Eosinophils in the GI tract: How many is too many and what ... · Eosinophils in the GI tract: How many is too many and what do they mean? Rhonda K Yantiss Pathology and Laboratory

Eosinophils in the GI tract: How many is toomany and what do they mean?Rhonda K Yantiss

Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA

Eosinophils are commonly detected in normal mucosal biopsies from all sites within the gastrointestinal tract

where they are dispersed in the lamina propria and, to a lesser extent, in the epithelium. The distinction between

the upper limit of normal and abnormally increased tissue eosinophils is not well defined. However, eosinophils

that infiltrate the epithelium in more than occasional numbers, coalesce to form aggregates, or show extensive

degranulation are always abnormal and raise a broad differential diagnosis. Although the differential diagnosis

of purely eosinophilic inflammation is largely limited to hypersensitivity reactions and some infections, they are

increased in several gastrointestinal conditions, including gastroesophageal reflux disease, autoimmune

gastritis, infections, drug reactions, inflammatory bowel disease, radiation enteritis, and collagen vascular

disease. These disorders feature eosinophils as one component of a mixed inflammatory infiltrate that can, in

some instances, be prominent enough to cause diagnostic confusion. The purpose of this review is to discuss

the normal distribution of eosinophils in the gastrointestinal tract and the differential diagnosis of inflammatory

conditions that feature prominent eosinophilia.Modern Pathology (2015) 28, S7–S21; doi:10.1038/modpathol.2014.132

Introduction

Eosinophils are normally detected in many parts ofthe tubular gut where they may be quite numerous.They can be present in any inflammatory conditionthat persists for days to weeks, as well as chronicdiseases that wax and wane over months to years.Indeed, patients who undergo appendectomy orcholecystectomy days after the onset of symptomscharacteristically have large numbers of eosinophilsin their appendices or gallbladders; an observationthat has led to overuse, and misuse, of terms such aseosinophilic appendicitis and eosinophilic chole-cystitis. Eosinophils are also increased, and may beprominent, in gastroesophageal reflux disease, auto-immune gastritis, infections, drug reactions, inflam-matory bowel disease, collagen vascular disease,radiation enteritis, neoplasms, and a host of otherdisorders. Most of these entities show mixed, oftenneutrophil-rich, inflammation and other featuresthat allow their distinction. However, strikingeosinophilia occasionally masks the nature ofunderlying disease and raises the possibility ofanother diagnosis, such as eosinophilic gastroenter-

itis. The purpose of this review is to discuss thenormal distribution of gastrointestinal eosinophilsas well as the differential diagnosis of inflammatoryconditions that feature prominent eosinophilia.

Eosinophils in normal biopsies of thegastrointestinal tract

Eosinophils are readily detected throughout thetubular gut and can be numerous in some patients,making it difficult to distinguish between variants ofnormal and inflammatory conditions. One mayencounter occasional eosinophils in distal esopha-geal biopsies obtained from healthy, asymptomaticpatients, but this finding does not correlate with thepresence of clinical symptoms or their response toacid suppressive therapy. Data regarding the mini-mal criteria for a histologic diagnosis of esophagitisare not established, although rare eosinophils in thedistal esophagus are generally considered insuffi-cient if other evidence of mucosal injury (eg, basalzone hyperplasia, elongated papillae, edema, bal-loon cells) is lacking. The normal gastric mucosacontains lymphocytes, occasional plasma cells, andscattered eosinophils. Lamina propria eosinophilsnumber fewer than nine per high-power field andgenerally less than five per high-power field, andintraepithelial eosinophils are absent, or rare.1

Eosinophils are more numerous in the intestinallamina propria, where counts frequently range up to

Correspondence: Dr RK Yantiss, MD, Pathology and LaboratoryMedicine, Weill Cornell Medical College, 1300 York Avenue,C-302, New York, NY 10065, USA.E-mail: [email protected] 23 April 2014; revised 24 June 2014; accepted 25 June2014

Modern Pathology (2015) 28, S7–S21

& 2015 USCAP, Inc. All rights reserved 0893-3952/15 $32.00 S7

www.modernpathology.org

http://dx.doi.org/10.1038/modpathol.2014.132

mailto:[email protected]

http://www.modernpathology.org

20–30 eosinophils per high-power field and occa-sionally approach 50 eosinophils per high-powerfield.2 Their numbers are greatest in mucosalbiopsies of the proximal colon where scatteredeosinophils may infiltrate the crypt epithelium.More than half of biopsies from the normal pro-ximal colon show occasional eosinophils in cryptepithelium, whereas fewer than 5% of distal colonicbiopsies from asymptomatic patients demonstratethis finding.3 The number of eosinophils normallypresent in colonic biopsies also varies as a result ofenvironmental influences. Some data suggest theyare more numerous during peak allergy seasons andamong individuals living in the southern UnitedStates compared to those of northeastern regions.3,4

As in the small intestine, colonic eosinophils areconsidered to represent normal constituents of themucosa when singly dispersed in the laminapropria. Eosinophils that infiltrate the epitheliumin more than occasional numbers, coalesce to formaggregates, or show extensive degranulation arealways abnormal.

The differential diagnosis of mucosaleosinophilia

Eosinophils as a Component of Mixed Inflammation

Eosinophils can be prominent in virtually anyinflammatory condition that persists for days toweeks. Esophageal eosinophilia most frequentlyreflects chronic mucosal injury due to gastroeso-phageal reflux disease, in which case the featuresshow considerable overlap with those of eosinophi-lic esophagitis, as described in subsequent sections.Mucosal eosinophilia is also commonly observed indrug-related and, to a lesser degree, in infectiousesophagitis. All of these disorders display variablenumbers of eosinophils in combination with intrae-pithelial lymphocytes and neutrophils, which tendto be present in higher numbers than eosinophils(Figure 1a). These forms of esophageal injury canalso cause erosions and ulcers, both of which areuncommon in patients with eosinophilic esophagi-tis. Detection of pill fragments, fungal forms, or viralinclusions are helpful clues that should, whenpresent, dissuade one from placing too muchemphasis on concomitantly increased eosinophils.

Mucosal eosinophilia may be seen in associationwith acute and chronic forms of gastric injury. Smallnumbers infiltrate the lamina propria singly or inclusters in cases of chemical gastropathy due to anycause, although they were once considered aspecific manifestation of injury due to non-steroidalanti-inflammatory drugs.5 Eosinophils comprisepart of the infiltrate of chronic gastritis and are farmore numerous in cases of autoimmune gastritisthan Helicobacter pylori-related gastritis.6 Indeed,autoimmune gastritis is always a diagnostic consi-deration when cases of chronic gastritis show

prominent eosinophils, particularly when seen inassociation with an infiltrate in the deep mucosa(Figure 1b).

Virtually any form of persistent enterocolitis canshow increased mucosal eosinophils. Eosinophilsare numerous in cases of infectious enterocolitis,medication-related injuries, radiation effect, andinflammatory bowel disease (Figure 1c). Fortu-nately, many of these disorders show other inflam-matory changes that facilitate their diagnosis.Bacterial and drug-induced injuries produce anacute self-limited colitis with neutrophil-richinflammation in the lamina propria and crypts, butrelatively fewer eosinophils (Figure 1d). Biopsiesfrom patients with Crohn disease and ulcerativecolitis may show striking mucosal eosinophilia,either in areas of active or quiescent disease.However, eosinophils are accompanied by neutro-philic crypt injury in cases of active colitis, andplasma cell-rich infiltrates and crypt architecturalchanges serve as helpful clues to the presence ofchronic colitis (Figures 1e and f).

Eosinophils are commonly observed in surgicalresection specimens from patients with appendicitisand cholecystitis, particularly when there is a slightdelay between the onset of symptoms and surgery.Approximately 40% of appendices removed within12–84 h of symptom onset display mural eosino-phils, often in combination with lymphocytes.7

Similarly, more than 20% of resected gallbladderscontain numerous eosinophils as well as other typesof inflammatory cells.8 Most data suggest that thesefindings reflect the ‘subacute’ phase of the inflam-matory process, rather than a primary eosinophilicdisorder, particularly if eosinophils are not themajor component of the infiltrate and are evenlydispersed among other inflammatory cells. How-ever, large numbers of eosinophils accounting formost (490%) of the infiltrate, aggregates ofeosinophils, and extensive degranulation shouldraise the possibility of other disorders, asdescribed below.9

Inflammatory Infiltrates Consisting Predominantly, orExclusively, of Eosinophils

Eosinophilic gastroenteritis. Eosinophilic gastro-enteritis is a general term describing disorderscharacterized by prominent eosinophil-rich inflam-matory infiltrates for which other etiologies cannotbe identified. Cases of eosinophilic gastroenteritisare classified as mucosal, mural, or serosal forms forhistorical reasons, although these variants are likelyunrelated disorders.10 The mucosal form of thedisease is a manifestation of hypersensitivitysimilar to eosinophilic (allergic) esophagitis, whichmay represent a milder or localized form ofdisease.11 In contrast, most examples of mural andserosal disease are unrelated to hypersensitivity andcan be attributed to other etiologies.12 The

Eosinophils in the GI tract

S8 RK Yantiss


Figure 1 This elderly patient with candidal esophagitis had biopsies from the mid esophagus that display scattered eosinophils in thesuperficial epithelium, some of which are clustered. Numerous lymphocytes are also present, as are scattered neutrophils (a). Theinflammatory infiltrate of autoimmune gastritis is associated with deep glands in oxyntic mucosa. Scattered eosinophils are a consistentfeature (b). Changes of radiation enteritis include intimal hyperplasia with obliteration of arteries and mural fibrosis. This case alsofeatures eosinophil-predominant inflammation (c). Acute self-limited colitis due to nonsteroidal anti-inflammatory drugs displaysnumerous eosinophils in the lamina propria as well as neutrophils in injured crypts (d). A case of chronic active ulcerative colitiscontains numerous eosinophils associated with neutrophilic crypt destruction. Branched, irregular crypts are present in the backgroundmucosa (e). Biopsies from this patient with Crohn disease displays multinucleated giant cells in the lamina propria. The backgroundinfiltrate is rich in eosinophils and plasma cells. Branched crypts are also present (f).



RK Yantiss S9

differential diagnosis includes a number of entitiesthat characteristically elicit an eosinophil-rich res-ponse, many of which cannot be distinguished fromeosinophilic gastroenteritis based on histology alone.

Mucosal eosinophilic gastroenteritis shows apredilection for males and is more common amongchildren. Most patients have one, or more, foodallergies and present with multiple lesions affectingany site within the gastrointestinal tract, includingthe esophagus. Cases that cannot be attributed toidentifiable allergic etiologies share many clinicaland pathologic features with those with definiteallergy associations, including a dramatic responseto corticosteroid therapy. Clinical symptoms includemalabsorptive diarrhea, failure to thrive, iron defi-ciency anemia, protein losing enteropathy, vomit-ing, abdominal pain, and rectal bleeding. Most(475%) patients have a peripheral eosinophilia aswell as elevated serum IgE levels. The diagnosis ofmucosal eosinophilic gastroenteritis requires exclu-sion of other disorders that show a prominenteosinophilic infiltrate, appropriate clinical andlaboratory findings, and a therapeutic response toelimination diet or corticosteroid therapy. Thedisease shows a predilection for the gastric antrumand commonly affects the small bowel, but color-ectal involvement is less frequent. Lesions may bepatchy and are typically associated with mildendoscopic abnormalities, so extensive sampling,often of normal-appearing areas, may be required toestablish a diagnosis. The diagnosis requires exclu-sion of other disorders that show a prominenteosinophilic infiltrate, appropriate clinical andlaboratory findings, and a therapeutic response toelimination diet or corticosteroid therapy.

Mucosal eosinophilic gastroenteritis displays nu-merous eosinophils that expand the lamina propriaand infiltrate the epithelium, producing variableepithelial cell injury. The diagnosis is straightfor-ward in mucosal biopsies of the esophagus andstomach because these sites normally contain mini-mal numbers of inflammatory cells and, thus, anyincrease in eosinophils is readily apparent. Thefeatures of eosinophilic gastroenteritis involving theesophagus are identical to those of eosinophilicesophagitis. Superficially oriented eosinophilspermeate the squamous epithelium and coalesce toform eosinophilic microabscesses (Figure 2a). Thebackground mucosa is edematous and often displaysbasal zone hyperplasia involving up to 50% of themucosal thickness (Figure 2b). Distinction fromeosinophilic esophagitis requires sampling of theduodenum and stomach, at least one of which isusually involved in cases of eosinophilic gastro-enteritis, but show sparing in cases of eosinophilicesophagitis. Gastric samples, particularly those ofthe antrum, contain aggregates of eosinophils sur-rounding gastric pits and glands with infiltration ofthe epithelium in some cases (Figures 2c and d).

Infiltrates in the intestines may be more difficultto recognize, particularly when eosinophils are less

abundant, as their numbers may be masked byinflammatory cells normally found in the mucosa.Counting mucosal eosinophils is of little practicalvalue because their distribution is often patchy ineosinophilic gastroenteritis and well-defined criter-ia for this diagnosis are lacking. More important istheir distribution in the mucosa. Eosinophils arenormally dispersed singly in the lamina propria andare infrequently observed in the crypts, so anyclustering, even of a few cells, in either location isan abnormal finding that should raise suspicion.Eosinophils within the muscularis mucosae are alsoabnormal and can be a helpful finding when thediagnosis is suspected. Patients with malabsorptivesymptoms may have small bowel biopsies that showeosinophilia as well as partial, or complete villousshortening with crypt hyperplasia and variableintraepithelial lymphocytosis that simulate celiacdisease.

Mural eosinophilic gastroenteritis is not related tomucosal disease, nor is it associated with a clinicalhistory of hypersensitivity. Most cases were reportedprior to the H. pylori eradication era and showed apredilection for the antrum, particularly the pre-pyloric region, where they formed solitary areas ofmural thickening that caused obstructive symp-toms.12 The entity is much less commonlydescribed in the current literature, but reportedlyresponds to H. pylori eradication, suggesting thatmany examples of mural eosinophilic gastroenteritisdescribe peptic ulcer disease.13,14 Other entities,including inflammatory fibroid polyp, Crohndisease, infection with parasites or specific fungi,and radiation may show striking eosinophilia in thebowel wall and result in an erroneous diagnosis ofmural gastroenteritis (Figure 3). Thus, potentialcases of mural eosinophilic gastroenteritis shouldbe carefully evaluated for the presence of underlyinggastritis, multifocality, mural lymphoid aggregates,and granulomata suggestive of Crohn disease, wormor egg fragments, fungi, and other clues to suggest amore specific diagnosis.

Serosal eosinophilic gastroenteritis is extremelyrare and unrelated to either mucosal or mural typesof disease. Patients typically lack a history ofhypersensitivity and present with acute onsetabdominal pain. Peritoneal washings demonstrateeosinophil-rich ascites due to eosinophilic infil-trates in the serosa and imaging may depict asciteswith variable bowel wall thickening. Given therarity of serosal eosinophilic gastroenteritis, as wellas a lack of cohesive clinical and laboratoryfindings, it is likely that this disorder results frommultiple different etiologies and is not a distinctentity (Figure 4). The most common mimic ofserosal eosinophilic gastroenteritis is parasiticinfestation, particularly anisakiasis, as described insubsequent sections.15,16 Similar changes can alsobe seen in patients with metal allergies, such asnickel and/or titanium, who have abdominal surgeryrequiring use of stapling devices.17,18



S10 RK Yantiss

Figure 2 Eosinophilic gastroenteritis involving the esophagus is endoscopically and histologically indistinguishable from allergic(eosinophilic) esophagitis. Biopsies from a young boy with failure to thrive reveal striking intercellular edema with numerouseosinophils (a). Clusters of degranulating eosinophils form microabscesses (arrow) near the epithelial surface (b). The antral mucosa ofthe same patient contains increased numbers of eosinophils that expand the lamina propria (c). Aggregates of degranulated eosinophilsand occasional intraepithelial eosinophils are also present (d). Eosinophilic gastroenteritis shows a predilection for the uppergastrointestinal tract, including the duodenum. Eosinophils are increased in the lamina propria and crypt epithelium of this patient (e).In contrast, colonic changes of eosinophilic gastroenteritis are often milder than those of the upper gastrointestinal tract. Biopsies fromthis patient with eosinophilic gastroenteritis show slightly increased eosinophils in the lamina propria and scattered eosinophils incolonic crypts (f).



RK Yantiss S11

Figure 3 Mural eosinophilic gastroenteritis shows dense eosinophilic infiltrates in the submucosa and muscularis propria (a). Sheets ofeosinophils are associated with mural edema (b). Most cases of mural eosinophilic gastroenteritis are likely secondary to other disorders.This actively inflamed gastric ulcer contains fibrin-rich granulation tissue with mixed inflammation, including numerous eosinophils(c). Sheets of eosinophils persist in the muscularis mucosae of a healing ulcer (d). Some fungi and parasites cause gastrointestinal diseasethat mimics mural eosinophilic gastroenteritis. Basidiobolus ranarum is a fungus that appears as optically clear pauciseptate branchingorganisms surrounded by Splendore-Hoeppli phenomenon (e). Sheets of eosinophils infiltrate the muscularis propria distant from thesite of infection (f). Failure to detect organisms may lead to an erroneous diagnosis of eosinophilic gastroenteritis. Images E and Fcourtesy of Dr Wade Samowitz, University of Utah, Salt Lake City, UT.



S12 RK Yantiss

Figure 4 The differential diagnosis of serosal eosinophilic gastroenteritis includes infection, particularly anisakiasis, as well as otherforms of hypersensitivity. Anisakis is surrounded by an eosinophil-rich abscess subjacent to the peritoneal surface with sparing of themuscularis propria (a). High magnification discloses a degenerated parasite surrounded by palisaded granulomatous inflammation andeosinophils (b). Intense mural and subserosal eosinophilia are present distant from the parasite (c). Necrotic, degranulated eosinophilsand Charcot-Leyden crystals on the serosa and in the peritoneum should raise suspicion for this parasite, as the latter are present in farfewer numbers in eosinophilic gastroenteritis (d). Another patient underwent surgical resection following acute onset of abdominal painand obstructive symptoms. The resection specimen displays striking subserosal edema (e) with clusters of eosinophils subjacent to themesothelial lining (f). Upon further investigation, the patient was found to have a titanium staple in the abdominal cavity and a longhistory of metal allergies.



RK Yantiss S13

Gastroesophageal reflux disease. Gastroesophagealreflux disease results from retrograde flow of acidicor alkaline fluid into the esophagus and producessymptoms of heartburn, acid regurgitation, dyspha-gia, chronic cough, and atypical chest pain. Endo-scopic features include diffuse or discontinuousinflammatory changes in the distal 5–10 cm of theesophagus, erythema, erosions, ulcers, exudates, orstrictures, although 50% of symptomatic patientshave normal-appearing mucosae or minimal hyper-emia.19 Intraepithelial inflammation is common:more than half of cases show eosinophils evenlydistributed throughout the epithelium orconcentrated around papillae (Figures 5a–c). Neu-trophils are identified in approximately 30% ofpatients, in which case their presence usuallyimplies erosive disease. Squamous hyperplasia withelongated papillae, expansion of the basal zone toapproximately 10–15% of the mucosal thickness,intercellular edema, and swollen and/or multinu-cleated squamous cells are often present.20,21 Thedifferential diagnosis of gastroesophageal refluxdisease includes other types of esophagitis, parti-cularly eosinophilic esophagitis. The formertypically displays squamous hyperplasia withelongated papillae and eosinophil-rich inflam-mation that is evenly dispersed throughout alllayers of the epithelium, but eosinophils tend tonumber fewer than 20 per high-power field. Clustersof eosinophils (microabscesses) are rare, even ifeosinophils are numerous.

‘Eosinophilic’ (allergic) esophagitis. Eosinophilicesophagitis is a poorly chosen term used to describea form of hypersensitivity limited to the esophagus.It is increasingly recognized among pediatric pa-tients and adults, particularly young men. Patientsmay have symptoms that simulate gastroesophagealreflux disease, although many present with progres-sive dysphagia and/or recurrent food impaction.The disease likely results from a combination ofgenetic, immunologic, and environmental factorsand is more common among patients with a historyof food allergies, atopic dermatitis, peripheraleosinophilia, or bronchial asthma. For these rea-sons, the entity is most appropriately termed‘allergic esophagitis,’ although ‘eosinophilic eso-phagitis’ has become popular in the literature andclinical practice. Endoscopic features include pla-ques of scale crust, linear furrows, and concentricrings that have been described as a feline, ortrachealized, esophagus.22 Mucosal tears and areasof luminal narrowing are common, although theesophagus is endoscopically normal in a minority ofcases.23 The patchy nature of eosinophilic eso-phagitis necessitates multiple tissue samples fromthe proximal, distal, and intervening esophagealmucosa, all submitted in separate containers.24,25

Affected biopsies typically contain numerous (415/high-power field) eosinophils that are moreabundant in the superficial epithelium where they

tend to cluster and form microabscesses (Figures5d–f). Eosinophil aggregates and degranulated eosi-nophils in adherent keratin are relatively specificfindings and helpful diagnostic clues, if present.26

The differential diagnosis of eosinophilic esopha-gitis includes eosinophilic gastroenteritis and gas-troesophageal reflux disease. Distinction fromeosinophilic gastroenteritis is somewhat arbitraryas the two have overlapping clinical and histologicfeatures and are likely related disorders differingonly with respect to disease extent and distribution.Indeed, they are histologically identical whenevaluation is limited to esophageal biopsies andcan be separated only if biopsies of the remaininggastrointestinal tract are also available. An absenceof eosinophilia in duodenal and/or gastric biopsiesis a pre-requisite to the diagnosis of eosinophilicesophagitis, whereas eosinophilic gastroenteritisinvolves the stomach in virtually 100% of cases.From a clinical standpoint, the diagnosis of eosino-philic esophagitis can certainly be suggested basedon analysis of esophageal biopsies alone, but cannotbe distinguished from eosinophilic gastroenteritis inthe absence of biopsies from other sites in thegastrointestinal tract.

Distinction between eosinophilic gastroenteritis/esophagitis and gastroesophageal reflux disease isusually straightforward (Table 1). Acid injury tendsto be worse in the distal esophagus, whereaseosinophilic esophagitis can affect any region ofthe esophagus. The latter characteristically displayssuperficial eosinophil microabscesses and degranu-lated eosinophils, as well as striking mucosaledema, all of which are less prominent in gastro-esophageal reflux disease. Eosinophilic esophagitismay also cause progressive lamina propria fibrosisthat can be a helpful feature in the distinctionfrom gastroesophageal reflux disease.27 Some casesof eosinophilic esophagitis lack characteristicfeatures to distinguish them from gastroesophagealreflux disease and, conversely, some cases ofgastroesophageal reflux disease show strikingeosinophilia, thereby mimicking eosinophilic eso-phagitis.26,28 Thus, occasional cases of eosinophilicesophagitis and gastroesophageal reflux disease arehistologically indistinguishable, particularly whenbiopsies are limited to the lower esophagus.29,30

Eosinophilic gastritis. Some investigators havesuggested that detection of more than 30 eosinophilsper high-power field in at least five examined fieldsof the gastric mucosa should be considered to re-present ‘histologic eosinophilic gastritis,’ althoughavailable data supporting this designation as aspecific clinicopathologic entity are lacking. Indeed,a substantial number of patients with markedlyelevated gastric eosinophils also have peripheraleosinophilia or increased eosinophils elsewherein the gastrointestinal tract, suggesting that aproportion of patients with ‘histologic eosinophilicgastritis’ are more appropriately diagnosed with



S14 RK Yantiss

Figure 5 The primary differential diagnosis of eosinophil-rich inflammation in the esophagus includes gastroesophageal reflux diseaseand eosinophilic esophagitis. Gastroesophageal reflux disease tends to cause more severe changes in the distal esophagus. Characteristicfeatures include elongated papillae and basal cell hyperplasia occupying approximately 10% of the mucosal thickness (a). Numerouseosinophils are evenly dispersed in the squamous mucosa or concentrated around papillae (b). Ballooned keratinocytes reflectintracellular edema (c). Eosinophilic esophagitis shows elongated papillae and increased eosinophils that tend to be superficiallyoriented (d). Some cases display prominent keratin crust containing degranulated eosinophils. Basal zone hyperplasia involves morethan 50% of the mucosal thickness (e). Striking mucosal edema is a helpful feature of eosinophilic esophagitis. This case also showsextensive infiltration by eosinophils with microabscesses (f).



RK Yantiss S15

eosinophilic gastroenteritis.1 Primary eosinophilicgastritis, in the absence of hypersensitivity orgeneralized involvement of the gastrointestinaltract, is extremely rare. Of note, drug reactionsare unlikely to cause intense eosinophilia of gastricmucosa.

Invasive gastric adenocarcinoma. One importantentity to consider in the differential diagnosis ofgastric eosinophilia is invasive adenocarcinoma.Intestinal-type adenocarcinomas may be infiltratedby neutrophils, whereas signet ring cell and diffuse-type carcinomas frequently recruit eosinophils. Theinfiltrate is variably prominent and can be limited tothe area of the tumor or emanate away from it,thereby simulating the appearance of ‘eosinophilicgastritis’ in biopsy samples (Figure 6a). More rarely,tumor cells are seen in combination with eosino-phils and plump spindle cells that resemble com-ponents of inflammatory fibroid polyp.31 Tumorcells form cohesive clusters or linear arraysenmeshed in collagenous stroma and are enhancedby cytokeratin immunostains (Figures 6b–d).

Parasitic infection. The possibility of parasiticinfestation should be considered in any series ofbiopsies that shows mucosal eosinophilia, particu-larly if eosinophils form large clusters or areassociated with granulomatous inflammation. Stron-gyloides and Schistosoma are the most commonparasites encountered in mucosal biopsies. Biopsiesfrom patients with heavy Strongyloides burdensshow larvae and eggs within crypt lumina that tendto be unassociated with a substantial inflammatoryresponse (Figure 7a). Once organisms breach thebasement membrane and invade the mucosa, theyelicit a brisk, eosinophil-rich inflammatory response(Figures 7b–f). In this situation, Strongyloides arefound in the deep mucosa surrounded by degranu-lated eosinophils with Charcot-Leyden crystals.32 Incontrast, schistosomal eggs are observed within thelumina of small vessels in the lamina propria, or inassociation with granulomatous inflammation in thelamina propria and submucosa.33 Inflammation isusually absent or mild around eggs confined tovascular lumina, whereas granulomata developwhen eggs erode through the vessels into conne-ctive tissue. It is important to remember that chronicinfestation with any type of parasite induces crypt

and villous architectural changes reminiscent ofidiopathic inflammatory bowel disease.34 Oneshould consider the possibility of parasiticinfestation when chronic colitis is accompanied bystriking mucosal eosinophilia.

Parasites are likely responsible for a substantialnumber of cases originally diagnosed as mural andserosal eosinophilic gastroenteritis. Anisakis is anematode that infects fish and marine invertebratesand an increasingly recognized cause of eosinophi-lic ascites. The organism causes gastrointestinaldisease in humans when contaminated raw orundercooked fish is ingested. Larval forms penetratethe mucosa and burrow into the bowel wall wherethey elicit an intense inflammatory reaction thatproduces symptoms of abdominal pain, hemorrhage,obstruction, and serositis.12,35 Inflammatorychanges in the wall and serosa are characterized byintense eosinophilia and edema that may extendaway from the site of infection (Figures 4a–d).Multiple sections are often required to demonstratethe organism.36,37

Fungal infection. Most fungal infections elicit achronic granulomatous inflammatory response withvariable numbers of neutrophils, although rarespecies cause infection that produces intense tissueeosinophilia. One of these, Basidiobolus ranarum,has been recently recognized as a human pathogenthat shows a predilection for the gastrointestinaltract. Infection may develop in immunocompetentor immunocompromised individuals and most casesin this country occur in patients who reside in thesouthwest, particularly Arizona. Infected patientspresent with peripheral eosinophilia and inflamma-tory masses that simulate malignancy, Crohndisease, or mural eosinophilic gastroenteritis.38

Symptoms include abdominal pain, fever, weightloss, and an abdominal mass that usually involvesthe colon. The mucosa may be normal or containmildly increased eosinophils, whereas inflam-matory masses destroy the bowel wall and extendinto surrounding soft tissue. Inflammatory changesinclude prominent eosinophilic infiltratesassociated with granulomatous inflammationaround fungal forms, many of which are surro-unded by a thick eosinophilic cuff (Splendore-Hoeppli phenomenon).39 Hyphae are irregularlybranching, thin-walled, and may show a few

Table 1 Distinguishing features of gastroesophageal reflux disease and eosinophilic esophagitis

Gastroesophageal reflux disease Eosinophilic esophagitis

Presence of 20 or more eosinophils per high-power field Uncommon (3–5%) Frequent (Z90%)Superficial eosinophil abscesses Quite uncommon Helpful, if presentEosinophils in adherent or detached keratin crust Quite uncommon Helpful, if presentMarked (450%) basal cell hyperplasia Uncommon (10%) Frequent (450%)Papillary elongation (450% of mucosal thickness) Not helpful, commonly present Not helpful, commonly presentBallooned keratinocytes Helpful, if present Not a characteristic feature



S16 RK Yantiss

Figure 6 Diffuse-type gastric carcinomas may elicit a striking eosinophil-rich inflammatory infiltrate. This patient with a signet ring cellcarcinoma had biopsies containing large clusters of eosinophils in the superficial mucosa, some of which infiltrated gastric glands (a).Another case of diffuse-type gastric cancer displays rare, keratin-positive tumor cells (arrow) enmeshed in a mixed inflammatorybackground with plump spindle cells mimicking inflammatory fibroid polyp (b). High magnification of the same case reveals lineararrangements of tumor cells (arrow) associated with scattered eosinophils and plasma cells (c). A keratin immunostain confirms plumpkeratin-positive tumor cells diffusely infiltrating the gastric wall (d).



RK Yantiss S17

septations (Figures 3e and f). They are usually 8–40 mm in width and are best seen in hematoxylin andeosin-stained sections. Eosinophil-rich inflamma-

tion permeates the muscularis propria distant fromthe site of infection, thereby simulating the appear-ance of mural eosinophilic gastroenteritis.

Figure 7 Adult Strongyloides reside in the gut lumen and deposit eggs. Both eggs and worms can be visualized in the crypts, where theyelicit minimal inflammatory changes (a). Rhabditiform larvae in the lumen can become filariform larvae that invade the mucosa, at whichpoint they elicit an eosinophil-rich inflammatory response (b). Clues to the presence of a parasitic infection include the localized natureof eosinophil infiltrates, particularly in the deep mucosa (c). Deeper tissue levels through these areas reveal larvae in eosinophilicabscesses (d). Chronic Strongyloides infection elicits crypt architectural changes that simulate features of inflammatory bowel disease.However, the background mucosa lacks dense chronic inflammation and shows sheets and clusters of eosinophils (e). Carefulexamination of eosinophil clusters in the same case reveals worm fragments (arrow) in the mucosa (f).



S18 RK Yantiss

Figure 8 Churg-Strauss vasculitis shows a predilection for small- and medium-sized vessels of the small bowel. Affected blood vesselsdisplay mural fibrin deposits in association with necrotic cellular debris (a). Eosinophils are concentrically arranged around bloodvessels and show degranulation (b). Inflammatory infiltrates also contain macrophages that circumferentially involve vascular walls orobliterate blood vessels (c). Although eosinophils are numerous in the mucosa, it also shows ischemic-type injury, which should be aclue to the diagnosis (d). Ischemic enteritis is not a feature of eosinophilic gastroenteritis or most infections that cause eosinophilia.



RK Yantiss S19

Allergic colitis and proctitis. Most patients withallergic proctocolitis are infants and young childrenunder the age of 2 years. Cow’s milk protein, eitheralone or in combination with soy protein, has beenimplicated as a major etiologic factor. Patientsgenerally respond to elimination of these foods fromthe diet and lose their sensitivity over several years,such that tolerance improves during adulthood.Most studies describing the features of allergicproctocolitis have limited their analyses to rectalbiopsy samples, although it is likely that abnormal-ities are present throughout the colon. Histologicfeatures are similar to those of eosinophilic gastro-enteritis. Biopsies reveal diffusely increased eosino-phils in the lamina propria with minimal epithelialcell damage and an absence of crypt architecturaldistortion or other features of chronic injury.Although it may be difficult to distinguish changesof allergic proctocolitis from normal tissue eosino-philia, the finding of more than 60 eosinophils per10 high-power fields and extension of eosinophilsinto the muscularis mucosae are suggestive ofallergic proctocolitis.40

Churg-strauss syndrome. Eosinophilic granuloma-tosis with polyangiitis (allergic granulomatosis) isan immune-mediated vasculitis of medium andsmall vessels in patients with a history of asthmaand/or allergic rhinitis. The syndrome is character-ized by the development of three clinical stages(allergic stage, eosinophilic stage, and vasculiticstage), although not all patients develop all threestages or progress from one stage to the next. Thisform of vasculitis shows a predilection for the smallintestine and proximal colon and is associated withcANCA autoantibodies, similar to microscopic poly-angiitis and Wegener granulomatosis.41 Resectionspecimens typically show fibrinoid necrosis ofvascular walls in association with intense eosino-phil-rich inflammatory cell infiltrates aroundmedium and small vessels in the submucosa anddeeper aspects of the bowel wall (Figure 8).Increased numbers of eosinophils may be presentin the mucosa, but superficial biopsies generallyshow striking ischemic changes that dominate thehistologic picture. Thus, the primary differentialdiagnosis includes other causes of ischemic entero-colitis, rather than eosinophilic gastroenteritis inmost cases.

Summary and conclusions

Eosinophils are commonly detected in mucosalbiopsies from all sites within the gastrointestinaltract. They can be considered to represent a normalfinding in most instances, provided they are evenlydispersed in the lamina propria, minimally involvethe epithelium, and do not coalesce into aggregatesor microabscesses. Increased numbers of eosino-phils are encountered in a variety of disorders.

When accompanied by abundant neutrophils orgranulomatous inflammation, one should considerinfectious etiologies or drug-induced injuries. Eosi-nophils are commonly encountered in cases ofidiopathic inflammatory bowel disease, in whichcase they are accompanied by other features ofchronic colitis, including crypt abscesses, lympho-plasmacytic inflammatory infiltrates, and cryptarchitectural abnormalities. Purely eosinophil-richinfiltrates are increasingly encountered in patientswith esophageal symptoms, in which case theirpresence typically reflects a hypersensitivity reac-tion (ie, eosinophilic esophagitis or eosinophilicgastroenteritis). However, generalized hypersensi-tivity of the gastrointestinal tract is infrequent, parti-cularly in the adult population. Thus, a diagnosis ofeosinophilic gastroenteritis should only be madeafter other, more common, etiologies are excluded.

Disclosure/conflict of interest

The author declares no conflict of interest.

References

1 Lwin T, Melton SD, Genta RM. Eosinophilic gastritis:histopathological characterization and quantificationof the normal gastric eosinophil content. Mod Pathol2011;24:556–563.

2 DeBrosse CW, Case JW, Putnam PE, et al. Quantity anddistribution of eosinophils in the gastrointestinal tractof children. Pediatr Dev Pathol 2006;9:210–218.

3 Polydorides AD, Banner BF, Hannaway PJ, et al.Evaluation of site-specific and seasonal variation incolonic mucosal eosinophils. Hum Pathol 2008;39:832–836.

4 Pascal RR, Gramlich TL, Parker KM, et al. Geographicvariations in eosinophil concentration in normalcolonic mucosa. Mod Pathol 1997;10:363–365.

5 El-Zimaity HM, Genta RM, Graham DY. Histologicalfeatures do not define NSAID-induced gastritis. HumPathol 1996;27:1348–1354.

6 Bettington M, Brown I. Autoimmune gastritis: novelclues to histological diagnosis. Pathology 2013;45:145–149.

7 Ciani S, Chuaqui B. Histological features of resolvingacute, non-complicated phlegmonous appendicitis.Pathol Res Pract 2000;196:89–93.

8 Dabbs DJ. Eosinophilic and lymphoeosinophilic cho-lecystitis. Am J Surg Pathol 1993;17:497–501.

9 Shakov R, Simoni G, Villacin A, et al. Eosinophiliccholecystitis, with a review of the literature. Ann ClinLab Sci 2007;37:182–185.

10 Talley NJ, Shorter RG, Phillips SF, et al. Eosinophilicgastroenteritis: a clinicopathological study of patientswith disease of the mucosa, muscle layer, andsubserosal tissues. Gut 1990;31:54–58.

11 Rothenberg ME. Eosinophilic gastrointestinal disor-ders (EGID). J Allergy Clin Immunol 2004;113:11–28;quiz 9.

12 Yun MY, Cho YU, Park IS, et al. Eosinophilicgastroenteritis presenting as small bowel obstruction:



S20 RK Yantiss

a case report and review of the literature. World JGastroenterol 2007;13:1758–1760.

13 Furuta K, Adachi K, Aimi M, et al. Case-control studyof association of eosinophilic gastrointestinal disor-ders with Helicobacter pylori infection in Japan. J ClinBiochem Nutr 2013;53:60–62.

14 Manatsathit W, Sermsathanasawadi R, Pongpaiboon A,et al. Mucosal-type eosinophilic gastroenteritis inThailand: 12-year retrospective study. J Med AssocThai 2013;96 Suppl 2:S194–S202.

15 Couture C, Measures L, Gagnon J, et al. Humanintestinal anisakiosis due to consumption of rawsalmon. Am J Surg Pathol 2003;27:1167–1172.

16 Walker NI, Croese J, Clouston AD, et al. Eosinophilicenteritis in northeastern Australia. Pathology, associa-tion with Ancylostoma caninum, and implications.Am J Surg Pathol 1995;19:328–337.

17 Lim CB, Goldin RD, Darzi A, et al. Characterization ofmaterials eliciting foreign body reaction in stapledhuman gastrointestinal anastomoses. Br J Surg2008;95:1044–1050.

18 Valentine-Thon E, Muller K, Guzzi G, et al. LTT-MELISA is clinically relevant for detecting andmonitoring metal sensitivity. Neuro Endocrinol Lett2006;27 Suppl 1:17–24.

19 Vakil N. Disease definition, clinical manifestations,epidemiology and natural history of GERD. Best PractRes Clin Gastroenterol 2010;24:759–764.

20 Johnson LF, Demeester TR, Haggitt RC. Esophagealepithelial response to gastroesophageal reflux. Aquantitative study. Am J Dig Dis 1978;23:498–509.

21 Singh SP, Odze RD. Multinucleated epithelial giantcell changes in esophagitis: a clinicopathologic studyof 14 cases. Am J Surg Pathol 1998;22:93–99.

22 Liacouras CA, Spergel JM, Ruchelli E, et al. Eosino-philic esophagitis: a 10-year experience in 381 chil-dren. Clin Gastroenterol Hepatol 2005;3:1198–1206.

23 Almansa C, Devault KR, Achem SR. A comprehensivereview of eosinophilic esophagitis in adults. J ClinGastroenterol 2011;45:658–664.

24 Shah A, Kagalwalla AF, Gonsalves N, et al. Histo-pathologic variability in children with eosinophilicesophagitis. Am J Gastroenterol 2009;104:716–721.

25 Potter JW, Saeian K, Staff D, et al. Eosinophilicesophagitis in adults: an emerging problem withunique esophageal features. Gastrointest Endosc 2004;59:355–361.

26 Dellon ES, Gonsalves N, Hirano I, et al. ACG clinicalguideline: Evidenced based approach to the diagnosisand management of esophageal eosinophilia andeosinophilic esophagitis (EoE). Am J Gastroenterol2013;108:679–692; quiz 93.

27 Li-Kim-Moy JP, Tobias V, Day AS, et al. Esophagealsubepithelial fibrosis and hyalinization are features ofeosinophilic esophagitis. J Pediatr Gastroenterol Nutr2011;52:147–153.

28 Rodrigo S, Abboud G, Oh D, et al. High intraepithelialeosinophil counts in esophageal squamous epitheliumare not specific for eosinophilic esophagitis in adults.Am J Gastroenterol 2008;103:435–442.

29 Dellon ES, Speck O, Woodward K, et al. Clinical andendoscopic characteristics do not reliably differentiateppi-responsive esophageal eosinophilia and eosino-philic esophagitis in patients undergoing upper endo-scopy: a prospective cohort study. Am J Gastroenterol2013;108:1854–1860.

30 Furuta GT, Liacouras CA, Collins MH, et al. Eosino-philic esophagitis in children and adults: a systematicreview and consensus recommendations for diagnosisand treatment. Gastroenterology 2007;133:1342–1363.

31 Caruso RA, Giuffre G, Inferrera C. Minute and smallearly gastric carcinoma with special reference toeosinophil infiltration. Histol Histopathol 1993;8:155–166.

32 Baez-Vallecillo L, Stewart BD, Kott MM, et al. Stron-gyloides hyperinfection as a mimic of inflammatorybowel disease. Am J Gastroenterol 2013;108:622–623.

33 Cao J, Liu WJ, Xu XY, et al. Endoscopic findings andclinicopathologic characteristics of colonic schistoso-miasis: a report of 46 cases. World J Gastroenterol2010;16:723–727.

34 Qu Z, Kundu UR, Abadeer RA, et al. Strongyloidescolitis is a lethal mimic of ulcerative colitis: the keymorphologic differential diagnosis. Hum Pathol2009;40:572–577.

35 Pravettoni V, Primavesi L, Piantanida M. Anisakissimplex: current knowledge. Eur Ann Allergy ClinImmunol 2012;44:150–156.

36 Perez-Naranjo S, Venturini-Diaz M, Colas-Sanz C, et al.Intestinal anisakiasis mimicking intestinal obstruc-tion. Eur J Med Res 2003;8:135–136.

37 Liu L, Liang XY, He H, et al. Clinical featuresof eosinophilic gastroenteritis with ascites. Z Gastro-enterol 2013;51:638–642.

38 Geramizadeh B, Foroughi R, Keshtkar-Jahromi M, et al.Gastrointestinal basidiobolomycosis, an emerginginfection in the immunocompetent host: a report of14 patients. J Med Microbiol 2012;61:1770–1774.

39 Yousef OM, Smilack JD, Kerr DM, et al. Gastrointest-inal basidiobolomycosis. Morphologic findings in acluster of six cases. Am J Clin Pathol 1999;112:610–616.

40 Winter HS, Antonioli DA, Fukagawa N, et al. Allergy-related proctocolitis in infants: diagnostic usefulnessof rectal biopsy. Mod Pathol 1990;3:5–10.

41 Pagnoux C, Mahr A, Cohen P, et al. Presentation andoutcome of gastrointestinal involvement in systemicnecrotizing vasculitides: analysis of 62 patientswith polyarteritis nodosa, microscopic polyangiitis,Wegener granulomatosis, Churg-Strauss syndrome, orrheumatoid arthritis-associated vasculitis. Medicine(Baltimore) 2005;84:115–128.



RK Yantiss S21

Documents

Eosinophils in the GI tract: How many is too many and what ... · Eosinophils in the GI tract: How many is too many and what do they mean? Rhonda K Yantiss Pathology and Laboratory