- Summary Primary myelofibrosis .
- Presenting Symptoms of Primary myelofibrosis
- Laboratory Features of Primary myelofibrosis
- Treatment of Primary myelofibrosis
Blood Cell Counts and Morphology of Primary myelofibrosis
The range of values for blood cell counts at the time of diagnosis is very broad. Normocytic–normochromic anemia is present in most, but not all, patients (see Table 91–2).7–15,262–265 Mean hemoglobin concentration in a series of patients at diagnosis is approximately 9.0 to 12.0 g/dL (range: 4–20 g/dL).7–15,264,265 Anisocytosis and poikilocytosis are a constant finding. In all cases, teardrop-shaped red cells (dacryocytes) are present in sufficient number to be found in every oil immersion field (Fig. 91–1). Nucleated red cells are present in the blood film of most patients and average 2 percent of nucleated cells (range: 0–30%). The percentage of reticulocytes is mildly increased but may vary widely in a given case. Anemia may be worsened by expansion of plasma volume and a higher than normal proportion of the red cell volume in an enlarged spleen. Ineffective erythropoiesis can result in a decrease in red cell mass.262 Erythroid hypoplasia is present in many patients.266,267 In some patients, hemolysis may be prominent, and polychromatophilia and very elevated reticulocyte counts can occur.263,264 The antiglobulin (Coombs) test usually is negative, but red cell autoantibodies can develop and lead to immune-mediated hemolysis,222,223,268 which rarely has been the presenting finding of the disease.224 Occasional patients have a positive acid hemolysis and sucrose hemolysis test, reflecting a concurrent clone of cells consistent with paroxysmal nocturnal hemoglobinuria.269 Acquired hemoglobin H disease, coincident with typical white cells and platelet changes of myelofibrosis, can occur270 and results in hemolysis, hypochromic–microcytic red cells, marked poikilocytosis, and hemoglobin H inclusions that stain with brilliant cresyl blue. Red cell aplasia, in association with myelofibrosis, has been observed.265,271
The total white cell count usually is mildly elevated as a result of granulocytosis.7–15 The mean total blood white cell count was 10,000 to 14,000/L (10 to 14 x 109/L) in four large studies. The range of white cell counts was 400 to 237,000/L (0.4 to 237 x 109/L) at the time of diagnosis.7–14,263,264 Myelocytes and promyelocytes are present in small proportions in most patients, and a low proportion of blast cells (0.5–2%) may be found in the blood film. The blood blast cells range from 0 to 20 percent at the time of diagnosis. In patients with blast counts at the high end, which is unusual at presentation, the disease has converged with AML. Hypersegmentation, hyposegmentation (acquired Pelger-Huët anomaly), and abnormal granulation of neutrophils may be present.7–15 Neutrophil alkaline phosphatase scores may be elevated (25% of patients) or decreased (25% of patients).272 The percentage of basophils may be slightly increased.264 Neutropenia is present in approximately 20 percent of patients at the time of diagnosis.7–15
The mean platelet count in patient series range from 175,000 to 580,000/L (175 to 580 x 109/L) at the time of diagnosis. Individual platelet counts can range from 15,000 to 3,215,000/L (15.0 to 3215 x 109/L).7–15,263,264 The platelet count is elevated in approximately 40 percent of patients.264 Mild to moderate thrombocytopenia is present in approximately one-third of patients at the time of diagnosis. Giant platelets and abnormal platelet granulation are characteristic features of the disease.
Approximately 10 percent of patients present with pancytopenia because of severe impairment of hematopoiesis affecting each cell lineage, coupled with sequestration in a massively enlarged spleen. Pancytopenia usually is associated with intense marrow fibrosis.
Increased concentrations of multipotential,273,274 granulocytic,275,276 monocytic,276 erythroid,277 and megakaryocytic278 progenitor cells are present in the blood of patients, as measured by clonogenic assays in semisolid cultures. The frequency of hematopoietic progenitor cells in the blood is correlated with the extent of marrow reticular fiber density.278 Megakaryocytes also are present in the systemic venous blood.279 An increase in blood CD34+ cells is very characteristic of primary myelofibrosis, and the concentration of these cells lends weight to the diagnosis. The height of the CD34+ cell count is correlated with the extent of disease and disease progression. Greater than 15 x 106/L blood CD34+ cells is virtually diagnostic of primary myelofibrosis, and patients with greater than 300 x 106/L CD34+ cells have more rapid progression of disease than patients with fewer CD34+ cells.274
Endothelial progenitor cells (CD+CD133+ and VEGFR2-positive cells) are significantly higher in the blood of primary myelofibrosis patients than of normal subjects.78
Mild lymphocytopenia resulting from decreased CD3+, CD4+, CD8+, and CD3–/CD56+ T cells is the rule.280
Functional Abnormalities of Blood Cells
The neutrophils of some patients have impaired phagocytosis, oxygen consumption, nitroblue tetrazolium reduction, and hydrogen peroxide generation, and decreased myeloperoxidase281,282 and glutathione reductase activities.282 CD34+ cells have impaired in vitro differentiation to natural killer cells, which appear to be related to a dysregulation in control of IL-15.283
Bleeding time can be prolonged out of proportion to the platelet count.284,285 Platelet abnormalities include impaired aggregation in response to epinephrine, depletion of dense granule adenosine diphosphate content,286 decreased platelet lipoxygenase pathway activity,287 and others.288,289 The correlation of bleeding or thrombosis with platelet functional abnormalities is weak.288,289 The lupus anticoagulant has been present, rarely.230
Marrow Examination of Primary myelofibrosis
In the fibrotic phase, marrow aspiration often is unsuccessful because of the fibrosis.7–15,86,87 The marrow biopsy specimen usually is cellular and shows granulocytic and megakaryocytic hyperplasia (see Fig. 91–1).7–15,273,274 Erythroid cells may be decreased, normal, or increased in number. Silver stain usually shows an increase in reticular fibers, and in half of patients a striking increase in reticular fibers is seen.274 Hematoxylin and eosin stains of the biopsy specimen may show mild collagen fibrosis; occasionally the fibrosis is extreme (see Fig. 91–1). Collagen fibrosis may be more evident using a Gomori trichrome stain with which collagen characteristically stains green. In intensely fibrotic marrows, cellularity may be markedly decreased but megakaryocytes usually remain evident.274 Giant megakaryocytes and micromegakaryocytes, abnormal nuclear lobulation, and naked megakaryocyte nuclei are present.7–15,290 Thrombopoietin receptors are decreased on megakaryocytes and platelets.81 Granulocytes may show hyperlobulation and hypolobulation of the nucleus, acquired Pelger-Huët anomaly, nuclear blebs, and nuclear–cytoplasmic maturation asynchrony.291 Clusters of blasts and CD34-positive cells are often present. Dilated marrow sinusoids are common. Intrasinusoidal, immature hematopoietic cells, and megakaryocytes are present.86 As a reflection of the high blood flow to marrow-bearing bone and the widened sinusoidal system, microvessel density is significantly increased in approximately 70 percent of patients.291 Histomorphometric analysis of marrow biopsies permit detection of osteosclerosis,251,253,254 but imaging is more readily available (see below).
The marrow in the prefibrotic stage usually has no or slight reticular fibrosis. The marrow is cellular and there is often an increase proportion of late neutrophil precursors (myelocytes, metamyelocytes, bands). Myeloblasts and CD34-positive cells are inconspicuous. Erythropoiesis may be slightly decreased. Increased and abnormal megakaryocytopoiesis is the hallmark of this phase. Clusters of megakaryocytes are present. Megakaryocytes are large and admixed with small megakaryocytes. Nuclei are often ballooned and have scalloped margins. Bare megakaryocyte nuclei are present. Megakaryocyte involvement is facilitated by staining the marrow with a megakaryocyte marker such as CD61.
Cytogenetic Findings of Primary myelofibrosis
Chromosome abnormalities of hematopoietic cells are evident in approximately 40 to 60 percent of patients at the time of diagnosis.293–298 The most frequent findings are partial trisomy 1q, interstitial deletion of a segment of the long arm of chromosome 13, del(13)(q12-22), which bears the retinoblastoma gene,55,294–296,299 del 20q, and trisomy 8.300 Involvement of chromosome 5, 6, 7, 9, 13, 20, or 21 occurs with heightened frequency.300 The 5q– abnormality is more prevalent in primary myelofibrosis that any chronic myeloproliferative disorder. Abnormality of chromosome 12 resulting from several translocations or deletion or inversion occurs in approximately 3 percent of patients.301 The del(13) and der(6)t(1;6)(q21-23;p21.3) are associated with myelofibrosis but are not exclusively seen in patients with primary myelofibrosis.302 Aneuploidy as a result of monosomy or trisomy is common. Pseudodiploidy, manifested by partial deletions and translocations, occurs. Patients with the clinical features of typical primary myelofibrosis very, very rarely have the Ph chromosome in their marrow cells.303 With increasing knowledge of the chromosomes commonly affected, interphase FISH of blood cells is used to look for prevalent abnormalities, compensating for the technical difficulties of harvesting cell suspensions, given the intense marrow fibrosis.296 Clonal chromosomal abnormalities found in hematopoietic cells have not been observed in marrow fibroblasts.129
Magnetic Resonance Imaging
Marrow fibrosis alters the hyperintensity of T1-weighted images that normally results from marrow fat. As cellularity and fibrosis progress, hypointensity of T1-weighted and T2-weighted images develops. MRI does not distinguish between primary myelofibrosis and secondary causes of fibrosis,251,304,305 but the clinical distinctions usually are very evident from the results of prior physical, blood, and marrow examinations. Patchy or diffuse osteosclerosis is a common finding, as are “sandwich vertebrae,” so called because of marked radiodensity of superior and inferior margins of the vertebral body. MRI can identify the uncommon periosteal reactions that usually occur in the distal femur, proximal tibia, or ankle. The reactions represent expansion of marrow cellularity into normally inactive regions of long bones or extramedullary space-occupying lesions of fibrohematopoietic tissue.252 The findings of sodium fluoride (18F) positron emission tomography can be virtually specific for osteosclerosis of primary myelofibrosis.306
Plasma and Urine Chemical Changes
Serum levels of uric acid, lactic dehydrogenase, bilirubin, alkaline phosphatase, and high-density lipoprotein frequently are elevated.7–15 Serum levels of albumin and cholesterol frequently are decreased.307 Hypocalcemia308 or hypercalcemia309 may occur. Plasma levels of thrombopoietin and IL-6 are elevated but do not correlate with either platelet or megakaryocyte mass.310,311 Elevated thrombopoietin is not explained by increased marrow hematopoietic or stromal cell production.312 Serum-soluble IL-2 receptor313 and serum vascular endothelial growth factor314 levels are increased. Urinary excretion of calmodulin is approximately three times normal.120 The serum contains evidence of increased collagen (see Table 91–1) and bone (see Table 91–2) synthesis.
Differential Diagnosis of Primary myelofibrosis
CML (see Chap. 90) should be considered in the differential diagnosis of primary myelofibrosis. In CML, the white cell count is greater than 30,000/L (30 x 109/L) in almost all patients and greater than 100,000/L (100 x 109/L) in half of patients. In myelofibrosis, the white cell count usually is less than 30,000/L (30 x 109/L) at the time of diagnosis. In CML, red cell shape usually is normal or slightly perturbed. In myelofibrosis, teardrop poikilocytes are present in every oil immersion field and exaggerated anisocytosis and anisochromia are often prominent. The marrow in CML shows intense granulocytic hyperplasia, with almost 100 percent cellularity and usually no or very slight fibrosis.315 In myelofibrosis, the marrow has mildly increased cellularity or is hypocellular, with moderate to marked reticulin fibrosis. Occasionally, patients with CML develop intense marrow fibrosis and dysmorphic blood cell changes that make distinction between the two diseases difficult.301 However, the Philadelphia (Ph) chromosome or the BCR-ABL fusion gene is present in CML and absent in primary myelofibrosis; whereas, the JAK2V617F mutation is present in approximately 50 percent of cases of primary myelofibrosis and absent in CML. Most cases are readily separable based on the aforementioned distinctions.
Patients with primary myelofibrosis may have pancytopenia or bicytopenia and in that respect mimic patients with oligoblastic leukemia (myelodysplasia [MDS]; see Chap. 88). Contrariwise, patients with oligoblastic leukemia may rarely have intense fibrosis.316 Prominent splenomegaly is expected in patients with primary myelofibrosis but not in patients with oligoblastic leukemia, which helps to distinguish the former from the latter patients. The absence of a high frequency of teardrop-shaped red cells, nucleated red cells, and striking anisopoikilocytosis in the blood film mitigates against primary myelofibrosis.
Because some patients with primary myelofibrosis have platelet counts greater than 450,000/L (450 x 109/L), the diagnosis of primary thrombocythemia may be considered. The anisopoikilocytosis, nucleated red cells, and myeloid immaturity in the blood film characteristic of myelofibrosis are not present in patients with thrombocythemia. Marrow fibrosis usually is insignificant in thrombocythemia, and splenic enlargement often is absent or slight. For these reasons, a clear distinction usually exists between the two disorders.264,317 The prefibrotic phase of primary myelofibrosis may mimic essential thrombocythemia, but the more prominent splenomegaly and the more disordered megakaryopoiesis in primary myelofibrosis can be used to distinguish the two entities, as does careful observation of disease evolution.318
Hairy cell leukemia (see Chap. 95), when associated with shape abnormalities of red cells, pancytopenia, splenomegaly, and fibrotic marrow, can closely mimic primary myelofibrosis.316,319 Usually, careful scrutiny of the blood and marrow by microscopy, histochemistry, and cell immunophenotype shows evidence of the abnormal mononuclear (hairy) cells characteristic of the disease.
Hepatic disease can be associated with cytopenias and splenomegaly, although the specific blood and marrow findings usually make the distinction with primary myelofibrosis obvious. In a review of 170 cases of splenomegaly in a county hospital, hepatic disease was the second most common cause of massive splenomegaly after primary myelofibrosis.320
Primary autoimmune myelofibrosis is characterized by intense marrow fibrosis and an increase in marrow polyclonal T and B lymphocytes.321,322 Serologic or clinical evidence of lupus erythematosus or other connective tissue diseases is absent, giving primary autoimmune myelofibrosis a definitive diagnostic niche. Cytopenias that occur may be immune mediated (e.g., immune hemolytic disease), and the blood cell findings (anisopoikilocytosis, nucleated red cells, myeloid immaturity) characteristic of primary myelofibrosis usually are absent. The marrow may be cellular with increased megakaryocytes, but strikingly dysmorphic megakaryocytopoiesis is absent. Splenomegaly, a nearly constant feature of primary myelofibrosis, usually is absent. Polyclonal hyperglobulinemia may be present.
Patients with sporadic idiopathic or familial pulmonary hypertension have significant marrow fibrosis. They can be distinguished from patients with primary myelofibrosis with pulmonary hypertension by the latter’s high-circulating CD34+ cell count, the presence of clonal platelets and granulocytes, a high frequency of dacryocytes in the blood film, and a JAK2 V617F mutation.323
Metastatic carcinoma, especially derived from carcinoma of breast or prostate324–329 or disseminated mycobacterial infection,330,331 can induce reactive marrow fibrosis and occasionally simulate primary myelofibrosis. Demonstration of metastatic carcinoma cells or mycobacteria in the marrow indicates the etiology. Other disorders reported with secondary myelofibrosis include mastocytosis,332–335 angioimmunoblastic lymphadenopathy,336 angiosarcoma,337 lymphoma,338–340 multiple myeloma,341–343 renal osteodystrophy,344 hypertrophic osteoarthropathy,345 gray platelet syndrome,346 systemic lupus erythematosus,239–242 polyarteritis nodosa,245 hypereosinophilic syndrome,347,348 kala azar,349 primary thrombocytopenic purpura,350 thrombotic thrombocytopenic purpura,351 tretinoin administration,352 neuroblastoma,353 giant lymph node hyperplasia,354 vitamin D-deficiency rickets,355–358 Langerhans cell histiocytosis,359 acute promyelocytic leukemia,360,361 and malignant histiocytosis.362 Correction or amelioration of the primary disorder can lead to disappearance of the marrow fibrosis.
Lymphoma,363,364 chronic lymphocytic leukemia,365,366 hairy cell leukemia,319,367 systemic mastocytosis,368 macroglobulinemia,369 amyloidosis,232,233 myeloma,370,371 malignant teratoma,372 and essential monoclonal gammopathy373 can coincide with primary myelofibrosis.
|Transitions to and from Myelofibrosis among Clonal HemopathiesAll clonal hematopoietic diseases (AML, CML, oligoblastic myelogenous leukemia [MDS], lymphomas) may have increased marrow reticulin fibers but only infrequently have collagen fibrosis.374 Acute megakaryoblastic leukemia is accompanied by intense marrow fibrosis (see Chap. 89). Approximately 15 percent of patients with polycythemia vera, whether treated by phlebotomy, alkylating agents, or 32P, develop a clinical state indistinguishable from primary myelofibrosis during 20 years of observation (see Chap. 86).375–377 Essential thrombocythemia may evolve into a myelofibrotic stage, estimated to occur in approximately 7 percent of cases (see Chap. 87). This estimate is complicated by the question of whether some cases of essential thrombocythemia actually are very early (prefibrotic) primary myelofibrosis.319 Sideroblastic anemia has progressed to primary myelofibrosis.378 Rarely, primary myelofibrosis reverts to polycythemia vera, with disappearance of marrow fibrosis.379,380 Even more rarely, primary myelofibrosis, carrying the JAK2 mutation, has undergone clonal evolution to BCR-ABL-positive CML or vice-versa.381,382|