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1310 Part X: Malignant Myeloid Diseases Chapter 85: Essential Thrombocythemia 1311

LEUKEMIC TRANSFORMATION analysis for MPL, and fragment length analysis for CALR exon 9. 25,51 In
Progression to acute myeloid leukemia (AML) occurs in a small minor- the absence of marrow cytogenetic analysis, molecular testing for the
ity of patients, with retrospective studies suggesting a prevalence of 1 BCR-ABL1 fusion gene is also recommended to exclude CML. Screen-
to 2.5 percent in the first decade after diagnosis, 5 to 8 percent in the ing for additional mutations (e.g., TET2) is currently of uncertain utility
second decade, and continuing to rise thereafter. 34,40,46 Therapeutic het- in routine clinical practice.
erogeneity in these studies, however, renders their findings difficult to
interpret. Studies in PV demonstrated a significantly increased risk of MARROW STUDIES
AML in patients receiving genotoxic agents such as radioactive phos-
phorus, chlorambucil, or busulphan. 47,48 The potential leukemogenicity Marrow aspiration and trephine biopsy is particularly recommended in
of hydroxyurea remains controversial (see “Choice of Cytoreductive suspected cases of ET that are negative for a relevant somatic mutation.
Agent” below). Importantly, transformation to leukemia has been Marrow studies may also be useful in cases showing atypical clinical or
reported in the absence of any cytoreductive therapy, 49,50 indicating that laboratory features (for example, palpable splenomegaly, unexplained
AML is part of the natural history of this disorder. anemia or blood film abnormalities) or in the context of a clinical study.
Therapy of post-ET AML is often limited by the older age of the The marrow aspirate in ET often shows large hyperlobulated megakary-
affected patients, in whom palliative treatment may be the most appro- ocytes (see Fig. 85–2B), and iron staining may be helpful in excluding
priate strategy. Overall the prognosis of secondary AML is poor (Chap. iron deficiency or the presence of ringed sideroblasts (see “Differential
88). Younger patients who do achieve remission with AML induction Diagnosis” below). The marrow trephine biopsy typically shows an
therapy may be considered for allogeneic hematopoietic stem cell increase in megakaryocyte frequency with megakaryocyte clustering
transplantation. and nuclear hyperlobulation in the absence of significant reticulin fibro-
sis (see Fig. 85–2C). Cellularity is usually normal or slightly increased,
but occasional cases may show a hypocellular marrow, for example, a
LABORATORY FEATURES proportion of those with mutations in MPL. 17,18
Chromosomal analysis, by G-banding or in situ fluorescent
An unexplained and persistently raised platelet count generally war- hybridization, is helpful in suspected cases of ET lacking a relevant
rants further investigation (Fig. 85–3). Establishing a diagnosis of ET somatic mutation, primarily to exclude lesions associated with other
requires exclusion of both reactive conditions and other myeloprolif- myeloid disorders such as t(9:22) (CML) or deletions of chromosome
erative or myelodysplastic disorders that may present with an isolated 5q (“5q-minus syndrome”; Chap. 87). Other karyotypic abnormalities,
thrombocytosis (Tables 85–1 and 85–2). mainly comprising deletions of chromosomes 20q or 13q or additional
copies of chromosomes 8 or 9, are found in approximately 5 percent of
ET patients and establish the existence of clonal hematopoiesis.
HEMATOLOGIC AND BIOCHEMICAL
PARAMETERS DIFFERENTIAL DIAGNOSIS

An elevated platelet count is invariably present and may be only slightly
increased (e.g., ≥ 400 × 10 /L) or massively elevated into the millions × REACTIVE THROMBOCYTOSIS
9
10 /L. Thus, the degree of thrombocytosis varies markedly between
9
patients. The white count may be slightly to mildly elevated but usu- A secondary increase in platelet count, initiated by cytokines such as
ally not above 20 × 10 /L as a result of neutrophilia. The hemoglobin interleukin-6 and directly driven by the induction of hepatic thrombo-
9
concentration may be normal or mildly reduced. If occult bleeding has poietin production is associated with a number of infectious, inflam-
been present, the hemoglobin may be further decreased and indications matory and malignant disorders (see Table 85–2; Chap. 119). In reports
of iron deficiency may be evident in the red cells (microcytosis and of unselected patients attending various hospital departments, an
hypochromia; see “Differential Diagnosis” below). Examination of the increased platelet count was attributable to reactive causes in more than
blood film often reveals large platelets which may stain poorly, and is 80 percent of cases; the degree of thrombocytosis did not permit dis-
useful in excluding features of PMF such as teardrop cells (dacryocytes) tinction between a clonal versus a reactive pathogenesis. 52,53
or circulating immature granulocyte precursors.
FAMILIAL THROMBOCYTOSIS
SERUM CHEMICAL FINDINGS Familial thrombocytosis is a rare disorder caused by mutations in the
Levels of thrombopoietin are normal or slightly elevated in ET and thrombopoietin gene, MPL, or other unknown genes. Changes in the
have no diagnostic utility. ET patients may show a spurious increase in 5´-untranslated region or splice donor/acceptor sites of the thrombo-
serum potassium level as a result of in vitro activation of platelets and poietin gene are associated with increased translation of thrombopoi-
54
leukocytes during processing of serum; this phenomenon can be cir- etin and consequent thrombocytosis. These alleles are dominantly
55
cumvented by using a plasma sample for biochemical analysis. inherited and have not been seen in clonal MPNs. A dominantly
inherited, activating MPL allele (MPL S505N ) has been reported in
Japanese and Italian kindreds. Of interest, this allele has also been
54
MOLECULAR TESTING reported as a somatic mutation in patients with a clonal MPN.
17
Molecular testing for genetic mutations has become the investigation Several different inherited JAK2 alleles have been reported in fami-
of choice for patients with an unexplained and persistent increase in lies with autosomal dominant thrombocytosis (including JAK2 R564Q ,
platelet count (see Fig. 85–3). A reasonable approach is to screen all JAK2 V617I , JAK2 R867Q , and JAK2 S755R/R938Q ). 56,57 Although complicated by
patients for the JAK2 V617F mutation, following by screening for muta- occasional thrombotic or bleeding episodes, the clinical phenotype of
tions in CALR and uncommon MPL in negative cases. Suitable tech- familial thrombocytosis is relatively mild, although exceptions occur.
54
niques include allele-specific or real-time polymerase chain reaction The genetic cause underlying a subset of familial cases remains to be
(PCR) for JAK2 V617F , pyrosequencing or high-resolution melt curve elucidated.

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