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Diagnosis

Currently, the diagnosis of myelofibrosis (MF) centers around the 2016 diagnostic criteria developed by the World Health Organization (WHO), which combine clinical, laboratory, genetic, and histologic assessments.¹

Clinical Assessments for MF Diagnosis

The primary clinical assessment should confirm palpable splenomegaly, which the WHO lists as 1 of 5 minor criteria for the diagnosis of MF.¹ Approximately 90% of patients who have MF present with splenomegaly, and approximately 35% have a massive spleen that is easily palpated on physical examination.²

Approximately 60% to 70% of patients with MF also present with hepatomegaly. Pallor is noted in 60% of MF patients. Other physical examination findings include lymphadenopathy (10% to 20%), petechiae and ecchymosis (20%), signs of portal hypertension (10% to 18%), and gout (6%).²

Read more about MF signs and symptoms

Laboratory Testing for MF Diagnosis

Basic Laboratory Testing

Basic laboratory testing includes a complete blood cell (CBC) count to detect anemia, leukopenia/leukocytosis, thrombocytopenia/thrombocytosis, and decreased hemoglobin levels.³ Anemia that is not otherwise explained and leukocytosis (white cell count ≥11 x 10⁹/L) are 2 of the 5 minor criteria included in the 2016 WHO diagnostic criteria for MF.¹

More than 60% of patients who have MF present with a hemoglobin level below 10 g/dL.Leukocytosis (one-third of patients) is more common than leukopenia (one-fourth of patients). Similarly, thrombocytosis occurs more frequently than thrombocytopenia, with disseminated intravascular coagulation (DIC) noted in 15% of patients.³

Advanced Laboratory Testing

Other laboratory tests include measurement of the serum lactate dehydrogenase (LDH) level and analysis of the peripheral blood smear.^1,3 Elevated LDH is 1 of the 5 minor criteria for a diagnosis of MF.¹ Increased serum LDH levels are a consequence of increased cell turnover due to clonal myeloproliferation, including leukocytosis, hemolysis causing anemia, and extramedullary hematopoiesis in the liver.⁴

Leukoerythroblastosis with teardrop poikilocytosis on the peripheral blood smear³ is the last of the 5 WHO minor criteria for a diagnosis of MF.¹ Leukoerythroblastosis in the peripheral blood includes nucleated red blood cells, immature granulocytes, and dacryocytes.¹ Leukoerythroblastosis is a typical characteristic of primary MF, but it is not always present and may be absent in prefibrotic cases.¹ Additionally, fragments of megakaryocytes and large platelets may be visible.³

Read more about MF clinical features

Imaging Studies for MF Diagnosis

Ultrasonography and computed tomography are used to measure the spleen and liver and can reveal enlargement that may not be detected by palpation during physical examination.⁵

Clinicians use magnetic resonance imaging to evaluate the severity and progression of MF. Marrow patterns in the proximal femur appear to correlate with clinical severity.⁵

Skeletal radiography may detect mottled, patchy spots and prominent bony trabeculae, indicative of increased bone density.⁵

Read more about MF prognosis

Genetic Testing for MF Diagnosis

The presence of JAK2, CALR, or MPL gene mutations, which usually correlate with bone marrow fibrosis, is one of the 3 WHO major criteria required for a diagnosis of MF.^1,6 Aberrations in other genes are possible, including TET2, although the contribution of this genetic mutation to the development of MF is unknown.⁶

Read more about MF genetics

Bone Marrow Aspiration and Biopsy for MF Diagnosis

The primary basis for a diagnosis of MF is bone marrow morphology.^1,7 The presence of typical megakaryocyte changes accompanied by grade 2 or higher reticulin/collagen fibrosis is another of the 3 major diagnostic criteria for a diagnosis of overtly fibrotic MF.¹

Bone marrow aspiration and biopsy reveal the extent of bone marrow fibrosis. Samples are usually obtained from the posterior iliac crest with specialized needles. Samples should not be taken from the sternum because of the high frequency of dry taps from this site.⁷

The last of the 3 major criteria required for a diagnosis of MF is failure to meet the WHO criteria for other myeloid neoplasms.¹Cytogenetic studies of a bone marrow sample, such as fluorescence in situ hybridization (FISH) testing or polymerase chain reaction (PCR) assay, help to rule out chronic myelogenous leukemia, myelodysplastic syndrome, and other chronic myeloid malignancies.⁸ BCR-ABL1 cytogenetic testing or molecular testing should be undertaken if dwarf megakaryocytes are present, which are suggestive of chronic myelogenous leukemia.¹

Nonclonal bone marrow fibrosis, which may occur in certain autoimmune conditions, should also be ruled out.¹

Read more about MF guideline recommendations

Diagnostic Classification of MF

Primary Versus Secondary Myelofibrosis

Prefibrotic MF may mimic essential thrombocythemia (ET).¹ It is important to assess for the presence of both ET and polycythemia vera (PV) at the time of diagnosis. MF may develop over time in individuals with pre-existing ET or PV. Post-ET or post-PV MF is therefore considered a form of secondary MF.¹

Primary MF Subtypes

Primary MF is subdivided at diagnosis into 2 categories: prefibrotic primary MF and overtly fibrotic primary MF.¹

In cases of overtly fibrotic primary myelofibrosis, grade 2 or higher reticulin/collagen fibrosis is seen on bone marrow biopsy, whereas cases of prefibrotic MF are characterized by grade 1 or lower reticulin/collagen fibrosis.¹ Histopathologists use either the Bauermeister system, established in 1971, to grade reticulin/collagen fibrosis (scale of 0 to 4) or the recently established European consensus system (scale of 0 to 3).⁹

The WHO includes the presence of leukoerythroblastosis on the peripheral blood smear as a minor criterion for overt fibrotic primary MF, but not for prefibrotic primary MF. Therefore, 5 minor criteria are used for a diagnosis of overt MF, but only 4 minor criteria for a diagnosis of prefibrotic MF.¹

Read about MF types

References

Tefferi A. Primary myelofibrosis: 2021 update on diagnosis, risk-stratification and management. Am J Hematol. 2021;96(1):145-162. doi:10.1002/ajh.26050
Lal A. Primary myelofibrosis clinical presentation: physical examination. Medscape. Updated September 21, 2022. Accessed December 8, 2022.
Lal A. Medscape. Primary myelofibrosis workup: complete blood count. Updated September 21, 2022. Accessed December 8, 2022.
Shah S, Mudireddy M, Barraco D, et al. Marked elevation of serum lactate dehydrogenase (LDH) in primary myelofibrosis: clinical and prognostic correlates. Blood. 2016;128(22):3113. doi:10.1182/blood.V128.22.3113.3113
Lal A. Primary myelofibrosis workup: imaging studies. Medscape. Updated September 21, 2022. Accessed December 8, 2022.
Primary myelofibrosis. MedlinePlus. Accessed December 8, 2022.
Lal A. Primary myelofibrosis workup: procedures and histologic findings. Medscape. Updated September 21, 2022. Accessed December 8, 2022.
Lal A. Primary myelofibrosis workup: genetic testing. Medscape. Updated September 21, 2022. Accessed December 8, 2022.
Zahr AA, Salama ME, Carreau N, et al. Bone marrow fibrosis in myelofibrosis: pathogenesis, prognosis and targeted strategies. Haematologica. 2016;101(6):660-671. doi:10.3324/haematol.2015.141283

Reviewed by Harshi Dhingra, MD, on 12/26/2022.

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.

Myelofibrosis (MF)