Page 884 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 55 Progress in the Classification of Hematopoietic and Lymphoid Neoplasms 767

accompanied cryptic deletions of antigen receptors, particularly BM (Table 55.5). As noted earlier, in the FAB scheme AML was
immunoglobulin heavy chain (IGH) gene rearrangement; this was defined by the presence of 30% or more blasts in the blood or BM.
recently shown to be specific for de novo disease. 20,21 This update is The FAB included CMML in the MDS category, although it was
also anticipated to include new and revised mutations subgroups. For recognized that CMML differed in that it had a proliferative compo-
example, AML with RUNX1 mutations will include only de novo nent with increased numbers of circulating monocytes. At times,
cases. AML with CEBPα will be heterozygous/double mutations (Fig. leukocytosis was a predominant feature of the so-called myeloprolifera-
55.1). In addition, NPM1 and double mutations in CEBPα will tive type of CMML, but this was considered to be a dysplastic form
trump multilineage dysplasia in de novo disease without MDS-related and was classified as a type of MDS when the white blood cell count
cytogenetics abnormalities other than del(9q). There will be a greater was less than 13,000/µL.
emphasis on the recognition of familial myeloid neoplasms, with an The 2001 WHO classification of MDS resulted in significant
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added classifications section. Overall, the 2016 WHO Classification changes to the classification of both MDS (Table 55.5) and AML (as
of AML will have limited changes but will recognize the importance discussed earlier). As mentioned previously, the most notable change
of mutations studies without making the classification overly complex. was the reduction in the blast percentage required for a diagnosis of
AML from 30% to 20%, leading to the elimination of the RAEB-T
category. The 2001 classification also included a new subtype of
The Myelodysplastic Syndromes MDS that, despite the lack of increased blasts (less than 5%), had a
more aggressive course, probably owing to the presence of more
The earliest recognition of myelodysplastic disorders as a clinical pronounced multilineage dysplasia. This category was called refractory
entity came with the identification of long-standing and treatment- cytopenia with multilineage dysplasia (RCMD), and it comprised a
refractory anemia as occasionally representing a preleukemic disorder substantial proportion of cases previously grouped in the low-grade
(see Chapters 60 and 63). MDS patients classically present with RA and RARS categories. Although the recognition of RCMD served
pancytopenias and a hypercellular BM with ineffective hematopoiesis to deemphasize the importance of the blast percentage for prognosis,
and multilineage dysplasia, with or without an increase in blast cell these classifications subdivided the RAEB category into two types,
numbers. Although this is fairly typical, it belies the wide pathologic with 5% to 9% blasts (RAEB-1) and 10% to 19% blasts (RAEB-2),
spectrum of MDS, which includes cases that are diagnostically chal- paradoxically emphasizing the prognostic significance of blast per-
lenging, and which can be difficult to distinguish on one hand centage in this category.
from benign causes of cytopenias in older adult patients, and on the An additional significant change in the WHO 2001 MDS clas-
other hand from AML and other more aggressive clonal myeloid sification scheme included the exclusion of CMML from the MDS
neoplasms. category, and the development of a separate nosologic group for
The FAB group proposed the first formal classification of MDS CMML and other diseases in which there were features of both
5
in 1982. In this classification scheme, the myelodysplastic disorders myelodysplasia and myeloproliferation at the time of diagnosis. These
were divided into four subtypes based on increasing blast cell numbers “overlap” disorders are mentioned briefly later.
or as chronic myelomonocytic leukemia (CMML). The four entities Further refinements in the WHO classification scheme for MDS
included refractory anemia (RA), refractory anemia with ring sidero- were made subsequently in 2008 (Table 55.5). These included
blasts (RARS), refractory anemia with excess of blasts (RAEB), and expanding low-grade MDS from refractory anemia to refractory
refractory anemia with excess of blasts in transformation (RAEB-T). cytopenia with unilineage dysplasia (RCUD), thereby recognizing
These entities differed mainly by the percentage of blasts seen in the that the megakaryocyte or granulocyte lineage could be equally

Fig. 55.1 ALIGNMENT DATA OF INTEGRATIVE GENOMICS VIEWER FOR DOUBLE CEBPA
MUTATIONS IDENTIFIED IN AN AML PATIENT. The left side shows c.63_64delinsA, p.Ser21fs, the
right side shows c.914A>C, p.Gln305Pro. The CEBPα N-terminal frame-shift mutation (p.Ser21fs) is pre-
dicted to disrupt the normal function of CEBPα. The other CEBPA mutation (c.914A>C, p.Gln305Pro) is
a C-terminal missense mutation that has been reported in AML patients. Double-CEBPα mutations (as seen
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in this patient) are found in 5% of patients with AML and are associated with a favorable outcome.
CEBPα-double mutant AML patients also had a significantly better overall survival at 8 years.