Mini-SymposiumGastric epithelial dysplasia: The Western perspective
Introduction
Gastric cancer remains a significant cause of morbidity and cancer related deaths worldwide, despite a marked decline in incidence in the West. Gastric adenocarcinoma, in most instances, represents the culmination of an inflammation–metaplasia–dysplasia–carcinoma sequence, which is described in literature as the Correa cascade of multi-step gastric carcinogenesis [1]. The prevalence of gastric cancer shows wide geographic variation and is closely related to prevalence of Helicobacter pylori infection. Gastric atrophy and intestinal metaplasia are lesions that confer a high risk for the development of gastric cancer while gastric epithelial dysplasia (GED), the penultimate stage of the sequence, is a neoplastic direct precursor lesion [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11]. 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 (HGD) has been identified in close proximity to 40–100% of early gastric cancers, and 5–80% of advanced adenocarcinomas [12], [13], [14]. Moreover, GED is also a marker of increased risk for cancer elsewhere in the gastric mucosa.
The prevalence of GED shows wide geographic variations; from 9–20% in high-risk areas such as Colombia and China, to 0.5–3.75% in the Western world [14], [15], [16], [17], [18]. This difference in prevalence of GED is likely to be a consequence of variations in the genetic background of the host population, and also of variations in environmental factors, such as the prevalence of H. pylori infection and the age at which the infection is acquired [1], [2], [3], [5], [7], [9], [10], [11], [19]. The frequency of GED also varies with the underlying aetiology. For instance, prevalence rates of up to 40% have been reported in patients with pernicious anaemia but the disease confers only a moderate increase in risk of developing gastric cancer [18], [20], [21], [22]. Patients with familial adenomatous polyposis (FAP) also develop flat or polypoid (i.e. adenomas) dysplasia in the stomach. These are typically located in the antrum, are frequently multiple, and may be seen in 2–50% of patients [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34]. Other patient subgroups, such as those with a gastric remnant status-post gastrectomy, Menetrier's disease, and Peutz-Jegher's syndrome may also be at increased risk for gastric cancer [35], [36], [37], [38].
Although the biological potential of GED as a precursor of gastric cancer has never been in doubt, the classification of these lesions has been controversial and fraught with marked variations in approach to diagnosis across the world. The Japanese have referred to these as borderline (Group 3 or 4) lesions while the terms gastric adenoma (for raised lesions) and gastric dysplasia (for flat/depressed lesions) have been widely used in the Western literature [39], [40], [41]. Furthermore, the complexity of cyto-architectural features has been considered to be of paramount importance for the diagnosis of carcinoma in Japan, while breach of the basement membrane and invasion into the lamina propria has been considered the sine qua non of malignancy and hence a pre-requisite for the diagnosis of cancer in the West [42], [43].
In the early 1980s, guidelines for the diagnosis and grading of GED were developed and a three-tiered classification of mild, moderate and severe dysplasia was proposed. Dysplasia was defined as “unequivocally neoplastic epithelium that may be associated with or give rise to invasive adenocarcinoma” [44], [45], [46]. Later classification schemes have moved towards a two-tiered system of low and high-grade dysplasia [12], [47], [48], [49] which has proven to be more reproducible and also provides a clinically meaningful risk stratification [39], [43] The World Health Organization now recommends the terminology of non-invasive low-grade and high-grade intraepithelial neoplasia and defines carcinoma as invasion into the lamina propria or beyond [50]. However, the terminology of adenoma/dysplasia is widely entrenched continues to be used in Western literature as well as in clinical practice. The Vienna classification for GED was developed as a consensus between Western and Asian investigators [49]. This consensus view takes into account the discrepancies in the reporting of dysplasia between Japanese and Western pathologists. As already mentioned above, non-invasive intramucosal neoplastic lesions with high-grade cellular and/or architectural atypia are termed “intramucosal carcinoma” in Japan, whereas the same lesions are diagnosed as HGD by most pathologists in the West. In the Vienna classification, high-grade lesions without invasion of the lamina propria and adenocarcinomas with invasion confined to the lamina propria, are now placed into a single diagnostic category (Table 1). The rationale behind this proposal is to put lesions with similar management implications together into one diagnostic category.
The vast majority of GED is of an “intestinal” phenotype resembling colonic adenomas. This is referred to as adenomatous (or type I) dysplasia (Fig. 1) and is characterized by crowded, tubular glands lined by columnar cells with overlapping, pencillate and hyperchromatic nuclei which show pseudostratification and inconspicuous nucleoli [51]. Other less common histologic variants of GED have also been recognized. Hyperplastic (type II or non-adenomatous) dysplasia (Fig. 2) is usually present in foveolar or pyloric gland type epithelium [51]. The distinctive feature of type II GED is the presence of glands lined by a low-cuboidal to columnar epithelium with pale-clear cytoplasm, round-oval, vesicular nuclei and variably prominent nucleoli. The degree of architectural complexity is variable and shows a wide spectrum of alterations. Cystic glandular dilatation, papillary infoldings and serration are also seen to a variable degree. Although prior studies have suggested that this form of GED is almost always low-grade, [52] more recent studies indicate that type II GED may be associated with distinct clinico-pathological characteristics and is more often high-grade when evaluated in a high-risk population [53]. In some series, type II GED has also been shown to be more commonly associated with poorly differentiated adenocarcinoma of the intestinal type [51], [54], [55]. The underlying genetic aberrations in adenomatous and foveolar types of GED and their prognostic and biological significance needs to be evaluated in future prospective studies.
Tubule neck (or globoid) dysplasia is exceedingly rare and is believed to be a precursor of diffuse-type gastric carcinoma [56]. It occurs in non-metaplastic gastric epithelium and appears as enlarged, clear cells occupying the gland neck region and confined within the basement membrane. There is sparing of both the mucosal surface and of the deeper glands [56], [57]. Differentiating this form of dysplasia from “cancerization” of glandular epithelium is nearly impossible and the diagnosis is often made only in the presence of an associated diffuse type gastric cancer.
Nearly 50% of all patients with an inherited germline E-cadherin/CDH1 gene mutation develop diffuse gastric cancer. Prophylactic gastrectomies performed in patients from these families have shown examples of “signet ring cell carcinoma in situ”, often with a “pagetoid” spread between the gastric foveolar and glandular epithelium within the basement membrane [58], [59]. These changes are often multifocal, occur in macroscopically normal stomach and show a predilection for the distal stomach and the body-antral transitional zone. Hence, targeting these areas on endoscopy enhances the likelihood of finding precursor lesions or early cancer in an otherwise normal appearing stomach [60].
The three tiered system of mild, moderate and severe dysplasia was abandoned following the realization that moderate and severe categories could not be reproducibly distinguished from each other and actually may co-exist in many cases [46]. A two-tiered scheme of low and high-grade GED was then adopted and is now widely used in all classifications of GED. In most practices, gastric surveillance biopsies need to be categorized by pathologists into one of several categories: negative for dysplasia, indefinite for dysplasia, low-grade GED/adenoma, high-grade GED/adenoma, intramucosal carcinoma or an invasive adenocarcinoma.
A wide array of reactive changes may mimic the morphological appearance of GED and are well recognized as a pitfall in diagnosis. Avoiding overdiagnosis of GED, thus, requires familiarity with the full spectrum of reactive alterations that may be seen in gastric mucosa. These include reparative changes that may occur around gastric erosions or ulcers, regeneration in severely inflamed mucosa or the basal “adenoma-like” appearance in foci of intestinal metaplasia. In the latter instance, the importance of surface maturation, which has been well emphasized in diagnosis of dysplasia associated with Barrett's oesophagus, is equally important in the diagnosis of GED when it occurs in a field of intestinal metaplasia. Severe mucin depletion and nuclear hyperchromasia seen in reactive/chemical gastropathy may also be mistaken for dysplasia (Fig. 3). Attention to the orderly arrangement of the gastric pits and lack of nuclear pleomorphism will avoid an overdiagnosis in most instances.
There are indeed cases where one cannot differentiate with certainty between reactive epithelial changes and GED. It must be emphasized, however, that a diagnosis of “indefinite for dysplasia” is not a biological entity, but rather a provisional designation that emphasizes the need to keep the patient in follow up and to obtain more biopsies to enable a definitive diagnosis. It should not be used as a wastebasket term for all cases with reactive atypia which are obviously in response to inflammatory or direct mucosal injury. Other clues to the reactive nature of the epithelial changes includes the presence of vascular congestion and a gradual rather then abrupt transition between the atypical and adjacent normal cells (Fig. 4) [45], [46]. When strict criteria are used, the category of “indefinite for dysplasia” is an uncommon diagnosis in our experience.
The term adenoma is used for elevated mucosal lesions and low-grade dysplasia for flat lesions that show minimal architectural disarray and cytological atypia [14], [39], [43], [45], [46]. As mentioned earlier, the morphological appearance is reminiscent of colonic adenomas and the lesions often occur in a background of intestinal metaplasia. The presence of tubular, back-to-back glands lined by columnar cells with pseudostratified, hyperchromatic, pencillate nuclei is diagnostic of adenomatous low-grade GED (Fig. 1) when the changes uniformly extend to involve the surface epithelium. The criteria for separating type II GED into low- and high-grade categories are not well established. The presence of gastric foveolar type epithelium with elongated, hyperchromatic nuclei that show some degree of pseudostratification is categorized as low-grade type II dysplasia (Fig. 2). This is best seen in fundic gland polyps with low-grade dysplasia that occur in patients with familial adenomatous polyposis. Although a designation of low-grade implies a comparatively reduced risk of malignant transformation, it must be recognized that low-grade dysplasia occurring in a background of extensive intestinal metaplasia may be associated with a higher risk of malignancy [61].
A diagnosis of HGD is made when either the cytological atypia or the architectural complexity is prominent. High-grade dysplastic glands may show marked crowding, budding and intra-luminal bridges, and are lined by rounded, pleomorphic nuclei that show prominent nucleoli and loss of polarity (Fig. 5). Marked irregularities of the nuclear membrane and clumping of chromatin are also features often associated with HGD. The foveolar type II HGD is distinguished morphologically, from the adenomatous HGD, by the presence of pale to clear cytoplasm of the neoplastic cells which often display bland, monomorphic nuclear features without significant pleomorphism. The presence of complex architectural formations allows a diagnosis of HGD in these cases (Fig. 6). Typical or atypical mitoses may be present in either low-grade or HGD, but are more often and more easily discernible in the latter category [39], [43], [48].
The controversy and disparity in literature regarding separation of “dysplasia” from “carcinoma” has already been alluded to above. The current approach to this problem is based on two facts: (1) “invasion” particularly when limited to the lamina propria is difficult to identify on routine histology, and (2) intramucosal adenocarcinomas have a less than 10% risk of nodal metastases [62] and neoplastic lesions with invasion of the lamina propria, but confined to the mucosa, are therefore, amenable to a conservative approach through endoscopic mucosal resection (EMR). Currently, lesions which show marked architectural atypia in the form of fused glandular pattern, cribriforming or intra-luminal necrosis, as well as those that show definite evidence of invasion into the lamina propria in the form of single cells or small clusters of cells, are categorized as intramucosal adenocarcinoma.
With the possible exception of diffuse type of gastric cancer, the diagnosis of an invasive adenocarcinoma seldom poses a diagnostic dilemma since biopsies are almost invariably obtained from a mass lesion. The presence of a desmoplastic stromal response around infiltrating glands, signet ring cells, large pools of extracellular mucin or definite evidence of submucosal invasion in larger EMR specimen are diagnostic of an invasive adenocarcinoma.
The progression of GED to carcinoma is paralleled by a stepwise accumulation of multiple genetic abnormalities. However, the precise sequence in which these changes occur is remains uncertain. APC gene is mutated in 20–76% of gastric adenomas and flat dysplasias and nuclear p53 staining may be seen in about one third of these cases [63], [64], [65], [66], [67], [68]. TP53 mutations have also been described in H. pylori gastritis and in foci of intestinal metaplasia suggesting these are early events in gastric carcinogenesis [69], [70], [71], [72], [73], [74], [75], [76], [77], [78], [79], [80], [81]. Microsatellite instability (MSI) may occur in about 21% of gastric adenomas, [65], [71], [76], [82], [83], [84], [85], [86], [87] while the exact role of KRAS oncogene mutation in gastric neoplasia is debatable [65], [66], [69], [82], [88], [89]. Criteria for diagnosis of MSI were developed primarily based on studies of colon cancer and tumours are classified as MSI-high when at least 30% of markers show MSI. MSI-high carcinomas are associated with loss of MLH-1 protein expression, [90] and foci of intestinal metaplasia associated with such cancers may also show low levels of MSI [85]. It has also been shown in previous studies that APC mutations do not occur in gastric adenomas/dysplasias that are of an MSI-high phenotype [63]. This would suggest the existence of two mutually exclusive molecular pathways of gastric carcinogenesis. Adenomas with TGFβRII gene mutation have been suggested to be more likely to progress to gastric cancer [91].
CpG island methylation occurs with ageing and is now well established as an important pathway underlying malignancy. An increasing frequency of promoter methylation involving multiple genes may occur in the progression from chronic gastritis–adenoma–dysplasia–carcinoma. Commonly methylated genes include tumour suppressor genes (APC), those involved in DNA repair (hMLH-1, MGMT), cell cycle regulators (p16, p14, Cox-2) and those involved in invasion and metastasis (E-cadherin, TIMP-3) [92], [93], [94], [95], [96]. Despite characterization of these genetic aberrations, there are currently no immunohistochemical or molecular assays that can help stratify the risk of progression to gastric cancer in dysplastic precursor lesions. It is worth mentioning in this context, that some recent studies have shown that a panel of immunohistochemical markers may be useful in stratifying the cancer risk in biopsies diagnosed as indefinite for dysplasia [97]. These findings need to be validated in future prospective studies which would be useful in developing more objective and rational surveillance guidelines. Until such time, however, the morphological evaluation of mucosal biopsies remains the gold standard for risk assessment of subsequent gastric cancer.
Section snippets
Low-grade dysplasia
Regression of low-grade dysplasia is difficult to assess because of sampling issues and also because of inter-observer variation in distinction of reactive atypia from true dysplasia. Nonetheless, low-grade dysplasia has been noted to regress in 38–75% and persist in 19–50% of cases [18], [98], [99]. Historical data have reported progression to adenocarcinoma in 0–23% of patients within a span of 1–4 years. More recent studies have confirmed the low risk of progression to cancer in patients
Summary
Gastric cancer remains the second most common cause of cancer related deaths worldwide. This emphasizes the need for early diagnosis of gastric cancer which can only be accomplished by the development of more precise methods of risk stratification which can then be used for the development of optimal surveillance strategies, particularly in high risk populations. A combination of morphological evaluation combined with the genetic constitution of the host, bacterial virulence factors and
Conflict of interest statement
None declared.
References (108)
- et al.
What role does Helicobacter pylori play in gastric cancer?
Gastroenterology
(1997) - et al.
Gastric dysplasia: a ten-year follow-up study
Pathol Res Pract
(1994) - et al.
Interleukin 1B and interleukin 1RN polymorphisms are associated with increased risk of gastric carcinoma
Gastroenterology
(2001) - et al.
Gastric lesions in familial adenomatosis coli: their incidence and histologic analysis
Hum Pathol
(1978) - et al.
Upper gastrointestinal polyps in Gardner's syndrome
Gastroenterology
(1984) - et al.
Gastroduodenal polyps in familial adenomatous polyposis
Surg Oncol
(1992) - et al.
Upper gastrointestinal cancer in patients with familial adenomatous polyposis
Lancet
(1989) - et al.
Gastric epithelial dysplasia and adenoma: historical review and histological criteria for grading
Hum Pathol
(1997) - et al.
Differences in diagnostic criteria for gastric carcinoma between Japanese and western pathologists
Lancet
(1997) - et al.
Dysplasia in inflammatory bowel disease: standardized classification with provisional clinical applications
Hum Pathol
(1983)
Gastric epithelial dysplasia: a prospective multicenter follow-up study from the Interdisciplinary Group on Gastric Epithelial Dysplasia
Hum Pathol
Histologic types and possible initial stages in early gastric carcinoma
Beitr Pathol
Genetic alterations in gastric adenomas of intestinal and foveolar phenotypes
Mod Pathol
Inverse relationship between APC gene mutation in gastric adenomas and development of adenocarcinoma
Am J Pathol
LOH at the APC/MCC gene (5Q21) in gastric cancer and preneoplastic lesions Prognostic implications
Pathol Res Pract
Epstein-Barr virus, p53 protein, and microsatellite instability in the adenoma-carcinoma sequence of the stomach
Hum Pathol
The molecular biology of esophageal and gastric cancer and their precursors: oncogenes, tumor suppressor genes, and growth factors
Hum Pathol
Microsatellite instability in gastric intestinal metaplasia in patients with and without gastric cancer
Am J Pathol
Genetic instability in intestinal metaplasia is a frequent event leading to well-differentiated early adenocarcinoma of the stomach
Eur J Cancer
Microsatellite instability in the adenoma-carcinoma sequence of the stomach
Lab Invest
Profile of aberrant CpG island methylation along the multistep pathway of gastric carcinogenesis
Lab Invest
Augmented intestinal trefoil factor (TFF3) and loss of pS2 (TFF1) expression precedes metaplastic differentiation of gastric epithelium
Lab Invest
A human model of gastric carcinogenesis
Cancer Res
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
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
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
Atlas of tumor pathology: tumors of the esophagus and stomach
Gastric mucosal dysplasia: what is its clinical significance?
Front Gastrointest Res
Typing and grading of gastric dysplasia
Precancerous lesions of the stomach
Scand J Gastroenterol Suppl
Early and advanced gastric cancer in the follow-up of moderate and severe gastric dysplasia patients A prospective study. I.G.G.E.D. – Interdisciplinary Group on Gastric Epithelial Dysplasia
Endoscopy
Gastric mucosal dysplasia: preliminary results of a prospective study of patients followed for periods of up to six years
Dysplasia and carcinoma in the Billroth II resected stomach 27–35 years post-operatively
Acta Pathol Microbiol Immunol Scand [A]
The clinical significance of gastric epithelial dysplasia
Endoscopy
Risk of cancers of the oesophagus and stomach by histology or subsite in patients hospitalised for pernicious anaemia
Gut
Gastroduodenal polyps in familial polyposis coli
Dis Colon Rectum
A prospective evaluation of the upper gastrointestinal tract and periampullary region in patients with Gardner syndrome
Am J Gastroenterol
Gastric and duodenal polyps in familial adenomatous polyposis: a prospective study of the nature and prevalence of upper gastrointestinal polyps
Gut
Upper gastrointestinal pathology in familial adenomatous polyposis: results from a prospective study of 102 patients
J Clin Pathol
Familial adenomatous polyposis: should patients undergo surveillance of the upper gastrointestinal tract?
Endoscopy
Dysplastic changes in gastric fundic gland polyps of patients with familial adenomatous polyposis
Ital J Gastroenterol Hepatol
Natural history of gastric adenomas in patients with familial adenomatosis coli/Gardner's syndrome
Cancer
Gastric lesion of familial polyposis coli
Cancer
Duodenogastric reflux and gastric stump carcinoma
Gastric Cancer
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2019, Gastrointestinal EndoscopyCitation Excerpt :The grouping of these pathologies therefore risks upstaging lymph node metastasis risk for lesions with HGD and may result in overtreatment and unnecessary distress for patients. Low-grade adenomatous dysplasia within the stomach has been shown to regress in 38% to 75%, persist in 19% to 50%, and transform to cancer in 0% to 9% during surveillance.26 Particular difficulties for Western endoscopists arise because there is no consistently reproducible data to guide the endoscopic discrimination of LGD or HGD from more advanced precursors of gastric cancer within a demarcated area of suspected dysplasia in the stomach, even in Japan.
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2015, Diagnostic HistopathologyCitation Excerpt :These lesions are described as resembling colonic adenomas composed of crowded glands lined by columnar cells with pseudostratified, pencillate hyperchromatic nucleoli and eosinophilic cytoplasm (Figure 1).30,31 Goblet cells and Paneth cells are frequently present, and required by some to make the diagnosis,32 while others use the presence of intestinal brush border (highlighted by CD10 immunostain)30 to confirm the intestinal phenotype. A second form, Type II (non-adenomatous) dysplasia (synonymous for hyperplastic, foveolar, or gastric dysplasia), has been established.
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2014, Pathology Research and PracticeCitation Excerpt :It is known that gastric adenocarcinoma, in most cases, represents the culmination of a chronic inflammation–metaplasia–dysplasia–carcinoma sequence, described as Correa cascade [6]. The need for early diagnosis of gastric cancer can only be accomplished by the development of more precise methods which depend on a combination of morphological assessment and molecular abnormalities in precancerous lesions, particularly in various degrees of dysplasia [7]. Morphological assessment is always simply attributed to pathological diagnosis; however, the molecular abnormalities need a certain biomarker specific to early stages of gastric cancer that could be detected using feasible methods.
Pathology of Gastric Cancer and Its Precursor Lesions
2013, Gastroenterology Clinics of North AmericaCitation Excerpt :The best independent predictors of progression of LGD to HGD or cancer are size greater than 2 cm and the presence of depression on endoscopic examination.68,70 HGD regresses in only 0% to 16% of cases, persists in 14% to 58%, and progresses in 10% to 100% of cases to invasive carcinoma.65 In a cohort of patients with premalignant gastric lesions approximately 25% of patients with HGD progressed to carcinoma within 1 year of follow-up.71