Hypereosinophilia in Solid Tumors—Case Report and Clinical Review

Background Renal cell cancer may cause various paraneoplastic syndromes; however, paraneoplastic hypereosinophilia occurs exceedingly rare. Thus far, only two cases of clear cell renal cell carcinoma (CCRCC) associated with hypereosinophilia have been reported. In this paper, we present a case of paraneoplastic hypereosinophilia associated with renal cell carcinoma and a review of the reported cases of hypereosinophilia in solid tumors. Methods The review is based on an electronic literature search performed in the PubMed database in September 2020 with the following key terms: eosinophilia & neoplasm; eosinophilia & cancer; eosinophilia & paraneoplastic syndrome. Papers were included based on screening the titles and/or abstracts. We also included the case of our patient in the analysis. Case presentation A 68-year-old Caucasian female patient with recurrent CCRCC was admitted to our Clinic for exacerbating dyspnea and chest and right upper abdominal pain, accompanied by confusion. Preliminary blood tests showed an increased white blood cell count of 40,770/μl, and an increased eosinophil count of 6,530/μl indicating eosinophilia. Several tests were carried out to rule out the noncancer causes of hypereosinophilia. The temporal appearance of eosinophilia and the recurrence of CCRCC without any other apparent potential causes led to the diagnosis of paraneoplastic hypereosinophilia. Despite treating with high doses of corticosteroids, only a transient decrement in eosinophil count was observed along with further deterioration of the patient’s condition. The patient succumbed to the disease 6 months following the tumor surgery and 2 months after the diagnosis of hypereosinophilia and tumor recurrence. Conclusion Our observations are in agreement with the majority of reports showing that the occurrence of eosinophilia following tumor resection may indicate a poor prognosis, tumor recurrence, and rapid disease progression.


INTRODUCTION
Eosinophilia, which is characterized by an increase in the count of circulating absolute eosinophils above the normal level of 500/ml, commonly occurs secondary to allergy, parasitic infections, collagen vascular disease, or drug hypersensitivity. Hypereosinophilia is marked by an elevated absolute eosinophil count (AEC) of more than 1,500/ml. Hematologic malignancies caused by somatic mutation have been reported with clonal expansion of eosinophils. Therefore, primary hypereosinophilia should be taken into consideration in the differential diagnosis of high AEC (1). However, in solid tumors, hypereosinophilia is a rare phenomenon and is mainly associated with carcinomas arising from the mucinsecreting epithelium (e.g. bronchus, gastrointestinal tract) (2).
Prolonged activation of eosinophils may cause migration into the skin, airway, gastrointestinal tract, cardiac, and nervous system, where they may cause end-organ damage principally through the induction of thrombosis and fibrosis. Therefore, all patients with hypereosinophilia must be evaluated for organ dysfunction attributable to eosinophilia (1).
It should be highlighted that peripheral blood eosinophilia counts are not strongly correlated and predictive of tissue eosinophilia. Moreover, tumor-associated tissue eosinophilia (TATE) is considered favorable in colorectal, breast, and prostate cancers, conversely, tumor-associated blood eosinophilia (TABE) generally occurs once the tumor has spread and its presence often leads to poor prognosis (3).
In this paper, we present a case of paraneoplastic blood eosinophilia associated with clear cell renal cell carcinoma (CCRCC) and a review of the reported cases of hypereosinophilia in solid tumors. The review is based on an electronic literature search performed in the PubMed database in September 2020 with the following key terms: eosinophilia & neoplasm; eosinophilia & cancer; eosinophilia & paraneoplastic syndrome. Papers were included based on screening the titles and/or abstracts. So far, only two cases of CCRCC associated with TABE have been reported (4,5).

CASE PRESENTATION
A 68-year-old Caucasian female was admitted to our Clinic on August 24, 2020, for exacerbating dyspnea and chest and right upper abdominal pain, accompanied by confusion for 3 weeks.
A computed tomography (CT) scan performed in July 2020, 3 months after the nephrectomy, revealed a retroperitoneal tumor mass in the surgical bed with hepatic and diaphragmatic invasion, and right pleural metastases. Histopathological assessment of liver infiltrates confirmed the diagnosis of local CCRCC relapse. During the diagnosis of tumor recurrence, the blood analysis showed a WBC count of 17,560/ml with 12.8% of eosinophilic granulocytes (AEC: 2,250/ml).
When abdominal pain and dyspnea occurred, palliative treatment with dexamethasone, pantoprazole, and buprenorphine were initiated. Moreover, targeted therapy for CCRCC was planned for the patient, but due to the rapid deterioration of health condition and a further increase of eosinophilic granulocyte count, the patient was admitted to our Clinic of Internal Medicine.
The past medical history also revealed that the patient had hypertension well controlled on bisoprolol only and underwent skin-sparing right mastectomy in 2005 for breast cancer (mammography and ultrasonography examination of the breasts, performed in August 2020, excluded the tumor recurrence). The patient had no history of alcohol abuse, asthma, or other allergic diseases.
On the day of admission to our Clinic, on examination, the patient appeared alert with mild functional cognitive disorder. Tachypnea and dullness over the right lung, up to seven intercostal spaces, were observed with the absence of breath sound. Abdomen tenderness during palpations and mild edema in distal parts of the lower limbs were also noticeable. Preliminary blood tests showed an increased C-reactive protein level of 240 mg/l, a WBC count of 40,770/ml, marked eosinophilia with an eosinophil count of 6,530/ml, mild anemia with a hemoglobin level of 11.6 g/dl, and a normal platelet count of 346,000/ml. A CT angiography of the chest revealed right-sided pleural effusion, pneumonia, and pulmonary microembolism.
Thoracentesis was performed for pleural effusion, and treatment with a broad-spectrum antibiotic (intravenous) and low-molecular-weight heparin (subcutaneous) were initiated. At that time, dexamethasone was discontinued due to the suspicion of infection disease and in purpose to carry out the differential diagnosis of hypereosinophilia. Despite the treatment, a further increase in leukocytes up to 56,000/ml with 33% of eosinophilic granulocytes (AEC: 18,500/ml) was observed.
Paraneoplastic eosinophilia is mainly associated with hematologic malignancies, although there is fairly extensive literature about eosinophilia in solid tumors, which mainly include case reports (4-96) ( Table 2).
Several tests were performed to rule out the noncancer causes of hypereosinophilia. There was no clinical or serologic evidence of an allergy, a parasitic infection, or vasculitis. Blood tests showed a normal total immunoglobulin E (IgE) level of 59.2 kUa/l (normal < 81 kUa/l), while specific IgE for Aspergillus fumigatus or antibodies against myeloperoxidase were not detectable. A bone marrow biopsy was performed which showed no evidence of leukemia. Fluorescent in situ hybridization showed no FIP1L1-PDGFRa fusion. The temporal appearance of eosinophilia and recurrence of CCRCC without any other apparent potential causes confirmed the paraneoplastic nature of hypereosinophilia in our patient.
A massive intravenous dose of corticosteroids (1.5 g methylprednisolone) was initiated, which caused a profound, albeit transient, decrement in the eosinophil count ( Figure 1). Unfortunately, the patient's condition further deteriorated despite the treatment, and so targeted therapy for CCRCC was not initiated. We discontinued the corticosteroids after three days to limit their toxicity. Due to the poor prognosis, the patient received only palliative support and succumbed to the disease 6 months following surgery and 2 months after the diagnosis of tumor recurrence. Permission for a postmortem examination of the body was not granted.

DISCUSSION
In this paper, we have described the case of a patient with blood hypereosinophilia associated with recurrent CCRCC and analyzed one hundred previously reported cases of hypereosinophilia in solid tumors.
Renal cell cancer may cause various paraneoplastic syndromes, the most frequent of which are hypercalcemia, polycythemia, thrombocytosis, hypertension, and secondary amyloidosis (97). However, eosinophilia associated with renal cell cancer is exceedingly rare. So far, only two cases of CCRCC (4, 5) and three with chromophobe RCC associated with hypereosinophilia (27) have been reported ( Table 1).
For patients diagnosed with life-threatening conditions that may reflect irreversible eosinophil-associated tissue damage, emergency treatment with high doses of steroids, leukapheresis, and/or cytoreduction may be warranted (98). The mechanism by which corticosteroids induce a reduction in the eosinophil count remains obscure and proposed explanations, including cessation of bone marrow release of eosinophils; reduction of bone marrow eosinophil production and adhesion; eosinophil destruction; reversible sequestration of eosinophils in extravascular locations, and inhibition of eosinophil chemotaxis (99).   We have summarized the one hundred previously reported cases of paraneoplastic hypereosinophilia secondary to solid tumors in the years 1938 -2020 in Table 2 (4-96). We included in the table data of tumor location, sex ratio, average age, average maximal absolute eosinophil count, and average survival time after the diagnosis of high AEC.
In conclusion, our observations presented in this paper are in line with most studies reflecting that paraneoplastic blood hypereosinophilia is characterized by a more advanced disease and poor prognosis. In our opinion, in all patients with life-threatening eosinophil-associated organ damage, prompt treatment should be initiated (3).

DATA AVAILABILITY STATEMENT
The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

ETHICS STATEMENT
The studies involving human participants were reviewed and approved by the Independent Bioethics Committee for Scientific Research at Medical University of Gdansk (NKBBN/622/2020). Written informed consent was not provided because the patient passed away. Written informed consent was obtained from her closest relative to publish the data.

AUTHOR CONTRIBUTIONS
EZ reviewed the literature, wrote the manuscript, and secured ethical approval for the study. ŁO and KS carried out critical interpretations. All authors contributed to the article and approved the submitted version.