Eosinophilic Esophagitis After Radiofrequency Ablation of Barrett’s Esophagus in a 41-Year-Old Man

Introduction

Eosinophilic esophagitis (EoE) is a chronic allergen-induced, type 2 immune-mediated disease of the esophagus, with a rising incidence rate [1–3].

EoE is diagnosed based on the presence of symptoms indicative of esophageal dysfunction and a finding of at least 15 eosinophils per high-power field (eos/hpf) on esophageal biopsy. The diagnosis is made after excluding non-EoE disorders that could cause or contribute to eosinophil infiltration in the esophagus [1]. In addition to eosinophils in esophageal biopsies, other histologic findings play a significant role in the diagnosis, such as basal cell hyperplasia, lamina propria fibrosis, and dilated intercellular spaces [1,2]. In adolescents and adults, dysphagia and food impaction are most common, although heartburn and chest pain can be present as well [4,5].

Although gastroesophageal reflux disease (GERD) can contribute to the development of esophageal eosinophilia and the development of Barrett’s esophagus (BE), associations between EoE and BE are extremely rare [4,6–8]. Radiofrequency ablation (RFA) is the recognized standard treatment of dysplastic BE [7,9]. This report describes a 41-year-old man with chronic GERD presenting with eosinophilic esophagitis following radiofrequency ablation of Barrett’s esophagus.

Case Report

A 41-year-old man had been under the care of an outpatient gastroenterology clinic for over 10 years. He had no record of tobacco use, allergies to medications, or environmental factors. His physical examination showed no notable findings.

Initially, he was treated for symptoms of reflux disease: heartburn and regurgitations. In 2012, a gastroscopic examination revealed BE C2M5, confirmed by a histopathological examination, and low-grade dysplasia was detected. In 2013, ablation of dysplastic BE was performed using the RFA with the HALO ablation system (BARRX Medical). The treatment involved the HALO 360 ablation catheter.

Follow-up gastroscopy with biopsy within 6 months after RFA showed no signs of metaplasia or dysplasia. The patient has been treated with PPIs, once or twice daily, depending on the severity of symptoms. Biopsy results from the surveillance endoscopy showed no signs of recurrence of BE. Multiple control biopsies confirmed the absence of dysplasia.

In April 2024, histopathological examination of routinely collected biopsies revealed the presence of eosinophils. As the threshold to diagnose EoE was not achieved, follow-up gastroscopy with multiple biopsies was conducted, showing significant findings along the entire length of the esophagus, including marked trachealization, longitudinal furrows, exudation, and edema (Eosinophilic Esophagitis Endoscopic Reference Score – EREFS: 1+1+1+2+0). A single erosion measuring up to 5 mm long was also observed above the cardia. In inversion, the cardia showed no signs of hiatal hernia (Figure 1). Histopathological analysis revealed over 15 eosinophils per high-power field (hpf) in the proximal squamous mucosa, with no signs of dysplasia (Figure 2).

An in-depth interview and detailed questions showed that there were also discrete symptoms of dysphagia.

Discussion

We present a rare case of the development of eosinophilic esophagitis after RFA in a patient with dysplastic BE, who was initially without any clinical or endoscopic signs of EoE.

GERD can be linked to eosinophilic infiltration of the esophagus, especially in the distal region [2,4]. In patients with nonerosive disease, the most consistent histological finding is dilatation of the intercellular spaces, basal hyperplasia, and papillary elongation. Eosinophilic infiltration can occur, but it is more commonly found in the proximal esophagus of patients with eosinophilic esophagitis. Therefore, distinguishing between these conditions is crucial [6,7]. This is why the guidelines require that at least 6 samples be taken from the lower and upper parts of the esophagus to confirm eosinophilic esophagitis.

However, coexistent eosinophilic esophagitis and BE remains rare, with only a few reported cases [2,8,10,11]. Both conditions are rapidly increasing in incidence, hence the suspicion that similar cases will be more common in the future [1,3].

Ameyaw PA et al (2024) reported a case of a patient with long-segment dysplastic BE who exhibited both endoscopic and histopathological features of EoE. Although the patient responded well to RFA, EoE emerged within the neosquamous mucosa 4 months after treatment [4]. The case described by Ameyaw et al involved EoE detected during the initial endoscopy, which distinguished it from our case, who had no symptoms or endoscopic appearance of EoE at that time. In our patient, the symptoms and endoscopic changes did not emerge until 10 years after the RFA. However, as in all cases of esophageal eosinophilia in BE patients after ablation, we did not have access to histopathology data from the pre-ablation squamous epithelium. This is because esophageal biopsies from squamous epithelium are not routinely collected from patients with BE during surveillance endoscopies.

Esophageal eosinophilia following RFA in patients without a prior EoE diagnosis has been documented in 2 studies. The reported incidence was 2.7% in a cohort of 140 patients and 9% following RFA or cryotherapy for dysplastic BE [12,13]. Additionally, a positive linear relationship was noted between the length of the BE segment and post-ablation eosinophilia [12,13]. Notably, none of the patients in these studies had a confirmed EoE diagnosis before undergoing RFA, and while eosinophilia was detected after the procedure, none progressed to overt EoE.

Halsey et al indicated that chronic inflammation caused by repetitive ablation-induced injury increased the sensitivity of the ablated epithelium to ingested antigens leads to post-RFA esophageal eosinophilia [12], but in our case, only 1 RFA session was performed. Additionally, there was no significant difference in the mean number of ablations between patients who developed esophageal eosinophilia (2.2 sessions) and those who did not (2.5), as reported by Villa et al, who described a total of 4 out of 148 (2.7%) patients who developed after RFA esophageal eosinophilia. None of the 4 patients had endoscopic features indicative of EoE, such as esophageal rings, linear furrows, or exudates, nor did they present with symptoms of esophageal dysfunction [13]. Furthermore, as previously noted, no biopsies were taken from the squamous esophagus before ablation. Consequently, it remains possible that esophageal eosinophilia was already present before the procedure but went undetected, as biopsies were only obtained from the columnar-lined esophagus [13,14].

The Swiss Eosinophilic Esophagitis Cohort Study (SEECS) characterized patients with coexisting BE and eosinophilia by analyzing prospectively collected clinical, endoscopic, and histological data from enrolled patients to examine differences between EoE patients with (EoE/BE+) versus those without BE (EoE/BE−) and determined the prevalence of BE in EoE patients. Among a total of 509 EoE patients, 24 (4.7%) had concomitant BE, and most were males. Odynophagia, poorer general well-being, and an increased incidence of fixed rings in the proximal esophagus were significantly more common in the EoE/BE+ group compared to the EoE/BE− group. Additionally, a greater proportion of EoE/BE+ patients exhibited severe fibrosis in the proximal histological specimen (8.7 vs 1.6% in EoE/BE, P=0.017) [15].

In the study by Villa et al, 3 of the 4 patients with esophageal eosinophilia were male, and all were white. Each patient had a history of GERD for at least 10 years before undergoing ablation and had been diagnosed with BE 1–11 years prior to the procedure. All patients had LGD, and all except 1 had long-segment BE. No statistically significant differences were found in the clinical or demographic characteristics of patients who developed EoE [13].

In the study by Halsey et al, comparison of those with and without post-ablation esophageal eosinophilia did not reveal clinical or statistically significant differences in terms of age or sex. Post-ablation eosinophilia was more frequent after cryotherapy (12/44, 27%) than after RFA (8/77, 10%) (P=0.02). Patients with esophageal eosinophilia were treated with more RFA sessions and had significantly longer follow-up times. Patients with esophageal eosinophilia had longer BE segments (median 6.0 cm, IQR 4.5) than those without esophageal eosinophilia (median 4.0 cm, IQR 5.0) (P=0.20) [12].

The issue of esophageal cancer risk in the context of eosinophilic esophagitis (EoE), particularly when coexisting with Barrett’s esophagus (BE) – a known precancerous condition – raises important clinical questions.

The incidence of EoE is increasing, the disease lasts for a long time, and is often diagnosed long after its onset, which raises some concern about possible long-term complications. Furthermore, there is a suspicion of cancer risk because of concomitant inflammation [2].

A study in Sweden assessed cancer risk in 1580 individuals with biopsy-confirmed EoE, comparing them to matched reference individuals. While EoE was not linked to an increased overall cancer risk, patients with EoE had a higher likelihood of developing esophageal cancer, although the absolute risk remained low. Subgroup analyses based on sex, follow-up duration, age at diagnosis, country of origin, and education level showed no significant differences between EoE patients and the general population. Notably, individuals with EoE had a significantly elevated risk of esophageal cancer, with an adjusted hazard ratio (aHR) of 25.20 (95% CI=2.28–278.80). However, this finding was based on only 2 cases among EoE patients (approximately 1 in 800), compared to a single case in the reference group. The median age at EoE diagnosis for those who later developed esophageal cancer was 57 years, with cancer being diagnosed at a median age of 59 years [16].

In the USA, a case-control study by Albaneze et al examined 5562 esophageal cancer cases and 55 620 matched controls. A history of EoE was rare in both groups. Only 2 esophageal cancer cases (0.04%) and 44 controls (0.08%) had evidence of an EoE diagnosis (OR 0.46; 95% CI 0.11–1.88). The authors concluded that EoE is not associated with the development of esophageal cancer in adults under 65 years old. The co-incidence of EoE and esophageal cancer was considered extremely rare [17].

Syed et al used the Explorys Platform (an electronic medical record platform), which is a database of more than 27 million subjects. Of these, approximately 5300 had EoE and none of these patients had a concomitant diagnosis of esophageal cancer [18].

The potential role of eosinophils in EoE-associated cancer remains unclear. Some studies suggest that eosinophils have anti-tumorigenic properties, as observed in breast and colorectal cancers, where higher eosinophil counts correlate with improved clinical outcomes [19,20]. Additionally, investigations using mouse models of EoE have explored the mechanistic influence of EoE on esophageal cancer development. Findings indicate that the esophageal epithelial remodeling characteristic of murine EoE inherently restricts esophageal carcinogenesis [21].

Although rare, the incidence of Barrett’s adenocarcinoma and eosinophilic esophagitis has been increasing in recent years. According to the literature, both Barrett’s segment length and the treatment modality were independently associated with post-ablation esophageal eosinophilia.

Further studies are required to confirm these findings, especially over longer follow-up periods, and to assess whether EoE might confer a protective effect against esophageal cancer.

Conclusions

Eosinophilia should be considered a potential consequence of RFA for BE. Further studies are needed to assess its clinical significance, determine the necessity of treatment, and determine whether it will ultimately lead to the development of EoE. Additionally, investigating the potential implications of post-RFA EoE could provide valuable insights into its pathophysiology, facilitate risk stratification, and help refine guidelines for post-ablation endoscopic surveillance.