Hypereosinophilia: A rare presentation of acute lymphoblastic leukaemia.

Acute lymphoblastic leukaemia (ALL) presenting as peripheral blood hypereosinophilia is very rare and the incidence is <1%. The characteristic feature of patients with ALL and hypereosinophilia is the absence of blasts in peripheral blood, and this might lead to misdiagnosis of ALL. It is important for clinicians and pathologists to be aware of this uncommon initial presentation of ALL to avoid delay in diagnosis. We report a 37-year-old man who presented with fever and respiratory symptoms and was found to have hypereosinophilia in peripheral blood. His bone marrow and lymph node biopsies were diagnostic of ALL.

Introduction

Severe eosinophilia defined as eosinophil count more than >5000/μL can occur with allergic disorders, parasitic infections and some malignancies.[1] However, acute lymphoblastic leukaemia (ALL) presenting as peripheral blood hypereosinophilia is very rare and the incidence is <1%.[2] The characteristic feature of patients with ALL and hypereosinophilia is the absence of blasts in peripheral blood, and this might lead to misdiagnosis of ALL. It is important for clinicians and pathologists to be aware of this uncommon initial presentation of ALL to avoid delay in diagnosis. We report a 37-year-old man who presented with hypereosinophilia and was diagnosed as ALL.

Case Report

A 37-year-old man presented with breathlessness, intermittent fever, loss of weight and appetite present for 2 months. On examination, he had pallor, bilateral pedal oedema, petechiae and purpura over trunk and extremities, bilateral supraclavicular and left cervical lymphadenopathy and hepatosplenomegaly. There was no neurological symptom or sign. His haemoglobin was 11.5 g/dl; total leucocyte count was 120,500/μL with a differential count of 15% polymorphs, 78% eosinophils and 7% lymphocytes. His absolute eosinophil count was 93,990/μL, and platelet count was 92,000/μL. A peripheral smear examination showed a markedly increased leucocyte count with 70% eosinophils [Figure 1a]. A bone marrow examination showed cellular marrow with sheets of immature cells admixed with eosinophils [Figure 1b]. A lymph node biopsy showed a neoplasm composed of tumour cells in diffuse sheets and focal collection of eosinophils with the Indian file pattern of tumour cells at the periphery [Figure 2]. On immunohistochemistry, the tumour cells were positive for PAX5, CD10, Tdt and CD34, and negative for Bcl6, CD20, CD5, CD7, MPO with an MIBI 40%. He was diagnosed as B lymphoblastic leukaemia. The bone marrow cytogenetic study was normal. A computed tomogram of the chest showed bilateral pleural effusion. He had a normal echocardiogram with the left ventricular ejection fraction of 55% and a normal cerebrospinal fluid study. While awaiting treatment, he developed acute myocardial infarction and expired.

Figure 1

(a) Peripheral smear examination showing marked eosinophilia. (b) Bone marrow smear showing immature cells

Figure 2

Lymph node biopsy showing sheets of tumour cells with focal collection of eosinophils (H and E, ×100)

Discussion

The eosinophil counts in a normal adult ranges from 20 to 500/μL; it constitutes 1%–3% of peripheral blood. Eosinophilia is classified as mild (500–1500/μL), moderate (1500–5000/μL) and severe (>5000/μL).[1] Our patient had severe eosinophilia. The haematologic malignancies usually associated with eosinophilia are Hodgkin's lymphoma and myeloproliferative neoplasms where the eosinophilia can be reactive or clonal.

Eosinophilia associated with ALL was first described by Spitzer in 1973.[3] The median age at diagnosis is 14 years; it shows a male preponderance and majority of cases are B-cell origin. Patients usually present with signs and symptoms of organ involvement due to infiltration of organs with eosinophils. The organ systems usually affected are the heart, lungs, skin, central nervous system (CNS), liver and spleen. The common symptoms are cough, shortness of breath, cardiomegaly and lung infiltrates seen in one-third to two-third of patients.[4] Eosinophilia generally precedes the diagnosis of ALL by several months to 2 years, and during this period, the patient may have urticaria rash, and other nonhaematological features of hypereosinophilic syndrome such as cardiomegaly, lung infiltrates and hepatosplenomegaly. Eosinophilia usually resolves on induction, but it returns with relapse of leukaemia. Eosinophilia in these patients is reactive as shown by normal cytogenetics in contrast to the blasts which show abnormal aneuploidy karyotype.[3]

Cytogenetic abnormalities are detected in about more than half the patients with ALL associated with hypereosinophilia.[4] The most common cytogenetic abnormality seen in patients with ALL associated with eosinophilia is t (5;14)(q31;q32) which is otherwise rare in ALL.[2] The eosinophilia is secondary to overproduction of interleukin 3, interleukin 5 and granulocyte stimulating factor by the blasts due to activation of growth factor gene on chromosome 5 when it is translocated adjacent to the immunoglobulin heavy chain gene on chromosome 14.[14] The chromosomal abnormality is usually seen only in leukaemic blasts, and the eosinophils had normal karyotype in 90% of cases supporting the hypothesis that the eosinophilia is reactive. In the 2008 WHO classification of lymphoid neoplasms, this entity is now included as “B lymphoblastic leukaemia/lymphoma with (5;14); IL3-IGH.” The other abnormalities occasionally seen are 45XY, t(7;12) (q22;p13), -9, hyperdiploidy with 5q deletion, or normal karyotype.[5] Our patient had a normal karyotype.

The myeloproliferative neoplasms which are associated with eosinophilia are chronic myeloid leukaemia, acute myeloid leukaemia with inv(16) or t(16;16), chronic eosinophilic leukaemia and myeloid neoplasms with platelet-derived growth factor receptor alpha (PDGFRA), PDGFR beta (PDGFRB) and fibroblast growth factor receptor 1 (FGFR1).[6] These malignancies usually have blasts in the peripheral blood in contrast to ALL with eosinophilia where there is paucity of leukaemia blasts in peripheral blood. In these conditions, there is the formation of fusion genes leading to constitutive stimulation of tyrosine kinase commonly PDGFRA, PDGFRB and FGFR1 which are responsible for eosinophilic proliferation.

Although our patient presented with severe eosinophilia, he did not have any organ involvement as shown by normal electrocardiogram, echocardiogram, absence of CNS involvement and skin rash. However, he died due to acute myocardial infarction before we could start specific treatment. Eosinophils secrete eosinophil granulated proteins which are responsible for the cardiotoxic effects manifesting as acute pericarditis, myocarditis or endocarditis, formation of thrombi adjacent to the injured myocardium and subsequent fibrosis leading to restrictive heart failure.[7] A 61-year-old man who presented with features of eosinophilic toxicity including myocardial infarction, eosinophilic pneumonia and urticaria subsequently was diagnosed to have B ALL.[8] Two patients with eosinophilia associated with ALL also developed myocardial infarction, respiratory failure and cerebrovascular accident as severe complications of eosinophilia.[9]

The prognosis of patients with ALL associated with hypereosinophilia is poor with a median survival of 7.5 months.[10] In a review of ALL associated with hypereosinophila, 26% deaths were eosinophilia related.[4] Since anthracyclines are an important component of chemotherapy for ALL, eosinophilic infiltration of the heart and lungs could compromise the treatment.

Conclusion

Hypereosinophilia in the peripheral blood can mask the diagnosis of ALL in this rare entity of ALL associated with hypereosinophilia. Since there is the absence of blasts in the peripheral blood, there may be a delay in diagnosis. Hence, clinicians and pathologists should be aware of this rare disease for early diagnosis and treatment.

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Conflicts of interest

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