—  SHORT COURSE #22  —

Diagnostic Problems in GI Pathology

Case 3 - Eosinophilic Disorders of the Gastrointestinal Tract

Lisa Yerian, John Hart and Amy Noffsinger


Introduction
The diagnosis of gastrointestinal diseases characterized by an increased number of eosinophils is challenging for several reasons: 1) the eosinophilic infiltrates are often quite patchy, making sampling error an important consideration; 2) eosinophils may infiltrate any bowel layer, and thus may be missed in mucosal biopsy specimens; 3) the normal range for eosinophil density in various parts of G.I. tract have not been well established; and 4) some of the disease states are poorly defined and have overlapping histologic features.

Recognition of eosinophils is usually not an issue for surgical pathologists, although degranulated forms may be overlooked. The appearance of eosinophils does vary somewhat depending on the fixative used – for instance, in Hollande's fixative eosinophils are relatively inconspicuous.

Eosinophil Density in Healthy Individuals
Several studies have quantitated eosinophil number in the rectal mucosa of normal infants that had undergone suction biopsy to rule out Hirschsprung's disease. In all of the studies there were a mean of less than 10 eosinophils /hpf. However, single fields with greater than 20 eosinophils were not uncommon. In an autopsy study of 44 children who died from accidents the mean and median number of eosinophils in the colonic mucosa was 17/hpf and 14/hpf respectively, with 28% of cases having more than 20/hpf. In a more detailed study of 11 of these autopsies the mean number of eosinophils was found to vary in different parts of the colon (35/hpf in the cecum, 20/hpf in the ascending colon, 17/hpf in the transverse colon, 15/hpf in the descending colon, and 10/hpf in the sigmoid and rectum). The number of eosinophils in the colonic mucosa of adults has not been well studied, but appears to be about the same as children. However, there does appear to be significant differences based on geographic location (significantly greater density in New Orleans compared to Boston). It is not uncommon to see individual eosinophils within crypt epithelium of scattered crypts in healthy individuals of any age.

The number of eosinophils normally present in the mucosa of other parts of the G.I. tract has been less well documented. One autopsy study indicates that eosinophils are quite rare in the gastric mucosa (less than 5/hpf), but are more numerous in the small bowel (15-20/hpf).

Eosinophilic Esophagitis

Clinical Features
In the past intramucosal eosinophils were regarded as a nearly pathognomic indicator of gastroesophageal reflux disease. Recently it was recognized that large numbers of intramucosal eosinophils and basal cell hyperplasia were sometimes present in biopsies from patients with dysphagia (rather than heartburn). The esophagus in such patients often exhibited a characteristic endoscopic appearance, different than that seen with reflux, characterized by a wrinkled or thickened mucosa, sometimes with circumferential rings, linear furrows, or tiny vesicles. Unlike patients with reflux, patients with so-called "eosinophilic esophagitis" often had a history of food allergy/asthma/atopy, and prior food bolus obstruction. Vomiting occurs with equal frequency in patients with eosinophilic esophagitis and reflux. Although this disorder has only recently recognized, retrospective studies have shown that in the past cases were mis-diagnosed as severe reflux esophagitis. Treatment with steroids or an elimination diet is usually effective, but esophageal stricture can develop in refractory cases. The available data suggest that at least in children, eosinophilic esophagitis is usually a manifestation of a food allergy. Whether eosinophilic esophagitis should be classified as the esophageal form of eosinophilic gastroenteritis is a matter of semantics.

Histologic Features
Biopsies of the esophagus typically revealed a heavy infiltrate of eosinophils, including clusters of eosinophils (microabscesses), often near the surface. Basal cell hyperplasia is usually prominent. A cut-off of 24 eosinophils/hpf has been suggested as useful in distinguishing between eosinophilic esophagitis and reflux esophagitis, but formal counts are not necessary in daily practice. In most cases of reflux esophagitis the density of intramucosal eosinophils is less than 7/hpf. The presence of changes that are equally severe in biopsies from the mid-esophagus and distal esophagus is a useful finding in making the diagnosis of eosinophilic esophagitis (since reflux changes are typically more severe distally than more proximally). However, in some cases it is not possible to make a firm histologic distinction between eosinophilic esophagitis and severe reflux esophagitis. Correlation with the clinical history (dysphagia versus heartburn) and the endoscopic appearance is often sufficient to arrive at the proper diagnosis, but 24 hour pH monitoring may be necessary in a few patients.

Eosinophilic Gastroenteritis

Clinical Features
This diagnosis is appropriate when no cause can be identified for a pathologic accumulation of eosinophils within the stomach, small bowel, or colon. A work-up must be performed to exclude parasitic infection, vasculitis, connective tissue disease, inflammatory bowel disease, drug reaction, or myeloproliferative disorder. In Australia many cases of presumed idiopathic eosinophilic enteritis actually were shown to be due to infestation by the canine hookworm (Ancylostoma caninum). Trichinella, Ascaris, Trichuris, and Schistosoma species have also been documented to cause marked intestinal tissue eosinophilia. The presenting symptoms depend on the portion of the G.I. tract and the bowel layers that are infiltrated by eosinophils. In general, mucosal infiltration results in diarrhea, while infiltration of the submucosa and/or muscularis propria produces obstruction and/or pain. Serosal infiltration can cause peritonitis-like symptoms and ascites. Gastric involvement may lead to nausea and vomiting or gastric outlet obstruction. Small bowel disease can produce malabsorption, protein losing enteropathy, occult blood loss, and weight loss. Colonic involvement most often results in diarrhea. Peripheral blood eosinophilia occurs in less than 50% of patients, and is typically mild. Patients may or may not have a past history of asthma, atopy or eczema.

Histologic Features
The histologic diagnosis of eosinophilic gastroenteritis can be quite difficult. The infiltrate of eosinophils may involve deep bowel layers not sampled in an endoscopic biopsy. In such patients laparoscopic full thickness biopsy is necessary. The presence of even an occasional eosinophil in the muscularis propria or subserosal tissues (in the absence of other findings) is quite rare, and eosinophilic gastroenteritis is the leading diagnostic consideration in such cases.

In mucosal disease the eosinophilic infiltrates can be quite patchy, thus requiring numerous biopsies to exclude the diagnosis. Since there is a wide variation in the normal density of mucosal eosinophils the presence of epithelial destruction by eosinophils (not simply infiltration of single eosinophils) or infiltration of the muscularis mucosae are very helpful in establishing a firm diagnosis.

As noted above, eosinophils are very uncommon in gastric mucosa. In H. pylori gastritis scattered eosinophils are seen, but are never a prominent component of the inflammatory cell infiltrate. NSAID gastritis is very common, typically in the form of focal erosions within otherwise normal mucosa. In some cases a diffuse reactive pattern is seen instead, with foveolar hyperplasia and marked mucin depletion, but notably little inflammation. In either pattern eosinophils are not prominent. Crohn's gastritis is characterized by strikingly focal inflammatory cell infiltrates (usually a mixture of lymphocytes and neutrophils) with inflammatory destruction of glandular or foveolar epithelium. Eosinophils may be admixed but are not prominent. Eosinophilic infiltrates are usually very prominent in cases of gastric involvement by Schistosomiasis, which occurs in patients with latent infection who become immunocompromised. The larval form of the organism is easily identified in the H&E stained section, as it is quite large and has refractile borders. Foreign bodies embedded in the gastric mucosa may also elicit strong eosinophilic reactions.

Gastric involvement by eosinophilic gastroenteritis can be diagnosed only when all of the above conditions have been ruled out. The diagnosis requires the presence of numerous eosinophils in the lamina propria, but an exact number has never been established. The presence of epithelial destruction by eosinophils and/or infiltration by eosinophils into the muscularis mucosa allows much greater confidence in the diagnosis. In the absence of these two features lamina propria infiltration by eosinophils would need to be at least focally massive (sheet-like) in order to make the diagnosis.

There are numerous causes of eosinophilic infiltration of the small bowel mucosa. In celiac disease eosinophils are often a prominent component of the lamina propria inflammatory cell population. Heavy eosinophil infiltrates are typically present in drug-induced enteritis, and this possibility must be excluded in every patient before a diagnosis of eosinophilic enteritis is made. Drugs that have been reported to cause eosinophilic enteritis include: trimethoprim-sulfonamide, L-tryptophan, gemfibrozil, carbamazepine, and enalapril. Parasitic infection must be ruled out by stool ova and parasite tests, since the organisms are sometimes not evident in tissue sections. Because lamina propria eosinophils can be numerous in the small bowel mucosa of healthy individuals, the diagnosis of eosinophilic enteritis should not be considered unless sheets of eosinophils are evident, or foci of epithelial destruction or muscularis mucosae infiltration are evident. There may be mild villous blunting in areas of massive eosinophilic infiltration, but overall villous architecture is usually well maintained. If villous architectural distortion is prominent the possibility of Crohn's disease should be considered clinically.

A diagnosis of idiopathic eosinophilic gastroenteritis involving the colon is not possible until several other possibilities have been excluded. Eosinophilic infiltration of the colonic mucosa is typical in inflammatory bowel disease (ulcerative colitis and Crohn's colitis), but the crypt architectural distortion seen in IBD does not occur in eosinophilic colitis. Parasitic infection and drug toxicity (especially NSAIDs) must be excluded on clinical grounds. Again, since the density of eosinophils in healthy individuals varies greatly, it is difficult to determine a numerical cut-off value diagnostic of a disease state. Destruction of crypt or surface epithelium or infiltration of the muscularis mucosae by eosinophils strongly suggests a pathologic condition. In the absence of these features eosinophils must be at least focally present in sheets in the lamina propria.

Allergic Gastroenteritis and Colitis

Clinical features
Intolerance to peptides from cow's milk or soy milk proteins is not uncommon among bottle fed infants. The presenting signs and symptoms include rectal bleeding, diarrhea, failure of gain weight, and vomiting. In severe cases metabolic acidosis may develop due to severe diarrhea and electrolyte loss. In children more than two years old constipation is the most common symptom. In many patients a presumptive diagnosis is made and the infant is switched to a soy based formula or hydrolase formula. Occasionally colonoscopic biopsies are obtained. This disorder can rarely occur in breast fed infants, due to the passage of peptides from the mother's diet into the breast milk. Other dietary proteins (from cereals, vegetables, poultry meats) have been implicated as well, but usually the patient also reacts to cow's or soy milk proteins as well. The peripheral blood eosinophil count is elevated in about 50% of cases, and the serum IgE level may also be increased. Most patients spontaneously lose intolerance to the protein as they age.

Histologic Features
Any portion of the G.I. tract may be involved. Sigmoidoscopic biopsies are easiest to obtain in infants and are the most common specimens seen by surgical pathologists. Normal crypt architecture is well preserved in all cases. The inflammatory infiltrates are usually eosinophil predominant, always distinctly patchy, and sometimes also include neutrophilic infiltrates. In fact, some of the biopsies from a given case may be entirely normal. More than 60 eosinophils/10 hpf has been used as a diagnostic cut-off for colonic biopsies, while other have suggested 20 eosinophils/hpf. However, most biopsies (from any site) also exhibit focal eosinophilic cryptitis and/or infiltration of the muscularis mucosae, and these features are useful to make a firm diagnosis. It must be emphasized that increased eosinophils are not present in every case, and the presence of a neutrophilic predominant colitis is also consistent with the diagnosis of allergic colitis. However, in that situation infectious colitis and Hirschsprung's disease associated colitis must also be ruled out clinically.

NSAID Colitis

Clinical Features
NSAID induced injury can occur anywhere in the G.I. tract, and with the increased use of "enteric-coated" preparations lower G.I. tract involvement is becoming increasing common. Most often NSAID medications produce focal erosions or ulcers. The formation of intestinal webs has also been described. Less commonly NSAIDs can induce a colitis, which manifests as diarrhea, sometimes with blood. It can involve any portion of the colon, and is usually patchy. In patients with diverticular disease the colitis may be limited to the diverticular segment.

Histologic Features
Biopsy specimens may exhibit a variety of inflammatory changes, but crypt architecture is well preserved. There may be a neutrophil or eosinophil predominant infiltrate, with or without foci of cryptitis and crypt abscesses. In some cases there may be prominent epithelial cell apoptosis and withering of scattered crypts. Patchy thickening of the subepithelial collagen layer is not uncommon. Confusion with collagenous colitis is avoided since the diarrhea is not chronic, the endoscopic appearance of the colonic mucosa is abnormal, and there is no intraepithelial lymphocytosis. The presence of neutrophils admixed with the eosinophils, epithelial cell apoptosis and crypt withering, and thickening of the subepithelial collagen layer suggest NSAID colitis rather than eosinophilic colitis.

Inflammatory Bowel Disease
Eosinophils are often a conspicuous component of the inflammatory cell infiltrates in biopsies from patients with either ulcerative colitis or Crohn's disease. For unknown reasons eosinophil infiltration may be a striking feature on rare occasions, with prominent eosinophilic crypt abscesses. While the possibility of a superimposed drug toxicity (e.g., NSAID or sulfasalazine) or parasitic infection must always be kept in mind, in most cases a second intestinal insult is never identified. The presence of crypt architectural distortion prevents any confusion with eosinophilic gastroenteritis. The published data regarding the prognostic impact of heavy eosinophilic infiltrates in patients with IBD is conflicting.

Hypereosinophilic Syndrome (HES)
The diagnosis of HES requires the following: 1) peripheral blood eosinophil count > 1,500/ul for more than six consecutive months; 2) negative exhaustive work-up for other known causes of hypereosinophilia; 3) evidence or organ damage and dysfunction due to infiltration by eosinophils.

The organs most often damaged in HES include the heart, lungs skin, and CNS. Involvement of the G.I. tract can cause confusion with eosinophilic gastroenteritis. HES is a much more severe disorder than eosinophilic gastroenteritis, with eosinophil infiltration of multiple organs and a tendency for a much high peripheral blood eosinophil count. There are a number of leukemias, myeloproliferative disorders, and myelodysplastic disorders in which massive peripheral blood and tissue eosinophilia develop, and these diseases must be ruled out before a diagnosis of HES is made. Recently a subgroup of patients with HES was identified to have an abnormal T-cell population that secretes IL-5 and may be responsible for eosinophil proliferation.

References

General
  1. Lowichik A, Weinberg AG. A quantitative evaluation of mucosal eosinophils in the pediatric gastrointestinal tract. Mod Pathol 1996; 9:110-14.

  2. Pascal RR et al. Geographic variations in eosinophil concentration in normal colonic mucosa. Mod Pathol 1997; 363-5.

  3. AGA Medical position statement: Guidelines for the evaluation of food allergies. Gastroenterology 2001; 120:1023-5.

  4. AGA Technical review: Evaluation of food allergy in gastrointestinal disorders. Gastroenterology 2001; 120:1026-40.

Eosinophilic Esophagitis
  1. Walsh SV et al. Allergic esophagitis in children: a clinicopathologic entity. Am J Surg Pathol 1999; 23:390-6.

  2. Straumann A et al. Natural history of primary eosinophilic esophagitis: a follow-up of 30 adult patients for up to 11.5 years. Gastroenterology 2003; 125:1660-9.

  3. Cheung KM et al. Esophageal eosinophilia in children with dysphasia. J Pediatr Gastroenterol Nutr 2003; 37:498-503

  4. De CarpiJM, Varea V. Eosinophilic oesophagitis as part of disseminated eosinophilic gastroenteritis. Dig Dis Sci 2006; 38:283-6.

Eosinophilic Gastroenteritis
  1. Klein NC et al. Eosinophilic gastroenteritis. Medicine 1970; 49:299-319.

  2. Naylor AR et al. Eosinophilic colitis. Dis Colon Rectum 1985; 28:615-8.

  3. Talley NJ et al. Eosinophilic gastroenteritis: a clinicopathological study of patients with disease of the mucosa, muscle layer, and subserosal tissues. Gut 1990; 31:54-8.

  4. Moore D et al. Eosinophilic gastroenteritis presenting in an adolescent with isolated colonic involvement. Gut 1986; 27:1219-22.

  5. Clouse RE et al. Pericrypt eosinophilic enterocolitis and chronic diarrhea. Gastroenterology 1992; 103:168-76.

  6. Lee CM et al. Eosinophilic gastroenteritis: 10 years experience. Amer J Gastroenterol 1993; 88:70-4.

  7. Rothenberg ME. Eosinophilic gastrointestinal disorders. J Allergy Clin Immunol 2004; 113:11-28.

  8. Khan S. Eosinophilic gastroenteritis. Best Pract Clin Gastroenterol 2005; 19:177-98.

Allergic Gastroenteritis and Colitis
  1. Goldman H, Proujansky R. Allergic proctitis and gastroenteritis in children. Am J Surg Pathol 1986; 10:75-86.

  2. Winter HS et al. Allergy-related proctocolitis in infants: diagnostic usefulness of rectal biopsy. Mod Pathol 1990; 3:5-10.

  3. Odze RD et al. Allergic proctocolitis in infants: a prospective clinicopathologic biopsy study. Hum Pathol 1993; 24:668-74.

  4. Machida HM et al. Allergic colitis in infancy: clinical and pathologic aspects. J Pediatr Gastroenterol Nutr 1994; 19:22-6.

  5. Iacono G et al. Intolerance of cow's mild and chronic constipation in children. N Eng J Med 1998; 339:1100-4.

  6. Chang JW et al. Colon mucosal pathology in infants under three months of age with diarrhea disorders. J Pediatr Gastroenteerol Nutr 2002; 35:386-90.

  7. Nowak-Wegrzyn A et al. Food protein-induced enterocolitis syndrome caused by solid food proteins. Pediatrics 2003; 111:829-35.

  8. Pensabene L et al. Evaluation of mucosal eosinophils in the pediatric colon. Dig Dis Sci

  9. Xanthakos SA et al. Prevalance and outcome of allergic colitis in healthy infants with rectal bleeding: a prospective cohort study. J Padiatr Gastroenterol Nutr 2005; 41:16-22.

NSAID Colitis
  1. Gibson GR et al. Colitis induced by nonsteroidal anti-inflammatory drugs: report of four cases and review of the literature. Arch Int med 1992; 152:625-32.

  2. Bjarnason I et al. Side effects of nonsteroidal anti-inflammatory drugs on the small and large intestine in humans. Gastroenterology 1993; 104;1832-47.

  3. Davies NM . Toxicity of non-steroidal anti-inflammatory drugs in the large intestine. Dis Colon Rectum 1995; 38:1311-21.

  4. Goldstein NS , Cinenza AN. The histopathology of nonsteroidal anti-inflammatory drug-associated colitis. Am J Clin Pathol 1998; 110:622-8.

  5. Puspok A et al. Clinical, endoscopic, and histologic spectrum of nonsteroidal anti-inflammatory drug-induced lesions in the colon. Dis Colon Rectum 2000; 43:685-91.

  6. Katsinelos P et al. Colopathy associated with the systemic use of nonsteroidal anti-inflammatory medications. Hepato-gastroentrol 2002; 49:345-8.

  7. Price AB. Pathology of drug-associated gastrointestinal disease. Br J Clin Pharmacol 2003; 56;477-82.

  8. Jimenez-Saenz M et al. Bleeding colonic ulcer and eosinophilic colitis: a rare comp-lication of non-steroidal anti-inflammatory drugs. J Clin Gastroenterol 2006; 40:84-5.

Hypereosinophilic Syndrome
  1. Roufosse F et al. The hypereosinophilic syndrome revisited. Annu Rev Med 2003; 54:169-84.

  2. Brito-Babapulle F. The eosinophilias, including the idiopathic hypereosinophilic syndrome. Br J Hematol 2003; 121:203-23.

  3. Scheurlen M et al. Hypereosinophilic syndrome resembling chronic inflammatory bowel disease with primary sclerosing cholangitis. J Clin Gastroenterol 1992; 14:59-63.

  4. Schoonbroodt D et al. Eosinophilic gastroenteritis presenting with colitis and cholangitis. Dig Dis Sci 1995; 40:308-14.