Myelofibrosis (MF)

Myelofibrosis (MF) is a rare hematologic cancer characterized by fibrosis, or scarring, within the bone marrow. Consequently, this bone marrow fibrosis disrupts the normal production of blood cells, causing other signs and symptoms such as anemia, splenomegaly, extramedullary hematopoiesis, and constitutional symptoms.¹

Optimal treatment of patients with MF requires prompt differential diagnosis from other disorders characterized by overlapping symptomology, such as diffuse bone sclerosis, splenomegaly, anemia (including hemolytic anemia and sickle cell anemia), thrombocytopenia, thrombocytosis, leukocytosis, and extramedullary hematopoiesis.²

Philadelphia-Negative Myeloproliferative Neoplasms

Essential thrombocythemia (ET), polycythemia vera (PV), and primary MF comprise the 3 classic Philadelphia-negative myeloproliferative neoplasms.³ Primary MF arises in the absence of an underlying condition. ET and PV may transform into secondary MF; therefore, establishing an initial diagnosis of ET or PV is important in the differentiation of primary and secondary MF.⁴

Read more about MF types 

Myeloproliferative Diseases

Myelofibrosis is a myeloproliferative neoplastic disorder; therefore, other myeloproliferative neoplasms must be ruled out, including²: 

• Essential thrombocythemia
• Polycythemia vera
• Chronic myelogenous leukemia (also known as chronic myeloid leukemia) (CML)
• Chronic neutrophilic leukemia
• Chronic eosinophilic leukemia
• B-cell and T-cell lymphoblastic leukemia/lymphoma
• Acute myeloid leukemia (AML)
• Myelodysplastic syndromes (MDS)
• Myelodysplastic/myeloproliferative neoplasms, such as chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, atypical CML, and MDS/myeloproliferative neoplasms with ring sideroblasts and thrombocytosis
• Mastocytosis
• Blastic plasmacytoid dendritic cell neoplasms 
• Other unclassifiable myeloproliferative neoplasms

Essential Thrombocythemia

The hallmark of ET is an unexplained elevation in platelet count of 450,000/µL or higher with platelet anisocytosis.⁵ ET and primary MF both may be caused by somatic mutations in the JAK2, CALR, or MPL genes.² The major differentiating factor between ET and primary MF is the extent of hypercellularity and bone marrow fibrosis present.² 

In ET, bone marrow biopsy reveals either normal or hypercellular bone marrow with no fibrosis (unless it transforms into secondary MF).² Additionally, bone marrow biopsy shows an absence of dyserythropoiesis, macrocytosis, and dysgranulopoiesis. When ET transforms into secondary MF, peripheral blood smears are notable for leukoerythroblastosis with teardrop-shaped erythrocytes and poikilocytosis.⁵

Read more about MF testing

Polycythemia Vera

Patients with PV often present with thrombocytosis (>400,000 platelets/µL), leukocytosis (>12,000/µL), and leukocyte alkaline phosphatase (LAP) scores of over 100 units/L without infection or fever.⁶ Fibrosis or hypercellularity of the bone marrow may occur in both PV and primary MF.² Bone marrow biopsy in PV may also reveal panmyelosis and variable proliferation of granulocyte precursors, erythroid cells, and megakaryocytes.⁵ Similar to ET, secondary MF resulting from the transformation of PV presents with leukoerythroblastosis and poikilocytosis.⁵

Elevated serum lactate dehydrogenase (LDH) level is not an isolated diagnostic feature of primary MF; however, mean LDH levels are often higher in patients with primary MF, occurring to a lesser extent in patients with PV or ET. Due to the lack of specificity for the diagnosis of primary MF, some studies suggest that elevated serum LDH levels may be influenced by other factors, such as genetics in the context of myeloproliferative neoplasms, and should not be used in the diagnostic classification system to differentiate between PV, ET, and primary MF.⁷

Read more about MF comorbidities

Chronic Myelogenous Leukemia

Chronic myelogenous leukemia can be reliably distinguished from MF by cytogenetic testing for the presence or absence of the BCR–ABL1 fusion gene within the Philadelphia chromosome. Patients with CML will test positive for this fusion gene in hematopoietic cells, while patients with MF are Philadelphia-negative.⁸

Other differentiators between CML and primary MF include⁸:

• Leukocyte counts (typically higher in CML and under 50,000/mm³ in primary MF)
• Left shift of granulocytes (less pronounced in primary MF)
• Poikilocytosis (notable in primary MF compared with CML)
• Bone marrow fibrosis (occurs in both primary MF and CML; however, megakaryocyte count is often increased in primary MF, while the most abnormal bone marrow finding in CML is myeloid hyperplasia)
• LAP score (variable in MF; a reduced level provides strong evidence for CML)

Acute Myeloid Leukemia

Myeloproliferative neoplasms such as PV, ET, and primary MF may transform into AML,⁹ particularly in patients with the JAK2 V617F mutation.¹⁰ Acute myeloid leukemia occurs more frequently in patients with primary MF (20% of patients over 10 years) than in those with PV (4%) or ET (1%) over the same time frame. This transformation to AML is indicated by the minimum presence of 20% blasts in the peripheral blood, also called the blast phase of myeloproliferative neoplasms.¹¹ 

Read more about MF complications

Myelodysplastic Syndromes 

Myelodysplastic syndromes are disorders characterized by bone marrow failure. They include hypocellular MDS, aplastic anemia, inherited bone marrow failure syndromes, large granular lymphocytosis, pure red cell aplasia, and paroxysmal nocturnal hemoglobinuria.⁹ MDS and myeloproliferative neoplasms such as MF share overlapping characteristic features including bone marrow fibrosis¹² and failure, making accurate differential diagnosis challenging.⁹

In addition to a comprehensive physical examination to ascertain clinical disease manifestations, differential diagnosis between MDS and myeloproliferative neoplasms requires bone marrow biopsy with aspiration to carefully evaluate marrow cellularity, the extent of fibrosis, dysplasia, and topography. Additional tools to assist with differential diagnosis include flow cytometry and cytogenetics.⁹ 

Read more about MF guidelines

Hairy Cell Leukemia

Hairy cell leukemia (HCL) may mimic MF due to the overlapping symptoms of various cytopenias and splenomegaly; however, a lymphoid infiltration test using CD20 staining can distinguish between HCL and MF.¹³

Tuberculosis

Tuberculosis (TB) should be assessed in any patient presenting with organomegaly, constitutional symptoms, and cytopenia.¹⁴ In addition to PV and ET, TB is one of the possible underlying conditions that may cause secondary MF.¹⁴ Mycobacterium tuberculosis infection causes increased secretion of interleukin-1 (IL-1), resulting in the activation of fibroblasts and induction of reactive bone marrow fibrosis.^14,15 

Tests for TB include the purified protein derivative (PPD) skin test, during which tuberculin is injected underneath the skin, and interferon-gamma release assays (IGRA) to confirm the diagnosis of TB.¹⁶ 

It is possible that these tests and sputum cultures may be negative for TB in the case of disseminated TB, making the differential diagnosis of TB from MF more difficult.¹⁴ Diagnosis in these cases may require cytogenetic testing to confirm the presence of myeloproliferative mutational markers in the JAK2, CALR, or MPL genes.^2,14

Read more about MF genetics

Infectious Diseases

Myelofibrosis must be differentiated from viral, bacterial, fungal, and parasitic infectious diseases that cause splenomegaly and/or extramedullary hematopoiesis and may mimic various signs and symptoms of MF.² Viral infections can include mononucleosis, cytomegalovirus, rubella, disseminated herpes simplex virus, and human immunodeficiency virus (HIV).² Bacterial infections may include tularemia, typhoid fever, syphilis, brucellosis, miliary TB, abscesses, and subacute bacterial endocarditis.² Fungal infections can include candidiasis and histoplasmosis.² 

Parasitic infections may include malaria, leishmaniasis, schistosomiasis, hydatid disease, rickettsial disease, and typhus.²

References

1. Primary myelofibrosis. MedlinePlus. Updated September 1, 2014. Accessed January 5, 2023.
2. Myelofibrosis differential diagnosis. WikiDoc. Updated November 12, 2019. Accessed January 5, 2023.
3. Sukrisman L. Clinical characteristics and prognostic risks of Philadelphia-negative myeloproliferative neoplasms at Cipto Mangunkusumo General Hospital. J Blood Med. 2022;13:495-503. doi:10.2147/JBM.S374636
4. Myelofibrosis. Cleveland Clinic. Accessed January 5, 2023.
5. Thapa B, Fazal S, Parsi M, Rogers HJ. Myeloproliferative neoplasms. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2022. Updated August 8, 2022. Accessed January 5, 2023.
6. Nagalla S. Polycythemia vera workup. Medscape. Updated August 31, 2022. Accessed January 5, 2023.
7. Beer PA, Campbell PJ, Green AR. Comparison of different criteria for the diagnosis of primary myelofibrosis reveals limited clinical utility for measurement of serum lactate dehydrogenase. Haematologica. 2010;95(11):1960-1963. doi:10.3324/haematol.2010.026708
8. Anju S, Jayalakshmy PL, Sundaram S. Chronic myeloid leukemia mimicking primary myelofibrosis: a case report. Arch Hematol Case Rep Rev. 2021;6(1):1-4. doi:10.17352/ahcrr.000029
9. DeZern AE, Sekeres MA. The challenging world of cytopenias: distinguishing myelodysplastic syndromes from other disorders of marrow failure. Oncologist. 2014;19(7):735-745. doi:10.1634/theoncologist.2014-0056
10. Alhuraiji A, Naqvi K, Huh YO, Ho C, Verstovsek S, Bose P. Acute lymphoblastic leukemia secondary to myeloproliferative neoplasms or after lenalidomide exposure. Clin Case Rep. 2017;6(1):155-161. doi:10.1002/ccr3.1264
11. Mannelli F. Acute myeloid leukemia evolving from myeloproliferative neoplasms: many sides of a challenging disease. J Clin Med. 2021;10(3):436. doi:10.3390/jcm10030436
12. Jain AG, Zhang L, Bennett JM, Komrokji R. Myelodysplastic syndromes with bone marrow fibrosis: an update. Ann Lab Med. 2022;42(3):299-305. doi:10.3343/alm.2022.42.3.299
13. DeAngelo DJ. Hairy cell leukemia. Cancer Therapy Advisor. Accessed January 5, 2023.
14. Khatuni M, Ghalamkari M, Ameli F, Yekehtaz H. Disseminated tuberculosis with myelofibrosis presentation: a case report. J Med Case Rep. 2021;15:550. doi:10.1186/s13256-021-03038-3
15. Verma SC, Agarwal P, Krishnan MY. Primary mouse lung fibroblasts help macrophages to tackle Mycobacterium tuberculosis more efficiently and differentiate into myofibroblasts up on bacterial stimulation. Tuberculosis (Edinb). 2016;97:172-180. doi:10.1016/j.tube.2015.10.009
16. Pahal P, Sharma S. PPD skin test. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2022. Updated January 24, 2022. Accessed January 5, 2023.

Reviewed by Hasan Avcu, MD, on 1/11/2023.

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Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT

Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT is a freelance medical writer and Doctor of Physical Therapy from Maryland. She has expertise in the therapeutic areas of orthopedics, neurology, chronic pain, gastrointestinal dysfunctions, and rare diseases especially Ehlers Danlos Syndrome.