Divergent Outcomes in Lung Adenocarcinoma with Paraneoplastic Hypereosinophilia in Patients Treated with Pembrolizumab: A Two-Case Report

Abstract

Paraneoplastic hypereosinophilia (PHE) is an underrecognized manifestation of solid tumors, particularly non-small cell lung cancer. We present two cases of metastatic lung adenocarcinoma with marked eosinophilia treated with PD-1 inhibitor immunotherapy, both of whom demonstrated changes in eosinophil counts but divergent clinical outcomes. While elevated eosinophil levels during immune checkpoint inhibitor therapy have been associated with improved treatment response in prior studies, the clinical significance of persistent or severe hypereosinophilia remains incompletely understood. These cases highlight the heterogeneous course of paraneoplastic hypereosinophilia and underscore the potential—yet uncertain—role of eosinophils as prognostic biomarkers in oncology, warranting further investigation to clarify the role of PHE as a prognostic or predictive biomarker in oncology.

Introduction

Hypereosinophilia, defined as a sustained eosinophil count greater than 1500 cells/µL, is often an incidental finding with a broad differential diagnosis, including allergic, immunologic, or infectious causes. Rarely, oncologic disease is associated with hypereosinophilia, which is estimated to occur in approximately 1% of all malignancies.¹ Although significant hypereosinophilia is classically associated with hematopoietic clonal production of eosinophils, solid tumors are an important yet often overlooked cause of secondary hypereosinophilia. Tumors arising from mucin-secreting epithelium, such as gastrointestinal tract or lung cancers, are most frequently implicated. The presence of paraneoplastic eosinophilia is associated with aggressive disease and poor prognosis.

Immunotherapy has become a mainstay of treatment in these malignancies of aggressive phenotype, particularly in non-small-cell lung cancer (NSCLC), where immune checkpoint inhibitors (ICI) such as pembrolizumab have been shown to prolong survival. However, this must be balanced with the risk of severe immune-related adverse events (irAEs). Currently, it is difficult to predict which patients remain at high risk of development of severe irAEs. As a result, identifying biomarkers that predict treatment response and toxicity remains a challenge.

Emerging evidence suggests that eosinophilia in various cancers may be associated with an increased risk of development of irAEs.² Proposed mechanisms for this include tumor-driven secretion of IL-5, CD4+ T-cell driven secretion of IL-5 after ICI treatment, and IL-33 mediated eosinophilic infiltration into tumors. However, these antitumor effects may also increase irAEs via eosinophilic infiltration into normal tissue.³

We present two cases of patients with lung adenocarcinoma treated with PD-1 inhibitor immunotherapy, who presented with hypereosinophilia and later developed pneumonitis with differing outcomes. These cases highlight the variable clinical course of paraneoplastic hypereosinophilia and may contribute to future understanding of eosinophils as a prognostic biomarker.

Case 1

A 66-year-old female with history of ischemic heart disease presented to the emergency department with chest pain that worsened with deep inspiration. She reported 6 months of weight loss, night sweats, dyspnea on exertion, and fatigue. CT chest revealed a 4.9 × 3.6 cm mediastinal mass. Biopsy confirmed a diagnosis of lung adenocarcinoma and subsequent imaging demonstrated extensive metastases to the liver, spleen, lymph nodes, bone, and brain. Treatment with pembrolizumab immunotherapy was initiated as first-line therapy.

One month prior to starting pembrolizumab, AEC was noted to be 2.2 K/UL. An absolute eosinophil count (AEC) elevation of 12.5 K/UL was discovered on routine labs after the first cycle (Figure 1). She was born in the Northeastern United States and had not traveled significantly outside of the region. Comprehensive work-up was negative for underlying parasitic infection or primary hypereosinophilic syndrome, including PDGFRA, PDGFRB, or FGR1 rearrangements. Paraneoplastic hypereosinophilia secondary to lung adenocarcinoma was therefore determined to be the underlying etiology.

Figure 1.

Absolute Eosinophil Count (AEC) Over Time.

Pembrolizumab was administered every three weeks. By cycle 3, AEC declined to 6.8 K/UL and further declined to 2.4 K/UL by cycle 6. Serial imaging with PET/CT during this time demonstrated improvements in hepatic, splenic, nodal, and bony metastases (Figure 2). Prior to cycle 10, AEC was 1.5 K/UL. However, after cycle 10, the patient developed ambulatory hypoxia and persistent dry cough. CT findings at the time demonstrated bilateral right greater than left interstitial lung fullness, diagnosed as checkpoint inhibitor-induced pneumonitis by her primary oncologist. This required prolonged taper of systemic corticosteroids, after which respiratory symptoms resolved. During steroid therapy, AEC normalized. Pembrolizumab was continued, and she responded positively to immunotherapy with the resolution of metastatic lesions in her brain, liver, and spleen, as well as stable disease in her lungs and lymph nodes. Two years later, she continues to do well on pembrolizumab with no further progression of adenocarcinoma and a stable AEC between 1.5 – 2.8 K/UL.

Figure 2.

Representative PET/CT images of Case 1. Left: At time of Diagnosis. Right: At time of stable disease.

Case 2

A 69-year-old male with history of type 2 diabetes, hypertension, and hyperlipidemia presented to the emergency department with 2 months of persistent worsening cough with occasional blood-tinged sputum and shortness of breath despite multiple antibiotic courses. Initial lab work demonstrated WBC 30 with AEC 9.0 K/µL. CT chest demonstrated a 6.4 × 5.5 x 7.5 cm left lower lobe necrotic mass with surrounding ground-glass opacities consistent with malignancy versus necrotizing pneumonia. He was born in Bangladesh and had moved to the United States 4 years prior. Initial infectious workup included negative sputum AFB smear for mycobacteria and negative serum and stool testing for parasites including paragonimiasis, echinococcus, and entamoeba. Lung biopsy showed poorly differentiated lung adenocarcinoma. Subsequent CT abdomen/pelvis and MRI brain demonstrated metastases to the pancreas, liver, peritoneum, and brain. Pembrolizumab was initiated after PD-L1 positivity was confirmed.

After initiation of cycle 1 of pembrolizumab, AEC initially rose to 23.9 K/UL. At cycle 2 of therapy, carboplatin and pemetrexed were added in addition to pembrolizumab for four total cycles with transition to pemetrexed/pembrolizumab thereafter. By cycle 3, AEC declined to 3.1 K/UL and normalized by cycle 4. The etiology of his AEC was determined to be paraneoplastic hypereosinophilia given response to chemoimmunotherapy. At cycle 4, he demonstrated radiographic response via PET/CT imaging with decreased metastatic involvement in the pancreas, liver, peritoneum, and bone (Figure 3). At cycle 7 of maintenance chemoimmunotherapy, repeat CT imaging demonstrated enlargement of the primary left lower lobe mass, consistent with progression of disease. AEC transiently increased to 4.8 K/UL at this time but then returned to normal limits. Given the progression of the disease, patient was at this time transitioned to second-line docetaxel and pembrolizumab per the PROLUNG trial.⁴ At cycle 5 of docetaxel and pembrolizumab, the patient developed hypoxic respiratory failure and septic shock. CT imaging demonstrated right lower lobe consolidation and bilateral ground glass opacities. Infectious workup including sputum cultures, bacterial cultures, and viral panel were negative. The diagnosis of ICI pneumonitis and pneumonia was made. Methylprednisolone 1 mg/kg, vancomycin and cefepime were started; however, given the rapidly progressive respiratory failure, he was transitioned to comfort measures and passed shortly thereafter. Despite this, from cycle 5 onwards, AEC remained 0 K/UL until his death.

Figure 3.

Representative PET/CT images of Case 2 (A) At time of diagnosis (B) At initial remission of disease (C) At time of recurrence (D) At time of pneumonitis and death.

Discussion

Hypereosinophilia secondary to solid tumors is uncommon and poorly understood. Paraneoplastic eosinophilia is most frequently seen in non-small cell lung cancers and is associated with aggressive tumors and poor prognosis.⁵ We reviewed 4 published cases of patients with paraneoplastic hypereosinophilia who were treated for lung adenocarcinoma – one with traditional chemotherapy (vinorelbine and cisplatin),⁶ one with an EGFR tyrosine kinase inhibitor (icotinib),⁶ and two with ICI immunotherapy (pembrolizumab).^7,8 Three patients demonstrated a reduction in AEC with treatment, followed by a subsequent increase with disease progression.^5–7 One experienced increasing eosinophilia and rapid progression of malignancy after starting pembrolizumab, though he only received 2 cycles prior to his death just 6 weeks after initial diagnosis.⁸

The proposed mechanism of paraneoplastic hypereosinophilia is by direct bone marrow stimulation by tumor secretion of IL-5.⁹ Eosinophils play both anti-tumorigenic and pro-tumorigenic roles. Their anti-tumorigenic mechanism occurs through the release of chemokines CXCL9 and CXCL10, which recruit and activate cytotoxic T-cells to directly attack malignant cells.⁹ Conversely, regulatory T-cell recruitment and suppression of the Type 1 immune response permits unopposed tumor growth.¹⁰ ICIs increase eosinophil production, and it has been suggested that initial rising eosinophil counts following ICI initiation may serve as an early predictive biomarker of therapeutic response. In one mouse model, depletion of eosinophils after administration of an ICI reversed the activation of intra-tumoral cytotoxic CD8+ T cells.¹¹ This finding suggests that eosinophils are essential for CD8+ T cell activation during ICI therapy.

Several studies of patients with NSCLC treated with ICIs have identified a correlation between higher AEC and increased irAEs, while also being associated with superior response to immunotherapy and prolonged progression-free survival.^12–14 However, the AEC range linked to improved outcomes was 0.125–0.890 K/µL, which is substantially below the levels detected in paraneoplastic hypereosinophilia. It is also worth noting that sustained hypereosinophilia carries significant risks, including myocarditis, thromboembolic complications, stroke, and pneumonia. Given the rarity of hypereosinophilia due to solid tumors, there is currently insufficient evidence to suggest that these individuals might experience a higher incidence of irAEs or enhanced response to immunotherapy.

Despite similar initial presentations, our two patients experienced considerably different outcomes and treatment effects on hypereosinophilia. In Case 1, despite serial AEC that would meet criteria for persistent hypereosinophilia, they demonstrated a more favorable response to pembrolizumab. In contrast, Case 2 exhibited rapid normalization of eosinophil count, but had limited clinical response with progression of malignancy necessitating change in therapy. It is difficult to fully explain the divergent clinical outcomes in our two cases. While the differing trends in AEC may support an association between mild eosinophil elevation and improved response to ICIs, as has been reported in several small retrospective studies, our small sample size limits any establishment of causality.^12–15 In addition, persistent hypereosinophilia need not necessarily warrant additional evaluation when other causes have been ruled out. Furthermore, differences in tumor biology, disease burden, and tumor immune microenvironment may have also influenced the clinical outcomes of the cases.

Further investigation of paraneoplastic hypereosinophilia in the context of immunotherapy may provide deeper insights into the role of eosinophils in the immunologic response, potentially improving our ability to identify patients most likely to benefit from these therapies.

Funding Statement

There is no funding to report.

Abbreviations

NSCLC, non-small cell lung cancer; ICI, immune checkpoint inhibitor; irAEs, immune-related adverse events; AEC, absolute eosinophil count; ULN, upper limit of normal; CT, computerized tomography; AFB, acid-fast bacilli; PD-1, Programmed Death 1; EGFR, Epidermal Growth Factor Receptor.

Ethics Statement

Institutional approval was not required to publish the case details.

Patient Consent

Written informed consent for publication of this case series and accompanying images was obtained from the patient or their legally authorized representative.

Disclosure

The authors report no conflicts of interest in this work.