Pernicious anemia and widespread absence of gastrointestinal endocrine cells in a patient with autoimmune polyglandular syndrome type I and malabsorption.

CONTEXT: Autoimmune polyglandular syndrome type I (APS I) is characterized by multiple endocrine gland failures, with other manifestations such as gastrointestinal (GI) symptoms. OBJECTIVE: The objective of the study was to study the histopathological and immunological findings in the GI mucosa of a patient with typical features of APS I, malabsorption, and pernicious anemia. DESIGN AND PATIENT: Biopsies from the GI tract of a patient with APS I were immunostained with chromogranin for GI endocrine cells (GIECs). Blinded slides were graded for numbers of endocrine cells. Normal gastric mucosa was exposed to the patient's serum to test for circulating anti-GIEC and antiparietal cell antibodies using indirect immunofluorescence. SETTING: The study was conducted at the Departments of Pediatrics and Medical Gastroenterology in an academic medical center. RESULTS: The patient's GI mucosa demonstrated absence of GIECs throughout, including gastric gastrin-secreting cells, and her laboratory tests for serum gastrin levels were low normal. Both GIECs and parietal cells were absent in her gastric corpus. The patient's serum contained anti-GIEC antibody but no antiparietal cell antibody. CONCLUSIONS: These observations suggest that GIECs in APS I are subject to an autoimmune destruction that can cause widespread GIEC loss. This could explain the GI dysfunctions that are often noted in the syndrome including malabsorption and atrophic gastric changes with pernicious anemia. We also hypothesize that absence of gastric parietal cells may result mainly from hypogastrinemia that is mainly the loss of gastrin-secreting cells rather than from immune-mediated destruction of parietal cells like that seen in the atrophic gastritis associated with adult-onset pernicious anemia.

Gastric polyps in pediatrics: an 18-year hospital-based analysis.

OBJECTIVE: Gastric polyps are recognized as either an incidental finding on routine gastroscopy or a frequent occurrence in patients with polyposis syndromes. The aim of this study is to determine the prevalence, clinical presentation, and histological subclassification of gastric polyps identified on esophagogastroduodenoscopy in pediatric patients. METHODS: We performed an 18-yr retrospective study of all pediatric (<21 yr) patients with gastric polyps diagnosed between 1983 and 2000 at The Johns Hopkins Children's Center. The histology slides were all evaluated at the time of the study according to the accepted histological classification of gastric polyps. RESULTS: Gastric polyps were reported in 40 procedures (0.7%) [corrected] performed in 35 (male:female 1.3:1) patients with a mean (SEM) age at diagnosis of 14.4 (0.9) yr. Polyps were more frequent in white than in black patients (adjusted ratio 1.4:1). The histological subtypes included hyperplastic-inflammatory (42%), fundic gland (40%), hamartomatous (10%), adenomatous (5%), and heterotopic polyps (3%). Fundic gland polyps were frequently encountered in patients with familial adenomatous polyposis (81%). These patients tended to be asymptomatic at the time of their surveillance esophagogastroduodenoscopy, and frequently harbored histological changes of either dysplasia (31%) or indeterminate of dysplasia (19%). CONCLUSIONS: Hyperplastic polyps are the most frequently identified gastric polyps in our pediatric population. Fundic gland polyps are common in patients with familial adenomatous polyposis wherein they tend to harbor histological changes of dysplasia. Future longitudinal studies are needed to evaluate the temporal progression of dysplasia to gastric cancer in patients with fundic gland polyps, and to establish esophagogastroduodenoscopy surveillance guidelines.

Hyperplastic polyps of the esophagus and esophagogastric junction: histologic and clinicopathologic findings.

Hyperplastic polyps of the esophagus and esophagogastric junction region (EGJ) are uncommon lesions characterized by hyperplastic epithelium (foveolar-type, squamous, or both) with variable amounts of inflamed stroma. They have been reported almost exclusively in the radiologic and clinical literature as occurring predominantly in association with gastroesophageal reflux disease (GERD). Comprehensive histologic and clinicopathologic evaluation of these polyps, their association with background mucosal pathology, and their association with Barrett's esophagus has not been previously performed. We studied 30 hyperplastic polyps from 27 patients and characterized the histologic, endoscopic, and clinical features of both the polyps and the background esophagus. Hyperplastic polyps were most common in the region of the EGJ (67%), followed by the distal esophagus (30%) and mid-esophagus (3%). Most (80%) were composed of predominantly cardiac-type mucosa, predominantly squamous mucosa (17%), or an admixture (3%). Intestinal metaplasia of the polyp was present in only 7% and low-grade dysplasia in only 3%. In the majority of cases (67%) hyperplastic polyps were associated with concurrent or recent ulcers or erosive esophagitis. In most cases (48%) esophageal injury was associated with GERD, but other potential etiologies included medications, infection, anastomotic or polypectomy sites, vomiting, and photodynamic therapy. Four patients (15%) had Barrett's esophagus, three of whom had or developed dysplastic Barrett's mucosa. These results underscore the pathogenesis of esophageal/EGJ region hyperplastic polyps as a mucosal regenerative response to surrounding mucosal injury. Careful clinical history and biopsy of the nonpolypoid mucosa are essential for determining the clinicopathologic context in which the polyps have developed.

Colchicine toxicity: distinct morphologic findings in gastrointestinal biopsies.

Colchicine is an alkaloid with antimitotic ability used to treat a variety of medical conditions. Colchicine toxicity can result in multiorgan failure and death. The histopathologic features of colchicine toxicity in gastrointestinal biopsies have not been reported. Twenty-one gastrointestinal mucosal biopsies obtained from nine patients receiving oral colchicine therapy were studied. Immunohistochemical staining for Ki67 proliferation antigen was performed, and medical records of each patient were reviewed. All patients had a history of gout. Four patients with chronic renal failure also had clinical evidence of colchicine toxicity, and the other five patients did not. Distinct morphologic changes, seen as metaphase mitoses, epithelial pseudostratification, and loss of polarity, were seen in biopsy material from 4 of 4 (100%) patients with clinical colchicine toxicity. Three of these four cases (75%) also contained abundant crypt apoptotic bodies. These morphologic features were best seen in the biopsies from duodenum and gastric antrum, with relative sparing of the gastric body in the upper gastrointestinal tract. Ki67 staining demonstrated an expansion of the proliferating region in three available cases with clinical colchicine toxicity. These distinctive morphologic features were not seen in the five patients without clinical colchicine toxicity. These results indicate that colchicine toxicity can produce diagnostic morphologic features in gastrointestinal mucosal biopsies. Recognition of these features is important because colchicine toxicity can be fatal if undiagnosed clinically.

Hyperplastic polyps of the stomach: associations with histologic patterns of gastritis and gastric atrophy.

Hyperplastic polyps are common gastric lesions characterized by hyperplastic foveolae with variable amounts of inflamed stroma. Their pathogenesis is unknown, but they have been reported to occur in association with various forms of chronic gastritis, particularly autoimmune gastritis and Helicobacter pylori gastritis. Comprehensive histologic evaluation of the background mucosal pathology in patients with hyperplastic polyps has not been previously performed. We studied 160 patients with gastric hyperplastic polyps and characterized endoscopic and histologic features of the polyps (i.e., location, multiplicity, and presence of dysplasia and adenocarcinoma) and the background gastric mucosa (i.e., intestinal metaplasia, dysplasia, carcinoma, and presence and classification of gastritis). Hyperplastic polyps were most common in the antrum (60%) and were multiple in 20% of patients. Focal intestinal metaplasia of the polyp was present in 16% and dysplasia in 4% of patients. Only one patient (0.6%) had adenocarcinoma within the polyp. Evaluation of the surrounding gastric mucosa showed at least focal intestinal metaplasia in 37% of patients, adenoma or low-grade flat epithelial dysplasia in 2%, and synchronous or metachronous adenocarcinoma in 6%. Eighty-five percent of patients had inflammatory mucosal pathology, most commonly active chronic H. pylori gastritis (25%), reactive or chemical gastropathy (21%), and metaplastic atrophic gastritis of the autoimmune (12%) or environmental (8%) type. These results indicate a strong association between various forms of gastritis and the development of hyperplastic polyps and further emphasize the importance of biopsy of the nonpolypoid gastric mucosa during endoscopic examination.

Esophageal lichen planus: case report and review of the literature.

Involvement of the esophagus by lichen planus is a rarely reported condition. The histologic features of esophageal lichen planus, which may differ from those of cutaneous disease, have only rarely been illustrated. We describe a 58-year-old woman with skin and oral lichen planus who presented with dysphagia and an esophageal stricture that were ultimately diagnosed as esophageal lichen planus. Multiple esophageal biopsies demonstrated a lichenoid, T cell-rich lymphocytic infiltrate, along with degeneration of the basal epithelium and Civatte bodies. Correct diagnosis of esophageal lichen planus is critical because of its prognostic and therapeutic distinction from other more common causes of esophagitis and stricture formation.

Erosive injury to the upper gastrointestinal tract in patients receiving iron medication: an underrecognized entity.

Severe gastrointestinal necrosis and strictures after an iron overdose are well described. However, mucosal injury in patients receiving therapeutic iron has received only scant recognition despite its wide use. We studied the clinical and histologic features of 36 upper gastrointestinal tract biopsies from 33 patients (24 gastric, 9 esophageal, 1 gastroesophageal junction, and 2 duodenal) containing characteristic brown crystalline iron material, and evaluated the amount and tissue distribution of the iron. In addition, we investigated the prevalence of iron-associated mucosal injury in upper gastrointestinal endoscopic examinations. The majority of the biopsies (32 of 36, 89%) contained luminal crystalline iron adjacent to the surface epithelium or admixed with luminal fibrinoinflammatory exudate. Thirty biopsies (83%) showed crystalline iron deposition in the lamina propria, either covered by an intact epithelium, subjacent to small superficial erosions, or admixed with granulation tissue. Three biopsies (8%) demonstrated iron-containing thrombi in mucosal blood vessels. Erosive or ulcerative mucosal injury was present in 30 of 36 biopsies (83%). The amount of iron accumulation in cases with mucosal injury was greater than in cases without mucosal injury (mean grades, 2.4+ vs. 1.3+ on a 1+ to 3+ scale; p = 0.002). Iron medication was confirmed in 25 of 33 patients (76%) 22 patients were receiving ferrous sulfate. Approximately half of the patients (17 of 33, 51%) also had underlying infectious, mechanical, toxic, or systemic medical conditions that could have initiated or exacerbated tissue injury. Crystalline iron deposition was found in 0.9% of upper gastrointestinal endoscopic examinations (12 of 1,300), and iron medication-associated erosive mucosal injury was present in 0.7% (9 of 1,300). These results indicate that crystalline iron deposition in the upper gastrointestinal tract is not uncommon. It can induce or exacerbate a distinctive histologic pattern of erosive mucosal injury, especially in patients with associated upper gastrointestinal disorders. Recognition of this pattern by pathologists and its communication to clinicians may aid in optimizing therapy.

Alendronate-associated esophageal injury: pathologic and endoscopic features.

Ingestion of alendronate sodium (Fosamax) by osteoporotic patients can be associated with esophagitis and esophageal ulcer. Alendronate can damage the esophagus both by toxicity from the medication itself and by nonspecific irritation secondary to contact between the pill and the esophageal mucosa, similar to other cases of "pill esophagitis." Despite its wide use, the histologic appearances of alendronate-associated esophageal ulceration have not been previously described in detail, nor is this type of medication-induced injury commonly appreciated by pathologists when evaluating biopsies from ulcer sites. We report a series of 10 patients who experienced erosive/ulcerative esophagitis while ingesting alendronate, and describe the associated endoscopic and pathologic features. Biopsies from all patients showed inflammatory exudate and inflamed granulation tissue as characteristic of any ulcer site. Polarizable crystalline foreign material was present in six of 10 biopsies (60%). Multinucleated giant cells within the inflammatory exudate were present near this crystalline foreign material in three of 10 biopsies (30%). Adjacent squamous epithelium typically showed active inflammation and a reactive appearance with enlarged, hyperchromatic nuclei. Multinucleated squamous epithelial giant cells were present in two of 10 cases (20%). Microorganisms were unusual; scattered fungi and/or viral inclusions were present in only two of 10 biopsies (20%). Recognition of alendronate-associated erosive or ulcerative esophagitis, particularly in postmenopausal women, and communication of this possibility to the clinician can improve patient care.

Dysplasia and dysregulation of proliferation in foveolar and surface epithelia of fundic gland polyps from patients with familial adenomatous polyposis.

Fundic gland polyps (FGPs) of the stomach are regarded as hamartomatous or hyperplastic/functional polyps that occur sporadically but at increased frequency in patients with familial adenomatous polyposis syndrome (FAP). There is controversy about the histopathology of FGPs, including occurrence of dysplasia. We, therefore, studied dysplasia in 270 sporadic FGPs from 216 patients and 49 FGPs from 24 patients with FAP. We evaluated dysregulation of epithelial proliferation manifested by loss of the normal inverse topographic distribution of Ki-67 proliferation marker and the cyclin-dependent kinase inhibitor p21(WAF1/CIP1) using immunohistochemistry in 27 sporadic FGPs and in 22 FGPs from patients with FAP. Dysplasia in foveolar and surface epithelia occurred in 12 of 49 (25%) FGPs in patients with FAP but in only 3 of 270 (1%) of sporadic FGPs (p < 0.000001). Fourteen of 49 (29%) of FGPs from patients with FAP were indefinite for dysplasia, as contrasted with 8 of 270 (3%) sporadic FGPs (p < 0.00001). The normal inverse topographic distribution of Ki-67 and p21(WAF1/CIP1) was maintained in 20 of 22 (91%) of FGPs negative for dysplasia but was lost in all (8 of 8) FGPs with dysplasia and in 11 of 19 (58%) FGPs that were indefinite for dysplasia (p = 0.00001). The results indicate that dysplasia can occur in foveolar and surface epithelia of FGPs, especially in patients with FAP, and often is preceded by dysregulation of epithelial proliferation when the morphologic abnormalities are indefinite for dysplasia.

Histological classification of gastritis and Helicobacter pylori infection: an agreement at last? The International Workshop on the Histopathology of Gastritis.

An international workshop has assessed and revised the Sydney System for the reporting of gastritis. Much of the original approach was retained including division into acute, chronic and special forms, and grading of chronic inflammation, polymorph activity, atrophy, intestinal metaplasia and H. pylori density into mild, moderate and marked categories. Visual analog scales have been introduced as a simple guide to grading. The four biopsy sites have been changed to optimize detection of H. pylori, and supplemented by a fifth biopsy from the incisura angularis, the site which is most likely to yield premalignant changes. Chronic gastritis is classified into non-atrophic and atrophic forms with the latter divided into autoimmune (diffuse corpus atrophy) and multifocal. Histological reporting of gastritis should take into account the topographical pattern (antral or corpus predominant), and the final diagnostic term should ideally combine morphology and etiology to maximize the clinical value of gastric biopsy diagnosis.

Genetic alterations and epithelial dysplasia in juvenile polyposis syndrome and sporadic juvenile polyps.

Juvenile polyps are regarded as hamartomatous polyps and occur in sporadic and familial syndromic settings. There is increased risk of gastrointestinal neoplasia in patients with juvenile polyposis syndrome, but the molecular mechanisms are not known. We therefore studied 78 colorectal juvenile polyposis from 12 patients with juvenile polyps syndrome and 34 sporadic juvenile polyps for epithelial dysplasia and genetic changes associated with colorectal neoplasia. Dysplasia occurred in 31% of syndromic juvenile polyps but not in sporadic juvenile polyps (P < 0.0001). Topographic control of proliferation and expression of the cyclin-dependent kinase inhibitor p21(WAFI/CIP1) seen in native colorectal epithelium was lost in 79% of dysplastic juvenile polyps and in 8% of nondysplastic juvenile polyps (P < 0.000001). Somatic mutations in the adenomatous polyposis coli (APC) gene were demonstrated in 50% of dysplastic juvenile polyps (3 of 6) but not in any of 16 juvenile polyps without dysplasia (P = 0.01). Both sporadic and syndromic juvenile polyps had K-ras mutations (14%) and there was no relationship to dysplasia. p53 gene product overexpression identified by immunohistochemical staining occurred rarely in dysplastic juvenile polyps (2 of 24, 8%). Our results indicate that the multiple genetic alterations involved in usual colorectal neoplasia also play a role in neoplastic transformation of juvenile polyps, predominantly in juvenile polyposis syndrome.

Classification and grading of gastritis. The updated Sydney System. International Workshop on the Histopathology of Gastritis, Houston 1994.

The Sydney System for the classification of gastritis emphasized the importance of combining topographical, morphological, and etiological information into a schema that would help to generate reproducible and clinically useful diagnoses. To reappraise the Sydney System 4 years after its introduction, a group of gastrointestinal pathologists from various parts of the world met in Houston, Texas, in September 1994. The aims of the workshop were (a) to establish an agreed terminology of gastritis; (b) to identify, define, and attempt to resolve some of the problems associated with the Sydney System. This article introduces the Sydney System as it was revised at the Houston Gastritis Workshop and represents the consensus of the participants. Overall, the principles and grading of the Sydney System were only slightly modified, the grading being aided by the provision of a visual analogue scale. The terminology of the final classification has been improved to emphasize the distinction between the atrophic and nonatrophic stomach; the names used for each entity were selected because they are generally acceptable to both pathologists and gastroenterologists. In addition to the main categories and atrophic and nonatrophic gastritis, the special or distinctive forms are described and their respective diagnostic criteria are provided. The article includes practical guidelines for optimal biopsy sampling of the stomach, for the use of the visual analogue scales for grading the histopathologic features, and for the formulation of a comprehensive standardized diagnosis. A glossary of gastritis-related terms as used in this article is provided.

Colorectal cancer in ulcerative colitis: survival in patients with and without colorectal cancer symptoms.

: Patients with ulcerative colitis are at increased risk for colorectal adenocarcinoma compared with the general population. Although surveillance for colorectal malignancy and dysplasia (a premalignant lesion) has been recommended, a benefit in reducing mortality from colorectal cancer via surveillance or prophylactic colectomy is still being debated. We reviewed the outcome of 40 consecutive patients with ulcerative colitis with colorectal adenocarcinoma diagnosed between 1956 and 1991 at The Johns Hopkins Hospital. The diagnosis of ulcerative colitis and the tumor, node, metastasis (TNM) stage of colorectal cancer were obtained from clinicopathologic records. Follow-up information was complete for all patients. Patients were divided into two groups: 18 asymptomatic patients who had colorectal cancer detected by colonoscopy, biopsies for dysplasia, or barium enema, or had undergone "prophylactic" colectomy as part of a colorectal cancer-prevention strategy (asymptomatic group), whereas 22 patients did not undergo cancer-prevention testing or prophylactic surgery and had symptoms of colorectal cancer (symptomatic group). Colorectal cancer was diagnosed at a statistically significantly earlier cancer stage in the asymptomatic group [12 (67%) of 18 at stage I or II] compared with those in the symptomatic group [two (9%) of 22 at stage I or II] (Wilcoxon test, p < 0.01). Colorectal cancer 5-year survival in the asymptomatic group was 89% [confidence limit (CL), 6197%] and in the symptomatic group, 19% (CL, 6-39%). Patients with ulcerative colitis and asymptomatic colorectal cancer detected as part of a prevention strategy had malignancies that were less invasive and showed greatly increased survival compared with patients with symptomatic colorectal cancer.

Eosinophilic esophagitis attributed to gastroesophageal reflux: improvement with an amino acid-based formula.

BACKGROUND & AIMS: Treatment for gastroesophageal reflux may be ineffective in patients with an eosinophilic infiltration of the esophagus. The aim of this study was to investigate whether unremitting symptoms of gastroesophageal reflux and biopsy abnormalities of the esophagus may be associated with the ingestion of certain foods. METHODS: Ten children previously diagnosed with gastroesophageal reflux by standard testing with long-standing symptoms (median, 34.3 months; range, 6-78 months) despite standard antireflux therapies, including Nissen fundoplication in 6 patients, were fed the elemental formulas Neocate or Neocate-1-Plus (Scientific Hospital Supplies Inc., Gaithersburg, MD) for a minimum of 6 weeks. Each child had repeat endoscopy followed by open food challenges. RESULTS: While receiving the formulas, patients had either resolution (n = 8) or improvement (n = 2) of symptoms. On follow-up esophageal biopsy, the maximal intraepithelial eosinophil counts decreased significantly before (median, 41; range, 15-100) to after (median, 0.5; range, 0-22) the formula trial (P = 0.005). Other reactive epithelial changes of the esophageal mucosa also improved significantly. All patients redeveloped their previous symptoms on open food challenges. CONCLUSIONS: Chronic gastrointestinal symptoms and histological changes of the esophagus unresponsive to standard treatments for gastroesophageal reflux were improved by the use of elemental formulas. Symptoms recurred when specific dietary proteins were reintroduced during open food challenges. The mechanism of these observations is unknown.

Cerebral ocular Whipple's disease: a 62-year odyssey from death to diagnosis.

A 47-year-old white man with dementia, supranuclear ophthalmoplegia, and myoclonic ocular and facial jerks died in 1931. The case report in 1936 by Ford and Walsh diagnosed encephalitis. In 1993, we made a clinical diagnosis of Whipple's disease on the basis of the 1936 publication. We restudied the pathologic material and found, in addition to extensive encephalitis, PAS-positive material in only the eye, brain, spinal cord, and pituitary. Electron microscopy demonstrated free and intracytoplasmic microorganisms in the eye and brain. We review the history of cerebral ocular Whipple's disease and the implications from this case, which occurred before the development of antibiotics.