Page 1351 - Williams Hematology ( PDFDrive )

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

sucrose hemolysis test, reflecting a concurrent clone of cells consistent natural killer cells, which appears to be related to a dysregulation in
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with paroxysmal nocturnal hemoglobinuria. Acquired hemoglobin control of IL-15. 298
H disease, coincident with typical white cells and platelet changes of Bleeding time can be prolonged disproportionately to the plate-
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myelofibrosis, can occur and results in hemolysis, hypochromic– let count. 299,300 Platelet abnormalities include impaired aggregation in
microcytic red cells, marked poikilocytosis, and hemoglobin H inclu- response to epinephrine, depletion of dense granule adenosine diphos-
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sions that stain with brilliant cresyl blue. Red cell aplasia, in association phate content, decreased platelet lipoxygenase pathway activity,
with primary myelofibrosis, has been observed. 280,286 and others. 303,304 The correlation of bleeding or thrombosis with platelet
The total white cell count usually is usually moderately elevated as functional abnormalities is weak. 303,304 The lupus anticoagulant has been
a result of granulocytosis. 8–16 The mean total blood white cell count was present, rarely. 242
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10,000 to 14,000/μL (10 to 14 × 10 /L) in four large studies. Neutropenia,
however, is present in approximately 20 percent of patients at the time
of diagnosis. 8–16 The range of white cell counts was 400 to 237,000/μL MARROW EXAMINATION
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(0.4 to 237.0 × 10 /L) at the time of diagnosis. 8–15,278,279 Myelocytes and Morphology
promyelocytes are present in small proportions in the blood film in most In the fibrotic phase, marrow aspiration often is unsuccessful because of the
patients, and a low proportion of blast cells (0.5 to 2.0 percent) may be fibrosis. 8–16,96,97 The marrow biopsy specimen usually is cellular and shows
found in the blood film. The blood blast cells range from 0 to 20 percent granulocytic and megakaryocytic hyperplasia (see Fig. 86–1). 8–16,288,289
at the time of diagnosis. In patients with blast counts at the high end, Erythroid cells may be decreased, normal, or increased in number.
which is unusual at presentation, the disease merges with or may prog- Silver stain usually shows an increase in reticular fibers, and in half of
ress rapidly to AML. Hypersegmentation, hyposegmentation (acquired patients a striking increase in reticular fibers is seen. Hematoxylin
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Pelger-Huët anomaly), and abnormal granulation of neutrophils may and eosin stains of the biopsy specimen may show mild collagen fibro-
be present. 8–16 Neutrophil alkaline phosphatase scores may be elevated sis; occasionally the fibrosis is extreme (see Fig. 86–1). Collagen fibro-
(25 percent of patients) or decreased (25 percent of patients). The sis may be more evident using a Gomori trichrome stain with which
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percentage of basophils may be slightly increased. The mean plate- collagen characteristically stains green. In intensely fibrotic marrows,
let count in patient series ranges from 175,000 to 580,000/μL (175 to cellularity may be markedly decreased but megakaryocytes usually
580 × 10 /L) at the time of diagnosis. Individual platelet counts can remain evident. Giant megakaryocytes and micromegakaryocytes,
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range from 15,000 to 3,215,000/μL (15 to 3215 × 10 /L). 8–16,278,279 The abnormal nuclear lobulation, and naked megakaryocyte nuclei are
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platelet count is elevated above the normal upper limit in approximately present. 8–16,305 Thrombopoietin receptors are decreased on megakary-
40 percent of patients. Mild to moderate thrombocytopenia is present ocytes and platelets. Granulocytes may show hyperlobulation and
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in approximately one-third of patients at the time of diagnosis, partic- hypolobulation of the nucleus, acquired Pelger-Huët anomaly, nuclear
ularly if splenomegaly is massive. Giant platelets and abnormal platelet blebs, and nuclear–cytoplasmic maturation asynchrony. Clusters
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granulation in the blood film are characteristic features of the disease. of blasts and CD34+ cells are often present. Dilated marrow sinus-
Approximately 10 percent of patients present with pancytopenia oids are common. Intrasinusoidal, immature hematopoietic cells, and
because of severe impairment of hematopoiesis affecting each cell lin- megakaryocytes are present. As a reflection of the high blood flow to marrow-
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eage, coupled with sequestration in a massively enlarged spleen. Pancy- bearing bone and the widened sinusoidal system, microvessel density
topenia usually is associated with intense marrow fibrosis. is significantly increased in approximately 70 percent of patients. 306,307
Increased concentrations of multipotential, 288,289 granulocytic, 290,291 Histomorphometric analysis of marrow biopsies permit detection of
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monocytic, erythroid, and megakaryocytic progenitor cells are osteosclerosis. 263,265,266 Grading of the degree of myelofibrosis has used
present in the blood of patients, as measured by clonogenic assays in the Bauermeister scale, which assesses fibrosis on a scale of 0 to 4, and
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semisolid cultures. The frequency of hematopoietic progenitor cells in the revised European grading scale of 0 to 3. Digital imaging may be
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the blood is correlated with the extent of marrow reticular fiber den- used for less subjective, quantitative grading of fibrosis or osteosclerosis,
sity. Megakaryocytes also are present in the systemic venous blood. if its utility is confirmed in additional studies. 310
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An increase in blood CD34+ cells is very characteristic of primary mye- The marrow in the prefibrotic stage usually has no or slight reticu-
lofibrosis, and the concentration of these cells lends weight to the diag- lar fibrosis. The marrow is cellular and there is often an increase propor-
nosis. The height of the CD34+ cell count is correlated with the extent of tion of late neutrophil precursors (myelocytes, metamyelocytes, bands).
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disease and disease progression. Greater than 15 × 10 /L blood CD34+ Myeloblasts and CD34+ cells are inconspicuous. Erythropoiesis may
cells is virtually diagnostic of primary myelofibrosis, and patients with be slightly decreased. Increased and abnormal megakaryocytopoiesis
greater than 300 × 10 /L CD34+ cells have more rapid progression of is the hallmark of this phase. Clusters of megakaryocytes are present.
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disease than patients with fewer CD34+ cells. 289 Megakaryocytes are large and admixed with small megakaryocytes.
Endothelial progenitor cells (CD34+CD133+ and VEGF receptor Nuclei are often ballooned and have scalloped margins. Bare megakary-
2–positive cells) are significantly higher in the blood of primary myelo- ocyte nuclei are present. Megakaryocyte involvement is facilitated by
fibrosis patients than of normal subjects. 89 staining the marrow with a megakaryocyte marker such as CD61.
Mild lymphocytopenia resulting from decreased CD3+, CD4+,
CD8+, and CD3–/CD56+ T cells is the rule. 295 Cytogenetic Findings
Chromosome abnormalities of hematopoietic cells are evident in
approximately 40 percent of patients at the time of diagnosis. 311–316 The
FUNCTIONAL ABNORMALITIES OF most frequent findings are partial trisomy 1q, interstitial deletion of a
segment of the long arm of chromosome 13, del(13)(q12–22), which
BLOOD CELLS bears the retinoblastoma gene, 312-314,317 del 20q, and trisomy 8. Involve-
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The neutrophils of some patients have impaired phagocytosis, oxygen ment of chromosome 5, 6, 7, 9, 13, 20, or 21 occurs with heightened
consumption, nitroblue tetrazolium reduction, and hydrogen peroxide frequency. The 5q– abnormality is more prevalent in primary myelofi-
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generation, and decreased myeloperoxidase 296,297 and glutathione reduc- brosis than any other chronic myeloproliferative disorder. Abnormality
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tase activities. CD34+ cells have impaired in vitro differentiation to of chromosome 12 resulting from several translocations or deletion or

Kaushansky_chapter 86_p1319-1340.indd 1326 9/18/15 10:23 AM