Myelofibrosis diagnostic study of choice

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Sujit Routray, M.D. [2]

Overview

Diagnosis of myelofibrosis may be made based upon a thorough clinical evaluation, detailed patient history, and specialized tests. The World Health Organization (WHO) has set the criteria for diagnosing primary myelofibrosis (PMF). It has determined set rules for distinguishing the prefibrotic/early (pre-primary myelofibrosis) phase and the overtly fibrotic (overt primary myelofibrosis) phase. The World Health Organization (WHO) has also introduced a proposed revised criteria for primary myelofibrosis (PMF).

Diagnostic Criteria

2001 World Health Organization (WHO) criteria for prefibrotic/early (pre-primary myelofibrosis) phase

Clinical findings	Morphological findings
Spleen and liver No or mild splenomegaly or hepatomegaly	Blood No or mild leukoerythroblastosis No or mild red blood cell poikilocytosis Few if any dacryocytes
Hematology (variable) Mild anemia Mild to moderate leukocytosis Mild to marked thrombocytosis	Bone marrow Hypercellularity Neutrophilic proliferation Megakaryocytic proliferation

2001 World Health Organization (WHO) criteria for overtly fibrotic (overt primary myelofibrosis) phase

Clinical findings	Morphological findings
Spleen and liver Moderate to marked splenomegaly or hepatomegaly	Blood Leukoerythroblastosis Prominent red blood cell poikilocytosis Prominent dacryocytosis
Hematology (variable) Leukoerythroblastosis White blood cells decreased to elevated Platelet count decreased to elevated	Bone marrow Reticulin and/or collagen fibrosis Decreased cellularity Dilated marrow sinuses Intraluminal hematopoiesis Neutrophilic proliferation Prominent megakaryocytic proliferation Megakaryocytic atypia* New bone formation (osteosclerosis) *Clustering of megakaryocytes, abnormally lobulated megakaryocytic nuclei, naked megakaryocytic nuclei

Proposed revised World Health Organization (WHO) criteria for primary myelofibrosis (PMF)

Clinical findings
Major criteria Presence of megakaryocyte proliferation and atypia,* usually accompanied by either reticulin and/or collagen fibrosis, or, in the absence of significant reticulin fibrosis, the megakaryocyte changes must be accompanied by an increased bone marrow cellularity characterized by granulocytic proliferation and often decreased erythropoiesis (ie, prefibrotic cellular-phase disease) Not meeting WHO criteria for PV, †CML, ‡ MDS, § or other myeloid neoplasm Demonstration of JAK2617V>F or other clonal marker (eg, MPL515W>L/K), or in the absence of a clonal marker, no evidence of bone marrow fibrosis due to underlying inflammatory or other neoplastic diseases¶
Minor criteria Leukoerythroblastosis∥ Increase in serum lactate dehydrogenase level∥ Anemia∥ Palpable splenomegaly∥ *Small to large megakaryocytes with an aberrant nuclear/cytoplasmic ratio and hyperchromatic, bulbous, or irregularly folded nuclei and dense clustering. †Requires the failure of iron replacement therapy to increase hemoglobin level to the polycythemia vera range in the presence of decreased serum ferritin. Exclusion of polycythemia vera is based on hemoglobin and hematocrit levels. Red cell mass measurement is not required. ‡Requires the absence of BCR-ABL. §Requires the absence of dyserythropoiesis and dysgranulopoiesis. ¶Secondary to infection, autoimmune disorder or other chronic inflammatory condition, hairy cell leukemia or other lymphoid neoplasm, metastatic malignancy, or toxic (chronic) myelopathies. It should be noted that patients with conditions associated with reactive myelofibrosis are not immune to primary myelofibrosis and the diagnosis should be considered in such cases if other criteria are met. ∥Degree of abnormality could be borderline or marked.

• Diagnosis requires meeting all 3 major criteria and 2 minor criteria.

According to the World Health Organization (WHO) diagnostic criteria for primary myelofibrosis, polycythemia vera, and essential thrombocythemia, the diagnosis of primary myelofibrosis is made when all three of the following major diagnostic criteria and at least two minor criteria are met.

Major Criteria	Minor Criteria
I. On bone marrow biopsy, proliferation and atypia of megakaryocytes, with or without reticulin or collagen fibrosis and it must be accompanied by hypercellular bone marrow II. Finding of JAK2-V617F mutation or other clonal marker III. Not meeting the WHO criteria for chronic myeloid leukemia (CML), polycythemia vera (PV), myelodysplastic syndrome (MDS), or other myeloid neoplasm	I. Anemia II. Increased serum lactate dehydrogenase (LDH) III. Leukoerythroblastosis on blood smear IV. Palpable splenomegaly