CHAPTER 95 IDIOPATHIC MYELOFIBROSIS (AGNOGENIC MYELOID METAPLASIA)
CHAPTER 95 IDIOPATHIC MYELOFIBROSIS (AGNOGENIC MYELOID METAPLASIA)
MARSHALL A. LICHTMAN
Definition and History
Etiology and Pathogenesis
Age and Sex
Special Clinical Features
Blood Cell Counts and Morphology
Functional Abnormalities of Blood Cells
Plasma and Urine Chemical Changes
Transitions to and from Myelofibrosis Among Clonal Hemopathies
The Decision to Treat
Androgens and Glucocorticoids
Recombinant Human Erythropoietin
Portal-Systemic Vascular Shunt Surgery
Marrow Curettage, Collagen Synthesis Inhibitors, Vitamin D Congeners, Immunoglobulins, and Cyclosporines
Course and Prognosis
Idiopathic myelofibrosis is one of several disorders in the spectrum of clonal hemopathies, malignant diseases that originate in the clonal expansion of a single neoplastic hematopoietic stem cell. It is characterized by anemia, mild neutrophilia, thrombocytosis, and splenomegaly. Immature myeloid and erythroid precursors, teardrop-shaped erythrocytes, and large platelets are constant features of the blood film. The marrow has increased reticulin fibers, and this reactive fibroplasia is the result of cytokines released locally by the numerous abnormal megakaryocytes. The disease may be complicated by portal hypertension, as a result of a very large splenic blood flow and the loss of compliance of hepatic vessels, and by fibrohematopoietic tumors that can develop in any tissue and lead to symptoms by compression of vital structures. Treatment may include hydroxyurea for thrombocytosis and massive splenomegaly, red cell transfusions for severe anemia, local irradiation of fibrohematopoietic tumors or of the spleen, and splenectomy. Portosystemic shunt surgery may be required for gastroesophageal variceal bleeding. The disease may remain indolent for years or may progress rapidly by further deterioration in hematopoiesis, by massive splenic enlargement and its sequelae, or by transformation to acute myelogenous leukemia. Overall median survival is about five years.
Acronyms and abbreviations that appear in this chapter include: G-6-PD, glucose-6-phosphate dehydrogenase; IL, interleukin.
DEFINITION AND HISTORY
Idiopathic myelofibrosis is a chronic myeloproliferative disorder characterized by (1) anemia, (2) splenomegaly, (3) immature granulocytes, erythroblasts, and teardrop-shaped red cells in the blood, and (4) marrow fibrosis. The disorder was originally described by Heuck in 1879 under the title “Two Cases of Leukemia and Peculiar Blood and Bone Marrow Findings.”1 Silverstein, in his monograph, traces the history of the concepts set forth during the first half of the twentieth century to explain the pathogenesis of this disease, including its origin in the marrow, the appearance of extramedullary hemopoiesis, and the relationship of fibrosis to hematopoietic changes.2 Over 30 designations for the disease have been proposed or used, and different ones are preferred in different countries.3 Agnogenic myeloid metaplasia and, more recently, idiopathic myelofibrosis are the two most frequently used terms for the disease. Neither designation accommodates the three key phenomena of a clonal hematopoietic stem cell abnormality, a propensity to extramedullary fibrohematopoietic tumors, and the secondary intense marrow fibrosis.302
ETIOLOGY AND PATHOGENESIS
Marrow fibrosis associated with compromise of intramedullary hematopoiesis and development of ectopic foci of hemopoiesis have been induced in animals by chemicals such as lead acetate and saponin, after infection with the Rauscher rat leukemia and S37 sarcoma viruses, by high doses of estrogens, and by overexpression of thrombopoietin.2,4 These models do not replicate the pathogenesis of human disease, which is the result of a somatic mutation in an hematopoietic stem cell.
Animals injected with marrow extracts, antimarrow serum, or egg albumin have developed marrow fibrosis and splenic hematopoiesis.2 These observations, along with reports of myelofibrosis in patients with lupus erythematosus, have suggested the possibility of immunologic-mediated hyperplasia of marrow connective tissue.2 This form of myelofibrosis is different from the monoclonal stem cell disease being considered in this chapter.
Exposure to benzene5,6 and 7 or very high dose ionizing radiation8,9 has preceded the development of idiopathic myelofibrosis in a small proportion of patients with the disease. These two incitants are well-established environmental causes of clonal myeloid disorders.
The disease arises from the neoplastic transformation of a single hemopoietic stem cell, a conclusion derived from studies in women with idiopathic myelofibrosis who were also heterozygous for isotypes A and B of G-6-PD.10,11 Although the nonhemopoietic tissues of these patients expressed both isotypes, each patient had blood cells with only one G-6-PD isotype. These findings strongly imply that the blood cells of each patient arose from only one transformed stem cell. Further, chromosome studies of colonies of hemopoietic progenitor cells in idiopathic myelofibrosis have established that a clonal cytogenetic abnormality is present in erythroblasts, neutrophils, macrophages, basophils, and megakaryocytes.12 These studies have been confirmed by (1) examining X-linked restriction fragment length polymorphisms in women with idiopathic myelofibrosis with heterozygosity for the X chromosome-linked genes13,14 and (2) verifying the presence of a mutation of codon 12 of the N-RAS gene in five blood cell lineages of a patient with the disease.15,16
Myeloproliferation is usually the dominant abnormality in the granulocytic and megakaryocytic marrow lineages resulting in blood granulocytosis and thrombocytosis. Ineffective or hypoplastic hemopoiesis can be present initially or emerge as the dominant pathogenetic process later, leading to granulocytopenia and/or thrombocytopenia. Anemia is a frequent finding as a result of a combination of hypoplastic erythropoiesis, shortened red cell survival, and the effects of massive splenomegaly on the distribution of red cells in the circulation. Hemolysis can be a prominent factor in some cases.
Four of the five major types of collagen17 are present in normal marrow: type I found in bone, type III found in blood vessels, and types IV and V found in basement membranes. The fine reticulin fibers that are visible after silver impregnation of normal marrow are principally type III collagen. They do not stain with trichrome dyes. The thicker collagen fibers are principally type I collagen and stain with trichrome dyes but do not impregnate with silver. The fine fibrous network in normal marrow that is stained by silver impregnation techniques18 is increased in amount in the marrow of virtually all patients with idiopathic myelofibrosis19 (Table 95-1). The fibrous network contains collagen and can progress occasionally to include thick collagen bands that are evident with trichrome stains. Collagen types I, III, IV, and V are increased in myelofibrosis, but type III collagen is increased uniformly and preferentially.20,21,22 and 23 The latter occurrence accounts also for the increase in the plasma concentration of procollagen III amino terminal peptide, a component of collagen type III, which is cleaved during the biosynthesis of collagen.22,24 Serum prolylhydroxylase and marrow and plasma fibronectin are also increased in patients with idiopathic myelofibrosis or myelofibrosis from other causes.14,21,22
TABLE 95-1 FIBROPLASIA IN IDIOPATHIC MYELOFIBROSIS
Marrow fibrosis in idiopathic myelofibrosis is most closely correlated with an increase of dysmorphic megakaryocytes in the marrow, and even densely fibrotic marrow with little residual granulopoiesis or erythropoiesis usually has numerous megakaryocytes scattered throughout the fibrotic areas.19,38
The enhanced collagen types I and III content of marrow is the result of release of fibroblast growth factors. These include platelet-derived growth factor,39,40 epidermal growth factor,41 endothelial cell growth factor,41 transforming growth factor-b42,43 and basic fibroblast growth factor,44 each of which is present in megakaryocyte a granules. Other factors, such as tumor necrosis factor-a and IL-1 a and b, which can be released from marrow cells, also can stimulate fibroblasts.45,46 Platelet factor 4, also derived from megakaryocytes, inhibits collagenase and could contribute to collagen accumulation,38 although studies showing a poor correlation between plasma platelet factor 4 concentration and marrow fibrosis have dampened enthusiasm for the role of this factor.47 The high urinary excretion of platelet-derived calmodulin, a putative fibroblast growth factor, in patients with myelofibrosis has added this compound to the array of factors that may contribute to the fibroplasia.45 The pathogenetic role of released growth factors in fibroplasia is incompletely understood. Generalizations from in vitro experiments or correlation between two variables provide only a limited perspective. For example, transforming growth factor-b can stimulate or inhibit fibroblast growth, depending on the repertoire of other growth factors in the environment.42,43
The fibroplasia in idiopathic myelofibrosis is associated with an increase in the number and size of marrow sinuses,19,48 the number of endothelial cells,49 an increase in vascular volume in the marrow,50 and an increase in blood flow through the marrow.27,51 These processes are responsible for the increase in marrow collagen types IV and V and laminin synthesized by endothelial cells in the marrow of patients with myelofibrosis.41
The fibroblastic proliferation in marrow is not an intrinsic part of the abnormal clonal expansion of hemopoiesis.52 In cases of idiopathic myelofibrosis in which G-6-PD isoenzyme studies or chromosome karyotyping establish monoclonal growth of hemopoietic cells, marrow fibroblasts contain both G-6-PD isoenzymes and do not share the clonal chromosome abnormality.53 These findings strongly imply that the fibroblasts differentiate from a primordial cell different from the hemopoietic stem cell and that their proliferation and enhanced collagen synthesis is a secondary result of the abnormal hemopoiesis.
Extramedullary hemopoiesis is consistently present in liver and spleen,54,55 and 56 where it contributes to organ enlargement. Escape of progenitor cells from marrow and their lodgment in other organs may contribute to extramedullary blood formation. Reversion of the liver and spleen to their fetal hemopoietic functions is not held to be a major factor in the extramedullary hemopoiesis, and quantitatively significant, effective hemopoiesis does not occur outside of the marrow.
AGE AND SEX
Idiopathic myelofibrosis characteristically occurs after age 50.2,54,55,56,57,58,59,60 and 61 The median age at diagnosis is about 65 years,57,58 and 59 but the disease can occur from the neonatal period to the ninth decade.57,58,62,63 Its occurrence in children is usually in the first 3 years of life.63,64 and 65 In adults the disease occurs with about equal frequency in men and women,57,58,59,60 and 61 whereas in young children girls are afflicted with the disease twice as frequently as boys.63 The disease, rarely, can be familial.67,68
About one-quarter of patients are asymptomatic at the time of diagnosis, being detected by medical examination for an unrelated reason. In symptomatic patients, fatigue, weakness, shortness of breath, and palpitations are nonspecific but frequent complaints.54,55 and 56 Weight loss is common, but anorexia is less so and night sweats occur very infrequently. A dragging sensation in the left upper abdomen caused by an enlarged spleen or early satiety from encroachment of the spleen on the stomach may occur. Severe left upper quadrant or left shoulder pain can occur from splenic infarction and perisplenitis. Patients may also report unexpected bleeding. Rarely, bone pain may be prominent, especially in the lower extremities.
Hepatomegaly is detectable in two-thirds of patients, and splenomegaly is present in virtually every patient at the time of diagnosis.2,54,55,56,57,58,59,60 and 61 The spleen is mildly enlarged in one-third and massively enlarged in one-third. Muscle wasting, peripheral edema, and purpura are present infrequently. Bone tenderness may be present.
Neutrophilic dermatosis, a syndrome that closely mimics the raised and tender plaques of Sweet syndrome may develop.69,70 and 71 It can be the presenting or a significant complicating feature of myelofibrosis and can progress to bullae or pyoderma gangrenosum.69,72 The dermatopathology of neutrophilic dermatosis is different from leukemia cutis and is unrelated to infection or vasculitis. The predominant lesion is an intense polymorphonuclear neutrophilic infiltrate.
Skin infiltrates related to hematopoietic cells (leukemia cutis) are very uncommon.73
SPECIAL CLINICAL FEATURES
FIBROHEMOPOIETIC EXTRAMEDULLARY TUMORS
Foci of hemopoiesis are often present in adrenals, kidneys, and lymph nodes and may become clinically apparent as fibrohemopoietic tumors in the adrenal glands,74 subcapsular renal space,75 and lymph nodes.76,77 Tumors composed of hemopoietic tissue, sometimes with intense fibrosis, can develop in the bowel,78,79,80 and 81 breast,82,83 and 84 lungs,85,86 mediastinum,85 mesentery,85 skin,87,88 synovium,89 thymus,85 thyroid,90 prostate,91 or the kidney and urinary tract.92,93,94,95 and 96
Extramedullary hemopoiesis in the intracranial or intraspinal epidural space can lead to serious neurologic complications, including subdural hemorrhage,97 delirium,98,99 increased intracranial pressure,99 papilledema,100 coma,101 motor and sensory impairment,102,103,104 and 105 spinal cord compression,103 and limb paralysis.102,103 Intraspinal myelography,103,104 computed axial tomography,97,99,101,106 positron emission tomography after 52Fe infusion,98 and magnetic resonance imaging107,108 each have been used to define the location and nature of the masses.
Hemopoietic foci on serosal surfaces can produce effusions, sometimes massive, in the thorax,109 abdomen,110,111 and pericardial space.112,113,114 and 115 The effusion fluid often contains megakaryocytes, immature granulocytes, and occasionally erythroblasts.116,117 and 118 Splenectomy is sometimes followed by extramedullary hemopoietic tumors in soft tissues,119 in body cavities, or on serosal surfaces,115 perhaps as a result of an increase in circulating hematopoietic progenitors120 and the loss of the filtration function of the spleen. In rare cases, extramedullary soft tissue megakaryoblastic tumors simulate the granulocytic sarcomas of other types of myelogenous leukemia.121,122
PORTAL HYPERTENSION AND VARICES
In patients with idiopathic myelofibrosis there can be a massive increase in splenoportal blood flow and a decrease in hepatic vascular compliance or the presence of hepatic vein thrombosis, either of which can result in severe portal hypertension, ascites, esophageal and gastric varices, intraluminal gastrointestinal bleeding, and hepatic encephalopathy.123,124 and 125 Perisinusoidal fibrosis,126,127 and 128 collagen bundles in the spaces of Disse,127 perisinusoidal fibroplasia,126,127,128 and 129 and foci of hemopoietic cells127 each appear to contribute to the decreased sinusoidal compliance.
Portal vein thrombosis is a complication of idiopathic myelofibrosis and can occasionally precede the onset of the disease.130
Abnormalities of humoral immune mechanisms have been observed in up to one-half of patients with idiopathic myelofibrosis.131,132,133,134,135 and 136 The array of immune products and events reported includes anti-red-cell antibodies,135,137 antiplatelet antibodies,138,139 antinuclear antibodies,131,132,136 elevated plasma soluble IL-2 receptor,140 anti-Gal (galactosidic determinants) antibodies,141 anti-gamma-globulins,131,132,136 antiphospholipid antibodies,136,142 antitissue or organ-specific antibodies,132,135 and circulating immune complexes,136,143,144 and 145 as well as complement activation,136,146 immune complex deposition,133 interstitial immunoglobulin deposition,133 increased numbers of marrow plasmacytoid lymphocytes,133,143 and the development of amyloidosis.144,147 Occasional reports of myelofibrosis associated with lupus erythematosus,148,149,150,151 and 152 vasculitis,153 polyarteritis nodosa,136,154 scleroderma,155 and acute reversible myelofibrosis responsive to glucocorticoids156 have raised the possibility that immune mechanisms may play a role in the development of marrow fibrosis in some circumstances.
A large proportion of patients develop osteosclerosis,57,157 reflected by increased bone density on radiographic studies and also evident on marrow biopsy.158 The proximal femur and humerus, pelvis, vertebrae, ribs, and skull may be involved. The x-ray picture may mimic the bone reaction to metastatic carcinoma. Osteolytic lesions are rare159 and may reflect a granulocytic sarcoma.160 Periostitis can lead to debilitating bone pain.54,55 and 56,161
BLOOD CELL COUNTS AND MORPHOLOGY
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.2,54,55,56,57,58,59 and 60,162,163,164 and 165 The mean hemoglobin concentration at diagnosis was 9.5 to 11.6 g/dl, with a range of 4 to 20 g/dl among a total of 539 patients in four studies.56,60,163,164 Anisocytosis and poikilocytosis are a constant finding, and teardrop-shaped red cells (dacrocytes) are present in all cases in sufficient number to be found in every oil-immersion field (Fig. 95-1). Nucleated red cells are present in the blood film of most patients and average 2 percent of nucleated cells, with a range of 0 to 30 percent. The percentage of reticulocytes is mildly increased but may vary widely in a given case. Anemia may be worsened by an 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,162 and erythroid hypoplasia is present in many patients.166,167 In some patients hemolysis may be prominent, and polychromatophilia and very elevated reticulocyte counts can occur.56,60,163,164 The antiglobulin (Coombs’) test is usually negative, but red cell autoantibodies can develop and lead to immune-mediated hemolysis.56,136,137,168 Occasional patients have a positive acid hemolysis and sucrose hemolysis test, reflecting concurrent paroxysmal nocturnal hemoglobinuria.169 Acquired hemoglobin H disease, coincident with typical white cells and platelet changes of myelofibrosis, can occur170 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 also been observed.165,171
FIGURE 95-1 Blood films from two patients with idiopathic myelofibrosis. (a) Characteristic teardrop poikilocytes, a nucleated red cell, and a segmented neutrophil are evident. (b) Teardrop red cells, a nucleated red cell, and a promyelocyte are present.
The total white cell count in patients with idiopathic myelofibrosis is usually elevated mildly as a result of granulocytosis.2,54,55,56,57,58,59,60 and 61 The mean total white cell count was 10 to 14 ×109/l in four large studies. The range of white cell counts was 0.4 to 237 × 109/l at the time of diagnosis.56,60,163,164 Myelocytes and promyelocytes are present in small proportions in most patients, and a low proportion of blast cells (1–2%) may be found in the blood film in many patients. The range of blood blast cells is zero to 20 percent at the time of diagnosis. Hypersegmentation, hyposegmentation (acquired Pelger-Huët anomaly), and abnormal granulation of neutrophils may be present.2,54,55 and 56 Neutrophil alkaline phosphatase scores may be elevated (25 percent of patients) or decreased (25 percent of patients).2,172 The percent of basophils may be slightly increased.164 Neutropenia is present in about 20 percent of patients at the time of diagnosis.58
The mean platelet count has ranged from 175 to 580 × 109/l, and the range of individual counts was from 15 to 3215 × 109/l.6,60,163,164 The platelet count is elevated in about 40 percent of patients.58,164 Mild to moderate thrombocytopenia is present in about one-third of patients at the time of diagnosis. Giant platelets and abnormal platelet granulation are characteristic features of this disease.
About 10 percent of patients may present with pancytopenia because of severe impairment of hematopoiesis affecting each cell lineage, coupled with sequestration in a massively enlarged spleen.2,54,55 Pancytopenia is usually associated with intense marrow fibrosis.
Increased concentrations of pluripotential,173 granulocytic,174,175 monocytic,176,177 and erythroid178 progenitor cells are present in the blood of patients as measured by clonogenic assays of blood cells in semisolid cultures. Megakaryocytes are also present in the systemic venous blood.177
FUNCTIONAL ABNORMALITIES OF BLOOD CELLS
The neutrophils of some patients have impaired phagocytosis, oxygen consumption, nitroblue tetrazolium reduction, and hydrogen peroxide generation, as well as decreased myeloperoxidase178,179 and glutathione reductase activities.179 Bleeding time can be prolonged out of proportion to the platelet count.180,181 Abnormalities of platelets in patients with idiopathic myelofibrosis include impaired aggregation in response to epinephrine, depletion of dense granule adenosine diphosphate content,182 decreased platelet lipoxygenase pathway activity,183 and others.184,185 The correlation of bleeding or thrombosis with platelet functional abnormalities is weak, however.184,185 The lupus anticoagulant has been present, but only rarely.141
Marrow aspiration is often unsuccessful because of the fibrosis.18,54,60 The marrow biopsy is often cellular and shows granulocytic and megakaryocytic hyperplasia.19,164 Erythroid cells may be decreased, normal, or increased in number. Hematoxylin and eosin stains of the biopsy may show slight collagen fibrosis, but this may be extreme on occasion. In some subjects, osteosclerosis is found.19,60,164 Silver stain shows an increase in reticulin fibers, and in half the patients a striking increase in reticulin fibers is present.60,164 In intensely fibrotic marrows cellularity may be decreased, but megakaryocytes usually remain evident.60,164 Giant megakaryocytes and micromegakaryocytes, abnormal nuclear lobulation, and naked megakaryocyte nuclei may be present.60,186 Granulocytes may show hyperlobulation and hypolobulation of the nucleus, acquired Pelger-Huët anomaly, nuclear blebs, and nuclear-cytoplasmic maturation asynchrony.187 Dilated marrow sinusoids are common. Intrasinusoidal, immature hemopoietic cells, and megakaryocytes are present.19,48
Chromosome abnormalities of hemopoietic cells are evident in about forty percent of the patients at the time of diagnosis.188,189,190 and 191 The most frequent findings are partial trisomy 1q, interstitial deletion of a segment of the long arm of chromosome 13, del 13 (q13q21), which bears the retinoblastoma gene,16,189,190 and 191 and del 20q. Involvement of chromosomes 5, 7, 9, 13, 20, or 21 occurs with heightened frequency. Aneuploidy, as a result of monosomy or trisomy, is common. Pseudodiploidy, manifested by partial deletions and translocations, occurs also. Patients with typical idiopathic myelofibrosis have had the Ph chromosome in their marrow cell.192 This association is rare, however. Clonal chromosomal abnormalities found in hemopoietic cells have not been found in fibroblasts.53
MAGNETIC RESONANCE IMAGING
Fibrosis in the marrow alters the hyperintensity of T1-weighted images that normally result from the marrow fat. As fibrosis progresses, hypointensity of T1- and T2-weighted images develops. These abnormalities are similar to those that occur with marrow hemosiderosis. Histologic confirmation by marrow biopsy of MR images is important for verification. MR imaging cannot distinguish between idiopathic myelofibrosis and secondary causes of fibrosis.193,194
PLASMA AND URINE CHEMICAL CHANGES
The serum levels of uric acid, lactic dehydrogenase, bilirubin, alkaline phosphatase, and high-density lipoprotein are frequently elevated,54,58 and those of albumin and cholesterol are frequently decreased.58,195 Hypocalcemia196 or hypercalcemia197 may occur. Plasma levels of thrombopoietin and IL-6 are elevated but do not correlate with either platelet or megakaryocyte mass.198 Urinary excretion of calmodulin is about three times normal.45
Chronic myelogenous leukemia (see Chap. 94) should be considered in the differential diagnosis of idiopathic myelofibrosis. In chronic myelogenous leukemia the white cell count is over 30 × 109/l (30,000/µl) in virtually all patients and over 100 × 109/liter (100,000/µl) in half the patients, but in myelofibrosis it is usually less than 30 × 109/l (30,000/µl) at the time of diagnosis. In chronic myelogenous leukemia red cell shape is usually normal or slightly perturbed, whereas in myelofibrosis teardrop poikilocytes are present in every oil-immersion field and exaggerated anisocytosis and anisochromia are often prominent. The marrow in chronic myelogenous leukemia shows intense granulocytic hyperplasia with virtually 100 percent cellularity and usually no or very slight fibrosis.199 In myelofibrosis, the marrow has mildly increased cellularity or is hypocellular, with moderate to marked fibrosis. The Ph chromosome or the BCR-ABL fusion gene is present in chronic myelogenous leukemia and absent in idiopathic myelofibrosis. Rarely, patients with chronic myelogenous leukemia may develop intense marrow fibrosis and dysmorphic blood cell changes that make distinction between the two diseases difficult.199 Most cases are readily separable on the basis of the aforementioned distinctions.
Patients with idiopathic myelofibrosis may have pancytopenia or bicytopenia and in that respect mimic patients with oligoblastic leukemia (myelodysplasia) (see Chap. 92). Contrariwise, patients with oligoblastic leukemia may rarely have intense fibrosis. Prominent splenomegaly is expected in patients with idiopathic myelofibrosis but not in patients with oligoblastic leukemia, which also 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 aniso-poikilocytosis would mitigate against idiopathic myelofibrosis.
Since some patients with idiopathic myelofibrosis have platelet counts over 600,000 × 109/l, the diagnosis of primary thrombocythemia may be considered. The aniso-poikilocytosis, nucleated red cells, and myeloid immaturity in the blood film characteristic of myelofibrosis is not present in patients with thrombocythemia. Marrow fibrosis is usually insignificant in thrombocythemia, and splenic enlargement is often absent or slight. There is for these reasons usually a clear distinction between the two disorders.164,200
Hairy cell leukemia (see Chap. 99), when it is associated with shape abnormalities of red cells, pancytopenia, splenomegaly, and fibrotic marrow, can mimic idiopathic myelofibrosis closely. Usually, careful scrutiny of the blood and marrow by microscopy, histochemistry, and cell immunophenotype will show evidence of the abnormal mononuclear (hairy) cells that characterizes the disease.
Metastatic carcinoma, especially derived from carcinoma of the breast or prostate tumors201,202,203,204,205 and 206 or from disseminated mycobacterial infection, can induce reactive marrow fibrosis207 and occasionally simulate idiopathic myelofibrosis. The demonstration of metastatic carcinoma cells or mycobacteria in the marrow indicates the etiology. Other disorders reported with secondary myelofibrosis include mastocytosis,208,209 angioimmunoblastic lymphadenopathy,210 lymphoma,211 multiple myeloma,212,213,214,215,216 and 217 renal osteodystrophy,218 hypertrophic osteoarthropathy,219 gray platelet syndrome,220 systemic lupus erythematosus,148,149,150 and 151 polyarteritis nodosa,153 hypereosinophilic syndrome,221 tretinoin administration,222 neuroblastoma,223 giant lymph node hyperplasia,224 vitamin D deficiency rickets,225,226 Langerhans cell histiocytosis,227 and malignant histiocytosis.228 Correction or amelioration of the primary disorder can lead to disappearance of the marrow fibrosis.
Lymphoma,229,230 chronic lymphocytic leukemia,231 hairy cell leukemia,232 macroglobulinemia,233 amyloidosis,144,147 myeloma,234,235 malignant teratoma,236 and essential monoclonal gammopathy237 have been reported to coincide with idiopathic myelofibrosis.
TRANSITIONS TO AND FROM MYELOFIBROSIS AMONG CLONAL HEMOPATHIES
All clonal hematopoietic diseases may have increased marrow reticulin fibers but only infrequently have collagen fibrosis.238 Acute megakaryoblastic leukemia is accompanied by intense marrow fibrosis (see Chap. 93). At least 25 percent of patients with polycythemia vera, whether treated by phlebotomy, alkylating agents, or 32P, develop a clinical state indistinguishable from idiopathic myelofibrosis during twenty years of observation239,240 and 241 (see Chap. 61).
Sideroblastic anemia has also been observed to progress to idiopathic myelofibrosis.242 Rarely, idiopathic myelofibrosis reverts to polycythemia vera, with disappearance of the marrow fibrosis.243,244 and 245
THE DECISION TO TREAT
A very large proportion of asymptomatic patients will remain stable for years, not requiring specific treatment.2,54,55,56,57,58,59,60 and 61
ANDROGENS AND GLUCOCORTICOIDS
Severe anemia may improve with androgen therapy in some patients.246,247,248 and 249 Testosterone, oxymethalone, and fluoxymesterone have been used but have virilizing effects, in addition to the potential for hepatic injury and other side effects. Danazol, 600 mg orally per day for weeks to months can be used. Patients on androgen therapy should have periodic assessment of liver size by physical examination, measurement of liver function tests, and if appropriate, ultrasound imaging to detect liver injury (e.g., peliosis) or tumors.250 Patients with significant hemolytic anemia may benefit from glucocorticoid therapy. A trial of prednisone, 25 mg/m2 per day, orally, can be tried. If tolerated, this dose can be continued for one to two months and thereafter tapered gradually. In children, high-dose glucocorticoid therapy has been reported to ameliorate marrow fibrosis and improve hematopoiesis.251,252
RECOMBINANT HUMAN ERYTHROPOIETIN
Serum erythropoietin levels are appropriate to the severity of anemia in patients with myelofibrosis.253 Use of erythropoietin to treat anemia has been largely unsuccessful.254,255
A variety of cytotoxic drugs have been used in the treatment of massive splenomegaly, thrombocytosis or constitutional symptoms. Hydroxyurea has become the most commonly used and preferred agent.256,257 and 258 Hydroxyurea can decrease the size of the spleen and liver; decrease or eliminate constitutional symptoms of night sweats or weight loss; and lead to an increase in hemoglobin concentration, a decrease of elevated platelet counts, and occasionally a decrease in the degree of marrow fibrosis. Patients with myelofibrosis often do not have the marrow tolerance to chemotherapy of patients with other chronic myeloproliferative diseases. Hydroxyurea can be administered in doses of 0.5 to 1.0 g per day or 1.0 to 2.0 g two to three times per week, orally, depending on the level of the pretreatment blood cell counts. Patients should be evaluated for dose adjustment at least every week for a month and, if appropriate, extended to every two weeks for two months. Thereafter, monthly evaluation of dose may be appropriate. Although alkylating agents, especially busulfan and other cytotoxic agents, have been used successfully they have largely been replaced by hydroxyurea.259
Ascites resulting from peritoneal hemopoietic implants has been treated by intraperitoneal cytarabine.260
Interferon alpha and interferon gamma act synergistically to inhibit myeloproliferation261 and are effective antiproliferative agents in chronic myelogenous leukemia (see Chap. 94). Although it has not been used extensively in idiopathic myelofibrosis, interferon alpha has been useful in treating splenic enlargement, bone pain, and thrombocytosis in selected patients.262 Trials comparing interferon therapy with chemotherapy have not been reported. Hydroxyurea is easier to use and has less frequent side effects than interferon.
Debilitating bone pain can be a vexing problem in some patients with osteosclerosis and periostitis. A report of dramatic improvement in bone pain and hematopoiesis after etidronate, 6 mg/kg, on alternate months may indicate the potential usefulness of this family of drugs.264
There are five situations in which radiotherapy can be useful for patients with idiopathic myelofibrosis: In the presence of (1) severe splenic pain (splenic infarctions) or (2) massive splenic enlargement with a contraindication to splenectomy (e.g., thrombocytosis),264,265 and 266 doses of 50 to 200 rad (0.5 to 2 Gy) to the spleen can produce an amelioration of pain. The other situations in which radiation may be useful are (3) ascites resulting from myeloid metaplasia of the peritoneum;267 (4) focal areas of severe bone pain (periostitis or the osteolysis of a granulocytic sarcoma);161,268 and (5) extramedullary fibrohemopoietic tumors,76 especially of the epidural space.104
Splenectomy is important in the management of idiopathic myelofibrosis.269,270,271 and 272,303 The major indications for splenectomy include (1) painful enlarged spleen, (2) excessive transfusion requirements or refractory hemolytic anemia, (3) severe thrombocytopenia, and (4) portal hypertension.
Patients who have a prolonged bleeding time or coagulation times are at serious risk of hemorrhage with surgery and should not have the procedure unless these abnormalities can be corrected by platelet transfusion or factor replacement therapy. Evidence of low-grade intravascular coagulation, such as elevated D-dimer levels, may require prophylactic heparin therapy and platelet transfusion should there be excessive bleeding. In one series 50 patients had splenectomy: 26 of 27 patients splenectomized for pain, 5 of 9 patients splenectomized for refractory hemolysis, 4 of 10 patients splenectomized for refractory thrombocytopenia, and 4 of 4 patients splenectomized for portal hypertension had improvement.271
Removal of the spleen in patients with idiopathic myelofibrosis may be difficult. The spleen is usually adherent to neighboring serosal surfaces and structures and has numerous collateral vessels and very dilated splenoportal arteries and veins. Immediate postoperative mortality is a function of surgical experience and skill and of the rapidity of recognition of postoperative complications. In experienced hands, perioperative mortality should be less than 10 percent. Postoperative morbidity from hemorrhage, subphrenic hematoma, subphrenic abscess, injury to the tail of the pancreas, pancreatic fistulas, or portal vein stump thrombosis occurs in about 30 percent of patients. Later, postoperative changes include liver enlargement,273 extramedullary hemopoietic tumors,115,119 and a decrease in teardrop-shaped red cells.274 Postoperative liver enlargement and thrombocytosis have responded to treatment with cladribine.275 Anagrelide may also be useful for exaggerated thrombocytosis (see Chap. 118). The morbidity and mortality from splenectomy and the modest extension of life on the average has led to increasing conservatism in its use.276 Splenectomy, however, can improve the state of patients who are selected carefully and in a timely fashion.
Five patients with idiopathic myelofibrosis were among 91 patients who had subtotal splenectomy, preserving the upper pole of the spleen and its blood supply. No surgical mortality occurred, but details of outcome were not reported.277
PORTAL-SYSTEMIC VASCULAR SHUNT SURGERY
Patients who are operated on for portal hypertension and bleeding varices or refractory ascites should have circulatory dynamic studies performed at the time of surgery. In patients in whom the hepatic wedge-pressure elevations are a result of the markedly increased blood flow from the spleen to the liver, the preferred treatment procedure for portal hypertension is splenectomy. In those patients who have portal hypertension as a result of intrahepatic block or hepatic vein thrombosis, a splenorenal shunt is usually performed.278
MARROW CURETTAGE, COLLAGEN SYNTHESIS INHIBITORS, VITAMIN d CONGENERS, IMMUNOGLOBULINS, AND CYCLOSPORINES
Several experimental forms of therapy have been used in a small number of patients. Hematologic remission has been described in one case of myelofibrosis treated by bilateral iliac-crest marrow curettage.279
Investigative approaches to the disease include the use of agents that prevent collagen formation, such as monoamine oxidase inhibitors and lysylaldehyde chelators such as dehydroproline.280
1,25-Dihydroxyvitamin D therapy was associated with improvement of patients with myelofibrosis, although hypercalcemia and hypophosphatemia may prevent continued use.281 The mechanism of action could relate to a profound antiproliferative effect of 1,25-dihydroxyvitamin D on megakaryocytes, which are the putative source of most of the fibroblast activation factors. In two other reports no benefit was found from administration of this vitamin D analog.282,283 1,25-Dihydroxycholecalciferol has also been reported to ameliorate myelofibrosis.284 Single cases of improvement in hematopoiesis and decrease in osteosclerosis after intravenous immune globulin285 and sustained improvement in anemia after cyclosporine286 have been reported.
Marrow transplantation therapy, which is efficacious in acute megakaryocytic leukemia with intense myelofibrosis, could be used in appropriate candidates who are under the age of 40 and have a histocompatible sibling.287,288 and 289 Patients engraft at a rate similar to patients with hematologic diseases without marrow fibrosis289 (see Chap. 18).
COURSE AND PROGNOSIS
The rate of progression of the disease has been associated with at least ten variables measured at the time of diagnosis. Shorter survival has been associated with older age, severity of anemia, severity of thrombocytopenia, exaggerated leukocytosis or leukopenia, the proportion of blast cells in the blood, degree of liver enlargement, extent of marrow fibrosis, abnormal clonal cytogenetic abnormalities, and constitutional symptoms of fever, sweating, or weight loss at the time of diagnosis. Each retrospective study has found a different subset of these factors to be significant prognostic factors. The most consistent predictive variables appear to be advanced age, severity of anemia, and clonal cytogenetic abnormality at the time of diagnosis, each of which represents a poor prognostic indicator.57,58,59 and 60,163,164,191,290
The median survival of all patients with idiopathic myelofibrosis is approximately 5 years from the time of diagnosis.57,58,59 and 60 The 5-year survival is about forty percent of that expected for healthy age- and sex-matched controls.2,55,291 Retrospective analysis of prognostic variables permits stratification of patients into slowly progressive and rapidly progressive cohorts.55,57,58 and 59,163,167,291
The major causes of death are infection, hemorrhage, postsplenectomy mortality, and acute leukemic transformation).2,54,55 and 56,292,293 and 294,301 Acute leukemia occasionally may be preceded by the development of granulocytic sarcomas.160,269,295 Evolution of the disease to acute lymphocytic leukemia or lymphoma also may occur.296,297 An increased risk of progression to leukemia has been reported in splenectomized patients.298 Rare spontaneous remissions of apparent idiopathic myelofibrosis have been documented.299,300
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Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn