Abstract
Few cases of eosinophilia associated with B cell acute lymphoblastic
leukemia (B-ALL) have been reported. This study reported a 16-year-old
male patient diagnosed with B-ALL and hypereosinophilia. He was admitted
to the emergency department (ED) with urticaria and generalized itching.
On initial examination, the skin was wholly erythematous, and urticarial
lesions were scattered throughout the body. Peripheral blood smear (PBS)
was examined, and eosinophils were seen in different fields. However,
blast cells were not seen in the PBS. In bone marrow examination,
terminal deoxynucleotidyl transferase (TdT)-positive and CD20-positive
lymphoid blasts were reported along with eosinophilia. In
immunohistochemical (IHC) staining, results were within normal limits
for the fibroblast growth factor receptor 1 (FGFR1), platelet-derived
growth factor receptor alpha (PDGFRα), and platelet-derived growth
factor receptor beta (PDGFRβ) genes expressions. Moreover, no breakpoint
cluster region (BCR)/Abelson murine leukemia 1 (ABL1) mRNA transcripts
and no Janus kinase 2 (JAK2) V617F mutation were detected. Eventually,
the B-ALL diagnosis was confirmed for the patient, and he was started on
the Berlin-Frankfurt-Münster (BFM) chemotherapy regimen. The patient was
transferred to another facility and is continuing his treatment there.
Introduction
Eosinophilia is a condition determined by an elevated absolute
eosinophil count (AEC). In case of severity, it is divided into three
grades: 1) mild (AEC = 500-1500/mm3), 2) moderate (AEC
= 1500-5000/mm3), and 3) severe (AEC >
5000/mm3) 1. It can also be
classified into primary (PE) and secondary (SE) forms. PE is mainly
related to clonal abnormalities of myeloid cells, while SE is often
reactive to the T cells’ cytokine production. Various conditions can
cause SE, such as infections (especially parasites), allergic reactions,
pulmonary, dermal, renal, or autoimmune diseases, immunodeficiencies,
and malignancies. Nevertheless, in very few cases (less than 1%),
hypereosinophilia (HE) is associated with acute lymphoblastic leukemia
(ALL) 2. This condition is mainly caused by the
translocation t(5;14)(q31;q32), which leads to overexpression of
interleukin (IL)-3 through a fusion gene called immunoglobulin heavy
locus (IGH)-IL3. Urticarial rash, fever, arthralgia, myalgia, sweating,
and dyspnea are the common symptoms in these cases. Notably, the lack or
absence of blasts in the peripheral blood smear (PBS) is the
characteristic feature in ALL with eosinophilia (ALL-eo)3,4.
Hypereosinophilic syndrome (HES), a rare hematological disorder, occurs
when eosinophils invade the vascular system, resulting in multi-organ
failure. It is defined as the existence of persistent eosinophilia (AEC
>1500 per mm3) along with evidence of
organ damage 5. It can affect almost all the organs,
including the skin, pulmonary and cardiovascular systems, central
nervous system, peripheral nervous system, eyes, gastrointestinal tract,
and coagulation system 6. In this study, we reported
an adolescent case with ALL-eo and HES, with absent blasts in the PBS.
Case presentation
A 16-year-old male patient presented with urticaria and generalized
itching to the emergency department (ED). He was referred to our
institute with leukocytosis (WBC = 160,000/ µL [normal range:
4,500-11,000/µL], with 90% eosinophils), anemia (Hb = 9.11 g/dL
[normal range: 13.5-17.5 g/dL]), and thrombocytopenia (platelets =
69,000/ µL [normal range: 150,000-450,000/µL]). In the initial skin
examination, erythematous and urticaria lesions were observed scattered
in all parts of his body. Only a splenomegaly was detected about 6-7 cm
below the rib edge during the physical examination. PBS showed
eosinophilia with different shapes and hypogranular appearances.
However, no blast was observed (Figure 1).
Due to hypereosinophilia, cardiac examination and high-sensitivity
cardiac troponin check were performed, which were reported positive (15
ng/L [normal range: > 14 ng/L]). Due to leukocytosis
and bicytopenia, bone marrow biopsy was performed, and
immunohistochemical (IHC) staining was performed for fibroblast growth
factor receptor 1 (FGFR1), platelet-derived growth factor receptor alpha
(PDGFRα), and platelet-derived growth factor receptor beta (PDGFRβ).
Moreover, breakpoint cluster region (BCR)/Abelson murine leukemia 1
(ABL1) and Janus kinase 2 (JAK2) V617F mutation were also requested
(Table 1). Cytogenetic examination of PBS showed the patient’s karyotype
was 47, XY, +mar in half of the analyzed cells and 46, XY in the other
half (Figure 2). In the bone marrow examination, along with
eosinophilia, terminal deoxynucleotidyl transferase (TdT)-positive and
CD20-positive lymphoid blasts were reported. Sections of the trephine
bone biopsy showed 100% cellularity in which a mixed population of
eosinophils precursors and some small blastoid cells were seen.
Morphological study and IHC staining were in accordance with acute
precursor B lymphoblastic leukemia/lymphoma with eosinophilia (Table 2).
According to cardiac conditions, glucocorticoid pulse therapy
(methylprednisolone 1000 mg IV daily for 3 consecutive days) was
started. Before starting the glucocorticoid pulse, ivermectin (200 µg/kg
per day) was also initiated due to the high prevalence of Strongyloides
stercoralis in the local area. The patient has been diagnosed with B-ALL
and was treated with Berlin-Frankfurt-Munich (BFM) protocol. He was then
transferred to another institute to continue his therapy.
Discussion
HES is divided into three classifications: 1) idiopathic HES (no
evidence for any underlying condition); 2) primary, neoplastic, or
clonal HES (including myeloproliferative disorders, chronic myeloid
disorders, and acute leukemias); 3) secondary or reactive HES (caused by
conditions like infectious diseases, medications, allergic reactions,
autoimmune diseases, metastases, and endocrinopathies)7. The first step in the classification of HE patients
is the assessment of secondary causes. In this regard, providing an
excellent medical history, evaluation of clinical manifestations, and
paraclinical investigations can make identifying the underlying cause
more available. After excluding secondary causes of HE, primary bone
marrow disorders must be assessed. It requires analyses over PBS and
morphologic, immunophenotypic, and cytogenetic features of bone marrow8.
Until now, very few cases of ALL-eo have been reported, mainly in male
patients. It shares some similar features with HES. First, they are both
more common in males (76%). Second, they are both presented with
nonspecific constitutional symptoms. Last, their morbidity rate is
mainly related to the site of eosinophilic infiltration and the extent
of it. Nonetheless, ALL-eo has been reported to occur at younger ages
(mean age of 14 years, with an age range of 2-58 years). HE-related
manifestations commonly precede classic ALL signs and symptoms2,9. ALL-eo-related indications are similar to HES and
can exacerbate multi-organ damage and thrombocytopenia4, as seen in our case, which was referred to the
hematology-oncology ward of our institute, with a platelet count of
69,000/µL. As mentioned before, due to severe eosinophilia, HES was
suspected. Thus, we performed heart monitoring and required paraclinical
tests to evaluate cardiac disorders. High-sensitivity cardiac troponin
was reported to be positive with a titer of 15 ng/L, suggesting
eosinophils infiltrating the heart, causing progressive restrictive
cardiomyopathy that may result in Loeffler endocarditis or even death2.
Our case also presented skin lesions, including urticaria and
generalized itching, reported in the previous studies9,10. Histopathological investigations of the lesions
revealed eosinophils, polymorphonuclear leukocytes, and monocytes
infiltrating the perivascular area with different numbers11. Urticarial lesions are usually present as a skin
manifestation of HES. However, unlike classic urticarial lesions,
HES-related lesions are persistent for more than 24 hours. In contrast
to urticarial vasculitis, they also demonstrate no vasculitis features
in histopathological studies 9.
The exact mechanism of the association between HE and ALL has not been
completely understood. It could be due to neoplastic antigens or
exogenous agents (like viral infections), which may stimulate T cells
and result in the over-production of eosinophil-stimulating growth
factors 8. Nevertheless, given the development of HE
in ALL patients, it appears to be the result of a mixture of reactive
and clonal pathways 12. A group of abnormalities such
as absent CD3 marker, presence of abnormal and immature T cell,
increased expression of CD5 on
CD3-CD4+ cells, and absence of
surface CD7 and CD27 marker expression has been frequently reported in
these patients. Lymphocytes carrying the mentioned abnormalities can
lead to the overproduction of Th2-related cytokines, including IL-3,
IL-4, IL-5, and IL-13, leading to the increased production and prolonged
survival of eosinophils 2,13. ALL-eo has been
repeatedly described as associated with translocation t(5;14)(q31;q32),
which juxtaposes the IL-3 gene with the IGH enhancer. This will lead to
a significant overproduction of IL-3 and, consequently, HE induction14. Finally, according to WHO, screening tests of the
PBS, including factors interacting with PAPOLA and CPSF1 (FIP1L1)/PDGFRA
gene fusion and reciprocal translocations that affect 9p24 (e.g., JAK2),
8p11–12 (e.g., FGFR1), 4q12 (e.g., PDGFRα), and 5q31-q33 (e.g.,
PDGFRβ), are recommended and can be helpful to determine the
risk-adapted therapy and risk of myeloid malignancies2,8.
Conclusion
The association of B cell ALL with HE is a rare condition. Patients may
present with various symptoms, generally related to the site of
eosinophil infiltration. Here, we reported a 16-year-old male patient
who was diagnosed with a case of B-ALL along with hypereosinophilia and
admitted to the ED with urticaria and generalized itching. Importantly,
blast cells were not seen in PBS. The patient has been diagnosed with a
case of B-ALL and was treated with BFM protocol.