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/μl, 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/μl. 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 mucin-secreting 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.

Five months earlier, in March 2020, she underwent radical right nephrectomy due to a CCRCC (tumor stage: pT3a, pNx, R0, M0). During the primary diagnosis, the blood analysis showed a white blood cell (WBC) count of 7,450/μl (reference range: 4,000–7,000/μl) with 1.1% (reference range: 1–6%) of eosinophilic granulocytes.

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/μl with 12.8% of eosinophilic granulocytes (AEC: 2,250/μl).

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/μl, marked eosinophilia with an eosinophil count of 6,530/μl, mild anemia with a hemoglobin level of 11.6 g/dl, and a normal platelet count of 346,000/μl. 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/μl with 33% of eosinophilic granulocytes (AEC: 18,500/μl) 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

Data of one hundred previously reported cases of hypereosinophilia in solid tumors.

Tumor	No.	M:F	Age avg	AEC max [G/l]	AEC avg [G/l]	SVavg[Mo]	Reference
SCC of the lung	8	7:1	63	37.1	16.81	1.7	(6–11)
Adenocarcinoma of the lung	8	8:0	60	114.39	47.8	7.4	(6, 16, 38, 49, 60, 71, 82, 93)
Large cell carcinoma of the lung	7	6:1	64	125.58	62.36	2.8	(12–15, 17–19)
Not further defined NSCLC	5	5:0	64	139.5	52.52	8.2	(20–22)
Pleomorphic carcinoma of the lung	1	1:0	55	7.1	–	NR	(23)
Gastric adenocarcinoma	7	5:2	65	71.51	14.62	3	(61–67)
Adenocarcinoma of the colon	5	3:2	50	141.5	40.29	3.7	(68–70, 72, 73)
Adenocarcinoma of the rectum	2	1:1	71	6.1	5.43	NR	(92, 94)
Adenocarcinoma of the pancreas	3	2:1	66	44.12	17.14	2	(52–54)
PNETs	3	3:0	62	99.6	42.9	4.4	(56–58)
IPMN of the pancreas	1	0:1	72	3.74	–	2	(55)
ACC of the pancreas	1	1:0	59	1.8	–	2.5	(59)
CCRCC	3	2:1	63	78	45.5	2.7	(4, 5)*
Chromophobe RCC	3	2:1	52	19.08	16.32	NR	(27)
Spindle cell sarcoma of the kidney	1	1:0	76	7.77	–	NR	(77)
Anaplastic thyroid cancer	4	2:2	74	51.3	21.19	0.5	(44–47)
Undifferentiated thyroid carcinoma	2	0:2	78	37.39	20.14	0.9	(48, 50)
Papillary thyroid cancer	2	1:1	49	81.9	44.55	9.5	(51, 95)
Uterine leiomyosarcoma	4	0:4	59	175	45.72	NR	(37, 39–41)
Uterine leiomyomas	2	0:2	53	5.04	3.44	NR	(42)
Metastatic melanoma	4	3:1	57	105.79	76.77	1.3	(24–26, 28)
Hepatocellular carcinoma	3	2:1	60	21.43	12.51	1	(29–31)
Prostatic adenocarcinoma	3	2:1	74	55.44	21.12	NR	(78–80)
UCC of the bladder	2	1:1	55	8.38	6.24	NR	(33, 34)
UCC of the renal pelvis	1	0:1	83	26.24	–	NR	(32)
Gallbladder cancer	2	2:0	58	65.5	34.81	2.3	(35, 36)
SCC of the tongue	2	2:0	70	9.7	9.6	8	(90)
SCC of the maxillary sinus	1	1:0	46	2.1	–	NR	(91)
SCC of the cervix	1	0:1	42	4.74	–	3	(87)
Spindle cell sarcoma of the knee	1	0:1	41	77.79	–	NR	(76)
MFH of the knee	1	0:1	30	160.7	–	18	(85)
STS of the left elbow	1	0:1	67	38.18	–	0.3	(86)
Endometrioid ovarian carcinoma	1	0:1	88	15.38	–	NR	(43)
Cardiac rhabdomyosarcoma	2	2:0	40	14.2	11.41	NR	(74, 89)
Peritoneal mesothelioma	1	1:0	56	6.15	–	2	(88)
Adenocarcinoma CUP	2	0:2	65	9.3	8.1	1.5	(24, 96)
Anaplastic CUP	1	1:0	65	19.45	–	NR	(75)

No.—number of reported cases, M:F—male-to-female ratio, AEC max—the highest absolute eosinophil count, AEC avg—average absolute eosinophil count, SV [Mo] – average survival time after diagnosis of hypereosinophilia in months, NR – not reported or insufficient data to calculate the average survival time, SCC—squamous cell carcinoma, NSCLC—non-small-cell carcinoma, PNETs—pancreatic neuroendocrine tumors, IPMN—intraductal papillary mucinous neoplasm, ACC—acinar cell carcinoma, CCRCC—clear cell renal cell cancer, RCC—renal cell cancer, UCC—urothelial carcinoma, MFH—malignant fibrous histiocytoma, STS—soft tissue sarcoma, CUP—carcinoma of unknown primary, * - Our case

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 ( ). 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.

Figure 1

Leukocyte and eosinophilic granulocyte count. Arrow: admission to our Clinic, MP: treatment with methylprednisolone.

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

Previously reported cases of renal cell carcinoma with hypereosinophilia.

	Age	Sex	AEC max [G/l]	Type	Tumor stage	Size [cm]	Recurrence	Follow-up
Todenhöfer et al. (4)	46	m	40	Clear cell RCC with sarcomatoid components	pT4, pNx, M1, L0, V1, Rx, G3	Not reported	Yes	Died of disease 4 months following surgery
Wei et al. (27)	53	m	17.5	Typical chromophobe RCC	T1b, N0, M0	7	No	1 year of follow-up
Wei et al. (27)	56	m	12.4	Typical chromophobe RCC	T1b, N0, M1	6.2	No	1 year of follow-up
Wei et al. (27)	48	f	19.1	Eosinophilic variant chromophobe RCC with sarcomatoid components	T2a, N0, M0	7.5	Yes	Died of disease 6 months following surgery
Zhou et al. (5)	75	m	78	Clear cell RCC	pT3a, pN1, M0, G4	2.5 × 1.7 × 1.3	Yes	Died of disease 2 months following surgery
Our case	67	f	18.5	Clear cell RCC	pT3a, pN1, M0, R0	10.8 × 10.3 × 11	Yes	Died of disease 8 months following surgery

AEC max—the highest absolute eosinophil count, RCC—renal cell carcinoma.

The mechanism contributing to eosinophilia in malignant diseases has not yet been fully determined. It has been suggested that three cytokines, namely interleukin-3 (IL-3), interleukin-5 (IL-5), and granulocyte-macrophage colony-stimulating factor (GM-CSF), may act as a potential eosinophilopoietin polypeptide (6, 13, 15, 24, 25, 29, 35, 50, 51, 76, 82, 83). Unfortunately, in our patient, neither the level of IL-5, IL-3, and GM-CSF in serum was determined nor immunohistochemical staining with indicated antibodies was performed.

Since eosinophilia occurs with several medical conditions, paraneoplastic eosinophilia can be diagnosed only after excluding all other causes. It is also necessary to rule out the following: infectious diseases (e.g. parasitic infections, allergic bronchopulmonary aspergillosis, coccidiomycosis); eosinophilias associated with medications (e.g. penicillins, cephalosporins, tetracyclines, sulfasalazine, nonsteroidal anti-inflammatory agents, hydrochlorothiazide, ranitidine, allopurinol, phenytoin, hydantoin, carbamazepine, cyclosporine, nevirapine); connective tissue and autoimmune diseases (e.g. eosinophilic fasciitis, eosinophilic granulomatosis with polyangiitis, sarcoidosis, bullous pemphigoid), and hematologic malignancies (e.g. chronic eosinophilic leukemia, B cell acute lymphoblastic leukemia, Hodgkin’s lymphomas) (1, 98).

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 (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.

Among the one hundred previously reported and analyzed by us cases of TABE, the death of 68 patients was reported (4, 7, 8, 10–14, 16–22, 24–28, 30, 32, 34–37, 39, 44, 46–51, 53–60, 65, 67–69, 71, 72, 74–76, 82–88, 94–96). About 90% of the deaths occurred within one year after the diagnosis of paraneoplastic hypereosinophilia. Moreover, 9 of the remaining 32 patients were diagnosed with disseminated cancer and referred to palliative care (9, 38, 60, 62–64, 80, 89, 93). Resolution of peripheral eosinophilia following surgical resection was reported in 18 of the remaining 32 patients, although only ten patients were followed-up between 6 to 30 months (15, 23, 27, 33, 40–43, 61, 66, 73, 77, 78, 91, 92). The reappearance of eosinophilia may herald the onset of tumor recurrence. Therefore, serial estimations of WBC with differential count should be an integral part of the follow-up (17, 18, 22, 41, 85, 95).

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.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.