Page 1270 - Hematology_ Basic Principles and Practice ( PDFDrive )

1116 Part VII Hematologic Malignancies

clustering of megakaryocytes, and a mild increase in BM fibrosis. The presence of clonal hematopoiesis, at least in one lineage,
Surprisingly, more prolonged follow-up of members of the Dutch quickly establishes the diagnosis of ET. Unfortunately, techniques to
family due to overproduction of thrombopoietin have revealed study clonality are currently not widely available and are restricted to
progression to symptomatic MF in one individual and progression the evaluation of female patients. Such studies may be particularly
to acute leukemia in a second family member. The patient with useful in young female patients with thrombocytosis. Probes for a
acute leukemia had not received any chemotherapeutic agents, and variety of genes on the X chromosome can be informative for clonal
evaluation of the strength of the relationship between this high analysis of blood cell production in more than 72% of female Ameri-
thrombopoietin condition and the development of acute leukemia cans. In such patients, analysis of restriction fragment length poly-
requires further investigation of these families. Similarly, patients morphisms can be used to establish a pattern of clonal hematopoiesis,
with an activating mutation of MPL, MPL-S505N, also have a high which is indicative of a hematologic malignancy and established the
incidence of major thrombotic events, including stroke, myocardial diagnosis of ET in a young female patient with thrombocytosis who
infarction, and Budd-Chiari syndrome. In adult patients, overt BM was lacking a driver mutation. Polyclonal hematopoiesis is found in
reticulin and collagen fibrosis associated with mild reductions in all cases of reactive and familial thrombocytosis. Polyclonal hemato-
hemoglobin levels have been observed, but differences in platelet poiesis, however, does not exclude the diagnosis of ET because in
counts, incidence in thrombotic episodes, or splenomegaly have several series almost one-third of patients who met the clinical criteria
not been observed when one compares these individuals with ET for ET had polyclonal hematopoiesis in all studied lineages. The
patients. In women with MPL-S505N, hematopoiesis was polyclonal, biogenesis of this polyclonal form of ET is poorly understood. Initial
and the mutation was observed not only in hematopoietic tissues but studies, however, have suggested that women with polyclonal hema-
also other somatic tissues. Family members who are affected by this topoiesis may have fewer thrombotic complications than those with
mutation appear to have a significantly shorter survival time than clonal hematopoiesis.
nonaffected family members who did not have thrombocytosis, with At times, it is impossible to define the cause of an individual
affected individuals dying most frequently of thrombotic events or patient’s thrombocytosis. In an asymptomatic patient, follow-up to
complications of MF. By contrast, individuals with either MPL-K39N determine whether the degree of thrombocytosis increases is war-
or MPL-P106L, which both involve the extracellular domain of MPL, ranted. If additional clues to the cause of the thrombocytosis are
affecting its ability to bind thrombopoietin, were not observed to subsequently revealed, a diagnosis will become apparent. Some reas-
have an increased risk for thrombosis, splenomegaly, or BM fibrosis. surance is provided by reports of larger cohorts of patients, each with
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Table 69.3 outlines the 2016 WHO criteria for the diagnosis of platelet counts of greater than 1000 × 10 /L, which have been fol-
ET that incorporates JAK2V7617F, CALR and MPL mutational lowed for years. Virtually none of the patients with reactive throm-
analyses. RBC mass and plasma volume studies, if available, are bocytosis developed a cerebrovascular accident, thrombophlebitis, or
sometimes helpful in differentiating between JAK2V617F-positive a peripheral arterial thrombosis.
ET with borderline elevated hematocrits from patients with PV, but
such patients likely represent a continuum of evolution of a
JAK2V617F-positive hematologic malignancy. BM karyotypic analy- PROGNOSIS
sis or studies of the BCR-ABL fusion gene are imperative in every
patient to exclude the diagnosis of CML or to detect another clonal The probability that a patient with ET will survive 10 years ranges
hematologic malignancy. This step is necessary because the natural from 64% to 80%. In a large study from Spain with extensive
history of these disorders is very different, and early therapeutic follow-up, there was no substantial difference between the probability
intervention with specific medical therapy for CML, such as a of survival of patients with ET and that of a control population.
BCR-ABL tyrosine kinase inhibitor is essential. However, a study of 322 consecutive patients seen at the Mayo Clinic
Occasionally, ET may be distinguished from RARS-T. These and followed for a median follow-up of 13.6 years showed a different
patients present with thrombocytosis that is associated with a pattern. Survival of patients with ET was similar to that of the control
moderate-to-severe anemia and frequently splenomegaly. Their BMs population during the first decade of disease, but the survival became
are characterized by the morphologic features of ET and the presence significantly worse thereafter. Multivariable analysis identified an age
of more than 15% ringed sideroblasts. This entity likely represents a at diagnosis of 60 years or older, leukocytosis (>15,000/µl), previous
heterogeneous, poorly defined disorder that includes a spectrum of venous thrombosis, tobacco use, and diabetes mellitus as independent
conditions sharing features of an MPN and a myelodysplastic disor- predictors of poor survival. The risk of developing leukemia or MF
der. This entity is associated with JAK2V617F in 58% of reported was low in the first 10 years (1.4% and 3.8%, respectively) but
patients, MPLW515 mutation in 7% of reported patients, and CALR increased substantially in the second (8.1% and 19.9%, respectively)
mutation in <5% of patients. Occasional patients with thrombocy- and third (24.0% and 28.9%, respectively) decades of the disease.
tosis and increased ringed sideroblasts but without anemia have also The presence of the JAK2V617F mutation did not influence either
been described. Patients with RARS-T have a similar prognosis as ET survival or the rate of leukemic transformation in this analysis. The
patients. RARS-T has been recently shown to be associated with rate of leukemic transformation was higher in patients with platelet
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somatic mutations of SF3B1, a gene encoding a core component of counts above 1000 × 10 /L and abnormal hemoglobin levels. The
the RNA splicing machinery. RARS-T therefore likely results from a development of MF was heralded by the appearance of immature
combination of SF3B1 and JAK2 or MPL mutations. About 25% of myeloid precursors and dacryocytes in the blood smear, and increased
patients with RARS-T have wild-type SF3B1, suggesting that other serum lactate dehydrogenase levels followed by a reduction in platelet
molecular defects can be associated with RARS-T. numbers and progressive splenomegaly. The presence of CALR,
Because patients with preMF frequently present with thrombocy- which occurs in 15–25% of patients with ET and is mutually exclu-
tosis, this form of PMF can frequently be difficult to distinguish from sive with mutations in JAK2 and MPL, is associated with younger
ET. This early form of PMF was previously referred to as a prefibrotic age, male sex and higher platelet counts, lower hemoglobin levels,
form of PMF. In prePMF, nucleated RBCs, teardrop-shaped RBCs, and a lower risk of thrombotic complications.
immature myeloid cells, and megathrombocytes are observed in the The International Prognostic Score for Essential Thrombocythe-
peripheral blood. In the BM biopsy, the megakaryocytes are markedly mia (IPSET) was developed from the retrospective review of clinical
abnormal, a morphologic finding that is helpful in distinguishing this outcome of 891 patients with ET diagnosed by WHO criteria in
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entity from ET. In prePMF, the megakaryocytes often appear in which age ≥60 years, leukocyte count ≥11 × 10 /L, and history of
clusters adjacent to the sinusoids; deviations in the nuclear cytoplas- thrombosis were determined to have prognostic significance for
1
mic ratio in the megakaryocytes are observed with abnormal patterns survival, with weighted values of 2, 1, and 1 points, respectively. The
of chromatin clumping, and plump clouds similar to a balloon- IPSET categories of low (no points), intermediate (1–2 points), or
shaped lobulation of the nuclei are observed associated with minimal high (3–4 points) had corresponding median survivals of not yet
fibrosis or even absent reticulin fibrosis during this stage of PMF. reached, 24.5 years, and 13.8 years, respectively. Analysis of this