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1324 Part X: Malignant Myeloid Diseases Chapter 86: Primary Myelofibrosis 1325

CLINICAL FEATURES size cells. Nuclear lobulation is abnormal, with bulky multilobulation,
hypolobulation, and free megakaryocyte nuclei in the marrow spaces.
PRESENTING SYMPTOMS In essential thrombocythemia, megakaryocytes are increased but they
Some patients are asymptomatic at the time of diagnosis; in which case do not display the dysmorphia observed in myelofibrosis. The prefi-
brotic disease usually evolves into fully developed myelofibrosis over
the disease is detected by medical examination for an unrelated reason. a period of years. Investigators, evaluating histopathology in a blind
In symptomatic patients, fatigue, weakness, shortness of breath, pruri- fashion, have confirmed the entity of prefibrotic myelofibrosis and this
tus, and palpitations are nonspecific but frequent complaints. 9–13 Fatigue abnormality predicts for progression to an overt primary myelofibrosis
is the most frequent self-reported complaint and is disproportionate to and, thus, has an impact on the risk of progression to acute leukemia
the degree of anemia. Weight loss is common, but anorexia is less so, and prognosis in general. 151
and fever and night sweats may occur. The term constitutional symp-
toms, often used in studies of the response to treatment of myelofibrosis, Extramedullary (Fibrohematopoietic) Tumors
refers specifically to the aggregate occurrence of fever, weight loss, and The appearance of symptoms or signs leading to (1) identification of
night sweats. A dragging sensation in the left upper abdomen caused a mass on imaging regardless of location, (2) appearance of signs or
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by an enlarged spleen or early satiety from encroachment of the spleen symptoms of an effusion in the thorax or abdomen, (3) unexpected
on the stomach may occur. Severe left upper quadrant or left shoul- neurologic signs, or (4) another finding that appears unexpected in
der pain can occur from splenic infarction and perisplenitis. Patients a patient with primary myelofibrosis should be considered a fibrohe-
may report unexpected bleeding. Occasionally, bone pain is promi- matopoietic (extramedullary) tumor(s) until proven otherwise. Foci of
nent, especially in the lower extremities. Fever, weight loss, cachexia, hematopoiesis may become clinically apparent as fibrohematopoietic
night sweats, and bone pain are more frequent later in the course of tumors in the adrenal glands, 152,153 renal parenchyma, 154–156 and lymph
the disease and are related to the increase in circulating inflammatory nodes. 157–159 Tumors composed of hematopoietic tissue, sometimes with
cytokines that are a key feature of the disease (see “Immune and Inflam- intense fibrosis, can develop in the bowel, 160–163 breast, 164–166 liver, 167,168
matory Manifestations” below).
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lungs, 169–171 mediastinum, pleura and mesentery, 169,171,173 skin, 174,175
synovium, thymus, thyroid, thorax, prostate, spleen, or
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PRESENTING SIGNS urinary tract. 178,181–184
Hepatomegaly is detectable in two-thirds of patients, and splenomegaly Extramedullary hematopoiesis in the intracranial or intraspinal
is present on palpation or imaging studies in almost all patients at the epidural space can lead to serious neurologic complications, including
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time of diagnosis. 8–12 The spleen is mildly enlarged in one-fourth, mod- subdural hemorrhage, delirium, 185,186 increased intracranial pres-
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erately enlarged in half, and massively enlarged in approximately one- sure, orbital apex syndrome, papilledema, cerebral tumor,
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fourth of patients. Muscle wasting, peripheral edema, and purpura are coma, motor and sensory impairment, 192,193 spinal cord compres-
present infrequently. Bone tenderness may be present. The latter signs sion, 194,195 and limb paralysis. 195,196 Intraspinal myelography, 193–199 com-
may develop in a larger proportion of patients over the course of the puted axial tomography, 185,187,191–197,199 positron emission tomography
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disease. after Fe infusion, and magnetic resonance imaging (MRI) 198,199 each
Neutrophilic dermatosis, a syndrome that closely mimics the has been used to define the location and nature of the masses.
raised and tender plaques of Sweet syndrome, may occur. 141–143 It can be Hematopoietic foci on serosal surfaces can produce effusions,
the presenting or a significant complicating feature, and can progress to sometimes massive, in the thorax, 178,180 abdomen, 172,173,201,202 and peri-
bullae or pyoderma gangrenosum. 141,144 The dermatopathology of neu- cardial space. 203–206 The effusion fluid often contains megakaryocytes,
trophilic dermatosis is different from leukemia cutis and is unrelated to immature granulocytes, and, occasionally, erythroblasts. 207–209 Splenec-
infection or vasculitis. The predominant histologic lesion is an intense tomy is sometimes followed by extramedullary hematopoietic tumors
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polymorphonuclear neutrophilic infiltrate. in soft tissues, in body cavities, or on serosal surfaces, perhaps as
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Skin infiltrates related to hematopoietic cells (leukemia cutis) are a result of an increase in circulating hematopoietic progenitors and
uncommon. These cutaneous lesions may have myeloid cells with loss of the filtration function of the spleen. In rare cases, extramedul-
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giant cells carrying CD61 markers characteristic of megakaryocytes. 146,147 lary soft-tissue megakaryoblastic tumors simulate the myeloid sarcoma
Skin lesions representing cutaneous fibrohematopoietic tumors may (synonyms: chloroma, granulocytic sarcoma) of other types of myelog-
occur. enous leukemia. 212,213
Portal Hypertension and Varices and Pulmonary Arterial
SPECIAL CLINICAL FEATURES Hypertension
Prefibrotic Primary Myelofibrosis In patients with primary myelofibrosis, there can be a massive increase
The presenting findings of the clonal myeloid diseases are changing in splenoportal blood flow and a decrease in hepatic vascular compli-
because of more and earlier access to healthcare in industrialized coun- ance or the presence of hepatic vein thrombosis, either of which can
tries (see Table 86–2). A subset of patients, perhaps as many as 25 per- result in severe portal hypertension, ascites, esophageal and gastric
cent, with primary myelofibrosis present without overt reticulin fibrosis varices, intraluminal gastrointestinal bleeding, and hepatic encephal-
in the marrow. 148,149 Blood hemoglobin may be normal and white cell opathy. 214–216 The hepatic venous pressure gradient, normally less than
count mildly elevated. The classic findings of frequent teardrop red cells, 6 torr, is markedly elevated. 217
myelocytes, and nucleated red cells in the blood film and palpable sple- Perisinusoidal fibrosis, 218–220 collagen bundles in the spaces of
nomegaly often are absent. Thrombocytosis is a constant finding. Essen- Disse, perisinusoidal fibroplasia, 218–221 and foci of hematopoietic
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tial thrombocythemia is closely simulated, but observation eventually cells 219,222 appear to contribute to the decreased sinusoidal compliance.
shows evolution to primary myelofibrosis. The most important distinc- Portal vein thrombosis is a complication of primary myelofibrosis and
tion with essential thrombocythemia is the nature of the megakaryo- occasionally precedes disease onset. 223
cytic expansion. In primary myelofibrosis, bizarre changes are evident Rarely, portal hypertension is accompanied by pulmonary hyper-
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with wide variation in megakaryocyte size, from very small to giant tension and may result from pulmonary fibrosis or hydrodynamic
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