Intestinal Metaplasia and Dysplasia in the Stomach - Diagnostic Difficulties and Clinical Consequences.
Dr MM Walker, Department of Histopathology, Imperial College School of Medicine at St Mary’s Campus, London W21PG
Gastric biopsies are performed to establish a diagnosis, give information on prognosis of a lesion and for follow up of treatment. In finding IM and dysplasia in the stomach pathologists are latecomers in the inflammation-metaplasia-dysplasia-cancer pathway1. IM is a precancerous condition and dysplasia is a precancerous lesion. The former is a clinical state associated with a significantly increased risk of cancer, whereas a precancerous lesion is a histopathological abnormality in which cancer is more likely to occur than in its apparently normal counterpart2. The relevance of diagnosis of IM and dysplasia is therefore to signal whether interventional measures are necessary.
Metaplasia is a potentially reversible change from a fully differentiated cell type to another cell type implying adaptation to environmental stimuli. In the stomach intestinal type metaplasia is most common. This occurs as a result of Helicobacter pylori infection, bile reflux3 or can be induced experimentally by irradiation4.
Dysplasia can be defined as histological abnormalities of cytology and/or architecture considered to be neoplastic but does not amount to unequivocal carcinoma1. Akin to dysplasia in inflammatory bowel disease, dysplasia is best divided into low grade, high grade or indefinite categories. Pathological features are well described, including separation of lesions showing “regenerative” atypia1, 5. There is a need to adopt universal agreement on terminology – the Vienna classification6 addresses this problem.
IM is recognisable if extensive and the endoscopist experienced. Biopsy should therefore be from sites that show the typical appearance of whitish plaques, patches or homogeneous discoloration. The accuracy of endoscopic diagnosis was 71.3% in a study from Taipei7.
Non-targeted biopsies in the stomach do not pick up neoplasia. The performance of routine biopsies (Sydney protocol) not targeted at a visible lesion from patients without previous diagnosis of neoplasia did not increase the detection of gastric malignancy8. Gastric ulcers and polyps are the commonest types of endoscopic lesions that may show dysplasia, although this may also present as a plaque or mucosal irregularity9.
Sampling errors beleaguer the diagnosis of IM and dysplasia, however, with the advent of more powerful endoscopes, this problem may resolve. There remains the problem of where to take biopsies in routine practice. The Sydney system provides practical guidelines for optimal biopsy sampling of the stomach, use of the visual analogue scales for grading the histopathological features, and formulation of a comprehensive standardised diagnosis10. However, a large study from Houston showed that intestinal metaplasia was missed in more than 50% of biopsies from Sydney sites in patients with confirmed intestinal metaplasia on multiple site sampling and concluded that current and future studies that use the Sydney System as basis for detecting intestinal metaplasia are not likely to be reliable11. H. pylori infection may have been underestimated in patients with IM because of the use of a single method of detection12. Extent and location of intestinal metaplasia - along the lesser curvature (from the cardia to the pre-pyloric zone) may identify patients with the highest cancer risk13.
Epidemiological studies have shown that IM and dysplasia in the stomach have a high cancer risk, for example a study carried out in two provinces in China with high and low cancer risk, the prevalence of IM and dysplasia much higher in area with high risk for gastric cancer14. Helicobacter pylori infection is also strong risk factor for the development of gastric cancer, through the pathway of developing atrophy, IM and dysplasia in chronic infection. Approximately 40-50% of infected subjects develop these conditions; the presence of these consecutive disorders leads to a 5-90-fold increased risk for cancer of the distal stomach, in particular the intestinal type. This risk is more than eight-fold increased over a long time interval (at least 15 years). Factors that influence the risk for both conditions in the presence of infection are the age at which infection occurred and the presence of cagA as a marker for more pathogenic H. pylori strains15. Within the gastric cancer risk index, the presence of intestinal metaplasia was the only criteria associated with the development of intestinal-type gastric cancer in Japan16.Whilst it seems that whilst IM is an important measure of risk, grade of body gastritis may be more important in assessment - in 50 H. pylori-infected gastric carcinoma patients the grade of corpus gastritis was significantly higher than in matched H. pylori-positive control subjects. Atrophy and IM occurred significantly more often in the antrum of carcinoma patients. The odds ratio for gastric carcinoma was 8.85 for high-grade corpus gastritis and 8.04 when atrophy in the antrum was present17.
Most patients diagnosed with high-grade dysplasia of the gastric mucosa will either already have or soon develop gastric cancer. In gastrectomy specimens for gastric cancer 20-40% of patients had associated dysplasia and progression of dysplasia to gastric cancer has been estimated at 21%, 33%, and 57% of cases of mild, moderate and severe dysplasia, respectively18.
Typing of IM is time consuming and most laboratories do not perform this routinely. There are cost effective alternatives to High Iron Diamine-Alcian Blue19, 20.
What is the evidence that typing is important? Type III IM has been shown to be a more specific marker of premalignancy, with relevance, in particular, to the early and intestinal type of cancer21. A particular type of very well differentiated adenocarcinoma of the stomach mimics Type 1IM, bringing into question the relevance of typing22 and critical reviews have found many exceptions to given types of IM as precursor lesions of cancer23. However, it is most likely that a combination of bacterial, host and environmental factors will lead to cancer rather than IM alone. Infection with cagA-positive H. pylori strains is associated with an increased prevalence and intensity of antral atrophy and intestinal metaplasia, in addition to higher degrees of gastritis24. Other studies have shown that a high PCNA-labelling index in the gastric mucosa, with a histological diagnosis of incomplete intestinal metaplasia, could constitute a good prognostic marker of the severity of the histological lesion. These parameters, together with others such as the presence of sulphomucins and of cells expressing anomalous Lewis a antigen, may be used to define patients with a high risk of developing a gastric neoplasia25.
Diagnosis of dysplasia – differing views on definitions:
The diagnosis of dysplasia and its classification is a vexed question for pathologists. Difficulties arise in the diagnosis of early gastric cancer (EGC) versus dysplasia, whether we should only report two grades -either high or low-grade dysplasia, or whether two pathologists should always concur on diagnosis. These problems have been well addressed in the literature in two early studies in particular. The first describes 132 patients classified as having early gastric cancer and 63 as dysplasia by a panel of experts on referral.. There was good agreement between pathologists as to whether the cases had cancer or dysplasia. The five-year survival rate of the cases agreed to be early gastric cancer by the panel was well over 90%26, but the four year survival rate of cases registered as 'early gastric cancer' but said by the panel to have more advanced disease was under 75%. The second study examined the natural history of gastric epithelial dysplasia and its relation to gastric cancer. Of 13 patients with high-grade dysplasia, 11 (85%) were found to have gastric cancer within 15 months. Of the 10 patients with high grade dysplasia who underwent gastrectomy, 6 were found to have early gastric cancer, 3 had cancer invading into the muscularis propria, and none had lymph node metastases. High-grade dysplasia was thus a marker of gastric cancer. Moreover, the cancers associated with high-grade dysplasia are usually pathologically favourable and curable. High-grade dysplasia is therefore an indication for radical surgical treatment, provided that the patient's age and general condition permit such an approach9.
The recent Vienna classification6 has tried to settle these arguments and recommends that gastrointestinal neoplasia is generally classified into five categories: (1) negative for neoplasia/dysplasia, (2) indefinite for neoplasia/dysplasia, (3) non-invasive low grade neoplasia (low grade adenoma/dysplasia), (4) non-invasive high grade neoplasia (high grade adenoma/dysplasia, non-invasive carcinoma and suspicion of invasive carcinoma), and (5) invasive neoplasia (intramucosal carcinoma, submucosal carcinoma or beyond). If this system is adopted universally, then studies can be comparative and terminological arguments cease.
Whilst this issue has been addressed extensively, there is no concerted view on regression of these lesions following eradication of H. pylori27. Recently a randomised one-year follow-up study reported that H. pylori eradication was beneficial in preventing progression of atrophy and intestinal metaplasia of the gastric mucosa28, although other studies are not so conclusive. In a 2- to 4-year prospective study there was no significant change in antral intestinal metaplasia during the 4 years of follow-up although antral atrophy declined significantly in the period from 1 to 3 years of follow-up29.
Regression of dysplasia was documented in 36%, 27%, and 0% of mild, moderate and severe dysplasia cases, respectively18. The important point in this study was the lack of regression of severe dysplasia, emphasising that progression of mild and moderate dysplastic lesions seems to be a slow process and is rare in mild dysplasia. However, severe dysplasia is highly predictive of subsequent cancer. It was suggested that a five-year follow up interval is sufficient in cases with mild dysplasia and two years in those with moderate dysplasia30.
It is important to establish a dialogue with clinicians treating the patient. Gastric cancer, even early gastric cancer kills patients31 and interventional measures are important with early diagnosis through precursor lesions of IM and dysplasia. Follow up of low-grade dysplasia and surgical intervention for high-grade dysplasia is mandatory. It is wise for two pathologists to agree on the diagnosis. Typing of IM does not probably add further prognostic value to the biopsy, however extent and location of intestinal metaplasia may identify patients with the high cancer risk13. In time reliable molecular markers may help identify those most at risk from development of cancer that is treatable in the early stages.
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