Keywords
Acute myeloid leukmia - cytogenetics - hypereosinophilia - splenomegaly
Introduction
Acute myeloid leukemia (AML) results from clonal proliferation of undifferentiated
myeloid precursors leading to bone marrow failure. Various subsets of AML have been
defined depending on the characteristic cytogenetic abnormality, which have prognostic
implications. One such subset is AML with t(8:21) (q22:q22), which has a favorable
prognosis and distinct biological characteristics.[1] It was the first cytogenetic abnormality detected in AML.[1] The translocation involves RUNX1 gene present on the chromosome 21 and RUNX1T1 gene
on chromosome 8. This abnormality is found in 5%–10% of all AML cases and is most
commonly seen in younger patients.[1] Morphologically, this category has characteristic blasts and increased numbers of
neutrophils, eosinophils, and their precursors to an extent that the picture sometimes
resembles that of a chronic myeloproliferative neoplasm, especially when the blast
counts are low.[1] However, AML with t(8:21) presenting initially with massive splenomegaly and hypereosinophilia
with many dysplastic eosinophils and their precursors is extremely rare. Hypereosinophilia
in itself enlists many differential diagnoses and is an alarming finding in rapid
turnover hematological states. It can be found either as an associated finding in
acute leukemia or as a clonal proliferation in chronic eosinophilic leukemia. The
dilemma might not always be entirely solved on morphology alone.
Case Report
An 8-year-old girl presented with fever for 3 months, pain in the abdomen, and progressive
abdominal distension for 1 month. Fever was intermittent, high grade, and was not
associated with vomiting. There was a history of weight loss, loss of appetite, and
generalized weakness. There was no breathing difficulty, bleeding from orifices, or
loose stools. On general examination, her general condition was poor. She was febrile
and pale. Few petechial spots could be identified over the abdomen. There was no lymphadenopathy
or icterus. On local examination, there was massive splenomegaly (10 cm below the
costal margin) and mild hepatomegaly (1 cm below costal margin).
Hemogram showed hemoglobin level of 8.4 g/dl and a total leukocyte count of 120,000/
cubic mm with eosinophils accounting for 52%. Peripheral blood film (PBF) examination
showed marked leukocytosis with striking predominance of eosinophils and their precursors,
including promyelocytes, metamyelocytes, and myelocytes along with few blasts. Eosinophils
and their precursors showed marked morphological abnormalities in the form of nuclear
hyperlobation, coarse granules, and cytoplasmic vacoulations [Figure 1]a]. Platelets were markedly reduced (10,000/ cubic mm). Myeloperoxidase cytochemistry
was strongly positive. Bone marrow biopsy was obtained, which showed a hypercellular
marrow with marked infiltration by eosinophilic precursors in interstitial and paratrabecular
pattern along with few immature precursor cells which were highlighted by immunohistochemistry
for CD34 and CD117. Megakaryocytes were markedly reduced [Figure 1]b], [Figure 1]c], [Figure 1]d].
Figure 1: (a) Peripheral blood smear shows eosinophils with dysplastic features such
as nuclear hyperlobation and coarse granules. Inset shows the presence of blasts (Giemsa,
×1000). (b and c) Diffuse replacement of bone marrow by eosinophils and their precursors
(H and E ×1000, 100 respectively). (d) Bone marrow blasts showing positivity for CD34
(Immunohistochemistry, ×1000)
Flow cytometry was performed on peripheral blood. Cells were gated on CD45 versus
side scatter. There were 17% blasts and 65% granulocytes (eosinophils and its precursors).
The predominant population in eosinophils and precursors were positive for CD34, CD117,
HLA-DR, and CD25 [Figure 2]a], [Figure 2]b], [Figure 2]c], [Figure 2]d], [Figure 2]e]. Based on the morphology and flow cytometry, showing predominant expression of variety
of immature markers over the eosinophils and its precursors (reflecting acute neoplastic
nature), the diagnosis considered was eosinophilic leukemia, and the possibility of
AML M4E0 was suggested. Cytogenetic studies were advised to confirm the same and rule
out other leukemic conditions associated with eosinophilia. Cytogenetic evaluation
for PDGFR alpha, PDGFR beta, FGFR1 rearrangements, BCR-ABL, and inv(16) was negative.
However, t(8:21) was positive in our case [Figure 2]f]. Thereafter, in conjunction with genetics, a final diagnosis of AML with t(8:21)
with hypereosinophilia was given. The patient was initially being treated with hydroxyurea
and steroids for symptomatic relief and now has been put up on therapy for AML, for
which she responded well.
Figure 2: (a) CD45 versus side scatter showing distinct populations of blasts (17%)
and granulocytes (55%). (b,d,e) The gated granulocytic population with increased expression
of HLA DR (42.6%), CD117 (43.2%), and CD34 (84.6%), respectively. (c) The gated blast
population showing CD34 expression (94.6%). (f) Chromosomal analysis: G-bands by trypsin
using Giemsa banding showing reciprocal translocation between the chromosomes 8 and
21, involving the region q22 and q22, respectively (arrow)
Discussion
At present, AML with specific genetic abnormalities has been classified by the WHO
under the broad category of “AML with recurrent genetic abnormalities.” These entities
are unique and are clinically, biologically, as well as prognostically distinct and
hence it is important to diagnose them. AML with t(8:21) is one such entity which
shows good response to the conventional chemotherapy and thus has a favorable prognosis.
It is also the most common chromosomal abnormality seen with AML. According to the
current WHO criteria, the diagnosis of AML can be made even when the blast percentage
(peripheral blood/bone marrow) is <20%, if associated with genetic abnormality such
as t(8:21), inv (16), and t(15:17).[1] Although specific morphological characteristics have been discussed with all these
entities, sometimes variations do occur and can lead to a diagnostic dilemma. This
type of AML has characteristic blast morphology and can be seen associated with bone
marrow eosinophilia.[1] We described the case of a girl where the presence of massive splenomegaly and great
morphological resemblance to eosinophilic leukemia on peripheral blood examination
with blast count <20%, gave an erroneous impression of a chronic myeloproliferative
neoplasm. These eosinophils also exhibited very prominent dysplastic features which
are very unusual in this category. AML with inv(16) usually displays eosinophilia
along with dysplasia in the form of abnormally large purple violet cytoplasmic granules.[2] These are the cases where cytogenetic evaluation has immense decisive role and is
the cornerstone to final diagnosis, as the etiology of eosinophilia is varied, encompassing
both lesions which are benign/reactive and those which are out rightly malignant.
Reactive causes of eosinophilia were ruled out in our case. Hematological malignancies
linked with eosinophilia include CML, JMML, CEL, AML M4E0, AML with inv (16), ALL,
myeloid, and lymphoid neoplasms associated with PDGFRA, PDGFRB, and FGFR1 rearrangements,
which require both morphological and genetic support for diagnosis.
In our case, the karyotypic abnormality, t(8:21), was positive and a final decision
of AML could be made even with low blast percentage. Immunophenotypically, the blast
and the immature eosinophilic precursors both exhibited immature markers, including
CD34, CD117, and HLA-DR. We also noticed increased CD25 expression, which has been
described as a prognostic marker, associated with aggressive clinical behavior.
Review of literature revealed very few reports available with similar presentation
with hypereosinophilia, rashes, and abnormal eosinophilic precursors in the bone marrow.[3],[4] However, the presence of eosinophils and its precursors in extreme numbers simulating
eosinophilic leukemia with prominent dysplastic features is extremely rare and is
uncommon in AML with t(8:21). This case report highlights the still another type of
morphology that can be seen with this karyotypic abnormality. The exact pathogenesis
behind eosinophilia observed in these cases is still unknown. However, a few published
reports have shown that these atypical eosinophils might be derived from the leukemic
clone itself by increased expression of interleukin-5 receptors as demonstrated byin
vitro studies.[5]
Due to a lack of much data on this, how well these patients respond to the conventional
antileukemic therapy is unknown. AML with t(8:21) in general has a favorable prognosis;
however, hypereosinophilia in itself can cause a lot of parenchymal damage to the
lungs, heart, and gastrointestinal tract due to the liberated cytokines, leading to
organ fibrosis and increased morbidity.[5]
Our patient received both steroids and antileukemic therapy with daunorubicin and
cytarabine. Repeat PBF after the completion of the first cycle showed marked reduction
in the total leukocyte counts including the absolute eosinophil numbers. The patient
is also recovering and is afebrile with moderate decrease in the spleen size.
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