Presenting Symptoms of Primary myelofibrosis 2

Clinical Features

Presenting Symptoms of Primary myelofibrosis

About one-fourth of patients are asymptomatic at the time of diagnosis; the disease is detected by medical examination for an unrelated reason. In symptomatic patients, fatigue, weakness, shortness of breath, pruritus, and palpitations are nonspecific but frequent complaints.8–12 Weight loss is common, but anorexia is less so and night sweats occur 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 report unexpected bleeding. Occasionally, bone pain is prominent, especially in the lower extremities. Fever, weight loss, night sweats, and bone pain are more frequent later in the course of the disease.

Presenting Signs of Primary myelofibrosis

Hepatomegaly is detectable in two-thirds of patients, and splenomegaly is present on palpation or imaging studies in almost all patients at the time of diagnosis.7–11 The spleen is mildly enlarged in one-fourth, moderately enlarged in half, and massively enlarged in approximately one-fourth of patients. Muscle wasting, peripheral edema, and purpura are present infrequently. Bone tenderness may be present. The latter signs may develop in a larger proportion of patients over the course of the disease.

Neutrophilic dermatosis, a syndrome that closely mimics the raised and tender plaques of Sweet syndrome, may occur.130–132 It can be the presenting or a significant complicating feature, and can progress to bullae or pyoderma gangrenosum.130,133 The dermatopathology of neutrophilic dermatosis is different from leukemia cutis and is unrelated to infection or vasculitis. The predominant histologic lesion is an intense polymorphonuclear neutrophilic infiltrate.

Skin infiltrates related to hematopoietic cells (leukemia cutis) are uncommon.134 These cutaneous lesions may have myeloid cells with giant cells carrying CD61 markers characteristic of megakaryocytes.135,136 Skin lesions representing cutaneous fibrohematopoietic tumors may occur.

Special Clinical Features of Primary myelofibrosis

Prefibrotic Primary Myelofibrosis

The presenting findings of the clonal myeloid diseases are changing because of more and earlier access to healthcare in industrialized countries (Table 91–2). A subset of patients, perhaps as many as 25 percent, with primary myelofibrosis present without overt reticulin fibrosis in the marrow.137,138 Blood hemoglobin may be normal and white cell count mildly elevated. The classic findings of frequent teardrop red cells, myelocytes, and nucleated red cells in the blood film and palpable splenomegaly often are absent. Thrombocytosis is a nearly constant finding. Essential thrombocythemia is closely simulated, but observation eventually shows evolution to primary myelofibrosis. The most important distinction with essential thrombocythemia is the nature of the megakaryocytic expansion.139 In primary myelofibrosis, bizarre changes are evident with wide variation in megakaryocyte size from very-small- to giant-size cells. Nuclear lobulation is abnormal, with bulky multilobulation, hypolobulation, and free megakaryocyte nuclei in the marrow spaces. In essential thrombocythemia, megakaryocytes are increased but they do not display the dysmorphia observed in myelofibrosis. The prefibrotic disease usually evolves into fully developed myelofibrosis over a period of years. Although blinded studies have raised questions about the ability to identify a prefibrotic stage, the presence of JAK2 617F mutations does lend support to such a concept.

Table 91–2. Diagnostic Findings in Idiopathic Myelofibrosis

Prefibrotic stage
Anemia may be absent or mild
Leukocytosis may be absent or slight
Thrombocythemia very frequent
BCR-ABL fusion gene absent
Presence of JAK2 mutation indicative of diagnosis of myeloproliferative disease
Cellular marrow with mild increase in granulopoiesis; increased megakaryocytes, clusters of very dysmorphic megakaryocytes and megakaryocytic nuclei; no to very slight increase in reticular fibers on silver stain
Palpable splenomegaly infrequent
Absent or slight anisopoikilocytosis including teardrop red cells
Fully developed stage
Marrow reticulin fibrosis plus or minus collagen fibrosis
BCR-ABL fusion gene absent
JAK2 mutation in approximately 50% of patients
Anisopoikilocytosis with teardrop red cells in every oil immersion field
Immature myeloid cells in blood
Increased CD34-positive cells in blood
Erythroblasts in blood
Marrow usually hypercellular but invariably has increased megakaryocytes, clusters of highly dysmorphic megakaryocytes, and megakaryocyte bare nuclei regardless of overall marrow cellularity

Fibrohematopoietic Extramedullary Tumors

The appearance of symptoms or signs leading to (1) identification of a mass on imaging regardless of location, (2) appearance of signs or symptoms of an effusion in the thorax or abdomen, (3) unexpected neurologic signs, or (4) another finding that appears unexpected in a patient with primary myelofibrosis should be considered a fibrohematopoietic tumor(s) until proven otherwise. Foci of hematopoiesis may become clinically apparent as fibrohematopoietic tumors in the adrenal glands,140,141 renal parenchyma,142–144 and lymph nodes.145–147 Tumors composed of hematopoietic tissue, sometimes with intense fibrosis, can develop in the bowel,148–151 breast,152–154 liver,155,156 lungs,157–159 mediastinum,160 pleura and mesentery,157,159,161 skin,162,163 synovium,164 thymus,157 thyroid,165 thorax,166 prostate,167 spleen,168 or urinary tract.166,169–172

Extramedullary hematopoiesis in the intracranial or intraspinal epidural space can lead to serious neurologic complications, including subdural hemorrhage,173 delirium,173,174 increased intracranial pressure,175 orbital apex syndrome,176 papilledema,177 cerebral tumor,178 coma,179 motor and sensory impairment,180,181 spinal cord compression,182,183 and limb paralysis.183,184 Intraspinal myelography,181–193 computed axial tomography,173,175,179–185 positron emission tomography after 52Fe infusion,174 and magnetic resonance imaging186,187 each has been used to define the location and nature of the masses.

Hematopoietic foci on serosal surfaces can produce effusions, sometimes massive, in the thorax,166,188 abdomen,160,161,189,190 and pericardial space.191–194 The effusion fluid often contains megakaryocytes, immature granulocytes, and occasionally erythroblasts.195–197 Splenectomy is sometimes followed by extramedullary hematopoietic tumors in soft tissues,198 in body cavities, or on serosal surfaces,197 perhaps as a result of an increase in circulating hematopoietic progenitors199 and loss of the filtration function of the spleen. In rare cases, extramedullary soft tissue megakaryoblastic tumors simulate the myeloid sarcomas of other types of myelogenous leukemia.200,201

Portal Hypertension and Varices and Pulmonary Arterial Hypertension

In patients with primary 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.202–204 The hepatic venous pressure gradient, normally less than 6 torr, is markedly elevated.205

Perisinusoidal fibrosis,206–208 collagen bundles in the spaces of Disse,207 perisinusoidal fibroplasia,206–209 and foci of hematopoietic cells207,210 each appears to contribute to the decreased sinusoidal compliance. Portal vein thrombosis is a complication of primary myelofibrosis and occasionally precedes disease onset.211

Rarely, portal hypertension is accompanied by pulmonary hypertension and may result from pulmonary fibrosis159 or hydrodynamic factors.212 Pulmonary arterial hypertension, also, may be the principal problem.213,214 Although as many as one-third of patients with primary myelofibrosis have an elevated systolic pulmonary artery pressures (>35 torr), the fraction that is symptomatic is very small. Elevated vascular endothelial growth factor (VEGF) levels, elevated circulating endothelial cells, and elevated marrow microvessel density in patients suggest that proangiogenic factors may contribute to the hypertension.215 Contrariwise, secondary myelofibrosis with polyclonal hematopoiesis and normal blood CD34 cell concentrations frequently occurs in patients with primary pulmonary hypertension.216

Immune and Inflammatory Manifestations

Abnormalities of humoral immune mechanisms have been observed in up to half of patients with primary myelofibrosis.217–222 The array of immune products and events reported includes anti–red cell antibodies,221,223–225 antiplatelet antibodies,226,227 antinuclear antibodies,217,218,222 elevated plasma-soluble IL-2 receptor,228 anti-Gal (galactosidic determinants) antibodies,229 anti–-globulins,217,219,222 antiphospholipid antibodies,222,230 antitissue or organ-specific antibodies,219,221 and circulating immune complexes,222,231–233 as well as complement activation,222,234 immune complex deposition,219 interstitial immunoglobulin deposition,219 increased numbers of marrow plasmacytoid lymphocytes,219,231 and development of amyloidosis.232–235

Inflammatory cytokines including IL-1, IL-6, IL-8, TNF-, TNF-RII, and C-reactive protein also are markedly elevated and play a role in the constitutional symptoms seen in patients with progressive disease.236

Occasional reports of nonclonal secondary myelofibrosis associated with lupus erythematosus,237–242 vasculitis,243 polyarteritis nodosa,222,243 ulcerative colitis,244 scleroderma,245 biliary cirrhosis,225,247 Sjögren syndrome,248 and acute reversible myelofibrosis responsive to glucocorticoids,249 although fundamentally different processes from primary myelofibrosis, have raised the possibility that immune mechanisms play a role in the development of marrow fibrosis in some circumstances.

Bone Changes

A large proportion of patients have osteosclerosis at diagnosis or develop osteosclerosis during the course of the disease,10–14,250–253 as reflected by increased bone density on imaging studies and histomorphometric analysis of a bone biopsy (Table 91–3).251–256 The proximal femur and humerus, pelvis, vertebrae, ribs, and skull may be involved. Magnetic resonance imaging (MRI) can uncover evidence of new bone formation and periosteal thickening. Lumbar spine dual-energy x-ray absorption studies and quantitative computed tomography provide evidence for increased bone formation, bone thickening, and higher proportions of cancellous and of woven bone.256,257 Osteolytic lesions are rare258 and may reflect a myeloid sarcoma.259 Periostitis, although infrequent, can lead to debilitating bone pain.260

Table 91–3. Serum, Urine, and Bone Changes Reflecting Osteosclerosis243,244
Increased serum alkaline phosphatase
Increased serum bone GLA-protein
Increased serum carboxytelopeptidase
Increased urinary deoxypyridinoline
Increased bone density by dual-energy x-ray absorption
Increased bone density by quantitative computed tomography
Increased percentage of cancellous bone volume to tissue volume
Increased bone formation and resorption (high turnover)
Increased trabecular plate thickness
Increased percentage of woven bone volume
Increased percentage of fibrous area
No evidence of mineralization defect


The risk of arterial and venous thrombosis is elevated in patients with primary myelofibrosis, although not to the degree seen in polycythemia vera or essential thrombocythemia.261 Approximately 10 percent of patients with myelofibrosis will develop a significant thrombotic event during the first 4 years of the disease. The two principal risk factors are an elevated platelet count and a cardiovascular risk factor, such as hypertension, hypercholesterolemia, or smoking. Multiple thrombotic episodes may occur and the thrombotic event may occur at or just before diagnosis.