Page 1344 - Williams Hematology ( PDFDrive )

1319

CHAPTER 86 DEFINITION AND HISTORY

PRIMARY MYELOFIBROSIS Primary myelofibrosis is a chronic clonal myeloid neoplasm character-
ized by (1) anemia; (2) neutrophilia and thrombocytosis or, in a minor-
ity, thrombocytopenia and leukopenia; (3) splenomegaly; (4) immature
granulocytes, increased cluster of differentiation (CD) 34+ cells, ery-
Marshall A. Lichtman and Josef T. Prchal throblasts, and teardrop-shaped red cells in the blood; (5) marrow fibro-
sis; and (6) osteosclerosis. The disorder originally was described by
Heuck in 1879 under the title “Two Cases of Leukemia and Peculiar
1
SUMMARY Blood and Bone Marrow Findings.” In his monograph, Silverstein
traced the history of the concepts set forth during the first half of the
20th century to explain the pathogenesis of this disease, including its
Primary myelofibrosis is one of several disorders in the spectrum of clonal origin in the marrow, the appearance of extramedullary hematopoiesis,
myeloid diseases, malignant diseases that originate in the clonal expansion of and the relationship of fibrosis to hematopoietic changes. The disease
2
a single hematopoietic multipotential cell reprogrammed by several somatic occurs, often, de novo but can develop as a later phase of polycythe-
mutations. It is one of the eight neoplasms, including polycythemia vera and mia vera (Chap. 84), essential thrombocythemia (Chap. 85), or, rarely,
essential thrombocythemia, classified as a myeloproliferative disease by the chronic myelogenous leukemia (Chap. 89), or an atypical myeloprolif-
World Health Organization. Approximately 90 percent of cases have a mutation erative disease (Chap. 89). It may be preceded by a prefibrotic phase (see
in the Janus kinase 2 (JAK2) gene (~50 percent), the calreticulin (CALR) gene “Special Clinical Features: Prefibrotic Primary Myelofibrosis” below).
(~35 percent), or the thrombopoietin receptor (MPL) gene (~4 percent). The Numerous designations for the disease have been proposed or used, and
3
disease is characterized, classically, by anemia, mild neutrophilia, thrombocy- different names were preferred in different countries. Primary myelofi-
tosis, and splenomegaly. Occasional cases may present with bi- or tricytopenias brosis has been designated the most recent “official” name of the disease
3
(~15 percent). Immature myeloid and nucleated red cells, teardrop-shaped by a working group on classification of the World Health Organization.
This compromise selection is unfortunate as the fibrosis is secondary,
erythrocytes, and large platelets (megakaryocyte cytoplasmic fragments) are not primary, and the choice omits focusing on the central pathologic
characteristic features of the blood film. The marrow contains an increased change: a clonal myeloid disease with the singular finding of neoplastic
number of neoplastic dysmorphic megakaryocytes and increased reticulin (dysmorphic) megakaryocytopoiesis. It is a disease of cells, not fibers,
4
fibers and, often later, collagen fibrosis. This reactive, polyclonal fibroplasia and is the only cancer in the medical lexicon not so designated; rather, it
is the result of cytokines (e.g., transforming growth factor-β) released locally is named for an epiphenomenon in the extracellular matrix.
by the numerous neoplastic megakaryocytes. Osteosclerosis, also, may be The discovery that the mutated Janus kinase 2 (JAK2) gene muta-
present. The disease may be complicated by (1) portal hypertension and gas- tion can play a role in the causation and behavior of several myeloprolif-
5
troesophageal varices as a result of a very large splenic blood flow and loss of erative diseases and that approximately 50 percent of cases of primary
6
compliance of hepatic vessels, (2) extramedullary fibrohematopoietic tumors myelofibrosis have a mutation of the JAK2 gene or, far less commonly,
that can develop in any tissue and lead to symptoms by compression of vital thrombopoietin receptor (MPL) gene has led to better understanding of
structures, and (3) abdominal vein thrombosis (Budd-Chiari syndrome). Newly the pathogenesis of the disease and its relationship to other myelopro-
liferative diseases. The JAK signaling pathways also represent an impor-
developed JAK2 inhibitors are now first-line therapy for splenomegaly and tant new target for therapy. The subsequent observation of mutations
constitutional symptoms (fever, night sweats, and weight loss). Other treat- of the calreticulin (CALR) gene in approximately 70 percent of patients
ment has included hydroxyurea for thrombocytosis and massive splenomeg- without a JAK2 or MPL mutation has provided deeper insights into the
aly, androgens, erythropoietin, or red cell transfusions for severe anemia, local pathogenesis of myelofibrosis, the opportunity to examine interactions
irradiation of fibrohematopoietic tumors or of a massive, symptomatic spleen, among somatic mutations in the cells of patents, and the opportunity for
or splenectomy for severe cytopenias, if splenic effects are not controlled by new therapeutic approaches (see “Etiology and Pathogenesis” below). 7
JAK2 inhibitors. Portosystemic shunt surgery may be required for gastroesoph-
ageal variceal bleeding. In younger patients, allogeneic hematopoietic stem
cell transplantation can be curative and nonmyeloablative transplantation has EPIDEMIOLOGY
been successful, at least up to age 60 years. The disease may remain indolent INCIDENCE
for years or may progress rapidly by further deterioration in hematopoiesis, by
massive splenic enlargement and its sequelae, or by transformation to acute Age and Sex 2,8–16
myelogenous leukemia. Primary myelofibrosis characteristically occurs after age 50 years.
The median age at diagnosis is approximately 65 to 70 years, 8,12–14,17 but
the disease also can occur in neonates and children. 2,12,14,18–20 In infants,
the disorder can mimic the classic disease or show certain features but
not others, such as absence of hepatosplenomegaly. Familial infantile
19
myelofibrosis mimics the adult disease and in some cases is transmit-
Acronyms and Abbreviations: AML, acute myelogenous leukemia; bFGF, basic ted by autosomal recessive inheritance. 20–23 The occurrence of primary
fibroblast growth factor; bp, base pair; CALR, calreticulin gene; CD, cluster of differen- myelofibrosis in children usually is in the first 3 years of life. 20,24,25 In
tiation; CML, chronic myelogenous leukemia; FISH, fluorescence in situ hybridization; young children, girls are afflicted with the disease twice as frequently
G6PD, glucose-6-phosphate dehydrogenase; G-CSF, granulocyte colony-stimulating as boys. In young and middle-age adults, the disease is similar to that
19
factor; IL, interleukin; JAK2, Janus kinase 2 gene; MPL, thrombopoietin receptor gene; in older subjects, although the proportion of indolent cases may be
MRI, magnetic resonance imaging; PDGF, platelet-derived growth factor; TGF, trans- higher. 18,20,26 In adults, the disease occurs with about equal frequency in
27
forming growth factor; TNFR, tumor necrosis factor receptor. men and women. 8,12–16 Like virtually all clonal myeloid diseases, pri-
mary myelofibrosis can cluster in families, suggesting transmission of

Kaushansky_chapter 86_p1319-1340.indd 1319 9/18/15 10:22 AM