Hypereosinophilia is most commonly associated with allergy and parasitic infections. Furthermore, several drugs, pulmonary and gastrointestinal diseases have been identified as important causes for hypereosinophilia [
8,
9]. Within recent years, a couple of molecular alterations have been identified to account for malignant hypereosinophilic syndromes including rearrangements of the PDGFR receptor [
8]. A mild to moderate increase (> 500/μl to < 1,500/μl) of eosinophils can be found in up to 5% of patients with malignancies [
10]. Severe peripheral hypereosinophilia (> 5,000/μl) has been described in a variety of hematologic and solid tumors including gastrointestinal tumors [
11,
12], bronchial carcinoma [
10], sarcomas [
13] and prostate cancer [
14]. Several cytokines produced by the primary tumor have been identified to account for increased production of eosinophilic granulocytes in the bone marrow including interleukin-3, interleukin-5 and GM-CSF (granulocytes macrophages stimulating factor) [
12,
15,
16]. Other mechanisms for hypereosinophilia in patients with malignancy include an eosinophilotactic response due to necrosis in the tumor and increased production of eosinophils due to tumor cell dissemination in the bone marrow [
9]. In the case presented here, we found increase of multiple cytokines at the time of massive leukocytosis and hypereosinophilia. G-CSF and GM-CSF which may be secreted by tumor cells and induce production of eosinophils [
17,
18] were significantly elevated. Soluble receptor of interleukin 2 (IL2-RA) has been shown to be an important mediator of autocrine and paracrine regulation of eosinophils [
19]. MIP-1a which is secreted by eosinophils and induces further leukocyte activation was also significantly elevated [
20]. Both, elevation of interleukin 8 and MCP-1, may be explained by TNF-mediated activation of eosinophils [
21]. All these cytokines were significantly lower at time of normal leukocyte count. However, it is not possible to define the exact mechanism of hypereosinophilia in this patient, as the source of the cytokines remained undefined and mediators causing hypereosinophilia may also be induced by eosinophils themselves. The tumor presented with extensive necrotic areas showing massive infiltration of eosinophils (Figure ). Tumor necrosis has been discussed as a factor promoting tumor related hypereosinophila [
22]. However, as a steady increase of leukocytes was observed after resection of the tumor with necrotic areas, tumor necrosis cannot be regarded as the only promoter of increasing eosinophils in the present case and other sources for cytokines promoting hypereosinophilia are probable.
Paraneolastic eosinophilia is usually mild without any clinical symptoms, but absolute counts may occasionally exceed 25,000/μl and may cause end-organ damage. In a few reported cases of paraneoplastic hypereosinophilia, neurological symptoms occurred due to thromboembolic events with multiple infarctions [
23,
24,
14]. Significantly reduced left ventricular function in our patient may be interpreted as end-organ damage as well.
Several studies have shown that paraneoplastic eosinophilia is a poor prognostic sign and indicates metastatic and extensive disease [
25,
26]. In a series of 36 cases with paraneoplastic hypereosinophilia, 32 patients had metastatic disease [
27]. The patient reported here had a disseminated disease with pulmonary and bone metastases and presented with extraordinary rapid disease progression with poor response to surgical and systemic treatment. In previously reported cases, peripheral eosinophil count correlated with disease activity [
28]. We could not find a clear correlation between tumor mass and absolute granulocyte count in the reported patient.
Symptomatic paraneoplastic eosinophilia could be treated with drugs leading to decreased production and function of eosinophilic granulocytes including glucocorticoids, hydroxyurea, vincristine [
29,
30]. Furthermore, reduction of tumor mass either by surgery or systemic treatment has been shown to reduce peripheral eosinophilic counts in paraneoplastic hypereosinophilia [
11,
28].
In the present case, a combination of drugs directly targeting function and production of granulocytes (prednisone, hydroxyurea, vincristin, cytarabine) and drugs targeting renal carcinoma (sunitinib and temsirolimus) led to a decrease of absolute leukocytes and eosinophils. Neurologic impairment and general status significantly improved with reduced numbers of eosonophilic granulocytes. First line sunitinib had to be temporarily replaced by temsirolimus, as swallowing difficulties did not permit oral therapy. Temsirolimus led to a short-term response (according to RECIST) 2 weeks after initiation. However, rapid progression was observed only 4 weeks after initiation of systemic therapy. As reduction of prednisone led to significant hypereosinophilia-associated reduction of vigilance with prompt improvement after increase of dosage we consider prednisone as a mainstay of the therapeutic approach. Hence, it leads to reduced eosinophilic count and improvement of hypereosinophilia associated symptoms.
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