Page 882 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 55 Progress in the Classification of Hematopoietic and Lymphoid Neoplasms 765

Mast cell disease is yet another disease related to abnormal TK type (M5A, M5B), a type with a prominent erythroid component
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signaling, in this case the KIT gene. Its classification system gener- (M6), and a megakaryoblastic type (M7) (Table 55.4).
ally considers systemic mastocytosis and cutaneous mastocytosis as FAB classification provided a framework and defined criteria for
main entities but also includes a mast cell proliferation associated different types of acute leukemia. However, leukemia-associated genetic
with clonal nonmast cell hematopoietic malignancies; this can be changes, first recognized in the 1980s, seemed to provide more
another myeloid malignancy or, less commonly, a lymphoid malig- important prognostic information and did not always correlate well
nancy. With the advances of comprehensive mutational profiling, it with the FAB-defined entities. As the cytogenetic abnormalities
is proposed that additional mutations in SRSF2, ASXL1 and/or became more widely appreciated and their prognostic implications
+
RUNX1 identify a high-risk group of patients with KIT D816V better understood, classification schemes based solely on the “favor-
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advanced systemic mastocytosis. A more recently improved under- able”, “intermediate”, and “adverse” prognostic cytogenetic findings
standing of the cellular and molecular basis of eosinophilic disorders were introduced and used along with or as an alternative to the FAB
has translated into more biologically oriented classification schemes scheme (Table 55.4).
that carry therapeutic implications. Thus in 2008 the WHO estab- The AML WHO classification published in 2001 provided a
lished a semimolecular classification scheme of separately listed different strategy from that used by the FAB in two important ways:
disease subgroups including “myeloid and lymphoid neoplasms with it redefined AML as requiring only 20% blasts in the BM or blood,
eosinophilia and abnormalities of platelet-derived growth factor and it emphasized the importance of the associated cytogenetic
receptors (PDGFRA, PDGFRB), or fibroblast growth factor receptor abnormalities. The change in blast percentage came from the recogni-
1(FGFR1)”, chronic eosinophilic leukemia (CEL), not otherwise tion that patients with 20% to 30% blasts, who previously were
specified (NOS), lymphocyte-variant hypereosinophilia, and idio- classified as having MDS (refractory anemia with excess of blasts in
pathic hypereosinophilic syndrome (see Chapter 71). Although quite transformation [RAEB-T] in the FAB MDS classification), often had
uncommon, these are noteworthy because, similar to CML, they have outcomes similar to those with AML and frequently required treat-
also been found to be caused by dysregulation of TK signaling (caused ment as if they had been diagnosed with AML. Furthermore, the
by mutations in PDGFRA, PDGFRB, or FGFRA) and at least partially inclusion of cytogenetics recognized the important prognostic infor-
successfully treated with TK inhibitors. 16 mation associated with these abnormalities, as well as the fact that
It is important to emphasize that diagnosis of the MPNs does not cytogenetics could point to the underlying molecular pathogenesis.
rest solely with the routine microscopic examination. The diagnostic As we learned from our experience with CML, this was critical in
work-up is more far-reaching and must include reviewing the clinical developing new drugs and treatment strategies. However, the WHO
history and pertinent physical findings, as well as obtaining and classification recognized that not all acute leukemias could be defined
assessing laboratory values, including recent complete blood cell by cytogenetic abnormalities and that some needed to be defined
counts. Examination of a well-prepared peripheral blood smear and either clinically or still based on morphologic findings. In this regard,
both BM aspirate and biopsy specimens are still crucial. However, the 2001 classification recognized four major subclasses of AML:
ancillary studies, such as cytogenetic and molecular analysis, as well AML with recurring cytogenetic abnormalities; therapy-related AML
as other more specific laboratory evaluations, are just as important in (subclassified further as those with etoposide treatment and those
formulating the correct diagnosis, and in particular, in distinguishing with a history of cytotoxic drug therapy or radiation); AML with
MPNs from reactive myeloid proliferations. This is particularly true, multilineage dysplasia; and cases that did not fit into the other sub-
for example, regarding the JAK2 V617F or other driver mutations, classes that are referred to as AML not otherwise categorized (Table
and the impact not only on the diagnosis but also on the prognostica- 55.4).
tion of MPNs. A 2008 revision of the 2001 classification scheme emphasized
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risk-based stratification and made a number of changes (Table 55.4).
In particular, it expanded the cytogenetic abnormality-associated
The Acute Myeloid Leukemias cases to those with some less common translocations. It added pro-
visional entities defined by mutations often occurring in cytogeneti-
The historical and emerging classifications systems for AML dramati- cally normal cases, namely those with NPM1 and CEBPA mutations.
cally illustrate the marked heterogeneity of these diseases. Despite this It combined the different types of therapy-related MDS/AML and
heterogeneity, however, to date a major breakthrough has not been renamed this category therapy-related myeloid neoplasm (t-MN). It also
made in the development of specific initial treatment for AML as an redefined the dysplasia-associated cases by allowing the cases to be
entity apart from acute promyelocytic leukemia. However, to a large identified by history (of previous MDS), morphology (with multilin-
extent this concept is changing as newer agents targeting molecularly eage dysplasia), or by cytogenetics (with defined chromosomal
or genetically defined AML have become available (e.g., FMS-like changes associated with dysplasia). Additional categories were also
tyrosine kinase-3 [FLT3] inhibitors for FLT3-mutated cases). 17,18 It added, including AML associated with Down syndrome, acute
is anticipated that the gap between the growing number of unique panmyelosis with MF, granulocytic sarcoma, and blastic plasmacytoid
or genetically defined acute leukemia types and the somewhat limited dendritic cell tumor. The 2008 classification eventually defined more
treatment options may begin to close. than 25 different types of AML. The advent of newer technologies,
The French–American–British (FAB) classification of AML, such as single-nucleotide polymorphism array karyotyping and next-
introduced in 1976 with its subsequent revision in 1985, provided generation sequencing, facilitated the recognition of several relevant
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the first real framework for classifying the AMLs. It also provided driver mutations. Molecular analysis for leukemic driver mutations,
fairly reproducible definitions of diseases. The classification was particularly in the cytogenetically normal AML subgroup (40% to
mainly based on morphologic and cytochemical features of the leu- 50% of AML patients), has been incorporated into routine clinical
kemic blasts in the BM. In general, the FAB scheme required that practice to assess disease progression and prognosis. Important muta-
30% of the BM-nucleated elements be blasts; then it further defined tions involve FLT3, NPM1, KIT, CEBPα, TET2, DNMT3A, and
AML subtypes based on the presence of maturation in the granulo- IDH1. Although the relevance of many of these mutations to prog-
cytic series, the presence of a monocytic component, and the presence nosis is defined, some are still debated and their coexisting conse-
of an erythroid component. Later, as immunophenotyping allowed quences are yet to be determined.
for improved identification of myeloid precursors, acute megakaryo- With the development of more sensitive analysis, the subclassifica-
blastic leukemia and AML with minimal differentiation were added. tion of AML patients has become more detailed. The proposed
The types of AML noted in the revised FAB scheme included one revisions to AML classification in 2016 remain largely unchanged
with minimal differentiation (MO), one without maturation (M1), for the entities of AML and NOS, with the exception of including
one with maturation (M2), and acute promyelocytic leukemia (M3). the erythroid/myeloid subtype of acute erythroid leukemia with
Also included were a type with combined monocytic and myeloid MDS. The 2016 revisions are expected to include recognition
(neutrophilic) components (M4), a pure monocytic or monoblastic of new cytogenetic subgroups such as AML with BCR-ABL and