A tricky and rare cause of pulmonary eosinophilia: myeloid/lymphoid neoplasm with eosinophilia and rearrangement of PDGFRA

Background Eosinophilic lung diseases represent a heterogeneous group of disorders with prominent infiltrate of eosinophils in lung interstitium and alveolar spaces. Peripheral blood eosinophilia is often present. Infections, drugs, allergens, toxic agents have to be evaluated as possible causes of eosinophilic lung infiltrates. The category of myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB, FGFR1 and PCM1-JAK2 represents an uncommon cause of eosinophilic lung infiltrate. Case presentation We report the case of a 70-year old man complaining of dry cough and dyspnea. Ground glass-opacities were seen on imaging studies and peripheral blood eosinophilia was present. A thorough step-wise patient’s evaluation led to identify the clonal nature of eosinophilia and the diagnosis of myeloid/lymphoid neoplasm with eosinophilia and rearrangement of PDGFRA was made. Conclusions Correlation with clinical history, laboratory tests and imaging studies is essential to achieve the correct diagnosis when facing with eosinophilic lung infiltrates. A prolonged eosinophilia can cause life-threatening organ damage. Identification of PDGFRA rearrangement, as in the present case, is particularly critical given the sensitivity and excellent response to imatinib, which has completely changed the natural history of this neoplasm.


Background
Eosinophilia comprises a heterogeneous group of disorders that, except for the eosinophilia feature itself, have few things in common [1]. As eosinophils can be found in different clinical settings, a careful investigation is essential to get to the correct diagnosis and adequate treatment [1].
The present challenging case of eosinophilia clarifies the progressive workup, which led to the diagnosis of myeloid/ lymphoid neoplasm with eosinophilia and rearrangement of PDGFRA, a rare disease with less than 1 case per 1000000 persons per year [8]. In the present case the PDGFRArearranged neoplasm sustaining eosinophilia was effectively treated with imatinib with complete remission.

Case presentation
A 70-year old man presented with dry cough and dyspnea on exertion over the preceding 8 months. He was afebrile, with no history of allergies, asthma, drug intake or travelling. Physical examination revealed a moderately enlarged spleen; wheezes were present at pulmonary auscultation. Blood tests showed an increasing leukocytosis (17000/ mmc) with up to 2000 eosinophils/mm3. Stool, urine and blood were negative for parasitic infections. Pulmonary function tests, with forced expiratory volume in 1 s (FEV1) of 60%, showed moderate small airway obstruction. High resolution computed tomography (HRCT) scan of the thorax revealed patchy ground-glass opacities bilaterally, predominantly in the lower pulmonary lobes (Fig. 1). Bronchioalveolar lavage (BAL) showed increased eosinophil percentage up to 60% of cells; most eosinophils appeared degranulated, with cytoplasmic vacuoles (Fig. 2a). Bone marrow aspirate showed numerous eosinophils and bone marrow trephine sections ( Fig. 2B) revealed an hypercellular marrow with markedly increased eosinophils in different stages of maturation, including features of hypogranulation and nuclear hypersegmentation or hyposegmentation. No increase in mast cells was noted. The spectrum of eosinophil maturation raised concern for a myeloid neoplasm with eosinophilia. Fluorescence in situ hybridization (FISH) analysis was carried out and the fusion gene FIPL1-PDGFRA, occurring as a result of a cryptic deletion at 4q12, was identified. A conclusive diagnosis of myeloid/lymphoid neoplasm with eosinophilia associated with PDGFRA rearrangement was rendered. The patient received imatinib (100 mg daily), achieving a complete clinical, radiological (Fig. 3) and molecular remission at 3 years from diagnosis.
The interest of our case resides mainly on the progressive thorough step-wise patient's study leading to diagnosis and adequate treatment. The clinical presentation together with radiological pulmonary findings led to think of an interstitial lung disease. BAL evaluation identified a high percentage of eosinophils. In BAL specimens eosinophils are frequently degranulated or show cytoplasmic vacuolization and may be overlooked and misinterpreted either as neutrophils or macrophages [10]. In the normal population, eosinophils represent less than 1% of cells in BAL [10]. Eosinophilia is defined as more than 5% eosinophils, while severe eosinophilia is defined as more than 25% eosinophils [10]. An increased eosinophil count in Fig. 1 Axial HRCT scan of the chest revealed patchy ground-glass opacities bilaterally, predominantly in the lower lobes of the lungs BAL may be seen in asthma, drug reactions, infections, toxic agents, interstitial lung disease and connective tissue disorders [10].
After secondary causes of eosinophilia were excluded, our patient's work-up proceeded to evaluate a primary bone marrow disorder. Bone marrow aspirate and trephine biopsy examination in conjunction with FISH analysis identified the presence of PDGFRA rearrangement.
In conclusion, recognizing the category of myeloid/ lymphoid neoplasms with eosinophilia is crucial for treatment [1][2][3][4][5][6]. The aberrant tyrosine kinase activity characterizing PDGFRA and PDGFRB rearrangements, makes these disorders exquisitely responsive to tyrosine kinase inhibitors as imatinib, often with excellent results, as in the present case [1][2][3][4][5][6]. To date for FGFR1rearranged neoplasms stem cell transplant represents the only potentially curative option; ongoing studies on the use of pemigatinib, a potent inhibitor of FGFR1, are showing promising efficacy in this group of neoplasms [11].