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Clinical manifestations and diagnosis of primary myelofibrosis

Clinical manifestations and diagnosis of primary myelofibrosis
Author:
Ayalew Tefferi, MD
Section Editor:
Richard A Larson, MD
Deputy Editor:
Alan G Rosmarin, MD
Literature review current through: Jan 2024.
This topic last updated: Sep 13, 2022.

INTRODUCTION — Primary myelofibrosis (PMF) is one of the chronic myeloproliferative disorders, which are collectively characterized by clonal proliferation of myeloid cells with variable morphologic maturity and hematopoietic efficiency. PMF was previously called chronic idiopathic myelofibrosis (CIMF) and agnogenic myeloid metaplasia (AMM).

Acute myelofibrosis, a term that has been applied to the clinical picture occasionally seen in patients with acute megakaryoblastic leukemia (FAB M7), is discussed separately. (See "Acute myeloid leukemia: Classification", section on 'Acute megakaryoblastic leukemia'.)

The clinical manifestations and diagnosis of PMF will be reviewed here. The pathogenetic mechanisms, prognosis, and treatment of this disorder are discussed separately. (See "Pathogenetic mechanisms in primary myelofibrosis" and "Myelofibrosis (MF): Management of primary MF and secondary MF" and "Prognosis of primary myelofibrosis".)

EPIDEMIOLOGY — PMF is the least frequent among the chronic myeloproliferative diseases. One study reported an estimated incidence of 1.5 per 100,000 per year in Olmsted County, Minnesota [1]. This incidence figure is higher than those reported from western Australia and northern Israel.

PMF occurs mainly in middle aged and older adults. The median age at presentation is 67 years [1]. Approximately 5 and 17 percent of the patients are diagnosed before the age of 40 and 50 years, respectively [2]. The condition is rare in childhood [3]; a familial occurrence has been reported in several kindreds. Both the familial and the idiopathic forms in childhood may be associated with congenital anomalies and chromosome abnormalities [4,5].

CLINICAL MANIFESTATIONS

Signs and symptoms — The most common presenting complaint in PMF is that of severe fatigue, occurring in 50 to 70 percent of patients (table 1) [1,2,6-9]. Symptoms due to an enlarged spleen have been described in 25 to 50 percent of patients, while a smaller number note weight loss and 5 to 20 percent experience other signs of a hypermetabolic state such as low grade fever, bone pain, and night sweats [2,8]. Approximately 15 to 30 percent are asymptomatic, with the diagnosis being made during investigation of splenomegaly (occurring in at least 90 percent of patients), hepatomegaly (40 to 70 percent), or abnormal blood findings [2,8,9]. Enlargement of the spleen and liver are due to the marked extramedullary hematopoiesis associated with PMF.

Pulmonary hypertension – Pulmonary hypertension has been detected in patients with PMF; while often asymptomatic, it has been associated with reduced overall survival [10-12].

Pruritus – In our series of 566 consecutive patients with PMF, pruritus was documented in 16 percent [13]. This symptom did not correlate with karyotype, risk category, overall survival, leukemic transformation, or plasma levels of 20 cytokines known to be abnormally expressed in PMF.

A symptom assessment form has been devised for measuring clinical improvement in therapeutic trials [14].

Thrombotic events — The incidence of arterial and venous thrombotic events in PMF (2 per 100 patient-years) is approximately the same as that seen in essential thrombocythemia (1 to 3 per 100 patient-years), and significantly lower than that seen in polycythemia vera (5.5 per 100 patient-years) [15]. In a retrospective analysis of 205 patients with PMF, 13.2 percent had experienced a thrombotic event at or prior to their diagnosis, and 10.7 percent developed post-diagnosis thrombosis at a median follow-up of 31 months [16]. On multivariate analysis, a history of thrombosis was the only predictive variable; 71 percent of the venous events were temporally associated with other exogenous risk factors for thrombosis (eg, surgery, central line placement, hormonal therapy).

Splenomegaly — Splenomegaly, often marked, is the hallmark of PMF [17]. The spleen may be so large that its lower border is below the pelvic brim and its right border extends across the midline. In two series, 38 percent of patients had splenomegaly that extended more than 10 cm below the left costal margin [18], and 23 percent had massive splenomegaly that extended over 16 cm below the left costal margin [2].

Symptoms due to splenic disease often figure prominently in PMF. Patients may note a dragging or heavy sensation in the left upper abdomen, and the spleen may compress the patient's stomach, leading to early satiety. Severe left upper quadrant pain, with or without left shoulder pain, may result from multiple and/or recurrent episodes of splenic infarction or inflammation of the tissues surrounding the spleen (ie, perisplenitis).

Hepatomegaly — Palpable hepatomegaly is present in 40 to 70 percent of patients. Portal hypertension may develop as a result of increased splanchnic flow due to splenomegaly and/or intrahepatic obstruction associated with extramedullary hematopoiesis [19]. Complications include ascites, esophageal and gastric varices, gastrointestinal bleeding, and hepatic encephalopathy.

Portal vein thrombosis is a recognized complication of PMF and other chronic myeloproliferative disorders [19] and may precede the clinical onset of the disease, similar to what has been documented in polycythemia vera [20]. (See "Risk and prevention of venous thromboembolism in adults with cancer".)

Extramedullary hematopoiesis — Foci of extramedullary hematopoiesis may occur in almost any organ [21-23]. Organ involvement may present as splenomegaly, hepatomegaly, lymphadenopathy; pleural, pericardial, or abdominal effusions; or involvement of the gastrointestinal or genitourinary tracts or lung, leading to symptoms such as dysuria and respiratory distress [24-28]. Involvement of the central nervous system may be associated with increased intracranial pressure, altered sensorium, motor and sensory impairment, including cord compression [29,30].

Involvement of the skin is rare but may present as erythematous plaques, nodules, erythema, ulcers, or bullae [31,32]. In a literature review of 13 such cases, nine showed that all three hematopoietic cell lines (myeloid, erythroid, and megakaryocytic) were present in these lesions [33].

In our series of 27 patients with an antemortem diagnosis of extramedullary hematopoiesis other than in the liver or spleen, involved sites were as follows [23]:

In or surrounding the vertebral column (especially thoracic) – 7

Lymph nodes – 4

Retroperitoneum – 4

Lungs or pleura – 3

Genitourinary system – 2

Skin – 2

Other sites (thalamus, right atrium, mouth, muscle, bowel) – 5

Foci of extramedullary hematopoiesis may develop and/or enlarge significantly after splenectomy, perhaps due to the loss of filtering function of the spleen [34,35]. This may be especially critical in the liver [26,36]. As an example, a study of 10 patients with PMF undergoing splenectomy found hepatic extramedullary hematopoiesis in all those in whom an intraoperative liver biopsy was performed [36]. Following splenectomy, a significant increase in liver size and in serum concentrations of alkaline phosphatase, bilirubin, and/or gamma-glutamyl transpeptidase were seen in all patients. Two patients developed acute liver failure and died three and four weeks postsplenectomy. In contrast, no liver changes were observed in 10 patients with chronic myeloid leukemia who also underwent splenectomy.

Bone and joint involvement — A number of skeletal changes may accompany the marrow fibrosis in PMF. These abnormalities may be asymptomatic but can cause severe bone and joint tenderness or pain, especially in the lower extremities, that is difficult to treat.

Osteosclerosis is characterized by a diffuse or patchy increase in bone density on radiologic studies and increased prominence of bony trabeculae. A mottled radiographic appearance of the bone has been described in 25 to 66 percent of patients with PMF [8]. This pattern may be confused with metastatic carcinoma.

Periostitis can lead to debilitating bony pain.

Cortical bone blood flow is considerably increased in PMF, resulting in a "superscan" phenomenon on bone scintigraphy. It is often clinically evident as an increase in warmth over the tibiae and knees.

Secondary gout due to chronic overproduction of uric acid can lead to acute monoarticular or chronic polyarticular arthritis. (See "Clinical manifestations and diagnosis of gout".)

Osteolytic lesions are rare, and usually reflect the presence of a solitary myeloid sarcoma, also called granulocytic sarcoma or chloroma [37]. (See "Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia", section on 'Myeloid sarcoma'.)

LABORATORY FINDINGS

Anemia — Anemia with hemoglobin less than 10 g/dL is seen in approximately 50 percent of patients with PMF, and 20 percent present with a hemoglobin less than 8 g/dL [2]. The causes are multiple and include:

Reduction in medullary erythropoietic sites

Ineffective erythropoiesis associated with extramedullary sites of red blood cell (RBC) production

Splenic sequestration and destruction of circulating RBCs

Bleeding due to thrombocytopenia or other complications such as varices resulting from portal vein thrombosis

Autoimmune hemolysis

Dilutional "anemia" may be present in patients with large spleens and expanded plasma volumes, but normal RBC mass

Influence of thrombopoietin receptor (Mpl) mutations [38]

One or more of the above mechanisms may be responsible for anemia in any particular patient. A number of isotopic techniques are available for assessment of these mechanisms but are rarely used [39].

After the onset of anemia, most patients experience a progressive decline in the hemoglobin concentration, requiring frequent RBC transfusions. The peripheral smear is quite characteristic, showing anisocytosis (ie, RBCs of varying size), poikilocytosis (ie, RBCs of varying shape), teardrop-shaped RBCs (dacrocytes), nucleated RBCs, and variable degrees of polychromasia (picture 1 and picture 2). Why dacrocytes form in PMF is not understood; splenectomy and chemotherapy reduce, but do not eliminate, the number of such cells in the circulation [40,41].

Platelet and white blood cell abnormalities — The platelet and white blood cell (WBC) counts are variable in PMF. Marked leukocytosis (WBC >30,000/microL) and thrombocytosis (platelet count >500,000/microL) occur at diagnosis in approximately 11 and 13 percent of patients, respectively, while leukopenia and thrombocytopenia are seen in 8 and 26 percent, respectively [2,18]. The variable leukocyte count reflects variation in the number of neutrophils. Immature cells from the neutrophilic series are always present as part of the leukoerythroblastic blood picture and myeloblasts may be seen in the peripheral smear, usually amounting to less than 5 percent of the total WBC count (picture 1). Hypersegmented neutrophils may also be seen (picture 3).

Thrombocytopenia becomes more common with disease progression. Platelets may be abnormally large with altered granulation; in addition, fragmented megakaryocytes are also seen on the peripheral smear. Abnormal platelet function is common [42] although the correlation between these abnormalities and clinical bleeding is weak.

Bleeding complications are usually associated with thrombocytopenia, esophageal or gastric varices, the use of nonsteroidal anti-inflammatory drug, and/or acquired deficiency of factor V [43]. A few patients have mild prolongation of the prothrombin and partial thromboplastin times along with decreased levels of factor V and VIII. Laboratory features of disseminated intravascular coagulation (DIC) may accompany these abnormalities and may not be apparent until surgery is performed. Extreme thrombocytosis (ie, platelets >1 million/microL) may promote a hemostatic defect due to the excessive adsorption of large von Willebrand factor multimers, such as that seen in essential thrombocythemia. (See "Essential thrombocythemia: Treatment and prognosis".)

Circulating CD34+ cells — In an Italian multicenter study, the median absolute number of circulating CD34+ hematopoietic precursor cells in 84 consecutive patients with PMF (92 CD34+ cells/microL; range: 0 to 2460) was 400 times that of healthy normal subjects (normal range: 0.15 to 0.35 cells/microL) [44]. A value of 15 CD34+ cells/microL in patients not on therapy could be used diagnostically to separate patients with PMF from those with Philadelphia chromosome negative chronic myeloproliferative diseases, with positive and negative predictive values of 98 and 85 percent, respectively.

In this study, CD34+ counts progressively increased as disease severity increased; overall survival and the interval to blast crisis were significantly shorter in patients with >300 CD34+ cells/microL. However, our serial studies in 94 patients did not support an independent prognostic value for peripheral blood CD34 counts in PMF [45].

Circulating endothelial progenitor cells with CD34, CD133, and VEGF receptor-2 positivity have also been detected in patients with PMF [46]. Their significance is unclear.

Abnormal laboratory tests — Patients with PMF may have nonspecific abnormalities in a variety of laboratory tests. These include: elevations in the serum concentrations of alkaline phosphatase, lactate dehydrogenase, uric acid, leukocyte alkaline phosphatase, and vitamin B12 [47,48]. The increase in alkaline phosphatase may be due to liver involvement or bone disease, the increase in lactate dehydrogenase may result from ineffective hematopoiesis, hyperuricemia is due to enhanced turnover of hematopoietic tissue and can cause gout or uric acid stones, and the increase in serum vitamin B12 reflects an increased neutrophil mass.

Bone marrow examination — There are a number of methodologies available for evaluation of marrow involvement in patients with PMF; although, as will be described in the next section, the diagnosis is often strongly suspected from the clinical presentation alone. Furthermore, the bone marrow may not reveal extensive replacement of the marrow by fibrosis, which has classically been considered to be the hallmark of the disease.

Marrow can be aspirated and/or biopsied directly, and it can be imaged with magnetic resonance imaging (MRI) or scintigraphy. These techniques can be used for initial diagnosis and prognosis, and for monitoring the course of the disease.

Bone marrow aspiration — The bone marrow in PMF is often difficult to aspirate, usually yielding a "dry" tap. In addition, the results of aspiration alone, if successful, are not diagnostic. The most common findings are neutrophilic and megakaryocytic hyperplasia.

Megakaryocytes are often morphologically abnormal with both micro- and macro-megakaryocytes. Granulocytes may show hyperlobulation, and erythroid precursors may be normal or increased. These morphologic changes in megakaryocytes help to distinguish early/prefibrotic PMF from essential thrombocythemia. (See 'Other chronic myeloid disorders' below.)

Bone marrow biopsy — Bone marrow biopsy is necessary to demonstrate fibrosis (picture 4) [49-51]. Some degree of fibrosis is seen in almost all patients; the fibrosis is typically extensive and visualized better with a silver stain (reticulin) or a trichrome stain (mature collagen) (picture 5). Bone marrow sinusoids are expanded and there is intravascular hematopoiesis. The fibrosis is generally associated with atypical megakaryocytic hyperplasia and thickening and distortion of the bony trabeculae (osteosclerosis).

Semiquantitative grading of bone marrow fibrosis (table 2) is critical for distinguishing between overt PMF and pre-PMF (table 3 and table 4).

In some patients, however, the bone marrow is markedly hypercellular with scant bone marrow fibrosis; this is called the cellular phase of PMF. The diagnosis of PMF in this setting is made from the clinical and peripheral smear findings after chronic myeloid leukemia and polycythemia vera have been excluded.

Bone marrow imaging with MRI — The major source of the MRI signal from bone is the fat and water content of bone marrow, with little or no signal arising from bone or normal marrow cells. Thus, MRI can demonstrate conversion of fatty marrow (intense or bright signal) to cellular and/or fibrotic marrow (markedly low intensity signal) [52,53]. However, the value of this technique for replacing bone marrow biopsy or for staging or prognostic purposes is not clear [54].

Isotopic marrow imaging — Erythropoietically active marrow can be directly imaged using isotopes of iron (Fe-52 or Fe-59) or indium (In-111) [55]. These techniques may be useful for determining patterns of marrow loss, extension into the long bones, or sites of extramedullary erythropoiesis.

Gene mutations — As with other myeloproliferative neoplasms, the vast majority of patients with PMF demonstrate mutually exclusive mutations in JAK2, MPL, or CALR. Rough estimates for the frequency at which these genes are mutated in PMF are as follows [56-59]:

JAK2 mutation – 60 to 65 percent

CALR mutation – 20 to 25 percent

MPL mutation – 5 percent

No JAK2, CALR, or MPL mutation ("triple negative") – 8 to 10 percent

A minority of "triple negative" PMF has non-canonical mutations in JAK2, MPL, and other genes on whole exome sequencing [60]. Further study is needed to elucidate the function of these other gene mutations in the pathogenesis of disease. The role of gene mutations on the pathogenesis of myeloproliferative neoplasms is discussed in more detail separately. (See "Overview of the myeloproliferative neoplasms", section on 'Mutations in PV, ET, and PMF'.)

Presence of these mutations, their allele burden, and their relationship to clinical manifestations, overall survival, and leukemic transformation, are under active investigation.

TRANSFORMATION TO ACUTE LEUKEMIA — Acute leukemia occurs as a terminal event in a minority of patients with PMF, but it is the most commonly identified cause of death [61,62]. Many of these patients have not had prior treatment with alkylating agents or radiotherapy [63-67]. Most of the leukemic transformations have been of myeloid origin; however, lymphoid, erythroid, megakaryocytic, and mixed lineage leukemias have occasionally been described. Localized foci of leukemic blasts (ie, myeloid sarcoma, also called granulocytic sarcoma or chloroma) are rarely seen in PMF.

The largest reported experience comes from our series of 2333 consecutive patients with PMF, 91 of whom (3.9 percent) fulfilled criteria for acute leukemic transformation; all were myeloid in origin [63]. A clonal abnormality was present in 49 of the 51 patients in whom cytogenetic studies were performed, and karyotypic evolution was documented in the majority of patients with serial studies.

In a separate analysis of 311 patients with PMF, the following two factors at the time of diagnosis were independent predictors of leukemic transformation [68]:

Circulating blasts ≥3 percent

Platelet count <100,000/microL

In this series, 77, 19, and 4 percent of patients had none, one, or both of these risk factors, respectively, with rates of leukemic transformation of 6, 18, and 18 percent, respectively. Treatment-related factors included use of an erythropoiesis-stimulating agent and danazol.

Establishing the presence of leukemic transformation in PMF is often difficult, primarily because abnormal cell counts and immature cells in the peripheral blood are part of the disease process. Furthermore, bone marrow biopsy may not reveal clear evidence of leukemia. In such patients, the diagnosis is established from tissue leukemic deposits or at autopsy.

Management of leukemic transformation of PMF is discussed separately. (See "Myelofibrosis (MF): Management of primary MF and secondary MF", section on 'Leukemic transformation'.)

EVALUATION AND DIAGNOSIS

Suspecting PMF — Patients with PMF first come to medical attention with some constellation of the following findings: nonspecific systemic symptoms, splenomegaly, hepatomegaly (both due to extramedullary hematopoiesis), anemia, and either high or low platelet and white blood cell (WBC) counts (table 1). The peripheral smear provides the first clue to the diagnosis of PMF. The characteristic features include teardrop-shaped red blood cells and the characteristic leukoerythroblastic findings of myelophthisis (replacement of normal marrow elements by fibrosis or tumor), nucleated erythrocytes and granulocyte precursors (myelocytes, metamyelocytes, and blasts) (picture 1).

However, a similar blood picture can be produced by bone marrow infiltration by metastatic cancer (especially prostate or breast) or infectious granulomata. Thus, bone marrow biopsy is required for demonstration of fibrosis and the absence of clusters of malignant cells (picture 6) or granulomata.

There is no "gold standard" for the diagnosis of PMF, although criteria have been proposed by the Italian Society of Hematology, the World Health Organization (WHO), and others [50,69-72].

The 2016 revisions to the WHO criteria offer diagnostic criteria for pre-PMF and overt PMF (table 3 and table 4) [50,72-74]. These are described in the following sections. The distinction between these entities is important because they differ in regard to patterns of presentation, survival, and disease progression [75].

Evaluation — The diagnosis of both overt PMF and pre-PMF requires bone marrow biopsy (including semiquantitative evaluation of fibrosis) and molecular analysis. It is our practice to include the following in the initial evaluation of a patient with suspected PMF:

Clinical – Focused history including an assessment of constitutional symptoms, disease tempo (with prior blood counts when available), prior transfusions, thrombotic/hemorrhagic events, and cardiovascular risk factors. Physical examination should include an assessment of spleen size by palpation.

Laboratory – Laboratory studies include a complete blood count with differential and review of the peripheral smear, chemistries with liver and renal function and electrolytes, lactate dehydrogenase (LDH), and uric acid. Peripheral blood fluorescence in situ hybridization (FISH) or reverse transcription polymerase chain reaction (RT-PCR) for BCR::ABL1 is sent to exclude chronic myeloid leukemia.

Bone marrow examination – Unilateral bone marrow aspirate and biopsy. This sample should be sent for pathologic review with trichrome and reticulin stains, cytogenetics, and molecular testing for JAK2 mutations. If JAK2 testing is negative, molecular testing is performed for CALR and MPL mutations. If these are negative and the diagnosis is still suspected, identification of other gene mutations may offer proof of clonality (ASXL1, EZH2, TET2, IDH1/IDH2, SRSF2, or SR3B1 mutation).

Diagnostic criteria — Diagnostic criteria distinguish overt PMF from early/prefibrotic PMF [76,77].

Overt PMF — Diagnosis of overt PMF requires all three of the following major criteria and at least one minor criterion (table 3) [76,77]:

Major criteria:

Megakaryocytic proliferation and atypia, accompanied by either reticulin and/or collagen fibrosis grades 2 or 3 (table 2).

WHO criteria for polycythemia vera (PV), essential thrombocythemia (ET), chronic myeloid leukemia (CML), myelodysplastic syndrome (MDS), or other myeloid neoplasm not met.

Demonstration of a JAK2, CALR, or MPL mutation or another clonal marker (ASXL1, EZH2, TET2, IDH1/IDH2, SRSF2, or SR3B1 mutation) or no identifiable cause of reactive fibrosis (eg, infection, autoimmune disorder, chronic inflammatory disorder, hairy cell leukemia or other lymphoid neoplasm, metastatic malignancy, or chronic toxic myelopathy).

Minor criteria (confirmed in two consecutive measurements):

Anemia not attributable to a comorbid condition

Leukocytosis ≥11 x 109/L (>11,000/microL)

Palpable splenomegaly

LDH above the upper limit of normal

Leukoerythroblastosis

Pre-PMF — Diagnosis of early/prefibrotic PMF requires all three of the following major criteria and at least one minor criterion (table 4) [76,77]. The diagnosis can be challenging as the presentation can mimic that of ET.

Major criteria:

Megakaryocytic proliferation and atypia, without reticulin fibrosis >grade 1, accompanied by increased age-adjusted bone marrow cellularity, granulocyte proliferation, and often decreased erythropoiesis. Grade 1 myelofibrosis is a loose network of reticulin with many intersections, especially in perivascular areas (table 2).

Criteria for PV, ET, CML, MDS, or other myeloid neoplasm not met.

Demonstration of a JAK2, CALR, or MPL mutation or another clonal marker (ASXL1, EZH2, TET2, IDH1/IDH2, SRSF2, or SR3B1 mutation) or no identifiable cause of reactive fibrosis (eg, infection, autoimmune disorder, chronic inflammatory disorder, hairy cell leukemia or other lymphoid neoplasm, metastatic malignancy, or chronic toxic myelopathy).

Minor criteria (must be confirmed in two consecutive measurements):

Anemia not attributable to a comorbid condition

Leukocytosis ≥11 x 109/L (>11,000/microL)

Palpable splenomegaly

LDH above the upper limit of normal

Distinction of pre-PMF from overt PMF is important because patients who present with pre-PMF have different patterns of clinical presentation, survival, and disease progression [75].

DIFFERENTIAL DIAGNOSIS — There are several other causes of bone marrow fibrosis that should be considered before the diagnosis of PMF is confirmed. PMF must be distinguished from rare cases of acute myelofibrosis and from other causes of chronic myelofibrosis.

Acute myelofibrosis — Acute myelofibrosis is a very rare form of acute myeloid leukemia (AML). It is characterized by the rapid onset of severe bone marrow fibrosis associated with fever and pancytopenia, teardrop-shaped red blood cells, and a leukoerythroblastic blood picture [78,79]. However, unlike PMF, the spleen is often not palpable in acute myelofibrosis and in some instances the bone marrow may show excess megakaryoblasts, suggesting a diagnosis of acute megakaryoblastic leukemia (FAB classification M7). This distinction is critical since the appropriate treatment for acute myelofibrosis is induction chemotherapy with or without hematopoietic cell transplantation. (See "Acute myeloid leukemia: Classification".)

Other chronic myeloid disorders — PMF must be distinguished from other chronic myeloid disorders that may also be accompanied by substantial bone marrow fibrosis. These include polycythemia vera (PV), essential thrombocythemia (ET), chronic myeloid leukemia (CML), myelodysplastic syndrome (MDS), myelodysplastic/myeloproliferative neoplasms (MDS/MPN), and mast cell disease [47,80-84]. It is therefore imperative that careful morphologic and cytogenetic examination be carried out before a diagnosis of PMF is made [50,51]:

Demonstration of the Philadelphia (Ph) chromosome by conventional cytogenetics or the BCR::ABL1 fusion signal by molecular genetics testing (FISH, PCR, sequencing) mandates a diagnosis of CML. (See "Molecular genetics of chronic myeloid leukemia".)

The presence of dyserythropoiesis (dysplastic bone marrow hyperplasia or even occasional hypoplasia, associated with variable degrees of peripheral blood cytopenia with or without monocytosis) suggests a diagnosis of MDS, especially in the absence of splenomegaly [81,82]. Chronic myelomonocytic leukemia (CMML) has features of both MDS and MPN, with dysplastic changes, monocytosis, hepatosplenomegaly, and lymphadenopathy. (See "Chronic myelomonocytic leukemia: Clinical features, evaluation, and diagnosis" and "Clinical manifestations, diagnosis, and classification of myelodysplastic syndromes (MDS)", section on 'Diagnosis'.)

The traditional group of Ph-negative chronic myeloproliferative neoplasms includes PMF, PV, and ET. Among these three disorders, PV is readily identified by the presence of an increased red cell mass. The differentiation between PMF and ET is dependent primarily on bone marrow morphology, the degree of bone marrow fibrosis and splenomegaly, and the presence of peripheral blood leukoerythroblastosis in PMF [85]. (See "Clinical manifestations and diagnosis of polycythemia vera".)

Early/prefibrotic PMF can mimic ET in its presentation; careful morphologic examination is necessary for distinguishing between the two (table 5 and table 4). Megakaryocytes are large and mature-appearing in ET, while those in prefibrotic PMF display abnormal maturation with hyperchromatic and irregularly folded nuclei [86,87]. This distinction is important since, in two studies, thrombotic complications, overall survival, leukemic transformation, and rates of progression to overt myelofibrosis were significantly worse in prefibrotic PMF [88,89]. (See 'Pre-PMF' above.)

Secondary myelofibrosis (post-PV or post-ET) — Patients with PV and ET can develop bone marrow fibrosis mimicking that of PMF. An International Working Group for Myelofibrosis Research and Treatment proposed the following criteria for the diagnosis of post-PV and post-ET myelofibrosis [90]:

Major criteria (both required):

Documentation of a previous diagnosis of either PV or ET as defined by WHO criteria

Presence of increased bone marrow fibrosis

Minor criteria (at least two required):

Progressive anemia or loss of phlebotomy requirement

Leukoerythroblastic blood picture

Increasing degree of splenomegaly

Development of constitutional symptoms (ie, weight loss, night sweats, unexplained fever)

Increased serum LDH (post-ET myelofibrosis only)

Other hematologic conditions — Other hematologic conditions associated with bone marrow fibrosis include hairy cell leukemia, lymphoma, and multiple myeloma [91-94].

A small percentage of patients with immune thrombocytopenia (ITP) will develop marrow fibrosis after treatment with the thrombopoiesis-stimulating agents romiplostim and eltrombopag [95]. (See "Second-line and subsequent therapies for immune thrombocytopenia (ITP) in adults", section on 'TPO receptor agonists'.)

Non-hematologic conditions — Non-hematologic causes of bone marrow fibrosis are rare and include the following:

Malignancy metastatic to the bone marrow [96-98]

Autoimmune disorders (eg, systemic lupus erythematosus, scleroderma, mixed connective tissue disease, polymyositis) and primary pulmonary hypertension [99-106]

Secondary hyperparathyroidism associated with vitamin D deficiency [107,108] or renal osteodystrophy [109-111]

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Myeloproliferative neoplasms".)

SUMMARY

Description – Primary myelofibrosis (PMF) is a myeloproliferative neoplasm (MPN) characterized by a leukoerythroblastic blood smear, proliferation of abnormal bone marrow megakaryocytes and granulocytes, variable marrow fibrosis, and extramedullary hematopoiesis with marked splenomegaly.

Epidemiology – PMF usually presents in middle-aged and older adults. (See 'Epidemiology' above.)

Clinical presentation – Severe fatigue is most common, but some patients have symptoms from an enlarged spleen, weight loss, constitutional symptoms, pulmonary hypertension, pruritus, or thrombosis; a minority of patients are asymptomatic. (See 'Signs and symptoms' above.)

Laboratory – Anemia is present in half of patients. White blood cell (WBC) and platelet counts are variable; some patients have marked leukocytosis and/or thrombocytosis, while others have leukopenia and/or thrombocytopenia. Immature neutrophils are present as part of the leukoerythroblastic blood picture and myeloblasts may be seen on the blood smear. (See 'Laboratory findings' above.)

Pathology – Bone marrow is often difficult to aspirate, yielding a "dry" tap.

Bone marrow biopsy demonstrates fibrosis (picture 4), which is best visualized with silver stain (reticulin) or trichrome stain (mature collagen) (picture 5). (See 'Bone marrow biopsy' above.)

Molecular abnormalitiesJAK2 mutation is present in two-thirds of patients, CALR mutation in one-quarter, MPL mutation in 5 percent, and "triple negative" disease (ie, no JAK2, CALR, or MPL mutation) in 10 percent.

When to suspect PMF – PMF should be suspected in a patient with splenomegaly with circulating granulocyte precursors (myelocytes, metamyelocytes, and blasts), nucleated red blood cells (RBCs), and teardrop-shaped RBCs in peripheral blood. (See 'Suspecting PMF' above.)

Diagnosis – PMF diagnosis requires all of the following (table 3 and table 4 and table 2) (see 'Diagnostic criteria' above):

Bone marrow – Megakaryocyte proliferation and atypia, usually accompanied by reticulin and/or collagen fibrosis.

Exclude other MPNs – Criteria for polycythemia vera (PV), chronic myeloid leukemia (CML), myelodysplastic syndrome (MDS), or other myeloid neoplasm are not met.

Clonality – Demonstration of JAK2, CALR, or MPL mutation or another clonal marker.

Minor criteria – At least one of the following:

-WBC ≥11 x 109/L

-Palpable splenomegaly

-Anemia not attributable to another condition

-Increased serum lactate dehydrogenase (LDH)

-Leukoerythroblastosis

Classification – Criteria to distinguish prefibrotic PMF from overt PMF, based on the degree of fibrosis (table 2) and leukoerythroblastosis are described. (See 'Overt PMF' above and 'Pre-PMF' above.)

Differential diagnosis – PMF must be distinguished from rare cases of acute myelofibrosis, other causes of chronic myelofibrosis, and other MPNs. (See 'Differential diagnosis' above.)

ACKNOWLEDGMENT — The editors of UpToDate acknowledge the contributions of Stanley L Schrier, MD as Section Editor on this topic, his tenure as the founding Editor-in-Chief for UpToDate in Hematology, and his dedicated and longstanding involvement with the UpToDate program.

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Topic 4529 Version 43.0

References

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