2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

Classification of Myeloproliferative
Neoplasms and Prognostic Factors
Overview: Myeloproliferative neoplasms (MPNs) are currently
diagnosed according to the World Health Organization
(WHO) criteria. Molecular profiling should include the analysis
of JAK2 V617F (first, exon 12 only in V617F-negative polycythemia
vera [PV]) and MPL mutations (in V617F-negative
essential thrombocythemia [ET] and myelofibrosis [MF]). For
patients with PV and ET, the risk stratification of low- and
high-risk disease requires only two parameters: older than
age 60 and prior history of thrombosis. Additionally, it might
be important to monitor leukocyte count and know the mutational
profile.
MPNs INCLUDE different entities summarized in
Table 1. 1 This article will focus on classical BCR-
ABL1-negative MPNs, including ET, PV, and primary myelofibrosis
(PMF).
Classification of MPNs
MPNs are clonal stem cell neoplasms found to share some
relevant biologic features. Recent molecular advances have
demonstrated that the abnormal myeloproliferation arises
from constitutively active signal transduction pathways,
caused by specific mutations affecting protein tyrosine kinases
or related molecules. Current classification of MPNs is
based on the WHO criteria established in the 2008 revision
(Tables 2-4), which, besides simple clinical parameters,
convey two novelties: molecular genetics and histopathology.
Complete Blood Count (CBC) for MPN Diagnosis
PV is suspected in men with hemoglobin levels greater
than 18.5 g/dL or 16.5 g/dL in women or hemoglobin levels
greater than 17 g/dL in men or 15 g/dL in women if
associated with a documented and sustained increase of at
least 2 g/dL from an individual’s baseline value. It is no
longer necessary to use red cell mass measurement to
exclude secondary polycythemia. In approximately 20% to
40% of PV cases, leukocytosis and/or thrombocytosis might
be present. Thrombocytosis remains a criterion for the
diagnosis of ET. In the revised WHO criteria, the platelet
threshold for the diagnosis of ET was lowered to 450 �
10 9 /L. This level of thrombocytosis is not specific for ET and
can be secondary to other conditions (e.g., iron deficiency,
trauma, infection, inflammation, bleeding), which must be
excluded first. Thrombocytosis can also be present in chronic
myeloid leukemia (CML; test for BCR-ABL1 fusion gene), in
refractory anemia with ringed sideroblasts associated with
marked thrombocytosis (RARS-T; signs of dyserythropoiesis
at morphological examination), and also in PV cases in
which erythrocytosis is not evident because of relative iron
deficiency. Concerning MF, anemia might be accompanied
with leukopenia/leukocytosis and/or thrombocytopenia/
thrombocytosis. Peripheral blood smear should be reviewed
in all MPN cases as microcytic red blood cells in PV/ET
might be a sign of iron deficiency, leukoerythroblastosis is
present in almost all PMF cases, and myeloid progenitors
are typical of CML.
By Francesco Passamonti, MD
Survival of patients with MF is defined by the International
Prognostic Scoring System (IPSS) model at diagnosis and the
Dynamic IPSS (DIPSS) anytime during the course of the
disease. The IPSS and the DIPSS are based on patient age
older than age 65, presence of constitutional symptoms,
hemoglobin level less than 10 g/dL, leukocyte count greater
than 25 � 10 9 /L, and circulating blast cells 1% or greater. The
DIPSS-plus adds critical prognostic information and suggests
also considering cytogenetic categories, platelet count, and
red blood cell transfusion need.
Molecular Genetics for MPN Diagnosis
Screening assays for MPN genetics are not standardized,
and the possibility of false-positives or false-negatives can be
an issue when using highly sensitive allele-specific assays
and in cases of low mutant allele burden. The JAK2 V617F
mutation is found in more than 95% of patients with PV and
in nearly 50% to 60% of those with ET and PMF. It has also
been found in other MPNs but not in nonmyeloid malignancies
or in cases of secondary polycythemia. Therefore, JAK2
V617F is a sensitive diagnostic marker of PV. Although low
JAK2 V617F allele burden is more distinctive of ET than of
PV and MF, mutational load measurement is not useful for
diagnostic purposes. Less than 3% of patients with PV carry
exon 12 mutations of JAK2, and, as different mutations do
not confer different phenotypes, a screening test highresolution
melting is adequate. 2 Exon 12 mutations of JAK2
should be screened in case of JAK2 V617F-negative erythrocytosis
with low erythropoietin level. A small portion of
patients with ET and PMF who lack a mutated JAK2 may
have activating mutations in MPL (mainly W515K/L). For
the time being, the study of JAK2 and MPL mutations is to
be included in the diagnostic workup of MPN, while all other
less prevalent mutations (LNK, NF1, cCBL, SOCS1, TET2,
EZH2, ASXL1, IDH1/2, DNMT3A) cannot enter into the
diagnostic process. 2
Serum Erythropoietin
A simple and timeless PV test is serum erythropoietin
dosage, which can discriminate PV (low level) from secondary
erythrocytosis (high level). In the absence of any JAK2
mutation or in case of unavailability of the JAK2 test, low
erythropoietin levels—if accompanied by MPN-consistent
bone marrow features—is of diagnostic value for PV.
Bone Marrow Histopathology
In the WHO classification, bone marrow histopathology
has assumed a critical diagnostic role, since the distinction
From the Division of Hematology, Department of Internal Medicine, University Hospital
Ospedale di Circolo e Fondazione Macchi, Varese, Italy.
Author’s disclosures of potential conflicts of interest are found at the end of this article.
Address reprint requests to Francesco Passamonti, MD, Division of Hematology, Department
of Internal Medicine, University Hospital Ospedale di Circolo e Fondazione Macchi,
Viale L. Borri 57, 21100 Varese, Italy; email: francesco.passamonti@ospedale.varese.it.
© 2012 by American Society of Clinical Oncology.
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