Case 5 -

Allergic / Eosinophilic Esophagitis Versus Reflux Esophagitis Alyssa Krasinskas, Jeffrey Goldsmith and Susan Abraham

Case Description: The attached photomicrographs were taken from two esophageal biopsies obtained from a 15 year old boy with a 6 month history of intermittent severe epigastric, burning pain that often radiated to his back. The patient reported that the pain seemed to be worse at night, and was exaggerated by ingestion of certain foods, such as orange juice, sodas, and chocolate. Due to the severe nature and the length of the patient's symptoms, his primary care physician referred him to a gastroenterologist who was similarly concerned. An upper endoscopy was performed. The duodenum and stomach were grossly normal. However, the esophageal mucosa appeared pale with red streaks; these findings were most prominent in the distal 5 cm; the proximal esophagus appeared normal. The endoscopist biopsied the pale area at 38 cm (figures 1-3) and the proximal esophagus at 20 cm (figures 4-6). The biopsy at 38 cm shows squamous mucosa with marked epithelial regenerative changes as the epithelial cells exhibit increased nuclear to cytoplasmic ratio throughout the entire thickness of the epithelium. Examination at higher power shows markedly increased numbers of intraepithelial eosinophils with up to 50 per high power field. Additionally, there are aggregates of 3-5 eosinophils in the superficial epithelium (termed 'eosinophilic microabscesses'), extensive eosinophilic degranulation, and increased density of eosinophils in the superficial epithelium compared with the basal epithelial cells. The biopsy at 20 cm, however, showed markedly decreased number of intraepithelial eosinophils, up to 10 per high power field, compared with the distal biopsy. The regenerative epithelial changes seen in the proximal biopsy were absent; also, there were no eosinophilic microabscesses. Mild amounts of eosinophilic degranulation were seen. Based on these findings the following diagnoses were rendered: Esophagus, 38 cm, biopsy: Moderately active esophagitis; see note. Esophagus, 20 cm, biopsy: Mildly active esophagitis; see note. Note: The distal biopsy shows up to 50 intraepithelial eosinophils per high power field with extensive eosinophilic degranulation, eosinophilic microabscesses, and increased density of eosinophils towards the luminal aspects of the epithelium. These features suggest allergic / eosinophilic esophagitis, however the marked decreased number of eosinophils in the proximal biopsy (up to 10 eosinophils per high power field) also raises the possibility of reflux esophagitis. Clinical correlation is required to make this distinction. The patient was started in high-dose proton pump inhibitors. Within one month, his symptoms disappeared. The patient was given a diagnosis of severe reflux esophagitis. Background & Pathogenesis: In a recent comprehensive review and consensus recommendation statement, Furuta et al., defined allergic / eosinophilic esophagitis (EE) as "a clinicopathologic disorder of the esophagus characterized by esophageal and/or upper gastrointestinal tract symptoms in association with esophageal mucosal biopsy specimens containing more than or equal to 15 intraepithelial eosinophils / high power field (HPF) in one or more biopsy specimens and absence of pathologic gastroesophageal reflux disease (GERD) as evidenced by a normal pH monitoring study of the distal esophagus or lack of response to high-dose proton pump inhibitor (PPI) medication [1]." The epidemiologic characteristics of EE remain somewhat unknown. However, it is clear that EE more often affects males in both the pediatric and adult populations with up to 75% of EE patients being male [2, 3, 4, 5, 6, 7]. Few studies have been performed that addressed the incidence and/or prevalence of disease; however, in a study performed on the population in Hamilton County, Ohio, the incidence of EE was up to 1.7 / 10,000 persons and the prevalence of disease was up to 3 / 10,000 people [8]; in longitudinal studies, the prevalence of disease has been noted to be increasing [7]. This is likely due to increasing recognition of disease; additionally, since EE is not associated with mortality, the prevalence of disease is expected to increase with time. It seems that there is significant ethnic variation in the distribution of EE with a majority of cases reported in Caucasians; however this topic has not been extensively studied. Unlike long-standing GERD, which has an association with the development of Barrett's esophagus, dysplasia, and adenocarcinoma, a long history of EE predisposes patients to esophageal mural fibrosis that results in stricture formation [7, 9]. These patients with strictures are more likely to suffer from dysphagia and food impaction. To date, an association with neoplasia has not been observed. The pathogenesis of EE remains relatively unclear. However, it is relatively certain that EE is an allergic disease since most patients have a history of environmental hypersensitivity as evidenced by positive RAST testing and/or positive skin prick testing [10]. Additionally, changes identical to EE can be reproduced in mouse models by exposing the animals to various allergens after sensitization [11]. It also seems that EE is associated with cytokines secreted by TH2 lymphocytes that directly act on and recruit eosinophils. These cytokines include IL-4, IL-5, and IL-13 and their secretion may act to recruit eosinophils to the squamous epithelium via the secretion of eosinophil-specific chemokines, the eotaxins, in appropriately stimulated hosts [12, 13]. Additionally, there has been an association with a single nucleotide polymorphism of the eotaxin-3 gene [12]. However, this genetic mutation has not been causally associated with the development of EE, and may predispose patients to the development of EE. Diagnosis of Eosinophilic / Allergic Esophagitis: Clinical Findings & Laboratory Studies: Classically, symptoms of EE closely mimic GERD, with substernal chest pain and referred pain to the back being common symptoms in both children and adults. However, dysphagia is the most frequent symptom in patients with EE in adults. Food impaction is also closely associated with EE, and was seen in 50% of patients in one case series of adult patients [5]. In children, feeding intolerance, failure to thrive, and vomiting can also be seen [14]. Intraesophageal pH probe monitoring is considered the gold standard for the diagnosis of acid reflux. In the early studies of EE, pH probe studies were performed to exclude GERD, and are negative in up to 80% of adult and pediatric patients with EE [15, 16, 17]. However, the current standard of care is to give patients a trial of proton-pump inhibitors to exclude GERD. If patients respond to this treatment, GERD is the presumed diagnosis [9]. Endoscopic findings: Endoscopically, a host of abnormal findings can be seen which include pale mucosa, white exudates, longitudinal furrows, strictures, and 'crepe paper esophagus'. The presence of multiple, transient mucosal rings, termed 'feline esophagus,' has also been reported in EE. Of these findings, the presence of longitudinal furrows and 'crepe paper' changes, in which the esophageal mucosa becomes pale and fragile-appearing, are most suggestive of EE [15, 18]. However, none of these findings is diagnostic. Histologic findings: In general, biopsy findings in patients with EE include reactive squamous epithelium, increased length of the submucosal papillae, and significant numbers of intraepithelial eosinophils. The intraepithelial eosinophils number in excess of 15 eosinophils per high-power field, and are typically distributed preferentially toward the luminal 1/2 or 1/3 of the squamous epithelium [19, 20]. Additionally, extensive eosinophilc degranulation [6] and collections of over 4 eosinophils, typically present in the superficial epithelium, termed 'eosinophilic microabscesses,' can be seen in EE [16]. Perhaps the most specific finding of EE is the presence of a superficial exudate of fibrin, eosinophils, and eosinophilic debris that is adherent to the epithelial surface; however, this finding is uncommonly seen. The distribution of eosinophilic inflammation along the esophageal length is typically uniform with similar numbers of intraepithelial eosinophils in both proximal and distal esophageal biopsies [16]. Lamina propria, when present, may show increased fibrosis [21]. Histologic Mimics Major mimic: Gastroesophageal reflux disease Gastroesophageal reflux disease can closely mimic EE. The histologic overlap between GERD and EE is sufficient such that a definitive pathologic diagnosis of EE or GERD should never be made when over 15 intraepithelial eosinophils per hpf are seen in any biopsy [22]. Rather, a description of the histologic findings should be given and an appropriate differential diagnosis should be delineated(see index case above). In general, however, the following histologic findings help to separate EE from GERD: 1. Numbers of intraepithelial eosinophils: EE generally has over 15-20 intraepithelial eosinophils per high-power field, whereas biopsies of GERD typically have substantially less than this number. When using this criterion, one should report the maximal number of eosinophils seen in a particular biopsy, not the average. 2. Distribution of eosinophils along the esophagus: When well-informed clinicians suspect EE based on clinical findings or the endoscopic appearance, they usually take biopsies from both the distal and proximal esophagus. In cases of GERD, the intraepithelial eosinophilia is most often exclusively present in the distal biopsy. If eosinophils are present in proximal biopsies, there are significantly reduced in number when compared to the distal biopsy. In cases of EE, the numbers of intraepithelial eosinophils remains relatively constant throughout the entire length of the esophagus. 3. Distribution of eosinophils throughout the epithelial thickness: In EE, the eosinophils show increased density towards the luminal aspect of the epithelium. Whereas, in GERD eosinphils are distributed evenly throughout the epithelium. 4. Eosinophilic microabscesses: Aggregates of more than 4 intraepithelial eosinophils within the superficial epithelium are more highly associated with EE. 5. Eosinophilic degranulation: Typically, biopsies of patients with EE show, sometimes extensive, eosinophilic degranulation. This is much less commonly seen in GERD. There is some recent evidence, however, that artifactual eosinophilic degranulation may be induced by biopsy procurement and/or manipulation of the biopsy specimen at the grossing bench [23, 24]. 6. "Eosinophilic Exudate": The presence of an adherent exudate composed of eosinophils, eosinophilic debris, and fibrin seems to be the most specific finding for the diagnosis of EE. However, this assertion requires further study. Sadly, however, this seems to be a specific, but not sensitive criterion. Other Mimics Although GERD is the most common mimic of EE, other esophagitides also enter the differential diagnosis. Other inflammatory conditions that may induce an eosinophilic response include the following: 1. Infections : While the inflammatory infiltrate in infectious esophagitis typically is composed of neutrophils, eosinophils can sometimes predominate. In these cases, the finding of the infectious organism, most commonly Candida pseudohyphae, would obviously help to arrive at the correct diagnosis. Other infectious organisms that might induce an inflammatory infiltrate composed partly of eosinophils include herpes simplex virus, and, less commonly, cytomegalovirus. Again, the finding of neutrophils within the inflammatory infiltrate should prompt a thorough search for an infectious etiology [25]. It is important to note that Candida esophagitis and EE can be coincident, since the main treatment for EE is topical steroid therapy which predisposes patients to esophageal candidiasis. 2. Crohn's Disease: Crohn's disease uncommonly involves the esophagus. Biopsies of esophageal involvement by Crohn's disease typically show ulceration with a brisk lymphocytic infiltrate; non-necrotizing granulomas are rarely seen. In a minority of cases, eosinophils may be a minor constituent of the infiltrate [26]. 3. Other diseases: For completeness sake, other diseases, such as chemical induced esophagitis, radiation damage, drugs, graft-versus-host disease, and various connective tissue diseases may cause eosinophilic inflammation in the esophagus. In these rare cases, the eosinophilic infiltrate is typically found in combination with other findings that lead to the correct diagnosis. For example, in radiation-induced esophagitis, the epithelium may contain a polymorphic infiltrate, including eosinophils. However, the submucosal tissue would contain the vascular changes, and atypical stromal cells typical of radiation-induced esophagitis. Treatment Eosinophilic/allergic esophgitis is typically treated with topical steroid therapy. Patients orally instill topical steroids from a metered dose inhaler. Instead of inhaling this preparation, patients swallow it. This action coats the esophageal mucosa with steroids which decreases the intraepithelial inflammation. Little of this swallowed steroid is absorbed systemically. Using this therapy, all patients studied to date have had a significant decrease in their symptoms, and about 75% of patients had complete symptomatic resolution [27, 28, 29]. Other treatments include systemic corticosteroids and dietary therapy. Systemic corticosteroids are not typically used due to long-term systemic side effects. However, if patients present with severe symptoms of EE, systemic corticosteroids may be used on a short-term basis to relieve acute symptoms. Institution of a food elimination diet has had variable success in the treatment of EE. However, the use of an amino acid-based diet is quite effective in treating EE with up to 98% of patients responding to this treatment modality [30]. However, this treatment is quite expensive and often requires installation through a nasogastric or percutaneous gastrostomy tube because the amino-acid based diet is unpalatable. Figure 1: Esophageal biopsy at 38 cm. At low power, the squamous epithelium appears regenerative with increased nuclear to cytoplastic ratio throughout the entire thickness of the epithelium. Figure 2: Esophageal biopsy at 38 cm. At intermediate power, the a dense eosinophilic infiltrate is appreciated. At this power, the density of the eosinophils increases towards the luminal aspect of the epithelium. Figure 3: Esophageal biopsy at 38 cm. At high power, approximately 50 eosinophils are seen. There are few clusters of 3-5 eosinophils present in the superficial epithelium. Also, significant eosinophilic degranulation is present. Figure 4: Esophageal biopsy at 20 cm. At low power, the epithelial reactive change seen in the distal biopsy is not seen. Figure 5: Esophageal biopsy at 20 cm. At intermediate power, the numbers of intraepithelial eosinophils is significantly reduced compared to the distal biopsy. These eosinophils are present singly and are disbursed evenly throughout the thickness of the epithelium. Figure 6: Esophageal biopsy at 20 cm. At high power, there are only 8-10 intraepithelial eosinophils per field . No eosinophilic microabscesses are seen, and there is minimal eosinophilic degranulation. 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