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Haematological Malignancies
Following molecular findings, the most recent edition of the WHO presence of the JAK2 gene mutation. The other major criterion is
Classification of Tumours of Haematopoietic and Lymphoid Tissues, verified concentration of haemoglobin needed for confirmation of
issued in 2008,
13
has named these disorders as myeloproliferative diagnosis (>16.5 and >18.5g/dl for women and men, respectively).
neoplasms (MPNs), including mastocytosis, taking into account the However, a haemoglobin concentration >15 and >17g/dl for women
origin of the mast cells. This change was based on strong evidence in and men, respectively, can be regarded as diagnostic if associated
terms of clonal mutations that confirmed that the neoplastic with a documented and sustained increase of at least 2g/dl from an
character of haematopoesis is responsible for the pathogenesis of the individual’s baseline. Such modification allows earlier diagnosis than
vast majority of diseases from this group. A well-described molecular was possible previously. It is worth noting that irrespective of time,
marker confirming the diagnosis can be found in most MPNs. The low erythropoietin (one of the minor criteria) is still of diagnostic
presence of the BCR-ABL fusion gene is a sine qua non condition for value, in contrast to splenomegaly.
21
The next two minor criteria are
the diagnosis of CML; mutation of the JAK2 (either JAK V617F in exon dedicated to changes in bone marrow histopathological examination
and assessment of erythroid colony growth in vitro.
Essential changes have been introduced to the diagnostic criteria
It is worth noting that irrespective of ET. The threshold value of a platelet count needed for the
diagnosis is lowered to 450G/l. The fourth criterion is the presence
of time, low erythropoietin (one of the
of mutation of the JAK2 gene or other clonal mutation (e.g. mutation
minor criteria) is still of diagnostic value of the MPL gene). Regrettably, in spite of the progress in molecular
studies, the diagnosis of ET is essentially based on exclusion of
in contrast to splenomegaly.
secondary causes of thrombocytosis.
According to the current WHO classification, the histological bone
14 or mutation, deletion and insertion in exon 12) gene
14
can be found marrow biopsy that reveals proliferation and atypia of megakaryocytes,
in more than 95% of patients with PV; and mutation at codon 816 accompanied by fibrosis, is the main diagnostic criterion for MF. The
(D816V) of the KIT gene is identified in the mast cells of 95% of adults second criterion is JAK2 or MPL gene mutation and, in its absence,
with systemic mastocytosis. In ET and MF, the characteristic mutation exclusion of BCR/ABL mutation. A definitive diagnosis of MF requires
of JAK2 and MPL genes can be found in about 50–60% of patients.
14,15
the fulfilment of at least two of the four minor criteria: presence of
leukoerytroblastosis in peripheral blood, increased serum lactate
It is possible that there is only one JAK2/MPL disorder with various dehydrogenase level, anaemia and splenomegaly.
clinical manifestations (TE-like, PV-like, MF-like), which may depend
on host genetic variations,
16
cells targeted by JAK2/MPL mutation,
17
Persistent eosinophilia ≥1.5G/l is fundamental for the diagnosis of
level of JAK2 kinase activity
18
or additional molecular events.
19,20
CEL NOS. To make the diagnosis of CEL NOS, clonal cytogenetic or
molecular abnormalities should be confirmed. As we mentioned, in
In the new WHO classification, CEL is included in the MPNs, but only
as the entity without molecular marker (not otherwise specified
According to the current WHO
[NOS]). In our opinion, it was not advisable to drop the well-defined
FLIP1L1-PDGFRA fusion gene from MPNs. Although there were some classification, the histological bone
reasons to combine myeloid and lymphoid neoplasms with
marrow biopsy that reveals proliferation
eosinophilia and abnormalities of the PDGFRA, PDGFRB and FGFR1
genes into one category, from a historical and practical point of view and atypia of megakaryocytes,
the exclusion of CEL with FLI1L1-PDGFRA fusion gene from the
accompanied by fibrosis, is the main
group of well-defined MPNs is a little anachronistic. The recent WHO
classification yielded changes in the diagnostic criteria of MPNs. diagnostic criterion for myelofibrosis.
Currently, the criteria are based on molecular markers and
accentuate the value of histopathological examination and verify the our opinion the FIP1L1-PDGFRA fusion gene should also be included.
usefulness of some earlier clinical and laboratory parameters. If no clonal marker is present, blast cells should be >2% in peripheral
blood or >5% in bone marrow.
Although the diagnostic criteria of CML were not essentially modified,
some interesting problems are discussed in the new proposal. The In terms of the possible treatment options, three subgroups of MPN
first one is the presence of monocytosis in rare cases of CML with can be discussed. The first are those diseases in which targeted
p190 BCR/ABL1 isoform, which can be the reason for a faulty therapy was shown to be successful. The second subgroup combines
diagnosis of chronic myelomonocytic leukaemia. The next problem is diseases in which the clinical effect of therapy directed to specific
focal infiltration of bone marrow in the initial period of the blast crisis. molecular marker still awaits confirmation. The third subgroup is
This phenomenon leads to the necessity for a histopathological aggregating diseases in which target therapy is not yet established.
assessment of bone marrow due to the suspicion of a blast crisis,
even when cytological examination does not show characteristic CML is the most representative disease for the first subgroup. The
changes for this phase of disease. treatment strategy for this disease has definitively changed over
the last 10 years. The validation of the effectiveness of imatinib, the
The diagnostic criteria for the last three classic MPN were significantly BCR-ABL kinase inhibitor, was the milestone in CML therapy. The
changed. For PV, there are only two major criteria, with the obligatory introduction of matinib to the therapy of CML made it possible to
58 EUROPEAN HAEMATOLOGY
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