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1326 Part X: Malignant Myeloid Diseases Chapter 86: Primary Myelofibrosis 1327

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inversion occurs in approximately 3 percent of patients. The del(13) almost 100 percent cellularity and usually no or very slight fibrosis. In
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and der(6)t(1;6)(q21–23;p21.3) are associated with myelofibrosis but myelofibrosis, the marrow has mildly increased cellularity or is hypocel-
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are not exclusively seen in patients with primary myelofibrosis. Aneu- lular, with moderate to marked reticulin fibrosis. Occasionally, patients
ploidy as a result of monosomy or trisomy is common. Pseudodiploidy, with CML develop intense marrow fibrosis and dysmorphic blood cell
manifested by partial deletions and translocations, occurs. Patients with changes that make distinction between the two diseases difficult on
the clinical features of typical primary myelofibrosis very rarely have the merely morphological grounds. However, the Ph chromosome or the
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Philadelphia (Ph) chromosome in their marrow cells. Approximately BCR-ABL fusion gene is present in CML and is absent in primary mye-
15 percent of patients present with unfavorable karyotypes, including lofibrosis; whereas, the JAK2 V617F or the CALR, or the MPL mutation is
three or more abnormalities, +9, –7/7q–, 5/5q–, i(17q), inv(3), 12p–, or present in approximately 90 percent of cases of primary myelofibrosis
11q23. An unfavorable karyotype is associated with a sixfold greater risk and absent in CML. Most cases are readily separable based on the afore-
of acute leukemic transformation than a favorable karyotype. With mentioned distinctions.
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increasing knowledge of the chromosomes commonly affected, inter- Patients with primary myelofibrosis may have pancytopenia or
phase FISH of blood cells is used to look for prevalent abnormalities, bicytopenia and in that respect mimic patients with oligoblastic mye-
compensating for the technical difficulties of harvesting cell suspen- logenous leukemia (myelodysplasia [MDS]; Chap. 87). Contrariwise,
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sions, given the intense marrow fibrosis. Clonal chromosomal abnor- patients with oligoblastic leukemia rarely have intense fibrosis. Prom-
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malities found in hematopoietic cells have not been observed in marrow inent splenomegaly is expected in patients with primary myelofibro-
fibroblasts. 139 sis but not in patients with oligoblastic myelogenous leukemia, which
helps to distinguish the former from the latter patients. The absence of
Magnetic Resonance Imaging a high frequency of teardrop-shaped red cells, nucleated red cells, and
Marrow fibrosis alters the hyperintensity of T1-weighted images that striking anisopoikilocytosis in the blood film mitigates against primary
normally results from marrow fat. As cellularity and fibrosis progress, myelofibrosis.
hypointensity of T1-weighted and T2-weighted images develops. MRI Because some patients with primary myelofibrosis have platelet
does not distinguish between primary myelofibrosis and secondary counts greater than 450,000/μL (450 × 10 /L), the diagnosis of primary
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causes of fibrosis, 264,323,324 but the clinical distinctions usually are very thrombocythemia may be considered. Moreover, some patients may be
evident from the results of prior physical, blood, and marrow examina- in transition from thrombocythemia to myelofibrosis. The anisopoiki-
tions and the evidence for mutations in JAK2, CALR, or MPL. Patchy or locytosis, nucleated red cells, and myeloid immaturity in the blood film
diffuse osteosclerosis is a common finding, as are “sandwich vertebrae,” characteristic of myelofibrosis are not present in patients with thrombo-
so called because of marked radiodensity of superior and inferior mar- cythemia. Marrow fibrosis usually is insignificant in thrombocythemia,
gins of the vertebral body. MRI can identify the uncommon periosteal and splenic enlargement often is absent or slight. For these reasons, a
reactions that usually occur in the distal femur, proximal tibia, or ankle. clear distinction usually exists between the two disorders. 279,339 The
The reactions represent expansion of marrow cellularity into normally prefibrotic phase of primary myelofibrosis may mimic essential throm-
inactive regions of long bones or extramedullary space-occupying bocythemia, but the more prominent splenomegaly and the more dis-
lesions of fibrohematopoietic tissue. The findings of sodium fluoride ordered and characteristic dysmorphic megakaryopoiesis in primary
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( F) positron emission tomography can be virtually specific for osteo- myelofibrosis can be used to distinguish the two entities by an experi-
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sclerosis of primary myelofibrosis. 325 enced hematopathologist. Careful observation of disease evolution is,
also, important. 341
PLASMA AND URINE CHEMICAL CHANGES Hairy cell leukemia (Chap. 93), when associated with shape
Serum levels of uric acid, lactic dehydrogenase, bilirubin, alkaline phos- abnormalities of red cells, pancytopenia, splenomegaly, and fibrotic
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Usually, careful
marrow, can closely mimic primary myelofibrosis.
phatase, and high-density lipoprotein frequently are elevated. 8–16 Serum scrutiny of the blood and marrow by microscopy, histochemistry, and
cholesterol is often decreased and is a negative prognostic factor. 326–328 cell immunophenotype shows evidence of the abnormal mononuclear
Serum levels of albumin and cholesterol frequently are decreased. (hairy) cells characteristic of the disease.
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Hypocalcemia or hypercalcemia may occur. Plasma levels of throm- Hepatic disease can be associated with cytopenias and sple-
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bopoietin and IL-6 are elevated but do not correlate with either platelet nomegaly, although the specific blood and marrow findings usually
or megakaryocyte mass. 332,333 Elevated thrombopoietin is not explained make the distinction with primary myelofibrosis obvious. In a review
by increased marrow hematopoietic or stromal cell production. of 170 cases of splenomegaly in a county hospital, hepatic disease was
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Serum-soluble IL-2 receptor and serum VEGF levels are increased. the second most common cause of massive splenomegaly after primary
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Urinary excretion of calmodulin is approximately three times normal. myelofibrosis. 343
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The serum contains evidence of increased collagen (see Table 86–1) and Primary autoimmune myelofibrosis is characterized by intense
bone (see Table 86–2) synthesis. marrow fibrosis and an increase in marrow polyclonal T and B lym-
phocytes. 344,345 Serologic or clinical evidence of lupus erythematosus or
DIFFERENTIAL DIAGNOSIS other connective tissue diseases is absent, giving primary autoimmune
myelofibrosis a definitive diagnostic niche. Cytopenias that occur may
CML (Chap. 89) should be considered in the differential diagnosis of be immune mediated (e.g., immune hemolytic disease), and the blood
primary myelofibrosis. In CML, the white cell count is usually greater cell findings (anisopoikilocytosis, nucleated red cells, myeloid imma-
than 30,000/μL (30 × 10 /L) in almost all patients and greater than turity) characteristic of primary myelofibrosis usually are absent. The
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100,000/μL (100 × 10 /L) in half of patients. In myelofibrosis, the white marrow may be cellular with increased megakaryocytes, but strikingly
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cell count usually is less than 30,000/μL (30 × 10 /L) at the time of diag- dysmorphic megakaryocytopoiesis is absent. Splenomegaly, a nearly
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nosis. In CML, red cell shape usually is normal or slightly perturbed. In constant feature of primary myelofibrosis, usually is absent. Polyclonal
myelofibrosis, teardrop poikilocytes are present in every oil immersion hyperglobulinemia may be present.
field and exaggerated anisocytosis and anisochromia are often promi- Patients with sporadic idiopathic or familial pulmonary hyperten-
nent. The marrow in CML shows intense granulocytic hyperplasia, with sion have significant marrow fibrosis. They can be distinguished from

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