Donald A. Antonioli

Prevalence of metaplasia at the gastro-oesophageal junction

Specialised columnar epithelium (SCE), a form of intestinal metaplasia usually found in Barretts oesophagus, cannot be distinguished endoscopically from normal gastric epithelium. Endoscopists seldom obtain biopsy specimens from a normal-appearing gastro-oesophageal junction, and therefore short segments of SCE in this region may go unrecognised. We studied patients who had short segments of SCE at the gastro-oesophageal junction. All patients scheduled for elective endoscopic examinations in our general endoscopy unit, irrespective of indication, were questioned for symptoms of gastro-oesophageal reflux disease. At endoscopy, severity of oesophagitis was graded, and biopsy specimens obtained from the squamocolumnar junction, irrespective of its appearance or location in the oesophagus. Among 142 patients without endoscopically apparent Barretts oesophagus, 26 (18%) were found to have SCE. All patients with SCE were white, and the male/female ratio was 1.9. In contrast, non-whites accounted for 14% of the 114 patients without SCE and the male/female ratio was 0.8. The groups did not differ significantly in the frequency of symptoms and endoscopic signs of gastrooesophageal reflux. We conclude that adults frequently have unrecognised segments of SCE at the gastro-oesophageal junction; this may underlie the rising frequency of cancer of the gastrooesophageal junction in the USA and Europe.

Differentiating ulcerative colitis from Crohn disease in children and young adults: report of a working group of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the Crohn's and Colitis Foundation of America.

Background: Studies of pediatric inflammatory bowel disease (IBD) have varied in the criteria used to classify patients as having Crohn disease (CD), ulcerative colitis (UC), or indeterminate colitis (IC). Patients undergoing an initial evaluation for IBD will often undergo a series of diagnostic tests, including barium upper gastrointestinal series with small bowel follow-through, abdominal CT, upper endoscopy, and colonoscopy with biopsies. Other tests performed less frequently include magnetic resonance imaging scans, serological testing, and capsule endoscopy. The large amount of clinical information obtained may make a physician uncertain as to whether to label a patient as having CD or UC. Nevertheless, to facilitate the conduct of epidemiological studies in children, to allow the entry of children into clinical trials, and to allow physicians to more clearly discuss diagnosis with their patients, it is important that clinicians be able to differentiate between CD and UC. Methods: A consensus conference regarding the diagnosis and classification of pediatric IBD was organized by the Crohns and Colitis Foundation of America. The meeting included 10 pediatric gastroenterologists and 4 pediatric pathologists. The primary aim was to determine the utility of endoscopy and histology in establishing the diagnosis of CD and UC. Each member of the group was assigned a topic for review. Topics evaluated included differentiating inflammatory bowel disease from acute self-limited colitis, endoscopic and histological features that allow differentiation between CD and UC, upper endoscopic features seen in both CD and UC, ileal inflammation and “backwash ileitis” in UC, patchiness and rectal sparing in pediatric IBD, periappendiceal inflammation in CD and UC, and definitions of IC. Results: Patients with UC may have histological features such as microscopic inflammation of the ileum, histological gastritis, periappendiceal inflammation, patchiness, and relative rectal sparing at the time of diagnosis. These findings should not prompt the clinician to change the diagnosis from UC to CD. Other endoscopic findings, such as macroscopic cobblestoning, segmental colitis, ileal stenosis and ulceration, perianal disease, and multiple granulomas in the small bowel or colon more strongly suggest a diagnosis of CD. An algorithm is provided to enable the clinician to differentiate more reliably between these 2 entities. Conclusions: The recommendations and algorithm presented here aim to assist the clinician in differentiating childhood UC from CD. We hope the recommendations in this report will reduce variability among practitioners in how they use the terms “ulcerative colitis,” “Crohn disease,” and “indeterminate colitis.” The authors hope that progress being made in genetic, serological, and imaging studies leads to more reliable phenotyping.

Eosinophils in the Esophagus—Peptic or Allergic Eosinophilic Esophagitis? Case Series of Three Patients with Esophageal Eosinophilia

OBJECTIVES:Scattered eosinophils in the distal esophagus traditionally provide the hallmark for peptic esophagitis, but the upper limit of eosinophils and the longitudinal extent of peptic inflammation along the esophagus are unknown. Recently, adults and children with upper intestinal symptoms and >20 eosinophils/high-power field (eos/HPF) have been given the diagnosis of allergic esophagitis. Standardized diagnostic criteria for allergic esophagitis are lacking and the isolated finding of large numbers of eosinophils in the squamous epithelium has been used as the defining feature. We cared for three patients with symptoms and endoscopic features of esophagitis with >20 eos/HPF in their esophageal mucosa. Symptoms, endoscopic features, and histologic findings resolved after 2 months of proton pump inhibitor (PPI) treatment. The aim of this case series is to demonstrate that features thought to be consistent with a diagnosis of allergic esophagitis are also observed in peptic esophagitis.METHODS:A retrospective chart review of three patients with esophagitis (>20 eos/HPF) whose symptoms and eosinophilia resolved with PPI treatment was performed. Esophageal biopsies were reviewed in a blinded manner by one pathologist.RESULTS:Patients (aged 14, 25, and 5 yr) presented with dysphagia, food impaction, and vomiting. Endoscopic features included white exudates and linear furrows. None of the patients received antiallergic treatments or dietary eliminations prior to endoscopy. Following treatment with PPIs alone, all patients became asymptomatic and endoscopic findings reverted to normal. In all three patients, pre- and post-PPI treatment eosinophil numbers/HPF decreased to normal/near normal (37 to 1, 21 to 3, and 52 to 0 eosinophils/HPF in patients 1, 2, and 3, respectively).CONCLUSION:Large numbers of eosinophils can be seen in peptic esophagitis. This histologic finding must be interpreted in the context of the clinical setting in which it is obtained.

Tumor necrosis factor-α, interleukin-1β, and interleukin-6 expression in inflammatory bowel disease

The etiology of ulcerative colitis (UC) and Crohns disease (CD) remains enigmatic. Infiltrating intestinal macrophages are capable of producing the proinflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6). We investigated the presence of IL-6, TNF-α and IL-1β mRNA transcripts in inflammatory bowel disease (IBD), normal, and other inflammatory intestinal specimens utilizing the polymerase chain reaction (PCR). TNF-α mRNA levels did not vary between inflammatory bowel disease and control specimens. IL-1β mRNA levels were highest in active UC and noninflammatory bowel disease inflammatory specimens while IL-6 mRNA levels were highest in active IBD specimens. Infiltrating T cells, macrophages, and B cells were identified as sources of IL-6 protein in inflammatory bowel disease specimens by immunofluorescent staining. IL-6 transcripts were elevated only in active inflammatory bowel disease specimens, suggesting that IL-6-mediated immune processes are ongoing in the inflammatory mucosal environment of CD and UC.

Allergic esophagitis in children: a clinicopathological entity.

Infiltration of esophageal epithelium by eosinophils is seen in reflux esophagitis and allergic gastroenteritis. This study was performed to identify differences between patients with acid reflux esophagitis and those with non-acid reflux, possibly allergic, esophagitis. Intraepithelial eosinophils were demonstrated in posttherapy esophageal biopsy specimens in 28 children treated for gastroesophageal reflux disease (GERD). These patients were divided into three groups based on their response to treatment and the results of esophageal pH probe monitoring. Eleven patients (Group A) had incomplete clinical response and normal pH probe monitoring results. Ten patients (Group B) had incomplete response but did not have pH probe monitoring. These two groups formed the index population. Seven patients (Group C) had clinical improvement with GERD therapy and abnormal pH probe monitoring characteristic of GERD; they constituted the control population. Clinical, laboratory, and pathologic features were evaluated to detect differences between index and control populations. Dysphagia, food impaction, failure to thrive, peripheral eosinophilia, and abnormal allergen skin test results were detected only in Group A and B patients. Biopsy specimens of the distal 9 cm of the esophagus, after GERD therapy, contained larger numbers of eosinophils in Groups A and B than in Group C as shown on high-power fields (HPF) (A: 31/HPF +/- 19.5; B: 28/HPF +/-23.7; versus C: 5/HPF +/-6.7; p = 0.009). Eosinophil aggregates were identified only in Groups A and B (p = 0.07). Eosinophils located preferentially in the superficial layers of the squamous epithelium were noted only in Groups A and B (p = 0.02). Group A and B patients demonstrated clinical improvement when given antiallergic therapy. The authors identified a group of pediatric patients characterized by an allergic history, lack of adequate response to GERD therapy, normal esophageal pH probe monitoring results, and large numbers of eosinophils in esophageal biopsy specimens obtained after GERD treatment. On the basis of these features, the authors propose that these patients represent examples of allergic esophagitis.

Phenotypic characteristics of a distinctive multilayered epithelium suggests that it is a precursor in the development of Barrett's esophagus.

A distinctive type of multilayered epithelium (ME) has been described at the neo-squamocolumnar junction and within columnar mucosa in patients with Barretts esophagus (BE). This epithelium has morphologic and ultrastructural features of both squamous and columnar epithelium. Multilayered epithelium may represent an early or intermediate stage of columnar metaplasia; therefore, we performed this study to determine the morphologic and biologic characteristics of this epithelium and to gain insight into its derivation. Esophageal mucosal biopsies containing ME from 17 patients with BE were evaluated morphologically, stained with a variety of mucin histochemical stains; and also immunostained with antibodies against cytokeratins (CK) 13 (squamous epithelium marker); 14 (basal squamous epithelium marker) 7, 8/18, 19, and 20 (columnar epithelium markers), MIB-1 (proliferation marker); villin (intestinal brush border protein); and TGF&agr;, EGFR, pS2, and hSP (enteric proliferation/differentiation regulatory peptides). The results were compared with normal esophageal squamous epithelium, normal gastric cardia epithelium, specialized-type intestinal epithelium (BE), and esophageal mucosal and submucosal gland duct epithelium. Multilayered epithelium expressed a pattern of mucin production (neutral mucin, sialomucin, and sulfomucin in 88%, 100%, and 71% of cases, respectively) and cytokeratin expression (CK 13 and 19 in the basal “squamoid” cells, CK 7, 8/18, 19, and 20 in the superficial “columnar” cells) similar to that of columnar epithelium in BE, and showed a high capacity for cellular proliferation (Ki-67-positive in 88% of cases) and differentiation (TGF&agr;, EGFR, pS2 and villin-positive in 100%, 100%, 93%, and 66% of cases, respectively). The mucosal gland duct epithelium showed a similar phenotypic pattern and, in one case, was seen to give rise to ME at the surface of the mucosa. These data provide evidence in support of the hypothesis that ME represents an early or intermediate stage in the development of esophageal columnar metaplasia (BE). The mucosal gland duct epithelium may contain progenitor cells that can give rise to ME.

Polypoid Dysplasia and Adenomas in Inflammatory Bowel Disease: A Clinical, Pathologic, and Follow-up Study of 89 Polyps From 59 Patients

Dysplasia in inflammatory bowel disease (IBD) is categorized as either flat or associated with a raised lesion or mass (dysplasia-associated lesion or mass [DALM]). One specific subtype of a dysplasia-associated lesion or mass consists of isolated discrete nodules or polyps that are difficult to distinguish from sporadic adenomas. Because the clinical management of these two lesions is different, we performed this study to (1) evaluate the clinical presentation, pathologic features, and natural history of polypoid dysplastic lesions and sporadic adenomas in patients with IBD and (2) determine whether there are clinical, endoscopic, or pathologic findings useful in differentiating between these two lesions. The morphologic features of 89 benign polypoid epithelial neoplasms from 59 patients with IBD (51 with ulcerative colitis, 8 with Crohns colitis) were evaluated and correlated with the clinical, endoscopic, and follow-up data. In a separate analysis, patients were categorized arbitrarily as having (1) a probable sporadic adenoma if the polypoid epithelial neoplasm was not located within areas of histologically proven colitis, (2) a probable IBD-associated polypoid dysplasia if the lesion developed within an area of colitis, and associated flat dysplasia or an adenocarcinoma was detected during follow-up evaluation or (3) an indeterminate polyp, which was seen in the remainder of the cases. The clinical, endoscopic, and histologic data were compared among these three patient and polyp subgroups. There were 35 males and 24 females (median age, 57 years; range, 27-85 years). Median duration of disease was 10 years. Forty-nine percent of the patients had pancolitis; 66% had histologically active disease at the time of presentation. Nearly 70% of patients had only one polyp; the majority occurred in either the left colon or the rectum (66%). Most polyps were described as a sessile nodule, whereas only 7 (7.8%) were pedunculated. Polyps ranged from 2 mm to 50 mm (median, 5 mm); most had a tubular architecture (84.3%) and contained low-grade dysplasia (64%). In addition, most polyps had mildly increased lamina propria and intraepithelial neutrophilic and mononuclear inflammation. At follow-up evaluation (40 patients; median follow-up time, 13 months; range, 1-78 months), a further neoplastic lesion developed in 20%; low-grade flat dysplasia was seen in 5 (12.5%), and adenocarcinoma developed in 3 (7.5%). However, dysplasia or adenocarcinoma did not develop in the patients who had polyps located outside of areas of histologically proven colitis. In addition, at least one more benign polypoid epithelial neoplasm developed in 15 of 40 patients (37.5%). Patients with probable IBD-associated polypoid dysplasia had a statistically significant (p < 0.05), longer disease duration than patients with probable sporadic adenoma. A statistically significant, higher proportion of polyps with tubullovillous or villous architecture, an admixture of normal and dysplastic epithelium at the surface of the polyps, and increased lamina propria mononuclear inflammation was noted in probable IBD-associated polypoid dysplastic lesions compared with those considered to be sporadic adenomas. Several clinical and pathologic features may be useful to help categorize a polypoid dysplastic lesion as a sporadic adenoma or an IBD-related neoplasm in a patient with IBD. This distinction is important because the natural history of these two lesions (as shown by the results of this study) and their subsequent management are quite different.

Changes in the location and type of gastric adenocarcinoma

To document our impression of major changes in aspects of gastric adenocarcinoma, we reviewed and compared 62 consecutive cases from 1975 through 1978 and 31 cases from 1938 through 1942. The average age at diagnosis increased from 58 to 68 years, the male to female ratio decreased to approximately 1:1, and carcinomas composed predominately (50% or more) of signet‐ring cells (SRC) increased from 9 to 39% of the total cases. In the recent series, carcinomas with SRC (compared with those without SRC) occurred nine years earlier, were more frequent in women, were located distally, and had an infiltrative growth pattern. Carcinomas originating in the proximal stomach (cardia) were not noted in the old series but formed 27% of the recent cases. These tumors showed a male predominance, contained SRC less often, and were less commonly associated with chronic gastritis. The implications of these observations are discussed.

Comparative features of esophageal and gastric adenocarcinomas: Recent changes in type and frequency

One hundred sixty consecutive cases of esophageal and gastric carcinoma were reviewed to evaluate the impression of recent changes in their types and characteristics. Esophageal adenocarcinomas accounted for 34 per cent of all esophageal cancers and 60 per cent of tumors confined to the lower third of the esophagus; all but one were associated with Barretts epithelium. Among the gastric cancers, previous observations of an increased prevalence of neoplasms confined to the cardia were extended. Proximal adenocarcinomas (arising from the esophagus, gastroesophageal junction, and cardia) constituted 34 per cent of all adenocarcinomas in this series and appeared to be a distinctive group with common features. Compared with other gastric cancers, the proximal carcinomas were associated with a lower mean age (65 years), higher male-to-female ratio (3.3:1), greater frequency of hiatal hernia (40 per cent), greater incidence of smoking and alcohol use, and lower prevalence of tumors composed predominantly of signet ring cells. Thus, proximal adenocarcinomas may form a specific category etiologically different from distal gastric cancers.

Intraepithelial eosinophils in endoscopic biopsies of adults with reflux esophagitis.

A consecutive series of 50 adult patients was reviewed to evaluate the utility of endoscopic grasp biopsies of the esophagus in the diagnosis of reflux esophagitis. Endoscopic and histologic features were independently recorded and correlated. Measurements of basal zone thickness, papillary height, and vascular dilatation were possible in only 14% of the cases because of limited specimen orientation. However, 62% of the patients had other histologic features of esophagitis, including intraepithelial eosinophils, intraepithelial neutrophils, and epithelial necrosis. Intraepithelial eosinophils were the most frequent abnormality; they were noted in 52% of the cases and correlated best with the gross endoscopic features. Eosinophils were easily identified even in the poorly oriented grasp biopsies and were the only histologic finding in seven patients (23% of the abnormal cases). Thus, we conclude that esophageal grasp biopsies taken at the time of endoscopy are of value in the assessment of patients with suspected reflux esophagitis, and intraepithelial eosinophils are the most common and useful histologic criterion. This feature was previously observed in children and occurs as well in adults with reflux esophagitis.