Gastric Preneoplastic Lesions and Epithelial Dysplasia

doi:10.1016/j.gtc.2007.08.008

Gastroenterology Clinics of North America

Volume 36, Issue 4, December 2007, Pages 813-829

https://doi.org/10.1016/j.gtc.2007.08.008 Get rights and content

The incidence of gastric cancer is declining; however, it remains the second most common cause of cancer-related deaths worldwide. This article describes gastric preneoplastic lesions and epithelial dysplasia. The possible role of Helicobacter pylori infection is emphasized.

Section snippets

Mucosal changes that precede gastric dysplasia

Epidemiological and morphological studies have demonstrated that intestinal gastric cancers usually are preceded by a sequence of histological events beginning with diffuse chronic gastritis and eventually leading to mucosal atrophy, intestinal metaplasia, and dysplasia [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12]. H pylori infection is associated with the induction of chronic inflammation in gastric mucosa and with the progressive development of metaplastic changes [7]. In fact,

Gastric epithelial dysplasia

Evidence for GED as a direct precursor of gastric adenocarcinoma stems primarily from observations in surgically resected gastric cancers. In this setting, high-grade dysplasia has been identified in close proximity to 40% to 100% of early gastric cancers, and 5% to 80% of advanced adenocarcinomas [35], [36], [37]. Moreover, GED is also a marker of risk for cancer elsewhere in the gastric mucosa. Thus, GED is often present in the background mucosa distant from foci of adenocarcinoma, and

Summary

Despite the declining incidence of gastric cancer, it remains the second most common cause of cancer-related deaths worldwide. More than a decade after H pylori was designated as a definite carcinogen by the WHO, several key questions remain to be answered. Only a small minority of patients infected with H pylori eventually develops gastric cancer, and eradication of H pylori in these patients does not seem to eliminate the risk of cancer completely. The optimal surveillance strategy for

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The natural history of gastric epithelial dysplasia and the consequential surveillance strategies are not well defined in the West. To date, the diagnosis relies on morphology, and no reliable adjunct methods, either immunohistochemical or molecular, have reproducibly been able to confirm the diagnosis and/or risk stratify gastric epithelial dysplasia. Yet, such a tool would be useful in confirming the diagnosis, and developing objective and rational surveillance guidelines. DNA flow cytometry was performed using formalin-fixed paraffin-embedded gastric tissue from 23 cases of high-grade dysplasia and 38 cases of low-grade dysplasia. Twenty-four benign background mucosal samples from the same cohort (20 biopsies and 4 surgical resections from 16 low- and 8 high-grade dysplasia cases) were utilized as controls. The presence of DNA content abnormality (aneuploidy or elevated 4N fraction) correlated with increasing levels of dysplasia, as DNA content abnormality was detected in 18 (78%) of 23 high-grade dysplasia, 5 (13%) of 38 low-grade dysplasia, and none of 24 non-dysplastic samples. 1 and 4-year detection rates of high-grade dysplasia or gastric adenocarcinoma in low-grade dysplasia patients with DNA content abnormality were 80% (p = 0.003) and 100% (p = 0.005), respectively, whereas patients with low-grade dysplasia but with normal DNA content had 1, 4, and 12-year detection rates of 23, 32, and 54%, respectively. The univariate hazard ratio (HR) for subsequent detection of high-grade dysplasia or gastric adenocarcinoma in low-grade dysplasia patients with DNA content abnormality was 6.9 (p = 0.001). Older patients (HR = 1.1, p = 0.005) and those with familial adenomatous polyposis (HR = 9.7, p = 0.029) also had an increased risk for developing high-grade dysplasia or gastric adenocarcinoma in the univariate analysis, but only DNA content abnormality demonstrated a significantly elevated HR of 5.9 in the multivariate analysis (p = 0.005). While older age showed a minimally elevated risk (HR = 1.1, p = 0.013), no other potential risk factors, including male gender, ethnicity, polypoid endoscopic appearance, Helicobacter pylori infection, and intestinal metaplasia, were significantly associated with subsequent detection of high-grade dysplasia or gastric adenocarcinoma in the multivariate analysis. Among the 18 high-grade dysplasia cases with DNA content abnormality, 13 cases (72%) developed gastric adenocarcinoma within a mean follow-up time of 9 months, conferring a HR of 2.5; however, this did not reach statistical significance. In conclusion, the presence of DNA content abnormality can identify a subset of low-grade dysplasia patients who are at increased risk for subsequent detection of high-grade dysplasia or gastric adenocarcinoma. It can also provide confirmatory evidence to a morphologic impression or suspicion of high-grade dysplasia. The majority of gastric epithelial dysplasia patients with DNA content abnormality developed high-grade dysplasia or gastric adenocarcinoma within a year and thus may benefit from more thorough and rigorous endoscopic surveillance.
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Once a diagnosis of dysplasia is rendered, patients should undergo re-evaluation of the gastric mucosa with enhancing techniques and extensive mucosal sampling, as described in the updated Sydney system.79 Some authors have suggested that patients with low-grade dysplasia should be endoscopically re-evaluated every 12 months, whereas patients with high-grade dysplasia require careful staging followed by complete excision.77 Invasive carcinomas limited to the mucosa are infrequently associated with regional lymph node metastases and, thus, may be treated with local excision, provided that they are adequately staged pre-operatively.
Carcinomas of the esophagus and stomach are major causes of morbidity and mortality, especially in high prevalence regions, such as eastern Asia. The incidence rate of adenocarcinoma of the gastroesophageal junction is also increasing in the United States. Most carcinomas of the upper gastrointestinal (GI) tract develop in association with dysplasia and occur in patients with long-standing mucosal injury, although some are derived from benign polyps on a background of normal mucosa. Not surprisingly, increased utilization of endoscopy and mucosal biopsy has led to the frequent detection of mucosal atrophy, intestinal metaplasia, and glandular dysplasia, as well as asymptomatic polyps of the duodenum, stomach, and gastroesophageal junction. Although appropriate classification of these lesions is straightforward in most cases, inflammation-induced epithelial changes may closely simulate, or mask, dysplasia, resulting in diagnostic confusion, or precluding definitive diagnosis in some cases. Emerging evidence also suggests that specific molecular changes in non-dysplastic esophageal and gastric mucosa herald development of dysplasia and/or carcinoma, indicating that ancillary molecular analyses may play a role in the future management of high-risk patients. The purpose of this review is to discuss the clinical, pathologic, and molecular features of pre-cancerous lesions of the upper GI tract, as well as the potential pitfalls in their recognition and classification.
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No evidence-based guidelines exist; therefore, local recommendations should be followed when available. The most common gastric neoplastic polyp is an epithelial dysplastic growth still commonly referred to as an adenoma, despite the new nomenclature (raised intraepithelial neoplasia) suggested by the World Health Organization.44,45 In the Western industrialized world, H pylori–related sporadic gastric adenomas have become rare, accounting for less than 1% of all gastric polyps.
The endoscopic finding of a gastric polyp and the histopathologic report that follows may leave clinicians with questions that have not been addressed in formal guidelines: do all polyps need to be excised, or can they just be sampled for biopsy? If so, which ones and how many should be sampled? What follow-up evaluation is needed, if any? This review relies on the existing literature and our collective experience to provide practical answers to these questions. Fundic gland polyps, now the most frequent gastric polyps in Western countries because of widespread use of proton pump inhibitors, and hyperplastic polyps, the second most common polyps notable for their association with gastritis and their low but important potential for harboring dysplastic or neoplastic foci, are discussed in greater detail. Adenomas have had their name changed to raised intraepithelial neoplasia and are decreasing in parallel with Helicobacter pylori infection; however, they do retain their importance as harbingers of gastric cancer, particularly in East Asia. Gastrointestinal stromal tumors have low incidence and no known associations, but their malignant potential is high; early diagnosis and proper management are crucial. Although rare and benign, inflammatory fibroid polyps need to recognized, particularly by pathologists, to avoid misdiagnosis. Gastric neuroendocrine tumors (carcinoids) are important because of their association with either atrophic gastritis or the multiple endocrine neoplasia syndromes; those that do not arise in these backgrounds have high malignant potential and require aggressive management. The review concludes with some practical suggestions on how to approach gastric polyps detected at endoscopy.

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Gastric Preneoplastic Lesions and Epithelial Dysplasia

Section snippets

Mucosal changes that precede gastric dysplasia

Gastric epithelial dysplasia

Summary

Gastroenterology

Gastroenterology

Hum Pathol

Am J Gastroenterol

Gastrointest Endosc

Hum Pathol

Hum Pathol

Pathol Res Pract

Hum Pathol

Gastroenterology

Surg Oncol

Lancet

Hum Pathol

Gastroenterology

Gastroenterology

Am J Gastroenterol

Gastroenterology

Beitr Pathol

Ann Diagn Pathol

Gastroenterology

The two histological main types of gastric carcinoma: diffuse and so-called intestinal-type carcinoma. An attempt at a histo–clinical classification

Acta Pathol Microbiol Scand

Helicobacter pylori infection and the risk of gastric carcinoma

N Engl J Med

Helicobacter pylori infection and gastric carcinoma among Japanese Americans in Hawaii

N Engl J Med

Epidemiology and mechanism of gastric carcinogenesis

An international association between Helicobacter pylori infection and gastric cancer. The EUROGAST Study Group

Lancet

Increased oxidative DNA damage in Helicobacter pylori-infected human gastric mucosa

Cancer Res

Role of intestinal metaplasia in the histogenesis of gastric carcinoma

J Clin Pathol

Stomach

A human model of gastric carcinogenesis

Cancer Res

The epidemiology and pathogenesis of chronic gastritis: three etiologic entities

Front Gastrointest Res

Clinical implications of recent developments in gastric cancer pathology and epidemiology

Semin Oncol

Gastric epithelial cell kinetics in the progression from normal mucosa to gastric carcinoma

Gut

Helicobacter pylori and gastric cancer

Scand J Gastroenterol Suppl

Patterns of gastric atrophy in intestinal type gastric carcinoma

Cancer

Randomized double-blind factorial trial of three treatments to reduce the prevalence of precancerous gastric lesions

J Natl Cancer Inst

Factors predicting progression of gastric intestinal metaplasia: results of a randomised trial on Helicobacter pylori eradication

Gut

The long-term effect of Helicobacter pylori eradication therapy on symptoms in dyspeptic patients with fundic atrophic gastritis

Aliment Pharmacol Ther

Observer agreement on the grading of gastric atrophy

Histopathology

Gastric mucosal atrophy: interobserver consistency using new criteria for classification and grading

Aliment Pharmacol Ther

Identification of a metaplastic cell lineage associated with human gastric adenocarcinoma

Lab Invest

Spasmolytic polypeptide-expressing metaplasia (SPEM) associated with gastric cancer in Iceland

Dig Dis Sci

Nonendoscopic diagnosis of atrophic gastritis with a blood test. Correlation between gastric histology and serum levels of gastrin-17 and pepsinogen I: a multicentre study

Eur J Gastroenterol Hepatol

Gastric and intestinal mixed and solely intestinal types of intestinal metaplasia in the human stomach

Pathol Int

Intestinal metaplasia of the stomach. A status report

Cancer

Altered mucin expression in the gastrointestinal tract: a review

J Cell Mol Med

Age-related trends of gastritis and intestinal metaplasia in gastric carcinoma patients and in controls representing the population at large

Br J Cancer

Distribution of marker enzymes and mucin in intestinal metaplasia in human stomach and relation to complete and incomplete types of intestinal metaplasia to minute gastric carcinomas

J Natl Cancer Inst

Gastric intestinal metaplasia: subtypes and natural history

J Clin Pathol

The long-term results of endoscopic surveillance of premalignant gastric lesions