Clinical Manifestations and Diagnosis of Primary Myelofibrosis

2/5/2018 Clinical manifestations and diagnosis of primary myelofibrosis - UpToDate
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Clinical manifestations and diagnosis of primary myelofibrosis
Author: Ayalew Tefferi, MD

Section Editor: Stanley L Schrier, MD
Deputy Editor: Alan G Rosmarin, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Apr 2018. | This topic last updated: Jun 30, 2017.
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 "Classification of acute myeloid leukemia",
section on 'Acute panmyelosis with myelofibrosis'.)
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 "Management of primary myelofibrosis" 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].
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● 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 (ET) (1 to 3 per 100 patient-years),
and significantly lower than that seen in polycythemia vera (PV) (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. (See "Management of primary myelofibrosis", section on
'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 "Prognosis and treatment of essential thrombocythemia", section
on 'Extreme thrombocytosis'.)
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 magnetic resonance imaging (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. (See "Prognosis of primary myelofibrosis", section
on 'JAK2, calreticulin, and MPL mutational burden'.)
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 "Management of primary

myelofibrosis", section on 'Transformation to acute leukemia'.)
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].
Diagnostic 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:
● 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 studies including 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.
● 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).
WHO diagnostic criteria: overt PMF — Diagnosis of overt PMF by the 2016 WHO criteria requires all three of
the following major criteria and at least one minor criterion (table 3) [72]:
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 (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
● Leukoerythroblastosis
WHO diagnostic criteria: pre-PMF — The diagnosis of early prefibrotic PMF (pre-PMF) can be challenging as
the presentation can mimic that of ET. WHO criteria require all three of the following major criteria and at least
one minor criterion (table 4) [72]:
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).
● WHO 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 [76,77]. 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 "Classification of acute myeloid leukemia".)
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 [47,78-82]. 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 [79,80]. Chronic myelomonocytic leukemia
(CMML) has features of both MDS and MPN, with dysplastic changes, monocytosis, hepatosplenomegaly,
and lymphadenopathy. (See "Clinical manifestations and diagnosis of the myelodysplastic syndromes",
section on 'Chronic myelomonocytic leukemia' and "Chronic myelomonocytic leukemia".)
● 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 [83].
(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
[84,85]. 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 [86,87]. (See 'WHO diagnostic criteria: pre-PMF' above.)
Myelofibrosis following PV or ET — Patients with polycythemia vera (PV) and essential thrombocythemia (ET)
can develop bone marrow fibrosis mimicking that of PMF. An International Working Group for Myelofibrosis
Research and Treatment has proposed the following criteria for the diagnosis of post-PV and post-ET
myelofibrosis [88]:
Major criteria (both required):
● Documentation of a previous diagnosis of either PV or ET as defined by World Health Organization 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 lactate dehydrogenase (post-ET myelofibrosis only)
Other hematologic conditions — Other hematologic conditions associated with bone marrow fibrosis include
hairy cell leukemia, lymphoma, and multiple myeloma [89-92].
A small percentage of patients with immune thrombocytopenia (ITP) will develop marrow fibrosis after treatment
with the thrombopoiesis-stimulating agents romiplostim and eltrombopag [93]. (See "Immune thrombocytopenia
(ITP) in adults: Second-line and subsequent therapies", section on 'Thrombopoietin receptor agonists'.)
Non-hematologic conditions — Non-hematologic causes of bone marrow fibrosis are rare and include the
following:
● Malignancy metastatic to the bone marrow [94-96]
● Autoimmune disorders (eg, systemic lupus erythematosus, scleroderma, mixed connective tissue disease,
polymyositis) and primary pulmonary hypertension [97-104]
● Secondary hyperparathyroidism associated with vitamin D deficiency [105,106] or renal osteodystrophy

[107-109]
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
disorders".)
SUMMARY
● Primary myelofibrosis (PMF) is an uncommon myeloproliferative neoplasm that usually presents in middle
aged and older adults. (See 'Epidemiology' above.)
● PMF is a clonal disorder characterized by myeloproliferation in the bone marrow, atypical megakaryocyte
hyperplasia, and bone marrow fibrosis resulting in impaired medullary hematopoiesis and increased
extramedullary hematopoiesis with marked splenomegaly and a leukoerythroblastic peripheral smear. (See
'Clinical manifestations' above and 'Laboratory findings' above.)
● PMF should be suspected in a patient presenting with splenomegaly along with granulocyte precursors
(myelocytes, metamyelocytes, and blasts), nucleated red cells, and teardrop-shaped red cells in the
peripheral blood. (See 'Suspecting PMF' above.)
● Evaluation of a patient with suspected PMF includes an assessment of the disease tempo, review of the
peripheral smear, and a bone marrow aspiration and biopsy with molecular testing to confirm a clonal
disease and rule out chronic myeloid leukemia and other myeloproliferative neoplasms. (See 'Diagnostic
evaluation' above.)
● The diagnosis of PMF is made in patients who meet all of the following four criteria (table 3 and table 4 and
table 2) (see 'Diagnosis' above):
• Presence of megakaryocyte proliferation and atypia on bone marrow examination, usually accompanied
by reticulin and/or collagen fibrosis
• World Health Organization (WHO) criteria for polycythemia vera (PV), chronic myeloid leukemia (CML),
myelodysplastic syndrome (MDS), or other myeloid neoplasm not met
• Demonstration of a clonal marker (eg, JAK2, CALR, or MPL mutation)
• At least one of the following minor criteria:
- Leukocytosis ≥11 x 109/L
- Palpable splenomegaly
- Anemia not attributable to another condition
- Increased serum lactate dehydrogenase level
- Leukoerythroblastosis
The WHO subclassifies patients with PMF into those with overt PMF and those with prefibrotic PMF based
on the degree of fibrosis. (See 'WHO diagnostic criteria: overt PMF' above and 'WHO diagnostic criteria: pre-
PMF' above.)
● PMF must be distinguished from rare cases of acute myelofibrosis and from other causes of chronic
myelofibrosis. (See 'Differential diagnosis' above.)
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Topic 4529 Version 35.0
GRAPHICS
Clinical and laboratory features of 1000 consecutive patients with primary

myelofibrosis
Feature Result (percent)
Median age, years (range) 65 (14 to 92)
Males 62
Constitutional symptoms 34
Spleen >10 cm below left costal margin 31
Red cell transfusions required 38
Hemoglobin <10 g/dL 54
White blood cell count >25,000/microL 16
White blood cell count <4000/microL 16
Platelet count <100,000/microL 26
Circulating blasts ≥1 percent 56
JAK2 V617F mutation present 61
MPL mutation present 8
IDH mutation present 4
Data from: Tefferi A, Lasho TL, Jimma T, et al. One thousand patients with primary myelofibrosis: the Mayo Clinic experience.
Mayo Clin Proc 2012; 87:25.
Graphic 75473 Version 1.0
Leukoerythroblastic peripheral blood smear
Leukoerythroblastic peripheral blood smear showing the presence of nucleated

red cells and immature white cells. This pattern occurs with marrow
replacement, usually due to fibrosis that may be idiopathic (eg, primary
myelofibrosis) or reactive to conditions such as metastatic cancer.
Courtesy of Carola von Kapff, SH (ASCP).
Normal peripheral blood smear
High-power view of a normal peripheral blood smear. Several platelets

(arrows) and a normal lymphocyte (arrowhead) can also be seen. The red
cells are of relatively uniform size and shape. The diameter of the normal red
cell should approximate that of the nucleus of the small lymphocyte; central
pallor (dashed arrow) should equal one-third of its diameter.
Teardrop-shaped red blood cells (dacrocytes)
This peripheral smear from a patient with bone marrow fibrosis shows numerous
teardrop-shaped red cells (arrows). Note that the teardrops are pointed in
several different directions, ruling out an artifact due to preparation of the
smear.

Megaloblastic blood picture
Peripheral blood smear showing a hypersegmented neutrophil (seven lobes) and

macro-ovalocytes, a pattern that can be seen with cobalamin or folate
deficiency.
Courtesy of Stanley L Schrier, MD.

Myelofibrosis bone marrow biopsy
Bone marrow biopsy in myelofibrosis shows replacement of the marrow with

fibrous tissue.
Normal bone marrow biopsy at low power
Low power view of a normal bone marrow biopsy. The overall cellularity is
between 30 and 70 percent, with the remainder of the space being occupied
by fat and stroma.
Bone marrow biopsy in primary myelofibrosis stained for

collagen
Bone marrow biopsy from a patient with primary myelofibrosis stained for
collagen (trichrome stain). The marrow cavity (arrows) is traversed by blue-
staining collagen bands.
Courtesy of Stephen A Landaw, MD.
WHO grading myelofibrosis
Grade Definition
MF-0 Scattered linear reticulin with no intersections (crossovers) corresponding to normal bone marrow
MF-1 Loose network of reticulin with many intersections, especially in perivascular areas
MF-2 Diffuse and dense increase in reticulin with extensive intersections, occasionally with focal bundles of
thick fibers mostly consistent with collagen, and/or focal osteosclerosis*
MF-3 Diffuse and dense increase in reticulin with extensive intersections and coarse bundles of thick fibers
consistent with collagen, usually associated with osteosclerosis*
Semiquantitative grading of bone marrow fibrosis with minor modifications concerning collagen and osteosclerosis.
Fiber density should be assessed only in hematopoietic areas.
MF: myelofibrosis.
* In grades MF-2 or MF-3 an additional trichrome stain is recommended.
Republished with permission of the American Society of Hematology, from Arber DA, Orazi A, Hasserjian R, et al. The 2016
revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 2016; 127:2391.
Copyright © 2016; permission conveyed through Copyright Clearance Center, Inc.
WHO diagnostic criteria overt primary myelofibrosis
Major criteria
1. Presence of megakaryocytic proliferation and atypia, 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
marker,* or absence of reactive myelofibrosis ¶
Minor criteria
Presence of at least 1 of the following, confirmed in 2 consecutive determinations:
a. Anemia not attributed to a comorbid condition
b. Leukocytosis ≥11 × 10 9/L
c. Palpable splenomegaly
d. LDH increased to above upper normal limit of institutional reference range
e. Leukoerythroblastosis
Diagnosis of overt PMF requires meeting all 3 major criteria, and at least 1 minor criterion
CML: chronic myeloid leukemia; ET: essential thrombocythemia; LDH: lactate dehydrogenase; PMF: primary myelofibrosis;
PV: polycythemia vera
* In the absence of any of the 3 major clonal mutations, the search for the most frequent accompanying mutations (eg,
ASXL1, EZH2, TET2, IDH1/IDH2, SRSF2, SF3B1) are of help in determining the clonal nature of the disease.
¶ Bone marrow fibrosis secondary to infection, autoimmune disorder, or other chronic inflammatory conditions, hairy cell
leukemia or other lymphoid neoplasm, metastatic malignancy, or toxic (chronic) myelopathies.
WHO diagnostic criteria pre-primary myelofibrosis
Major criteria
1. Megakaryocytic proliferation and atypia, without reticulin fibrosis >grade 1, accompanied by increased age-
adjusted bone marrow cellularity, granulocytic proliferation, and often decreased erythropoiesis
2. Not meeting the WHO criteria for BCR-ABL1 + CML, PV, ET, 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
marker,* or absence of minor reactive bone marrow reticulin fibrosis ¶
Minor criteria
Presence of at least 1 of the following, confirmed in 2 consecutive determinations:
a. Anemia not attributed to a comorbid condition
b. Leukocytosis ≥11 × 10 9/L
c. Palpable splenomegaly
d. LDH increased to above upper normal limit of institutional reference range
Diagnosis of prePMF requires meeting all 3 major criteria, and at least 1 minor criterion
CML: chronic myeloid leukemia; ET: essential thrombocythemia; PMF: primary myelofibrosis; PV: polycythemia vera; WHO:
World Health Organization
* In the absence of any of the 3 major clonal mutations, the search for the most frequent accompanying mutations (eg,
ASXL1, EZH2, TET2, IDH1/IDH2, SRSF2, SF3B1) are of help in determining the clonal nature of the disease.
¶ Minor (grade 1) reticulin fibrosis secondary to infection, autoimmune disorder or other chronic inflammatory conditions,
hairy cell leukemia or other lymphoid neoplasm, metastatic malignancy, or toxic (chronic) myelopathies.
Clump of tumor cells in the bone marrow
Bone marrow aspirate from a patient with carcinoma metastatic to the bone
marrow, illustrating the presence of a large clump of tumor cells (arrow),
surrounded by normal marrow elements. Note that the cellular outlines within
the clump of tumor cells are indistinct. This is not a characteristic of any group
of cells normally seen in the bone marrow.
Courtesy of David S Rosenthal, MD and Anna J Mitus, MD.
WHO diagnostic criteria essential thrombocythemia
Major criteria
1. Platelet count ≥450 × 10 9/L
2. Bone marrow biopsy showing proliferation mainly of the megakaryocyte lineage with increased numbers of
enlarged, mature megakaryocytes with hyperlobulated nuclei. No significant increase or left shift in neutrophil
granulopoiesis or erythropoiesis and very rarely minor (grade 1) increase in reticulin fibers.
3. Not meeting WHO criteria for BCR-ABL1 + CML, PV, PMF, myelodysplastic syndromes, or other myeloid neoplasms
4. Presence of JAK2, CALR, or MPL mutation
Minor criterion
1. Presence of a clonal marker or absence of evidence for reactive thrombocytosis
Diagnosis of ET requires meeting all 4 major criteria or the first 3 major criteria and the minor criterion
CML: chronic myeloid leukemia; ET: essential thrombocythemia; PMF: primary myelofibrosis; PV: polycythemia vera; WHO:
World Health Organization
Contributor Disclosures
Ayalew Tefferi, MD Nothing to disclose Stanley L Schrier, MD Nothing to disclose Alan G Rosmarin,
MD Nothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must conform to
UpToDate standards of evidence.
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Clinical Manifestations and Diagnosis of Primary Myelofibrosis - UpToDate

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Clinical Manifestations and Diagnosis of Primary Myelofibrosis - UpToDate

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2/5/2018 Clinical manifestations and diagnosis of primary myelofibrosis - UpToDate

Official reprint from UpToDate®

Author: Ayalew Tefferi, MD

Hepatomegaly — Palpable hepatomegaly is present in 40 to 70 percent of patients. Portal hypertension may

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

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

● Periostitis can lead to debilitating bony pain.

● Reduction in medullary erythropoietic sites

● Splenic sequestration and destruction of circulating RBCs

● Influence of thrombopoietin receptor (Mpl) mutations [38]

● 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

TRANSFORMATION TO ACUTE LEUKEMIA — Acute leukemia occurs as a terminal event in a minority of

● Circulating blasts ≥3 percent

● Platelet count <100,000/microL

Management of leukemic transformation of PMF is discussed separately. (See "Management of primary

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

● Anemia not attributable to a comorbid condition

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

● LDH above the upper limit of normal

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

● Anemia not attributable to a comorbid condition

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

● LDH above the upper limit of normal

thrombocythemia (ET), chronic myeloid leukemia (CML), myelodysplastic syndrome (MDS),

Major criteria (both required):

● Documentation of a previous diagnosis of either PV or ET as defined by World Health Organization 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

● Increased serum lactate dehydrogenase (post-ET myelofibrosis only)

● Malignancy metastatic to the bone marrow [94-96]

● Secondary hyperparathyroidism associated with vitamin D deficiency [105,106] or renal osteodystrophy

• Demonstration of a clonal marker (eg, JAK2, CALR, or MPL mutation)

• At least one of the following minor criteria:

- Leukocytosis ≥11 x 109/L

- Anemia not attributable to another condition

- Increased serum lactate dehydrogenase level

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Topic 4529 Version 35.0

Clinical and laboratory features of 1000 consecutive patients with primary

Feature Result (percent)

Median age, years (range) 65 (14 to 92)

Spleen >10 cm below left costal margin 31

Red cell transfusions required 38

Hemoglobin <10 g/dL 54

White blood cell count >25,000/microL 16

White blood cell count <4000/microL 16

Platelet count <100,000/microL 26

Circulating blasts ≥1 percent 56

JAK2 V617F mutation present 61

MPL mutation present 8

IDH mutation present 4

Graphic 75473 Version 1.0

Leukoerythroblastic peripheral blood smear

Leukoerythroblastic peripheral blood smear showing the presence of nucleated

Courtesy of Carola von Kapff, SH (ASCP).

Graphic 68110 Version 3.0

Normal peripheral blood smear