Clinical Chemistry 46: 1252-1259, 2000;
(Clinical Chemistry. 2000;46:1252-1259.)
© 2000 American Association for Clinical Chemistry, Inc.
Multifaceted Approach to the Diagnosis and Classification of Acute Leukemias
Robert W. McKenna1
1
Department of Pathology, University of Texas, Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9072. Fax 214-648-4070; e-mail rmcken{at}mednet.swmed.edu
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Abstract
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Until recently, the diagnosis and classification of acute myeloid (AML)
and acute lymphoblastic (ALL) leukemias was based almost exclusively on
well-defined morphologic criteria and cytochemical stains. Although
most cases can be diagnosed by these methods, there is only modest
correlation between morphologic categories and treatment responsiveness
and prognosis. The expansion of therapeutic options and improvement in
remission induction and disease-free survival for both AML and ALL have
stimulated emphasis on defining good and poor treatment response
groups. This is most effectively accomplished by a multifaceted
approach to diagnosis and classification using immunophenotyping,
cytogenetics, and molecular analysis in addition to the traditional
methods. Immunophenotyping is important in characterizing
morphologically poorly differentiated acute leukemias and in defining
prognostic categories of ALL. Cytogenetic and molecular studies provide
important prognostic information and are becoming vitally important in
determining the appropriate treatment protocol. With optimal
application of these techniques in the diagnosis of acute leukemias,
treatment strategies can be more specifically directed and new
therapeutic approaches can be evaluated more effectively.
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Introduction
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Information obtained from immunophenotyping, cytogenetics, and
molecular analysis has substantially advanced our understanding of the
biology of hematologic malignancies. The evolution of these techniques
from primarily research applications to routine components in the
diagnosis of hematopoietic neoplasms has expanded the diagnostic
capabilities of hematopathology laboratories. This report will discuss
how these techniques contribute to a multifaceted approach to diagnosis
and classification of hematopoietic neoplasms and provide important
treatment and prognostic information. Although acute leukemia will
serve as the model to illustrate the value of immunophenotyping and
cytogenetic/molecular analysis, these studies also play an important
role in the diagnosis of virtually all other types of hematopoietic
malignancies.
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Diagnosis of Acute Leukemia
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The diagnosis of acute leukemia entails a stepwise approach. First
in sequence and importance is the distinction of acute leukemia from
other neoplastic diseases and reactive disorders. Second is
differentiating acute myeloid
(AML)1
and acute lymphoblastic (ALL) leukemia. The third facet is the
classification of AML and ALL into categories that define treatment and
prognostic groups.
morphology and cytochemistry in the diagnosis of acute leukemia
In most cases, the first two facets of the diagnosis of acute
leukemia can be achieved by careful morphological assessment of blood
and bone marrow smears and marrow trephine biopsy sections. The usual
cytologic features of AML and ALL are listed in Table 1
(1)(2). By assessing these morphologic
features together, a majority of cases of AML and ALL can be accurately
diagnosed (Figs. 1
and 2
). In some cases of poorly differentiated acute
leukemia, however, the morphologic features may be equivocal, requiring
additional studies. Cytochemical stains often are useful in
distinguishing poorly differentiated AML from ALL and in identifying
subsets of AML (1)(2). Table 2
shows the cytochemical profiles of acute leukemias for the most
commonly applied cytochemical stains. The myeloperoxidase and Sudan
black B stains are the most commonly used and the most valuable in
distinguishing AML from ALL. In the majority of cases of AML, a
variable proportion of the leukemic cells (blasts) are reactive for
myeloperoxidase and Sudan black B, whereas the stains are uniformly
negative in ALL. With the addition of cytochemistry to the morphologic
assessment, most cases of acute leukemia can be appropriately
designated as either AML or ALL. However, there remains a significant
minority of cases that cannot be definitively diagnosed by these
methods.
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Figure 1. Blood smear (A), flow cytometric
histograms (B), and bone marrow chromosome karyotype
(C) from a 28-year-old man with acute promyelocytic
leukemia, microgranular variant.
(A), the leukemic cells show reniform nuclei and minimal
small granules in the cytoplasm. Identification of this type of AML has
important clinical and therapeutic significance, but its recognition is
often difficult on morphologic assessment alone. (B),
the leukemic cells (red) exhibit increased orthogonal
scatter indicative of cytoplasmic complexity, i.e., granules, and
express CD13, CD33, myeloperoxidase (MPO), and partial
CD11b. They lack expression of HLA-DR and CD34, which is typical of
acute PML and contrasts with most other types of AML.
(C), bone marrow chromosome karyotype shows a single
abnormality, t(15;17)(q22;q21) (arrows). This translocation
involves the PML gene at band q22 on chromosome 15 and
the RAR gene on chromosome 17 band q21, producing a
PML-RAR fusion gene. This fusion gene is present in
all cases of acute PML. The karyotypic or molecular identification of
this translocation is necessary to consider treatment with ATRA because
leukemias with this molecular translocation are the only ones that will
respond. (Karyotype courtesy of Nancy Schneider, MD, PhD,
University of Texas, Southwestern Medical Center, Dallas,
TX).
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Figure 2. Blood smear (A), flow cytometric histograms
(B), and bone marrow chromosome karyotype
(C) from a 12-year-old boy with ALL.
(A), the blasts are relatively small, and have condensed
chromatin and little cytoplasm. These morphologic features are typical
of many cases of ALL and have no prognostic significance.
(B), the leukemic lymphoblasts (red)
express CD19, CD10, partial CD20, CD34, and partial aberrant expression
of CD11b. They lack expression of CD13, CD2, and  and  light
chains. These findings are typical of precursor B-cell ALL. The two
small populations of cells shown in green and
blue are healthy B cells and T cells,
respectively. (C), bone marrow chromosome karyotype in
this case shows a t(9;22)(q34;q11) (Philadelphia chromosome;
arrows). This cytogenetic abnormality in ALL is associated
with a poor prognosis. Unlike most other precursor B-cell ALLs in
children, those with a t(9;22) respond poorly to chemotherapy and have
a poor prognosis. An allogeneic bone marrow transplant should be
performed if a suitable donor is available. (Courtesy of Dr.
Nancy Schneider, MD, PhD, University of Texas, Southwestern Medical
Center, Dallas, TX).
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immunophenotyping in the diagnosis of acute leukemia
The lineage of most cases of morphologically and cytochemically
poorly differentiated acute leukemia can be accurately characterized by
immunophenotyping. Additionally, immunophenotypic subsets of AML and
ALL can be determined (3)(4). Multiparametric
flow cytometry is the preferred method for immunophenotyping acute
leukemias. There is an abundance of monoclonal and polyclonal
antibodies available to assess myeloid and lymphoid lineage-associated
antigens by cytometry, and blood and bone marrow aspirate specimens
lend themselves particularly well to flow cytometric analysis because
the cells are naturally in a fluid suspension. Multicolor flow
cytometry allows for the characterization of up to four different
antigens on a single cell. This permits precise immunophenotypic
characterization of leukemic cells even when they are present in low
numbers. Immunohistochemical staining can be used to immunophenotype
leukemias when a specimen is not submitted for flow cytometry or only
bone marrow trephine biopsies are available for examination. An array
of antibodies to myeloid- and lymphoid-associated antigens is also
available for immunohistochemical stains.
The lineage of hematopoietic cells is defined both by antigens
expressed and the absence of expression of antigens associated with a
different lineage. Leukemia cells, however, may aberrantly express some
antigens of another lineage or lack expression of an expected antigen
(5). It is important, therefore, to use panels that include
sufficient numbers of antibodies to assess a spectrum of both myeloid
and lymphoid antigens. The choice of antibody panels varies among
laboratories; some choose to use a large panel routinely, others screen
with a small panel and add additional antibodies as necessary.
Table 3
shows profiles of antigen expression for various categories of
AML (see Classification of Acute Leukemias). In AMLs,
immunophenotyping is most important in distinguishing poorly
differentiated cases from ALL and in characterizing a few AML subsets
(Fig. 1
). For ALLs, the immunophenotypic categories are particularly
important because they identify distinctive treatment and prognostic
groups (4)(6)(7). The
immunophenotypic classification of ALL is shown in Table 4
. Approximately 80% of cases of ALL have a B-cell precursor
immunophenotype (Fig. 2
) (4)(7)(8). Lymphoblasts in
B-cell precursor ALL express a variable spectrum of early and pan
B-cell antigens but lack surface immunoglobulin, which is found on
mature B lymphocytes. They also contain terminal deoxynucleotidyl
transferase, a nuclear enzyme present in both B- and
T-lymphocyte precursors but not in mature lymphocytes. Approximately
15% of ALLs have an antigen profile of T-cell precursors (thymic T
cells) (6). T-cell lymphoblasts variably express early and
pan T-cell antigens and terminal deoxynucleotidyl transferase. They
often lack surface CD3 but express it in their cytoplasm. A small group
of cases (<5%) of ALL have the immunophenotypic profile of more
mature B cells, i.e., surface immunoglobulin. The importance of
defining the immunophenotype in ALL lies in its correlation with
response to treatment and prognosis (4)(7). In
childhood ALL, immunophenotype is a major factor in determining the
chemotherapy protocol. The immunophenotypic prognostic groups of ALL
are shown in Table 5
. B-cell precursor ALLs have a more favorable prognosis than the
other groups; however, within the B-cell precursor category, there are
subsets with a poor prognosis (7). Most of the favorable and
unfavorable prognostic groups of B-cell precursor ALL can be identified
by their cytogenetic karyotype or molecular features (8).
Immunophenotyping has become a standard diagnostic procedure in
evaluation of acute leukemias. Immunophenotype should be assessed for
diagnosis in all cases of morphologically poorly differentiated acute
leukemia and in every case of ALL because of the important treatment
and prognostic information that it provides.
cytogenetics in the diagnosis of acute leukemias
Clonal cytogenetic abnormalities are identified in 60–80% of
cases of AML and ~80% of cases of ALL (9)(10)(11). Both
numerical and structural abnormalities are common. Tables
6 and
7 list some of the more frequently encountered cytogenetic
abnormalities and their relationships to prognosis
(9)(10)(12)(13)(14)(15)(16).
Hyperdiploidy with >50 chromosomes is the most common cytogenetic
abnormality (
25%) in B-cell precursor ALL (9). It
generally is found in patients between 2 and 10 years of age and is
associated with low or intermediate leukemic cell counts in the blood.
There often is an extra copy of chromosome(s) 4 and/or 10, which seems
to impart a particularly favorable prognosis. ALLs with hyperdiploidy
with >50 chromosomes in children are highly sensitive to
antimetabolite drugs and have a complete remission rate approaching
100% with an ~80% long-term disease-free survival (9).
Structural abnormalities in childhood B-cell precursor ALL are more
often associated with an intermediate or poor prognosis. One exception
is the 12;21 translocation [t(12;21)(p12;q22)], which is observed in
~20–25% of cases (17). This change usually is not
evident by cytogenetic karyotyping and must be identified by molecular
cytogenetic studies [fluorescent in situ hybridization (FISH)] or
PCR (17)(18). Cases of ALL with a
t(12;21) are always B-cell precursor type but are distinct from the
hyperdiploidy with >50 chromosomes group. They are highly sensitive to
antimetabolite drugs and have a high rate of complete remission and
presumably a high incidence of long-term disease-free survival
(19). Patients with B-cell precursor ALL with a 9;22
translocation [t(9/22)(q24;q11)] or abnormalities involving
chromosome 11q23, most often a t(4;11)(q21;q23), have an unfavorable
prognosis (Fig. 2
) (14)(20)(21)(22)(23)(24). In cases with
either of these chromosome rearrangements, the complete remission rate
is lower and the relapse rate is very high; the long-term prognosis is
poor. Allogeneic bone marrow transplantation should be considered as a
primary treatment in patients with these cytogenetic findings. In
childhood B-cell precursor ALL, the likelihood of long-term
disease-free survival or relapse and the decision for low-risk or more
aggressive chemotherapy or a bone marrow transplant are commonly
dictated by cytogenetic findings.
In AMLs, cytogenetic findings are also clinically important. This is
particularly true of cases with the 15;17 translocation
[t(15;17)(q22;q21); Fig. 1
]. The t(15;17) is always associated with
acute promyelocytic leukemia (PML), which usually has distinct clinical
and morphologic features (13)(15). The
translocation involves the PML gene on chromosome 15
and the retinoic acid receptor (RAR) gene on
chromosome 17 (25). The fusion messenger RNA product that
results inhibits maturation of the affected cells, leading to a
proliferation of large numbers of atypical promyelocytes. Treatment
with all-trans-retinoic acid (ATRA) can overcome the
maturation blockage in most cases and lead to temporary complete
remission of the disease (25)(26)(27). Treatment with standard
chemotherapy with or after ATRA therapy is required to sustain
remission. Other types of AML do not respond to ATRA therapy.
Other important cytogenetic abnormalities in AML include
t(8;21)(q22;q22); an inverted chromosome 16 [inv(16)(p13;q22)];
abnormalities involving 11q23, -7 or deletions of 7q, -5 or 5q; and
various translocations involving chromosome 17
(10)(24)(28)(29)(30)(31). Several of these
have been found to have either good or bad prognostic significance as
shown in Table 6
.
Bone marrow cytogenetic findings are a major independent indicator of
prognosis for both AML and ALL, and define treatment groups. They are
essential in the assessment of patients with acute leukemia and should
be performed in every case.
molecular analysis of acute leukemia
In the diagnosis of acute leukemias, molecular analysis may be
used to establish clonality or to identify molecular translocations
producing fusion gene products
(8)(15)(17)(24)(32)(33).
Molecular studies are also powerful tools for the identification of
minimal residual disease and early relapse
(34)(35). Techniques for molecular analysis of
leukemias include Southern blot, PCR, and FISH.
Molecular techniques for identifying T-cell receptor or immunoglobulin
gene rearrangements are valuable in diagnosis of some cases of lymphoma
and other lymphoproliferative disorders but are less commonly required
in the diagnosis of acute leukemia. However, gene rearrangements may
serve as a fingerprint for later identification of minimal residual
leukemia when there are too few leukemic cells present to be recognized
by morphologic examination or immunophenotyping (34).
Identification of the fusion genes that result from cytogenetic
translocations such as the PML-RAR gene in acute PML and
the ABL-BCR (p190) gene in ALL has treatment and prognostic
importance as described in Cytogenetics in the Diagnosis of Acute
Leukemia above
(11)(21)(25)(26). In
some cases, molecular translocations are present when karyotypic
changes are not evident. An example of this is the TEL-AML1
fusion gene resulting from the t(12;21)(p12;q22) translocation.
This chromosomal translocation generally is cryptic and can only be
identified by molecular analysis, i.e., PCR or FISH
(17)(19). This is occasionally the case with
other well-established translocations in acute leukemia in which the
involved chromosome segments are too small for detection by karyotyping
or because the translocation is complex and involves several
chromosomes. It is important, therefore, to perform molecular analysis
when the presence of a fusion gene that would impact treatment
decisions is suspected. Tables
8 and
9 show examples of major molecular genetic abnormalities and
their associated cytogenetic translocations in AML and ALL,
respectively (8).
In some cases, PCR or FISH studies may be performed in search of a
specific fusion gene without first doing cytogenetic karyotyping. The
advantages of this approach are a shortened result turnaround time and
reduced expense. However, the molecular probes for each of the fusion
products are specific and identify only that product. Because routine
cytogenetic studies identify a spectrum of chromosome abnormalities
that may occur in acute leukemia, they should always be performed at
initial diagnosis. Molecular analysis should be used to supplement
cytogenetics when a specific question is being addressed. Molecular
studies may be performed in the absence of parallel cytogenetic
analysis when there is a focused purpose for the study, such as
identification of minimal residual disease.
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Classification of Acute Leukemias
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It is obvious that immunophenotyping, cytogenetics, and molecular
analysis are vitally important in the diagnosis of acute leukemia. The
information provided by these techniques and its direct impact on
treatment decisions and prognosis presents a logical argument for
incorporating results from these studies into a new classification of
acute leukemias. The following discussion deals with issues and
controversies related to classification and how immunophenotyping and
cytogenetic/molecular information is changing the classification of
acute leukemias.
The modern era for classification of acute leukemias dates to 1976 when
two proposals appeared. One was published by a cooperative group of
hematologists and hematopathologists from France, America, and Britain
and was designated the French-American-British (FAB) classification
(36). The other was the WHO proposal
(37). Although the WHO classification was never widely used,
the FAB proposal was adopted internationally. It provided long needed
standard terminology for the acute leukemias and was quickly accepted
by most of the multiinstitutional study groups.
The FAB classification of AML divides cases into eight major groups
with subtypes for three of them (Table 10
) (38). The classification criteria are based on
morphologic and cytochemical features; for some of the categories,
immunophenotyping is necessary (39)(40). The FAB
classification of AML is a lineage-based morphologic classification
that categorizes cases according to the degree of maturation of the
leukemic cells and their lineage differentiation. The FAB
classification of ALL is simpler than the one for AML, but the criteria
that distinguish the categories are less precise (Table 11
) (41). The major advantage of the FAB lineage-based
classification system is its ease of use. The cytologic criteria
are well defined; they do not require high technology and can be
applied in most laboratories throughout the world. The classifications
are also applicable to the majority of cases of acute leukemia, and
they partially define prognostic groups. The major disadvantage is
their modest clinical relevance; they do not adequately define biologic
and treatment groups.
Several clinically important categories of acute leukemia have been
defined by cytogenetic/molecular studies during the past two decades.
As a result, there are proponents for abandoning the lineage-based
classifications and developing an exclusively cytogenetic/molecular
analysis-based classification of acute leukemias. Clearly,
cytogenetic/molecular analysis-based groupings better define biologic
and prognostic groups. The requirement for technology that is not
always available at present is a negative aspect of an exclusively
cytogenetic/molecular classification. In addition, currently the
majority of cases of AML do not express recurrent cytogenetic changes,
and only slightly more than one-half of cases of childhood ALL do.
In the mid 1990s, the Society for Hematopathology in the United States
and the European Association for Hematopathology were enlisted by WHO
to update the WHO classification of hematopoietic neoplasms. The
revised WHO classifications of AML and ALL have recently been completed
and will be published in monograph form within the next year. A preview
of the WHO classifications was published recently in a journal article
(42). The newly revised WHO classifications of acute
leukemias are shown in Tables
12 and
13. These classifications address the problems of an exclusively
lineage-based or an exclusively cytogenetic/molecular classification by
combining the best features of both. The result is a classification
that enhances clinical and prognostic utility and retains usability.
In the who classification of AML there are four major categories:
- AML with recurrent cytogenetic translocations
- AML with multilineage dysplasia
- therapy-related (secondary) AML
- AML not otherwise categorized (includes the former FAB categories)
Within the major categories, there are several subtypes (Table 12
). This proposal retains and even expands morphologic criteria but
includes categories defined by cytogenetic/molecular studies that have
important prognostic implications.
There are three major categories of ALL in the revised WHO
classification, defined by immunophenotype (Table 13
):
- B-cell precursor
- T-cell precursor
- Burkitt cell leukemia
Within the B-cell precursor category there are several subtypes
identified by cytogenetic/molecular abnormalities. The major treatment
and prognostic groups in childhood ALL are identified in this
classification.
With the present explosion of cytogenetic and molecular information,
the new WHO classifications of acute leukemia must be considered works
in progress. It will be necessary to update them periodically as new
discoveries provide a better understanding of the biology of the acute
leukemias and as additional distinctive clinical and prognostic
subtypes are identified.
The evolution of new technology in hematopathology has added several
new tools for diagnosis, classification, patient management, and
determining prognosis of leukemia. The refinements in diagnosis that
they provide have set the stage for more specifically directed
treatment regimens. Defining the appropriate clinical indications for
new techniques, understanding their limitations, and integrating them
with existing standard diagnostic methods are all vitally important in
realizing their full potential.
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Footnotes
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1 Nonstandard abbreviations: AML, acute myeloid leukemia; ALL, acute lymphoblastic leukemia; FISH, fluorescent in situ hybridization; PML, promyelocytic leukemia; RAR, retinoic acid receptor ; ATRA, all-trans-retinoic acid; and FAB, French-American-British. 
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Abstract
Introduction
