≥ 1%
      • Platelet count < 100 × 109/L
    • Risk status is defined by the number of adverse prognostic factors present: 0 (low risk), 1 (intermediate - 1 risk), 2 or 3 (intermediate - 2 risk) or > 4 (high risk)
  • Absolute monocyte count ≥ 1 × 109/L confers an unfavorable outcome
  • Unfavorable karyotype
    • Complex karyotype, sole abnormality
    • 2 abnormalities that include +8, -7 / 7q-, i(17q), inv(3), -5 / del(5q), 12p- or 11q23.3 rearrangement
  • CALR mutation confers a better prognosis compared to other mutations
Case reports
Treatment
  • Management based on the risk stratification by
    • GIPSS (Genetically Inspired Prognostic Scoring System): uses karyotyping, driver mutations and HMA mutations
    • MIPSS70+ v2.0 (Mutation and Karyotype Enhanced International Prognostic Scoring System) criteria: uses clinical information, karyotyping and mutations
  • Higher risk:
    • Eligible for transplantation: allogeneic hematopoietic cell transplantation
    • Ineligible for transplantation: enrollment in a clinical trial or treatment with ruxolitinib or hydroxyurea for relief of symptoms (N Engl J Med 2012;366:787)
  • Lower risk:
    • Asymptomatic: observation
    • Symptomatic: treatment with ruxolitinib or hydroxyurea
Microscopic (histologic) description
  • 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 nuclear/cytoplasmic 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
    • Fibrotic phase:
      • Hypocellular and diffusely fibrotic bone marrow 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

Contributed by Hatem Kaseb, M.D., Ph.D., M.P.H.

Atypical megakaryocytes

Fibrotic bone marrow


AFIP images

Blast transformation

Peripheral smear description
  • Leukoerythroblastosis (immature granulocytes and normoblasts in peripheral blood) is common in later phases; also dacrocytes (teardrop erythrocytes)
Peripheral smear images

Contributed by Hatem
Kaseb, M.D., Ph.D., M.P.H.

Dacrocytes



AFIP images

Cell intermediate
between
megakaryoblast and
micromegakaryocyte

Blast transformation

Positive stains
Flow cytometry description
  • Normal number and phenotype myeloblasts with normal myeloid scatter by CD45 / side scatter
  • Normal CD10 / CD13 / CD16 / CD11b myeloid maturation pattern and all other myeloid markers are normally expressed, hence there is no immunophenotypic evidence of myelodysplasia
  • No evidence for monoclonal B cell lymphoproliferative disease
  • Although no unusual phenotype T cells are identified, surface markers will not routinely detect monoclonal T lymphocytes
Flow cytometry images

Contributed by Hatem Kaseb, M.D., Ph.D., M.P.H.

Normal myeloid maturation

Molecular / cytogenetics description
  • No specific genetic marker
  • No BCR-ABL fusion gene (or classify as chronic myeloid leukemia); presence of del(13)(q12-22) or der(6)t(1;6)(q21-23;p21.3) is strongly suggestive of primary myelofibrosis
  • Shows karyotypic abnormalities in up to 50% of cases
    • Frequent abnormalities include del(20q), del(13q), +8, +9 and abnormalities of 1q
  • Driver mutations
    • JAK2 V617F mutation (50 - 60%)
    • CALR mutations (25 - 30%)
    • MPL mutations (5 - 10%)
    • Triple negative for mutations in JAK2, CALR and MPL (8 - 12%)
    • Other gene mutations include ASXL1, EZH2, TET2, IDH1 / IDH2, SRSF2 or SR3B1
  • Driver mutational profile is associated with overall survival
    • CALR mutated cases have better survival compared to others
    • Triple negative cases have the shortest survival compared to others
Sample pathology report
  • Bone marrow, biopsy and aspirate:
    • Myeloproliferative neoplasm, favoring prefibrotic primary myelofibrosis (see comment)
    • Comment: The marrow biopsy shows morphologic features of a myeloproliferative neoplasm, in conjunction with thrombocytosis. The major differential diagnosis includes essential thrombocythemia and prefibrotic stage of primary myelofibrosis. Overall, we favor a diagnosis of the latter, due to hypercellular marrow, distribution of megakaryocytes (focal clusters) and markedly dysplastic cytology of megakaryocytes. Recommend correlation with clinical findings (presence of splenomegaly and disease progression) and molecular studies (JAK2, CALR and MPL mutational studies).
    • Complete blood count (9/17/2018), by report: hemoglobin - 11.4 g/dL, mean corpuscular volume - 100 fL, white blood cells - 21.7 K/uL, platelets - 698 K/uL
  • Bone marrow biopsy microscopic description:
    • Hypercellular marrow for age (80% cellular). Megakaryocytes are increased in number, forming focal loose clusters and showing abnormal morphology including hypersegmented nuclei with hyperchromasia. The myeloid:erythroid ratio is markedly increased. Erythroid elements exhibit maturation. Myeloid elements exhibit maturation. Myeloblasts appear to be increased. No lymphoid aggregates are identified. Granulomas are absent. Reticulin stain reveals that reticulin is mildly increased (MF1/3). Trabecular bone is normal.
  • Bone marrow aspirate microscopic description:
    • The marrow aspirate smears are spicular and cellular. Megakaryocytes are increased and show prominent dysmegakaryopoiesis, including hyper and hyposegmented nuclei and increased nuclear/cytoplasmic ratio. The myeloid:erythroid ratio is approximately 4:1. Erythroid maturation is identified. Myeloid maturation is slightly left shifted. Prussian blue iron stain shows # storage iron and no significant increase in ring sideroblasts.
    • Aspirate cell count: A 207 cell count reveals 1% blasts, 15% promyelocytes / myelocytes, 57% maturing granulocyte forms, 20% erythroid forms, 3% lymphocytes, 2% eosinophils, 1% plasma cells, 1% basophils / mast cells and 2% monocytes.
Differential diagnosis
  • Other causes of leukoerythroblastosis or dry taps:
  • Other myeloid disorders:
    • Myeloproliferative neoplasms:
    • Myelodysplastic / myeloproliferative neoplasms:
      • Show hybrid myelodysplastic and myeloproliferative features manifested by at least 1 cytopenia and at least 1 cytosis in blood
      • Myeloid maturation is intact and usually mature cells predominate
      • Exact subtype should be diagnosed based on the specific criteria of the entity
    • Myelodysplastic syndromes are a heterogeneous group of entities that demonstrate:
      • Variable degrees of ineffective hematopoiesis
      • < 20% blasts in marrow
      • Peripheral blood with unexplained and persistent cytopenia(s), < 20% blasts, < 1.0 x 109/L monocytes and dysplasia in 1 or more myeloid lineages
    • Mastocytosis:
      • Shows focal, compact aggregates of mast cells in bone marrow core biopsy
      • Cells can show the following patterns of infiltration: paratrabecular, perivascular or parafollicular
      • Presence of atypical mast cell supports the diagnosis
      • Most cases will harbor a KIT D816V mutation
  • Reactive thrombocythemia:
    • Causes include exercise, allergic reaction, reaction to medications, inflammatory disorders, asplenism, infection, connective tissue disorders, metastatic cancer, lymphoproliferative disorders and iron deficiency
  • Acute myelofibrosis:
    • Subtype of acute myeloid leukemia that shows > 20% blasts in peripheral blood or bone marrow
    • Patients also present with bone marrow fibrosis, fever and pancytopenia
  • Autoimmune myelofibrosis: generally shows diffuse reticulin fibrosis and an associated autoimmune disease such as rheumatoid arthritis
  • Primary hyperparathyroidism: rarely causes myelofibrosis and pancytopenia (Int J Lab Hematol 2007;29:464)
Board review question #1
A 57 year old man presented with fatigue, splenomegaly and hepatomegaly. A complete blood count demonstrated anemia and thrombocytosis. A bone marrow aspirate and biopsy were ordered (shown below). What is the most likely diagnosis?



  1. Acute myeloid leukemia
  2. Chronic myelogenous leukemia
  3. Myelodysplastic syndrome
  4. Primary myelofibrosis
Board review answer #1
D. Primary myelofibrosis. The symptoms and bone marrow biopsy support the diagnosis of primary myelofibrosis. The biopsy above shows hypercellular bone marrow with granulocytic and atypical megakaryocytic proliferations.

Reference: Primary myelofibrosis

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Board review question #2
What is the most common genetic mutation in primary myelofibrosis?

  1. ABL
  2. CALR
  3. JAK2
  4. MPL
Board review answer #2
C. JAK2. Primary myelofibrosis cases harbor a phenotypic driver mutation in JAK2 V617F mutation (50 - 60%), CALR mutations (25 - 30%), MPL mutations (5 - 10%), triple negative for mutations in JAK2, CALR and MPL (8 - 12%).

Reference: Primary myelofibrosis

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