Review Article

Acute Erythroid Leukemia

Zhuang Zuo, MD, PhD; Jacek M. Polski, MD; Armen Kasyan, MD; L. Jeffrey Medeiros, MD

Nmon
Context.—Acute erythroid leukemia (AEL) is an uncom-
type of acute myeloid leukemia (AML), representing
Data Sources.—Clinicopathologic, cytogenetic, and mo-
lecular information were extracted from our review of
less than 5% of all cases. Acute erythroid leukemia is pertinent literature and a subset of AEL cases in the files of
characterized by a predominant erythroid proliferation, The University of Texas M. D. Anderson Cancer Center
and in the current World Health Organization (WHO) (Houston) and University of South Alabama (Mobile).
classification scheme there are 2 subtypes: erythroleuke- Conclusions.—The current WHO criteria for establish-
mia (erythroid/myeloid leukemia) and pure erythroid ing the diagnosis of AEL reduce the frequency of this entity,
leukemia. Morphologic findings are most important for as cases once classified as the erythroleukemia subtype are
establishing the diagnosis. The erythroleukemia subtype, now reclassified as other types of AML, particularly AML
which is most common, is defined as the presence of 50% with myelodysplasia-related changes and therapy-related
or more erythroid precursors and 20% or more blasts in AML. This reclassification also may have prognostic
the nonerythroid component. The pure erythroid leukemia significance for patients with the erythroleukemia subtype
subtype is composed of 80% or more immature erythro- of AEL. In contrast, the current WHO criteria appear to
blasts. Although these morphologic criteria appear have little impact on the frequency and poor prognosis of
straightforward, AEL overlaps with other types of AML patients with the pure erythroid leukemia subtype of AEL.
and myelodysplastic syndrome that are erythroid rich. Molecular studies, preferably using high-throughput meth-
Objective.—To provide an update of AEL, including ods, are needed for a better understanding of the
clinical presentation, morphologic features, immunophe- pathogenesis of AEL, and for developing diagnostic and
notype, and cytogenetic and molecular data. As the prognostic markers.
erythroleukemia subtype is most common, the literature (Arch Pathol Lab Med. 2010;134:1261–1270)
and this review are biased towards this subtype of AEL.

BACKGROUND quently referred to by others as true erythroleukemia,

Acute erythroid leukemia (AEL) is an uncommon type minimally differentiated erythroleukemia, and pure ery-
of acute myeloid leukemia (AML) and the criteria for throid leukemia. Later, Dameshek and others on advo-
establishing the diagnosis have evolved substantially over cated the terms Di Guglielmo syndrome and Di Guglielmo
time. The first case report of AEL appears to have been disease in honor of Di Guglielmo’s contribution to the
contributed in 1912 by Copelli,1 who described a hema- understanding of this disease.5
tologic disorder, erythromatosis. It was Giovanni Di In 1976, the French-American-British (FAB) Coopera-
Guglielmo, however, who more fully developed the tive Group designated AEL as AML-M6, defined as the
understanding of this disease in a series of articles2,3 presence of 30% or more blasts, with the denominator
beginning in 1917. Di Guglielmo described 2 forms of being that all nucleated bone marrow cells and 10% or
what is now known as AEL. The more common variant, more erythroid precursors show dyserythropoiesis.6 In the
referred to as erythremic myelosis, and subsequently as subsequent revision of the FAB classification in 1985,7 the
erythroleukemia and erythroid/myeloid leukemia by criteria for the diagnosis of AML-M6 were refined to
others, is composed of immature erythroid and myeloid include the following: (1) erythroblasts that represent 50%
elements. Over time the myeloblasts progressively in- or more of all nucleated bone marrow cells; (2) prominent
crease, and the disease evolves into AML.4 Di Guglielmo dyserythropoiesis; (3) and myeloblasts that represent 30%
described a second variant characterized by a pure or more of the nonerythroid cells in the bone marrow. The
normoblastic proliferation, acute erythremia, subse- entity currently known as pure erythroid leukemia did not
meet the requirements of the FAB classification for the
Accepted for publication January 15, 2010. diagnosis of acute leukemia and was therefore most often
From the Department of Hematopathology, University of Texas M. D.
Anderson Cancer Center, Houston (Drs Zuo, Kasyan, and Medeiros);
classified as a myelodysplastic syndrome (MDS) with
and the Department of Pathology, University of South Alabama, Mobile erythroid predominance, usually in the category of
(Dr Polski). refractory anemia with excess of blasts in transformation
The authors have no relevant financial interest in the products or (RAEB-T).
companies described in this article. Although the FAB classification has not been formally
Reprints: Zhuang Zuo, MD, PhD, Department of Hematopathology,
Unit 0149, The University of Texas M. D. Anderson Cancer Center, updated since its 1985 revision, other investigators
1515 Holcombe Blvd, Houston, TX 77030 (e-mail: zzuo@mdanderson. modified the FAB classification informally by expanding
org). the M6 category to include M6a and M6b subtypes. M6a
Arch Pathol Lab Med—Vol 134, September 2010 Acute Erythroid Leukemia—Zuo et al 1261
 Table 1. Comparison of French-American-British (FAB) and World Health Organization (WHO) Classifications for Acute
Erythroid Leukemia
WHO Classification

FAB Classification 2001 Criteria 2008 Criteria

1976 1985 Acute Erythroid Leukemia Acute Erythroid Leukemia

Criteria Criteria Pure Pure
Erythroleukemia Erythroid Erythroid
Name AML-M6 AML-M6 (Erythroid/Myeloid) Leukemia Erythroleukemia Leukemia
BM findings
Erythroid precursors $30% $50% $50% $80% $50% $80%
Blast of nonerythroid $30% $20% $20%
cells
Dyserythropoiesis $10% Prominent Prominent Prominent Prominent Prominent
Other findings No multilineage involvement No multilineage involvement; no prior
erythropoietin therapy
Abbreviations: AML, acute myeloid leukemia; BM, bone marrow.

was equivalent to the initial designation of M6 in the FAB disease, in part, is a diagnosis of exclusion. Another
scheme. M6b was more akin to the pure erythroid consequence of these refinements is that the frequency of
leukemia subtype of AEL, although different investigators AEL has been reduced.
had different definitions. Mazzella and colleagues8 and In the remainder of this review we discuss the clinical,
Kowal-Vern and colleagues,9 for example, defined M6b morphologic, immunophenotypic, and cytogenetic find-
and proposed a third category, M6c. As with M6a, in both ings in AEL. We also review the molecular data available,
M6b and M6c the erythroid precursors represented 50% which is relatively scant. Because of the extreme rarity
or more of the nucleated cells. In M6b, 30% or more of the pure erythroid leukemia subtype, this review
pronormoblasts were present, with an insignificant is heavily biased toward the erythroleukemia subtype
myeloblastic component. The M6c category was defined of AEL.
by the presence of 30% or more myeloblasts and 30% or
more pronormoblasts. Mazzella and colleagues suggested
that the M6a, M6b, and M6c types most likely represented CLINICAL FEATURES
different phases of the same disease. Acute erythroid leukemia is a rare type of AML,
The 2001 World Health Organization (WHO) classifica- representing less than 5% of all cases, characterized by a
tion10 lowered the blast percentage threshold to at least predominant ($50%) erythroid population in the bone
20% for establishing the diagnosis of all types of AML, marrow. Most cases of AEL develop de novo, accounting
thereby eliminating the RAEB-T category. This classifica- for approximately 1% of all de novo AML, and the disease
tion also used the term acute erythroid leukemia and is not associated with any identifiable risk factors. Rare
recognized 2 subtypes. The erythroid/myeloid subtype cases of de novo familial erythroleukemia, being auto-
was defined by a neoplastic proliferation of myeloblasts somal dominant with variable penetrance, have been
(20% or more of the nonerythroid cells in bone marrow) in described.12 Cases of AEL evolving from other antecedent
a background of erythroid hyperplasia (50% or more of diseases have been reported in the literature, and
erythroid precursors). The pure erythroid leukemia these cases are often referred to as so-called secondary
subtype was defined by the presence of immature cells AEL. Common antecedent diseases or factors include
committed exclusively to the erythroid lineage ($80% of MDS (for example, refractory anemia with excess of blasts
bone marrow cells), with no evidence of a significant or refractory cytopenia with multilineage dysplasia),
myeloblastic component. The so-called M6c category was myeloproliferative neoplasms (for example, chronic mye-
not specifically recognized in the WHO classification. logenous leukemia with erythroblastic crisis),13 and
The 2008 WHO classification11 closely follows the exposure to toxins such as benzene. Secondary AEL also
previous version, but makes the criteria for its diagnosis has been reported in patients with a history of other types
more rigorous. Cases with 20% or more blasts and of cancer treated with chemotherapy, immunosuppres-
dysplasia involving at least 50% of cells in 2 or more sive treatment, or ionizing radiation. Other than the de
lineages are now moved to the category of AML with novo and familial categories of disease, in our view, many
myelodysplasia-related changes, even in the face of of the cases of secondary AEL (usually designated as
erythroid predominance. The 2008 WHO classification erythroleukemia or AML-M6 in the literature) should be
recognizes that therapy, particularly erythropoietin, can viewed with skepticism. With the current WHO classifica-
cause erythroid predominance that may result in a tion, it seems highly likely that many of these cases would
morphologic picture that mimics AEL. Both the 2001 and not be classified as AEL, and would fit better either as
2008 versions of the WHO classification also recognized AML with myelodysplasia-related changes or therapy-
the category of therapy-related AML, another type of related AML. Nevertheless, here we attempt to review the
AML that can be associated with numerous erythroid literature as it is, with the caveat that at least some cases
precursors. A comparison of these classification schemes in the literature designated as erythroleukemia or AML-
is listed in Table 1. One of the consequences of these M6 do not meet the current WHO classification criteria
refinements in criteria for the diagnosis of AEL is that this for AEL.
1262 Arch Pathol Lab Med—Vol 134, September 2010 Acute Erythroid Leukemia—Zuo et al
 the blood smear include mild to marked neutropenia and
thrombocytopenia, and pseudo–Pelger-Huët neutrophils.
In bone marrow aspirate smears and touch imprints, by
definition, erythroid precursors predominate ($50%) in
AEL. In the erythroleukemia subtype, maturation of
erythroid precursors is often left shifted and dysplasia is
identified in all maturation stages. Findings of dysplasia
include 1 or more of the following: abundant megalo-
blastoid forms, nuclear budding, bizarre nuclear shapes,
multinucleation, foamy cytoplasmic vacuoles, or cytoplas-
mic pseudopods (Figure 2, A and B). Prominent multi-
lineage dysplasia is common, but variable, involving
granulocytes (Figure 2, C) or megakaryocytes (Figure 2,
D) or both. Auer rods are unusual but can be seen in
myeloblasts. The natural history of the erythroleukemia
subtype is for the disease to accrue blasts of myeloid or
myelomonocytic lineage with variable differentiation.
Thus, over time the morphologic picture of the erythro-
Figure 1. Peripheral blood smear in a patient with acute erythroid leukemia subtype can progress to AML with minimal
leukemia, pure erythroid leukemia subtype. In this patient the smear differentiation, AML without maturation, AML with
showed hypochromic, normocytic anemia, leukopenia, and thrombo-
cytopenia. No blasts were identified (Giemsa, original magnification maturation, or acute myelomonocytic leukemia.
31000). In the pure erythroid leukemia subtype of AEL, most
($80%) of the cells in the aspirate smears are erythroid
Acute erythroid leukemia is a disease of adults that precursors (Figure 3). Erythroid maturation is left shifted
primarily affects people older than 50 years. Some studies9 with increased pronormoblasts. Pronormoblasts are inter-
have shown a bimodal age distribution, with a smaller mediate in size to large, with round nuclei, fine chromatin,
often prominent nucleoli, and deeply basophilic and
peak below the age of 20 and a more definitive and
agranular cytoplasm. Cytoplasmic vacuoles are variably
broader peak in the seventh decade of life. The rare
present and can be prominent in pronormoblasts (Fig-
familial cases usually manifest in the sixth decade of life.12
ure 3, A). In occasional cases erythroblasts can be smaller,
There is a slight male predominance. The clinical features
in the size range of lymphoblasts or lymphoma cells.
are often relatively nonspecific, and include pallor, fever,
Dysplasia is common in the erythroid elements but is
and hepatosplenomegaly. Extramedullary presentation as
generally a minor feature in the other lineages. Myelo-
a myeloid sarcoma is unusual in patients with AEL, but blasts are very few in the pure erythroid leukemia subtype
extramedullary sites can be involved and the diagnosis of of AEL.
AEL has been established by lymph node biopsy.14 The bone marrow aspirate clot and biopsy specimens
Anemia is often severe in patients with AEL, with a mean are usually hypercellular in both subtypes of AEL.
hemoglobin level of 7.5 g/dL reported in 1 study.15 Dysplasia of megakaryocytes often can be appreciated in
Thrombocytopenia and leukopenia, to varying degrees, the erythroleukemia subtype, whereas the neoplasm can
are also common. Up to one-third of the patients can have appear completely undifferentiated in cases of the pure
hemorrhage, hepatomegaly, or splenomegaly.14 Severe erythroid leukemia subtype (Figure 3, B). Markedly
hemolysis can sometimes occur.16 Patients can be sympto- increased erythroid precursors can be appreciated in
matic for an interval of time before diagnosis, but usually sections of the clot and biopsy specimens of AEL cases, but
the diagnosis is established in 1 to 3 months. It is rare for it is difficult to exactly count the various cell types or
patients with AEL to have symptoms that last for longer assess dysplasia in tissue sections of the clot and biopsy
than 6 months before an initial diagnosis. We also have specimens, particularly in routinely processed, paraffin-
observed patients with AEL who, although symptomatic, embedded specimens. Perhaps more data can be derived
were highly functional at time of diagnosis, leading from clot and biopsy specimens that are embedded in
clinicians to initially doubt the diagnosis and consider plastic, allowing the preparation of very thin tissue
trial therapy for nutritional deficiency. In these few sections, but we have no personal experience with these
patients, the disease clinically declared itself more fully methods in the study of AEL.
within a short follow-up interval. Many cytochemical stains have been used to character-
ize the cells of AEL. In both the erythroleukemia and pure
MORPHOLOGIC AND CYTOCHEMICAL FINDINGS
erythroid leukemia subtypes, erythroblasts are often
The diagnosis of AEL requires morphologic examina- highlighted by the periodic acid–Schiff (PAS) reaction in
tion of the bone marrow. Although a striking erythro- either a globular or diffuse pattern, with the diffuse
blastemia can sometimes be identified in affected patients, pattern occurring in more mature erythroblasts (Figure 3,
examination of peripheral blood smears can be misleading C). Periodic acid–Schiff positivity in AEL is thought to
because blood smears are often devoid of blasts and show reflect a cytoplasmic maturation defect. An iron stain
only cytopenias (Figure 1). Nonspecific red blood cell usually shows increased iron stores and may show ring
abnormalities can be present, such as anisocytosis, sideroblasts (Figure 2, B [inset]). Myeloblasts (but not
poikilocytosis, anisochromia, basophilic stippling, schis- erythroblasts) are usually positive for myeloperoxidase
tocytes, and erythrocytes that are poorly hemoglobinized. (MPO), Sudan Black B, and, often, chloroacetate esterase.
Normoblasts may or may not be observed in the blood A nonspecific esterase reaction will highlight a monocytic
smear. Other nonspecific findings that can be observed in component that can predominate in a subset of cases. In
Arch Pathol Lab Med—Vol 134, September 2010 Acute Erythroid Leukemia—Zuo et al 1263
Figure 2. Representative morphologic changes in bone marrow of patient with acute erythroid leukemia, erythroleukemia subtype. A and B,
Erythroid hyperplasia, increased blasts, dyserythropoiesis, and ring sideroblasts (B, inset). C, Dysplasia in granulocytes, D, Dysplasia in
megakaryocytes (Wright-Giemsa, original magnifications 3400 [A and C] and 31000 [B]; Perl Prussian blue, original magnification 31000 [B,
inset]; hematoxylin-eosin, original magnification 3400 [D]).

the pure erythroid leukemia subtype, PAS staining is leukemia subtype express myeloid-associated markers
commonly positive, often in cytoplasmic vacuoles in a including CD13, CD33, CD117 (KIT), and MPO, with or
blocklike pattern (Figure 3, C). Ring sideroblasts are without expression of CD34 and HLA-DR. Figure 4 shows
uncommon. The blasts are negative for MPO (Figure 3, an example, using the CD45 and side scatter gating
D), Sudan Black B, and chloroacetate esterase. Erythroid strategy (Figure 4, A), to illustrate myeloblasts in one case
precursors also can be positive for the a-naphthyl acetate of AEL that expressed CD33, CD34 (Figure 4, B), CD13
esterase and a-naphthyl butyrate esterase. (Figure 4, C), and MPO (Figure 4, D).
Others17 have reported that cases of AEL, particularly
IMMUNOPHENOTYPIC FINDINGS the pure erythroid leukemia subtype, can express the
Immunophenotyping of AEL is best performed by flow megakaryocyte-associated antigens CD41 and CD61.
cytometry because a wider array of antibodies is available Expression is often of low intensity (dim) or partial.
than with immunohistochemistry. Erythroblasts in both Whether these cases are truly AEL or a mixed lineage
subtypes of AEL express erythrocyte-associated antigens, neoplasm with both erythroid and megakaryocytic differ-
and expression correlates with the degree of differentia- entiation is unclear, but our bias is to keep the category of
tion or maturation of the neoplastic cells. Erythroblasts AEL pure.
usually express CD71 (transferrin receptor), but occasion- Immunohistochemistry has a role in the workup of
ally CD71 expression can be aberrantly dim. Erythroblasts cases of AEL, particularly in cases in which the aspirate
variably express hemoglobin A, glycophorin A, spectrin, material is scant. Here we mention markers or applica-
ABH blood group antigens, and HLA-DR, and are tions not already addressed in the flow cytometry section
negative for myeloid-associated markers such as MPO. above. The anti-CD61 antibody can be useful for identify-
The Gerbich blood group (Gero) antibody, carbonic ing micromegakaryocytes. Blasts in the erythroleukemia
anhydrase 1, and CD36 can be expressed by more type of AEL can be positive for lysozyme or CD68. Results
immature erythroblasts. The myeloblasts of the erythro- with MPO are typically negative. In our experience, the
1264 Arch Pathol Lab Med—Vol 134, September 2010 Acute Erythroid Leukemia—Zuo et al
Figure 3. Representative morphologic changes in bone marrow of patient with acute erythroid leukemia, pure erythroid leukemia subtype. A,
Many large pronormoblasts with prominent cytoplasmic vacuoles were present in this case. A subset of smaller blasts is also seen in this field. B,
Bone marrow core biopsy specimen shows marked hypercellularity and left shift in maturation. C, A pronormoblast is shown with cytoplasmic,
globular periodic acid–Schiff (PAS) reactivity. D, The blasts are negative for myeloperoxidase. Neutrophils present in the field exhibit weak reactivity
and the control (not shown) was strongly positive. E, Immunohistochemistry results for glycophorin A are negative in the blasts (erythrocytes in the
field stain positively); (Wright-Giemsa, original magnification 31000 [A]; hematoxylin-eosin, original magnification 3200 [B]; PAS, original
magnification 3400 [C]; myeloperoxidase, original magnification 3400 [D]; anti-glycophorin A, original magnification 3400 [E]).

Arch Pathol Lab Med—Vol 134, September 2010 Acute Erythroid Leukemia—Zuo et al 1265
Figure 4. Flow cytometric immunophenotypic analysis documenting myeloid lineage of the blasts in a case of acute erythroid leukemia,
erythroleukemia subtype. A, The CD45 and side scatter (SS) gating strategy. B, The blasts are positive for CD34 and partially positive for CD33. C,
The blasts are positive for CD13. D, The blasts are positive for myeloperoxidase (MPO).

blasts in the pure erythroid type of AEL are often negative To date, no specific chromosome abnormalities have
for all erythroid-associated antibodies assessed by im- been described in AEL. Depending on the study, 50% to
munohistochemistry because many of the target antigens 80% of patients have an abnormal karyotype.8,18–20 Com-
require some degree of erythroid maturation to be plex karyotypes with multiple structural abnormalities are
expressed and very dim expression may not be detectable common. The most frequent abnormalities include
by immunohistochemistry (Figure 3, E). Most results with monosomy 5 or del(5q), monosomy 7 or del(7q) and
myeloid-associated antigens are negative with the excep- trisomy 8.21 Complex karyotypes (3 or more cytogenetic
tion of CD117, which can be weakly expressed in a subset abnormalities) also have been reported in AEL cases.22,23
of cases of the pure erythroid subtype (similar to normal Rare cases of erythroleukemia with der(1;7)(q10;p10) have
pronormoblasts). Staining for terminal deoxynucleotidyl been reported, especially in East Asian individuals.24,25
transferase is usually negative in AEL. Additionally, t(8;16)(p11.2;p13.3) in AEL has been re-
ported to be associated with erythrophagocytosis and
CYTOGENETIC FINDINGS coagulopathy.18 Cytogenetic features in AEL can be used
Most cytogenetic data available for AEL cases are to stratify patients into prognostic groups. Patients with
derived from conventional cytogenetic analysis of the 25/del(5q), 27/del(7q), inv(3q), +8, 11q abnormalities,
most common subtype, erythroleukemia. However, as 17p abnormalities, del(20q), +13, and complex karyotypes
stated above, a subset of cases in the literature that were are generally associated with unfavorable outcomes.
classified by using older terms that appear equivalent to Although we have no doubt that cytogenetic abnor-
AEL probably do not fulfill the criteria for this disease in malities correlate with prognosis, as has been shown in
the current WHO classification. This subset of cases is many studies of AML in general, the spectrum and types
difficult to tease out of the various individual publications of the reported cytogenetic abnormalities in cases classi-
and we therefore present the data as it is, as not all fied previously as erythroleukemia suggest that this
relevant information is provided. ‘‘entity’’ has been highly heterogeneous. The high
1266 Arch Pathol Lab Med—Vol 134, September 2010 Acute Erythroid Leukemia—Zuo et al
frequency of 25/del(5q) and 27/del(7q) supports the
concept that a subset of reported cases of erythroleukemia
are closely related to MDS, and that some reported cases
may be better designated as AML with myelodysplasia-
related changes. This was predicted in the 2008 WHO
classification. Cases of so-called erythroleukemia with
t(9;22)/BCR-ABL1, as reported in the literature, would
most likely be designated as chronic myelogenous
leukemia currently. Similarly, cases reported as erythro-
leukemia that carry chromosomal translocations asso-
ciated with specific types of AML, such as t(8;21)
(q22;q22)/RUNX1-RUNX1T1, would currently be classi-
fied according to the chromosomal abnormality. For
example, Virchis et al26 described a case of erythroleuke-
mia associated with t(15;17)(PML-RARA). This case
would be classified as acute promyelocytic leukemia with
current criteria. Virtually all cases of erythroleukemia in
patients with a history of cancer that were treated with
chemotherapy or radiation therapy would be classified as
therapy-related AML with erythroid predominance with
the current WHO classification.
MOLECULAR FINDINGS
Because of the rarity of AEL, relatively few cases have
been assessed at the molecular level, and the cases
assessed have been primarily of the erythroleukemia
subtype. In addition, the few cases of AEL assessed by
molecular methods are found within large studies of AML
including all types, without a focus on AEL. As a result,
less than a complete picture is available, and one should
certainly use some caution when interpreting some of
these results.
The nucleophosmin gene (NPM1) is commonly mutated
in AML, and found in up to 50% to 60% of cases, especially
in patients with normal karyotype. In the absence of
coexisting fms-related tyrosine kinase 3 gene (FLT3) Figure 5. A suggested diagnostic algorithm for acute erythroleukemia
mutations, NPM1 mutations are thought to be a favorable (AEL) is shown. The highlighted path directs one to the diagnosis of
AEL. See text for details. Abbreviations: AML, acute myeloid leukemia;
prognostic marker for patients with AML.27 In one study,28 AML-MRC, acute myeloid leukemia with myelodysplasia-related
NPM1 mutation was found in 1 of 5 cases (20%) of AEL. changes; ANC, all nucleated cells; BM, bone marrow; Epo, Erythro-
Although a very small number of cases, this apparent poietin; Hx, history of; MDS, myelodysplastic syndrome; NEC, non-
frequency of 20% in AEL was second only to AMLs with erythroid cells; R/O, rule out; t-AML or t-MDS, therapy-related
monocytic differentiation (acute myelomonocytic or myeloid neoplasms.
monocytic leukemia).28 FLT3 is also commonly mutated
in AML, and seen in up to 30% of adult cases. In AEL,
however, FLT3 mutations are rare.29 In our own limited
experience, FLT3 mutations occur in approximately 10% confirmed in studies with larger cohorts of patients with
of cases of AEL (Z.Z., L.J.M., unpublished data, October AEL.
2008). Nevertheless, FLT3 expression levels in AEL are
‘‘LOW BLAST COUNT’’ CASES OF AEL
reported to be among the highest of all AML types,
suggesting that FLT3 may be involved in pathogenesis.30 There is a subset of cases of AEL, erythroleukemia
NRAS mutations are rare in AEL (Z.Z., L.J.M., unpub- subtype, in which the overall blast count can be low.
lished data, October 2008) as compared to the 10% to 20% Specifically, the overall blast count is in the range of 5% to
overall frequency in all types of AML. Mutation of Janus 10%, far below the WHO classification blast cutoff for
kinase 2 (JAK2), commonly found in myeloproliferative AML of at least 20%, but these cases have numerous
neoplasms, was identified in 1 of 12 cases (8.3%) of AEL by erythroid precursors (70% to 90%). As a result, the blasts
1 group.31 Auewarakul and colleagues32 reported muta- can represent 20% or more of the nonerythroid cells,
tions of the core binding factor gene, RUNX1 (also known thereby allowing the diagnosis of AEL. Selby and
as AML1), which normally is involved in myeloid colleagues34 have questioned whether these cases should
differentiation, in 2 of 7 (28.6%) AEL cases. The TP53 be designated as AEL, as this diagnosis may lead to overly
tumor suppressor gene was in the wild-type form in all 5 aggressive therapy for these patients. In our experience, a
cases of AEL assessed in 1 study, 33 unlike the greater than subset of patients with ‘‘low blast count’’ AEL do not have
10% frequency of p53 mutations in AML overall. Taken associated cytogenetic abnormalities, perhaps supporting
together, this molecular profile suggests that AEL may the view that these cases are more akin to MDS than to
arise by pathogenetic mechanisms that are distinct from AEL.20 Follow-up data on patients such as these are
those of other types of AML. This concept needs to be needed to address this issue.
Arch Pathol Lab Med—Vol 134, September 2010 Acute Erythroid Leukemia—Zuo et al 1267
 DIFFERENTIAL DIAGNOSIS The differential diagnosis of the pure erythroid leuke-
The differential diagnosis for AEL includes both mia subtype of AEL includes other types of AML, acute
neoplastic and benign diseases. A suggested diagnostic lymphoblastic leukemia (ALL), lymphomas, plasma cell
algorithm is illustrated in Figure 5. For the erythroleuke- myeloma, and several nonneoplastic disorders that are
mia subtype, the most important entities in the differential characterized by increased erythroid precursors with
diagnosis include MDS with erythroid predominance, dyserythropoiesis.37,38 Cases of the pure erythroid leuke-
AML with myelodysplasia-related changes, and other mia subtype in which there is clear evidence of erythroid
types of AML with increased erythroid precursors. The maturation are relatively easier to recognize. However,
most important distinguishing features for this differen- many cases of the pure erythroid leukemia subtype of
tial diagnosis are blast percentage and the presence of AEL show minimal or no erythroid maturation and are
composed of numerous immature blasts. Although the
multilineage dysplasia (2 or 3 lineages) in at least 50% of
blast cell cytoplasm is deeply basophilic, this feature is not
cells of a given lineage. In the WHO classification, this
specific. For these cases, cytochemistry and immunophe-
degree of dysplasia is considered a surrogate for cytoge-
notypic analysis are necessary. The blasts of AML
netic abnormalities associated with MDS.11
undifferentiated type (FAB-M0), for example, are negative
Patients with MDS usually have anemia, and the bone
for MPO by cytochemistry, similarly to the blasts of pure
marrow can show erythroid predominance, reflecting an
erythroid leukemia. However, the blasts of undifferen-
attempt to compensate for the anemia.35 Morphologically,
tiated AML often express a variety of myeloid-associated
erythroid dysplasia and ring sideroblasts are commonly antigens, as shown by flow cytometry or immunohisto-
observed in MDS as well as in the erythroleukemia chemistry, and therefore this neoplasm can be reliably
subtype of AEL. The key distinguishing factor is the bone distinguished from pure erythroid leukemia. Acute
marrow blast percentage. If the blast count is less than 20% megakaryoblastic leukemia can be more difficult to
of all nucleated cells and also less than 20% of the distinguish from pure erythroid leukemia. With cyto-
nonerythroid elements, a diagnosis of MDS is most chemistry, MPO staining is negative in both diseases and
appropriate. PAS can show cytoplasmic positivity in both. Immuno-
Acute myeloid leukemia with myelodysplasia-related phenotypic analysis is essential in this case. Cases of pure
changes is a recently proposed entity in the 2008 WHO erythroid leukemia express 1 or more erythroid-asso-
classification. These cases are characterized by 20% or ciated antigens (eg, hemoglobin A, glycophorin, or others)
more blasts and multilineage dysplasia in at least 50% of and cases of acute megakaryoblastic leukemia express
cells in 2 or more lineages. Cases of AML with megakaryocyte-associated antigens such as CD41, CD61,
myelodysplasia-related changes can be erythroid rich, and factor VIII. However, in highly immature neoplasms,
with 50% or more erythroid precursors, but these cases are many of these antigens may be absent. In addition, cases
not classified as AEL, erythroleukemia subtype with of pure erythroid leukemia are reported with partial
current WHO criteria. Moreover, cases with at least 20% expression of either CD41 or CD61. Whether these cases
peripheral blood or bone marrow blasts and MDS-related are better classified as acute mixed erythroid-megakaryo-
cytogenetic abnormalities or a prior history of MDS, even blastic leukemia or not is uncertain. Electron microscopy
when associated with a population of erythroid precur- to show platelet peroxidase can be helpful to diagnose
sors in the bone marrow of 50% or more, should be acute megakaryoblastic leukemia. The t(1;22)(p13;q13)
considered as AML with myelodysplasia-related changes anomaly and abnormalities involving chromosome 3q26
rather than AEL. also support the diagnosis of acute megakaryoblastic
Other types of AML also can be associated with leukemia. In some cases of pure erythroid leukemia, the
increased numbers of erythroid precursors when they are blasts may be intermediate in size or small, falling into the
initially diagnosed. In all of these cases, blasts represent size range of ALL and malignant lymphoma. Immuno-
20% or more of all nucleated bone marrow cells. When phenotyping will be helpful to distinguish these entities,
erythroid precursors represent 50% or more of nucleated as ALL and lymphomas express either B- or T-cell
cells, in our experience, the most common explanation is antigens, and ALL is usually positive for terminal
prior erythropoietin therapy, which can increase erythroid deoxynucleotidyl transferase. The basophilic cytoplasm
precursors (including immature erythroblasts) and cause of erythroblasts and neoplastic plasma cells also can be
dyserythropoiesis. In the face of erythropoietin therapy it confused morphologically.37 Immunophenotypic analysis
is difficult to reliably establish the diagnosis of AML, is useful for this differential diagnosis, as plasma cells
unless at time of relapse in a patient with history of this express CD38, CD138, and cytoplasmic immunoglobulin,
disease. We recently reviewed a large number of cases in unlike the pure erythroid leukemia subtype of AEL.
which erythroid precursors were predominant and the A number of nonneoplastic diseases can cause erythroid
diagnosis of AEL (or older, equivalent terms) had been predominance in the bone marrow and therefore must be
made or suggested for a number of years at The University excluded before the diagnosis of AEL can be established
of Texas M.D. Anderson Cancer Center (Houston).36 (Table 2). The most common nonneoplastic disorders that
According to the criteria of the 2008 WHO classification, need to be excluded before the diagnosis of AEL is
an appreciable subset of these cases had a history of established include megaloblastic anemia due to nutri-
erythropoietin therapy, known mostly in retrospect, tional deficiency (either vitamin B12 or folate), heavy
thereby calling the diagnosis of AEL into question.36 Prior metal intoxication (eg, arsenic), drug effects (such as
chemotherapy also can result in a rebound erythrocytosis antineoplastic agents or chloramphenicol), and congenital
and can complicate the analysis of follow-up specimens dyserythropoiesis.38 Prior chemotherapy or erythropoietin
after therapy. As is illustrated in this discussion of the therapy also can induce erythrocytosis and be associated
differential diagnosis, the diagnosis of erythroleukemia is, with dyserythropoiesis in the bone marrow. A complete
in part, one of exclusion. history and necessary laboratory tests can often help to
1268 Arch Pathol Lab Med—Vol 134, September 2010 Acute Erythroid Leukemia—Zuo et al
 Table 2. Diseases or Conditions to Be Excluded PROGNOSIS
Before Establishing the Diagnosis of Acute In general, AEL has been associated with an aggressive
Erythroid Leukemia clinical course. A less favorable outcome is observed in
Bone marrow insult (resulting in granulocytopenia) elderly patients, in patients who previously had a
Drug diagnosis of MDS, or in patients who have been treated
Viral infection with chemotherapy for another neoplasm before devel-
Exposure to toxic chemicals oping AML. As has been stated, many of these cases
Therapy for cytopenias reported in the literature may not fulfill the criteria for
Erythropoietin AEL when using up-to-date classification criteria. In a
G-CSF/GM-CSF recent large study by Santos and colleagues,20 the
Blood loss pathologic diagnosis of AEL did not impart, by itself, a
Bleeding worse outcome and there was no difference in complete
Hemolysis remission rate when compared with other types of AML,
Medical conditions (including causes of hemolysis) not otherwise specified.
Hypersplenism Santos et al42 and others43 have emphasized that
Endocrine diseases response to chemotherapy and length of survival for
Valvular heart disease patients with AEL are dependent on a number of factors,
Hemoglobinopathies with the most important being cytogenetic abnormalities.
Intrinsic erythrocyte diseases Liu and colleagues44 showed that the complete remission
Nutritional deficiency rate of patients with AEL associated with an aberrant
Pernicious anemia karyotype was significantly lower than that of corre-
Folate deficiency sponding patients with a normal karyotype (37% versus
Iron deficiency 83%). In another study, the complete remission of patients
Abbreviations: G-CSF, granulocyte colony-stimulating factor; GM-CSF, with AEL and 5q or 7q abnormalities was approximately
granulocyte-macrophage colony-stimulating factor. 50%, with a median survival of 16 weeks, compared to
89% and 77 weeks for patients without these abnormal-
ities.15 MDR1 expression also correlates with unfavorable
rule out these possibilities. For some patients, a trial with cytogenetic findings and may explain the poorer response
vitamin B12 or folate may be helpful. to chemotherapy and shorter survival time. A history of
MDS appears to be another unfavorable factor. The
CURRENT TREATMENT complete remission rate of patients with a history of
Clinically, patients with AEL are usually treated MDS was 42.8%, compared to 85.2% for patients without
similarly to patients with other types of AML, not previous MDS history.44
otherwise specified.20 Stem cell transplantation (SCT) is
potentially curative, but is associated with procedure- SUMMARY
related morbidity and mortality, particularly for allo- The entity of AEL has been somewhat controversial
geneic SCT. Nevertheless, data have shown that SCT can since its original conception by Di Guglielmo almost a
substantially improve the outcome of this disease, with 5- century ago. Overt, qualitative abnormalities of erythro-
year leukemia-free survival reaching approximately 60% blasts are common in many AML cases, if methods for
after HLA-identical sibling SCT.5 No therapeutic agents detecting erythroid differentiation more sensitive than
that target specific pathways or molecules are currently light microscopy are used, which challenges the unique-
available for this disease, reflecting the lack of under- ness of this neoplasm.22,23 Perhaps as a response to this, the
standing of pathogenetic mechanisms. Clinical remission criteria for the diagnosis of AEL have become more
can be achieved for many patients when treated according rigorous with each new classification scheme. Further-
to the standard chemotherapy protocols for AML, with more, the pure erythroid leukemia subtype of AEL, not
cytarabine being the most active agent. Contrary to their recognized in the original FAB classification, is now
antiapoptotic and progrowth effects, high-dose erythro- accepted as a subtype of AEL in the current WHO
poietin and granulocyte colony-stimulating factor have classification. Two net effects of the changing criteria
been reported to induce clinical remission in a few elderly have been (1) a decrease in the overall frequency of AEL;
patients.39 If validated in larger, more rigorous clinical and (2) the calling into question of much of the data
studies, this approach could serve as an alternative reported previously in the literature for this entity, as the
therapy for patients whose disease is refractory to or for patient group appears to be highly heterogeneous when
patients who are ineligible for standard chemotherapy. using the criteria of older classification systems.
Common issues during treatment of patients with AEL For the present, the diagnosis of AEL is, in large part, a
include primary induction failure, relapse, and toxicity of morphologic diagnosis and a diagnosis of exclusion. It
chemotherapeutic agents. Refractoriness or relapse may also should be a diagnosis established with caution,
be explained by overexpression of the multidrug resis- particularly for patients with an overall low blast count
tance gene product, P-glycoprotein. In one study,40 AEL of (ie, ,10%), even when blasts represent 20% or more of all
the erythroleukemia subtype had very high levels of P- nonerythroid cells, as the diagnosis of AEL can lead to
glycoprotein expression as compared to that of other types aggressive therapy for patients with this constellation of
of AML. Modulators of multidrug resistance, such as findings. In our opinion, it seems unlikely that increased
cyclosporin A, quinidine, verapamil, and PSC 833, have understanding of this disease will come from the applica-
been used in a clinical trial in an attempt to overcome the tion of traditional pathologic methods. Molecular studies,
resistance and improve therapeutic response.41 preferably using high-throughput methods, are most
Arch Pathol Lab Med—Vol 134, September 2010 Acute Erythroid Leukemia—Zuo et al 1269
likely needed for a better understanding of disease 22. Niu Y, Chen SC, Jiang B, Li DG, Ge CW, Li RS. Erythroleukemia—a
subtype of myelodysplastic syndrome? [in Chinese]. Zhongguo Shi Yan Xue Ye
mechanisms and the development of diagnostic and Xue Za Zhi. 2007;15(2):219–223.
prognostic markers. 23. Honda Y, Manabe A, Tsuchida M, et al. Clinicopathological character-
istics of erythroblast-rich RAEB and AML M6a in children. Int J Hematol. 2008;
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