Encyclopedia of Pathology

Living Edition
| Editors: J.H.J.M. van Krieken

Primary Myelofibrosis (PMF)

  • Hans Michael KvasnickaEmail author
Living reference work entry
DOI: https://doi.org/10.1007/978-3-319-28845-1_3853-1

Synonyms

Definition

Primary myelofibrosis (PMF) is a clonal myeloproliferative neoplasm (MPN) characterized by a stepwise evolution from an initial prefibrotic/early phase (prePMF) characterized by a hypercellular BM with absent or minimal reticulin fibrosis to a fibrotic phase with marked reticulin or collagen fibrosis in the BM, and often osteosclerosis (Table 1). The initial stage of disease often is presenting with a marked thrombocytosis which clinically might mimic ET, but without sign of myeloid metaplasia. Fibrotic stages of PMF are clinically characterized by splenomegaly and leukoerythroblastosis in the blood with occurrence of teardrop-shaped red cells. One of the hallmarks of PMF is a proliferation of predominantly megakaryocytes and granulocytes in the bone marrow that in fully developed fibrotic disease stages is associated with hepatosplenomegaly, leukoerythroblastosis in the peripheral blood, cytopenias, teardrop-shaped red cells, extramedullary hematopoiesis, increased marrow microvessel density, and constitutive mobilization of CD34+ hematopoietic progenitors and stem cells as well as endothelial progenitor cells into the peripheral blood.
Table 1

WHO diagnostic criteria for early stage/prefibrotic and overt PMF

prePMF

Overt PMF

Major criteria

1. Megakaryocytic proliferation and atypia, without reticulin fibrosis >grade 1 and accompanied by increased age-adjusted bone marrow cellularity, granulocytic proliferation, and often decreased erythropoiesis

2. Not meeting WHO criteria for ET, PV, BCR-ABL1+ CML, myelodysplastic syndromes, or other myeloid neoplasms

3. Presence of JAK2, CALR, or MPL mutation or, in the absence of these mutations, presence of another clonal markera or absence of minor reactive myelofibrosisb

Major criteria

1. Presence of megakaryocytic proliferation and atypia, usually accompanied by either reticulin and/or collagen fibrosis grades 2 or 3

2. Not meeting WHO criteria for ET, PV, BCR-ABL1+ CML, myelodysplastic syndromes, or other myeloid neoplasms

3. Presence of JAK2, CALR, or MPL mutation or, in the absence of these mutations, presence of another clonal markera or absence of reactive myelofibrosisb

Minor criteriac

(a) Anemia not attributed to a comorbid condition

(b) Leukocytosis ≥11 × 109/L

(c) Palpable splenomegaly

(d) LDH increased to above upper normal limit of institutional reference range

Minor criteriac

(a) Anemia not attributed to a comorbid condition

(b) Leukocytosis ≥11 × 109/L

(c) Palpable splenomegaly

(d) LDH increased to above upper normal limit of institutional reference range

(e) Leukoerythroblastosis

Diagnosis of prePMF requires meeting all three major criteria and at least one minor criteria

Diagnosis of overt PMF requires meeting all three major criteria and at least one minor criteria

aIn the absence of any of the 3 major clonal mutations, the search for the most frequent accompanying mutations (ASXL1, EZH2, TET2, IDH1/IDH2, SRSF2, SF3B1) is of help in determining the clonal nature of the disease

bBone marrow fibrosis secondary to infection, autoimmune disorder or other chronic inflammatory condition, hairy cell leukemia or other lymphoid neoplasm, metastatic malignancy, or toxic (chronic) myelopathies

cConfirmed in two consecutive determinations

The striking variability in the hematological findings of patients with PMF at the first time of presentation is paralleled by corresponding bone marrow features that may very initially present a hypercellular BM without or with only slight reticulin myelofibrosis. Therefore, overt myelofibrosis is not a necessary diagnostic feature of this MPN subtype. However, in the overt stage, profound marrow fibrosis is a response to the clonal proliferation of hematopoietic stem cells. Collagen type 3, also known as reticulin, and collagen type 1 are the predominant extracellular components of marrow fibrosis in PMF. These matrix components are produced by marrow fibroblasts that do not belong to the malignant clone. This deposition of collagen is a result of the release of fibrogenic cytokines by abnormal megakaryocytes and monocytes derived from the malignant stem cell population. However, bone marrow fibrosis is not unique to PMF and may be secondary to many other conditions.

Clinical Features

  • Incidence

    The reported annual incidence of PMF is estimated at 0.5–1.5 per 100,000 individuals per year. Disease onset is most commonly in the sixth to seventh decade of life, but rarely children may be affected.

  • Clinical Presentation

    In the initial prefibrotic phase of PMF, the only relevant hematological finding may be sustained thrombocytosis mimicking ET but no significant anemia and/or splenomegaly. In the overt stages of the disease, extramedullary hematopoiesis in the spleen is a common finding; however, the liver, lymph nodes, and other organs or soft tissue are other possible sites. Early stages of PMF with only mild increase in reticulin (fibrosis grades MF-0 or MF-1) may not be recognized by clinical features alone, and thus a significant number of these patients are asymptomatic at time of first diagnosis and fortuitously discovered by detection of an increased serum level of LDH and marginal splenomegaly during a routine physical examination and/or presence of borderline anemia, leukocytosis, and/or thrombocytosis in routine blood counts.

  • Outcome

    Patients with overt stage of PMF have a median survival of less than 5 years; however, newer targeted treatment strategies like JAK2-inhibitor therapy could demonstrate a significant survival benefit. In general, younger patients may experience longer survival. However, the overall prognosis significantly depends on the stage in which PMF is firstly diagnosed. Adverse prognostic factors generally include higher age (>65 years), anemia (Hb <10 g/dL), leukocyte count greater than 25 × 109/L, presence of circulating blast cells, thrombocytopenia (platelet count <100 × 109/L), abnormal karyotype, and a high molecular risk status with additional somatic mutations. Major causes of death are represented by the sequelae of portal hypertension or hepatic-splenoportal thrombosis, thromboses in various anatomic sites, heart failure due to splenic pooling, infections, pulmonary hypertension, bleeding caused by thrombocytopenia, or hemostatic defects. Terminal leukemic transformation is seen in about 5–30% of cases as part of the natural history.

Microscopy

Initial Prefibrotic Stage of Primary Myelofibrosis (prePMF)

Histopathology of BM biopsy samples in prePMF reveals a hypercellularity (age-matched) by a prominent neutrophil granulocytic and megakaryocytic proliferation often associated with a concomitant reduction of nucleated red cell precursors in the absence of relevant BM fibrosis (Fig. 1, Table 2). Therefore, the demonstration of reticulin fibrosis, although characteristic, is not a required criterion for the diagnosis of PMF. The megakaryocytes in PMF are characterized by a more pronounced degree of cytological atypia (megakaryocytic maturation defects) than in any other MPN, particularly ET. Significant anomalies of megakaryocytes include a high degree of cellular pleomorphism with variations in size that range from small to giant forms and abnormal nuclear foldings and an aberration of the nuclear cytoplasmic ratio created by large bulbous and hyperchromatic cloud-like shaped nuclei. Apart from their disorganized nuclear lobulation, there are many so-called naked (bare) megakaryocytic nuclei observable. In addition, extensive clustering of megakaryocytes with loose to dense groupings with abnormal localization toward the endosteal borders is seen (Figs. 2 and 3). There may be a mild left shift in granulopoiesis, but usually metamyelocytes, bands, and segmented forms predominate. Myeloblasts are not increased in percentage, and conspicuous clusters of blasts or of CD34+ progenitors are not observed. Increased vascular proliferation is usual in the bone marrow, and lymphoid nodules are found in about 20–30% of cases. It must be kept in mind that early stages of disease with only borderline to mild increase in reticulin may not be recognized and discriminated from ET by clinical features alone, and therefore careful evaluation of bone marrow morphology including assessment of megakaryocytic dysplasia is key for the differential diagnosis of cases with accompanying thrombocytosis (Fig. 4).
Table 2

Key features of prePMF according to WHO

Increased cellularity (age-matched) with predominant neutrophil granulopoiesis

Increased megakaryopoiesis, small to large

Atypical histotopography of megakaryocytes

 Endosteal translocation

 Formation of dense clusters (WHO definition of a megakaryocyte cluster: 3 or more megakaryocytes lying strictly adjacent – without other hematopoietic cells lying in between)

Distinctive nuclear features of megakaryocytes

 Hypolobulation (bulbous/cloud-like)

 Maturation defects

Fig. 1

PrePMF presenting with hypercellular BM with atypical megakaryocyte and granulocyte proliferation

Fig. 2

PrePMF with atypical clustering of megakaryocytes

Fig. 3

Megakaryocytes in PMF generally are characterized by hypolobulated nuclei (bulbous/cloud-like). Granulopoiesis is increased and left-shifted

Fig. 4

PrePMF with only minimal increase in bone marrow reticulin (MF-1)

Overt (Classical) Primary Myelofibrosis

Advanced stages of PMF are consistent with classical myelofibrosis with myeloid metaplasia. The clinical picture of overt PMF includes a leukoerythroblastic peripheral blood smear with teardrop poikilocytosis, splenomegaly, and anemia of varying degree. BM cellularity may be variable and often patchy separated by adipose tissue or grossly developed fibrosis generating a streaming effect. Neutrophil granulopoiesis as well as erythropoiesis are usually reduced in areas revealing still existing hematopoiesis. Foci of immature cells may be more prominent, although myeloblasts account for fewer than 10% of the marrow cells. Similar, but often more pronounced compared to the early stages, abnormalities of megakaryocytes are prevalent including a prominent clustering and deployment along the dilated large BM vessels or together with other precursors an intraluminal dislocation. An overtly expressed myelofibrosis displaying a tight network of reticulin and dense bundles of collagen fibers is recognizable, often associated with initial to gross osteosclerosis conforming with grades 2 and 3 of the WHO-adopted scoring system (Figs. 5 and 6). Progression of myelofibrosis is significantly associated with a significant alteration of the vascular architecture including not only a remarkable increase in quantity of the microvasculature but also a conspicuous sinusoidal dilatation and tortuosity. Within the dilated marrow sinusoides, an intraluminal hematopoiesis including atypical megakaryocytes is in most cases a prominent finding. Profound marrow fibrosis is a response to the clonal proliferation of hematopoietic stem cells. Collagen type 3, also known as reticulin, and collagen type 1 are the predominant extracellular components of marrow fibrosis in PMF.
Fig. 5

Overt stage of PMF presenting with hypocellular bone marrow. Prominent osteosclerosis and atypical megakaryocytes

Fig. 6

Overt stage of PMF with marked bone marrow fibrosis (MF-3) and new bone formation (osteosclerosis)

Rarely the BM is almost devoid of hematopoietic cells in these cases, showing mainly dense reticulin or collagen fibrosis with small islands of hematopoietic precursors situated mostly within the vascular sinusoids. In osteosclerotic terminal phase of PMF, the marrow space is progressively replaced by broad, irregular trabeculae and appositional bud-like endophytic new bone formation. Increase in blood and/or marrow blasts (<20%) as well as in numbers of CD34+ cells with cluster formation and/or an abnormal endosteal location in the marrow indicates an accelerated phase of the disease, whereas 20% or more blasts is considered as blastic transformation, i.e., acute leukemia.

Molecular Features

Approximately 50–60% of patients present with a JAK2V617F or a functionally similar mutation, in about 30% cases CALR are visible, and in 8% MPL mutation can be found. About 10% of patients are clonally not defined and therefore labelled as so-called triple negative. These cases are characterized by a detrimental prognosis, whereas CALR-positive patients, specifically CALR type-1/like mutations, generally exert a favorable prognosis. The presence of either del(13)(q12-22) or der(6)t(1;6) (q21-23;p21.3) is strongly suggestive but not diagnostic of PMF. The most common recurring abnormalities include del (20q), and partial trisomy 1q, although +9 and/or +8 are also reported. Deletions affecting the long arms of chromosomes 7 and 5 occur as well but may be associated with prior cytotoxic therapy used to treat the myeloproliferative process. In general, clinical parameters like hemoglobin <10 g/dL, leukocytes >25 × 109/L, platelets <100 × 109/L, and circulating blasts ≥2% are regarded as the most important risk factors for overall survival; however, recent prognostic data also identified bone marrow fibrosis grade ≥2, constitutional symptoms, and high molecular risk (HMR) genetic mutations as negatively associated with outcome (ASXLI, SRSF2, EZH2, IDH1, IDH2).

Differential Diagnosis

In early phase of PMF, i.e., prePMF, which might present with high platelet counts at onset, the distinction of other MPN subtype is of therapeutic importance. In these early stages, the careful evaluation of megakaryocyte morphology is key to exclude ET or even PV. As a prominent bone marrow fibrosis may be observed in other hematological malignancies like lymphomas or bone marrow involvement in carcinomas, the presence of an MPN-associated driver mutation supports the diagnosis of PMF. Detection of characteristic JAK2, CALR, or MPL driver mutations will distinguish an MPN from reactive conditions, although not all cases of PMF express one of these major clonal markers. In the absence of mutations in any of these genes, clonality should be confirmed whenever possible. The identification of other mutations frequently associated with myeloid neoplasms (e.g., ASXL1, EZH2, TET2, IDH1, IDH2, SRSF2, SF3B1) can be useful to confirm the presence of clonal hematopoiesis. However, acquired clonal mutations including some of those mentioned above can also occur in the hematopoietic cells of apparently healthy aged individuals without a myeloid neoplasm. Cytogenetic abnormalities occur in up to 30% of patients and can be useful in confirming clonality. Secondary transformations to manifest overt stage myelofibrosis may also occur in PV and rarely also in ET; therefore the clinical history of the patient is important. Performing testing for BCR/ABL gene rearrangements is important to exclude chronic myelogenous leukemia which can also present with a significant increase in bone marrow fibers in some cases. Cases with prominent cytopenia and/or accompanying significant myelodysplastic changes should be better categorized as myelodysplastic/myeloproliferative neoplasm (MDS/MPN).

References and Further Reading

  1. Barbui, T., Thiele, J., Gisslinger, H., Finazzi, G., Vannucchi, A. M., & Tefferi, A. (2016). The 2016 revision of WHO classification of myeloproliferative neoplasms: Clinical and molecular advances. Blood Reviews, 30(6), 453–459.CrossRefGoogle Scholar
  2. Finazzi, G., Carobbio, A., Thiele, J., Passamonti, F., Rumi, E., Ruggeri, M., et al. (2012). Incidence and risk factors for bleeding in 1104 patients with essential thrombocythemia or prefibrotic myelofibrosis diagnosed according to the 2008 WHO criteria. Leukemia, 26(4), 716–719.CrossRefGoogle Scholar
  3. Gianelli, U., Bossi, A., Cortinovis, I., Sabattini, E., Tripodo, C., Boveri, E., et al. (2014). Reproducibility of the WHO histological criteria for the diagnosis of Philadelphia chromosome-negative myeloproliferative neoplasms. Modern Pathology, 27(6), 814–822.CrossRefGoogle Scholar
  4. Guglielmelli, P., Pietra, D., Pane, F., Pancrazzi, A., Cazzola, M., Vannucchi, A. M., et al. (2017). Recommendations for molecular testing in classical Ph1-neg myeloproliferative disorders-A consensus project of the Italian Society of Hematology. Leukemia Research, 58, 63–72.CrossRefGoogle Scholar
  5. Kvasnicka, H. M., & Thiele, J. (2010). Prodromal myeloproliferative neoplasms: The 2008 WHO classification. American Journal of Hematology, 85(1), 62–69.PubMedGoogle Scholar
  6. Tefferi, A., & Barbui, T. (2015). Polycythemia vera and essential thrombocythemia: 2015 update on diagnosis, risk-stratification and management. American Journal of Hematology, 90(2), 162–173.CrossRefGoogle Scholar
  7. Tefferi, A., Guglielmelli, P., Larson, D. R., Finke, C., Wassie, E. A., Pieri, L., et al. (2014). Long-term survival and blast transformation in molecularly annotated essential thrombocythemia, polycythemia vera, and myelofibrosis. Blood, 124(16), 2507–2513.CrossRefGoogle Scholar
  8. Thiele, J., Kvasnicka, H. M., Mullauer, L., Buxhofer-Ausch, V., Gisslinger, B., & Gisslinger, H. (2011). Essential thrombocythemia versus early primary myelofibrosis: A multicenter study to validate the WHO classification. Blood, 117(21), 5710–5718.CrossRefGoogle Scholar
  9. Thiele, J., Orazi, A., Kvasnicka, H. M., Franco, V., Boveri, E., Gianelli, U., et al. (2012). European Bone Marrow Working Group trial on reproducibility of World Health Organization criteria to discriminate essential thrombocythemia from prefibrotic primary myelofibrosis. Haematologica, 97(3), 360–365. Haematologica. 2012;97(3):e5–e6; discussion e7–e8.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Institute of Pathology and Department of Molecular PathologyUniversity Clinic Wuppertal, University of Witten/HerdeckeWuppertalGermany