Establishing a Diagnosis of Eosinophilic Esophagitis
Establishing a Diagnosis of Eosinophilic Esophagitis
Objectives: Eosinophilic esophagitis (EoE) is characterized clinically by dysphagia, chest pain, and food impaction, and morphologically by increased numbers of intraepithelial eosinophils and marked basal hyperplasia of the squamous mucosa. The consensus criteria for a diagnosis of EoE include the presence of ≥15 eosinophils/HPF in biopsies from both proximal and distal esophagus in the absence of other causes of esophageal eosinophilia, and the lack of clinical response to proton pump inhibitor therapy. Because of the variability in the distribution of intraepithelial eosinophils among biopsy fragments and the lack of standardized biopsy practices, we sought to determine the optimal number of esophageal biopsies from the mid and distal esophagus needed to reach the minimum morphologic criteria of ≥15 eosinophils/HPF.
Methods: From 5 January 2009 to 26 September 2011, 771 patients were diagnosed with EoE at our institution. From that patient population, 102 sequential cases were chosen for further study, all of whom had biopsies taken from the mid and distal esophagus. Cases with only gastric mucosa present and biopsies taken from patients with a previous diagnosis of EoE were excluded. The original H&E-stained slides were reviewed, and the number of biopsy fragments containing squamous mucosa was recorded. By using a × 40 objective and × 10 oculars (field diameter=0.52 mm, field area=0.21 mm), the number of eosinophils per high power field (EOS/HPF) in up to three HPFs was counted in each biopsy fragment.
Results: The EOS/HPF were counted in 1,342 biopsy fragments. The number of biopsy fragments obtained from the mid esophagus ranged from 1 to 20 (mean 7; median 7) and those obtained from the distal esophagus ranged from 1 to 18 (mean 6; median 5). There was no significant difference between the mean number of EOS/HPF from the mid (26) and lower (25) esophagus or between the mean peak number of EOS/HPF from the mid (69.1) and lower (60.4) esophagus. The probability of one, four, five, and six biopsy fragments containing >15 EOS/HPF was 0.63, 0.98, 0.99, and >0.99, respectively.
Conclusions: From these data, at least four biopsy fragments should be submitted from the mid and/or proximal esophagus to optimize the chances of a positive diagnosis of EoE in populations not known to have undergone previous proton pump inhibitor therapy. However, the yield is not increased beyond six biopsy fragments. In order to morphologically exclude a diagnosis of reflux esophagitis as the cause of intraepithelial eosinophilia, distal esophageal biopsies, if obtained, must be accompanied by more proximal biopsies (i.e., mid esophagus or higher).
Esophageal eosinophilia is associated with a number of diseases, most notably gastroesophageal reflux disease (GERD) and eosinophilic esophagitis (EoE). EoE is a chronic immune-mediated disease characterized clinically by symptoms of esophageal dysfunction and esophageal eosinophilia on biopsy. Reported across all age groups, EoE is clinically characterized by eating difficulties and a failure to thrive, particularly in children, chest and/or abdominal pain, dysphagia, food impaction, and the lack of response to proton pump inhibitor (PPI) therapy. Commonly associated with allergic or atopic diseases, studies have shown that EoE is associated with immune-mediated hypersensitivity reactions to various food and environmental allergens. Endoscopic features of EoE include a diminished vascular pattern, linear furrowing, surface white spots or exudate, and proximal corrugated rings or trachealization. However, in a study by Liacouras et al. of 381 pediatric patients with histologic evidence of EoE, 32% of patients had biopsies from endoscopically unremarkable mucosa. Other studies have also demonstrated endoscopically normal mucosa in patients with EoE.
EoE was initially reported in an adult patient with achalasia in 1978 and was further characterized in 1993 in a report of 12 patients with numerous intraepithelial eosinophils on biopsy and normal acid exposure on 24-h pH monitoring. Originally considered quite rare, epidemiological reports confirm up to a fourfold increase in the diagnosis of EoE in the last decade, with an estimated prevalence of 3 or 4 cases per 10,000 people. EoE has been reported worldwide and throughout the human lifespan, with a strong male prevalence.
The endoscopic features of EoE are not pathognomonic, therefore esophageal biopsy is necessary to establish the presence of increased numbers of intraepithelial eosinophils and other features of EoE, which are supported by clinical symptoms and endoscopic features. However, due to the heterogeneous, patchy distribution of esophageal involvement, multiple biopsy samples are necessary to either detect or rule out EoE (Figure 1). Furthermore, lack of a diagnostic standard impedes the ability to accurately compare studies on biopsy practices for the detection of EoE. Dellon et al. examined the variability of diagnostic criteria for EoE in the literature and found at least 10 histologic threshold points of esophageal eosinophilia (ranging from 5 to 30 eosinophils/high-power field (EOS/HPF)), definitions of HPF that could render a variability of eosinophil density up to 23-fold, and disparity among esophageal biopsy protocols and methods of counting eosinophils. Current consensus on the diagnostic criteria for EoE includes the presence of ≥15 EOS/HPF in 2–4 biopsy samples taken from both the proximal and distal esophagus in the absence of other causes of esophageal eosinophilia, and lack of a clinical response to proton pump inhibitor (PPI) therapy. Consequently, unless a previous PPI therapy trial is conducted to rule out GERD, biopsies from the lower esophagus alone may not be sufficient to exclude reflux as the cause of increased eosinophils. Because of the variability in the distribution of intraepithelial eosinophils among biopsy fragments and the lack of standardized biopsy practices, we sought to determine the optimum number of esophageal biopsies from the mid and distal esophagus that were needed to support a morphologic diagnosis of EoE based on numbers of intraepithelial eosinophils.
(Enlarge Image)
Figure 1.
The heterogeneous distribution of eosinophilic esophagitis. Two fragments from the same biopsy with numerous (a) and fewer (b) intraepithelial eosinophils, demonstrating the patchiness of the disease.
Abstract and Introduction
Abstract
Objectives: Eosinophilic esophagitis (EoE) is characterized clinically by dysphagia, chest pain, and food impaction, and morphologically by increased numbers of intraepithelial eosinophils and marked basal hyperplasia of the squamous mucosa. The consensus criteria for a diagnosis of EoE include the presence of ≥15 eosinophils/HPF in biopsies from both proximal and distal esophagus in the absence of other causes of esophageal eosinophilia, and the lack of clinical response to proton pump inhibitor therapy. Because of the variability in the distribution of intraepithelial eosinophils among biopsy fragments and the lack of standardized biopsy practices, we sought to determine the optimal number of esophageal biopsies from the mid and distal esophagus needed to reach the minimum morphologic criteria of ≥15 eosinophils/HPF.
Methods: From 5 January 2009 to 26 September 2011, 771 patients were diagnosed with EoE at our institution. From that patient population, 102 sequential cases were chosen for further study, all of whom had biopsies taken from the mid and distal esophagus. Cases with only gastric mucosa present and biopsies taken from patients with a previous diagnosis of EoE were excluded. The original H&E-stained slides were reviewed, and the number of biopsy fragments containing squamous mucosa was recorded. By using a × 40 objective and × 10 oculars (field diameter=0.52 mm, field area=0.21 mm), the number of eosinophils per high power field (EOS/HPF) in up to three HPFs was counted in each biopsy fragment.
Results: The EOS/HPF were counted in 1,342 biopsy fragments. The number of biopsy fragments obtained from the mid esophagus ranged from 1 to 20 (mean 7; median 7) and those obtained from the distal esophagus ranged from 1 to 18 (mean 6; median 5). There was no significant difference between the mean number of EOS/HPF from the mid (26) and lower (25) esophagus or between the mean peak number of EOS/HPF from the mid (69.1) and lower (60.4) esophagus. The probability of one, four, five, and six biopsy fragments containing >15 EOS/HPF was 0.63, 0.98, 0.99, and >0.99, respectively.
Conclusions: From these data, at least four biopsy fragments should be submitted from the mid and/or proximal esophagus to optimize the chances of a positive diagnosis of EoE in populations not known to have undergone previous proton pump inhibitor therapy. However, the yield is not increased beyond six biopsy fragments. In order to morphologically exclude a diagnosis of reflux esophagitis as the cause of intraepithelial eosinophilia, distal esophageal biopsies, if obtained, must be accompanied by more proximal biopsies (i.e., mid esophagus or higher).
Introduction
Esophageal eosinophilia is associated with a number of diseases, most notably gastroesophageal reflux disease (GERD) and eosinophilic esophagitis (EoE). EoE is a chronic immune-mediated disease characterized clinically by symptoms of esophageal dysfunction and esophageal eosinophilia on biopsy. Reported across all age groups, EoE is clinically characterized by eating difficulties and a failure to thrive, particularly in children, chest and/or abdominal pain, dysphagia, food impaction, and the lack of response to proton pump inhibitor (PPI) therapy. Commonly associated with allergic or atopic diseases, studies have shown that EoE is associated with immune-mediated hypersensitivity reactions to various food and environmental allergens. Endoscopic features of EoE include a diminished vascular pattern, linear furrowing, surface white spots or exudate, and proximal corrugated rings or trachealization. However, in a study by Liacouras et al. of 381 pediatric patients with histologic evidence of EoE, 32% of patients had biopsies from endoscopically unremarkable mucosa. Other studies have also demonstrated endoscopically normal mucosa in patients with EoE.
EoE was initially reported in an adult patient with achalasia in 1978 and was further characterized in 1993 in a report of 12 patients with numerous intraepithelial eosinophils on biopsy and normal acid exposure on 24-h pH monitoring. Originally considered quite rare, epidemiological reports confirm up to a fourfold increase in the diagnosis of EoE in the last decade, with an estimated prevalence of 3 or 4 cases per 10,000 people. EoE has been reported worldwide and throughout the human lifespan, with a strong male prevalence.
The endoscopic features of EoE are not pathognomonic, therefore esophageal biopsy is necessary to establish the presence of increased numbers of intraepithelial eosinophils and other features of EoE, which are supported by clinical symptoms and endoscopic features. However, due to the heterogeneous, patchy distribution of esophageal involvement, multiple biopsy samples are necessary to either detect or rule out EoE (Figure 1). Furthermore, lack of a diagnostic standard impedes the ability to accurately compare studies on biopsy practices for the detection of EoE. Dellon et al. examined the variability of diagnostic criteria for EoE in the literature and found at least 10 histologic threshold points of esophageal eosinophilia (ranging from 5 to 30 eosinophils/high-power field (EOS/HPF)), definitions of HPF that could render a variability of eosinophil density up to 23-fold, and disparity among esophageal biopsy protocols and methods of counting eosinophils. Current consensus on the diagnostic criteria for EoE includes the presence of ≥15 EOS/HPF in 2–4 biopsy samples taken from both the proximal and distal esophagus in the absence of other causes of esophageal eosinophilia, and lack of a clinical response to proton pump inhibitor (PPI) therapy. Consequently, unless a previous PPI therapy trial is conducted to rule out GERD, biopsies from the lower esophagus alone may not be sufficient to exclude reflux as the cause of increased eosinophils. Because of the variability in the distribution of intraepithelial eosinophils among biopsy fragments and the lack of standardized biopsy practices, we sought to determine the optimum number of esophageal biopsies from the mid and distal esophagus that were needed to support a morphologic diagnosis of EoE based on numbers of intraepithelial eosinophils.
(Enlarge Image)
Figure 1.
The heterogeneous distribution of eosinophilic esophagitis. Two fragments from the same biopsy with numerous (a) and fewer (b) intraepithelial eosinophils, demonstrating the patchiness of the disease.